WorldWideScience

Sample records for falciparum multidrug resistance

  1. Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes

    DEFF Research Database (Denmark)

    Venkatesan, Meera; Gadalla, Nahla B; Stepniewska, Kasia

    2014-01-01

    Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated...

  2. Combating multidrug-resistant Plasmodium falciparum malaria.

    Science.gov (United States)

    Thu, Aung Myint; Phyo, Aung Pyae; Landier, Jordi; Parker, Daniel M; Nosten, François H

    2017-08-01

    Over the past 50 years, Plasmodium falciparum has developed resistance against all antimalarial drugs used against it: chloroquine, sulphadoxine-pyrimethamine, quinine, piperaquine and mefloquine. More recently, resistance to the artemisinin derivatives and the resulting failure of artemisinin-based combination therapy (ACT) are threatening all major gains made in malaria control. Each time resistance has developed progressively, with delayed clearance of parasites first emerging only in a few regions, increasing in prevalence and geographic range, and then ultimately resulting in the complete failure of that antimalarial. Drawing from this repeated historical chain of events, this article presents context-specific approaches for combating drug-resistant P. falciparum malaria. The approaches begin with a context of drug-sensitive parasites and focus on the prevention of the emergence of drug resistance. Next, the approaches address a scenario in which resistance has emerged and is increasing in prevalence and geographic extent, with interventions focused on disrupting transmission through vector control, early diagnosis and treatment, and the use of new combination therapies. Elimination is also presented as an approach for addressing the imminent failure of all available antimalarials. The final drug resistance context presented is one in which all available antimalarials have failed; leaving only personal protection and the use of new antimalarials (or new combinations of antimalarials) as a viable strategy for dealing with complete resistance. All effective strategies and contexts require a multipronged, holistic approach. © 2017 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

  3. Survey of Plasmodium falciparum multidrug resistance-1 and chloroquine resistance transporter alleles in Haiti.

    Science.gov (United States)

    Elbadry, Maha A; Existe, Alexandre; Victor, Yves S; Memnon, Gladys; Fukuda, Mark; Dame, John B; Yowell, Charles A; Okech, Bernard A

    2013-11-19

    In Haiti where chloroquine (CQ) is widely used for malaria treatment, reports of resistance are scarce. However, recent identification of CQ resistance genotypes in one site is suggestive of an emerging problem. Additional studies are needed to evaluate genetic mutations associated with CQ resistance, especially in the Plasmodium falciparum multi-drug resistance-1 gene (pfmdr1) while expanding the already available information on P. falciparum CQ transporter gene (pfcrt) in Haiti. Blood samples were collected on Whatman filter cards (FTA) from eight clinics spread across Haiti. Following the confirmation of P. falciparum in the samples, PCR protocols were used to amplify regions of pfmdr1and pfcrt codons of interest, (86, 184, 1034, 1042, and 1246) and (72-76), respectively. Sequencing and site-specific restriction enzyme digestions were used to analyse these DNA fragments for the presence of single nucleotide polymorphisms (SNPs) known to confer resistance to anti-malarial drugs. P. falciparum infection was confirmed in160 samples by amplifying a segment of the P. falciparum 18S small subunit ribosomal RNA gene (pfssurrna). The sequence of pfmdr1 in 54 of these samples was determined between codons 86,184 codons 1034, 1042 and 1246. No sequence differences from that of the NF54 clone 3D7 were found among the 54 samples except at codon 184, where a non-silent mutation was found in all samples predicted to alter the amino acid sequence replacing tyrosine with phenylalanine (Y184F). This altered sequence was also confirmed by restriction enzyme digestion. The sequence of pfmdr1 at codons 86, 184, 1034 and 1042 encoded the NFSN haplotype. The sequence of pfcrt codons 72-76 from 79 samples was determined and found to encode CVMNK, consistent with a CQ sensitive genotype. The presence of the Y184F mutation in pfmdr1 of P. falciparum parasites in Haiti may have implications for resistance to antimalarial drugs. The absence of mutation in pfcrt at codon 76 among 79

  4. Identification and deconvolution of cross-resistance signals from antimalarial compounds using multidrug-resistant Plasmodium falciparum strains.

    Science.gov (United States)

    Chugh, Monika; Scheurer, Christian; Sax, Sibylle; Bilsland, Elizabeth; van Schalkwyk, Donelly A; Wicht, Kathryn J; Hofmann, Natalie; Sharma, Anil; Bashyam, Sridevi; Singh, Shivendra; Oliver, Stephen G; Egan, Timothy J; Malhotra, Pawan; Sutherland, Colin J; Beck, Hans-Peter; Wittlin, Sergio; Spangenberg, Thomas; Ding, Xavier C

    2015-02-01

    Plasmodium falciparum, the most deadly agent of malaria, displays a wide variety of resistance mechanisms in the field. The ability of antimalarial compounds in development to overcome these must therefore be carefully evaluated to ensure uncompromised activity against real-life parasites. We report here on the selection and phenotypic as well as genotypic characterization of a panel of sensitive and multidrug-resistant P. falciparum strains that can be used to optimally identify and deconvolute the cross-resistance signals from an extended panel of investigational antimalarials. As a case study, the effectiveness of the selected panel of strains was demonstrated using the 1,2,4-oxadiazole series, a newly identified antimalarial series of compounds with in vitro activity against P. falciparum at nanomolar concentrations. This series of compounds was to be found inactive against several multidrug-resistant strains, and the deconvolution of this signal implicated pfcrt, the genetic determinant of chloroquine resistance. Targeted mode-of-action studies further suggested that this new chemical series might act as falcipain 2 inhibitors, substantiating the suggestion that these compounds have a site of action similar to that of chloroquine but a distinct mode of action. New antimalarials must overcome existing resistance and, ideally, prevent its de novo appearance. The panel of strains reported here, which includes recently collected as well as standard laboratory-adapted field isolates, is able to efficiently detect and precisely characterize cross-resistance and, as such, can contribute to the faster development of new, effective antimalarial drugs.

  5. Complex polymorphisms in the Plasmodium falciparum multidrug resistance protein 2 gene and its contribution to antimalarial response.

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    Veiga, Maria Isabel; Osório, Nuno S; Ferreira, Pedro Eduardo; Franzén, Oscar; Dahlstrom, Sabina; Lum, J Koji; Nosten, Francois; Gil, José Pedro

    2014-12-01

    Plasmodium falciparum has the capacity to escape the actions of essentially all antimalarial drugs. ATP-binding cassette (ABC) transporter proteins are known to cause multidrug resistance in a large range of organisms, including the Apicomplexa parasites. P. falciparum genome analysis has revealed two genes coding for the multidrug resistance protein (MRP) type of ABC transporters: Pfmrp1, previously associated with decreased parasite drug susceptibility, and the poorly studied Pfmrp2. The role of Pfmrp2 polymorphisms in modulating sensitivity to antimalarial drugs has not been established. We herein report a comprehensive account of the Pfmrp2 genetic variability in 46 isolates from Thailand. A notably high frequency of 2.8 single nucleotide polymorphisms (SNPs)/kb was identified for this gene, including some novel SNPs. Additionally, we found that Pfmrp2 harbors a significant number of microindels, some previously not reported. We also investigated the potential association of the identified Pfmrp2 polymorphisms with altered in vitro susceptibility to several antimalarials used in artemisinin-based combination therapy and with parasite clearance time. Association analysis suggested Pfmrp2 polymorphisms modulate the parasite's in vitro response to quinoline antimalarials, including chloroquine, piperaquine, and mefloquine, and association with in vivo parasite clearance. In conclusion, our study reveals that the Pfmrp2 gene is the most diverse ABC transporter known in P. falciparum with a potential role in antimalarial drug resistance.

  6. Mutations in the Plasmodium falciparum Cyclic Amine Resistance Locus (PfCARL Confer Multidrug Resistance

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    Gregory LaMonte

    2016-07-01

    Full Text Available Mutations in the Plasmodium falciparum cyclic amine resistance locus (PfCARL are associated with parasite resistance to the imidazolopiperazines, a potent class of novel antimalarial compounds that display both prophylactic and transmission-blocking activity, in addition to activity against blood-stage parasites. Here, we show that pfcarl encodes a protein, with a predicted molecular weight of 153 kDa, that localizes to the cis-Golgi apparatus of the parasite in both asexual and sexual blood stages. Utilizing clustered regularly interspaced short palindromic repeat (CRISPR-mediated gene introduction of 5 variants (L830V, S1076N/I, V1103L, and I1139K, we demonstrate that mutations in pfcarl are sufficient to generate resistance against the imidazolopiperazines in both asexual and sexual blood-stage parasites. We further determined that the mutant PfCARL protein confers resistance to several structurally unrelated compounds. These data suggest that PfCARL modulates the levels of small-molecule inhibitors that affect Golgi-related processes, such as protein sorting or membrane trafficking, and is therefore an important mechanism of resistance in malaria parasites.

  7. Polymorphism of the Plasmodium falciparum multidrug resistance and chloroquine resistance transporter genes and in vitro susceptibility to aminoquinolines in isolates from the Peruvian Amazon.

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    Huaman, Maria Cecilia; Roncal, Norma; Nakazawa, Shusuke; Long, Ton That Ai; Gerena, Lucia; Garcia, Coralith; Solari, Lely; Magill, Alan J; Kanbara, Hiroji

    2004-05-01

    In vitro drug sensitivity to chloroquine (CQ), mefloquine (MQ) and quinine was investigated in 60 culture-adapted Plasmodium falciparum isolates from malaria patients in Padrecocha, a village in the Amazonian Department of Loreto, Peru. All isolates showed resistance to CQ, decreased susceptibility to quinine, and sensitivity to MQ. These isolates were examined for mutations in the P. falciparum multidrug resistance 1 (pfmdr1) and chloroquine resistance transporter (pfcrt) genes previously linked to CQ resistance. The mutations N86Y and D1246Y, two of the five mutations commonly observed in the pfmdr1 gene of CQ-resistant clones, were not found. The pfcrt mutation K76T, associated with CQ resistance, was identified in all the isolates tested. Sequence analysis of codons 72-76 in the pfcrt gene showed the haplotypes SVMNT and CVMNT.

  8. Rapid selection of Plasmodium falciparum chloroquine resistance transporter gene and multidrug resistance gene-1 haplotypes associated with past chloroquine and present artemether-lumefantrine use in Inhambane District, southern Mozambique

    DEFF Research Database (Denmark)

    Thomsen, Thomas T; Madsen, Laura B; Hansson, Helle H;

    2013-01-01

    Chloroquine (CQ) use in Mozambique was stopped in 2002 and artemether-lumefantrine (AL) was implemented in 2008. In light of no use of CQ and extensive use of AL, we determined the frequency of molecular markers of Plasmodium falciparum drug resistance/tolerance to CQ and AL in persons living...... in Linga-Linga, an isolated peninsula and in Furvela village, which is located 8 km inland. The P. falciparum chloroquine resistance transporter gene CVMNK wild type increased in frequency from 43.9% in 2009 to 66.4% in 2010 (P = 0.001), and combined P. falciparum multidrug resistance gene 1 N86-184F-D1246...... haplotype increased significantly between years (P = 0.039). The combination of P. falciparum chloroquine resistance transporter gene CVMNK and P. falciparum multidrug resistance gene NFD increased from 24.3% (2009) to 45.3% in (2010, P = 0.017). The rapid changes observed may largely be caused by decreased...

  9. Polymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether-lumefantrine and artesunate-amodiaquine.

    Science.gov (United States)

    Venkatesan, Meera; Gadalla, Nahla B; Stepniewska, Kasia; Dahal, Prabin; Nsanzabana, Christian; Moriera, Clarissa; Price, Ric N; Mårtensson, Andreas; Rosenthal, Philip J; Dorsey, Grant; Sutherland, Colin J; Guérin, Philippe; Davis, Timothy M E; Ménard, Didier; Adam, Ishag; Ademowo, George; Arze, Cesar; Baliraine, Frederick N; Berens-Riha, Nicole; Björkman, Anders; Borrmann, Steffen; Checchi, Francesco; Desai, Meghna; Dhorda, Mehul; Djimdé, Abdoulaye A; El-Sayed, Badria B; Eshetu, Teferi; Eyase, Frederick; Falade, Catherine; Faucher, Jean-François; Fröberg, Gabrielle; Grivoyannis, Anastasia; Hamour, Sally; Houzé, Sandrine; Johnson, Jacob; Kamugisha, Erasmus; Kariuki, Simon; Kiechel, Jean-René; Kironde, Fred; Kofoed, Poul-Erik; LeBras, Jacques; Malmberg, Maja; Mwai, Leah; Ngasala, Billy; Nosten, Francois; Nsobya, Samuel L; Nzila, Alexis; Oguike, Mary; Otienoburu, Sabina Dahlström; Ogutu, Bernhards; Ouédraogo, Jean-Bosco; Piola, Patrice; Rombo, Lars; Schramm, Birgit; Somé, A Fabrice; Thwing, Julie; Ursing, Johan; Wong, Rina P M; Zeynudin, Ahmed; Zongo, Issaka; Plowe, Christopher V; Sibley, Carol Hopkins

    2014-10-01

    Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001 : were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine. © The American Society of Tropical Medicine and Hygiene.

  10. Surveillance of artemether-lumefantrine associated Plasmodium falciparum multidrug resistance protein-1 gene polymorphisms in Tanzania

    DEFF Research Database (Denmark)

    Kavishe, Reginald A; Paulo, Petro; Kaaya, Robert D

    2014-01-01

    BACKGROUND: Resistance to anti-malarials is a major public health problem worldwide. After deployment of artemisinin-based combination therapy (ACT) there have been reports of reduced sensitivity to ACT by malarial parasites in South-East Asia. In Tanzania, artemether-lumefantrine (ALu) is the re...... pharmacovigilance studies to monitor any delayed parasite clearance by the drug....

  11. Multidrug resistance associated proteins in multidrug resistance

    OpenAIRE

    Sodani, Kamlesh; Patel, Atish; Kathawala, Rishil J.; Chen, Zhe-Sheng

    2012-01-01

    Multidrug resistance proteins (MRPs) are members of the C family of a group of proteins named ATP-binding cassette (ABC) transporters. These ABC transporters together form the largest branch of proteins within the human body. The MRP family comprises of 13 members, of which MRP1 to MRP9 are the major transporters indicated to cause multidrug resistance in tumor cells by extruding anticancer drugs out of the cell. They are mainly lipophilic anionic transporters and are reported to transport fr...

  12. Multidrug resistance associated proteins in multidrug resistance

    Institute of Scientific and Technical Information of China (English)

    Kamlesh Sodani; Atish Patel; Rishil J. Kathawala; Zhe-Sheng Chen

    2012-01-01

    Multidrug resistance proteins (MRPs) are members of the C family of a group of proteins named ATP-binding cassette (ABC) transporters.These ABC transporters together form the largest branch of proteins within the human body.The MRP family comprises of 13 members,of which MRP1 to MRP9 are the major transporters indicated to cause multidrug resistance in tumor cells by extruding anticancer drugs out of the cell.They are mainly lipophilic anionic transporters and are reported to transport free or conjugates of glutathione (GSH),glucuronate,or sulphate.In addition,MRP1 to MRP3 can transport neutral organic drugs in free form in the presence of free GSH.Collectively,MRPs can transport drugs that differ structurally and mechanistically,including natural anticancer drugs,nucleoside analogs,antimetabolites,and tyrosine kinase inhibitors.Many of these MRPs transport physiologically important anions such as leukotriene C4,bilirubin glucuronide,and cyclic nucleotides.This review focuses mainly on the physiological functions,cellular resistance characteristics,and probable in vivo role of MRP1 to MRP9.

  13. Multidrug-Resistant Tuberculosis

    Centers for Disease Control (CDC) Podcasts

    2008-10-28

    In this podcast, Dr. Oeltmann discusses multidrug-resistant tuberculosis. An outbreak occurred in Thailand, which led to 45 cases in the U.S. This serious illness can take up to 2 years to treat. MDR TB is a real threat and a serious condition.  Created: 10/28/2008 by Emerging Infectious Diseases.   Date Released: 10/28/2008.

  14. Ex Vivo Activity of Endoperoxide Antimalarials, Including Artemisone and Arterolane, against Multidrug-Resistant Plasmodium falciparum Isolates from Cambodia

    Science.gov (United States)

    2014-10-01

    2. Dong Y, Chollet J, Matile H, Charman SA, Chiu FC, Charman WN, Scorneaux B, Urwyler H, Santo Tomas J, Scheurer C, Snyder C, Dorn A, Wang X, Karle JM...Malaria burden and artemisinin resistance in the mobile and migrant population on the Thai-Myanmar border, 1999- 2011: an observational study. PLoS Med. 10...36. Vennerstrom JL, Arbe-Barnes S, Brun R, Charman SA, Chiu FCK, Chollet J, Dong Y, Dorn A, Hunziker D, Matile H, McIntosh K, Padmanilayam M, Santo

  15. Multidrug-resistant tuberculosis

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    McNerney Ruth

    2008-01-01

    Full Text Available Abstract Background With almost 9 million new cases each year, tuberculosis remains one of the most feared diseases on the planet. Led by the STOP-TB Partnership and WHO, recent efforts to combat the disease have made considerable progress in a number of countries. However, the emergence of mutated strains of Mycobacterium tuberculosis that are resistant to the major anti-tuberculosis drugs poses a deadly threat to control efforts. Multidrug-resistant tuberculosis (MDR-TB has been reported in all regions of the world. More recently, extensively drug resistant-tuberculosis (XDR-TB that is also resistant to second line drugs has emerged in a number of countries. To ensure that adequate resources are allocated to prevent the emergence and spread of drug resistance it is important to understand the scale of the problem. In this article we propose that current methods of describing the epidemiology of drug resistant tuberculosis are not adequate for this purpose and argue for the inclusion of population based statistics in global surveillance data. Discussion Whereas the prevalence of tuberculosis is presented as the proportion of individuals within a defined population having disease, the prevalence of drug resistant tuberculosis is usually presented as the proportion of tuberculosis cases exhibiting resistance to anti-tuberculosis drugs. Global surveillance activities have identified countries in Eastern Europe, the former Soviet Union and regions of China as having a high proportion of MDR-TB cases and international commentary has focused primarily on the urgent need to improve control in these settings. Other regions, such as sub-Saharan Africa have been observed as having a low proportion of drug resistant cases. However, if one considers the incidence of new tuberculosis cases with drug resistant disease in terms of the population then countries of sub-Saharan Africa have amongst the highest rates of transmitted MDR-TB in the world. We propose

  16. Induction of Multidrug Tolerance in Plasmodium falciparum by Extended Artemisinin Pressure.

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    Ménard, Sandie; Ben Haddou, Tanila; Ramadani, Arba Pramundita; Ariey, Frédéric; Iriart, Xavier; Beghain, Johann; Bouchier, Christiane; Witkowski, Benoit; Berry, Antoine; Mercereau-Puijalon, Odile; Benoit-Vical, Françoise

    2015-10-01

    Plasmodium falciparum resistance to artemisinin derivatives in Southeast Asia threatens global malaria control strategies. Whether delayed parasite clearance, which exposes larger parasite numbers to artemisinins for longer times, selects higher-grade resistance remains unexplored. We investigated whether long-lasting artemisinin pressure selects a novel multidrug-tolerance profile. Although 50% inhibitory concentrations for 10 antimalarial drugs tested were unchanged, drug-tolerant parasites showed higher recrudescence rates for endoperoxides, quinolones, and an antifolate, including partner drugs of recommended combination therapies, but remained susceptible to atovaquone. Moreover, the age range of intraerythrocytic stages able to resist artemisinin was extended to older ring forms and trophozoites. Multidrug tolerance results from drug-induced quiescence, which enables parasites to survive exposure to unrelated antimalarial drugs that inhibit a variety of metabolic pathways. This novel resistance pattern should be urgently monitored in the field because this pattern is not detected by current assays and represents a major threat to antimalarial drug policy.

  17. Primary multidrug resistant tuberculosis

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    Sarkar Supriya

    2007-01-01

    Full Text Available A 37-year old man presented at our institution with back pain, low-grade fever and weight-loss. X-ray of chest (postero-anterior view showed multiple opacities with erosion of right 2nd and left 6th ribs. CT-scan of thorax and CT-guided FNAC con-firmed the diagnosis of tuberculosis of ribs. Even after 5-months of treatment with four first line drugs, the patient developed a cold abscess at the back. Mycobacterial culture and drug sensitivity of material aspirated by Radiometric method from the cold abscess showed growth of Mycobacterium tuberculosis, and those bacilli were resistant to both isoniazide and rifampicin. The patient did not have anti-tubercu-lar medication in the past, and that established the diagnosis of primary multidrug resistant tuberculosis of ribs. Patient was treated successfully with 2nd line drugs at the cost of moderate degree of hearing loss. After one and half years of treatment X-ray of chest (PA view showed complete healing of rib erosions with new bone formation.

  18. Randomized trials of artemisinin-piperaquine, dihydroartemisinin-piperaquine phosphate and artemether-lumefantrine for the treatment of multi-drug resistant falciparum malaria in Cambodia-Thailand border area

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    Song Jianping

    2011-08-01

    Full Text Available Abstract Background Drug resistance of falciparum malaria is a global problem. Sulphadoxine/pyrimethamine-resistant and mefloquine-resistant strains of falciparum malaria have spread in Southeast Asia at lightning speed in 1980s-1990s, and the Cambodia-Thailand border is one of the malaria epidemic areas with the most severe forms of multi-drug resistant falciparum malaria. Methods Artemisinin-piperaquine (AP, dihydroartemisinin-piperaquine phosphate (DHP and artemether-lumefantrine (AL were used to treat 110, 55 and 55 uncomplicated malaria patients, respectively. The total dosage for adults is 1,750 mg (four tablets, twice over 24 hours of AP, 2,880 mg (eight tablets, four times over two days of DHP, and 3,360 mg (24 tablets, six times over three days of AL. The 28-day cure rate, parasite clearance time, fever clearance time, and drug tolerance of patients to the three drugs were compared. All of the above methods were consistent with the current national guidelines. Results The mean parasite clearance time was similar in all three groups (66.7 ± 21.9 hrs, 65.6 ± 27.3 hrs, 65.3 ± 22.5 hrs in AP, DHP and AL groups, respectively, and there was no remarkable difference between them; the fever clearance time was also similar (31.6 ± 17.7 hrs, 34.6 ± 21.8 hrs and 36.9 ± 15.4 hrs, respectively. After following up for 28-days, the cure rate was 95.1%(97/102, 98.2%(54/55 and 82.4%(42/51; and the recrudescence cases was 4.9%(5/102, 1.8%(1/55 and 17.6%(9/51, respectively. Therefore, the statistical data showed that 28-day cure rate in AP and DHP groups was superior to AL group obviously. The patients had good tolerance to all the three drugs, and some side effects (anoxia, nausea, vomiting, headache and dizziness could be found in every group and they were self-limited; patients in control groups also had good tolerance to DHP and AL, there was no remarkable difference in the three groups. Conclusions AP, DHP and AL all remained efficacious

  19. Multidrug-Resistant TB

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    Cox, Helen; Coomans, Fons

    2016-01-01

    Abstract The right to enjoy the benefits of scientific progress (REBSP) is a little-known but potentially valuable right that can contribute to rights-based approaches to addressing multidrug-resistant TB (MDR-TB). We argue that better understanding of the REBSP may help to advance legal and civil society action for health rights. While the REBSP does not provide an individual entitlement to have a new drug developed for MDR-TB, it sets up entitlements to expect a state to establish a legislative and policy framework aimed at developing scientific capacity to address the most important health issues and at disseminating the outcomes of scientific research. By making scientific findings available and accessible, people can be enabled to claim the use of science for social benefits. Inasmuch as the market fails to address neglected diseases such as MDR-TB, the REBSP provides a potential counterbalance to frame a positive obligation on states to both marshal their own resources and to coordinate the actions of multiple other actors towards this goal, including non-state actors. While the latter do not hold the same level of accountability as states, the REBSP can still enable the recognition of obligations at a level of “soft law” responsibilities.

  20. Compliance with a three-day course of artesunate-mefloquine combination and baseline anti-malarial treatment in an area of Thailand with highly multidrug resistant falciparum malaria

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    Na-Bangchang Kesara

    2010-02-01

    and primaquine levels were observed in 24 and 16% of the patients. Conclusion The current first-line treatment and a three-day combination regimen of artesunate-mefloquine provides excellent patient compliance with good efficacy and tolerability in the treatment of highly multidrug resistance falciparum malaria. Previous treatment with mefloquine and primaquine were common in this area.

  1. Molecular monitoring of Plasmodium falciparum resistance to artemisinin in Tanzania

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    Genton Blaise

    2006-12-01

    Full Text Available Abstract Artemisinin-based combination therapies (ACTs are recommended for use against uncomplicated malaria in areas of multi-drug resistant malaria, such as sub-Saharan Africa. However, their long-term usefulness in these high transmission areas remains unclear. It has been suggested that documentation of the S769N PfATPase6 mutations may indicate an emergence of artemisinin resistance of Plasmodium falciparum in the field. The present study assessed PfATPase6 mutations (S769N and A623E in 615 asymptomatic P. falciparum infections in Tanzania but no mutant genotype was detected. This observation suggests that resistance to artemisinin has not yet been selected in Tanzania, supporting the Ministry of Health's decision to adopt artemether+lumefantrine as first-line malaria treatment. The findings recommend further studies to assess PfATPase6 mutations in sentinel sites and verify their usefulness in monitoring emergency of ACT resistance.

  2. Effects of mefloquine use on Plasmodium vivax multidrug resistance.

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    Khim, Nimol; Andrianaranjaka, Voahangy; Popovici, Jean; Kim, Saorin; Ratsimbasoa, Arsene; Benedet, Christophe; Barnadas, Celine; Durand, Remy; Thellier, Marc; Legrand, Eric; Musset, Lise; Menegon, Michela; Severini, Carlo; Nour, Bakri Y M; Tichit, Magali; Bouchier, Christiane; Mercereau-Puijalon, Odile; Ménard, Didier

    2014-10-01

    Numerous studies have indicated a strong association between amplification of the multidrug resistance-1 gene and in vivo and in vitro mefloquine resistance of Plasmodium falciparum. Although falciparum infection usually is not treated with mefloquine, incorrect diagnosis, high frequency of undetected mixed infections, or relapses of P. vivax infection triggered by P. falciparum infections expose non-P. falciparum parasites to mefloquine. To assess the consequences of such unintentional treatments on P. vivax, we studied variations in number of Pvmdr-1 (PlasmoDB accession no. PVX_080100, NCBI reference sequence NC_009915.1) copies worldwide in 607 samples collected in areas with different histories of mefloquine use from residents and from travelers returning to France. Number of Pvmdr-1 copies correlated with drug use history. Treatment against P. falciparum exerts substantial collateral pressure against sympatric P. vivax, jeopardizing future use of mefloquine against P. vivax. A drug policy is needed that takes into consideration all co-endemic species of malaria parasites.

  3. Role of multidrug resistance in photodynamic therapy

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    Diddens, Heyke C.

    1992-06-01

    Multidrug resistance in cancer chemotherapy is a well established phenomenon. One of the most common phenotypical changes in acquired or intrinsic multidrug resistance in human tumor cells is the overexpression of the mdrl gene product P-glycoprotein, which acts as an active efflux pump. Increased levels of P-glycoprotein are associated with resistance to a variety of anticancer drugs commonly used in tumor chemotherapy like anthracyclins, vinca- alcaloids, epipodophyllotoxins or actinomycin D. We investigated the efficacy or photodynamic therapy in the treatment of tumor cells expressing the multidrug resistance phenotype. Our data show that multidrug resistant cells are highly cross resistant to the phototoxic stain rhodamine 123 but exhibit only low degrees of cross resistance (2 - 3 -folds) to the photosensitizers Photosan-3, Clorin-2, methylene blue and meso-tetra (4- sulfonatophenyl) porphine (TPPS4). Resistance is associated with a decrease in intracellular accumulation of the photosensitizer. Verapamil, a membrane active compound known to enhance drug sensitivity in multidrug resistant cells by inhibition of P-glycoprotein, also increases phototoxicity in multidrug resistant cells. Our results imply that tumors expressing the multidrug resistance phenotype might fail to respond to photochemotherapy with rhodamine 123. On the other hand, multidrug resistance may not play an important role in photodynamic therapy with Photosan-3, Chlorin-2, methylene blue or TPPS4.

  4. Short report: polymorphisms in the chloroquine resistance transporter gene in Plasmodium falciparum isolates from Lombok, Indonesia.

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    Huaman, Maria Cecilia; Yoshinaga, Kazumi; Suryanatha, Aan; Suarsana, Nyoman; Kanbara, Hiroji

    2004-07-01

    The polymorphisms in the Plasmodium falciparum multidrug resistance 1 (pfmdr1) and P. falciparum chloroquine resistance transporter (pfcrt) genes, which are associated with chloroquine resistance, were examined in 48 P. falciparum isolates from uncomplicated malaria patients from the West Lombok District in Indonesia. The point mutation N86Y in pfmdr1 was present in 35.4% of the isolates and mutation K76T in pfcrt was found in all but one of the samples studied. Identified pfcrt haplotypes were mainly identical to the Papua New Guinea type S(agt)VMNT (42 of 48, 87.5%), and a few isolates had the Southeast Asia type CVIET (5 of 48, 10.4%). Moreover, one P. falciparum isolate harbored the K76N mutation, giving rise to the haplotype CVMNN, which was not previously reported in field isolates. Our findings suggest that chloroquine resistance in this area might have the same origin as in Papua New Guinea.

  5. Multidrug Resistance: An Emerging Crisis

    Directory of Open Access Journals (Sweden)

    Jyoti Tanwar

    2014-01-01

    Full Text Available The resistance among various microbial species (infectious agents to different antimicrobial drugs has emerged as a cause of public health threat all over the world at a terrifying rate. Due to the pacing advent of new resistance mechanisms and decrease in efficiency of treating common infectious diseases, it results in failure of microbial response to standard treatment, leading to prolonged illness, higher expenditures for health care, and an immense risk of death. Almost all the capable infecting agents (e.g., bacteria, fungi, virus, and parasite have employed high levels of multidrug resistance (MDR with enhanced morbidity and mortality; thus, they are referred to as “super bugs.” Although the development of MDR is a natural phenomenon, the inappropriate use of antimicrobial drugs, inadequate sanitary conditions, inappropriate food-handling, and poor infection prevention and control practices contribute to emergence of and encourage the further spread of MDR. Considering the significance of MDR, this paper, emphasizes the problems associated with MDR and the need to understand its significance and mechanisms to combat microbial infections.

  6. Multidrug resistance: an emerging crisis.

    Science.gov (United States)

    Tanwar, Jyoti; Das, Shrayanee; Fatima, Zeeshan; Hameed, Saif

    2014-01-01

    The resistance among various microbial species (infectious agents) to different antimicrobial drugs has emerged as a cause of public health threat all over the world at a terrifying rate. Due to the pacing advent of new resistance mechanisms and decrease in efficiency of treating common infectious diseases, it results in failure of microbial response to standard treatment, leading to prolonged illness, higher expenditures for health care, and an immense risk of death. Almost all the capable infecting agents (e.g., bacteria, fungi, virus, and parasite) have employed high levels of multidrug resistance (MDR) with enhanced morbidity and mortality; thus, they are referred to as "super bugs." Although the development of MDR is a natural phenomenon, the inappropriate use of antimicrobial drugs, inadequate sanitary conditions, inappropriate food-handling, and poor infection prevention and control practices contribute to emergence of and encourage the further spread of MDR. Considering the significance of MDR, this paper, emphasizes the problems associated with MDR and the need to understand its significance and mechanisms to combat microbial infections.

  7. 3-Halo Chloroquine Derivatives Overcome Plasmodium falciparum Chloroquine Resistance Transporter-Mediated Drug Resistance in P. falciparum.

    Science.gov (United States)

    Edaye, Sonia; Tazoo, Dagobert; Bohle, D Scott; Georges, Elias

    2015-12-01

    Polymorphism in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) was shown to cause chloroquine resistance. In this report, we examined the antimalarial potential of novel 3-halo chloroquine derivatives (3-chloro, 3-bromo, and 3-iodo) against chloroquine-susceptible and -resistant P. falciparum. All three derivatives inhibited the proliferation of P. falciparum; with 3-iodo chloroquine being most effective. Moreover, 3-iodo chloroquine was highly effective at potentiating and reversing chloroquine toxicity of drug-susceptible and -resistant P. falciparum.

  8. No seasonal accumulation of resistant P. falciparum when high-dose chloroquine is used

    DEFF Research Database (Denmark)

    Ursing, Johan; Kofoed, Poul-Erik; Rodrigues, Amabelia

    2009-01-01

    BACKGROUND: Potentially chloroquine resistant P. falciparum, identified by the 76T haplotype in the chloroquine resistance transporter (pfcrt 76T), are highly prevalent throughout Africa. In Guinea-Bissau, normal and double dose chloroquine have respective efficacies of 34% and 78% against P...... increase of pfcrt 76T if the high doses of CQ commonly used are effective. METHODS AND FINDINGS: P. falciparum parasite density, age, sex, the proportion of chloroquine resistance associated haplotypes pfcrt 76T and P. falciparum multidrug resistance gene 1 86Y were assessed in 988 samples collected from...... children between 2002 and 2007. There was no seasonal accumulation of any allele. During the high and low transmission periods the pfcrt 76T proportions were 24% (95% CI, 21-27%) and 26% (95% CI, 20-33%). There was no significant change of pfcrt 76T (OR 1.05, 95% CI; 0.94-1.16 p = 0.39) or pfmdr1 86Y (OR 0...

  9. The ABCs of multidrug resistance in malaria.

    NARCIS (Netherlands)

    Koenderink, J.B.; Kavishe, R.A.; Rijpma, S.R.; Russel, F.G.M.

    2010-01-01

    Expanding drug resistance could become a major problem in malaria treatment, as only a limited number of effective antimalarials are available. Drug resistance has been associated with single nucleotide polymorphisms and an increased copy number of multidrug resistance protein 1 (MDR1), an ATP-bindi

  10. Drug efflux proteins in multidrug resistant bacteria

    NARCIS (Netherlands)

    vanVeen, HW; Konings, WN

    1997-01-01

    Bacteria contain an array of transport proteins in their cytoplasmic membrane. Many of these proteins play an important role in conferring resistance to toxic compounds. The multidrug efflux systems encountered in prokaryotic cells are very similar to those observed in eukaryotic cells. Therefore, a

  11. Multidrug resistance: Physiological principles and nanomedical solutions.

    Science.gov (United States)

    Kunjachan, Sijumon; Rychlik, Błażej; Storm, Gert; Kiessling, Fabian; Lammers, Twan

    2013-11-01

    Multidrug resistance (MDR) is a pathophysiological phenomenon employed by cancer cells which limits the prolonged and effective use of chemotherapeutic agents. MDR is primarily based on the over-expression of drug efflux pumps in the cellular membrane. Prominent examples of such efflux pumps, which belong to the ATP-binding cassette (ABC) superfamily of proteins, are Pgp (P-glycoprotein) and MRP (multidrug resistance-associated protein), nowadays officially known as ABCB1 and ABCC1. Over the years, several strategies have been evaluated to overcome MDR, based not only on the use of low-molecular-weight MDR modulators, but also on the implementation of 1-100(0) nm-sized drug delivery systems. In the present manuscript, after introducing the most important physiological principles of MDR, we summarize prototypic nanomedical strategies to overcome multidrug resistance, including the use of carrier materials with intrinsic anti-MDR properties, the use of nanomedicines to modify the mode of cellular uptake, and the co-formulation of chemotherapeutic drugs together with low- and high-molecular-weight MDR inhibitors within a single drug delivery system. While certain challenges still need to be overcome before such constructs and concepts can be widely applied in the clinic, the insights obtained and the progress made strongly suggest that nanomedicine formulations hold significant potential for improving the treatment of multidrug-resistant malignancies.

  12. Multidrug resistance: Physiological principles and nanomedical solutions

    NARCIS (Netherlands)

    Kunjachan, S.; Rychlik, B.; Storm, G.; Kiessling, F.; Lammers, T.G.G.M.

    2013-01-01

    Multidrug resistance (MDR) is a pathophysiological phenomenon employed by cancer cells which limits the prolonged and effective use of chemotherapeutic agents. MDR is primarily based on the over-expression of drug efflux pumps in the cellular membrane. Prominent examples of such efflux pumps, which

  13. Drug efflux proteins in multidrug resistant bacteria

    NARCIS (Netherlands)

    vanVeen, HW; Konings, WN

    Bacteria contain an array of transport proteins in their cytoplasmic membrane. Many of these proteins play an important role in conferring resistance to toxic compounds. The multidrug efflux systems encountered in prokaryotic cells are very similar to those observed in eukaryotic cells. Therefore, a

  14. Bacterial multidrug resistance mediated by a homologue of the human multidrug transporter P-glycoprotein

    NARCIS (Netherlands)

    Konings, WN; Poelarends, GJ

    2002-01-01

    Most ATP-binding cassette (ABC) multidrug transporters known to date are of eukaryotic origin, such as the P-glycoproteins (Pgps) and multidrug resistance-associated proteins (MRPs). Only one well-characterized ABC multidrug transporter, LmrA, is of bacterial origin. On the basis of its structural a

  15. Primary disseminated extrapulmonary multidrug resistant tuberculosis

    Directory of Open Access Journals (Sweden)

    S K Das

    2012-01-01

    Full Text Available Disseminated tuberculosis is a common mode of presentation of tuberculosis in patients both with and without HIV/AIDS in India. However, primary multidrug resistance in disseminated tuberculosis involving only the extrapulmonary sites in an immunocompetent adult is rare. Here, we report a case of a 19-year-old man who had disseminated tuberculosis involving left pleura, pericardium, peritoneum and intraabdominal lymph nodes. He was initially taking WHO category I antituberculous drugs, but was not responding in spite of 5 months of chemotherapy. Culture of the pleural biopsy specimen grew Mycobacterium tuberculosis which was resistant to isoniazid and rifampicin. He was put on therapy for multidrug resistant tuberculosis,following 24 months of chemotherapyhe had an uneventful recovery.

  16. [Travellers and multi-drug resistance bacteria].

    Science.gov (United States)

    Takeshita, Nozomi

    2012-02-01

    The number of international travellers has increased. There is enormous diversity in medical backgrounds, purposes of travel, and travelling styles among travellers. Travellers are hospitalized abroad because of exotic and common diseases via medical tourism. This is one way of transporting and importing human bacteria between countries, including multi-drug resistant organisms. In developing countries, the antimicrobial resistance in Shigella sp. and Salmonella sp. have been a problem, because of this trend, the first choice of antibiotics has changed in some countries. Community acquired infections as well as hospital acquired infections with MRSA, multi-drug resistance (MDR) Pseudomonas aeruginosa, and ESBL have been a problem. This review will discuss the risk of MDR bacterial infectious diseases for travellers.

  17. Polycyclic amines as chloroquine resistance modulating agents in Plasmodium falciparum.

    Science.gov (United States)

    Joubert, Jacques; Kapp, Erika; Taylor, Dale; Smith, Peter J; Malan, Sarel F

    2016-02-15

    Pentacycloundecylamines (PCUs) and adamantane amines, such as NGP1-01 (1) and amantadine, have shown significant channel blocking activities. They are postulated to act as chemosensitizers and circumvent the resistance of the plasmodia parasite against chloroquine (CQ) by inhibiting the p-glycoprotein efflux pump and enabling the accumulation of CQ inside the parasite digestive vacuole. Twelve polycyclic amines containing either a PCU or adamantane amine moiety conjugated to different aromatic functionalities through various tethered linkers were selected based on their channel blocking abilities and evaluated as potential chemosensitizers. Compounds 2, 4, 5 and 10 showed significant voltage-gated calcium channel (VGCC) blocking ability (IC50=0.27-35 μM) and were able to alter the CQ IC50 in differing degrees (45-81%) in the multidrug resistant Plasmodium falciparum Dd2 isolate. Among them, the PCU-dansyl amine compound (4) displayed the best potential to act as a chemosensitizer against the Dd2 strain at a 1 μM concentration (RMI=0.19) while displaying moderate antiplasmodial activity (Dd2 IC50=6.25 μM) and low in vitro cytotoxicity against a mammalian cell line (CHO, IC50=119 μM). Compounds 2 and 10 also showed some promising chemosensitizing abilities (RMI=0.36 and 0.35 respectively). A direct correlation was found between the VGCC blocking ability of these polycyclic amines and their capacity to act as CQ resistance modulating agents.

  18. Chromosomal Instability Confers Intrinsic Multidrug Resistance

    DEFF Research Database (Denmark)

    Lee, Alvin J. X.; Endesfelder, David; Rowan, Andrew J.

    2011-01-01

    their diploid parental cells only with increasing chromosomal heterogeneity and isogenic cell line models of CIN+ displayed multidrug resistance relative to their CIN- parental cancer cell line derivatives. In a meta-analysis of CRC outcome following cytotoxic treatment, CIN+ predicted worse progression......-free or disease-free survival relative to patients with CIN- disease. Our results suggest that stratifying tumor responses according to CIN status should be considered within the context of clinical trials to minimize the confounding effects of tumor CIN status on drug sensitivity. Cancer Res; 71(5); 1858-70. (c......Aneuploidy is associated with poor prognosis in solid tumors. Spontaneous chromosome missegregation events in aneuploid cells promote chromosomal instability (CIN) that may contribute to the acquisition of multidrug resistance in vitro and heighten risk for tumor relapse in animal models...

  19. Study of multidrug resistance and radioresistance

    Energy Technology Data Exchange (ETDEWEB)

    Kang, Yoon Koo; Yoo, Young Do

    1999-04-01

    We investigated the mechanism of 5-FU, adriamycin, radiation resistance in Korean gastric cancer cells. First we investigated the relation between Rb and multidrug resistance. Rb stable transfectants exhibited 5- to 10- fold more resistance to adriamycin than the control cells. These Rb transfectants showed increased MDR1 expression. We also investigated up-regulation in radiation-resistant tumor tissues. HSP27, MRP-8, GST, and NKEF-B were up-regulated in radiation resistant tumor. Expression of NKEF-B was also increased by radiation exposure in Head and Neck cells. These results demonstrated that NKEF-B is a stress response protein and it may have an important role in radiation resistance.

  20. New Fixed-Dose Artesunate-Mefloquine Formulation against Multidrug-Resistant Plasmodium falciparum in Adults: a Comparative Phase IIb Safety and Pharmacokinetic Study with Standard-Dose Nonfixed Artesunate plus Mefloquine▿

    Science.gov (United States)

    Krudsood, S.; Looareesuwan, S.; Tangpukdee, N.; Wilairatana, P.; Phumratanaprapin, W.; Leowattana, W.; Chalermrut, K.; Ramanathan, S.; Navaratnam, V.; Olliaro, P.; Vaillant, M.; Kiechel, J. R.; Taylor, W. R. J.

    2010-01-01

    A new fixed-dose artesunate (AS)-mefloquine (MQ) was assessed in adults hospitalized for 28 days with uncomplicated drug-resistant falciparum malaria. The patients (n = 25/arm) were treated with (i) two fixed-dose tablets (AS-MQ arm; 100 mg AS-200 mg MQ/tablet) daily for 3 days (days 0, 1, and 2) or (ii) nonfixed AS (AS-plus-MQ arm; 4 mg/kg of body weight/day for 3 days) plus MQ (15 mg/kg on day 1 and 10 mg/kg on day 2), dosed by weight. Clinical laboratory electrocardiogram (ECG), adverse events (AEs), efficacy, and pharmacokinetic parameters were assessed over 28 days. Both regimens were well tolerated. No AEs were drug related. Two serious AEs of malaria-induced hypotension occurring in the AS-MQ arm necessitated rescue treatment. There were no significant changes in hematology, biochemistry, or PR and QRS intervals. For all patients, mean Fridericia-corrected QT intervals were significantly (P ≤ 0.0027) prolonged on day 3 (407 ms) and day 7 (399 ms) versus day 0 (389 ms), in parallel with significant (P ≤ 0.0003) falls in heart rates (67 [day 3], 73 [day 7], and 83 [day 0] beats/minute). Fixed-nonfixed formulations were bioequivalent for MQ, but not for AS and dihydroartemisinin (DHA). One AS-MQ patient developed a new infection on day 28; his day 28 plasma MQ concentration was 503.8 ng/ml. Fixed-dose AS-MQ was well tolerated, had pharmacokinetic (PK) profiles broadly similar to those of nonfixed AS plus MQ, and is a suitable replacement. PMID:20547795

  1. Artemisinin-Resistant Plasmodium falciparum Malaria.

    Science.gov (United States)

    Fairhurst, Rick M; Dondorp, Arjen M

    2016-06-01

    For more than five decades, Southeast Asia (SEA) has been fertile ground for the emergence of drug-resistant Plasmodium falciparum malaria. After generating parasites resistant to chloroquine, sulfadoxine, pyrimethamine, quinine, and mefloquine, this region has now spawned parasites resistant to artemisinins, the world's most potent antimalarial drugs. In areas where artemisinin resistance is prevalent, artemisinin combination therapies (ACTs)-the first-line treatments for malaria-are failing fast. This worrisome development threatens to make malaria practically untreatable in SEA, and threatens to compromise global endeavors to eliminate this disease. A recent series of clinical, in vitro, genomics, and transcriptomics studies in SEA have defined in vivo and in vitro phenotypes of artemisinin resistance, identified its causal genetic determinant, explored its molecular mechanism, and assessed its clinical impact. Specifically, these studies have established that artemisinin resistance manifests as slow parasite clearance in patients and increased survival of early-ring-stage parasites in vitro; is caused by single nucleotide polymorphisms in the parasite's K13 gene, is associated with an upregulated "unfolded protein response" pathway that may antagonize the pro-oxidant activity of artemisinins, and selects for partner drug resistance that rapidly leads to ACT failures. In SEA, clinical studies are urgently needed to monitor ACT efficacy where K13 mutations are prevalent, test whether new combinations of currently available drugs cure ACT failures, and advance new antimalarial compounds through preclinical pipelines and into clinical trials. Intensifying these efforts should help to forestall the spread of artemisinin and partner drug resistance from SEA to sub-Saharan Africa, where the world's malaria transmission, morbidity, and mortality rates are highest.

  2. High-Dose Chloroquine for Treatment of Chloroquine-Resistant Plasmodium falciparum Malaria.

    Science.gov (United States)

    Ursing, Johan; Rombo, Lars; Bergqvist, Yngve; Rodrigues, Amabelia; Kofoed, Poul-Erik

    2016-04-15

    Due to development of multidrug-resistant Plasmodium falciparum new antimalarial therapies are needed. In Guinea-Bissau, routinely used triple standard-dose chloroquine remained effective for decades despite the existence of "chloroquine-resistant" P. falciparum. This study aimed to determine the in vivo efficacy of higher chloroquine concentrations against P. falciparum with resistance-conferring genotypes. Standard or double-dose chloroquine was given to 892 children aged <15 years with uncomplicated malaria during 3 clinical trials (2001-2008) with ≥ 35 days follow-up. The P. falciparum resistance-conferring genotype (pfcrt 76T) and day 7 chloroquine concentrations were determined. Data were divided into age groups (<5, 5-9, and 10-14 years) because concentrations increase with age when chloroquine is prescribed according to body weight. Adequate clinical and parasitological responses were 14%, 38%, and 39% after standard-dose and 66%, 84%, and 91% after double-dose chloroquine in children aged <5, 5-9, and 10-14 years, respectively, and infected with P. falciparum genotypes conferring chloroquine resistance (n = 195, P < .001). In parallel, median chloroquine concentrations were 471, 688, and 809 nmol/L for standard-dose and 1040, 1494, and 1585 nmol/L for double-dose chloroquine. Chloroquine resistance is dose dependent and can be overcome by higher, still well-tolerated doses. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  3. Yeast ABC proteins involved in multidrug resistance.

    Science.gov (United States)

    Piecuch, Agata; Obłąk, Ewa

    2014-03-01

    Pleiotropic drug resistance is a complex phenomenon that involves many proteins that together create a network. One of the common mechanisms of multidrug resistance in eukaryotic cells is the active efflux of a broad range of xenobiotics through ATP-binding cassette (ABC) transporters. Saccharomyces cerevisiae is often used as a model to study such activity because of the functional and structural similarities of its ABC transporters to mammalian ones. Numerous ABC transporters are found in humans and some are associated with the resistance of tumors to chemotherapeutics. Efflux pump modulators that change the activity of ABC proteins are the most promising candidate drugs to overcome such resistance. These modulators can be chemically synthesized or isolated from natural sources (e.g., plant alkaloids) and might also be used in the treatment of fungal infections. There are several generations of synthetic modulators that differ in specificity, toxicity and effectiveness, and are often used for other clinical effects.

  4. Multidrug-resistant breast cancer: current perspectives

    Directory of Open Access Journals (Sweden)

    Martin HL

    2014-01-01

    Full Text Available Heather L Martin,1 Laura Smith,2 Darren C Tomlinson11BioScreening Technology Group, Leeds Institutes of Molecular Medicine, University of Leeds, Leeds, UK; 2Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UKAbstract: Breast cancer is the most common cancer in women worldwide, and resistance to the current therapeutics, often concurrently, is an increasing clinical challenge. By understanding the molecular mechanisms behind multidrug-resistant breast cancer, new treatments may be developed. Here we review the recent advances in this understanding, emphasizing the common mechanisms underlying resistance to both targeted therapies, notably tamoxifen and trastuzumab, and traditional chemotherapies. We focus primarily on three molecular mechanisms, the phosphatidylinositide 3-kinase/Akt pathway, the role of microRNAs in gene silencing, and epigenetic alterations affecting gene expression, and discuss how these mechanisms can interact in multidrug resistance. The development of therapeutics targeting these mechanisms is also addressed.Keywords: PI3K/Akt, epigenetics, miRNA, ER, HER2, triple negative

  5. Doctors Seeing More HIV Patients with Multidrug Resistance

    Science.gov (United States)

    ... html Doctors Seeing More HIV Patients With Multidrug Resistance People resistant to older medication also have problems ... to modern drugs had HIV mutations linked with resistance to older drugs called thymidine analogues. Among patients ...

  6. Multidrug-Resistant Tuberculosis Complicated by Nosocomial Infection with Multidrug-Resistant Enterobacteriaceae

    NARCIS (Netherlands)

    Gröschel, Matthias I; Omansen, Till F; de Lange, Wiel; van der Werf, Tjip S; Lokate, M.; Bathoorn, Erik; Akkerman, Onno W; Stienstra, Ymkje

    2016-01-01

    Treatment of mycobacterial diseases such as tuberculosis (TB) entails long and intense antimicrobial therapy. TB patients are at risk of coinfection with other multidrug-resistant bacteria, such as those from Enterobacteriaceae family, because of antimicrobial selection pressure and nosocomial trans

  7. Prolonged weightlessness affects promyelocytic multidrug resistance.

    Science.gov (United States)

    Piepmeier, E H; Kalns, J E; McIntyre, K M; Lewis, M L

    1997-12-15

    An immortalized promyelocytic cell line was studied to detect how doxorubicin uptake is affected by microgravity. The purpose of this experiment was to identify the effect that microgravity may have on multidrug resistance in leukocytes. HL60 cells and HL60 cells resistant to anthracycline (HL60/AR) were grown in RPMI and 10% FBS. Upon reaching orbit in the Space Shuttle Endeavour, the cells were robotically mixed with doxorubicin. Three days after mixing, cells were fixed with paraformaldehyde/glutaraldehyde. Ground control experiments were conducted concurrently using a robot identical to the one used on the Shuttle. Fixed cells were analyzed within 2 weeks of launch. Confocal micrographs identified changes in cell structure (transmittance), drug distribution (fluorescence), and microtubule polymerization (fluorescence). Flight cells showed a lack of cytoskeletal polymerization resulting in an overall amorphic globular shape. Doxorubicin distribution in ground cells included a large numbers of vesicles relative to flight cells. There was a greater amount of doxorubicin present in flight cells (85% +/- 9.7) than in ground control cells (43% +/- 26) as determined by image analysis. Differences in microtubule formation between flight cells and ground cells could be partially responsible for the differences in drug distribution. Cytoskeletal interactions are critical to the function of P-glycoprotein as a drug efflux pump responsible for multidrug resistance.

  8. ABC transporters and multidrug resistance in Aspergillus nidulans

    OpenAIRE

    ANDRADE, A. C.

    2000-01-01

    The term multidrug resistance (MDR) stands for simultaneous cellular resistance to chemically unrelated toxicants and is often associated with overproduction of multidrug-efflux proteins of the A TP- b inding- c assette (ABC) superfamily. The ABC transporters comprise a large and multifunctional family of proteins. Besides multidrug transporters, the superfamily includes proteins involved in transmembrane transport of various substances such as ions, amino acids, peptides, sugars, vitamins, s...

  9. ABC transporters and multidrug resistance in Aspergillus nidulans

    NARCIS (Netherlands)

    Andrade, A.C.

    2000-01-01

    The term multidrug resistance (MDR) stands for simultaneous cellular resistance to chemically unrelated toxicants and is often associated with overproduction of multidrug-efflux proteins of the A TP- b inding- c assette (ABC) superfamily. The ABC tr

  10. Role of Different Pfcrt and Pfmdr-1 Mutations in Conferring Resistance to Antimalaria Drugs in Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Zaid O. Ibraheem

    2014-01-01

    Full Text Available Emergence of drugs resistant strains of Plasmodium falciparum has augmented the scourge of malaria in endemic areas. Antimalaria drugs act on different intracellular targets. The majority of them interfere with digestive vacuoles (DVs while others affect other organelles, namely, apicoplast and mitochondria. Prevention of drug accumulation or access into the target site is one of the mechanisms that plasmodium adopts to develop resistance. Plasmodia are endowed with series of transporters that shuffle drugs away from the target site, namely, pfmdr (Plasmodium falciparum multidrug resistance transporter and pfcrt (Plasmodium falciparum chloroquine resistance transporter which exist in DV membrane and are considered as putative markers of CQ resistance. They are homologues to human P-glycoproteins (P-gh or multidrug resistance system and members of drug metabolite transporter (DMT family, respectively. The former mediates drifting of xenobiotics towards the DV while the latter chucks them outside. Resistance to drugs whose target site of action is intravacuolar develops when the transporters expel them outside the DVs and vice versa for those whose target is extravacuolar. In this review, we are going to summarize the possible pfcrt and pfmdr mutation and their role in changing plasmodium sensitivity to different anti-Plasmodium drugs.

  11. Border Malaria Associated with Multidrug Resistance on Thailand-Myanmar and Thailand-Cambodia Borders: Transmission Dynamic, Vulnerability, and Surveillance

    Directory of Open Access Journals (Sweden)

    Adisak Bhumiratana

    2013-01-01

    Full Text Available This systematic review elaborates the concepts and impacts of border malaria, particularly on the emergence and spread of Plasmodium falciparum and Plasmodium vivax multidrug resistance (MDR malaria on Thailand-Myanmar and Thailand-Cambodia borders. Border malaria encompasses any complex epidemiological settings of forest-related and forest fringe-related malaria, both regularly occurring in certain transmission areas and manifesting a trend of increased incidence in transmission prone areas along these borders, as the result of interconnections of human settlements and movement activities, cross-border population migrations, ecological changes, vector population dynamics, and multidrug resistance. For regional and global perspectives, this review analyzes and synthesizes the rationales pertaining to transmission dynamics and the vulnerabilities of border malaria that constrain surveillance and control of the world’s most MDR falciparum and vivax malaria on these chaotic borders.

  12. [Research Progress on Artemisinin Resistance in Plasmodium falciparum].

    Science.gov (United States)

    Zhang, Yi-long; Pan, Wei-qing

    2015-12-01

    Artemisinin (ART) is a novel and effective antimalarial drug discovered in China. As recommended by the World Health Organization, the ART-based combination therapies (ACTs) have become the first-line drugs for the treatment of falciparum malaria. ART and its derivatives have contributed greatly to the effective control of malaria globally, leading to yearly decrease of malaria morbidity and mortality. However, there have recently been several reports on the resistance of Plasmodium falciparum to ART in Southeast Asia. This is deemed a serious threat to the global malaria control programs. In this paper, we reviewed recent research progress on ART resistance to P. falciparum, including new tools for resistance measurement, resistance-associated molecular markers, and the origin and spread of the ART-resistant parasite strains.

  13. Molecular surveillance as monitoring tool for drug-resistant Plasmodium falciparum in Suriname.

    Science.gov (United States)

    Adhin, Malti R; Labadie-Bracho, Mergiory; Bretas, Gustavo

    2013-08-01

    The aim of this translational study was to show the use of molecular surveillance for polymorphisms and copy number as a monitoring tool to track the emergence and dynamics of Plasmodium falciparum drug resistance. A molecular baseline for Suriname was established in 2005, with P. falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance (pfmdr1) markers and copy number in 40 samples. The baseline results revealed the existence of a uniformly distributed mutated genotype corresponding with the fully mefloquine-sensitive 7G8-like genotype (Y184F, S1034C, N1042D, and D1246Y) and a fixed pfmdr1 N86 haplotype. All samples harbored the pivotal pfcrtK76T mutation, showing that chloroquine reintroduction should not yet be contemplated in Suriname. After 5 years, 40 samples were assessed to trace temporal changes in the status of pfmdr1 polymorphisms and copy number and showed minor genetic alterations in the pfmdr1 gene and no significant changes in copy number, thus providing scientific support for prolongation of the current drug policy in Suriname.

  14. Radioiodinated agents for imaging multidrug resistant tumors.

    Science.gov (United States)

    Kortylewicz, Zbigniew P; Augustine, Ann M; Nearman, Jessica; McGarry, Jonathon; Baranowska-Kortylewicz, Janina

    2009-03-01

    Diagnostic agents enabling characterization of multidrug resistance (MDR) in tumors can aid in the selection of chemotherapy regimens. We report here synthesis and evaluation of radiopharmaceuticals based on the second-generation MDR-reversing drug MS-209. 5-[3-{4-(2-Phenyl-2-(4'-[(125)I]iodo-phenyl)acetyl)piperazin-1-yl}-2-hydroxypropoxy]quino-line (17) was prepared from the 4'-tributylstannyl precursor (16) in >95% radiochemical yield. (16) was synthesized in a six-step process with the overall yield of 25%. In vitro studies were conducted in MES-SA (drug-sensitive) and MES-SA/Dx5 (MDR) human uterine sarcoma cell lines. In vivo studies were performed in athymic mice bearing MES-SA and MES-SA/Dx5 xenografts. The uptake of (17) is higher in MES-SA than MES-SA/Dx5 cells. The uptake and efflux of (17) depend on temperature and concentration, and indicate active transport mechanism(s). Incubation of drug sensitive MES-SA cells with verapamil or (15), a nonradioactive analog of (17), alters the cellular retention of radioactivity only marginally. However, MES-SA/Dx5 cells retain approximately 12% more of (17) when incubated with 10 muM verapamil. The addition of (15) or high concentrations of (17) also increase the uptake of (17) in MES-SA/Dx5 up to 200%, depending on the concentration and temperature. The dependence of (17) uptake on the MDR status is also evident in the ex vivo binding studies. In vivo tests in mice xenografted simultaneously with both tumor cell lines indicate distinct pharmacokinetics for each tumor. The absorption half-life in MES-SA/Dx5 xenograft is approximately 10x shorter and the mean residence time approximately 50% shorter compared to MES-SA xenograft in the same mouse. Radioiodinated derivatives of MS-209 appear to be good indicators of multidrug resistance.

  15. Mechanisms of multidrug resistance in cancer.

    Science.gov (United States)

    Gillet, Jean-Pierre; Gottesman, Michael M

    2010-01-01

    The development of multidrug resistance (MDR) to chemotherapy remains a major challenge in the treatment of cancer. Resistance exists against every effective anticancer drug and can develop by numerous mechanisms including decreased drug uptake, increased drug efflux, activation of detoxifying systems, activation of DNA repair mechanisms, evasion of drug-induced apoptosis, etc. In the first part of this chapter, we briefly summarize the current knowledge on individual cellular mechanisms responsible for MDR, with a special emphasis on ATP-binding cassette transporters, perhaps the main theme of this textbook. Although extensive work has been done to characterize MDR mechanisms in vitro, the translation of this knowledge to the clinic has not been crowned with success. Therefore, identifying genes and mechanisms critical to the development of MDR in vivo and establishing a reliable method for analyzing clinical samples could help to predict the development of resistance and lead to treatments designed to circumvent it. Our thoughts about translational research needed to achieve significant progress in the understanding of this complex phenomenon are therefore discussed in a third section. The pleotropic response of cancer cells to chemotherapy is summarized in a concluding diagram.

  16. Multidrug resistance in tumour cells: characterisation of the multidrug resistant cell line K562-Lucena 1

    Directory of Open Access Journals (Sweden)

    VIVIAN M. RUMJANEK

    2001-03-01

    Full Text Available Multidrug resistance to chemotherapy is a major obstacle in the treatment of cancer patients. The best characterised mechanism responsible for multidrug resistance involves the expression of the MDR-1 gene product, P-glycoprotein. However, the resistance process is multifactorial. Studies of multidrug resistance mechanisms have relied on the analysis of cancer cell lines that have been selected and present cross-reactivity to a broad range of anticancer agents. This work characterises a multidrug resistant cell line, originally selected for resistance to the Vinca alkaloid vincristine and derived from the human erythroleukaemia cell K562. This cell line, named Lucena 1, overexpresses P-glycoprotein and have its resistance reversed by the chemosensitisers verapamil, trifluoperazine and cyclosporins A, D and G. Furthermore, we demonstrated that methylene blue was capable of partially reversing the resistance in this cell line. On the contrary, the use of 5-fluorouracil increased the resistance of Lucena 1. In addition to chemotherapics, Lucena 1 cells were resistant to ultraviolet A radiation and hydrogen peroxide and failed to mobilise intracellular calcium when thapsigargin was used. Changes in the cytoskeleton of this cell line were also observed.A resistência a múltiplos fármacos é o principal obstáculo no tratamento de pacientes com câncer. O mecanismo responsável pela resistência múltipla mais bem caracterizado envolve a expressão do produto do gene MDR-1, a glicoproteína P. Entretanto, o processo de resistência tem fatores múltiplos. Estudos de mecanismos de resistência m��ltipla a fármacos têm dependido da análise de linhagens celulares tumorais que foram selecionadas e apresentam reatividade cruzada a uma ampla faixa de agentes anti-tumorais. Este trabalho caracteriza uma linhagem celular com múltipla resistência a fármacos, selecionada originalmente pela resistência ao alcalóide de Vinca vincristina e derivado

  17. Epidemiology of Primary Multidrug-Resistant Tuberculosis, Vladimir Region, Russia.

    Science.gov (United States)

    Ershova, Julia V; Volchenkov, Grigory V; Kaminski, Dorothy A; Somova, Tatiana R; Kuznetsova, Tatiana A; Kaunetis, Natalia V; Cegielski, J Peter; Kurbatova, Ekaterina V

    2015-11-01

    We studied the epidemiology of drug-resistant tuberculosis (TB) in Vladimir Region, Russia, in 2012. Most cases of multidrug-resistant TB (MDR TB) were caused by transmission of drug-resistant strains, and >33% were in patients referred for testing after mass radiographic screening. Early diagnosis of drug resistance is essential for preventing transmission of MDR TB.

  18. Isolation and characterization of multidrug-resistant side population ...

    African Journals Online (AJOL)

    Isolation and characterization of multidrug-resistant side population cells in prostate carcinoma. ... PROMOTING ACCESS TO AFRICAN RESEARCH ... Keywords: Side population cells, ABC transporters, Cancer stem cells, Chemotherapy, ...

  19. Epidemiologic analysis: Prophylaxis and multidrug-resistance in surgery

    Directory of Open Access Journals (Sweden)

    H. Solís-Téllez

    2017-04-01

    Conclusions: The prophylactic guidelines are not strictly adhered to in our environment. There was a significant association between the development of nosocomial infections from multidrug-resistant germs and admission to the intensive care unit.

  20. High prevalence of drug-resistance mutations in Plasmodium falciparum and Plasmodium vivax in southern Ethiopia

    OpenAIRE

    Schunk, Mirjam; Kumma, Wondimagegn P.; Barreto Miranda, Isabel; Maha E. Osman; Roewer, Susanne; Alano, Abraham; Loescher, Thomas; Bienzle, Ulrich; Mockenhaupt, Frank P

    2006-01-01

    Background: In Ethiopia, malaria is caused by both Plasmodium falciparum and Plasmodium vivax. Drug resistance of P. falciparum to sulfadoxine-pyrimethamine (SP) and chloroquine (CQ) is frequent and intense in some areas. Methods: In 100 patients with uncomplicated malaria from Dilla, southern Ethiopia, P. falciparum dhfr and dhps mutations as well as P. vivax dhfr polymorphisms associated with resistance to SP and P. falciparum pfcrt and pfmdr1 mutations conferring CQ resistance were assesse...

  1. Unusual Complication of Multidrug Resistant Tuberculosis

    Directory of Open Access Journals (Sweden)

    Prerna Sharma

    2017-01-01

    Full Text Available Introduction. Capreomycin is a second-line drug often used for multidrug-resistant tuberculosis which can result in nephrotoxic effects similar to other aminoglycosides. We describe a case of capreomycin induced Bartter-like syndrome with hypocalcemic tetany. Case Report. 23-year-old female patient presented with carpopedal spasms and tingling sensations in hands. Patient was being treated with capreomycin for two months for tuberculosis. On further investigation, hypocalcemia, hyponatremia, hypomagnesemia, hypokalemia, and hypochloremic metabolic alkalosis were noted. Vitamin D and serum PTH levels were within normal limits. Hypercalciuria was confirmed by urine calcium/creatinine ratio. Calcium, potassium, and magnesium supplementation was given and capreomycin was discontinued. Electrolytes normalized in two days after cessation of capreomycin with no further abnormalities on repeat investigations. Discussion. Aminoglycosides can result in renal tubular dysfunction leading to Fanconi syndrome, Bartter syndrome, and distal tubular acidosis. Impaired mitochondrial function in the tubular cells has been hypothesized as the possible cause of these tubulopathies. Acquired Bartter-like syndrome phenotypically resembles autosomal dominant type 5 Bartter syndrome. Treatment consists of correction of electrolyte abnormalities, indomethacin, and potassium-sparing diuretics. Prompt diagnosis and treatment of severe dyselectrolytemia are warranted in patients on aminoglycoside therapy.

  2. Prevalence of Single Nucleotide Polymorphisms in the Plasmodium falciparum Multidrug Resistance Gene (Pfmdr-1) in Korogwe District in Tanzania Before and After Introduction of Artemisinin-Based Combination Therapy

    DEFF Research Database (Denmark)

    Thomsen, Thomas T; Ishengoma, Deus S; Mmbando, Bruno P;

    2011-01-01

    Abstract. Tanzania implemented artemether-lumefantrine (AL) as the first-line treatment for uncomplicated malaria in November of 2006 because of resistance to sulfadoxine-pyrimethamine. AL remains highly efficacious, but widespread use may soon facilitate emergence of artemisinin tolerance/resist.......9). The observed changes may be because of introduction of AL, and if so, this finding gives cause for concern and argues for continued surveillance of these molecular markers....

  3. Pharmacokinetics of ertapenem in patients with multidrug-resistant tuberculosis

    NARCIS (Netherlands)

    van Rijn, Sander P; van Altena, Richard; Akkerman, Onno W; van Soolingen, Dick; van der Laan, Tridia; de Lange, Wiel C M; Kosterink, Jos G W; van der Werf, Tjip S; Alffenaar, Jan-Willem C

    2016-01-01

    Treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) is becoming more challenging because of increased levels of drug resistance against second-line TB drugs. One promising group of antimicrobial drugs is carbapenems. Ertapenem is an attractive carbapenem for

  4. Multidrug-resistant tuberculosis in Europe, 2010-2011

    NARCIS (Netherlands)

    Gunther, G.; Leth, F. van; Alexandru, S.; Altet, N.; Avsar, K.; Bang, D.; Barbuta, R.; Bothamley, G.; Ciobanu, A.; Crudu, V.; Davilovits, M.; Dedicoat, M.; Duarte, R.; Gualano, G.; Kunst, H.; Lange, W. de; Leimane, V.; Magis-Escurra Ibanez, C.; McLaughlin, A.M.; Muylle, I.; Polcova, V.; Pontali, E.; Popa, C; Rumetshofer, R.; Skrahina, A.; Solodovnikova, V.; Spinu, V.; Tiberi, S.; Viiklepp, P.; Lange, C.

    2015-01-01

    Drug-resistant Mycobacterium tuberculosis is challenging elimination of tuberculosis (TB). We evaluated risk factors for TB and levels of second-line drug resistance in M. tuberculosis in patients in Europe with multidrug-resistant (MDR) TB. A total of 380 patients with MDR TB and 376 patients with

  5. Multidrug-Resistant Tuberculosis in Europe, 2010-2011

    NARCIS (Netherlands)

    Guenther, Gunar; van Leth, Frank; Alexandru, Sofia; Altet, Neus; Avsar, Korkut; Bang, Didi; Barbuta, Raisa; Bothamley, Graham; Ciobanu, Ana; Crudu, Valeriu; Danilovits, Manfred; Dedicoat, Martin; Duarte, Raquel; Gualano, Gina; Kunst, Heinke; de Lange, Wiel; Leimane, Vaira; Magis-Escurra, Cecile; McLaughlin, Anne-Marie; Muylle, Inge; Polcova, Veronika; Pontalli, Emanuele; Popa, Christina; Rumetshofer, Rudolf; Skrahina, Alena; Solodovnikova, Varvara; Spinu, Victor; Tiberi, Simon; Viiklepp, Piret; Lange, Christoph

    2015-01-01

    Drug-resistant Mycobacterium tuberculosis is challenging elimination of tuberculosis (TB). We evaluated risk factors for TB and levels of second-line drug resistance in M. tuberculosis in patients in Europe with multidrug-resistant (MDR) TB. A total of 380 patients with MDR TB and 376 patients with

  6. Characterization of a multidrug-resistant, novel Bacteroides genomospecies.

    Science.gov (United States)

    Salipante, Stephen J; Kalapila, Aley; Pottinger, Paul S; Hoogestraat, Daniel R; Cummings, Lisa; Duchin, Jeffrey S; Sengupta, Dhruba J; Pergam, Steven A; Cookson, Brad T; Butler-Wu, Susan M

    2015-01-01

    Metronidazole- and carbapenem-resistant Bacteroides fragilis are rare in the United States. We isolated a multidrug-resistant anaerobe from the bloodstream and intraabdominal abscesses of a patient who had traveled to India. Whole-genome sequencing identified the organism as a novel Bacteroides genomospecies. Physicians should be aware of the possibility for concomitant carbapenem- and metronidazole-resistant Bacteroides infections.

  7. Multidrug-resistant tuberculosis in Europe, 2010-2011

    DEFF Research Database (Denmark)

    Günther, Gunar; van Leth, Frank; Alexandru, Sofia

    2015-01-01

    Drug-resistant Mycobacterium tuberculosis is challenging elimination of tuberculosis (TB). We evaluated risk factors for TB and levels of second-line drug resistance in M. tuberculosis in patients in Europe with multidrug-resistant (MDR) TB. A total of 380 patients with MDR TB and 376 patients wi...

  8. Multidrug-Resistant Gram-Negative Bacilli: Infection Control Implications.

    Science.gov (United States)

    Adler, Amos; Friedman, N Deborah; Marchaim, Dror

    2016-12-01

    Antimicrobial resistance is a common iatrogenic complication of both modern life and medical care. Certain multidrug resistant and extensively drug resistant Gram-negative organisms pose the biggest challenges to health care today, predominantly owing to a lack of therapeutic options. Containing the spread of these organisms is challenging, and in reality, the application of multiple control measures during an evolving outbreak makes it difficult to measure the relative impact of each measure. This article reviews the usefulness of various infection control measures in containing the spread of multidrug-resistant Gram-negative bacilli. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Multidrug-resistant Mycoplasma genitalium infections in Europe.

    Science.gov (United States)

    Braam, J F; van Dommelen, L; Henquet, C J M; van de Bovenkamp, J H B; Kusters, J G

    2017-03-30

    In Japan and Australia, multidrug-resistant Mycoplasma genitalium infections are reported with increasing frequency. Although macrolide-resistant M. genitalium strains are common in Europe and North America, fluoroquinolone-resistant strains are still exceptional. However, an increase of multidrug-resistant M. genitalium in Europe and America is to be expected. The aim of this paper is to increase awareness on the rising number of multidrug-resistant M. genitalium strains. Here, one of the first cases of infection with a genetically proven multidrug-resistant M. genitalium strain in Europe is described. The patient was a native Dutch 47-year-old male patient with urethritis. Mycoplasma genitalium was detected, but treatment failed with azithromycin, doxycycline and moxifloxacin. A urogenital sample was used to determine the sequence of the 23S rRNA, gyrA, gyrB and parC genes. The sample contained an A2059G single nucleotide polymorphism (SNP) in the 23S rRNA gene and an SNP in the parC gene, resulting in an amino acid change of Ser83 → Ile, explaining both azithromycin and moxifloxacin treatment failure. The SNPs associated with resistance were probably generated de novo, as a link with high-prevalence areas was not established. It is, thus, predictable that there is going to be an increase of multidrug-resistant M. genitalium strains in Europe. As treatment options for multidrug-resistant M. genitalium are limited, the treatment of M. genitalium infections needs to be carefully considered in order to limit the rapid increase of resistance to macrolides and fluoroquinolones.

  10. Treatment of falciparum malaria in the age of drug resistance

    Directory of Open Access Journals (Sweden)

    Shanks G

    2006-01-01

    Full Text Available The growing problem of drug resistance has greatly complicated the treatment for falciparum malaria. Whereaschloroquine and sulfadoxine/pyrimethamine could once cure most infections, this is no longer true and requiresexamination of alternative regimens. Not all treatment failures are drug resistant and other issues such asexpired antimalarials and patient compliance need to be considered. Continuation of a failing treatment policyafter drug resistance is established suppresses infections rather than curing them, leading to increasedtransmission of malaria, promotion of epidemics and loss of public confidence in malaria control programs.Antifolate drug resistance (i.e. pyrimethamine means that new combinations are urgently needed particularlybecause addition of a single drug to an already failing regimen is rarely effective for very long. Atovaquone/proguanil and mefloquine have been used against multiple drug resistant falciparum malaria with resistance toeach having been documented soon after drug introduction. Drug combinations delay further transmission ofresistant parasites by increasing cure rates and inhibiting formation of gametocytes. Most currentlyrecommended drug combinations for falciparum malaria are variants of artemisinin combination therapy wherea rapidly acting artemisinin compound is combined with a longer half-life drug of a different class. Artemisininsused include dihydroartemisinin, artesunate, artemether and companion drugs include mefloquine, amodiaquine,sulfadoxine/pyrimethamine, lumefantrine, piperaquine, pyronaridine, chlorproguanil/dapsone. The standard ofcare must be to cure malaria by killing the last parasite. Combination antimalarial treatment is vital not only tothe successful treatment of individual patients but also for public health control of malaria.

  11. Artemisinin resistance in Plasmodium falciparum: A process linked to dormancy?

    Science.gov (United States)

    Cheng, Qin; Kyle, Dennis E; Gatton, Michelle L

    2012-12-01

    Artemisinin (ART) based combination therapy (ACT) is used as the first line treatment of uncomplicated falciparum malaria in over 100 countries and is the cornerstone of malaria control and elimination programs in these areas. However, despite the high potency and rapid parasite killing action of ART derivatives there is a high rate of recrudescence associated with ART monotherapy and recrudescence is not uncommon even when ACT is used. Compounding this problem are reports that some parasites in Cambodia, a known foci of drug resistance, have decreased in vivo sensitivity to ART. This raises serious concerns for the development of ART resistance in the field even though no major phenotypic and genotypic changes have yet been identified in these parasites. In this article we review available data on the characteristics of ART, its effects on Plasmodium falciparum parasites and present a hypothesis to explain the high rate of recrudescence associated with this potent class of drugs and the current enigma surrounding ART resistance.

  12. Resistance patterns, prevalence, and predictors of fluoroquinolones resistance in multidrug resistant tuberculosis patients.

    Science.gov (United States)

    Ahmad, Nafees; Javaid, Arshad; Sulaiman, Syed Azhar Syed; Ming, Long Chiau; Ahmad, Izaz; Khan, Amer Hayat

    2016-01-01

    Fluoroquinolones are the backbone of multidrug resistant tuberculosis treatment regimens. Despite the high burden of multidrug resistant tuberculosis in the country, little is known about drug resistance patterns, prevalence, and predictors of fluoroquinolones resistance among multidrug resistant tuberculosis patients from Pakistan. To evaluate drug resistance patterns, prevalence, and predictors of fluoroquinolones resistance in multidrug resistant tuberculosis patients. This was a cross-sectional study conducted at a programmatic management unit of drug resistant tuberculosis, Lady Reading Hospital Peshawar, Pakistan. Two hundred and forty-three newly diagnosed multidrug resistant tuberculosis patients consecutively enrolled for treatment at study site from January 1, 2012 to July 28, 2013 were included in the study. A standardized data collection form was used to collect patients' socio-demographic, microbiological, and clinical data. SPSS 16 was used for data analysis. High degree of drug resistance (median 5 drugs, range 2-8) was observed. High proportion of patients was resistant to all five first-line anti-tuberculosis drugs (62.6%), and more than half were resistant to second line drugs (55.1%). The majority of the patients were ofloxacin resistant (52.7%). Upon multivariate analysis previous tuberculosis treatment at private (OR=1.953, p=0.034) and public private mix (OR=2.824, p=0.046) sectors were predictors of ofloxacin resistance. The high degree of drug resistance observed, particularly to fluoroquinolones, is alarming. We recommend the adoption of more restrictive policies to control non-prescription sale of fluoroquinolones, its rational use by physicians, and training doctors in both private and public-private mix sectors to prevent further increase in fluoroquinolones resistant Mycobacterium tuberculosis strains. Copyright © 2015 Elsevier Editora Ltda. All rights reserved.

  13. Resistance patterns, prevalence, and predictors of fluoroquinolones resistance in multidrug resistant tuberculosis patients

    Directory of Open Access Journals (Sweden)

    Nafees Ahmad

    Full Text Available Abstract Background Fluoroquinolones are the backbone of multidrug resistant tuberculosis treatment regimens. Despite the high burden of multidrug resistant tuberculosis in the country, little is known about drug resistance patterns, prevalence, and predictors of fluoroquinolones resistance among multidrug resistant tuberculosis patients from Pakistan. Objective To evaluate drug resistance patterns, prevalence, and predictors of fluoroquinolones resistance in multidrug resistant tuberculosis patients. Methods This was a cross-sectional study conducted at a programmatic management unit of drug resistant tuberculosis, Lady Reading Hospital Peshawar, Pakistan. Two hundred and forty-three newly diagnosed multidrug resistant tuberculosis patients consecutively enrolled for treatment at study site from January 1, 2012 to July 28, 2013 were included in the study. A standardized data collection form was used to collect patients’ socio-demographic, microbiological, and clinical data. SPSS 16 was used for data analysis. Results High degree of drug resistance (median 5 drugs, range 2–8 was observed. High proportion of patients was resistant to all five first-line anti-tuberculosis drugs (62.6%, and more than half were resistant to second line drugs (55.1%. The majority of the patients were ofloxacin resistant (52.7%. Upon multivariate analysis previous tuberculosis treatment at private (OR = 1.953, p = 0.034 and public private mix (OR = 2.824, p = 0.046 sectors were predictors of ofloxacin resistance. Conclusion The high degree of drug resistance observed, particularly to fluoroquinolones, is alarming. We recommend the adoption of more restrictive policies to control non-prescription sale of fluoroquinolones, its rational use by physicians, and training doctors in both private and public–private mix sectors to prevent further increase in fluoroquinolones resistant Mycobacterium tuberculosis strains.

  14. Multidrug-resistant tuberculosis and leprosy: An unsolved mystery

    Directory of Open Access Journals (Sweden)

    Robin Gupta

    2017-01-01

    Full Text Available Tuberculosis (TB and leprosy are two age-old infections, which we are facing even today. With drug-resistant TB on the rise, we report a case of multidrug-resistant TB with leprosy, which has never been reported previously. The peculiar course of this case forces us to rethink about the upcoming challenges due to their cooccurrence.

  15. Multidrug-resistant tuberculosis and leprosy: An unsolved mystery.

    Science.gov (United States)

    Gupta, Robin; Garg, Kranti; Bhalla, Mala; Janmeja, Ashok K

    2017-01-01

    Tuberculosis (TB) and leprosy are two age-old infections, which we are facing even today. With drug-resistant TB on the rise, we report a case of multidrug-resistant TB with leprosy, which has never been reported previously. The peculiar course of this case forces us to rethink about the upcoming challenges due to their cooccurrence.

  16. Carriage and transmission dynamics of multidrug-resistant Enterobacteriaceae

    NARCIS (Netherlands)

    Haverkate, M.R.

    2015-01-01

    Antimicrobial-resistant bacteria cause big problems in health care. Infections with these bacteria are hard to treat and lead to high morbidity, mortality, and costs. In this PhD thesis, carriage and transmission dynamics of multidrug-resistant Enterobacteriaceae have been investigated in various se

  17. Multidrug-resistant tuberculosis, Somalia, 2010-2011.

    Science.gov (United States)

    Sindani, Ireneaus; Fitzpatrick, Christopher; Falzon, Dennis; Suleiman, Bashir; Arube, Peter; Adam, Ismail; Baghdadi, Samiha; Bassili, Amal; Zignol, Matteo

    2013-03-01

    In a nationwide survey in 2011, multidrug-resistant tuberculosis (MDR TB) was found in 5.2% and 40.8% of patients with new and previously treated TB, respectively. These levels of drug resistance are among the highest ever documented in Africa and the Middle East. This finding presents a serious challenge for TB control in Somalia.

  18. Multidrug resistant to extensively drug resistant tuberculosis: What is next?

    Indian Academy of Sciences (India)

    Amita Jain; Pratima Dixit

    2008-11-01

    Drug resistant tuberculosis is a man made problem. While tuberculosis is hundred percent curable, multidrug resistant tuberculosis (MDR-TB) is difficult to treat. Inadequate and incomplete treatment and poor treatment adherence has led to a newer form of drug resistance known as extensively drug resistant tuberculosis (XDR-TB). XDR-TB is defined as tuberculosis caused by Mycobacterium tuberculosis strain, which is resistant to at least rifampicin and isoniazid among the first line anti tubercular drugs (MDR-TB) in addition to resistance to any fluroquinolones and at least one of three injectable second line anti tubercular drugs i.e. amikacin, kanamycin and/or capreomycin. Mismanagement of tuberculosis paves the way to drug resistant tuberculosis. Emergence of XDR-TB is reported world wide. Reported prevalence rates of XDR-TB of total MDR cases are; 6.6% overall worldwide, 6.5% in industrialized countries, 13.6% in Russia and Eastern Europe, 1.5% in Asia, 0.6% in Africa and Middle East and 15.4% in Republic of Korea. Better management and control of tuberculosis specially drug resistant TB by experienced and qualified doctors, access to standard microbiology laboratory, co-morbitidy of HIV and tuberculosis, new anti-TB drug regimens, better diagnostic tests, international standards for second line drugs (SLD)-susceptibility testing, invention of newer anti-tubercular molecules and vaccines and knowing the real magnitude of XDR-TB are some of the important issues to be addressed for effective prevention and management of XDR-TB.

  19. Ex Vivo Drug Susceptibility Testing and Molecular Profiling of Clinical Plasmodium falciparum Isolates from Cambodia from 2008 to 2013 Suggest Emerging Piperaquine Resistance.

    Science.gov (United States)

    Chaorattanakawee, Suwanna; Saunders, David L; Sea, Darapiseth; Chanarat, Nitima; Yingyuen, Kritsanai; Sundrakes, Siratchana; Saingam, Piyaporn; Buathong, Nillawan; Sriwichai, Sabaithip; Chann, Soklyda; Se, Youry; Yom, You; Heng, Thay Kheng; Kong, Nareth; Kuntawunginn, Worachet; Tangthongchaiwiriya, Kuntida; Jacob, Christopher; Takala-Harrison, Shannon; Plowe, Christopher; Lin, Jessica T; Chuor, Char Meng; Prom, Satharath; Tyner, Stuart D; Gosi, Panita; Teja-Isavadharm, Paktiya; Lon, Chanthap; Lanteri, Charlotte A

    2015-08-01

    Cambodia's first-line artemisinin combination therapy, dihydroartemisinin-piperaquine (DHA-PPQ), is no longer sufficiently curative against multidrug-resistant Plasmodium falciparum malaria at some Thai-Cambodian border regions. We report recent (2008 to 2013) drug resistance trends in 753 isolates from northern, western, and southern Cambodia by surveying for ex vivo drug susceptibility and molecular drug resistance markers to guide the selection of an effective alternative to DHA-PPQ. Over the last 3 study years, PPQ susceptibility declined dramatically (geomean 50% inhibitory concentration [IC50] increased from 12.8 to 29.6 nM), while mefloquine (MQ) sensitivity doubled (67.1 to 26 nM) in northern Cambodia. These changes in drug susceptibility were significantly associated with a decreased prevalence of P. falciparum multidrug resistance 1 gene (Pfmdr1) multiple copy isolates and coincided with the timing of replacing artesunate-mefloquine (AS-MQ) with DHA-PPQ as the first-line therapy. Widespread chloroquine resistance was suggested by all isolates being of the P. falciparum chloroquine resistance transporter gene CVIET haplotype. Nearly all isolates collected from the most recent years had P. falciparum kelch13 mutations, indicative of artemisinin resistance. Ex vivo bioassay measurements of antimalarial activity in plasma indicated 20% of patients recently took antimalarials, and their plasma had activity (median of 49.8 nM DHA equivalents) suggestive of substantial in vivo drug pressure. Overall, our findings suggest DHA-PPQ failures are associated with emerging PPQ resistance in a background of artemisinin resistance. The observed connection between drug policy changes and significant reduction in PPQ susceptibility with mitigation of MQ resistance supports reintroduction of AS-MQ, in conjunction with monitoring of the P. falciparum mdr1 copy number, as a stop-gap measure in areas of DHA-PPQ failure.

  20. Lack of Evidence for Chloroquine-Resistant Plasmodium falciparum Malaria, Leogane, Haiti

    Science.gov (United States)

    Neuberger, Ami; Zhong, Kathleen; Kain, Kevin C

    2012-01-01

    Plasmodium falciparum malaria in Haiti is considered chloroquine susceptible, although resistance transporter alleles associated with chloroquine resistance were recently detected. Among 49 patients with falciparum malaria, we found neither parasites carrying haplotypes associated with chloroquine resistance nor instances of chloroquine treatment failure. Continued vigilance to detect emergence of chloroquine resistance is needed. PMID:22932030

  1. Lack of evidence for chloroquine-resistant Plasmodium falciparum malaria, Leogane, Haiti.

    Science.gov (United States)

    Neuberger, Ami; Zhong, Kathleen; Kain, Kevin C; Schwartz, Eli

    2012-09-01

    Plasmodium falciparum malaria in Haiti is considered chloroquine susceptible, although resistance transporter alleles associated with chloroquine resistance were recently detected. Among 49 patients with falciparum malaria, we found neither parasites carrying haplotypes associated with chloroquine resistance nor instances of chloroquine treatment failure. Continued vigilance to detect emergence of chloroquine resistance is needed.

  2. Linezolid susceptibility in Helicobacter pylori, including strains with multidrug resistance.

    Science.gov (United States)

    Boyanova, Lyudmila; Evstatiev, Ivailo; Gergova, Galina; Yaneva, Penka; Mitov, Ivan

    2015-12-01

    Only a few studies have evaluated Helicobacter pylori susceptibility to linezolid. The aim of the present study was to assess linezolid susceptibility in H. pylori, including strains with double/multidrug resistance. The susceptibility of 53 H. pylori strains was evaluated by Etest and a breakpoint susceptibility testing method. Helicobacter pylori resistance rates were as follows: amoxicillin, 1.9%; metronidazole, 37.7%; clarithromycin, 17.0%; tetracycline, 1.9%; levofloxacin, 24.5%; and linezolid (>4 mg/L), 39.6%. The linezolid MIC50 value was 31.2-fold higher than that of clarithromycin and 10.5-fold higher than that of levofloxacin; however, 4 of 11 strains with double/multidrug resistance were linezolid-susceptible. The MIC range of the oxazolidinone agent was larger (0.125-64 mg/L) compared with those in the previous two reports. The linezolid resistance rate was 2.2-fold higher in metronidazole-resistant strains and in strains resistant to at least one antibiotic compared with the remaining strains. Briefly, linezolid was less active against H. pylori compared with clarithromycin and levofloxacin, and linezolid resistance was linked to resistance to metronidazole as well as to resistance to at least one antibiotic. However, linezolid activity against some strains with double/multidrug resistance may render the agent appropriate to treat some associated H. pylori infections following in vitro susceptibility testing of the strains. Clinical trials are required to confirm this suggestion.

  3. Ecotope-Based Entomological Surveillance and Molecular Xenomonitoring of Multidrug Resistant Malaria Parasites in Anopheles Vectors

    Directory of Open Access Journals (Sweden)

    Prapa Sorosjinda-Nunthawarasilp

    2014-01-01

    Full Text Available The emergence and spread of multidrug resistant (MDR malaria caused by Plasmodium falciparum or Plasmodium vivax have become increasingly important in the Greater Mekong Subregion (GMS. MDR malaria is the heritable and hypermutable property of human malarial parasite populations that can decrease in vitro and in vivo susceptibility to proven antimalarial drugs as they exhibit dose-dependent drug resistance and delayed parasite clearance time in treated patients. MDR malaria risk situations reflect consequences of the national policy and strategy as this influences the ongoing national-level or subnational-level implementation of malaria control strategies in endemic GMS countries. Based on our experience along with current literature review, the design of ecotope-based entomological surveillance (EES and molecular xenomonitoring of MDR falciparum and vivax malaria parasites in Anopheles vectors is proposed to monitor infection pockets in transmission control areas of forest and forest fringe-related malaria, so as to bridge malaria landscape ecology (ecotope and ecotone and epidemiology. Malaria ecotope and ecotone are confined to a malaria transmission area geographically associated with the infestation of Anopheles vectors and particular environments to which human activities are related. This enables the EES to encompass mosquito collection and identification, salivary gland DNA extraction, Plasmodium- and species-specific identification, molecular marker-based PCR detection methods for putative drug resistance genes, and data management. The EES establishes strong evidence of Anopheles vectors carrying MDR P. vivax in infection pockets epidemiologically linked with other data obtained during which a course of follow-up treatment of the notified P. vivax patients receiving the first-line treatment was conducted. For regional and global perspectives, the EES would augment the epidemiological surveillance and monitoring of MDR falciparum and

  4. Synthesis of 5-oxyquinoline derivatives for reversal of multidrug resistance

    Directory of Open Access Journals (Sweden)

    Torsten Dittrich

    2012-10-01

    Full Text Available The inhibition of ABC (ATP binding cassette transporters is considered a powerful tool to reverse multidrug resistance. Zosuquidar featuring a difluorocyclopropyl-annulated dibenzosuberyl moiety has been found to be an inhibitor of the P-glycoprotein, one of the best-studied multidrug efflux pumps. Twelve 5-oxyisoquinoline derivatives, which are analogues of zosuquidar wherein the dibenzosuberyl-piperazine moiety is replaced by either a diarylaminopiperidine or a piperidone-derived acetal or thioacetal group, have been synthesized as pure enantiomers. Their inhibitory power has been evaluated for the bacterial multidrug-resistance ABC transporter LmrCD and fungal Pdr5. Four of the newly synthesized compounds reduced the transport activity to a higher degree than zosuquidar, being up to fourfold more efficient than the lead compound in the case of LmrCD and about two times better for Pdr5.

  5. Multidrug-Resistant Candida: Epidemiology, Molecular Mechanisms, and Treatment.

    Science.gov (United States)

    Arendrup, Maiken Cavling; Patterson, Thomas F

    2017-08-15

    Invasive Candida infections remain an important cause of morbidity and mortality, especially in hospitalized and immunocompromised or critically ill patients. A limited number of antifungal agents from only a few drug classes are available to treat patients with these serious infections. Resistance can be either intrinsic or acquired. Resistance mechanisms are not exchanged between Candida; thus, acquired resistance either emerges in response to an antifungal selection pressure in the individual patient or, more rarely, occur due to horizontal transmission of resistant strains between patients. Although multidrug resistance is uncommon, increasing reports of multidrug resistance to the azoles, echinocandins, and polyenes have occurred in several Candida species, most notably Candida glabrata and more recently Candida auris. Drivers are overall antifungal use, subtherapeutic drug levels at sites of infection/colonization, drug sequestration in the biofilm matrix, and, in the setting of outbreaks, suboptimal infection control. Moreover, recent research suggests that DNA mismatch repair gene mutations may facilitate acquisition of resistance mutations in C. glabrata specifically. Diagnosis of antifungal-resistant Candida infections is critical to the successful management of patients with these infections. Reduction of unnecessary use of antifungals via antifungal stewardship is critical to limit multidrug resistance emergence. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  6. Bacterial Multidrug Efflux Pumps: Much More Than Antibiotic Resistance Determinants

    Science.gov (United States)

    Blanco, Paula; Hernando-Amado, Sara; Reales-Calderon, Jose Antonio; Corona, Fernando; Lira, Felipe; Alcalde-Rico, Manuel; Bernardini, Alejandra; Sanchez, Maria Blanca; Martinez, Jose Luis

    2016-01-01

    Bacterial multidrug efflux pumps are antibiotic resistance determinants present in all microorganisms. With few exceptions, they are chromosomally encoded and present a conserved organization both at the genetic and at the protein levels. In addition, most, if not all, strains of a given bacterial species present the same chromosomally-encoded efflux pumps. Altogether this indicates that multidrug efflux pumps are ancient elements encoded in bacterial genomes long before the recent use of antibiotics for human and animal therapy. In this regard, it is worth mentioning that efflux pumps can extrude a wide range of substrates that include, besides antibiotics, heavy metals, organic pollutants, plant-produced compounds, quorum sensing signals or bacterial metabolites, among others. In the current review, we present information on the different functions that multidrug efflux pumps may have for the bacterial behaviour in different habitats as well as on their regulation by specific signals. Since, in addition to their function in non-clinical ecosystems, multidrug efflux pumps contribute to intrinsic, acquired, and phenotypic resistance of bacterial pathogens, the review also presents information on the search for inhibitors of multidrug efflux pumps, which are currently under development, in the aim of increasing the susceptibility of bacterial pathogens to antibiotics. PMID:27681908

  7. Invasive Infections with Multidrug-Resistant Yeast Candida auris, Colombia

    Science.gov (United States)

    Morales-López, Soraya E.; Parra-Giraldo, Claudia M.; Ceballos-Garzón, Andrés; Martínez, Heidys P.; Rodríguez, Gerson J.; Álvarez-Moreno, Carlos A.

    2017-01-01

    Candida auris is an emerging multidrug-resistant fungus that causes a wide range of symptoms. We report finding 17 cases of C. auris infection that were originally misclassified but correctly identified 27.5 days later on average. Patients with a delayed diagnosis of C. auris had a 30-day mortality rate of 35.2%. PMID:27983941

  8. Multidrug-Resistant Pathogens in Hospitalized Syrian Children

    Science.gov (United States)

    Kassem, Diana Faour; Hoffmann, Yoav; Shahar, Naama; Ocampo, Smadar; Salomon, Liora; Zonis, Zeev

    2017-01-01

    Since 2013, wounded and ill children from Syria have received treatment in Israel. Screening cultures indicated that multidrug-resistant (MDR) pathogens colonized 89 (83%) of 107 children. For 58% of MDR infections, the pathogen was similar to that identified during screening. MDR screening of these children is valuable for purposes of isolation and treatment. PMID:27618479

  9. Antimicrobial activity of peptidomimetics against multidrug-resistant Escherichia coli

    DEFF Research Database (Denmark)

    Jahnsen, Rasmus D; Frimodt-Møller, Niels; Franzyk, Henrik

    2012-01-01

    -lactamase-producing Escherichia coli was assessed by testing an array comprising different types of cationic peptidomimetics obtained by a general monomer-based solid-phase synthesis protocol. Most of the peptidomimetics possessed high to moderate activity toward multidrug-resistant E. coli as opposed to the corresponding...

  10. Confronting multidrug-resistant Acinetobacter baumannii: a review.

    Science.gov (United States)

    Neonakis, Ioannis K; Spandidos, Demetrios A; Petinaki, Efthimia

    2011-02-01

    Multidrug-resistant Acinetobacter baumannii (MDR-AB) infections are difficult to treat owing to the extremely limited armamentarium. The present review reports all available treatment options against MDR-AB, including single molecules, combination schemes, and alternative modes of antimicrobial administration. Additionally, a group of recently reported peptides with anti-MDR-AB activity is described.

  11. Infection by multidrug-resistant Elizabethkingia meningoseptica: case reports

    Directory of Open Access Journals (Sweden)

    Jailton Lobo da Costa Lima

    2014-12-01

    Full Text Available We report two cases of sepsis in critically ill patients in two tertiary care hospitals in Recife-PE, Brazil. The first case is an 87-year-old patient with chronic myeloid leukemia and sepsis; and the second case is a 93-year-old patient with prostate cancer and septic shock caused by multidrug-resistant (MDR Elizabethkingia meningoseptica.

  12. Multidrug transporters and antibiotic resistance in Lactococcus lactis

    NARCIS (Netherlands)

    Poelarends, GJ; Mazurkiewicz, P; Konings, WN

    2002-01-01

    The Gram-positive bacterium Lactococcus lactis produces two distinct multidrug transporters, designated LmrA and LmrP, that both confer resistance to a wide variety of cationic lipophilic cytotoxic compounds as well as to many clinically relevant antibiotics. While LmrP is a proton/drug antiporter

  13. Bedaquiline in the multidrug-resistant tuberculosis treatment: Belarus experience

    Directory of Open Access Journals (Sweden)

    Alena Skrahina

    2016-01-01

    Conclusion: Our interim results on safety and effectiveness of bedaquiline-containing regimens in multidrug and extensively drug-resistant tuberculosis (M/XDR-TB patients are encouraging. They will add value to understanding role and place of this new anti-TB drug in M/XDR-TB treatment.

  14. Multidrug transporters and antibiotic resistance in Lactococcus lactis

    NARCIS (Netherlands)

    Poelarends, GJ; Mazurkiewicz, P; Konings, WN

    2002-01-01

    The Gram-positive bacterium Lactococcus lactis produces two distinct multidrug transporters, designated LmrA and LmrP, that both confer resistance to a wide variety of cationic lipophilic cytotoxic compounds as well as to many clinically relevant antibiotics. While LmrP is a proton/drug antiporter t

  15. Drug accumulation in the presence of the multidrug resistance pump

    DEFF Research Database (Denmark)

    Ayesh, S; Litman, Thomas; Stein, W D

    1997-01-01

    We studied the interaction between the multidrug transporter, P-glycoprotein, and two compounds that interact with it: vinblastine, a classical substrate of the pump, and verapamil, a classical reverser. Steady-state levels of accumulation of these two drugs were determined in a multidrug resistant...... P388 leukemia cell line, P388/ADR. The time course of accumulation of these drugs, and the effect of energy starvation and the presence of chloroquine on the level of their steady-state accumulation were quite disparate. Vinblastine inhibited the accumulation of verapamil whereas it enhanced...

  16. Plasmodium falciparum drug resistance in Angola.

    Science.gov (United States)

    Fançony, Cláudia; Brito, Miguel; Gil, Jose Pedro

    2016-02-09

    Facing chloroquine drug resistance, Angola promptly adopted artemisinin-based combination therapy as the first-line to treat malaria. Currently, the country aims to consolidate malaria control, while preparing for the elimination of the disease, along with others African countries in the region. However, the remarkable capacity of Plasmodium to develop drug resistance represents an alarming threat for those achievements. Herein, the available, but relatively scarce and dispersed, information on malaria drug resistance in Angola, is reviewed and discussed. The review aims to inform but also to encourage future research studies that monitor and update the information on anti-malarial drug efficacy and prevalence of molecular markers of drug resistance, key fields in the context and objectives of elimination.

  17. Plasmodium falciparum drug resistance in Angola

    OpenAIRE

    Fançony, Cláudia; Brito, Miguel; Gil, Jose Pedro

    2016-01-01

    Facing chloroquine drug resistance, Angola promptly adopted artemisinin-based combination therapy as the first-line to treat malaria. Currently, the country aims to consolidate malaria control, while preparing for the elimination of the disease, along with others African countries in the region. However, the remarkable capacity of Plasmodium to develop drug resistance represents an alarming threat for those achievements. Herein, the available, but relatively scarce and dispersed, information ...

  18. Survey of chloroquine-resistant mutations in the Plasmodium falciparum pfcrt and pfmdr-1 genes in Hadhramout, Yemen.

    Science.gov (United States)

    Bamaga, Omar A A; Mahdy, Mohammed A K; Lim, Yvonne A L

    2015-09-01

    Malaria is still a major public health problem in Yemen. More than 95% of the malaria cases are due to Plasmodium ‎falciparum‎. Recently in Yemen, the antimalarial treatment policy was changed from chloroquine (CQ) to artemisinin combination therapy (ACTs). However, CQ is still available and prescribed in the Yemeni market. The persistence of CQ resistance will be prolonged if the shift to ACT and the simultaneous withdrawal of CQ are not rigorously implemented. The aim of the current survey is to detect chloroquine-resistant mutations in P. falciparum chloroquine-resistance transporter (pfcrt) and P. falciparum multi-drug resistance-1 (pfmdr1) genes. These data will be important for future monitoring and assessment of antimalarial drug policy in Yemen. Blood specimens were collected from 735 individuals from different districts of the Hadhramout province, Yemen by house-to-house visit. Mutation-specific nested polymerase chain reaction (PCR) and restriction fragment length polymorphism (PCR-RFLP) methods were used to investigate the mutations in the pfmdr1(codons 86 and 1246) and pfcrt (codons 76, 271, 326, 356 and 371) genes. The overall prevalence of pfcrt mutations at codons 76, 271, 326 and 371 were 50.4%, 58.7%, 54.3% and 44.9%, respectively. All isolates had wild-type pfcrt 356 allele. The majority of pfmdr1 86 alleles (83.3%) and all pfmdr1 1246 alleles were wild type. There was no association between pfcrt mutations and symptomatology, gender and age groups. In conclusion, point mutations in codons 76, 271, 326 and 371 of pfcrt of P. falciparum are high suggesting a sustained high CQ resistance even after 4 years of shifting to ACTs. These findings warrant complete withdrawal of CQ use from the Yemeni market for P. falciparum and careful usage of CQ for treating Plasmodium vivax.

  19. Horizontal gene transfer—emerging multidrug resistance in hospital bacteria

    Institute of Scientific and Technical Information of China (English)

    SenkaDZIDIC; VladimirBEDEKOVIC

    2003-01-01

    The frequency and spectrum of antibiotic resistant infections have increased worldwide during the past few decades. This increase has been attributed to a combination of microbial characteristics, the selective pressure of antimicrobial use, and social and technical changes that enhance the transmission of resistant organisms. The resistance is acquired by mutational changer or by the acquisition of resistance-encoding genetic material which is transfered from another bacteria. The spread of antibiotic resistance genes may be causally related to the overuse of antibiotics in human health care and in animal feeds, increased use of invasive devices and procedures, a greater number of susceptible hosts, and lapses in infection control practices leading to increased transmission of resistant organisms. The resistance gene sequences are integrated by recombination into several classes of naturally occurring gene expression cassettes and disseminated within the microbial population by horizontal gene transfer mechanisms: transformation, conjugation or transduction. In the hospital, widespread use of antimicrobials in the intensive care units (ICU) and for immunocompromised patients has resulted in the selection of multidrug-resistant organisms. Methicilin-resistant Staphylococci, vancomycin resistant Enterococci and extended-spectrum betalactamase(ESBL) producing Gram negative bacilli are identified as major phoblem in nosocomial infections. Recent surveillance studies have demonstrated trend towares more seriously ill patients suffering from multidrug-resistant nosocomial infections. Emergence of multiresistant bacteria and spread of resistance genes should enforce the aplication of strict prevention strategies, including changes in antibiotic treatment regimens, hygiene measures, infection prevention and control of horizontal nosocomial transmission of organisms.

  20. Multidrug-Resistant Enterococci Lack CRISPR-cas

    OpenAIRE

    Palmer, Kelli L.; Michael S Gilmore

    2010-01-01

    Clustered, regularly interspaced short palindromic repeats (CRISPR) provide bacteria and archaea with sequence-specific, acquired defense against plasmids and phage. Because mobile elements constitute up to 25% of the genome of multidrug-resistant (MDR) enterococci, it was of interest to examine the codistribution of CRISPR and acquired antibiotic resistance in enterococcal lineages. A database was built from 16 Enterococcus faecalis draft genome sequences to identify commonalities and polymo...

  1. Modulation of Bacterial Multidrug Resistance Efflux Pumps of the Major Facilitator Superfamily

    Directory of Open Access Journals (Sweden)

    Sanath Kumar

    2013-01-01

    Full Text Available Bacterial infections pose a serious public health concern, especially when an infectious disease has a multidrug resistant causative agent. Such multidrug resistant bacteria can compromise the clinical utility of major chemotherapeutic antimicrobial agents. Drug and multidrug resistant bacteria harbor several distinct molecular mechanisms for resistance. Bacterial antimicrobial agent efflux pumps represent a major mechanism of clinical resistance. The major facilitator superfamily (MFS is one of the largest groups of solute transporters to date and includes a significant number of bacterial drug and multidrug efflux pumps. We review recent work on the modulation of multidrug efflux pumps, paying special attention to those transporters belonging primarily to the MFS.

  2. Multidrug resistant bacteria isolated from septic arthritis in horses

    Directory of Open Access Journals (Sweden)

    Rodrigo G. Motta

    Full Text Available ABSTRACT: Septic arthritis is a debilitating joint infectious disease of equines that requires early diagnosis and immediate therapeutic intervention to prevent degenerative effects on the articular cartilage, as well as loss of athletic ability and work performance of the animals. Few studies have investigated the etiological complexity of this disease, as well as multidrug resistance of isolates. In this study, 60 horses with arthritis had synovial fluid samples aseptically collected, and tested by microbiological culture and in vitro susceptibility test (disk diffusion using nine antimicrobials belonging to six different pharmacological groups. Bacteria were isolated in 45 (75.0% samples, as follows: Streptococcus equi subsp. equi (11=18.3%, Escherichia coli (9=15.0%, Staphylococcus aureus (6=10.0%, Streptococcus equi subsp. zooepidemicus (5=8.3%, Staphylococcus intermedius (2=3.3%, Proteus vulgaris (2=3.3%, Trueperella pyogenes (2=3.3%, Pseudomonas aeruginosa (2=3.3%, Klebsiella pneumoniae (1=1.7%, Rhodococcus equi (1=1.7%, Staphylococcus epidermidis (1=1.7%, Klebsiella oxytoca (1=1.7%, Nocardia asteroides (1=1.7%, and Enterobacter cloacae (1=1.7%. Ceftiofur was the most effective drug (>70% efficacy against the pathogens in the disk diffusion test. In contrast, high resistance rate (>70% resistance was observed to penicillin (42.2%, enrofloxacin (33.3%, and amikacin (31.2%. Eleven (24.4% isolates were resistant to three or more different pharmacological groups and were considered multidrug resistant strains. The present study emphasizes the etiological complexity of equine septic arthritis, and highlights the need to institute treatment based on the in vitro susceptibility pattern, due to the multidrug resistance of isolates. According to the available literature, this is the first report in Brazil on the investigation of the etiology. of the septic arthritis in a great number of horses associated with multidrug resistance of the isolates.

  3. Caspar controls resistance to Plasmodium falciparum in diverse anopheline species.

    Directory of Open Access Journals (Sweden)

    Lindsey S Garver

    2009-03-01

    Full Text Available Immune responses mounted by the malaria vector Anopheles gambiae are largely regulated by the Toll and Imd (immune deficiency pathways via the NF-kappaB transcription factors Rel1 and Rel2, which are controlled by the negative regulators Cactus and Caspar, respectively. Rel1- and Rel2-dependent transcription in A. gambiae has been shown to be particularly critical to the mosquito's ability to manage infection with the rodent malaria parasite Plasmodium berghei. Using RNA interference to deplete the negative regulators of these pathways, we found that Rel2 controls resistance of A. gambiae to the human malaria parasite Plasmodium falciparum, whereas Rel 1 activation reduced infection levels. The universal relevance of this defense system across Anopheles species was established by showing that caspar silencing also prevents the development of P. falciparum in the major malaria vectors of Asia and South America, A. stephensi and A. albimanus, respectively. Parallel studies suggest that while Imd pathway activation is most effective against P. falciparum, the Toll pathway is most efficient against P. berghei, highlighting a significant discrepancy between the human pathogen and its rodent model. High throughput gene expression analyses identified a plethora of genes regulated by the activation of the two Rel factors and revealed that the Toll pathway played a more diverse role in mosquito biology than the Imd pathway, which was more immunity-specific. Further analyses of key anti-Plasmodium factors suggest they may be responsible for the Imd pathway-mediated resistance phenotype. Additionally, we found that the fitness cost caused by Rel2 activation through caspar gene silencing was undetectable in sugar-fed, blood-fed, and P. falciparum-infected female A. gambiae, while activation of the Toll pathway's Rel1 had a major impact. This study describes for the first time a single gene that influences an immune mechanism that is able to abort

  4. Caspar controls resistance to Plasmodium falciparum in diverse anopheline species.

    Science.gov (United States)

    Garver, Lindsey S; Dong, Yuemei; Dimopoulos, George

    2009-03-01

    Immune responses mounted by the malaria vector Anopheles gambiae are largely regulated by the Toll and Imd (immune deficiency) pathways via the NF-kappaB transcription factors Rel1 and Rel2, which are controlled by the negative regulators Cactus and Caspar, respectively. Rel1- and Rel2-dependent transcription in A. gambiae has been shown to be particularly critical to the mosquito's ability to manage infection with the rodent malaria parasite Plasmodium berghei. Using RNA interference to deplete the negative regulators of these pathways, we found that Rel2 controls resistance of A. gambiae to the human malaria parasite Plasmodium falciparum, whereas Rel 1 activation reduced infection levels. The universal relevance of this defense system across Anopheles species was established by showing that caspar silencing also prevents the development of P. falciparum in the major malaria vectors of Asia and South America, A. stephensi and A. albimanus, respectively. Parallel studies suggest that while Imd pathway activation is most effective against P. falciparum, the Toll pathway is most efficient against P. berghei, highlighting a significant discrepancy between the human pathogen and its rodent model. High throughput gene expression analyses identified a plethora of genes regulated by the activation of the two Rel factors and revealed that the Toll pathway played a more diverse role in mosquito biology than the Imd pathway, which was more immunity-specific. Further analyses of key anti-Plasmodium factors suggest they may be responsible for the Imd pathway-mediated resistance phenotype. Additionally, we found that the fitness cost caused by Rel2 activation through caspar gene silencing was undetectable in sugar-fed, blood-fed, and P. falciparum-infected female A. gambiae, while activation of the Toll pathway's Rel1 had a major impact. This study describes for the first time a single gene that influences an immune mechanism that is able to abort development of P. falciparum

  5. Molecular characterisation of drug-resistant Plasmodium falciparum from Thailand

    Directory of Open Access Journals (Sweden)

    Gil José

    2002-10-01

    Full Text Available Abstract Background The increasing levels of Plasmodium falciparum resistance to chloroquine (CQ in Thailand have led to the use of alternative antimalarials, which are at present also becoming ineffective. In this context, any strategies that help improve the surveillance of drug resistance, become crucial in overcoming the problem. Methods In the present study, we have established the in vitro sensitivity to CQ, mefloquine (MF, quinine (QUIN and amodiaquine (AMQ of 52 P. falciparum isolates collected in Thailand, and assessed the prevalence of four putative genetic polymorphisms of drug resistance, pfcrt K76T, pfmdr1 N86Y, pfmdr1 D1042N and pfmdr1 Y1246D, by PCR-RFLP. Results The percentage of isolates resistant to CQ, MF, and AMQ was 96% (50/52, 62% (32/52, and 58% (18/31, respectively, while all parasites were found to be sensitive to QUIN. In addition, 41 (79% of the isolates assayed were resistant simultaneously to more than one drug; 25 to CQ and MF, 9 to CQ and AMQ, and 7 to all three drugs, CQ, MF and AMQ. There were two significant associations between drug sensitivity and presence of particular molecular markers, i CQ resistance / pfcrt 76T (P = 0.001, and ii MF resistance / pfmdr1 86N (P Conclusions i In Thailand, the high levels of CQ pressure have led to strong selection of the pfcrt 76T polymorphism and ii pfmdr1 86N appears to be a good predictor of in vitro MF resistance.

  6. A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria.

    Science.gov (United States)

    Mbengue, Alassane; Bhattacharjee, Souvik; Pandharkar, Trupti; Liu, Haining; Estiu, Guillermina; Stahelin, Robert V; Rizk, Shahir S; Njimoh, Dieudonne L; Ryan, Yana; Chotivanich, Kesinee; Nguon, Chea; Ghorbal, Mehdi; Lopez-Rubio, Jose-Juan; Pfrender, Michael; Emrich, Scott; Mohandas, Narla; Dondorp, Arjen M; Wiest, Olaf; Haldar, Kasturi

    2015-04-30

    Artemisinins are the cornerstone of anti-malarial drugs. Emergence and spread of resistance to them raises risk of wiping out recent gains achieved in reducing worldwide malaria burden and threatens future malaria control and elimination on a global level. Genome-wide association studies (GWAS) have revealed parasite genetic loci associated with artemisinin resistance. However, there is no consensus on biochemical targets of artemisinin. Whether and how these targets interact with genes identified by GWAS, remains unknown. Here we provide biochemical and cellular evidence that artemisinins are potent inhibitors of Plasmodium falciparum phosphatidylinositol-3-kinase (PfPI3K), revealing an unexpected mechanism of action. In resistant clinical strains, increased PfPI3K was associated with the C580Y mutation in P. falciparum Kelch13 (PfKelch13), a primary marker of artemisinin resistance. Polyubiquitination of PfPI3K and its binding to PfKelch13 were reduced by the PfKelch13 mutation, which limited proteolysis of PfPI3K and thus increased levels of the kinase, as well as its lipid product phosphatidylinositol-3-phosphate (PI3P). We find PI3P levels to be predictive of artemisinin resistance in both clinical and engineered laboratory parasites as well as across non-isogenic strains. Elevated PI3P induced artemisinin resistance in absence of PfKelch13 mutations, but remained responsive to regulation by PfKelch13. Evidence is presented for PI3P-dependent signalling in which transgenic expression of an additional kinase confers resistance. Together these data present PI3P as the key mediator of artemisinin resistance and the sole PfPI3K as an important target for malaria elimination.

  7. Amplification of a Gene Related to Mammalian mdr Genes in Drug-Resistant Plasmodium falciparum

    Science.gov (United States)

    Wilson, Craig M.; Serrano, Adelfa E.; Wasley, Annemarie; Bogenschutz, Michael P.; Shankar, Anuraj H.; Wirth, Dyann F.

    1989-06-01

    The malaria parasite Plasmodium falciparum contains at least two genes related to the mammalian multiple drug resistance genes, and at least one of the P. falciparum genes is expressed at a higher level and is present in higher copy number in a strain that is resistant to multiple drugs than in a strain that is sensitive to the drugs.

  8. Origin and evolution of sulfadoxine resistant Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Sumiti Vinayak

    2010-03-01

    Full Text Available The Thailand-Cambodia border is the epicenter for drug-resistant falciparum malaria. Previous studies have shown that chloroquine (CQ and pyrimethamine resistance originated in this region and eventually spread to other Asian countries and Africa. However, there is a dearth in understanding the origin and evolution of dhps alleles associated with sulfadoxine resistance. The present study was designed to reveal the origin(s of sulfadoxine resistance in Cambodia and its evolutionary relationship to African and South American dhps alleles. We sequenced 234 Cambodian Plasmodium falciparum isolates for the dhps codons S436A/F, A437G, K540E, A581G and A613S/T implicated in sulfadoxine resistance. We also genotyped 10 microsatellite loci around dhps to determine the genetic backgrounds of various alleles and compared them with the backgrounds of alleles prevalent in Africa and South America. In addition to previously known highly-resistant triple mutant dhps alleles SGEGA and AGEAA (codons 436, 437, 540, 581, 613 are sequentially indicated, a large proportion of the isolates (19.3% contained a 540N mutation in association with 437G/581G yielding a previously unreported triple mutant allele, SGNGA. Microsatellite data strongly suggest the strength of selection was greater on triple mutant dhps alleles followed by the double and single mutants. We provide evidence for at least three independent origins for the double mutants, one each for the SGKGA, AGKAA and SGEAA alleles. Our data suggest that the triple mutant allele SGEGA and the novel allele SGNGA have common origin on the SGKGA background, whereas the AGEAA triple mutant was derived from AGKAA on multiple, albeit limited, genetic backgrounds. The SGEAA did not share haplotypes with any of the triple mutants. Comparative analysis of the microsatellite haplotypes flanking dhps alleles from Cambodia, Kenya, Cameroon and Venezuela revealed an independent origin of sulfadoxine resistant alleles in each

  9. Origin and evolution of sulfadoxine resistant Plasmodium falciparum.

    Science.gov (United States)

    Vinayak, Sumiti; Alam, Md Tauqeer; Mixson-Hayden, Tonya; McCollum, Andrea M; Sem, Rithy; Shah, Naman K; Lim, Pharath; Muth, Sinuon; Rogers, William O; Fandeur, Thierry; Barnwell, John W; Escalante, Ananias A; Wongsrichanalai, Chansuda; Ariey, Frederick; Meshnick, Steven R; Udhayakumar, Venkatachalam

    2010-03-26

    The Thailand-Cambodia border is the epicenter for drug-resistant falciparum malaria. Previous studies have shown that chloroquine (CQ) and pyrimethamine resistance originated in this region and eventually spread to other Asian countries and Africa. However, there is a dearth in understanding the origin and evolution of dhps alleles associated with sulfadoxine resistance. The present study was designed to reveal the origin(s) of sulfadoxine resistance in Cambodia and its evolutionary relationship to African and South American dhps alleles. We sequenced 234 Cambodian Plasmodium falciparum isolates for the dhps codons S436A/F, A437G, K540E, A581G and A613S/T implicated in sulfadoxine resistance. We also genotyped 10 microsatellite loci around dhps to determine the genetic backgrounds of various alleles and compared them with the backgrounds of alleles prevalent in Africa and South America. In addition to previously known highly-resistant triple mutant dhps alleles SGEGA and AGEAA (codons 436, 437, 540, 581, 613 are sequentially indicated), a large proportion of the isolates (19.3%) contained a 540N mutation in association with 437G/581G yielding a previously unreported triple mutant allele, SGNGA. Microsatellite data strongly suggest the strength of selection was greater on triple mutant dhps alleles followed by the double and single mutants. We provide evidence for at least three independent origins for the double mutants, one each for the SGKGA, AGKAA and SGEAA alleles. Our data suggest that the triple mutant allele SGEGA and the novel allele SGNGA have common origin on the SGKGA background, whereas the AGEAA triple mutant was derived from AGKAA on multiple, albeit limited, genetic backgrounds. The SGEAA did not share haplotypes with any of the triple mutants. Comparative analysis of the microsatellite haplotypes flanking dhps alleles from Cambodia, Kenya, Cameroon and Venezuela revealed an independent origin of sulfadoxine resistant alleles in each of these regions.

  10. Multidrug evolutionary strategies to reverse antibiotic resistance

    Science.gov (United States)

    Baym, Michael; Stone, Laura K.; Kishony, Roy

    2017-01-01

    Antibiotic treatment has two conflicting effects: the desired, immediate effect of inhibiting bacterial growth and the undesired, long-term effect of promoting the evolution of resistance. Although these contrasting outcomes seem inextricably linked, recent work has revealed several ways by which antibiotics can be combined to inhibit bacterial growth while, counterintuitively, selecting against resistant mutants. Decoupling treatment efficacy from the risk of resistance can be achieved by exploiting specific interactions between drugs, and the ways in which resistance mutations to a given drug can modulate these interactions or increase the sensitivity of the bacteria to other compounds. Although their practical application requires much further development and validation, and relies on advances in genomic diagnostics, these discoveries suggest novel paradigms that may restrict or even reverse the evolution of resistance. PMID:26722002

  11. The secondary resistome of multidrug-resistant Klebsiella pneumoniae

    Science.gov (United States)

    Jana, Bimal; Cain, Amy K.; Doerrler, William T.; Boinett, Christine J.; Fookes, Maria C.; Parkhill, Julian; Guardabassi, Luca

    2017-01-01

    Klebsiella pneumoniae causes severe lung and bloodstream infections that are difficult to treat due to multidrug resistance. We hypothesized that antimicrobial resistance can be reversed by targeting chromosomal non-essential genes that are not responsible for acquired resistance but essential for resistant bacteria under therapeutic concentrations of antimicrobials. Conditional essentiality of individual genes to antimicrobial resistance was evaluated in an epidemic multidrug-resistant clone of K. pneumoniae (ST258). We constructed a high-density transposon mutant library of >430,000 unique Tn5 insertions and measured mutant depletion upon exposure to three clinically relevant antimicrobials (colistin, imipenem or ciprofloxacin) by Transposon Directed Insertion-site Sequencing (TraDIS). Using this high-throughput approach, we defined three sets of chromosomal non-essential genes essential for growth during exposure to colistin (n = 35), imipenem (n = 1) or ciprofloxacin (n = 1) in addition to known resistance determinants, collectively termed the “secondary resistome”. As proof of principle, we demonstrated that inactivation of a non-essential gene not previously found linked to colistin resistance (dedA) restored colistin susceptibility by reducing the minimum inhibitory concentration from 8 to 0.5 μg/ml, 4-fold below the susceptibility breakpoint (S ≤ 2 μg/ml). This finding suggests that the secondary resistome is a potential target for developing antimicrobial “helper” drugs that restore the efficacy of existing antimicrobials. PMID:28198411

  12. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria

    Science.gov (United States)

    Ariey, Frédéric; Witkowski, Benoit; Amaratunga, Chanaki; Beghain, Johann; Langlois, Anne-Claire; Khim, Nimol; Kim, Saorin; Duru, Valentine; Bouchier, Christiane; Ma, Laurence; Lim, Pharath; Leang, Rithea; Duong, Socheat; Sreng, Sokunthea; Suon, Seila; Chuor, Char Meng; Bout, Denis Mey; Ménard, Sandie; Rogers, William O.; Genton, Blaise; Fandeur, Thierry; Miotto, Olivo; Ringwald, Pascal; Le Bras, Jacques; Berry, Antoine; Barale, Jean-Christophe; Fairhurst, Rick M.; Benoit-Vical, Françoise; Mercereau-Puijalon, Odile; Ménard, Didier

    2014-01-01

    Plasmodium falciparum resistance to artemisinin derivatives in southeast Asia threatens malaria control and elimination activities worldwide. To monitor the spread of artemisinin resistance, a molecular marker is urgently needed. Here, using whole-genome sequencing of an artemisinin-resistant parasite line from Africa and clinical parasite isolates from Cambodia, we associate mutations in the PF3D7_1343700 kelch propeller domain (`K13-propeller') with artemisinin resistance in vitro and in vivo. Mutant K13-propeller alleles cluster in Cambodian provinces where resistance is prevalent, and the increasing frequency of a dominant mutant K13-propeller allele correlates with the recent spread of resistance in western Cambodia. Strong correlations between the presence of a mutant allele, in vitro parasite survival rates and in vivo parasite clearance rates indicate that K13-propeller mutations are important determinants of artemisinin resistance. K13-propeller polymorphism constitutes a useful molecular marker for large-scale surveillance efforts to contain artemisinin resistance in the Greater Mekong Subregion and prevent its global spread.

  13. Multidrug-Resistant Escherichia fergusonii: a Case of Acute Cystitis▿

    Science.gov (United States)

    Savini, Vincenzo; Catavitello, Chiara; Talia, Marzia; Manna, Assunta; Pompetti, Franca; Favaro, Marco; Fontana, Carla; Febbo, Fabio; Balbinot, Andrea; Di Berardino, Fabio; Di Bonaventura, Giovanni; Di Zacomo, Silvia; Esattore, Francesca; D'Antonio, Domenico

    2008-01-01

    We report a case in which Escherichia fergusonii, an emerging pathogen in various types of infections, was associated with cystitis in a 52-year-old woman. The offending strain was found to be multidrug resistant. Despite in vitro activity, beta-lactam treatment failed because of a lack of patient compliance with therapy. The work confirms the pathogenic potential of E. fergusonii. PMID:18256229

  14. Multidrug-Resistant Tuberculosis: Treatment and Outcomes of 93 Patients

    Directory of Open Access Journals (Sweden)

    Sarah K Brode

    2015-01-01

    Full Text Available BACKGROUND: Tuberculosis (TB remains a leading cause of death worldwide and the emergence of multidrug-resistant TB (MDR TB poses a threat to its control. There is scanty evidence regarding optimal management of MDR TB. The majority of Canadian cases of MDR TB are diagnosed in Ontario; most are managed by the Tuberculosis Service at West Park Healthcare Centre in Toronto. The authors reviewed 93 cases of MDR TB admitted from January 1, 2000 to December 31, 2011.

  15. Chromosomal Instability Confers Intrinsic Multi-Drug Resistance

    Science.gov (United States)

    Lee, Alvin J X; Endesfelder, David; Rowan, Andrew J; Walther, Axel; Birkbak, Nicolai J; Futreal, P Andrew; Downward, Julian; Szallasi, Zoltan; Tomlinson, Ian P M; Kschischo, Maik; Swanton, Charles

    2011-01-01

    Aneuploidy is associated with poor prognosis in solid tumours. Spontaneous chromosome mis-segregation events in aneuploid cells promote Chromosomal Instability (CIN) that may contribute to the acquisition of multi-drug resistance in vitro and heighten risk for tumour relapse in animal models. Identification of distinct therapeutic agents that target tumour karyotypic complexity has important clinical implications. In order to identify distinct therapeutic approaches to specifically limit the growth of CIN tumours we focussed on a panel of colorectal cancer (CRC) cell lines, previously classified as either chromosomally-unstable (CIN+) or diploid/near-diploid (CIN−), and treated them individually with a library of kinase inhibitors targeting components of signal transduction, cell cycle and trans-membrane receptor signalling pathways. CIN+ cell lines displayed significant intrinsic multi-drug resistance compared to CIN− cancer cell lines and this appeared to be independent of somatic mutation status and proliferation rate. Confirming the association of CIN rather than ploidy status with multi-drug resistance, tetraploid isogenic cells that had arisen from diploid cell lines displayed lower drug sensitivity than their diploid parental cells only with increasing chromosomal heterogeneity, and isogenic cell line models of CIN+ displayed multi-drug resistance relative to their CIN− parental cancer cell line derivatives. In a meta-analysis of CRC outcome following cytotoxic treatment, CIN+ predicted worse progression-free or disease-free survival relative to patients with CIN− disease. Our results suggest that stratifying tumour responses according to CIN status should be considered within the context of clinical trials to minimize the confounding effects of tumour CIN status on drug sensitivity. PMID:21363922

  16. Antiviral Drug- and Multidrug Resistance in Cytomegalovirus Infected SCT Patients

    Directory of Open Access Journals (Sweden)

    Katharina Göhring

    2015-01-01

    Full Text Available In pediatric and adult patients after stem cell transplantation (SCT disseminated infections caused by human cytomegalovirus (HCMV can cause life threatening diseases. For treatment, the three antivirals ganciclovir (GCV, foscarnet (PFA and cidofovir (CDV are approved and most frequently used. Resistance to all of these antiviral drugs may induce a severe problem in this patient cohort. Responsible for resistance phenomena are mutations in the HCMV phosphotransferase-gene (UL97 and the polymerase-gene (UL54. Most frequently mutations in the UL97-gene are associated with resistance to GCV. Resistance against all three drugs is associated to mutations in the UL54-gene. Monitoring of drug resistance by genotyping is mostly done by PCR-based Sanger sequencing. For phenotyping with cell culture the isolation of HCMV is a prerequisite. The development of multidrug resistance with mutation in both genes is rare, but it is often associated with a fatal outcome. The manifestation of multidrug resistance is mostly associated with combined UL97/UL54-mutations. Normally, mutations in the UL97 gene occur initially followed by UL54 mutation after therapy switch. The appearance of UL54-mutation alone without any detection of UL97-mutation is rare. Interestingly, in a number of patients the UL97 mutation could be detected in specific compartments exclusively and not in blood.

  17. Tracking Origins and Spread of Sulfadoxine-Resistant Plasmodium falciparum dhps Alleles in Thailand▿

    OpenAIRE

    Alam, Md Tauqeer; Vinayak, Sumiti; Congpuong, Kanungnit; Wongsrichanalai, Chansuda; Satimai, Wichai; Slutsker, Laurence; Escalante, Ananias A.; Barnwell, John W.; Udhayakumar, Venkatachalam

    2010-01-01

    The emergence and spread of drug-resistant Plasmodium falciparum have been a major impediment for the control of malaria worldwide. Earlier studies have shown that similar to chloroquine (CQ) resistance, high levels of pyrimethamine resistance in P. falciparum originated independently 4 to 5 times globally, including one origin at the Thailand-Cambodia border. In this study we describe the origins and spread of sulfadoxine-resistance-conferring dihydropteroate synthase (dhps) alleles in Thail...

  18. Natural History of Multi-Drug Resistant Organisms in a New Military Medical Facility

    Science.gov (United States)

    2013-12-01

    Staphylococcus saprophyticus 14 (3) Enterococcus (faecium and faecalis) 11 (2) The remaining 11 species each comprised less than 2% of total 169 (32...environment plays in the transmission of multidrug-resistant Gram-negative bacteria and methicillin-resistant Staphylococcus aureus (MDRO) is increasingly...Pseudomonas aeruginosa, methicillin- resistant Staphylococcus aureus (MRSA); Klebsiella pneumoniea; and Clostridium difficile. Multidrug- resistance (MDR

  19. Reversal of Multidrug Resistance in Breast Cancer

    Science.gov (United States)

    1994-08-23

    cellular resistance to multiple therapeutic agents such as anthracyclines, vinca alkaloids , epipodophyllotoxins, taxol, and actinomycin-D. MDR1 gene...Sci USA 84:3004.1987. Zacher, V., Thomas, R.A., and Goustin, A.S. Absolute quantification of target DNA: a simple competitive PCR for efficient...target appears to be the microtubular apparatus, but unlike vinca alkaloids or epipodophyllotoxin, Paclitaxel actually promotes microtubular assemblyin

  20. Chloroquine- and sulfadoxine-pyrimethamine-resistant falciparum malaria in vivo - a pilot study in rural Zambia

    NARCIS (Netherlands)

    Bijl, HM; Kager, J; Koetsier, DW; van der Werf, TS

    2000-01-01

    BACKGROUND Chloroquine (CQ) and Sulfadoxine-Pyrimethamine (SP) are the predominantly used antimalarials in Zambia and other parts of East Africa, but increasing resistance of P. falciparum is a major concern. METHODS Seventy consecutive patients with uncomplicated falciparum malaria were enrolled.

  1. Overcoming Multidrug Resistance in Cancer Stem Cells

    Directory of Open Access Journals (Sweden)

    Karobi Moitra

    2015-01-01

    Full Text Available The principle mechanism of protection of stem cells is through the expression of ATP-binding cassette (ABC transporters. These transporters serve as the guardians of the stem cell population in the body. Unfortunately these very same ABC efflux pumps afford protection to cancer stem cells in tumors, shielding them from the adverse effects of chemotherapy. A number of strategies to circumvent the function of these transporters in cancer stem cells are currently under investigation. These strategies include the development of competitive and allosteric modulators, nanoparticle mediated delivery of inhibitors, targeted transcriptional regulation of ABC transporters, miRNA mediated inhibition, and targeting of signaling pathways that modulate ABC transporters. The role of ABC transporters in cancer stem cells will be explored in this paper and strategies aimed at overcoming drug resistance caused by these particular transporters will also be discussed.

  2. Photoexcited quantum dots for killing multidrug-resistant bacteria

    Science.gov (United States)

    Courtney, Colleen M.; Goodman, Samuel M.; McDaniel, Jessica A.; Madinger, Nancy E.; Chatterjee, Anushree; Nagpal, Prashant

    2016-05-01

    Multidrug-resistant bacterial infections are an ever-growing threat because of the shrinking arsenal of efficacious antibiotics. Metal nanoparticles can induce cell death, yet the toxicity effect is typically nonspecific. Here, we show that photoexcited quantum dots (QDs) can kill a wide range of multidrug-resistant bacterial clinical isolates, including methicillin-resistant Staphylococcus aureus, carbapenem-resistant Escherichia coli, and extended-spectrum β-lactamase-producing Klebsiella pneumoniae and Salmonella typhimurium. The killing effect is independent of material and controlled by the redox potentials of the photogenerated charge carriers, which selectively alter the cellular redox state. We also show that the QDs can be tailored to kill 92% of bacterial cells in a monoculture, and in a co-culture of E. coli and HEK 293T cells, while leaving the mammalian cells intact, or to increase bacterial proliferation. Photoexcited QDs could be used in the study of the effect of redox states on living systems, and lead to clinical phototherapy for the treatment of infections.

  3. MULTIDRUG RESISTANT BACTERIA IN A TERTIARY CARE HOS PITAL.

    Directory of Open Access Journals (Sweden)

    Sujata

    2012-12-01

    Full Text Available ABSTRACT: BACKGROUND: Antibiotic resistance is a global problem in the hos pitals as well as in the community. Selection pressure exerted by over use of antimicrobial agents is the commonest predisposing factor of development of resist ance. Problems faced are especially with Methicillin Resistant Staphylococcus aureus (MR SA, Vancomycin Resistant Enterococci (VRE and Multidrug resistant Gram-negative bacilli (MDR-GNB. AIMS: A study was undertaken to find out the prevalence of all bacteri a isolated in this hospital from different specimens, which are resistant to first line antibio tics and their antimicrobial susceptibility pattern with higher antibiotics during a six-month pe riod. MATERIAL AND METHODS: All isolates from different specimens were processed by s tandard techniques and identified by standard biochemical tests. Antibiotic susceptibilit y was performed on Mueller Hinton Agar (MHA by Kirby-Bauer Disc Diffusion Method (KBDDM, according to CLSI guidelines. Those resistant to first line antibiotics were further te sted for higher antibiotics. For Extended Spectrum β -lactamse (ESBL detection, double disc synergy met hod was carried out for all Gram-negative bacilli. RESULTS: Out of 2987 bacteria grown, 904 (30.3% were multi drug resistant bacteria. Resistance to first line antib iotics was 83.4% and resistance to all higher antibiotics tested was 16.6%. Sixty percent of Staph ylococcus aureus was MRSA and all were sensitive to vancomycin. Prevalence of VRE was 5.3 %. Carbapenem resistant Pseudomonas aeruginosa and Acinetobacter species were 19.1% and 9.8% respectively and 10.1% of Klebsiella species was carbapenem resistant. CONCLUSIONS: This study highlights the extensive problem of antibiotic resistance encounter ed in this hospital. Thus, prudent and appropriate uses of antibiotics are required to reduce the emergence of resistance. Each hospital should also have its own antibiotic policy based on the susceptibility pattern of

  4. Expression of multidrug resistance-related markers in primary neuroblastoma

    Institute of Scientific and Technical Information of China (English)

    吕庆杰; 董芳; 张锦华; 李晓晗; 马颖; 姜卫国

    2004-01-01

    Background Multidrug resistance is associated with a poor prognosis in various human cancers. However, the clinical significance of the expression of multidrug resistance-related markers in neuroblastoma is still on debate. In this study, the effect of the expression of p-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and lung resistance protein (LRP) in neuroblastoma was evaluated. Methods The streptavidin-biotin immunoperoxidase (SP) technique was used to evaluate the expression of P-gp, MRP, and LRP in 70 cases of untreated primary neuroblastoma. Results The frequencies of the expression of P-gp, MRP, and LRP were 61.4%, 38.6%, and 24.3%, respectively. A significant positive correlation was observed between P-gp and MRP expression (P=0.001), as well as between LRP and MRP expression (P=0.01). The rates of expression of P-gp and MRP were higher in tumors from patients aged greater than one year old than in tumors from patients aged less than 1 year old at time of diagnosis (P=0.01 and 0.018, respectively). MRP expression in tumors that had metastasized was significantly more frequent than in tumors that had not metastasized (P=0.015). The expression of all tested proteins showed a significant relationship with whether or not the tumor had differentiated (P=0.006, 0.000 or 0.001, respectively). MRP expression was significantly associated with a reduction in both median survival time and 2-year cumulative survival (P=0.02). By contrast, P-gp and MRP expression did not correlate with survival. According to Cox regression analysis, only the co-expression of P-gp and MRP had significant prognostic value (relative hazard, 3.513, P=0.033). Conclusions The intrinsic, multidrug resistance of neuroblastoma involves the combined effects of P-gp, MRP, and LRP. MRP expression may be an important factor determining prognosis in neuroblastoma.

  5. Possible treatment failure of artemether-lumefantrine in an Italian traveler with uncomplicated falciparum malaria.

    Directory of Open Access Journals (Sweden)

    Ernestina Carla Repetto

    2011-10-01

    Full Text Available Artemisinin-combination therapies (ACTs are recommended for the treatment of uncomplicated malaria in endemic areas with multidrug resistant Plasmodium falciparum. We report a case of possible artemether-lumefantrine failure in an Italian traveler with uncomplicated P. falciparum malaria imported from Democratic Republic of Congo.

  6. Possible clinical failure of artemether-lumefantrine in an italian traveler with uncomplicated falciparum malaria.

    Science.gov (United States)

    Repetto, Ernestina C; Traverso, Antonio; Giacomazzi, Claudio G

    2011-01-01

    Artemisinin-combination therapies (ACTs) are recommended for the treatment of uncomplicated malaria in endemic areas with multidrug resistant Plasmodium falciparum. We report a case of possible artemether-lumefantrine clinical failure in an Italian traveler with uncomplicated P. falciparum malaria imported from Democratic Republic of Congo.

  7. Possible Clinical Failure of Artemether-Lumefantrine in an Italian Traveler with Uncomplicated Falciparum Malaria.

    Science.gov (United States)

    Repetto, Ernestina C.; Traverso, Antonio; Giacomazzi, Claudio G.

    2011-01-01

    Artemisinin-combination therapies (ACTs) are recommended for the treatment of uncomplicated malaria in endemic areas with multidrug resistant Plasmodium falciparum. We report a case of possible artemether-lumefantrine clinical failure in an Italian traveler with uncomplicated P. falciparum malaria imported from Democratic Republic of Congo. PMID:22084655

  8. Epidemiologic analysis: Prophylaxis and multidrug-resistance in surgery.

    Science.gov (United States)

    Solís-Téllez, H; Mondragón-Pinzón, E E; Ramírez-Marino, M; Espinoza-López, F R; Domínguez-Sosa, F; Rubio-Suarez, J F; Romero-Morelos, R D

    Surgical site infection is defined as an infection related to the surgical procedure in the area of manipulation occurring within the first 30 postoperative days. The diagnostic criteria include: purulent drainage, isolation of microorganisms, and signs of infection. To describe the epidemiologic characteristics and differences among the types of prophylactic regimens associated with hospital-acquired infections at the general surgery service of a tertiary care hospital. The electronic case records of patients that underwent general surgery at a tertiary care hospital within the time frame of January 1, 2013 and December 31, 2014 were reviewed. A convenience sample of 728 patients was established and divided into the following groups: Group 1: n=728 for the epidemiologic study; Group 2: n=638 for the evaluation of antimicrobial prophylaxis; and Group 3: n=50 for the evaluation of multidrug-resistant bacterial strains in the intensive care unit. The statistical analysis was carried out with the SPSS 19 program, using the Mann-Whitney U test and the chi-square test. A total of 728 procedures were performed (65.9% were elective surgeries). Three hundred twelve of the patients were males and 416 were females. Only 3.98% of the patients complied with the recommended antimicrobial prophylaxis, and multidrug-resistant bacterial strains were found in the intensive care unit. A single prophylactic dose is effective, but adherence to this recommendation was not adequate. The prophylactic guidelines are not strictly adhered to in our environment. There was a significant association between the development of nosocomial infections from multidrug-resistant germs and admission to the intensive care unit. Copyright © 2016 Asociación Mexicana de Gastroenterología. Publicado por Masson Doyma México S.A. All rights reserved.

  9. Concordance of resistance profiles in households of patients with multidrug-resistant tuberculosis.

    Science.gov (United States)

    Parr, Jonathan B; Mitnick, Carole D; Atwood, Sidney S; Chalco, Katiuska; Bayona, Jaime; Becerra, Mercedes C

    2014-02-01

    We estimated the proportion of household contacts whose drug-susceptibility test results matched those of the purported source patient with multidrug-resistant tuberculosis. Ninety-nine (88.4%) contacts had isolates resistant to isoniazid and rifampin, and 41 (36.6%) contacts had isolates with results that also matched the purported source for ethambutol, streptomycin, and pyrazinamide.

  10. Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis.

    NARCIS (Netherlands)

    Gandhi, N.R.; Nunn, P.; Dheda, K.; Schaaf, H.S.; Zignol, M.; Soolingen, D. van; Jensen, P.; Bayona, J.

    2010-01-01

    Although progress has been made to reduce global incidence of drug-susceptible tuberculosis, the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis during the past decade threatens to undermine these advances. However, countries are responding far too slowly. Of

  11. Recurrence after treatment for pulmonary multidrug-resistant tuberculosis.

    Science.gov (United States)

    Becerra, Mercedes C; Appleton, Sasha C; Franke, Molly F; Chalco, Katiuska; Bayona, Jaime; Murray, Megan B; Mitnick, Carole D

    2010-09-15

    We estimated the proportion of recurrence within 2 years among adults cured by individualized multidrug-resistant tuberculosis regimens in Peru. Among 310 individuals with at least 24 months of follow-up, 16 experienced an episode of recurrent tuberculosis. If we assume the worst for treatment effectiveness-that all 16 episodes were caused by the original tuberculosis strain-then 5.2% (95% confidence interval, 3.0%-8.2%) experienced true relapse. This is an upper-bound estimate of relapse on which new regimens must improve.

  12. Overcoming multidrug resistance(MDR) in cancer by nanotechnology

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    The emerging nanotechnology-based drug delivery holds tremendous potential to deliver chemotherapeutic drugs for treatment of multidrug resistance(MDR) cancer.This drug delivery system could improve the pharmacokinetic behavior of antitumor drugs,deliver chemotherapeutic drugs to target sites,control release of drugs,and reduce the systemic toxicity of drugs in MDR cancer.This review addresses the use of nanotechnology to overcome MDR classified on the bases of the fundamental mechanisms of MDR and various approaches to deliver drugs for treatment of MDR cancer.

  13. Human Multidrug Resistance 1 gene polymorphisms and Idiopathic Pulmonary Fibrosis

    Science.gov (United States)

    Martinelli, Marcella; Scapoli, Luca; Pacilli, Angela Maria Grazia; Carbonara, Paolo; Girardi, Ambra; Mattei, Gabriella; Rodia, Maria Teresa; Solmi, Rossella

    2015-01-01

    Background: For the first time we tested an association between the human multidrug resistance gene 1 (MDR1) polymorphisms (SNPs) and idiopathic pulmonary fibrosis (IPF). Several MDR1 polymorphisms are associated with pathologies in which they modify the drug susceptibility and pharmacokinetics. Materials and Methods: We genotyped three MDR1 polymorphisms of 48 IPF patients and 100 control subjects with Italian origins. Results: No evidence of association was detected. Conclusion: There are 50 known MDR1 SNPs, and their role is explored in terms of the effectiveness of drug therapy. We consider our small-scale preliminary study as a starting point for further research. PMID:25767528

  14. [Multidrug-resistant tuberculosis: current epidemiology, therapeutic regimens, new drugs].

    Science.gov (United States)

    Gómez-Ayerbe, C; Vivancos, M J; Moreno, S

    2016-09-01

    Multidrug and extensively resistant tuberculosis are especially severe forms of the disease for which no efficacious therapy exists in many cases. All the countries in the world have registered cases, although most of them are diagnosed in resource-limited countries from Asia, Africa and South America. For adequate treatment, first- and second-line antituberculosis drugs have to be judiciously used, but the development of new drugs with full activity, good tolerability and little toxicity is urgently needed. There are some drugs in development, some of which are already available through expanded-access programs.

  15. Effect of methylglyoxal on multidrug-resistant Pseudomonas aeruginosa

    Directory of Open Access Journals (Sweden)

    Katsuhiko eHayashi

    2014-04-01

    Full Text Available Honey has a complex chemistry, and its broad-spectrum antimicrobial activity varies with floral source, climate, and harvesting conditions. Methylglyoxal was identified as the dominant antibacterial component of manuka honey. Although it has been known that methylglyoxal has antibacterial activity against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus, there is not much information describing its activity against gram-negative bacteria. In this study, we report the effect of methylglyoxal against multidrug-resistant Pseudomonas aeruginosa (MDRP using 53 clinically isolated strains. We also assessed the effect of deleting the five multidrug efflux systems in P. aeruginosa, as well as the efflux systems in Escherichia coli and Salmonella enterica serovar Typhimurium, on MICs of methylglyoxal. Our results indicate that methylglyoxal inhibits the growth of MDRP at concentrations of 128–512 µg/ml (1.7–7.1 mM and is not recognized by drug efflux systems.

  16. Fighting drug-resistant Plasmodium falciparum: the challenge of artemisinin resistance.

    Science.gov (United States)

    Wongsrichanalai, C; Sibley, C H

    2013-10-01

    Following a decade-long scale up of malaria control through vector control interventions, the introduction of rapid diagnostic tests and highly efficacious Artemisinin-based Combination Therapy (ACT) along with other measures, global malaria incidence declined significantly. The recent development of artemisinin resistance on the Cambodia-Thailand border, however, is of great concern. This review encompasses the background of artemisinin resistance in Plasmodium falciparum, its situation, especially in the Greater Mekong Sub-region (GMS), and the responses taken to overcome this resistance. The difficulties in defining resistance are presented, particularly the necessity of measuring the clinical response to artemisinins using the slow parasite-clearance phenotype. Efforts to understand the molecular basis of artemisinin resistance and the search for molecular markers are reviewed. The markers, once identified, can be applied as an efficient tool for resistance surveillance. Despite the limitation of current surveillance methods, it is important to continue vigilance for artemisinin resistance. The therapeutic efficacy "in vivo study" network for monitoring antimalarial resistance in the GMS has been strengthened. GMS countries are working together in response to artemisinin resistance and aim to eliminate all P. falciparum parasites. These efforts are crucial since a resurgence of malaria due to drug and/or insecticide resistance, program cuts, lack of political support and donor fatigue could set back malaria control success in the sub-region and threaten malaria control and elimination if resistance spreads to other regions.

  17. Synergy of four macrolide antibiotics with chloroquine against chloroquine-resistant Plasmodium falciparum in vitro.

    Science.gov (United States)

    Gershon, P; Howells, R E

    1986-01-01

    The antimalarial activity of four macrolide antibiotics was investigated against the multidrug resistant K1 strain of Plasmodium falciparum in vitro. ID50 (50% inhibitory concentration) values for erythromycin, spiramycin, tylosin tartrate and oleandomycin phosphate in 48-hour assays were 1.6 X 10(-4)M, 2.5 X 10(-5)M, 1.2 X 10(-5)M and 9 X 10(-6)M respectively, and in 96 hour assays were 10(-5)M, 2.6 X 10(-6)M, 2.6 X 10(-6) and 3 X 10(-6)M, respectively. Comparable values were obtained in assays in which drug effect was quantified from either parasite counts or 14C isoleucine incorporation. Each of the four macrolides displayed synergy with chloroquine at the IC90 (90% inhibitory concentration) level, but at the IC50 level synergy was either less pronounced or absent. For each combination this difference in the degree of synergy was significant at the 95% level of confidence. In replicate assays in which 3H hypoxanthine was the marker of drug effect, synergy between chloroquine and either erythromycin or spiramycin could not be detected.

  18. Natural product modulators to overcome multidrug resistance in cancer.

    Science.gov (United States)

    Cort, Aysegul; Ozben, Tomris

    2015-01-01

    Multidrug resistance (MDR) is a condition that makes cells simultaneously unresponsive to different drugs, unrelated to their chemical structure and mechanism of action. MDR caused by the presence and overexpression of ABC transporters makes obstacles in cancer treatment and lower the effectiveness of chemotherapy. Natural products are investigated by many researchers as MDR modulators for their low toxicity and potent, selective behavior. When coadministered, MDR modulators compete with cytotoxic agents for binding to the active site of the membrane transporters and reduce drug efflux. Natural product-based drugs are important in struggling against drug resistance during cancer therapy. This review is focused on the potential mechanisms against drug resistance, the development of inhibitors for ABC drug transporters, natural product modulators, and nanoparticle drug delivery.

  19. Characterization of multidrug-resistant diabetic foot ulcer enterococci.

    Science.gov (United States)

    Semedo-Lemsaddek, Teresa; Mottola, Carla; Alves-Barroco, Cynthia; Cavaco-Silva, Patrícia; Tavares, Luís; Oliveira, Manuela

    2016-02-01

    Diabetes mellitus is a highly prevalent chronic progressive disease with complications that include diabetic-foot ulcers. Enterococci isolated from diabetic-foot infections were identified, evaluated by macro-restriction analysis, and screened for virulence traits and antimicrobial resistance. All isolates were considered multidrug-resistant, cytolysin and gelatinase producers, and the majority also demonstrated the ability to produce biofilms. These results indicate the importance of enterococci in diabetic-foot infection development and persistence, especially regarding their biofilm-forming ability and resistance to clinically relevant antibiotics. Copyright © 2015 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  20. Second-line drug resistance in multidrug-resistant tuberculosis cases of various origins in the Netherlands.

    NARCIS (Netherlands)

    Ingen, J. van; Boeree, M.J.; Wright, A.; Laan, T.; Dekhuijzen, P.N.R.; Soolingen, D van

    2008-01-01

    SETTING: The Netherlands. OBJECTIVE: To investigate the frequency of resistance to second-line drugs among multidrug-resistant tuberculosis (MDR-TB) cases and its correlation with patients' geographic origin. DESIGN: Retrospective laboratory database study of multidrug-resistant Mycobacterium tuberc

  1. On the mechanism of chloroquine resistance in Plasmodium falciparum.

    KAUST Repository

    Chinappi, Mauro

    2010-11-19

    Resistance to chloroquine of malaria strains is known to be associated with a parasite protein named PfCRT, the mutated form of which is able to reduce chloroquine accumulation in the digestive vacuole of the pathogen. Whether the protein mediates extrusion of the drug acting as a channel or as a carrier and which is the protonation state of its chloroquine substrate is the subject of a scientific debate. We present here an analytical approach that explores which combination of hypotheses on the mechanism of transport and the protonation state of chloroquine are consistent with available equilibrium experimental data. We show that the available experimental data are not, by themselves, sufficient to conclude whether the protein acts as a channel or as a transporter, which explains the origin of their different interpretation by different authors. Interestingly, though, each of the two models is only consistent with a subset of hypotheses on the protonation state of the transported molecule. The combination of these results with a sequence and structure analysis of PfCRT, which strongly suggests that the molecule is a carrier, indicates that the transported species is either or both the mono and di-protonated forms of chloroquine. We believe that our results, besides shedding light on the mechanism of chloroquine resistance in P. falciparum, have implications for the development of novel therapies against resistant malaria strains and demonstrate the usefulness of an approach combining systems biology strategies with structural bioinformatics and experimental data.

  2. Nanodrug Delivery in Reversing Multidrug Resistance in Cancer Cells

    Directory of Open Access Journals (Sweden)

    Sonali eKapse-Mistry

    2014-07-01

    Full Text Available Different mechanisms in cancer cells become resistant to one or more chemotherapeutics is known as multidrug resistance(MDR which hinders chemotherapy efficacy. Potential factors for MDR includes enhanced drug detoxification, decreased drug uptake, increased intracellular nucleophiles levels, enhanced repair of drug induced DNA damage, overexpression of drug transporter such as P-glycoprotein(P-gp, multidrug resistance-associated proteins(MRP1, MRP2 and breast cancer resistance protein(BCRP. Currently nanoassemblies such as polymeric/solid lipid/inorganic/metal nanoparticles, quantum dots, dendrimers, liposomes, micelles has emerged as an innovative, effective and promising platforms for treatment of drug resistant cancer cells. Nanocarriers have potential to improve drug therapeutic index, ability for multifunctionality, divert ABC-transporter mediated drug efflux mechanism and selective targeting to tumor cells, cancer stem cells, tumor initiating cells or cancer microenvironment. Selective nanocarrier targeting to tumor overcomes dose-limiting side effects, lack of selectivity, tissue toxicity, limited drug access to tumor tissues, high drug doses and emergence of multiple drug resistance with conventional or combination chemotherapy. Current review highlights various nanodrug delivery systems to overcome mechanism of MDR by neutralizing, evading or exploiting the drug efflux pumps and those independent of drug efflux pump mechanism by silencing Bcl-2 and HIF1 gene expressions by siRNA and miRNA, modulating ceramide levels and targeting NF-B. Theragnostics combining a cytotoxic agent, targeting moiety, chemosensitizing agent and diagnostic imaging aid are highlighted as effective and innovative systems for tumor localization and overcoming MDR. Physical approaches such as combination of drug with thermal/ultrasound/photodynamic therapies to overcome MDR are focused. The review focuses on newer drug delivery systems developed to overcome

  3. Multidrug-resistant pathogens in the food supply.

    Science.gov (United States)

    Doyle, Marjorie E

    2015-04-01

    Antimicrobial resistance, including multidrug resistance (MDR), is an increasing problem globally. MDR bacteria are frequently detected in humans and animals from both more- and less-developed countries and pose a serious concern for human health. Infections caused by MDR microbes may increase morbidity and mortality and require use of expensive drugs and prolonged hospitalization. Humans may be exposed to MDR pathogens through exposure to environments at health-care facilities and farms, livestock and companion animals, human food, and exposure to other individuals carrying MDR microbes. The Centers for Disease Control and Prevention classifies drug-resistant foodborne bacteria, including Campylobacter, Salmonella Typhi, nontyphoidal salmonellae, and Shigella, as serious threats. MDR bacteria have been detected in both meat and fresh produce. Salmonellae carrying genes coding for resistance to multiple antibiotics have caused numerous foodborne MDR outbreaks. While there is some level of resistance to antimicrobials in environmental bacteria, the widespread use of antibiotics in medicine and agriculture has driven the selection of a great variety of microbes with resistance to multiple antimicrobials. MDR bacteria on meat may have originated in veterinary health-care settings or on farms where animals are given antibiotics in feed or to treat infections. Fresh produce may be contaminated by irrigation or wash water containing MDR bacteria. Livestock, fruits, and vegetables may also be contaminated by food handlers, farmers, and animal caretakers who carry MDR bacteria. All potential sources of MDR bacteria should be considered and strategies devised to reduce their presence in foods. Surveillance studies have documented increasing trends in MDR in many pathogens, although there are a few reports of the decline of certain multidrug pathogens. Better coordination of surveillance programs and strategies for controlling use of antimicrobials need to be implemented in

  4. [Is Plasmodium falciparum, the parasite responsible for tropical malaria, resistant to fansidar?].

    Science.gov (United States)

    Holzer, B; Keller, H; Frossard, E; Stürchler, D

    1980-03-01

    A world-wide increase of malaria infections is observed. Malaria is imported into Switzerland mainly by tourists and recently by refugees from South East Asia. The strains of P. falciparum resistant to treatment are of increasing importance. A patient with P. falciparum infection from Cambodia is reported, who suffered from three episodes of malaria recrudescence within ten weeks, in spite of adequate therapy with quinine and Fansidar. The definition, the significance and the geographical distribution of resistances and the possible cause for a P. falciparum recrudescence are discussed. For the treatment of repeating recrudescence quinine and Fansidar are recommended, followed by a suppressive Fansidar prophylaxy for 4--8 weeks.

  5. Multidrug resistance reversal in human gastric carcinoma cells by neferine

    Institute of Scientific and Technical Information of China (English)

    Jian-Guo Cao; Xiao-Qing Tang; Shu-Hong Shi

    2004-01-01

    AIM: To investigate the reversal effect of neferine on multidrug resistance in human gastric carcinoma cell line.METHODS: Cells of a human gastric cancer cells line, SGC7901,and its vincristine (VCR) -resistant variant, SGC7901/VCR,were cultivated with or without neferine and/or VCR. The cytotoxic effect of VCR was evaluated by the MTT assay. Cell apoptosis induced by VCR was determined by flow cytometry (FCM). The expression of P-glycoprotein (P-gp) and a multidrug-resistance-associated protein (MRP) in cells was examined by immunofluorescence and FCM.RESULTS: Neferine at the concentration from 2.5 μmol/L to 10 μmol/L had no cytotoxicity to SGC7901 cells, and its variant SGC7901/VCR cells. The IC50 of VCR against SGC7901 and SGC7901/VCR cells was 0.059 μg/mL and 2.32 μg/mL,respectively, indicating that SGC7901/VCR cells were 39 times more resistant to VCR than its parent SGC7 901 cells. After treatment with neferine at concentrations of 2.5, 5 and 10 μmol/L, the IC50 of VCR to SGC7901/VCR cell line decreased to 0.340, 0.128 and 0.053 μg/mL, respectively,thus, increased the chemosensitivity by 6.8-, 18.1- and 43.8-fold, respectively. SGC7901/VCR cells were apoptosis resistant to VCR. Neferine (2.5, 5 and 10 μmol/L) promoted the VCR-induced apoptosis of SGC7901/VCR cells in a dosedependent manner. The expressions of P-gp and MRP were strongly positive in SGC7901/VCR cells, which were significantly down-regulated after treatment with neferine (10 μmol/L)for 24 h.CONCLUSION: Neferine reverses multidrug resistance of human gastric carcinoma SGC7901/VCR cells, which may be associated with the down-regulations of P-gp and MRP expression in SGC701/VCR cells.

  6. Molecular Pathways: Regulation and Therapeutic Implications of Multidrug Resistance

    Science.gov (United States)

    Chen, Kevin G.; Sikic, Branimir I.

    2012-01-01

    Multidrug transporters constitute major mechanisms of multidrug resistance (MDR) in human cancers. The ABCB1 (MDR1) gene encodes a well-characterized transmembrane transporter, termed P-glycoprotein (P-gp), which is expressed in many normal human tissues and cancers. P-gp plays a major role in the distribution and excretion of drugs, and is involved in intrinsic and acquired drug resistance of cancers. The regulation of ABCB1 expression is complex, and has not been well studied in a clinical setting. In this review, we elucidate molecular signaling and epigenetic interactions that govern ABCB1 expression and the development of MDR in cancer. We focus on acquired expression of ABCB1 that is associated with genomic instability of cancer cells, including mutational events that alter chromatin structures, gene rearrangements, and mutations in tumor suppressor proteins (e.g., mutant p53) that guard the integrity of genome. In addition, epigenetic modifications of the ABCB1 proximal and far upstream promoters by either demethylation of DNA or acetylation of histone H3 play a pivotal role in inducing ABCB1 expression. We describe a molecular network that coordinates genetic and epigenetic events leading to the activation of ABCB1. These mechanistic insignts provide additional translational targets and potential strategies to deal with clinical MDR. PMID:22344233

  7. Tailoring Cytotoxicity of Antimicrobial Peptidomimetics with High Activity against Multidrug-Resistant Escherichia coli

    DEFF Research Database (Denmark)

    Jahnsen, Rasmus D; Sandberg-Schaal, Anne; Vissing, Karina Juul

    2014-01-01

    Infections with multidrug-resistant pathogens are an increasing concern for public health. Recently, subtypes of peptide-peptoid hybrids were demonstrated to display potent activity against multidrug-resistant Gram-negative bacteria. Here, structural variation of these antibacterial peptidomimeti...

  8. The lactococcal secondary multidrug transporter LmrP confers resistance to lincosamides, macrolides, streptogramins and tetracyclines

    NARCIS (Netherlands)

    Putman, M; van Veen, HW; Degener, JE; Konings, WN

    2001-01-01

    The active efflux of toxic compounds by (multi)drug transporters is one of the mechanisms that bacteria have developed to resist cytotoxic drugs. The authors describe the role of the lactococcal secondary multidrug transporter LmrP in the resistance to a broad range of clinically important antibioti

  9. Draft Genome of the Multidrug-Resistant Acinetobacter baumannii Strain A155 Clinical Isolate.

    Science.gov (United States)

    Arivett, Brock A; Fiester, Steven E; Ream, David C; Centrón, Daniela; Ramírez, Maria S; Tolmasky, Marcelo E; Actis, Luis A

    2015-03-26

    Acinetobacter baumannii is a bacterial pathogen with serious implications on human health, due to increasing reports of multidrug-resistant strains isolated from patients. Total DNA from the multidrug-resistant A. baumannii strain A155 clinical isolate was sequenced to greater than 65× coverage, providing high-quality contig assemblies.

  10. How to Measure Export via Bacterial Multidrug Resistance Efflux Pumps

    Directory of Open Access Journals (Sweden)

    Jessica M. A. Blair

    2016-07-01

    Full Text Available Bacterial multidrug resistance (MDR efflux pumps are an important mechanism of antibiotic resistance and are required for many pathogens to cause infection. They are also being harnessed to improve microbial biotechnological processes, including biofuel production. Therefore, scientists of many specialties must be able to accurately measure efflux activity. However, myriad methodologies have been described and the most appropriate method is not always clear. Within the scientific literature, many methods are misused or data arising are misinterpreted. The methods for measuring efflux activity can be split into two groups, (i those that directly measure efflux and (ii those that measure the intracellular accumulation of a substrate, which is then used to infer efflux activity. Here, we review the methods for measuring efflux and explore the most recent advances in this field, including single-cell or cell-free technologies and mass spectrometry, that are being used to provide more detailed information about efflux pump activity.

  11. Photodynamic therapy of cancer — Challenges of multidrug resistance

    Directory of Open Access Journals (Sweden)

    Zheng Huang

    2015-01-01

    Full Text Available Photodynamic therapy (PDT of cancer is a two-step drug-device combination modality, which involves the topical or systemic administration of a photosensitizer followed by light illumination of cancer site. In the presence of oxygen molecules, the light illumination of photosensitizer (PS can lead to the generation of cytotoxic reactive oxygen species (ROS and consequently destroy cancer. Similar to many other anticancer therapies, PDT is also subject to intrinsic cancer resistance mediated by multidrug resistance (MDR mechanisms. This paper will review the recent progress in understanding the interaction between MDR transporters and PS uptake. The strategies that can be used in a clinical setting to overcome or bypass MDR will also be discussed.

  12. STUDIES ON ANTIBACTERIAL EFFECT OF APAMARGA (ACHYRANTHES ASPERA ON MULTI-DRUG RESISTANT CLINICAL ISOLATES

    Directory of Open Access Journals (Sweden)

    Patil Usha

    2013-04-01

    Full Text Available Recent reports on emergence of multidrug resistant bacteria are cause of concern in medical world. Several ayurvedic drugs have been proved to contain the antimicrobial activity. Literature on effect of ayurvedic drugs on multidrug resistant bacterial pathogens is limited. Present study reports the antimicrobial effect of Achyranthes aspera (Apamarga crude extracts on the clinical isolates of multidrug resistant bacteria. The drug was evaluated by using phytochemical tests. Crude extracts of aqueous, methanol, ethanol and chloroform was prepared. Antibacterial activity against clinically isolated multidrug resistant bacteria belonging to groups of bacillus, citrobacter, E.coli, klebsiella, proteus and salmonella was tested. The drug showed highest efficacy against Bacillus organism while least effectiveness on Proteus spp bacteria. Results of the study conclude that the medicinal plant A. aspera might be useful against multidrug resistance in pathogens of clinical importance.

  13. Effect of multidrug resistance 1/P-glycoprotein on the hypoxia-induced multidrug resistance of human laryngeal cancer cells.

    Science.gov (United States)

    Li, Dawei; Zhou, Liang; Huang, Jiameng; Xiao, Xiyan

    2016-08-01

    In a previous study, it was demonstrated that hypoxia upregulated the multidrug resistance (MDR) of laryngeal cancer cells to chemotherapeutic drugs, with multidrug resistance 1 (MDR1)/P-glycoprotein (P-gp) expression also being upregulated. The present study aimed to investigate the role and mechanism of MDR1/P-gp on hypoxia-induced MDR in human laryngeal carcinoma cells. The sensitivity of laryngeal cancer cells to multiple drugs and cisplatin-induced apoptosis was determined by CCK-8 assay and Annexin-V/propidium iodide staining analysis, respectively. The accumulation of rhodamine 123 (Rh123) in the cells served as an estimate of drug accumulation and was evaluated by flow cytometry (FCM). MDR1/P-gp expression was inhibited using interference RNA, and the expression of the MDR1 gene was analyzed using reverse transcription-quantitative polymerase chain reaction and western blotting. As a result, the sensitivity to multiple chemotherapeutic agents and the apoptosis rate of the hypoxic laryngeal carcinoma cells increased following a decrease in MDR1/P-gp expression (PP-gp markedly increased intracellular Rh123 accumulation (PP-gp serves an important role in regulating hypoxia-induced MDR in human laryngeal carcinoma cells through a decrease in intracellular drug accumulation.

  14. Lipoteichoic acid synthesis inhibition in combination with antibiotics abrogates growth of multidrug-resistant Enterococcus faecium

    NARCIS (Netherlands)

    Paganelli, Fernanda L.|info:eu-repo/dai/nl/357297849; van de Kamer, Tim; Brouwer, Ellen C.|info:eu-repo/dai/nl/304815667; Leavis, Helen L.|info:eu-repo/dai/nl/304820717; Woodford, Neil; Bonten, Marc J M|info:eu-repo/dai/nl/123144337; Willems, Rob J L|info:eu-repo/dai/nl/106866370; Hendrickx, Antoni P A|info:eu-repo/dai/nl/304820741

    Enterococcus faecium is a multidrug-resistant (MDR) nosocomial pathogen causing significant morbidity in debilitated patients. New antimicrobials are needed to treat antibiotic-resistant E. faecium infections in hospitalised patients. E. faecium incorporates lipoteichoic acid (LTA)

  15. Antibiotic resistance determinants of a group of multidrug-resistant Acinetobacter baumannii in China.

    Science.gov (United States)

    Xiao-Min, Xu; You-Fen, Fan; Wei-Yun, Feng; Zu-Huang, Mi; Xing-Bei, Weng

    2014-06-01

    A group of Acinetobacter baumannii confers multidrug resistance, but the molecular epidemiology and multidrug resistance mechanisms are poorly understood. Nineteen isolates were identified, and the antimicrobial susceptibility profile was determined using the disc diffusion method. Then, PCR of 78 kinds of resistance-associated genes were performed. A novel variant of blaADC gene: blaADC-67 gene (Genbank accession No. JX169789) was prevalent in all 19 isolates. Moreover, ISAba1 could also provide strong promoter to upregulate the expression of blaADC67 to confer resistance to beta-lactam. This is the first report of emergence of blaADC-67 in A. baumannii worldwide, which might confer resistance to beta-lactam.

  16. Functional study of the novel multidrug resistance gene HA117 and its comparison to multidrug resistance gene 1

    Directory of Open Access Journals (Sweden)

    Chen Tingfu

    2010-07-01

    Full Text Available Abstract Background The novel gene HA117 is a multidrug resistance (MDR gene expressed by all-trans retinoic acid-resistant HL-60 cells. In the present study, we compared the multidrug resistance of the HA117 with that of the classical multidrug resistance gene 1 (MDR1 in breast cancer cell line 4T1. Methods Transduction of the breast cancer cell line 4T1 with adenoviral vectors encoding the HA117 gene and the green fluorescence protein gene (GFP (Ad-GFP-HA117, the MDR1 and GFP (Ad-GFP-MDR1 or GFP (Ad-GFP was respectively carried out. The transduction efficiency and the multiplicity of infection (MOI were detected by fluorescence microscope and flow cytometry. The transcription of HA117 gene and MDR1 gene were detected by reverse transcription polymerase chain reaction (RT-PCR. Western blotting analysis was used to detect the expression of P-glycoprotein (P-gp but the expression of HA117 could not be analyzed as it is a novel gene and its antibody has not yet been synthesized. The drug-excretion activity of HA117 and MDR1 were determined by daunorubicin (DNR efflux assay. The drug sensitivities of 4T1/HA117 and 4T1/MDR1 to chemotherapeutic agents were detected by Methyl-Thiazolyl-Tetrazolium (MTT assay. Results The transducted efficiency of Ad-GFP-HA117 and Ad-GFP-MDR1 were 75%-80% when MOI was equal to 50. The transduction of Ad-GFP-HA117 and Ad-GFP-MDR1 could increase the expression of HA117 and MDR1. The drug resistance index to Adriamycin (ADM, vincristine (VCR, paclitaxel (Taxol and bleomycin (BLM increased to19.8050, 9.0663, 9.7245, 3.5650 respectively for 4T1/HA117 and 24.2236, 11.0480, 11.3741, 0.9630 respectively for 4T1/MDR1 as compared to the control cells. There were no significant differences in drug sensitivity between 4T1/HA117 and 4T1/MDR1 for the P-gp substrates (ADM, VCR and Taxol (P Conclusions These results confirm that HA117 is a strong MDR gene in both HL-60 and 4T1 cells. Furthermore, our results indicate that the MDR

  17. Antibiotics: Pharmacokinetics, toxicity, resistance and multidrug efflux pumps.

    Science.gov (United States)

    Yılmaz, Çiğdem; Özcengiz, Gülay

    2017-06-01

    The discovery of penicillin followed by streptomycin, tetracycline, cephalosporins and other natural, semi-synthetic and synthetic antimicrobials completely revolutionized medicine by reducing human morbidity and mortality from most of the common infections. However, shortly after they were introduced to clinical practice, the development of resistance was emerged. The decreasing interest from antibiotic industry in spite of rapid global emergence of antibiotic resistance is a tough dilemma from the pointview of public health. The efficiency of antimicrobial treatment is determined by both pharmacokinetics and pharmacodynamics. In spite of their selective toxicity, antibiotics still cause severe, life-threatening adverse reactions in host body mostly due to defective drug metabolism or excessive dosing regimen. The present article aims at updating current knowledge on pharmacokinetics/pharmacodynamics concepts and models, toxicity of antibiotics as well as antibiotic resistance mechanisms, resistome analyses and search for novel antibiotic resistance determinants with special emphasis given to the-state-of-the-art regarding multidrug efflux pumps and their additional physiological functions in stress adaptation and virulence of bacteria. All these issues are highly linked to each other and not only important for most efficient and prolonged use of current antibiotics, but also for discovery and development of new antibiotics and novel inhibitors of antibiotic resistance determinants of pathogens. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Molecular assessment of artemisinin resistance markers, polymorphisms in the k13 propeller, and a multidrug-resistance gene in the eastern and western border areas of Myanmar.

    Science.gov (United States)

    Nyunt, Myat Htut; Hlaing, Thaung; Oo, Htet Wai; Tin-Oo, Lu-Lu Kyaw; Phway, Hnin Phyu; Wang, Bo; Zaw, Ni Ni; Han, Soe Soe; Tun, Thurein; San, Kyaw Kyaw; Kyaw, Myat Phone; Han, Eun-Taek

    2015-04-15

    As K13 propeller mutations have been recently reported to serve as molecular markers, assessment of K13 propeller polymorphisms in multidrug-resistant gene in isolates from Myanmar, especially the eastern and western border areas, is crucial if we are to understand the spread of artemisinin resistance. A 3-day surveillance study was conducted in the eastern and western border areas in Myanmar, and K13 propeller and Plasmodium falciparum multidrug resistance-associated protein 1 (pfmrp1) mutations were analyzed. Among the 1761 suspected malaria cases screened, a total of 42 uncomplicated falciparum cases from the eastern border and 49 from the western border were subjected to 3 days of surveillance after artemether-lumefantrine treatment. No parasitemic case showing positivity on day 3 was noted from the western border, but 26.2% (11/42) of cases were positive in the eastern border. Although we found no marked difference in the prevalence of the pfmrp1 mutation in the eastern and western borders (36% vs 31%, respectively), K13 mutations were more frequent in the eastern border area (where the 3-day persistent cases were detected; 48% vs 14%). C580Y, M476I, A481V, N458Y, R539T, and R516Y accounted for 68.9% of all K13 mutations significantly associated with day 3 parasitaemia. The K13 mutations were significantly associated with day 3 parasitaemia, emphasizing the importance of K13 surveillance. The low prevalence of K13 mutations and the absence of day 3 parasitaemic cases indicate that artemisinin resistance may not have spread to the western Myanmar border region. Although analysis of multiple K13 mutations is challenging, it should be done at various sentinel sites in Myanmar. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  19. Purification of a Multidrug Resistance Transporter for Crystallization Studies

    Directory of Open Access Journals (Sweden)

    Kamela O. Alegre

    2015-03-01

    Full Text Available Crystallization of integral membrane proteins is a challenging field and much effort has been invested in optimizing the overexpression and purification steps needed to obtain milligram amounts of pure, stable, monodisperse protein sample for crystallography studies. Our current work involves the structural and functional characterization of the Escherichia coli multidrug resistance transporter MdtM, a member of the major facilitator superfamily (MFS. Here we present a protocol for isolation of MdtM to increase yields of recombinant protein to the milligram quantities necessary for pursuit of structural studies using X-ray crystallography. Purification of MdtM was enhanced by introduction of an elongated His-tag, followed by identification and subsequent removal of chaperonin contamination. For crystallization trials of MdtM, detergent screening using size exclusion chromatography determined that decylmaltoside (DM was the shortest-chain detergent that maintained the protein in a stable, monodispersed state. Crystallization trials of MdtM performed using the hanging-drop diffusion method with commercially available crystallization screens yielded 3D protein crystals under several different conditions. We contend that the purification protocol described here may be employed for production of high-quality protein of other multidrug efflux members of the MFS, a ubiquitous, physiologically and clinically important class of membrane transporters.

  20. Polymorphisms of the oxidant enzymes glutathione S-transferase and glutathione reductase and their association with resistance ofPlasmodium falciparum isolates to antimalarial drugs

    Institute of Scientific and Technical Information of China (English)

    Raewadee Wisedpanichkij; Wanna Chaicharoenkul; Poonuch Mahamad; Prapichaya Prompradit; Kesara Na-Bangchang

    2010-01-01

    Objective:To investigate the association between amplification of the two regulatory genes controlling glutathione(GSH)levels, glutathione reductase(PfGR)and glutathione S-transferase (PfGST) genes and sensitivity ofPlasmodium falciparum (P. falciparum)isolates collected from different malaria endemic areas of Thailand to standard antimalarial drugs.Methods: A total of70P. falciparum isolates were collected from endemic areas of multi-drug resistance (Tak, Chantaburi and Ranong Provinces) during the year2008-2009. The in vitro assessment of antimalarial activity ofP. falciparumclones (K1- and Dd2 chloroquine resistant and3D7-chloroquine sensitive) and isolates to chloroquine, quinine, mefloquine and arteusnate was performed based onSYBR Green modified assay.Results:68 (97.14%), 11 (15.71%) and28 (40%) isolates respectively were classified as chloroquine-, quinine- and mefloquine-resistant isolates. With this limited number ofP. falciparum isolates included in the analysis, no significant association between amplification ofPfGST gene and sensitivity of the parasite to chloroquine, quinine, mefloquine and quinine was found. Based onPCR analysis,Dd2, K1 and3D7clones all contained only one copy of thePfGST gene. All isolates (70) also carried only one copy number of PfGST gene. There appears to be an association between amplification ofPfGR gene and chloroquine resistance. The3D7and Dd2 clones were found to carry only onePfGR gene copy, whereas the K1 clone carried two gene copies.Conclusions: Chloroquine resistance is likely to be a consequence of multi-factors and enzymes in theGSH system may be partly involved. Larger number of parasite isolates are required to increase power of the hypothesis testing in order to confirm the involvement of both genes as well as other genes implicated in glutathione metabolism in conferring chloroquine resistance.

  1. Establishment of a Multidrug Resistance Cell Line A549/cDDP of Human Lung Adenocarcinoma and Expression Analysis of Multidrug Resistance-Associated Genes

    Directory of Open Access Journals (Sweden)

    Yongcheng PAN

    2009-03-01

    Full Text Available Background and objective It has been proven that chemotherapy failure caused by multidrug resistance in lung tumor cells is the main cause for the patient's survival rate. The aim of this study is to establish a multidrug resistance cell line of human lung adenocarcinoma and study the mechanism of multidrug resistance. Methods Human lung adenocarcinoma cell line A549 was induced to multidrug resistance cell line A549/cDDP by intermittentadministration of high dose of cisplatin (cDDP. The multidrug resistance was detected by using MTT assay. The levels of expression of MDR-1 gene-coded P-glycoportein (P-gp, multidrug resistance-associated protein (MRP, and GSH/GST were examined by flow cytometric assay. The levels of expression of MDR and MRP gene were also detected by RTPCR in both A549/cDDP and A549 cell lines. Results A549/cDDP was resistant to many anti-tumor agents. The IC50 of A549/cDDP was 16.87 times higher than that of A549. The expressions of P-gp and MRP in A549/cDDP were increased significantly to (70.5±4.9% and (29.4±2.9%, respectively, vs (42.4±5.6% and (21.4±3.5% in A549. There was no difference of the GSH/GST expression between A549/cDDPand A549 cells. Conclusion A549/cDDP is a model with multidrug resistance and the levels of MDR and MRP mRNA expressions are remarkably higher in A549/cDDP than those in A549.

  2. Resistant plasmid profile analysis of multidrug resistant Escherichia ...

    African Journals Online (AJOL)

    Objectives: This study was carried out to determine the resistant plasmids of ... resistance pattern of micro-organisms to common an- tibiotics1 ... ment has necessitated the need for regular monitoring of antibiotics susceptibility trends to provide the basis for developing rational prescription programs, mak- ..... Paediatrics and.

  3. Susceptibility of multidrug resistant clinical pathogens to a chlorhexidine formulation.

    Science.gov (United States)

    Günther, F; Kaiser, S J; Fries, T; Frank, U; Mutters, N T

    2015-01-01

    Multidrug resistant pathogens are a widespread problem in the hospital setting especially on intensive care units (ICU). This study evaluated the susceptibility of clinical isolates of gramnegative extensively drug resistant organisms (XDR), methicillinresistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE) to a proprietary chlorhexidine digluconate (CHG) formulation used in one brand of CHG-impregnated cloths. Ten isolates each of XDR Pseudomonas aeruginosa, XDR Acinetobacter baumannii, XDR Klebsiella pneumoniae, XDR Escherichia coli, MRSA, and vancomycin-resistant Enterococcus faecium from our hospital were tested. All isolates were susceptible to the proprietary CHG formulation (0.5%, 1%, 2%), with 99% to 100% suppression of growth at the earliest time point in time kill assays (1 minute for gram-positive and 15 seconds for gram-negative organisms). Minimum inhibitory concentrations ranged from 1 : 4096 to 1 : 65536 for MRSA, 1 : 1024 to 1 : 2048 for VRE, 1 : 2048 to 1 : 4096 for XDR E. coli, 1 : 512 to 1 : 2048 for XDR A. baumannii, 1 : 512 to 1 : 1024 for XDR P. aeruginosa, and 1 : 512 to 1 : 1024 for XDR K. pneumoniae. Cloths impregnated with this CHG formulation provide effective protection against colonization and infection by many pathogens. This study provides in vitro evidence that the proprietary CHG formulation used in one brand of CHG-impregnated cloths is effective against XDR gram-negative organisms, MRSA, and VRE.

  4. Imaging multidrug resistance with 4-[18F]fluoropaclitaxel.

    Science.gov (United States)

    Kurdziel, Karen A; Kalen, Joseph D; Hirsch, Jerry I; Wilson, John D; Agarwal, Rakesh; Barrett, Daniel; Bear, Harry D; McCumiskey, James F

    2007-10-01

    Multidrug resistance (MDR) is a cause of treatment failure in many cancer patients. MDR refers to a phenotype whereby a tumor is resistant to a large number of natural chemotherapeutic drugs. Having prior knowledge of the presence of such resistance would decrease morbidity from unsuccessful therapy and allow for the selection of individuals who may benefit from the coadministration of MDR-inhibiting drugs. The Tc-99m-labeled single-photon-emitting radiotracers sestamibi and tetrofosmin have shown some predictive value. However, positron-emitting radiotracers, which allow for dynamic quantitative imaging, hold promise for a more accurate and specific identification of MDRtumors.MDR-expressing tumors are resistant to paclitaxel, which is commonly used as a chemotherapeutic agent. 4-[18F]Fluoropaclitaxel (FPAC) is a PET-radiolabeled analogue of paclitaxel. Preclinical studies have shown the uptake of FPAC to be inversely proportional to tumor MDR expression. FPAC PET imaging in normal volunteers shows biodistribution to be similar to that in nonhuman primates. Imaging in a breast cancer patient showed FPAC localization in a primary tumor that responded to chemotherapy, while failure to localize in mediastinal disease corresponded with only partial response.FPAC PET imaging shows promise for the noninvasive pretreatment identification of MDR-expressing tumors. While much additional work is needed, this work represents a step toward image-guided personalized medicine.

  5. Imaging multidrug resistance with 4-[{sup 18}F]fluoropaclitaxel

    Energy Technology Data Exchange (ETDEWEB)

    Kurdziel, Karen A. [Department of Radiology, Virginia Commonwealth University, Richmond, VA (United States)], E-mail: kurdziel@vcu.edu; Kalen, Joseph D. [School of Medicine, Virginia Commonwealth University, Richmond, VA (United States)], E-mail: jdkalen@vcu.edu; Hirsch, Jerry I. [School of Medicine, Virginia Commonwealth University, Richmond, VA (United States)], E-mail: jihirsch@vcu.edu; Wilson, John D. [School of Medicine, Virginia Commonwealth University, Richmond, VA (United States)], E-mail: wilsonjd@hsc.vcu.edu; Agarwal, Rakesh [Surgical Oncology, Virginia Commonwealth University, Richmond, VA (United States)], E-mail: dbarrett@vcu.edu; Barrett, Daniel [School of Medicine, Virginia Commonwealth University, Richmond, VA (United States)], E-mail: ragarwal@vcu.edu; Bear, Harry D. [Surgical Oncology, Virginia Commonwealth University, Richmond, VA (United States)], E-mail: 9jmccumi@mail2.vcu.edu; McCumiskey, James F. [Department of Radiology, Virginia Commonwealth University, Richmond, VA (United States)], E-mail: hbear@hsc.vcu.edu

    2007-10-15

    Multidrug resistance (MDR) is a cause of treatment failure in many cancer patients. MDR refers to a phenotype whereby a tumor is resistant to a large number of natural chemotherapeutic drugs. Having prior knowledge of the presence of such resistance would decrease morbidity from unsuccessful therapy and allow for the selection of individuals who may benefit from the coadministration of MDR-inhibiting drugs. The Tc-99m-labeled single-photon-emitting radiotracers sestamibi and tetrofosmin have shown some predictive value. However, positron-emitting radiotracers, which allow for dynamic quantitative imaging, hold promise for a more accurate and specific identification of MDRtumors.MDR-expressing tumors are resistant to paclitaxel, which is commonly used as a chemotherapeutic agent. 4-[{sup 18}F]Fluoropaclitaxel (FPAC) is a PET-radiolabeled analogue of paclitaxel. Preclinical studies have shown the uptake of FPAC to be inversely proportional to tumor MDR expression. FPAC PET imaging in normal volunteers shows biodistribution to be similar to that in nonhuman primates. Imaging in a breast cancer patient showed FPAC localization in a primary tumor that responded to chemotherapy, while failure to localize in mediastinal disease corresponded with only partial response.FPAC PET imaging shows promise for the noninvasive pretreatment identification of MDR-expressing tumors. While much additional work is needed, this work represents a step toward image-guided personalized medicine.

  6. Characterization of multidrug-resistant Escherichia coli by antimicrobial resistance profiles, plasmid replicon typing, and pulsed-field gel electrophoresis

    Science.gov (United States)

    Aim: Plasmid characterization has particular clinical importance because genes encoding significant traits including antimicrobial resistance are frequently carried on plasmids. The objective of this study was to examine the distribution of multidrug resistance (MDR) in Escherichia coli in relation ...

  7. Bacteriophages: biosensing tools for multi-drug resistant pathogens.

    Science.gov (United States)

    Tawil, N; Sacher, E; Mandeville, R; Meunier, M

    2014-03-21

    Pathogen detection is of utmost importance in many sectors, such as in the food industry, environmental quality control, clinical diagnostics, bio-defence and counter-terrorism. Failure to appropriately, and specifically, detect pathogenic bacteria can lead to serious consequences, and may ultimately be lethal. Public safety, new legislation, recent outbreaks in food contamination, and the ever-increasing prevalence of multidrug-resistant infections have fostered a worldwide research effort targeting novel biosensing strategies. This review concerns phage-based analytical and biosensing methods targeted towards theranostic applications. We discuss and review phage-based assays, notably phage amplification, reporter phage, phage lysis, and bioluminescence assays for the detection of bacterial species, as well as phage-based biosensors, including optical (comprising SPR sensors and fiber optic assays), electrochemical (comprising amperometric, potentiometric, and impedimetric sensors), acoustic wave and magnetoelastic sensors.

  8. Preparation of silver nanoparticles fabrics against multidrug-resistant bacteria

    Science.gov (United States)

    Hanh, Truong Thi; Thu, Nguyen Thi; Hien, Nguyen Quoc; An, Pham Ngoc; Loan, Truong Thi Kieu; Hoa, Phan Thi

    2016-04-01

    The silver nanoparticles (AgNPs)/peco fabrics were prepared by immobilization of AgNPs on fabrics in which AgNPs were synthesized by γ-irradiation of the 10 mM AgNO3 chitosan solution at the dose of 17.6 kGy. The AgNPs size has been estimated to be about 11 nm from TEM image. The AgNPs content onto peco fabrics was of 143±6 mg/kg at the initial AgNPs concentration of 100 ppm. The AgNPs colloidal solution was characterized by UV-vis spectroscopy and TEM image. The antibacterial activity of AgNPs/peco fabrics after 60 washings against Staphylococcus aureus and Klebsiella pneumoniae was found to be over 99%. Effects of AgNPs fabics on multidrug-resistant pathogens from the clinical specimens were also tested.

  9. Detection of multidrug resistance using molecular nuclear technique

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jae Tae; Ahn, Byeong Cheol [School of Medicine, Kyungpook National Univ., Daegu (Korea, Republic of)

    2004-04-01

    Although the outcome of cancer patients after cytotoxic chemotherapy is related diverse mechanisms, multidrug resistance (MDR) for chemotherapeutic drugs due to cellular P-glycoprotein (Pgp) or multidrug-resistance associated protein (MRP) is most important factor in the chemotherapy failure to cancer. A large number of pharmacologic compounds, including verapamil, quinidine, tamoxifen, cyclosporin A and quinolone derivatives have been reported to overcome MDR. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are available for the detection of Pgp and MRP-mediated transporter. {sup 99}m-Tc-MIBI and other {sup 99}m-Tc-radiopharmaceuticals are substrates for Pgp and MRP, and have been used in clinical studies for tumor imaging, and to visualize blockade of Pgp-mediated transport after modulation of Pgp pump. Colchicine, verapamil and daunorubicin labeled with {sup 11}C have been evaluated for the quantification of Pgp-mediated transport with PET in vivo and reported to be feasible substrates with which to image Pgp function in tumors. Leukotrienes are specific substrates for MRP and N-({sup 11}C)acetyl-leukotriene E4 provides an opportunity to study MRP function non-invasively in vivo. SPECT and PET pharmaceuticals have successfully used to evaluate pharmacologic effects of MDR modulators. Imaging of MDR and reversal of MDR with bioluminescence in a living animal is also evaluated for future clinical trial. We have described recent advances in molecular imaging of MDR and reviewed recent publications regarding feasibility of SPECT and PET imaging to study the functionality of MDR transporters in vivo.

  10. Balancing drug resistance and growth rates via compensatory mutations in the Plasmodium falciparum chloroquine resistance transporter.

    Science.gov (United States)

    Petersen, Ines; Gabryszewski, Stanislaw J; Johnston, Geoffrey L; Dhingra, Satish K; Ecker, Andrea; Lewis, Rebecca E; de Almeida, Mariana Justino; Straimer, Judith; Henrich, Philipp P; Palatulan, Eugene; Johnson, David J; Coburn-Flynn, Olivia; Sanchez, Cecilia; Lehane, Adele M; Lanzer, Michael; Fidock, David A

    2015-07-01

    The widespread use of chloroquine to treat Plasmodium falciparum infections has resulted in the selection and dissemination of variant haplotypes of the primary resistance determinant PfCRT. These haplotypes have encountered drug pressure and within-host competition with wild-type drug-sensitive parasites. To examine these selective forces in vitro, we genetically engineered P. falciparum to express geographically diverse PfCRT haplotypes. Variant alleles from the Philippines (PH1 and PH2, which differ solely by the C72S mutation) both conferred a moderate gain of chloroquine resistance and a reduction in growth rates in vitro. Of the two, PH2 showed higher IC50 values, contrasting with reduced growth. Furthermore, a highly mutated pfcrt allele from Cambodia (Cam734) conferred moderate chloroquine resistance and enhanced growth rates, when tested against wild-type pfcrt in co-culture competition assays. These three alleles mediated cross-resistance to amodiaquine, an antimalarial drug widely used in Africa. Each allele, along with the globally prevalent Dd2 and 7G8 alleles, rendered parasites more susceptible to lumefantrine, the partner drug used in the leading first-line artemisinin-based combination therapy. These data reveal ongoing region-specific evolution of PfCRT that impacts drug susceptibility and relative fitness in settings of mixed infections, and raise important considerations about optimal agents to treat chloroquine-resistant malaria.

  11. Multidrug resistance and ESBL-producing Salmonella spp. isolated from broiler processing plants.

    Science.gov (United States)

    Ziech, Rosangela Estel; Lampugnani, Camila; Perin, Ana Paula; Sereno, Mallu Jagnow; Sfaciotte, Ricardo Antônio Pilegi; Viana, Cibeli; Soares, Vanessa Mendonça; Pinto, José Paes de Almeida Nogueira; Bersot, Luciano dos Santos

    2016-01-01

    The aim of this study was to investigate the occurrence of multidrug-resistant, extended spectrum beta-lactamase (ESBL) producing Salmonella spp. isolated from conveyor belts of broiler cutting rooms in Brazilian broiler processing plants. Ninety-eight strains of Salmonella spp. were analyzed. Multidrug resistance was determined by the disk diffusion test and the susceptibility of the isolated bacteria was evaluated against 18 antimicrobials from seven different classes. The double disk diffusion test was used to evaluate ESBL production. Of the 98 strains tested, 84 were multidrug resistant. The highest rates of resistance were against nalidixic acid (95%), tetracycline (91%), and the beta-lactams: ampicillin and cefachlor (45%), followed by streptomycin and gentamicin with 19% and 15% of strain resistance, respectively. By contrast, 97% of the strains were sensitive to chloramphenicol. 45% of the strains were positive for the presence of ESBL activity. In this study, high rates of multidrug resistance and ESBL production were observed in Salmonella spp.

  12. Nanodrugs: optimism for emerging trend of multidrug resistance

    Directory of Open Access Journals (Sweden)

    Khan AU

    2012-08-01

    Full Text Available Asad U KhanMedical Microbiology and Molecular Biology Laboratory, Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, IndiaThis is with reference to an article published recently in your journal regarding the antibiotic activity of chitosan-coated silver nanoparticles.1 This is an inspiring move towards control of infection caused by multidrug-resistant bacteria which has become a serious problem for clinicians and physicians worldwide.2 At the moment, carbapenems are being used as the drugs of choice to combat infections. However, the emergence of carbapenem resistance has changed current remedial approaches in the management of serious infections. One of the latest enzymes, NDM-1 (New Delhi metallo-β-lactamase-1, first identified in a Swedish patient of Indian origin in 2008,3 has been key in the development of resistance to almost all antibiotics. Infection caused by NDM-1 producers is widespread on the Indian subcontinent,4 and is now emerging in the US and other countries throughout the world.5View original paper by Jena and colleagues.

  13. [Multidrug-resistant tuberculosis: challenges of a global emergence].

    Science.gov (United States)

    Comolet, T

    2015-10-01

    Drug-resistant tuberculosis, in particular Multi-Drug Resistant (MDR-TB) is an increasing global concern and a major burden for some developing countries, especially the BRICS. It is assumed that every year roughly 350 000 new MDR-TB cases occur in the world, on average in 20.5% of TB patients that have been previously treated but also in 3.5% of persons that have never been on TB treatment before. The global distribution of cases is very heterogeneous and is now better understood thanks to a growing number of specific surveys and routine surveillance systems: incidence is much higher in southern Africa and in all countries formerly part of the USSR. Countries with weak health systems and previously inefficient TB control programs are highly vulnerable to MDR epidemics because program failures do help creating, maintaining and spreading resistances. Global response is slowly rolled out and diagnosis capacities are on the rise (mostly with genotypic methods) but adequate and successful treatment and care is still limited to a minority of global cases. From a public health perspective the MDR-TB growing epidemics will not be controlled merely by the introduction of few new antibiotics because it is also linked to patient's compliance and adequate case management supported by efficient TB program. In depth quality improvement will only be achieved after previous errors are thoroughly analyzed and boldly corrected.

  14. "Emergence of Multidrug Resistant Strains of Escherichia coli Isolated from Urinary Tract Infections"

    OpenAIRE

    R Moniri; Khorshidi, A; H Akbari

    2003-01-01

    The emergence of multidrug resistant strains of Escherichia coli has complicated treatment decision and may lead to treatment failures. From April to November 2001 we prospectively evaluated the prevalence of resistance to trimethoprim-sulfamethoxazole (SXT), gentamicin, cephalothin, ciprofloxacin, and nitrofurantoin in 220 Escherichia coli isolates from patients with urinary tract infections in kashan, Iran. To assess the current breadth of multidrug resistance among urinary isolates of E. c...

  15. Higher Desolvation Energy Reduces Molecular Recognition in Multi-Drug Resistant HIV-1 Protease

    Directory of Open Access Journals (Sweden)

    Ladislau C. Kovari

    2012-05-01

    Full Text Available Designing HIV-1 protease inhibitors that overcome drug-resistance is still a challenging task. In this study, four clinical isolates of multi-drug resistant HIV-1 proteases that exhibit resistance to all the US FDA-approved HIV-1 protease inhibitors and also reduce the substrate recognition ability were examined. A multi-drug resistant HIV-1 protease isolate, MDR 769, was co-crystallized with the p2/NC substrate and the mutated CA/p2 substrate, CA/p2 P1’F. Both substrates display different levels of molecular recognition by the wild-type and multi-drug resistant HIV-1 protease. From the crystal structures, only limited differences can be identified between the wild-type and multi-drug resistant protease. Therefore, a wild-type HIV-1 protease and four multi-drug resistant HIV-1 proteases in complex with the two peptides were modeled based on the crystal structures and examined during a 10 ns-molecular dynamics simulation. The simulation results reveal that the multi-drug resistant HIV-1 proteases require higher desolvation energy to form complexes with the peptides. This result suggests that the desolvation of the HIV-1 protease active site is an important step of protease-ligand complex formation as well as drug resistance. Therefore, desolvation energy could be considered as a parameter in the evaluation of future HIV-1 protease inhibitor candidates.

  16. Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates.

    Science.gov (United States)

    Straimer, Judith; Gnädig, Nina F; Witkowski, Benoit; Amaratunga, Chanaki; Duru, Valentine; Ramadani, Arba Pramundita; Dacheux, Mélanie; Khim, Nimol; Zhang, Lei; Lam, Stephen; Gregory, Philip D; Urnov, Fyodor D; Mercereau-Puijalon, Odile; Benoit-Vical, Françoise; Fairhurst, Rick M; Ménard, Didier; Fidock, David A

    2015-01-23

    The emergence of artemisinin resistance in Southeast Asia imperils efforts to reduce the global malaria burden. We genetically modified the Plasmodium falciparum K13 locus using zinc-finger nucleases and measured ring-stage survival rates after drug exposure in vitro; these rates correlate with parasite clearance half-lives in artemisinin-treated patients. With isolates from Cambodia, where resistance first emerged, survival rates decreased from 13 to 49% to 0.3 to 2.4% after the removal of K13 mutations. Conversely, survival rates in wild-type parasites increased from ≤0.6% to 2 to 29% after the insertion of K13 mutations. These mutations conferred elevated resistance to recent Cambodian isolates compared with that of reference lines, suggesting a contemporary contribution of additional genetic factors. Our data provide a conclusive rationale for worldwide K13-propeller sequencing to identify and eliminate artemisinin-resistant parasites.

  17. [Progress in researches on molecular markers of Plasmodium falciparum drug resistance].

    Science.gov (United States)

    Zhang, Mei-hua; Lu, Feng; Cao, Jun; Gao, Qi

    2015-06-01

    Effective chemotherapy is the mainstay of malaria control. However, it is undergoing the serious threat by resis- tance of falciparum malaria to antimalarial drugs. In recent years, with the development of molecular biology technology, molec- ular markers have been widely used to monitor antimalarial drug resistance. This paper reviews the researches on the common molecular markers related to Plasmodiumfalciparum drug resistance.

  18. Molecular characterization of multidrug-resistant Klebsiella pneumoniae isolates.

    Science.gov (United States)

    Hou, Xiang-hua; Song, Xiu-yu; Ma, Xiao-bo; Zhang, Shi-yang; Zhang, Jia-qin

    2015-01-01

    Klebsiella pneumoniae is an important cause of healthcare-associated infections worldwide. Selective pressure, the extensive use of antibiotics, and the conjugational transmission of antibiotic resistance genes across bacterial species and genera facilitate the emergence of multidrug-resistant (MDR) K. pneumoniae. Here, we examined the occurrence, phenotypes and genetic features of MDR K. pneumoniae isolated from patients in intensive care units (ICUs) at the First Affiliated Hospital of Xiamen University in Xiamen, China, from January to December 2011. Thirty-eight MDR K. pneumoniae strains were collected. These MDR K. pneumoniae isolates possessed at least seven antibiotic resistance determinants, which contribute to the high-level resistance of these bacteria to aminoglycosides, macrolides, quinolones and β-lactams. Among these isolates, 24 strains were extended-spectrum β-lactamase (ESBL) producers, 2 strains were AmpC producers, and 12 strains were both ESBL and AmpC producers. The 38 MDR isolates also contained class I (28/38) and class II integrons (10/38). All 28 class I-positive isolates contained aacC1, aacC4, orfX, orfX' and aadA1 genes. β-lactam resistance was conferred through bla SHV (22/38), bla TEM (10/38), and bla CTX-M (7/38). The highly conserved bla KPC-2 (37/38) and bla OXA-23(1/38) alleles were responsible for carbapenem resistance, and a gyrAsite mutation (27/38) and the plasmid-mediated qnrB gene (13/38) were responsible for quinolone resistance. Repetitive-sequence-based PCR (REP-PCR) fingerprinting of these MDR strains revealed the presence of five groups and sixteen patterns. The MDR strains from unrelated groups showed different drug resistance patterns; however, some homologous strains also showed different drug resistance profiles. Therefore, REP-PCR-based analyses can provide information to evaluate the epidemic status of nosocomial infection caused by MDR K. pneumoniae; however, this test lacks the power to discriminate some

  19. Molecular characterization of multidrug-resistant Klebsiella pneumoniae isolates

    Directory of Open Access Journals (Sweden)

    Xiang-hua Hou

    2015-09-01

    Full Text Available Klebsiella pneumoniae is an important cause of healthcare-associated infections worldwide. Selective pressure, the extensive use of antibiotics, and the conjugational transmission of antibiotic resistance genes across bacterial species and genera facilitate the emergence of multidrug-resistant (MDR K. pneumoniae. Here, we examined the occurrence, phenotypes and genetic features of MDR K. pneumoniae isolated from patients in intensive care units (ICUs at the First Affiliated Hospital of Xiamen University in Xiamen, China, from January to December 2011. Thirty-eight MDR K. pneumoniae strains were collected. These MDR K. pneumoniae isolates possessed at least seven antibiotic resistance determinants, which contribute to the high-level resistance of these bacteria to aminoglycosides, macrolides, quinolones and β-lactams. Among these isolates, 24 strains were extended-spectrum β-lactamase (ESBL producers, 2 strains were AmpC producers, and 12 strains were both ESBL and AmpC producers. The 38 MDR isolates also contained class I (28/38 and class II integrons (10/38. All 28 class I-positive isolates contained aacC1, aacC4, orfX, orfX’ and aadA1 genes. β-lactam resistance was conferred through blaSHV (22/38, blaTEM (10/38, and blaCTX-M (7/38. The highly conserved blaKPC-2 (37/38 and blaOXA-23(1/38 alleles were responsible for carbapenem resistance, and a gyrAsite mutation (27/38 and the plasmid-mediated qnrB gene (13/38 were responsible for quinolone resistance. Repetitive-sequence-based PCR (REP-PCR fingerprinting of these MDR strains revealed the presence of five groups and sixteen patterns. The MDR strains from unrelated groups showed different drug resistance patterns; however, some homologous strains also showed different drug resistance profiles. Therefore, REP-PCR-based analyses can provide information to evaluate the epidemic status of nosocomial infection caused by MDR K. pneumoniae; however, this test lacks the power to discriminate some

  20. Antimicrobial resistance determinant microarray for analysis of multi-drug resistant isolates

    Science.gov (United States)

    Taitt, Chris Rowe; Leski, Tomasz; Stenger, David; Vora, Gary J.; House, Brent; Nicklasson, Matilda; Pimentel, Guillermo; Zurawski, Daniel V.; Kirkup, Benjamin C.; Craft, David; Waterman, Paige E.; Lesho, Emil P.; Bangurae, Umaru; Ansumana, Rashid

    2012-06-01

    The prevalence of multidrug-resistant infections in personnel wounded in Iraq and Afghanistan has made it challenging for physicians to choose effective therapeutics in a timely fashion. To address the challenge of identifying the potential for drug resistance, we have developed the Antimicrobial Resistance Determinant Microarray (ARDM) to provide DNAbased analysis for over 250 resistance genes covering 12 classes of antibiotics. Over 70 drug-resistant bacteria from different geographic regions have been analyzed on ARDM, with significant differences in patterns of resistance identified: genes for resistance to sulfonamides, trimethoprim, chloramphenicol, rifampin, and macrolide-lincosamidesulfonamide drugs were more frequently identified in isolates from sources in Iraq/Afghanistan. Of particular concern was the presence of genes responsible for resistance to many of the last-resort antibiotics used to treat war traumaassociated infections.

  1. Assessment of Markers of Antimalarial Drug Resistance in Plasmodium falciparum Isolates from Pregnant Women in Lagos, Nigeria.

    Directory of Open Access Journals (Sweden)

    Chimere Obiora Agomo

    Full Text Available The use of antimalarial drugs for prevention and treatment is a major strategy in the prevention of malaria in pregnancy. Although sulphadoxine-pyrimethamine (SP is currently recommended for intermittent preventive treatment of malaria during pregnancy in Nigeria, previously used drugs for prophylaxis such as chloroquine (CQ and pyrimethamine are accessible as they are purchased over the counter. This study describes the markers of absence or presence of resistance to quinoline (Pfcrt and Pfmdr 1 and type 1 antifolate antimalarial medicines (Pfdhfr.Plasmodium falciparum-positive dried blood spots from pregnant women attending antenatal clinics for the first time during current pregnancy were investigated for the presence of mutations at codons 72-76 of Plasmodium falciparum chloroquine resistance transporter (Pfcrt gene by real time polymerase chain reaction (PCR using haplotype-specific probes. PCR followed by sequence analysis was used to identify mutations at codons 86, 184, 1034, 1042 and 1246 of P. falciparum multi-drug resistance-1 (Pfmdr1 gene; and codons 16, 50, 51, 59, 108, 140 and 164 of Pfdhfr gene.Two haplotypes of Pfcrt (n = 54 were observed: CVMNK 13(24.2% and CVIET 41 (75.9% of the samples. The SVMNT haplotype was absent in this population. The Pfmdr1 (n = 28 haplotypes were NYSND 15(53.6%, YYSND 5(17.9%, NFSND 6(21.4% and YFSND 2(7.1%. The Pfdhfr (n = 15 were ACNCSVI 4(26.7%, and ACICNSVI 1(6.7% and ACIRNVI 10 (66.7%. The rate of occurrence of Pfcrt 76T, Pfdhfr108N, Pfmdr186Y and 184F were 75.9%, 73.3%, 25% and 28.1% respectively. The Pfmdr1 86Y was associated with low parasitaemia (median = 71 parasites/μl, P = 0.024 while Pfcrt 76T was associated with young maternal age (mean 24.1 ± 4.5 years; P = 0.006. The median parasitaemia were similar (P>0.05 in wild and mutant strains of Pfcrt 76, Pfmdr1 184 and Pfdhfr 108. There was no association between gravidity or gestational age of the women and presence of mutations in the Pfcrt

  2. What's new in multidrug-resistant pathogens in the ICU?

    Science.gov (United States)

    Zilahi, Gabor; Artigas, Antonio; Martin-Loeches, Ignacio

    2016-12-01

    Over the last several decades, antibacterial drug use has become widespread with their misuse being an ever-increasing phenomenon. Consequently, antibacterial drugs have become less effective or even ineffective, resulting in a global health security emergency. The prevalence of multidrug-resistant organisms (MDROs) varies widely among regions and countries. The primary aim of antibiotic stewardship programs is to supervise the three most influential factors contributing to the development and transmission of MDROs, namely: (1) appropriate antibiotic prescribing; (2) early detection and prevention of cross-colonization of MDROs; and (3) elimination of reservoirs. In the future, it is expected that a number of countries will experience a rise in MDROs. These infections will be associated with a high consumption of healthcare resources manifested by a prolonged hospital stay and high mortality. As a counteractive strategy, minimization of broad-spectrum antibiotic use and prompt antibiotic administration will aid in reduction of antibiotic resistance. Innovative management approaches include development and implementation of rapid diagnostic tests that will help in both shortening the duration of therapy and allowing early targeted therapy. The institution of more accessible therapeutic drug monitoring will help to optimize drug administration and support a patient-specific approach. Areas where further research is required are investigation into the heterogeneity of critically ill patients and the need for new antibacterial drug development.

  3. Molecular markers associated with resistance to commonly used antimalarial drugs among Plasmodium falciparum isolates from a malaria-endemic area in Taiz governorate-Yemen during the transmission season.

    Science.gov (United States)

    Alareqi, Lina M Q; Mahdy, Mohammed A K; Lau, Yee-Ling; Fong, Mun-Yik; Abdul-Ghani, Rashad; Mahmud, Rohela

    2016-10-01

    Since 2005, artesunate (AS) plus sulfadoxine/pyrimethamine (SP) combination has been adopted as the first-line treatment for uncomplicated malaria in Yemen in response to the high level of Plasmodium falciparum resistance to chloroquine (CQ). Therefore, the aim of the present study was to determine the frequency distribution of molecular markers associated with resistance to CQ and AS plus SP combination among P. falciparum isolates from a malaria-endemic area in Taiz governorate, Yemen. Fifty P. falciparum isolates were collected during a cross-sectional study in Mawza district, Taiz, in the period from October 2013 to April 2014. The isolates were investigated for drug resistance-associated molecular markers in five genes, including P. falciparum CQ resistance transporter (pfcrt) 76T and P. falciparum multidrug resistance 1 (pfmdr1) 86Y as markers of resistance to CQ, mutations in the Kelch 13 (K13) propeller domain for resistance to AS, and P. falciparum dihydrofolate reductase (pfdhfr) and P. falciparum dihydropteroate synthase (pfdhps) genes for resistance to SP. Nested polymerase chain reaction was used to amplify target genes in DNA extracts of the isolates followed by restriction fragment length polymorphism for detecting 76T and 86Y mutations in pfcrt and pfmdr1, respectively, and by DNA sequencing for detecting mutations in K13, pfdhfr and pfdhps. All the investigated isolates from Mawza district were harboring the pfcrt 76T mutant and the pfmdr1 N86 wild-type alleles. The pfdhfr 51I/108N double mutant allele was found in 2.2% (1/45) of the isolates; however, no mutations were detected at codons 436, 437, 540, 581 and 613 of pfdhps. All P. falciparum isolates that were successfully sequenced (n=47) showed the K13 Y493, R539, I543 and C580 wild-type alleles. In conclusion, the pfcrt 76T mutant allele is fixed in the study area about six years after the official withdrawal of CQ, possibly indicating its over-the-counter availability and continued use as a

  4. Interplay Between Antibiotic Resistance and Virulence During Disease Promoted by Multidrug-Resistant Bacteria.

    Science.gov (United States)

    Geisinger, Edward; Isberg, Ralph R

    2017-02-15

    Diseases caused by antibiotic-resistant bacteria in hospitals are the outcome of complex relationships between several dynamic factors, including bacterial pathogenicity, the fitness costs of resistance in the human host, and selective forces resulting from interventions such as antibiotic therapy. The emergence and fate of mutations that drive antibiotic resistance are governed by these interactions. In this review, we will examine how different forms of antibiotic resistance modulate bacterial fitness and virulence potential, thus influencing the ability of pathogens to evolve in the context of nosocomial infections. We will focus on 3 important multidrug-resistant pathogens that are notoriously problematic in hospitals: Pseudomonas aeruginosa, Acinetobacter baumannii, and Staphylococcus aureus. An understanding of how antibiotic resistance mutations shape the pathobiology of multidrug-resistant infections has the potential to drive novel strategies that can control the development and spread of drug resistance. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, email: journals.permissions@oup.com.

  5. Risk factors for nosocomial bloodstream infection caused by multidrug resistant gram-negative bacilli in pediatrics

    Directory of Open Access Journals (Sweden)

    Mariana V. Arnoni

    2007-04-01

    Full Text Available The aim of this study was to identify the risk factors for nosocomial bloodstream infections by multidrug resistant Gram-negative bacilli. From November 2001 to December 2003, in the Pediatric Department of the Santa Casa de São Paulo, a retrospective case-control study was developed concerning patients who had nosocomial bloodstream infection caused by Gram-negative bacilli. Patients with multidrug resistant infections were designated as case patients, and control patients were those with an infection that did not meet the criteria for multidrug resistance. Previous use of central venous catheter and previous use of vancomycin plus third generation cephalosporins were associated to a higher chance of infections by multidrug resistant Gram-negative bacilli (Odds ratio - 5.8 and 5.2, respectively. Regarding sensitivity of the isolated agents, 47.8% were multidrug resistant, 54.2% were Klebsiella spp. ESBL producers and 36.4% were imipenem resistant Pseudomonas aeruginosa. The lethality rate was 36.9% in the studied cases and this rate was significantly higher in the group of patients with multidrug resistant infections (p=0.013. Risk factor identification as well as the knowledge of the susceptibility of the nosocomial infectious agents gave us the possibility to perform preventive and control strategies to reduce the costs and mortality related to these infections.

  6. Dissemination of multidrug-resistant, class 1 integron-carrying Acinetobacter baumannii isolates in Taiwan

    National Research Council Canada - National Science Library

    Huang, L.-Y; Chen, T.-L; Lu, P.-L; Tsai, C.-A; Cho, W.-L; Chang, F.-Y; Fung, C.-P; Siu, L. K

    2008-01-01

    In this study, 283 multidrug-resistant Acinetobacter baumannii (MDR-AB) bloodstream isolates were collected between 1996 and 2004, from three teaching hospitals located in different regions of Taiwan...

  7. Impact of fungal drug transporters on fungicide sensitivity, multidrug resistance and virulence

    NARCIS (Netherlands)

    Waard, de M.A.; Andrade, A.C.; Hayashi, K.; Schoonbeek, H.; Stergiopoulos, I.; Zwiers, L.H.

    2006-01-01

    Drug transporters are membrane proteins that provide protection for organisms against natural toxic products and fungicides. In plant pathogens, drug transporters function in baseline sensitivity to fungicides, multidrug resistance (MDR) and virulence on host plants. This paper describes drug transp

  8. Biofilm formation in clinical isolates of nosocomial Acinetobacter baumannii and its relationship with multidrug resistance

    Directory of Open Access Journals (Sweden)

    Ebrahim Babapour

    2016-06-01

    Conclusions: Since most of the multidrug resistant strains produce biofilm, it seems necessary to provide continuous monitoring and determination of antibiotic susceptibility of clinical A. baumannii. This would help to select the most appropriate antibiotic for treatment.

  9. Phenotypic and genotypic analysis of multidrug-resistant tuberculosis in Ethiopia.

    NARCIS (Netherlands)

    Agonafir, M.; Lemma, E.; Wolde-Meskel, D.; Goshu, S.; Santhanam, A.; Girmachew, F.; Demissie, D.; Getahun, M.; Gebeyehu, M.; Soolingen, D. van

    2010-01-01

    SETTING: National Tuberculosis Reference Laboratory, Addis Ababa, Ethiopia. OBJECTIVES: To determine the drug susceptibility pattern of Mycobacterium tuberculosis isolates and to genetically characterise multidrug-resistant tuberculosis (MDR-TB) isolates. DESIGN: A total of 107 M. tuberculosis isola

  10. Emergence and spread of a human-transmissible multidrug-resistant nontuberculous mycobacterium

    DEFF Research Database (Denmark)

    Bryant, Josephine M; Grogono, Dorothy M; Rodriguez-Rincon, Daniela

    2016-01-01

    Lung infections with Mycobacterium abscessus, a species of multidrug-resistant nontuberculous mycobacteria, are emerging as an important global threat to individuals with cystic fibrosis (CF), in whom M. abscessus accelerates inflammatory lung damage, leading to increased morbidity and mortality....

  11. Ontogeny, aging, and gender-related changes in hepatic multidrug resistant protein genes in rats.

    Science.gov (United States)

    Zhu, Qiong-Ni; Hou, Wei-Yu; Xu, Shang-Fu; Lu, Yuan-Fu; Liu, Jie

    2017-02-01

    Multidrug resistance proteins (Mrps) are efflux transporters playing important roles in endogenous substances and xenobiotics transport out of the liver. Children, elderly, gender and physio-pathological conditions could influence their expression and result in changes in drug disposition.

  12. Hospital costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition.

    Science.gov (United States)

    Morales, Eva; Cots, Francesc; Sala, Maria; Comas, Mercè; Belvis, Francesc; Riu, Marta; Salvadó, Margarita; Grau, Santiago; Horcajada, Juan P; Montero, Maria Milagro; Castells, Xavier

    2012-05-23

    We aimed to assess the hospital economic costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition. A retrospective study of all hospital admissions between January 1, 2005, and December 31, 2006 was carried out in a 420-bed, urban, tertiary-care teaching hospital in Barcelona (Spain). All patients with a first positive clinical culture for P. aeruginosa more than 48 h after admission were included. Patient and hospitalization characteristics were collected from hospital and microbiology laboratory computerized records. According to antibiotic susceptibility, isolates were classified as non-resistant, resistant and multi-drug resistant. Cost estimation was based on a full-costing cost accounting system and on the criteria of clinical Activity-Based Costing methods. Multivariate analyses were performed using generalized linear models of log-transformed costs. Cost estimations were available for 402 nosocomial incident P. aeruginosa positive cultures. Their distribution by antibiotic susceptibility pattern was 37.1% non-resistant, 29.6% resistant and 33.3% multi-drug resistant. The total mean economic cost per admission of patients with multi-drug resistant P. aeruginosa strains was higher than that for non-resistant strains (15,265 vs. 4,933 Euros). In multivariate analysis, resistant and multi-drug resistant strains were independently predictive of an increased hospital total cost in compared with non-resistant strains (the incremental increase in total hospital cost was more than 1.37-fold and 1.77-fold that for non-resistant strains, respectively). P. aeruginosa multi-drug resistance independently predicted higher hospital costs with a more than 70% increase per admission compared with non-resistant strains. Prevention of the nosocomial emergence and spread of antimicrobial resistant microorganisms is essential to limit the strong economic impact.

  13. Hospital costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition

    Directory of Open Access Journals (Sweden)

    Morales Eva

    2012-05-01

    Full Text Available Abstract Background We aimed to assess the hospital economic costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition. Methods A retrospective study of all hospital admissions between January 1, 2005, and December 31, 2006 was carried out in a 420-bed, urban, tertiary-care teaching hospital in Barcelona (Spain. All patients with a first positive clinical culture for P. aeruginosa more than 48 h after admission were included. Patient and hospitalization characteristics were collected from hospital and microbiology laboratory computerized records. According to antibiotic susceptibility, isolates were classified as non-resistant, resistant and multi-drug resistant. Cost estimation was based on a full-costing cost accounting system and on the criteria of clinical Activity-Based Costing methods. Multivariate analyses were performed using generalized linear models of log-transformed costs. Results Cost estimations were available for 402 nosocomial incident P. aeruginosa positive cultures. Their distribution by antibiotic susceptibility pattern was 37.1% non-resistant, 29.6% resistant and 33.3% multi-drug resistant. The total mean economic cost per admission of patients with multi-drug resistant P. aeruginosa strains was higher than that for non-resistant strains (15,265 vs. 4,933 Euros. In multivariate analysis, resistant and multi-drug resistant strains were independently predictive of an increased hospital total cost in compared with non-resistant strains (the incremental increase in total hospital cost was more than 1.37-fold and 1.77-fold that for non-resistant strains, respectively. Conclusions P. aeruginosa multi-drug resistance independently predicted higher hospital costs with a more than 70% increase per admission compared with non-resistant strains. Prevention of the nosocomial emergence and spread of antimicrobial resistant microorganisms is essential to limit the strong economic impact.

  14. Modulation of multidrug resistance by flavonoids. Inhibitors of glutathione conjugation and MRP-mediated transport

    OpenAIRE

    Zanden, van, J.J.

    2005-01-01

    In this thesis, the use of flavonoids for inhibition of two important players in the glutathione related biotransformation system involved in multidrug resistance was investigated using several in vitro model systems. The enzymes of interest included the phase II glutathione S-transferase enzyme GSTP1-1, able to detoxify anticancer agents through conjugation with glutathione and the two multidrug resistance proteins MRP1 and MRP2 involved in glutathione mediated cellular efflux of, amongst ot...

  15. Influence of efflux pump inhibitors on the multidrug resistance of Helicobacter pylori

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    AIM:To evaluate the effect of efflux pump inhibitors (EPIs) on multidrug resistance of Helicobacter pylori (H. pylori).METHODS: H. pylori strains were isolated and cultured on Brucella agar plates with 10% sheep's blood. The multidrug resistant (MDR) H. pylori were obtained with the inducer chloramphenicol by repeated doubling of the concentration until no colony was seen, then the susceptibilities of the MDR strains and their parents to 9 antibiotics were assessed with agar dilution tests. The present stud...

  16. Prevalence of Multidrug Resistant Mycobacterium tuberculosis by Mycobacteria growth

    Directory of Open Access Journals (Sweden)

    Livani S

    2012-01-01

    Full Text Available Background and objectives: Identification and monitoring ofmultidrugresistant Mycobacterium tuberculosis strains (MDR ishighlighted by the high risk of their spreading in different areas.Prevalence of these strains was evaluated in Golestan province innortheast of Iran.Material and Methods: Drug susceptibility testing to Isoniazid andrifampin was carried out for 148 clinical samples that had grown inMycobacteria growth indicator tube (MGIT system, according to themanufacturer's instructions (Becton-Dickinson, USA. The associationof drug resistance frequency with demographic characteristics andgrowth time were investigated. The appropriate statistical tests, X2 andstudent Ttest were performed for comparison of these variants. A pvalue>0.05 was considered significant in all cases.Results: The turnaround time required for growth of Mycobacteriumtuberculosis in MGIT system was between 2 to 55 days (mean16.3±10.4 days. Of all samples studied, 17.6% and 3.4% wereresistant to Isoniazid and rifampin, respectively, and 3.4% (5 sampleswere MDR (CI 95%; 1- 6%. The turnaround time required fordetermining MDR cases was 9.6 days. No statistically significantassociation was found between the resistance to the drugs and none ofthe factors including sex, age, type of clinical sample, and positivity ofthe smear.Conclusion: The prevalence of MDR in the studied region wasdetermined to be 3.4% which is similar to the country-wideevaluations. The turnaround time for Mycobacterium growth and antidrug susceptibility result can be shortened by MGIT method.Key words: Mycobacterium tuberculosis, Mycobacterium GrowthIndicator Tube, Multidrug Resistant

  17. [Fosfomycin--its significance for treatment of diseases due to multidrug-resistant bacteria].

    Science.gov (United States)

    Stock, Ingo

    2015-01-01

    Fosfomycin is a bactericidal phosphonic acid derivative, which engages by inhibiting pyruvyltransferase at an early stage in the peptidoglycan synthesis. It shows a broad spectrum of activity that includes many multidrug-resistant gram-negative and gram-positive bacteria. Fosfomycin is active against most strains of Pseudomonas aeruginosa and several multidrug-resistant Enterobacteriaceae, e.g., Escherichia coli strains expressing extended spectrum beta-lactamases (ESBL) and Klebsiella pneumoniae strains with decreased susceptibilities to carbapenems. Most methicillin-resistant Staphylococcus aureus (MRSA) strains as well as enterococci with and without vancomycin resistance are also sensitive to fosfomycin. During the last decade, a variety of studies showed that fosfomycin is not only suitable for treating uncomplicated urinary tract diseases, but also for the treatment of many other diseases caused by bacterial pathogens with and without multidrug resistance. However, large controlled studies demonstrating the efficacy of the drug to treat diseases caused by multidrug-resistant bacteria are still missing. Considering the low number of antibacterial agents with good activity against multidrug-resistant bacteria, fosfomycin should be evaluated as an important antibiotic for the treatment of several severe illnesses due to these pathogens. However, because some multidrug-resistant bacteria are also resistant to fosfomycin, this agent should only be applied if the pathogen is sensitive to this drug. In addition, because rapid development of resistance cannot be excluded if fosfomycin will be applied alone, this drug should only be given in combination with other effective drugs for the treatment of serious systemic diseases due to multidrug-resistant bacterial pathogens.

  18. Bedaquiline in the multidrug-resistant tuberculosis treatment: Belarus experience.

    Science.gov (United States)

    Skrahina, Alena; Hurevich, Hennadz; Falzon, Dennis; Zhilevich, Liudmila; Rusovich, Valiantsin; Dara, Masoud; Setkina, Svetlana

    2016-12-01

    Outcomes of treatment for multidrug-resistant tuberculosis (MDR-TB) remain poor worldwide. Among patients with MDR-TB in Belarus who started treatment in 2012, only 54% completed it successfully, with treatment failure reported in 22% of the patients; additionally, 11% died and 13% were lost to follow-up or remained unevaluated. In Belarus, to improve outcomes, bedaquiline was introduced in MDR-TB treatment in June 2015. The national TB program developed measures to monitor safety and effectiveness of bedaquiline-containing regimens in line with the World Health Organization recommendations. After enrollment of patients, clinical, radiological, laboratory, and microbiological data were carefully collected at start, during treatment, and at follow-up. A total of 197 patients were enrolled: male, 140 (71%); female, 57 (29%); new TB cases, 83 (42%); previously treated, 114 (58%); extensively drug-resistant-TB (XDR-TB), 128 (65%), pre-XDR-TB (fluoroquinolone resistant), 34 (17%), pre-XDR-TB (injectables resistant), 25 (13%), and other MDR-TB cases, 10 (5%). According to the intermediate analysis, 186 patients currently are continuing with the treatment, two patients died, and nine patients were lost to follow-up. Sputum culture conversion were observed in 186 patients (94%) at 6months and one (0.5%) of these 197 patients started treatment; six patients (3%) remain sputum culture positive. The safety data were as follows: 135 patients (68%) experienced metabolism and nutrition disorders (hyperuricemia being the most common), 127 patients (64%) experienced hepatobiliary disorders (hepatic functions abnormality being the most common), 93 patients (47%) experienced electrolyte disorders (hypomagnesemia being the most common), 80 patients (41%) experienced cardiac disorders (abnormal electrocardiogram and arrhythmia being the most common), 68 patients (35%) experienced gastrointestinal system disorders (nausea, vomiting, and abdominal pain being the most common disorders

  19. The emergence and outbreak of multidrug-resistant typhoid fever in China.

    Science.gov (United States)

    Yan, Meiying; Li, Xinlan; Liao, Qiaohong; Li, Fang; Zhang, Jing; Kan, Biao

    2016-06-22

    Typhoid fever remains a severe public health problem in developing countries. The emergence of resistant typhoid, particularly multidrug-resistant typhoid infections, highlights the necessity of monitoring the resistance characteristics of this invasive pathogen. In this study, we report a typhoid fever outbreak caused by multidrug-resistant Salmonella enterica serovar Typhi strains with an ACSSxtT pattern. Resistance genes conferring these phenotypes were harbored by a large conjugative plasmid, which increases the threat of Salmonella Typhi and thus requires close surveillance for dissemination of strains containing such genes.

  20. Molecular surveillance of drug resistance through imported isolates of Plasmodium falciparum in Europe

    DEFF Research Database (Denmark)

    Jelinek, Tomas; Peyerl-Hoffmann, Gabriele; Mühlberger, Nikolai;

    2002-01-01

    BACKGROUND: Results from numerous studies point convincingly to correlations between mutations at selected genes and phenotypic resistance to antimalarials in Plasmodium falciparum isolates. In order to move molecular assays for point mutations on resistance-related genes into the realm of applied...... tools for surveillance, we investigated a selection of P. falciparum isolates that were imported during the year 2001 into Europe to study the prevalence of resistance-associated point mutations at relevant codons. In particular, we tested for parasites which were developing resistance to antifolates...... and chloroquine. The screening results were used to map the prevalence of mutations and, thus, levels of potential drug resistance in endemic areas world-wide. RESULTS: 337 isolates have been tested so far. Prevalence of mutations that are associated with resistance to chloroquine on the pfcrt and pfmdr genes...

  1. Tetracyclines for multidrug-resistant Acinetobacter baumannii infections.

    Science.gov (United States)

    Falagas, Matthew E; Vardakas, Konstantinos Z; Kapaskelis, Anastasios; Triarides, Nikolaos A; Roussos, Nikolaos S

    2015-05-01

    Multidrug-resistant (MDR) Acinetobacter baumannii infections have emerged as a serious threat worldwide. As novel agents have yet to be developed, understanding the effectiveness and safety of older antibiotics has become a priority. The purpose of this systematic review was to summarise the available clinical evidence on the use of tetracyclines for the treatment of A. baumannii infections. Ten retrospective studies regarding doxycycline and minocycline for the treatment of 185 A. baumannii infections (of which 65.4% were respiratory infections and 13% were bloodstream infections) in 156 patients were available. In most cases (86.4%), tetracyclines were administered in combination with another agent. The usual dosage of doxycycline or minocycline was 100mg intravenous or per os twice daily (usually with a 200mg loading dose for minocycline). Clinical success was achieved in 120 (76.9%) of 156 patients; in 87 (71.9%) of 121 respiratory infections and in 21 (87.5%) of 24 bloodstream infections. Twenty-two deaths occurred in 100 recorded cases. Microbiological eradication was attained in 72 (71.3%) of 101 available cases and documented microbiological eradication was reached in 59 (66.3%) of 89 available cases. Adverse events were noted in only 1 of 88 cases. Overall, although tetracycline-containing regimens showed encouraging results, more data from larger comparative trials are required to establish a role for these antibiotics in the treatment of MDR A. baumannii infections.

  2. Marine Natural Products as Models to Circumvent Multidrug Resistance.

    Science.gov (United States)

    Long, Solida; Sousa, Emília; Kijjoa, Anake; Pinto, Madalena M M

    2016-07-08

    Multidrug resistance (MDR) to anticancer drugs is a serious health problem that in many cases leads to cancer treatment failure. The ATP binding cassette (ABC) transporter P-glycoprotein (P-gp), which leads to premature efflux of drugs from cancer cells, is often responsible for MDR. On the other hand, a strategy to search for modulators from natural products to overcome MDR had been in place during the last decades. However, Nature limits the amount of some natural products, which has led to the development of synthetic strategies to increase their availability. This review summarizes the research findings on marine natural products and derivatives, mainly alkaloids, polyoxygenated sterols, polyketides, terpenoids, diketopiperazines, and peptides, with P-gp inhibitory activity highlighting the established structure-activity relationships. The synthetic pathways for the total synthesis of the most promising members and analogs are also presented. It is expected that the data gathered during the last decades concerning their synthesis and MDR-inhibiting activities will help medicinal chemists develop potential drug candidates using marine natural products as models which can deliver new ABC transporter inhibitor scaffolds.

  3. Intracellular pH and the Control of Multidrug Resistance

    Science.gov (United States)

    Simon, Sanford; Roy, Deborshi; Schindler, Melvin

    1994-02-01

    Many anticancer drugs are classified as either weak bases or molecules whose binding to cellular structures is pH dependent. Accumulation of these drugs within tumor cells should be affected by transmembrane pH gradients. Indeed, development of multidrug resistance (MDR) in tumor cells has been correlated with an alkaline shift of cytosolic pH. To examine the role of pH in drug partitioning, the distribution of two drugs, doxorubicin and daunomycin, was monitored in fibroblasts and myeloma cells. In both cell types the drugs rapidly accumulated within the cells. The highest concentrations were measured in the most acidic compartments-e.g., lysosomes. Modifying the cellular pH in drug-sensitive cells to mimic reported shifts in MDR caused an immediate change in the cellular drug concentration. Drug accumulation was enhanced by acidic shifts and reversed by alkaline shifts. All of these effects were rapid and reversible. These results demonstrate that the alkaline shift observed in MDR is sufficient to prevent the accumulation of chemotherapeutic drugs independent of active drug efflux.

  4. Multidrug resistant citrobacter: an unusual cause of liver abscess.

    Science.gov (United States)

    Kumar, Prabhat; Ghosh, Soumik; Rath, Deepak; Gadpayle, A K

    2013-04-22

    Liver abscesses are infectious, space occupying lesions in the liver, the two most common abscesses being pyogenic and amoebic. A pyogenic liver abscess (PLA) is a rare condition with a reported incidence of 20 per 100 000 hospital admissions in the western population. The right lobe of the liver is the most common site in both types of liver abscess. Clinical presentation is elusive with complaints of fever, right upper quadrant pain in the abdomen and hepatomegaly with or without jaundice. The aetiology of PLA has changed in the past few decades and may be of biliary, portal, arterial or traumatic origin, but many cases are still cryptogenic. The most common organisms causing PLA are Gram-negative aerobes, especially Escherichia coli and Klebsiella pneumoniae. Studies have shown a high degree of antimicrobial susceptibility of isolated organism resulting in an overall lower mortality in PLA. Here, we present a case of PLA caused by multidrug-resistant Citrobacter freundii, which is an unusual organism to be isolated.

  5. Dominance of multidrug resistant CC271 clones in macrolide-resistant streptococcus pneumoniae in Arizona

    Directory of Open Access Journals (Sweden)

    Bowers Jolene R

    2012-01-01

    Full Text Available Abstract Background Rates of resistance to macrolide antibiotics in Streptococcus pneumoniae are rising around the world due to the spread of mobile genetic elements harboring mef(E and erm(B genes and post-vaccine clonal expansion of strains that carry them. Results Characterization of 592 clinical isolates collected in Arizona over a 10 year period shows 23.6% are macrolide resistant. The largest portion of the macrolide-resistant population, 52%, is dual mef(E/erm(B-positive. All dual-positive isolates are multidrug-resistant clonal lineages of Taiwan19F-14, mostly multilocus sequence type 320, carrying the recently described transposon Tn2010. The remainder of the macrolide resistant S. pneumoniae collection includes 31% mef(E-positive, and 9% erm(B-positive strains. Conclusions The dual-positive, multidrug-resistant S. pneumoniae clones have likely expanded by switching to non-vaccine serotypes after the heptavalent pneumococcal conjugate vaccine release, and their success limits therapy options. This upsurge could have a considerable clinical impact in Arizona.

  6. [Significance of efflux pumps in multidrug resistance of Gram-negative bacteria].

    Science.gov (United States)

    Wiercińska, Olga; Chojecka, Agnieszka; Kanclerski, Krzysztof; Rőhm-Rodowald, Ewa; Jakimiak, Bożenna

    2015-01-01

    The phenomenon of multidrug. resistance of bacteria is a serious problem of modern medicine. This resistance largely is a consequence of abuse and improper use of antibacterial substances, especially antibiotics and chemotherapeutics in hospital settings. Multidrug resistance is caused by a number of interacting mechanisms of resistance. Recent studies have indicated that efflux pumps and systems of efflux pumps are an important determinant of this phenomenon. Contribute to this particular RND efflux systems of Gram-negative bacteria, which possess a wide range of substrates such as antibiotics, dyes, detergents, toxins and active substances of disinfectants and antiseptics. These transporters are usually encoded on bacterial chromosomes. Genes encoding efflux pumps' proteins may also be carried on plasmids and other mobile genetic elements. Such pumps are usually specific to a small group of substrates, but as an additional mechanism of resistance may contribute to the multidrug resistance.

  7. Diverse and abundant multi-drug resistant E. coli in Matang mangrove estuaries, Malaysia.

    Science.gov (United States)

    Ghaderpour, Aziz; Ho, Wing Sze; Chew, Li-Lee; Bong, Chui Wei; Chong, Ving Ching; Thong, Kwai-Lin; Chai, Lay Ching

    2015-01-01

    E.coli, an important vector distributing antimicrobial resistance in the environment, was found to be multi-drug resistant, abundant, and genetically diverse in the Matang mangrove estuaries, Malaysia. One-third (34%) of the estuarine E. coli was multi-drug resistant. The highest antibiotic resistance prevalence was observed for aminoglycosides (83%) and beta-lactams (37%). Phylogenetic groups A and B1, being the most predominant E. coli, demonstrated the highest antibiotic resistant level and prevalence of integrons (integron I, 21%; integron II, 3%). Detection of phylogenetic group B23 downstream of fishing villages indicates human fecal contamination as a source of E. coli pollution. Enteroaggregative E. coli (1%) were also detected immediately downstream of the fishing village. The results indicated multi-drug resistance among E. coli circulating in Matang estuaries, which could be reflective of anthropogenic activities and aggravated by bacterial and antibiotic discharges from village lack of a sewerage system, aquaculture farms and upstream animal husbandry.

  8. In vitro evaluation of verapamil and other modulating agents in Brazilian chloroquine-resistant Plasmodium falciparum isolates Avaliação in vitro do verapamil e de outros agentes moduladores em isolados de Plasmodium falciparum resistentes à cloroquina

    Directory of Open Access Journals (Sweden)

    Carla M.S. Menezes

    2003-01-01

    Full Text Available Verapamil, was assayed to record its modulating effect upon Brazilian Plasmodium falciparum isolates resistant to chloroquine. Other cardiovascular drugs known to be modulating agents in resistant malaria and/or multidrug-resistant neoplasias, including nifedipine, nitrendipine, diltiazem and propranolol, were also evaluated. Concentrations similar to those for cardiovascular therapy were used in the in vitro microtechnique for antimalarial drug susceptibility. Intrinsic antiplasmodial activity was observed from the lowest concentrations without a significant modulating action. Other reported modulating agents, such as the antipsychotic drug trifluoperazine and the antidepressants desipramine and imipramine, demonstrated similar responses under the same experimental conditions. Results suggest a much higher susceptibility of Brazilian strains, as well as an indifferent behaviour in relation to modulating agents.Verapamil foi ensaiado quanto ao efeito modulador em isolados brasileiros de Plasmodium falciparum resistentes à cloroquina. Outros agentes cardiovasculares, considerados como moduladores da resistência em malária e/ou em neoplasias multiresistentes a fármacos, como nifedipino, nitrendipino, diltiazem e propranolol foram ensaiados quanto ao mesmo efeito. Concentrações semelhantes às da terapia cardiovascular foram empregadas no ensaio de microtécnica de sensibilidade para fármacos antimaláricos. Atividade antiplasmódica intrínsica foi observada desde as menores concentrações, sem, entretanto, ocorrência de modulação significativa da resistência. Sob as mesmas condições experimentais, respostas semelhantes foram observadas para outros agentes moduladores conhecidos como o antipsicótico trifluoperazina e os antidepressivos desipramina e imipramina. Em conjunto, estes resultados sugerem alta sensibilidade e comportamento indiferente de cepas brasileiras ao efeito de agentes moduladores da resistência.

  9. Emergence of fluoroquinolones-resistant strains of Salmonella typhi: Watch on multidrug-resistant isolates

    Directory of Open Access Journals (Sweden)

    Subhash C Arya

    2010-05-01

    Full Text Available Subhash C Arya, Nirmala Agarwal, Shekhar Agarwal, Dolly WadhwaSant Parmanand Hospital, Delhi, IndiaEmergence of multidrug-resistant Salmonella typhi has been responsible for clinical challenges for clinicians. Recently, frequent isolation and dissemination of fluoroquinolones-resistant strains of S. enterica in Surabaya, Indonesia was in the news. Subsequently, Yangai and colleagues1 recommended regular communications between laboratory professionals and clinicians. Collaboration between laboratory personnel and clinicians would be essential to offer a rational empiric antibiotic recipe while awaiting antibiotic susceptibility test results (AST for any patient.

  10. Modulation of breast cancer resistance protein mediated atypical multidrug resistance using RNA interference delivered by adenovirus

    Institute of Scientific and Technical Information of China (English)

    LI Wen-tong; ZHOU Geng-yin; WANG Chun-ling; GUO Cheng-hao; SONG Xian-rang; CHI Wei-ling

    2005-01-01

    @@ Clinical multidrug resistance (MDR) of malignancies to many antineoplastic agents is the major obstacle in the successful treatment of cancer. The emergence of breast cancer resistance protein (BCRP), a member of the adenosine triphosphate (ATP) binding cassette (ABC) transporter family, has necessitated the development of antagonists. To overcome the BCRP-mediated atypical MDR, RNA interference (RNAi) delivered by adenovirus targeting BCRP mRNA was used to inhibit the atypical MDR expression by infecting MCF-7/MX100 cell lines with constructed RNAi adenovirus.

  11. Quinine dimers are potent inhibitors of the Plasmodium falciparum chloroquine resistance transporter and are active against quinoline-resistant P. falciparum.

    Science.gov (United States)

    Hrycyna, Christine A; Summers, Robert L; Lehane, Adele M; Pires, Marcos M; Namanja, Hilda; Bohn, Kelsey; Kuriakose, Jerrin; Ferdig, Michael; Henrich, Philipp P; Fidock, David A; Kirk, Kiaran; Chmielewski, Jean; Martin, Rowena E

    2014-03-21

    Chloroquine (CQ) resistance in the human malaria parasite Plasmodium falciparum is primarily conferred by mutations in the "chloroquine resistance transporter" (PfCRT). The resistance-conferring form of PfCRT (PfCRT(CQR)) mediates CQ resistance by effluxing the drug from the parasite's digestive vacuole, the acidic compartment in which CQ exerts its antiplasmodial effect. PfCRT(CQR) can also decrease the parasite's susceptibility to other quinoline drugs, including the current antimalarials quinine and amodiaquine. Here we describe interactions between PfCRT(CQR) and a series of dimeric quinine molecules using a Xenopus laevis oocyte system for the heterologous expression of PfCRT and using an assay that detects the drug-associated efflux of H(+) ions from the digestive vacuole in parasites that harbor different forms of PfCRT. The antiplasmodial activities of dimers 1 and 6 were also examined in vitro (against drug-sensitive and drug-resistant strains of P. falciparum) and in vivo (against drug-sensitive P. berghei). Our data reveal that the quinine dimers are the most potent inhibitors of PfCRT(CQR) reported to date. Furthermore, the lead compounds (1 and 6) were not effluxed by PfCRT(CQR) from the digestive vacuole but instead accumulated to very high levels within this organelle. Both 1 and 6 exhibited in vitro antiplasmodial activities that were inversely correlated with CQ. Moreover, the additional parasiticidal effect exerted by 1 and 6 in the drug-resistant parasites was attributable, at least in part, to their ability to inhibit PfCRT(CQR). This highlights the potential for devising new antimalarial therapies that exploit inherent weaknesses in a key resistance mechanism of P. falciparum.

  12. Plasmodium falciparum kelch 13: a potential molecular marker for tackling artemisinin-resistant malaria parasites.

    Science.gov (United States)

    Mita, Toshihiro; Tachibana, Shin-Ichiro; Hashimoto, Muneaki; Hirai, Makoto

    2016-01-01

    Although artemisinin combination therapies have been deployed as a first-line treatment for uncomplicated malaria in almost all endemic countries, artemisinin-resistant parasites have emerged and have gradually spread across the Greater Mekong subregions. There is growing concern that the resistant parasites may migrate to or emerge indigenously in sub-Saharan Africa, which might provoke a global increase in malaria-associated morbidity and mortality. Therefore, development of molecular markers that enable identification of artemisinin resistance with high sensitivity is urgently required to combat this issue. In 2014, a potential artemisinin-resistance responsible gene, Plasmodium falciparum kelch13, was discovered. Here, we review the genetic features of P. falciparum kelch13 and discuss its related resistant mechanisms and potential as a molecular marker.

  13. High level of resistance of Plasmodium falciparum to sulfadoxine-pyrimethamine in children in Tanzania

    DEFF Research Database (Denmark)

    Rønn, A M; Msangeni, H A; Mhina, J

    1996-01-01

    In many areas of tropical Africa affected by chloroquine-resistant Plasmodium falciparum, a combination of sulfadoxine and pyrimethamine (S-P) is used for alternative medication, especially in young children. In Magoda village in Muheza District, north-eastern Tanzania, 38 children 1-10 years...

  14. Independent origin of Plasmodium falciparum antifolate super-resistance, Uganda, Tanzania, and Ethiopia

    DEFF Research Database (Denmark)

    Alifrangis, Michael; Nag, Sidsel; Schousboe, Mette L

    2014-01-01

    Super-resistant Plasmodium falciparum threatens the effectiveness of sulfadoxine-pyrimethamine in intermittent preventive treatment for malaria during pregnancy. It is characterized by the A581G Pfdhps mutation on a background of the double-mutant Pfdhps and the triple-mutant Pfdhfr. Using sample...

  15. High-Dose Chloroquine for Treatment of Chloroquine-Resistant Plasmodium falciparum Malaria

    DEFF Research Database (Denmark)

    Ursing, Johan; Rombo, Lars; Bergqvist, Yngve;

    2016-01-01

    to determine the in vivo efficacy of higher chloroquine concentrations against P. falciparum with resistance-conferring genotypes. METHODS:  Standard or double-dose chloroquine was given to 892 children aged malaria during 3 clinical trials (2001-2008) with ≥35 days follow...

  16. In-vitro antimalarial activity of azithromycin against chloroquine sensitive and chloroquine resistant Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Biswas S

    2001-10-01

    Full Text Available BAKGROUND: The spread of drug resistance in Plasmodium falciparum has made the situation essential to look into new effective therapeutic agents like antibiotics. Azithromycin is a potential, chemotherapeutic agent which possesses antimalarial activity and favourable pharmacokinetic properties. It is an azalide microbiocide derived semi-synthetically from macrolide erythromycin. Like other antibiotics, the azalide azithromycin has ability to inhibit protein synthesis on 70S ribosomes. SETTINGS: Experimental study. SUBJECTS AND METHODS: The parasiticidal profile was studied in five chloroquine sensitive and five chloroquine resistant P. falciparum isolates obtained from various places of India. The antimalarial activity was evaluated in P. falciparum schizont maturation by short term culture for 24 hours and by exposing the parasites to the drug for 96 hours. Parasites synchronized at ring stage were put for culture with various concentrations of azithromycin dihydrate (0.01-40 micro/ml. RESULTS: At highest concentration (40 micro/ml, parasite growth was inhibited totally in all 10 isolates. Antimalarial activity at 96 hours was greater than at 24 hours in both chloroquine sensitive and resistant parasites, which may indicate that the inhibition of parasite growth may occur at clinically achievable concentration of the drug when parasites were exposed for several asexual cycles. CONCLUSION: Azithromycin shows a potential for eventual use alone or in combination in the treatment of chloroquine sensitive and resistant P. falciparum malaria.

  17. Neuronal monoamine reuptake inhibitors enhance in vitro susceptibility to chloroquine in resistant Plasmodium falciparum.

    OpenAIRE

    Coutaux, A F; Mooney, J. J.; Wirth, D. F.

    1994-01-01

    Chloroquine resistance in Plasmodium falciparum was reversed in vitro by the neuronal monoamine reuptake inhibitors and antidepressants desipramine, sertraline, fluoxetine, and norfluoxetine but not by carbamazepine, an antiseizure and mood-stabilizing tricyclic drug resembling desipramine which only weakly inhibits neuronal monoamine reuptake. These findings have important clinical implications for drug combination therapy.

  18. Combinatorial Genetic Modeling of pfcrt-Mediated Drug Resistance Evolution in Plasmodium falciparum.

    Science.gov (United States)

    Gabryszewski, Stanislaw J; Modchang, Charin; Musset, Lise; Chookajorn, Thanat; Fidock, David A

    2016-06-01

    The emergence of drug resistance continuously threatens global control of infectious diseases, including malaria caused by the protozoan parasite Plasmodium falciparum A critical parasite determinant is the P. falciparum chloroquine resistance transporter (PfCRT), the primary mediator of chloroquine (CQ) resistance (CQR), and a pleiotropic modulator of susceptibility to several first-line artemisinin-based combination therapy partner drugs. Aside from the validated CQR molecular marker K76T, P. falciparum parasites have acquired at least three additional pfcrt mutations, whose contributions to resistance and fitness have been heretofore unclear. Focusing on the quadruple-mutant Ecuadorian PfCRT haplotype Ecu1110 (K76T/A220S/N326D/I356L), we genetically modified the pfcrt locus of isogenic, asexual blood stage P. falciparum parasites using zinc-finger nucleases, producing all possible combinations of intermediate pfcrt alleles. Our analysis included the related quintuple-mutant PfCRT haplotype 7G8 (Ecu1110 + C72S) that is widespread throughout South America and the Western Pacific. Drug susceptibilities and in vitro growth profiles of our combinatorial pfcrt-modified parasites were used to simulate the mutational trajectories accessible to parasites as they evolved CQR. Our results uncover unique contributions to parasite drug resistance and growth for mutations beyond K76T and predict critical roles for the CQ metabolite monodesethyl-CQ and the related quinoline-type drug amodiaquine in driving mutant pfcrt evolution. Modeling outputs further highlight the influence of parasite proliferation rates alongside gains in drug resistance in dictating successful trajectories. Our findings suggest that P. falciparum parasites have navigated constrained pfcrt adaptive landscapes by means of probabilistically rare mutational bursts that led to the infrequent emergence of pfcrt alleles in the field.

  19. Prevalence of resistance associated polymorphisms in Plasmodium falciparum field isolates from southern Pakistan

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    Beg Mohammad A

    2011-01-01

    Full Text Available Abstract Background Scarce data are available on Plasmodium falciparum anti-malarial drug resistance in Pakistan. The aim of this study was, therefore, to determine the prevalence of P. falciparum resistance associated polymorphisms in field isolates from southern Pakistan. Methods Blood samples from 244 patients with blood-slide confirmed P. falciparum mono-infections were collected between 2005-2007. Single nucleotide polymorphisms in the P. falciparum chloroquine resistance transporter (pfcrt K76T, multi drug resistance (pfmdr1 N86Y, dihydrofolate reductase (pfdhfr A16V, N51I, C59R, S108N, I164L and dihydropteroate synthetase (pfdhps A436S, G437A and E540K genes and pfmdr1 gene copy numbers were determined using PCR based methods. Results The prevalence of pfcrt 76T and pfmdr1 86Y was 93% and 57%, respectively. The prevalence of pfdhfr double mutations 59R + 108N/51R + 108N was 92%. The pfdhfr triple mutation (51I, 59R, 108N occurred in 3% of samples. The pfdhfr (51I, 59R, 108N and pfdhps (437G, 540E quintuple mutation was found in one isolate. Pfdhps 437G was observed in 51% and 540E in 1% of the isolates. One isolate had two pfmdr1 copies and carried the pfmdr1 86Y and pfcrt 76T alleles. Conclusions The results indicate high prevalence of in vivo resistance to chloroquine, whereas high grade resistance to sulphadoxine-pyrimethamine does not appear to be widespread among P. falciparum in southern Pakistan.

  20. Plasmodium falciparum In Vitro Resistance to Monodesethylamodiaquine, Dakar, Senegal, 2014.

    Science.gov (United States)

    Fall, Bécaye; Madamet, Marylin; Camara, Cheikhou; Amalvict, Rémy; Fall, Mansour; Nakoulima, Aminata; Diatta, Bakary; Diémé, Yaya; Wade, Boubacar; Pradines, Bruno

    2016-05-01

    We successfully cultured 36 Plasmodium falciparum isolates from blood samples of 44 malaria patients admitted to the Hôpital Principal de Dakar (Dakar, Senegal) during August-December 2014. The prevalence of isolates with in vitro reduced susceptibility was 30.6% for monodesethylamodiaquine, 52.8% for chloroquine, 44.1% for mefloquine, 16.7% for doxycycline, 11.8% for piperaquine, 8.3% for artesunate, 5.9% for pyronaridine, 2.8% for quinine and dihydroartemisinin, and 0.0% for lumefantrine. The prevalence of isolates with reduced in vitro susceptibility to the artemisinin-based combination therapy partner monodesethylamodiaquine increased from 5.6% in 2013 to 30.6% in 2014. Because of the increased prevalence of P. falciparum parasites with impaired in vitro susceptibility to monodesethylamodiaquine, the implementation of in vitro and in vivo surveillance of all artemisinin-based combination therapy partners is warranted.

  1. Engineered resistance to Plasmodium falciparum development in transgenic Anopheles stephensi.

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    Alison T Isaacs

    2011-04-01

    Full Text Available Transposon-mediated transformation was used to produce Anopheles stephensi that express single-chain antibodies (scFvs designed to target the human malaria parasite, Plasmodium falciparum. The scFvs, m1C3, m4B7, and m2A10, are derived from mouse monoclonal antibodies that inhibit either ookinete invasion of the midgut or sporozoite invasion of salivary glands. The scFvs that target the parasite surface, m4B7 and m2A10, were fused to an Anopheles gambiae antimicrobial peptide, Cecropin A. Previously-characterized Anopheles cis-acting DNA regulatory elements were included in the transgenes to coordinate scFv production with parasite development. Gene amplification and immunoblot analyses showed promoter-specific increases in transgene expression in blood-fed females. Transgenic mosquito lines expressing each of the scFv genes had significantly lower infection levels than controls when challenged with P. falciparum.

  2. Draft genome sequence of a multidrug-resistant Chryseobacterium indologenes isolate from Malaysia

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    Choo Yee Yu

    2016-03-01

    Full Text Available Chryseobacterium indologenes is an emerging pathogen which poses a threat in clinical healthcare setting due to its multidrug-resistant phenotype and its common association with nosocomial infections. Here, we report the draft genome of a multidrug-resistant C. indologenes CI_885 isolated in 2014 from Malaysia. The 908,704-kb genome harbors a repertoire of putative antibiotic resistance determinants which may elucidate the molecular basis and underlying mechanisms of its resistant to various classes of antibiotics. The genome sequence has been deposited in DDBJ/EMBL/GenBank under the accession number LJOD00000000.

  3. Multidrug resistant Acinetobacter baumannii in veterinary medicine--emergence of an underestimated pathogen?

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    Müller, Stefanie; Janssen, Traute; Wieler, Lothar H

    2014-01-01

    The proportion of multidrug resistant bacteria causing infections in animals has continuously been increasing. While the relevance of ESBL (extended spectrum beta-lactamase)-producing Enterobacteriaceae spp. and MRSA (methicillin resistant Staphylococcus aureus) is unquestionable, knowledge about multidrug resistant Acinetobacter baumannii in veterinary medicine is scarce. This is a worrisome situation, as A. baumannii are isolated from veterinary clinical specimens with rising frequency. The remarkable ability of A. baumannii to develop multidrug resistance and the high risk of transmission are known in human medicine for years. Despite this, data regarding A. baumannii isolates of animal origin are missing. Due to the changing role of companion animals with closer contact between animal and owner, veterinary intensive care medicine is steadily developing. It can be assumed that the number of "high risk" patients with an enhanced risk for hospital acquired infections will be rising simultaneously. Thus, development and spread of multidrug resistant pathogens is envisioned to rise. It is possible, that A. baumannii will evolve into a veterinary nosocomial pathogen similar to ESBL-producing Enterobacteriaceae and MRSA. The lack of attention paid to A. baumannii in veterinary medicine is even more worrying, as first reports indicate a transmission between humans and animals. Essential questions regarding the role of livestock, especially as a potential source of multidrug resistant isolates, remain unanswered. This review summarizes the current knowledge on A. baumannii in veterinary medicine for the first time. It underlines the utmost significance of further investigations of A. baumannii animal isolates, particularly concerning epidemiology and resistance mechanisms.

  4. Current Status on Marine Products with Reversal Effect on Cancer Multidrug Resistance

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    Huiqin Guo

    2012-10-01

    Full Text Available The resistance of tumor cells to a broad range of anticancer agents continues to be a problem for the success of cancer chemotherapy. Multidrug resistance (MDR is due in part to three drug transporter proteins: ABCB1/P-glycoprotein (P-gp, ABCC1/multidrug resistance protein 1 (MRP1 and ABCG2/breast cancer resistance protein (BCRP. These transporters are part of the ATP-binding cassette (ABC superfamily, whose members function as ATP-dependent drug-efflux pumps. Their activity can be blocked by various drugs such as verapamil (calcium channel blocker and cyclosporin A (immunosuppressive agent, etc. These compounds are called MDR modulators or reversals. This review highlights several marine natural products with reversal effect on multidrug resistance in cancer, including agosterol A, ecteinascidin 743, sipholane triterpenoids, bryostatin 1, and welwitindolinones.

  5. ACTION OF NEWER DISINFECTANTS ON MULTIDRUG RESISTANT BACTERIA

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    Bipasa

    2014-03-01

    Full Text Available BACKGROUND: Current procedures for infection control in hospital environments have not been successful in curbing the rise in infections by multi-drug-resistant (MDR pathogens. Emergence of resistance to chemical disinfectants is increasing steadily and has been reported worldwide. So prevention of multidrug-resistant health care associated infections (HAI has become a priority issue and great challenge to clinicians. This requires appropriate sterilization and disinfection procedures and strict adherence to protocol in infection control policy. There is a need to evaluate the efficacy of newer disinfectants which have come into the market for better control of HAI. AIMS AND OBJECTIVES: The aim of this study was to evaluate and compare disinfection efficacy of three newer disinfectants– Novacide (didecyldimethylammonium chloride and polyhexamethylene biguanide, Silvicide a strong oxidizing agent (hydrogen peroxide and silver nitrate and Virkon, a powerful oxidizing agent (a stabilized blend of peroxygen compounds and potassium salts, pitting them against two time-honored conventional disinfectants phenol and lysol and testing them against common MDR clinical isolates, reference strains and spores. MATERIALS AND METHODS: All the disinfectants at different dilutions were tested for bactericidal efficacy by liquid suspension time-kill tests. A heavy initial microbial load was simulated by preparing bacterial inoculum. Numbers of viable cells were counted and reduction in microbial colony counts before and after disinfectant exposure was expressed as log reduction. RESULTS: Among the disinfectants, Novacide was most effective. All clinical MDR bacterial isolates and reference strains were killed within 30 seconds of exposure at 0.156% solution, whereas spores got killed after 30 minutes of exposure at 2.5% solution which is the recommended concentration. For Silvicide all vegetative bacteria were killed at 5% solution after 20 minutes contact time

  6. Multidrug resistant Gram-negative bacilli in lower respiratory tract infections.

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    Vishwanath, Shashidhar; Chawla, Kiran; Gopinathan, Anusha

    2013-12-01

    Lower respiratory tract infections are among important causes of morbidity and mortality for all age groups. The emergence of multidrug resistant Gram-negative bacilli is an issue of increasing concern. A retrospective study including respiratory specimens (sputum and BAL) was conducted in our tertiary care centre. Samples were processed for microscopy, culture and susceptibility testing following standard methods. Multidrug resistant Gram-negative bacilli causing lower respiratory tract infections were studied for their causation of disease. The effect of appropriate treatment on clinical outcome was observed. A total of 472 Gram-negative pathogens were isolated from sputum and broncho-alveolar lavage fluid specimens during the study period. Among these Gram-negative pathogens 175 (37%) were found to be multidrug resistant. Klebsiella pneumoniae 85 (48.6%) and Acinetobacter spp. 59 (33.7%) were the predominant multidrug resistant Gram-negative bacilli isolated. Based on clinico-microbiological correlation, 138 (78.9%) multidrug resistant isolates were found to be pathogenic and the rest 37 (21.1%) were considered as colonizers. After initiating appropriate antibiotic therapy, clinical improvement was seen in 110 (79.7%) patients. In the patients who showed improvement, amikacin (34.3%) and cefoperazone-sulbactum (21.8%) were found to be the most effective drugs. A large majority of the isolated multidrug resistant Gram-negative bacilli were found to be pathogenic. Regular surveillance which directs appropriate empirical therapy; and good clinic-microbiological workup of each case of lower respiratory tract infection can reduce the morbidity and mortality associated with multidrug resistant organisms.

  7. Multidrug resistant Gram-negative bacilli in lower respiratory tract infections.

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    Shashidhar Vishwanath

    2013-12-01

    Full Text Available Lower respiratory tract infections are among important causes of morbidity and mortality for all age groups. The emergence of multidrug resistant Gram-negative bacilli is an issue of increasing concern.A retrospective study including respiratory specimens (sputum and BAL was conducted in our tertiary care centre. Samples were processed for microscopy, culture and susceptibility testing following standard methods. Multidrug resistant Gram-negative bacilli causing lower respiratory tract infections were studied for their causation of disease. The effect of appropriate treatment on clinical outcome was observed.A total of 472 Gram-negative pathogens were isolated from sputum and broncho-alveolar lavage fluid specimens during the study period. Among these Gram-negative pathogens 175 (37% were found to be multidrug resistant. Klebsiella pneumoniae 85 (48.6% and Acinetobacter spp. 59 (33.7% were the predominant multidrug resistant Gram-negative bacilli isolated. Based on clinico-microbiological correlation, 138 (78.9% multidrug resistant isolates were found to be pathogenic and the rest 37 (21.1% were considered as colonizers. After initiating appropriate antibiotic therapy, clinical improvement was seen in 110 (79.7% patients. In the patients who showed improvement, amikacin (34.3% and cefoperazone-sulbactum (21.8% were found to be the most effective drugs.A large majority of the isolated multidrug resistant Gram-negative bacilli were found to be pathogenic. Regular surveillance which directs appropriate empirical therapy; and good clinic-microbiological workup of each case of lower respiratory tract infection can reduce the morbidity and mortality associated with multidrug resistant organisms.

  8. Aggressive regimens for multidrug-resistant tuberculosis reduce recurrence.

    Science.gov (United States)

    Franke, Molly F; Appleton, Sasha C; Mitnick, Carole D; Furin, Jennifer J; Bayona, Jaime; Chalco, Katiuska; Shin, Sonya; Murray, Megan; Becerra, Mercedes C

    2013-03-01

    Recurrent tuberculosis disease occurs within 2 years in as few as 1% and as many as 29% of individuals successfully treated for multidrug-resistant (MDR) tuberculosis. A better understanding of treatment-related factors associated with an elevated risk of recurrent tuberculosis after cure is urgently needed to optimize MDR tuberculosis therapy. We conducted a retrospective cohort study among adults successfully treated for MDR tuberculosis in Peru. We used multivariable Cox proportional hazards regression analysis to examine whether receipt of an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion from positive to negative was associated with a reduced rate of recurrent tuberculosis. Among 402 patients, the median duration of follow-up was 40.5 months (interquartile range, 21.2-53.4). Receipt of an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion was associated with a lower risk of recurrent tuberculosis (hazard ratio, 0.40 [95% confidence interval, 0.17-0.96]; P = .04). A baseline diagnosis of diabetes mellitus also predicted recurrent tuberculosis (hazard ratio, 10.47 [95% confidence interval, 2.17-50.60]; P = .004). Individuals who received an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion experienced a lower rate of recurrence after cure. Efforts to ensure that an aggressive regimen is accessible to all patients with MDR tuberculosis, such as minimization of sequential ineffective regimens, expanded drug access, and development of new MDR tuberculosis compounds, are critical to reducing tuberculosis recurrence in this population. Patients with diabetes mellitus should be carefully managed during initial treatment and followed closely for recurrent disease.

  9. Identification and bioinformatic characterization of a multidrug resistance associated protein (ABCC) gene in Plasmodium berghei

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    González-Pons, María; Szeto, Ada C; González-Méndez, Ricardo; Serrano, Adelfa E

    2009-01-01

    Background The ATP-binding cassette (ABC) superfamily is one of the largest evolutionarily conserved families of proteins. ABC proteins play key roles in cellular detoxification of endobiotics and xenobiotics. Overexpression of certain ABC proteins, among them the multidrug resistance associated protein (MRP), contributes to drug resistance in organisms ranging from human neoplastic cells to parasitic protozoa. In the present study, the Plasmodium berghei mrp gene (pbmrp) was partially characterized and the predicted protein was classified using bioinformatics in order to explore its putative involvement in drug resistance. Methods The pbmrp gene from the P. berghei drug sensitive, N clone, was sequenced using a PCR strategy. Classification and domain organization of pbMRP were determined with bioinformatics. The Plasmodium spp. MRPs were aligned and analysed to study their conserved motifs and organization. Gene copy number and organization were determined via Southern blot analysis in both N clone and the chloroquine selected line, RC. Chromosomal Southern blots and RNase protection assays were employed to determine the chromosomal location and expression levels of pbmrp in blood stages. Results The pbmrp gene is a single copy, intronless gene with a predicted open reading frame spanning 5820 nucleotides. Bioinformatic analyses show that this protein has distinctive features characteristic of the ABCC sub-family. Multiple sequence alignments reveal a high degree of conservation in the nucleotide binding and transmembrane domains within the MRPs from the Plasmodium spp. analysed. Expression of pbmrp was detected in asexual blood stages. Gene organization, copy number and mRNA expression was similar in both lines studied. A chromosomal translocation was observed in the chloroquine selected RC line, from chromosome 13/14 to chromosome 8, when compared to the drug sensitive N clone. Conclusion In this study, the pbmrp gene was sequenced and classified as a member of

  10. Susceptibility of Colombian Plasmodium falciparum isolates to 4-aminoquinolines and the definition of amodiaquine resistance in vitro

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    Diego F Echeverry

    2006-05-01

    Full Text Available There are wide variations in the threshold used to define in vitro resistance of Plasmodium falciparum to amodiaquine (AQ, probably due to differences in methodology and interpretation. In vitro susceptibility data of Colombian P. falciparum strains to AQ and N-desethylamodiaquine is used to illustrate the need to standardized methodologies and compare inhibitory concentrations, instead of resistant/susceptible phenotypes, when studying the mechanisms of resistance to AQ and monitoring drug susceptibility trends in the field.

  11. Molecular characterization of multidrug resistant hospital isolates using the antimicrobial resistance determinant microarray.

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    Tomasz A Leski

    Full Text Available Molecular methods that enable the detection of antimicrobial resistance determinants are critical surveillance tools that are necessary to aid in curbing the spread of antibiotic resistance. In this study, we describe the use of the Antimicrobial Resistance Determinant Microarray (ARDM that targets 239 unique genes that confer resistance to 12 classes of antimicrobial compounds, quaternary amines and streptothricin for the determination of multidrug resistance (MDR gene profiles. Fourteen reference MDR strains, which either were genome, sequenced or possessed well characterized drug resistance profiles were used to optimize detection algorithms and threshold criteria to ensure the microarray's effectiveness for unbiased characterization of antimicrobial resistance determinants in MDR strains. The subsequent testing of Acinetobacter baumannii, Escherichia coli and Klebsiella pneumoniae hospital isolates revealed the presence of several antibiotic resistance genes [e.g. belonging to TEM, SHV, OXA and CTX-M classes (and OXA and CTX-M subfamilies of β-lactamases] and their assemblages which were confirmed by PCR and DNA sequence analysis. When combined with results from the reference strains, ~25% of the ARDM content was confirmed as effective for representing allelic content from both Gram-positive and -negative species. Taken together, the ARDM identified MDR assemblages containing six to 18 unique resistance genes in each strain tested, demonstrating its utility as a powerful tool for molecular epidemiological investigations of antimicrobial resistance in clinically relevant bacterial pathogens.

  12. Multidrug resistance 1 gene polymorphisms may determine Crohn's disease behavior in patients from Rio de Janeiro

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    Ana Teresa P. Carvalho

    2014-01-01

    Full Text Available OBJECTIVES: Conflicting data from studies on the potential role of multidrug resistance 1 gene polymorphisms in inflammatory bowel disease may result from the analysis of genetically and geographically distinct populations. Here, we investigated whether multidrug resistance 1 gene polymorphisms are associated with inflammatory bowel diseases in patients from Rio de Janeiro. METHODS: We analyzed 123 Crohn's disease patients and 83 ulcerative colitis patients to determine the presence of the multidrug resistance 1 gene polymorphisms C1236T, G2677T and C3435T. In particular, the genotype frequencies of Crohn's disease and ulcerative colitis patients were analyzed. Genotype-phenotype associations with major clinical characteristics were established, and estimated risks were calculated for the mutations. RESULTS: No significant difference was observed in the genotype frequencies of the multidrug resistance 1 G2677T/A and C3435T polymorphisms between Crohn's disease and ulcerative colitis patients. In contrast, the C1236T polymorphism was significantly more common in Crohn's disease than in ulcerative colitis (p = 0.047. A significant association was also found between the multidrug resistance 1 C3435T polymorphism and the stricturing form of Crohn's disease (OR: 4.13; p = 0.009, whereas no association was found with penetrating behavior (OR: 0.33; p = 0.094. In Crohn's disease, a positive association was also found between the C3435T polymorphism and corticosteroid resistance/refractoriness (OR: 4.14; p = 0.010. However, no significant association was found between multidrug resistance 1 gene polymorphisms and UC subphenotypic categories. CONCLUSION: The multidrug resistance 1 gene polymorphism C3435T is associated with the stricturing phenotype and an inappropriate response to therapy in Crohn's disease. This association with Crohn's disease may support additional pathogenic roles for the multidrug resistance 1 gene in regulating gut

  13. Diminished expression of multidrug resistance-associated protein 1 (MRP1) in bronchial epithelium of COPD patients

    NARCIS (Netherlands)

    van der Deen, Margaretha; Marks, Hendrik; Willemse, Brigitte W. M.; Postma, Dirkje S.; Muller, Michael; Smit, Egbert F.; Scheffer, George L.; Scheper, Rik J.; de Vries, Elisabeth G. E.; Timens, Wim

    2006-01-01

    Cigarette smoke is the principal risk factor for chronic obstructive pulmonary disease (COPD). Multidrug resistance proteins, such as multidrug resistance-associated protein-1 (MRP1), P-glycoprotein (P-gp), and lung resistance-related protein (LRP), may protect against oxidative stress and toxic com

  14. Tracing the origins and signatures of selection of antifolate resistance in island populations of Plasmodium falciparum

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    Pinto João

    2010-06-01

    Full Text Available Abstract Background Resistance of the malaria parasite Plasmodium falciparum to sulfadoxine-pyrimethamine (SP has evolved worldwide. In the archipelago of São Tomé and Principe (STP, West Africa, although SP resistance is highly prevalent the drug is still in use in particular circumstances. To address the evolutionary origins of SP resistance in these islands, we genotyped point mutations at P. falciparum dhfr and dhps genes and analysed microsatellites flanking those genes. Methods Blood samples were collected in July and December 2004 in three localities of São Tomé Island and one in Principe Island. Species-specific nested-PCR was used to identify P. falciparum infected samples. Subsequently, SNPs at the dhfr and dhps genes were identified through PCR-RFLP. Isolates were also analysed for three microsatellite loci flanking the dhfr gene, three loci flanking dhps and four loci located at putative neutral genomic regions. Results An increase of resistance-associated mutations at dhfr and dhps was observed, in particular for the dhfr/dhps quintuple mutant, associated with clinical SP failure. Analysis of flanking microsatellites suggests multiple independent introductions for dhfr and dhps mutant haplotypes, possibly from West Africa. A reduced genetic diversity and increased differentiation at flanking microsatellites when compared to neutral loci is consistent with a selective sweep for resistant alleles at both loci. Conclusions This study provides additional evidence for the crucial role of gene flow and drug selective pressures in the rapid spread of SP resistance in P. falciparum populations, from only a few mutation events giving rise to resistance-associated mutants. It also highlights the importance of human migration in the spread of drug resistant malaria parasites, as the distance between the islands and mainland is not consistent with mosquito-mediated parasite dispersal.

  15. Molecular surveillance of antimalarial drug resistance related genes in Plasmodium falciparum isolates from Eritrea.

    Science.gov (United States)

    Menegon, Michela; Nurahmed, Abduselam M; Talha, Albadawi A; Nour, Bakri Y M; Severini, Carlo

    2016-05-01

    The introduction of artemisinin-based combination therapy has led to extraordinary results in malaria control, however the recent emergence of partial resistance to artemisinin therapy in Southeast Asia jeopardizes these successes. This study aimed at investigating resistance to the antimalarial drugs by evaluating the polymorphisms in the PfK13, Pfcrt and Pfmdr1 genes in Plasmodium falciparum isolates obtained from patients in Eritrea.

  16. CD44-engineered mesoporous silica nanoparticles for overcoming multidrug resistance in breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Xin; Liu, Ying; Wang, Shouju; Shi, Donghong [Department of Radiology, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing 210002 (China); Zhou, Xianguang [National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing 210016 (China); Wang, Chunyan; Wu, Jiang; Zeng, Zhiyong; Li, Yanjun; Sun, Jing [Department of Radiology, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing 210002 (China); Wang, Jiandong [Department of Pathology, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing 210002 (China); Zhang, Longjiang [Department of Radiology, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing 210002 (China); Teng, Zhaogang, E-mail: tzg@fudan.edu.cn [Department of Radiology, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing 210002 (China); State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093 (China); Lu, Guangming, E-mail: cjr.luguangming@vip.163.com [Department of Radiology, Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing 210002 (China); State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093 (China)

    2015-03-30

    Graphical abstract: - Highlights: • CD44-engineered mesoporous silica nanoparticles are synthesized. • The mechanism of CD44-engineered mesoporous silica nanoparticles is revealed. • This new delivery system increased the drug accumulation in vitro and in vivo. • This new delivery system offers an effective approach to treat multidrug resistance. - Abstract: Multidrug resistance is a major impediment for the successful chemotherapy in breast cancer. CD44 is over-expressed in multidrug resistant human breast cancer cells. CD44 monoclonal antibody exhibits anticancer potential by inhibiting proliferation and regulating P-glycoprotein-mediated drug efflux activity in multidrug resistant cells. Thereby, CD44 monoclonal antibody in combination with chemotherapeutic drug might be result in enhancing chemosensitivity and overcoming multidrug resistance. The purpose of this study is to investigate the effects of the CD44 monoclonal antibody functionalized mesoporous silica nanoparticles containing doxorubicin on human breast resistant cancer MCF-7 cells. The data showed that CD44-modified mesoporous silica nanoparticles increased cytotoxicity and enhanced the downregulation of P-glycoprotein in comparison to CD44 antibody. Moreover, CD44-engineered mesoporous silica nanoparticles provided active target, which promoted more cellular uptake of DOX in the resistant cells and more retention of DOX in tumor tissues than unengineered counterpart. Animal studies of the resistant breast cancer xenografts demonstrated that CD44-engineered drug delivery system remarkably induced apoptosis and inhibited the tumor growth. Our results indicated that the CD44-engineered mesoporous silica nanoparticle-based drug delivery system offers an effective approach to overcome multidrug resistance in human breast cancer.

  17. Treatment of multidrug-resistant pseudomonas aeruginosa using extended-infusion antimicrobial regimens.

    Science.gov (United States)

    Heil, Emily L; Lowery, Ashleigh V; Thom, Kerri A; Nicolau, David P

    2015-01-01

    In the management of multidrug-resistant infections in critically ill patients with multiorgan dysfunction, consideration must be given to the pharmacokinetics and pharmacodynamics of an antimicrobial agent to optimize dosing. We describe a 25-year-old woman who was undergoing thrice-weekly hemodialysis and developed multidrug-resistant Pseudomonas aeruginosa bacteremia secondary to infected left and right ventricular assist devices. After multiple courses of antibiotics, her blood cultures revealed that the infecting organism was becoming progressively more resistant to antibiotic options. Cefepime 2 g administered over 3 hours/day (in combination with colistimethate) provided adequate drug levels for multidrug-resistant, cefepime-intermediate P. aeruginosa bacteremia in this patient. We present the clinical case of this patient, followed by a discussion of possible therapeutic approaches to be considered, including illustration of the principles of using extended-infusion antimicrobial regimens, and present the patient's resulting clinical course.

  18. Drug resistance and genetic diversity of Plasmodium falciparum parasites from suriname.

    Science.gov (United States)

    Peek, Ron; VAN Gool, Tom; Panchoe, Daynand; Greve, Sophie; Bus, Ellen; Resida, Lesley

    2005-11-01

    Plasmodium falciparum in Suriname was studied for the presence of drug resistance and genetic variation in blood samples of 86 patients with symptomatic malaria. Drug resistance was predicted by determining point mutations in the chloroquine resistance marker of the P. falciparum chloroquine resistance transporter (pfcrt) gene (codon 76) and the pyrimethamine-sulfadoxine resistance markers in the dihydrofolate reductase (dhfr) gene (codons 16, 51, 59, 108, and 164) and dihydropteroate synthase (dhps) gene (codons 436, 437, 540, 581, and 613). Genetic variability was determined by sequence analysis of the polymorphic segments of the merozoite surface protein 2 (msp-2) and glutamate-rich protein (glurp) genes. Mutations in the pfcrt, dhps, and dhfr genes were found in all samples tested, suggesting that resistance to chloroquine and antifolate drugs is present at a high frequency. A low number of alleles was found for the msp-2 and glurp genes. This indicates limited genetic diversity and, based on geographic data, a genetically homogeneous P. falciparum population in Suriname.

  19. Tracking origins and spread of sulfadoxine-resistant Plasmodium falciparum dhps alleles in Thailand.

    Science.gov (United States)

    Alam, Md Tauqeer; Vinayak, Sumiti; Congpuong, Kanungnit; Wongsrichanalai, Chansuda; Satimai, Wichai; Slutsker, Laurence; Escalante, Ananias A; Barnwell, John W; Udhayakumar, Venkatachalam

    2011-01-01

    The emergence and spread of drug-resistant Plasmodium falciparum have been a major impediment for the control of malaria worldwide. Earlier studies have shown that similar to chloroquine (CQ) resistance, high levels of pyrimethamine resistance in P. falciparum originated independently 4 to 5 times globally, including one origin at the Thailand-Cambodia border. In this study we describe the origins and spread of sulfadoxine-resistance-conferring dihydropteroate synthase (dhps) alleles in Thailand. The dhps mutations and flanking microsatellite loci were genotyped for P. falciparum isolates collected from 11 Thai provinces along the Burma, Cambodia, and Malaysia borders. Results indicated that resistant dhps alleles were fixed in Thailand, predominantly being the SGEGA, AGEAA, and SGNGA triple mutants and the AGKAA double mutant (mutated codons are underlined). These alleles had different geographical distributions. The SGEGA alleles were found mostly at the Burma border, while the SGNGA alleles occurred mainly at the Cambodia border and nearby provinces. Microsatellite data suggested that there were two major genetic lineages of the triple mutants in Thailand, one common for SGEGA/SGNGA alleles and another one independent for AGEAA. Importantly, the newly reported SGNGA alleles possibly originated at the Thailand-Cambodia border. All parasites in the Yala province (Malaysia border) had AGKAA alleles with almost identical flanking microsatellites haplotypes. They were also identical at putatively neutral loci on chromosomes 2 and 3, suggesting a clonal nature of the parasite population in Yala. In summary, this study suggests multiple and independent origins of resistant dhps alleles in Thailand.

  20. Multidrug resistance in Pseudomonas aeruginosa isolated from nosocomial respiratory and urinary infections in Aleppo, Syria.

    Science.gov (United States)

    Mahfoud, Maysa; Al Najjar, Mona; Hamzeh, Abdul Rezzak

    2015-02-19

    Pseudomonas aeruginosa represents a serious clinical challenge due to its frequent involvement in nosocomial infections and its tendency towards multidrug resistance. This study uncovered antibiotic susceptibility patterns in 177 isolates from inpatients in three key hospitals in Aleppo, the largest city in Syria. Exceptionally low susceptibility to most routinely used antibiotics was uncovered; resistance to ciprofloxacin and gentamicin was 64.9% and 70.3%, respectively. Contrarily, susceptibility to colistin was the highest (89.1%). Multidrug resistance was rife, found at a rate of 53.67% among studied P. aeruginosa isolates.

  1. Virulence and genomic feature of multidrug resistant Campylobacter jejuni isolated from broiler chicken

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    Haihong Hao

    2016-10-01

    Full Text Available The aim of this study was to reveal the molecular mechanism involved in multidrug resistance and virulence of Campylobacter jejuni isolated from broiler chickens. The virulence of six multidrug resistant C. jejuni was determined by in vitro and in vivo methods. The de novo whole genome sequencing technology and molecular biology methods were used to analyze the genomic features associated with the multidrug resistance and virulence of a selected isolate (C. jejuni 1655. The comparative genomic analyses revealed a large number of single nucleotide polymorphisms, deletions, rearrangements, and inversions in C. jejuni 1655 compared to reference C. jejuni genomes. The co-emergence of Thr-86-Ile mutation in gyrA gene, A2075G mutation in 23S rRNA gene, tetO, aphA and aadE genes and pTet plasmid in C. jejuni 1655 contributed its multidrug resistance to fluoroquinolones, macrolides, tetracycline and aminoglycosides. The combination of multiple virulence genes may work together to confer the relative higher virulence in C. jejuni 1655. The co-existence of mobile gene elements (e.g. pTet and CRISPR-Cas system in C. jejuni 1655 may play an important role in the gene transfer and immune defense. The present study provides basic information of phenotypic and genomic features of C. jejuni 1655, a strain recently isolated from a chicken displaying multidrug resistance and relatively high level of virulence.

  2. Virulence and Genomic Feature of Multidrug Resistant Campylobacter jejuni Isolated from Broiler Chicken

    Science.gov (United States)

    Hao, Haihong; Ren, Ni; Han, Jing; Foley, Steven L.; Iqbal, Zahid; Cheng, Guyue; Kuang, Xiuhua; Liu, Jie; Liu, Zhenli; Dai, Menghong; Wang, Yulian; Yuan, Zonghui

    2016-01-01

    The aim of this study was to reveal the molecular mechanism involved in multidrug resistance and virulence of Campylobacter jejuni isolated from broiler chickens. The virulence of six multidrug resistant C. jejuni was determined by in vitro and in vivo methods. The de novo whole genome sequencing technology and molecular biology methods were used to analyze the genomic features associated with the multidrug resistance and virulence of a selected isolate (C. jejuni 1655). The comparative genomic analyses revealed a large number of single nucleotide polymorphisms, deletions, rearrangements, and inversions in C. jejuni 1655 compared to reference C. jejuni genomes. The co-emergence of Thr-86-Ile mutation in gyrA gene, A2075G mutation in 23S rRNA gene, tetO, aphA and aadE genes and pTet plasmid in C. jejuni 1655 contributed its multidrug resistance to fluoroquinolones, macrolides, tetracycline, and aminoglycosides. The combination of multiple virulence genes may work together to confer the relative higher virulence in C. jejuni 1655. The co-existence of mobile gene elements (e.g., pTet) and CRISPR-Cas system in C. jejuni 1655 may play an important role in the gene transfer and immune defense. The present study provides basic information of phenotypic and genomic features of C. jejuni 1655, a strain recently isolated from a chicken displaying multidrug resistance and relatively high level of virulence. PMID:27790202

  3. Nuclear multidrug-resistance related protein 1 contributes to multidrug-resistance of mucoepidermoid carcinoma mainly via regulating multidrug-resistance protein 1: a human mucoepidermoid carcinoma cells model and Spearman's rank correlation analysis.

    Directory of Open Access Journals (Sweden)

    Bolei Cai

    Full Text Available BACKGROUND: Multidrug resistance-related protein 1 (MRP1/ABCC1 and multidrug resistance protein 1 (MDR1/P-glycoprotein/ABCB1 are both membrane-bound drug transporters. In contrast to MDR1, MRP1 also transports glutathione (GSH and drugs conjugated to GSH. Due to its extraordinary transport properties, MRP1/ABCC1 contributes to several physiological functions and pathophysiological incidents. We previously found that nuclear translocation of MRP1 contributes to multidrug-resistance (MDR of mucoepidermoid carcinoma (MEC. The present study investigated how MRP1 contributes to MDR in the nuclei of MEC cells. METHODS: Western blot and RT-PCR was carried out to investigate the change of multidrug-resistance protein 1 (MDR1 in MC3/5FU cells after MRP1 was downregulated through RNA interference (RNAi. Immunohistochemistry (IHC staining of 127 cases of MEC tissues was scored with the expression index (EI. The EI of MDR1 and MRP1 (or nuclear MRP1 was analyzed with Spearman's rank correlation analysis. Using multiple tumor tissue assays, the location of MRP1 in other tissues was checked by HIC. Luciferase reporter assays of MDR1 promoter was carried out to check the connection between MRP1 and MDR1 promoter. RESULTS: MRP1 downregulation led to a decreased MDR1 expression in MC3/5FU cells which was caused by decreased activity of MDR1 promoter. IHC study of 127 cases of MEC tissues demonstrated a strong positive correlation between nuclear MRP1 expression and MDR1 expression. Furthermore, IHC study of multiple tumor tissue array sections showed that although nuclear MRP1 widely existed in MEC tissues, it was not found in normal tissues or other tumor tissues. CONCLUSIONS: Our findings indicate that nuclear MRP1 contributes to MDR mainly through regulating MDR1 expression in MEC. And the unique location of MRP1 made it an available target in identifying MEC from other tumors.

  4. Mutational and acquired carbapenem resistance mechanisms in multidrug resistant Pseudomonas aeruginosa clinical isolates from Recife, Brazil

    Science.gov (United States)

    Cavalcanti, Felipe Lira de Sá; Mirones, Cristina Rodríguez; Paucar, Elena Román; Montes, Laura Álvarez; Leal-Balbino, Tereza Cristina; de Morais, Marcia Maria Camargo; Martínez-Martínez, Luis; Ocampo-Sosa, Alain Antonio

    2015-01-01

    An investigation was carried out into the genetic mechanisms responsible for multidrug resistance in nine carbapenem-resistant Pseudomonas aeruginosaisolates from different hospitals in Recife, Brazil. Susceptibility to antimicrobial agents was determined by broth microdilution. Polymerase chain reaction (PCR) was employed to detect the presence of genes encoding β-lactamases, aminoglycoside-modifying enzymes (AMEs), 16S rRNA methylases, integron-related genes and OprD. Expression of genes coding for efflux pumps and AmpC cephalosporinase were assessed by quantitative PCR. The outer membrane proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The blaSPM-1, blaKPC-2 and blaGES-1 genes were detected in P. aeruginosaisolates in addition to different AME genes. The loss of OprD in nine isolates was mainly due to frameshift mutations, premature stop codons and point mutations. An association of loss of OprD with the overexpression of MexAB-OprM and MexXY-OprM was observed in most isolates. Hyper-production of AmpC was also observed in three isolates. Clonal relationship of the isolates was determined by repetitive element palindromic-PCR and multilocus sequence typing. Our results show that the loss of OprD along with overexpression of efflux pumps and β-lactamase production were responsible for the multidrug resistance in the isolates analysed. PMID:26676375

  5. A novel multidrug resistance plasmid isolated from an Escherichia coli strain resistant to aminoglycosides.

    Science.gov (United States)

    Sun, Hui; Li, Shasha; Xie, Zhijing; Yang, Fangfang; Sun, Yani; Zhu, Yanli; Zhao, Xiaomin; Jiang, Shijin

    2012-07-01

    Previous studies have reported several different plasmids that confer multidrug resistance (MDR) including resistance to aminoglycosides. In this study, we investigated the aminoglycoside resistance patterns for 224 Escherichia coli isolates from diseased chickens and ducks in China, characterized a novel MDR plasmid, and collected prevalence data on similar resistance plasmids. Antibiotic susceptibilities were determined using disc diffusion and the microdilution method. The plasmid pXZ was analysed by restriction fragment length polymorphism (RFLP) with EcoRI and SalI, and sequenced. The prevalence of similar resistance plasmids was assessed by multiplex PCR and by RFLP analysis. Among the 224 E. coli isolates, 189 (84.4%) were resistant to streptomycin, 125 (55.8%) were resistant to kanamycin, 116 (51.8%) were resistant to gentamicin, 106 (47.3%) were resistant to neomycin and 98 (43.8%) were resistant to amikacin. Among the 224 E. coli isolates, 17 contained a plasmid with the MDR-encoding region of pXZ, which showed high-level resistance to aminoglycosides (MICs of gentamicin and amikacin ≥ 512 mg/L). The plasmid pXZ was digested into five fragments by EcoRI and six fragments by SalI. The plasmid pXZ was a circular DNA molecule of 76635 bp with a 51.65% guanine + cytosine content and included four resistance genes (rmtB, fosA3, bla(TEM-1) and bla(CTX-M-24)). A novel MDR plasmid, pXZ, harbouring four resistance genes (rmtB, fosA3, bla(TEM-1) and bla(CTX-M)) was identified. To our knowledge, this is the first report of an aminoglycoside resistance plasmid harbouring the fosA3 gene.

  6. Molecular characterisation of multidrug-resistant Salmonella enterica serovar Typhimurium isolates from Gomel region, Belarus

    DEFF Research Database (Denmark)

    Tapalski, D.; Hendriksen, Rene S.; Hasman, Henrik;

    2007-01-01

    an infection outside hospitals in the Gomel region of Belarus. Thirty-one isolates were highly similar according to PFGE and MLVA typing, were multidrug-resistant, including resistance to ceftiofur, and harboured the bla(CTX-M-5) gene. These results indicate that a common source may have been responsible...

  7. Multidrug-Resistant Bacteroides fragilis Bacteremia in a US Resident: An Emerging Challenge

    Directory of Open Access Journals (Sweden)

    Cristian Merchan

    2016-01-01

    Full Text Available We describe a case of Bacteroides fragilis bacteremia associated with paraspinal and psoas abscesses in the United States. Resistance to b-lactam/b-lactamase inhibitors, carbapenems, and metronidazole was encountered despite having a recent travel history to India as the only possible risk factor for multidrug resistance. Microbiological cure was achieved with linezolid, moxifloxacin, and cefoxitin.

  8. Biofilm-Forming Capability of Highly Virulent, Multidrug-Resistant Candida auris

    Science.gov (United States)

    Sherry, Leighann; Ramage, Gordon; Kean, Ryan; Borman, Andrew; Johnson, Elizabeth M.; Richardson, Malcolm D.

    2017-01-01

    The emerging multidrug-resistant yeast pathogen Candida auris has attracted considerable attention as a source of healthcare–associated infections. We report that this highly virulent yeast has the capacity to form antifungal resistant biofilms sensitive to the disinfectant chlorhexidine in vitro. PMID:28098553

  9. Multidrug resistance in oncology and beyond : from imaging of drug efflux pumps to cellular drug targets

    NARCIS (Netherlands)

    Nagengast, Wouter B; Oude Munnink, Thijs H; Dijkers, Eli; Hospers, Geesiena; Brouwers, Adrienne H; Schröder, Carolien P; Lub-de Hooge, Marjolijn; de Vries, Elisabeth G E

    2010-01-01

    Resistance of tumor cells to several structurally unrelated classes of natural products, including anthracyclines, taxanes, and epipodophyllotoxines, is often referred as multidrug resistance (MDR). This is associated with ATP-binding cassette transporters, which function as drug efflux pumps such a

  10. Highly successful treatment outcome of multidrug-resistant tuberculosis in the Netherlands, 2000-2009

    NARCIS (Netherlands)

    van Altena, R.; de Vries, G.; Haar, C. H.; de Lange, W. C. M.; Magis-Escurra, C.; van den Hof, S.; van Soolingen, D.; Boeree, M. J.; van der Werf, T. S.

    2015-01-01

    SETTING: Resistance to the two key anti-tuberculosis drugs isoniazid and rifampicin is a characteristic of multidrug-resistant tuberculosis (MDR-TB). MDR-TB is a scourge requiring toxic, prolonged treatment and is associated with poor outcomes. The Netherlands is a country with a long-standing, inte

  11. Multi-drug resistant tuberculosis in the Netherlands : Personalised treatment and outcome

    NARCIS (Netherlands)

    van Altena, Richard

    2016-01-01

    Tuberculosis (TB) caused by bacilli that are resistant to the two major drugs, rifampicin and isoniazid is defined as Multi-Drug Resistant TB or MDRTB. MDRTB kills around 50% of people affected around the world. In contrast, treatment results of MDR-TB in the Netherlands (1985-2013) have consistentl

  12. Folate concentration dependent transport activity of the Multidrug Resistance Protein 1 (ABCC1).

    NARCIS (Netherlands)

    Hooijberg, J.H.; Jansen, G.; Assaraf, Y.G.; Kathmann, I.; Pieters, R.; Laan, AC; Veerman, A.J.P.; Kaspers, G.J.L.; Peters, G.J.

    2004-01-01

    The Multidrug Resistance Protein MRP1 (ABCC1) can confer resistance to a variety of therapeutic drugs. In addition, MRP1/ABCC1 mediates cellular export of natural folates, such as folic acid and l-leucovorin. In this study we determined whether cellular folate status affected the functional activity

  13. Role of multidrug resistance protein (MRP) in glutathione S-conjugate transport in mammalian cells

    NARCIS (Netherlands)

    Muller, M; deVries, EGE; Jansen, PLM

    1996-01-01

    The human multidrug resistance protein (MRP), a 190-kDa member of the ABC-protein superfamily, is an ATP-dependent glutathione S-conjugate carrier (GS-X pump) and is present in membranes of many, if not all, cells, Overexpression of MRP in tumor cells contributes to resistance to natural product dru

  14. Antibiotic resistance: What is so special about multidrug-resistant Gram-negative bacteria?

    Directory of Open Access Journals (Sweden)

    Exner, Martin

    2017-04-01

    Full Text Available In the past years infections caused by multidrug-resistant Gram-negative bacteria have dramatically increased in all parts of the world. This consensus paper is based on presentations, subsequent discussions and an appraisal of current literature by a panel of international experts invited by the Rudolf Schülke Stiftung, Hamburg. It deals with the epidemiology and the inherent properties of Gram-negative bacteria, elucidating the patterns of the spread of antibiotic resistance, highlighting reservoirs as well as transmission pathways and risk factors for infection, mortality, treatment and prevention options as well as the consequences of their prevalence in livestock. Following a global, One Health approach and based on the evaluation of the existing knowledge about these pathogens, this paper gives recommendations for prevention and infection control measures as well as proposals for various target groups to tackle the threats posed by Gram-negative bacteria and prevent the spread and emergence of new antibiotic resistances.

  15. Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study.

    Science.gov (United States)

    Amaratunga, Chanaki; Lim, Pharath; Suon, Seila; Sreng, Sokunthea; Mao, Sivanna; Sopha, Chantha; Sam, Baramey; Dek, Dalin; Try, Vorleak; Amato, Roberto; Blessborn, Daniel; Song, Lijiang; Tullo, Gregory S; Fay, Michael P; Anderson, Jennifer M; Tarning, Joel; Fairhurst, Rick M

    2016-03-01

    Artemisinin resistance in Plasmodium falciparum threatens to reduce the efficacy of artemisinin combination therapies (ACTs), thus compromising global efforts to eliminate malaria. Recent treatment failures with dihydroartemisinin-piperaquine, the current first-line ACT in Cambodia, suggest that piperaquine resistance may be emerging in this country. We explored the relation between artemisinin resistance and dihydroartemisinin-piperaquine failures, and sought to confirm the presence of piperaquine-resistant P falciparum infections in Cambodia. In this prospective cohort study, we enrolled patients aged 2-65 years with uncomplicated P falciparum malaria in three Cambodian provinces: Pursat, Preah Vihear, and Ratanakiri. Participants were given standard 3-day courses of dihydroartemisinin-piperaquine. Peripheral blood parasite densities were measured until parasites cleared and then weekly to 63 days. The primary outcome was recrudescent P falciparum parasitaemia within 63 days. We measured piperaquine plasma concentrations at baseline, 7 days, and day of recrudescence. We assessed phenotypic and genotypic markers of drug resistance in parasite isolates. The study is registered with ClinicalTrials.gov, number NCT01736319. Between Sept 4, 2012, and Dec 31, 2013, we enrolled 241 participants. In Pursat, where artemisinin resistance is entrenched, 37 (46%) of 81 patients had parasite recrudescence. In Preah Vihear, where artemisinin resistance is emerging, ten (16%) of 63 patients had recrudescence and in Ratanakiri, where artemisinin resistance is rare, one (2%) of 60 patients did. Patients with recrudescent P falciparum infections were more likely to have detectable piperaquine plasma concentrations at baseline compared with non-recrudescent patients, but did not differ significantly in age, initial parasite density, or piperaquine plasma concentrations at 7 days. Recrudescent parasites had a higher prevalence of kelch13 mutations, higher piperaquine 50% inhibitory

  16. Dihydroartemisinin–piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study

    Science.gov (United States)

    Amaratunga, Chanaki; Lim, Pharath; Suon, Seila; Sreng, Sokunthea; Mao, Sivanna; Sopha, Chantha; Sam, Baramey; Dek, Dalin; Try, Vorleak; Amato, Roberto; Blessborn, Daniel; Song, Lijiang; Tullo, Gregory S; Fay, Michael P; Anderson, Jennifer M; Tarning, Joel; Fairhurst, Rick M

    2016-01-01

    Background Artemisinin resistance in Plasmodium falciparum threatens to reduce the efficacy of artemisinin combination therapies (ACTs), thus compromising global efforts to eliminate malaria. Recent treatment failures with dihydroartemisinin-piperaquine, the current first-line ACT in Cambodia, suggest that piperaquine resistance may be emerging in this country. We explored the relation between artemisinin resistance and dihydroartemisinin–piperaquine failures, and sought to confirm the presence of piperaquine-resistant P falciparum infections in Cambodia. Methods In this prospective cohort study, we enrolled patients aged 2–65 years with uncomplicated P falciparum malaria in three Cambodian provinces: Pursat, Preah Vihear, and Ratanakiri. Participants were given standard 3-day courses of dihydroartemisinin–piperaquine. Peripheral blood parasite densities were measured until parasites cleared and then weekly to 63 days. The primary outcome was recrudescent P falciparum parasitaemia within 63 days. We measured piperaquine plasma concentrations at baseline, 7 days, and day of recrudescence. We assessed phenotypic and genotypic markers of drug resistance in parasite isolates. The study is registered with ClinicalTrials.gov, number NCT01736319. Findings Between Sept 4, 2012, and Dec 31, 2013, we enrolled 241 participants. In Pursat, where artemisinin resistance is entrenched, 37 (46%) of 81 patients had parasite recrudescence. In Preah Vihear, where artemisinin resistance is emerging, ten (16%) of 63 patients had recrudescence and in Ratanakiri, where artemisinin resistance is rare, one (2%) of 60 patients did. Patients with recrudescent P falciparum infections were more likely to have detectable piperaquine plasma concentrations at baseline compared with non-recrudescent patients, but did not differ significantly in age, initial parasite density, or piperaquine plasma concentrations at 7 days. Recrudescent parasites had a higher prevalence of kelch13 mutations

  17. In vivo resistance to chloroquine by Plasmodium vivax and Plasmodium falciparum at Nabire, Irian Jaya, Indonesia.

    Science.gov (United States)

    Baird, J K; Wiady, I; Fryauff, D J; Sutanihardja, M A; Leksana, B; Widjaya, H; Kysdarmanto; Subianto, B

    1997-06-01

    A survey of resistance to chloroquine by Plasmodium vivax and P. falciparum was conducted during May 1995 at three mesoendemic villages 30 km southeast of Nabire, near the central northern coast of Irian Jaya, Indonesia. The prevalence of malaria at Urusumu (n = 157), Margajaya (n = 573), and Topo (n = 199) was 18%. 9%, and 9%, respectively, with spleen rates among children of 79%, 10%, and 27%. Infected patients among those screened formed a study population of 64 subjects eligible for a 28-day in vivo test of resistance to chloroquine. Sixty-three patients successfully completed the test; 45 males and 18 females 1-60 years of age, of whom 29 were Javanese transmigrants of five years residence in Irian Jaya and 34 were native to Irian Jaya. The seven-day day cumulative incidence of therapeutic failure for P. vivax and P. falciparum was 15% (n = 34) and 30% (n = 37). The 14- and 28-day estimates of cumulative incidence were 45% and 64% for P. vivax and 58% and 89% for P. falciparum. Almost all recurrences appeared in the face of ordinarily effective levels of chloroquine and its major metabolite, desethylchloroquine, in whole blood (> or = 100 ng/ml). Four infections by P. malariae in subjects enrolled in this study cleared by day 2 and none reappeared within 28 days. Chloroquine no longer provides effective therapy for falciparum or vivax malaria along the northern coast of Irian Jaya, Indonesia.

  18. Enterococcus faecalis as multidrug resistance strains in clinical isolates in Imam Reza Hospital in Kermanshah, Iran.

    Science.gov (United States)

    Mohammadi, F; Ghafourian, S; Mohebi, R; Taherikalani, M; Pakzad, I; Valadbeigi, H; Hatami, V; Sadeghifard, N

    2015-01-01

    The current study aimed to investigate the prevalence of vancomycin-resistant Enterococcus in E. faecalis and E. faecium and antimicrobial susceptibility patterns, then dominant genes responsible for vancomycin resistance were determined. For this propose, 180 clinical isolates of Enterococcus were subjected for identification and antibiotic susceptibility assay. Then, the gene responsible vancomycin resistant strains were determined. The results demonstrated the E. faecalis as a dominant Enterococcus. Resistance to erythromycin was dominant and multidrug resistance strains observed in E. faecalis. vanA was responsible for vancomycin resistance. In conclusion, a high rate of resistance to antibiotics in Enterococcus is clearly problematic, and a novel strategy is needed to decrease resistance in Enterococcus.

  19. UDP-galactose and acetyl-CoA transporters as Plasmodium multidrug resistance genes.

    Science.gov (United States)

    Lim, Michelle Yi-Xiu; LaMonte, Gregory; Lee, Marcus C S; Reimer, Christin; Tan, Bee Huat; Corey, Victoria; Tjahjadi, Bianca F; Chua, Adeline; Nachon, Marie; Wintjens, René; Gedeck, Peter; Malleret, Benoit; Renia, Laurent; Bonamy, Ghislain M C; Ho, Paul Chi-Lui; Yeung, Bryan K S; Chow, Eric D; Lim, Liting; Fidock, David A; Diagana, Thierry T; Winzeler, Elizabeth A; Bifani, Pablo

    2016-01-01

    A molecular understanding of drug resistance mechanisms enables surveillance of the effectiveness of new antimicrobial therapies during development and deployment in the field. We used conventional drug resistance selection as well as a regime of limiting dilution at early stages of drug treatment to probe two antimalarial imidazolopiperazines, KAF156 and GNF179. The latter approach permits the isolation of low-fitness mutants that might otherwise be out-competed during selection. Whole-genome sequencing of 24 independently derived resistant Plasmodium falciparum clones revealed four parasites with mutations in the known cyclic amine resistance locus (pfcarl) and a further 20 with mutations in two previously unreported P. falciparum drug resistance genes, an acetyl-CoA transporter (pfact) and a UDP-galactose transporter (pfugt). Mutations were validated both in vitro by CRISPR editing in P. falciparum and in vivo by evolution of resistant Plasmodium berghei mutants. Both PfACT and PfUGT were localized to the endoplasmic reticulum by fluorescence microscopy. As mutations in pfact and pfugt conveyed resistance against additional unrelated chemical scaffolds, these genes are probably involved in broad mechanisms of antimalarial drug resistance.

  20. Sequence and gene expression of chloroquine resistance transporter (pfcrt in the association of in vitro drugs resistance of Plasmodium falciparum

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    Bray Patrick G

    2011-02-01

    Full Text Available Abstract Background Plasmodium falciparum chloroquine resistance (CQR transporter protein (PfCRT is known to be the important key of CQR. Recent studies have definitively demonstrated a link between mutations in the gene pfcrt and resistance to chloroquine in P. falciparum. Although these mutations are predictive of chloroquine resistance, they are not quantitatively predictive of the degree of resistance. Methods In this study, a total of 95 recently adapted P. falciparum isolates from Thailand were included in the analysis. Parasites were characterized for their drug susceptibility phenotypes and genotypes with respect to pfcrt. From the original 95 isolates, 20 were selected for complete pfcrt sequence analysis. Results Almost all of the parasites characterized carried the previously reported mutations K76T, A220S, Q271E, N326S, I356T and R371I. On complete sequencing, isolates were identified with novel mutations at K76A and E198K. There was a suggestion that parasites carrying E198K were less resistant than those that did not. In addition, pfcrt and pfmdr1 gene expression were investigated by real-time PCR. No relationship between the expression level of either of these genes and response to drug was observed. Conclusion Data from the present study suggest that other genes must contribute to the degree of resistance once the resistance phenotype is established through mutations in pfcrt.

  1. A four-year surveillance program for detection of Plasmodium falciparum chloroquine resistance in Honduras

    Directory of Open Access Journals (Sweden)

    Gustavo A Fontecha

    2014-07-01

    Full Text Available Countries could use the monitoring of drug resistance in malaria parasites as an effective early warning system to develop the timely response mechanisms that are required to avert the further spread of malaria. Drug resistance surveillance is essential in areas where no drug resistance has been reported, especially if neighbouring countries have previously reported resistance. Here, we present the results of a four-year surveillance program based on the sequencing of the pfcrt gene of Plasmodium falciparum populations from endemic areas of Honduras. All isolates were susceptible to chloroquine, as revealed by the pfcrt “CVMNK” genotype in codons 72-76.

  2. A four-year surveillance program for detection of Plasmodium falciparum chloroquine resistance in Honduras.

    Science.gov (United States)

    Fontecha, Gustavo A; Sanchez, Ana L; Mendoza, Meisy; Banegas, Engels; Mejía-Torres, Rosa E

    2014-07-01

    Countries could use the monitoring of drug resistance in malaria parasites as an effective early warning system to develop the timely response mechanisms that are required to avert the further spread of malaria. Drug resistance surveillance is essential in areas where no drug resistance has been reported, especially if neighbouring countries have previously reported resistance. Here, we present the results of a four-year surveillance program based on the sequencing of the pfcrt gene of Plasmodium falciparum populations from endemic areas of Honduras. All isolates were susceptible to chloroquine, as revealed by the pfcrt "CVMNK" genotype in codons 72-76.

  3. Effects of multidrug resistance, antisense RNA on the chemosensitivity of hepatocellular carcinoma cells

    Institute of Scientific and Technical Information of China (English)

    Bo Li; Jian-Ping Gong; Tian Ye; Lei Zhao; De-Hua Li; Xing-Hua Gou; Lan-Ying Zhao; Lei Han; Lin Chen; Lu-Nan Yan

    2006-01-01

    BACKGROUND: Multidrug resistance is a major obstacle in cancer chemotherapy. We examined whether the antisense RNA of multidrug resistance gene 1 (mdr1) could reverse multidrug resistance in the human hepatocellular carcinoma (HCC) cell line SMMC7721/ADM. METHODS: The recombinant adenoviruses pAdEasy-GFP-ASmdr1 product was produced by the adenoviral vector AdEasy system, which can express antisense RNA against the mdr1 gene. Following that, the recombinant adenovirus was transfected into the P-glycoprotein-producing multidrug resistance cell line, SMMC7721/ADM human HCC cells resistant to adriamycin (ADM) and daunorubicin (DNR). In order to investigate the reversal of multidrug resistance phenotype, we measured the expression of mdr1 mRNA by RT-PCR and the production of P-glycoprotein by lfow cytometry. The sensitivities for ADM and DNR SMMC7721/ADM cells were examined by [3-(4, 5-dimethylthi-azol-2-yl)-2,5 diphenyl-terazolium bromide] (MTT) analysis. RESULTS: The low-level expression of mdr1 mRNA and P-glycoprotein production were observed in parental sensitive cells SMMC/7721 in addition to the overexpression of mdr1 mRNA and P-glycoprotein in SMMC7721/ADM cells. The transfection of antisense-RNA into SMMC7721/ADM cells resulted in decreases of mdr1 mRNA and P-glycoprotein, but increase of drug sensitivities. The sensitivities of transfected SMMC7721/ADM cells to ADM and DNR in IC50 reduced by 31.25% and 62.96%respectively. CONCLUSIONS: Mdr1 antisense RNA can increase the sensitivities of SMMC7721/ADM cells to anticancer drug by decreasing the expression of the mdr1 gene and inhibiting P-glycoprotein expression. This strategy may be applicable to cancer patients with P-glycoportein mediated multidrug resistance.

  4. Multidrug Resistant Salmonella typhi in Asymptomatic Typhoid Carriers among Food Handlers in Namakkal District, Tamil Nadu

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    Senthilkumar B

    2005-01-01

    Full Text Available Purpose: to screen Salmonella typhi in asymptomatic typhoid carriers and to find out drug resistance and ability of the strains to transmit drug resistance to other bacteria. Methods: Cultural characters, biochemical tests, antibiotic sensitivity test (disc diffusion, agarose gel electrophoresis, and conjugation protocols were done. Thirty five stool samples were collected from the suspected food handlers for the study. Results: Among 35 samples, (17.14% yielded a positive result. Out of these 4 (20.0% were women and 2 (13.33% were men. The isolates were tested with a number of conventional antibiotics viz, amikacin, amoxicillin, ampicillin, chloramphenicol, ciprofloxacin, co-trimaxazole, rifampicin, gentamicin, nalidixic acid, ofloxacin and tetracycline. Five isolates were having the multidrug resistant character. Four (66.66% multidrug resistant isolates were found to have plasmids, while one (16.66% multidrug resistant isolate had no plasmid and the chromosome encoded the resistance. Only one strain (16.66% showed single antibiotic resistance in the study and had no plasmid DNA. The molecular weights of the plasmids were determined and found to be 120 kb.The mechanism of spreading of drug resistance through conjugation process was analyzed. In the conjugation studies, the isolates having R+ factor showed the transfer of drug resistance through conjugation, which was determined by the development of antibiotic resistance in the recipients. Conclusion: This study shows that drug resistant strains are able to transfer genes encoding drug resistance.

  5. Falciparum malaria in the north of Laos: the occurrence and implications of the Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene haplotype SVMNT

    DEFF Research Database (Denmark)

    Dittrich, Sabine; Alifrangis, Michael; Stohrer, Jörg M;

    2005-01-01

    OBJECTIVE: The Pfcrt-gene encodes a transmembrane protein located in the Plasmodium falciparum digestive vacuole. Chloroquine resistant (CQR) strains of African and Southeast Asian origin carry the Pfcrt-haplotype (c72-76) CVIET, whereas most South American and Papua New Guinean CQR stains carry...

  6. Colonization with Multidrug-Resistant Bacteria – On the Efficiency of Local Decolonization Procedures

    Science.gov (United States)

    Münch, Julia; Hagen, Ralf Matthias; Müller, Martin; Kellert, Viktor; Wiemer, Dorothea Franziska; Hinz, Rebecca; Schwarz, Norbert Georg; Frickmann, Hagen

    2017-01-01

    The effectiveness of a disinfectant-based decolonization strategy for multidrug-resistant bacteria like extended spectrum β-lactamase (ESBL)-positive Gram-negative bacteria with or without additional fluoroquinolon and carbapenem resistance as well as vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus was assessed. Between 2011 and 2015, 25 patients from Libya, Syria, and the Ukraine with war traumata were treated at the Bundeswehr hospital Hamburg. The patients were heavily colonized and infected with multidrug-resistant bacteria, altogether comprising 371 distinct combinations of pathogens and isolation sites. Local disinfection was assessed for effectiveness regarding successful decolonization of multidrug-resistant bacteria. Altogether, 170 cases of successful decolonization were observed, comprising 95 (55.8%) such events at sampling sites that were accessible to disinfecting procedures. The remaining 75 (44.2%) decolonization events had to be considered as spontaneous. In contrast, 95 out of 172 (55.2%) colonized isolation sites that were accessible to disinfection procedures were successfully decolonized. Patient compliance with the enforced hygiene procedures was associated with decolonization success. Systemic antibiotic therapy did not relevantly affect isolation time. Disinfecting washing moderately supports local decolonization of multidrug-resistant pathogens in comparison with spontaneous decolonization rates if the patients’ compliance with the applied hygiene procedures is ensured. PMID:28690877

  7. Multiple origins and regional dispersal of resistant dhps in African Plasmodium falciparum malaria.

    Directory of Open Access Journals (Sweden)

    Richard J Pearce

    2009-04-01

    Full Text Available Although the molecular basis of resistance to a number of common antimalarial drugs is well known, a geographic description of the emergence and dispersal of resistance mutations across Africa has not been attempted. To that end we have characterised the evolutionary origins of antifolate resistance mutations in the dihydropteroate synthase (dhps gene and mapped their contemporary distribution.We used microsatellite polymorphism flanking the dhps gene to determine which resistance alleles shared common ancestry and found five major lineages each of which had a unique geographical distribution. The extent to which allelic lineages were shared among 20 African Plasmodium falciparum populations revealed five major geographical groupings. Resistance lineages were common to all sites within these regions. The most marked differentiation was between east and west African P. falciparum, in which resistance alleles were not only of different ancestry but also carried different resistance mutations.Resistant dhps has emerged independently in multiple sites in Africa during the past 10-20 years. Our data show the molecular basis of resistance differs between east and west Africa, which is likely to translate into differing antifolate sensitivity. We have also demonstrated that the dispersal patterns of resistance lineages give unique insights into recent parasite migration patterns.

  8. Multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii: resistance mechanisms and implications for therapy.

    Science.gov (United States)

    Zavascki, Alexandre P; Carvalhaes, Cecília G; Picão, Renata C; Gales, Ana C

    2010-01-01

    Pseudomonas aeruginosa and Acinetobacter baumannii are major nosocomial pathogens worldwide. Both are intrinsically resistant to many drugs and are able to become resistant to virtually any antimicrobial agent. An increasing prevalence of infections caused by multidrug-resistant (MDR) isolates has been reported in many countries. The resistance mechanisms of P. aeruginosa and A. baumannii include the production of beta-lactamases, efflux pumps, and target-site or outer membrane modifications. Resistance to multiple drugs is usually the result of the combination of different mechanisms in a single isolate or the action of a single potent resistance mechanism. There are many challenges in the treatment of MDR P. aeruginosa and A. baumannii, especially considering the absence of new antimicrobials in the drug-development pipeline. In this review, we present the major resistance mechanisms of P. aeruginosa and A. baumannii, and discuss how they can affect antimicrobial therapy, considering recent clinical, microbiological, pharmacokinetic and pharmacodynamic findings of the main drugs used to treat MDR isolates.

  9. Identification of mutations conferring streptomycin resistance in multidrug-resistant tuberculosis of China.

    Science.gov (United States)

    Zhao, Li-Li; Liu, Hai-Can; Sun, Qing; Xiao, Tong-Yang; Zhao, Xiu-Qin; Li, Gui-Lian; Zeng, Chun-Yan; Wan, Kang-Lin

    2015-10-01

    We investigated the spectrum and frequency of mutations in rpsL, rrs, and gidB among 140 multidrug-resistant tuberculosis (MDR-TB) clinical isolates from China. The association between mutations and different genotypes was also analyzed. Our data revealed that 65.7% of MDR-TB were resistant to streptomycin (STR), and 90.2% of STR-resistant isolates were Beijing strains. STR resistance was correlated with Beijing family (P=0.00). Compared with phenotypic data, detection of mutations for the combination of these 3 genes exhibited 94.6% sensitivity, 91.7% specificity, and 93.6% accuracy. The most common mutations in STR-resistant isolates were rpsL128, 262, and rrs514, of which rpsL128 showed association with Beijing lineage (P=0.00). A combination of these 3 mutations can serve as the reliable predictors for STR resistance, showing the sensitivity, specificity, and accuracy of 85.9%, 97.9%, and 90.0%, respectively. Furthermore, gidBA276C, not A615G, was Beijing lineage specific. These findings are useful to develop rapid molecular diagnostic methods for STR resistance in China.

  10. Reversal of HCC Drug Resistance by Using Hammerhead Ribozymes against Multidrug Resistance 1 Gene

    Institute of Scientific and Technical Information of China (English)

    QIAO Sen; WANG Hai; CHEN Xiaoping

    2005-01-01

    To reverse multidrug resistance(MDR) of HepG2 by anti-MDR1 hammerhead ribozyme,an anti-MDR1 hammerhead ribozyme was developed and delivered to P-gp-overproducing human hepatocarcinoma cell line HepG2 by a retroviral vector containing RNA polymerase Ⅲ promoter.The expression of mdr1/Pgp and Rz was detected in HepG2, HepG2 multidrug-resistant cell line and HepG2 Rz-transfected cells by semi quantitative RT-PCR and Western blot methods. Moreover, MTT assay was employed to detect the sensitivity of these ribozyme-transfected cells, and Rhodamine123 (Rh123) was used to test the function of Pgp. The Rz- transfected HepG2 cells became doxorubicin-sensitive, which was concomitant with the decreased MDR1 expression. The study showed that the retrovirus vector encoding the anti-MDR1 ribozyme may be applicable to the treatment of MDR cells.

  11. Management of patients with multidrug-resistant/extensively drug-resistant tuberculosis in Europe : a TBNET consensus statement

    NARCIS (Netherlands)

    Lange, Christoph; Abubakar, Ibrahim; Alffenaar, Jan-Willem C.; Bothamley, Graham; Caminero, Jose A.; Carvalho, Anna Cristina C.; Chang, Kwok-Chiu; Codecasa, Luigi; Correia, Ana; Crudu, Valeriu; Davies, Peter; Dedicoat, Martin; Drobniewski, Francis; Duarte, Raquel; Ehlers, Cordula; Erkens, Connie; Goletti, Delia; Guenther, Gunar; Ibraim, Elmira; Kampmann, Beate; Kuksa, Liga; de lange, Wiel; van Leth, Frank; van Lunzen, Jan; Matteelli, Alberto; Menzies, Dick; Monedero, Ignacio; Richter, Elvira; Ruesch-Gerdes, Sabine; Sandgren, Andreas; Scardigli, Anna; Skrahina, Alena; Tortoli, Enrico; Volchenkov, Grigory; Wagner, Dirk; van der Werf, Marieke J.; Williams, Bhanu; Yew, Wing-Wai; Zellweger, Jean-Pierre; Cirillo, Daniela Maria

    2014-01-01

    The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) substantially challenges TB control, especially in the European Region of the World Health Organization, where the highest prevalence of MDR/XDR cases is reported. The current management of patients wit

  12. Resistant plasmid profile analysis of multidrug resistant Escherichia coli isolated from urinary tract infections in Abeokuta, Nigeria.

    Science.gov (United States)

    Akingbade, O; Balogun, S; Ojo, D; Akinduti, P; Okerentugba, P O; Nwanze, J C; Okonko, I O

    2014-12-01

    Multi-drug resistant Escherichia coli has become a major threat and cause of many urinary tract infections (UTIs) in Abeokuta, Nigeria. This study was carried out to determine the resistant plasmids of multidrug resistant Escherichia coli isolated from (Urinary tract infections)UTIs in Abeokuta. A total of 120 Escherichia coli isolates were obtained from urine samples collected from patients attending inpatient and outpatient clinics presenting UTI; with their biodata. Antibiotics susceptibility was performed and multi-drug resistant isolates were selected for plasmid profiling. Plasmids were extracted by the alkaline lysis method, electrophoresed on 0.8% agarose gel and profiled using a gel-photo documentation system gel. Escherichia coli isolates obtained shows high resistance to cloxacillin (92.5%), amoxicillin (90.8%), ampicillin (90.8%), erythromycin (75.8%), cotrimoxazole (70.0%), streptomycin (70.0%) and tetracycline (68.3%) while 85.8% and 84.2% were susceptible to gentamycin and ceftazidime respectively. Sixteen Escherichia coli strains were observed to be resistant to more than two classes of antibiotics. The resistant plasmid DNA was detectable in 6(37.5%) of the 16 multidrug resistant Escherichia coli having single sized plasmids of the same weight 854bp and were all resistant to erythromycin, cefuroxime, cloxacillin, amoxicillin, ampicillin and cotrimoxazole. This study has highlighted the emergence of multidrug resistant R-plasmids among Escherichia coli causing urinary tract infections in Abeokuta, Nigeria. There is a high level of resistance to many antimicrobials that are frequently used in Abeokuta, Nigeria.

  13. Multidrug resistance and ESBL-producing Salmonella spp. isolated from broiler processing plants

    Science.gov (United States)

    Ziech, Rosangela Estel; Lampugnani, Camila; Perin, Ana Paula; Sereno, Mallu Jagnow; Sfaciotte, Ricardo Antônio Pilegi; Viana, Cibeli; Soares, Vanessa Mendonça; de Almeida Nogueira Pinto, José Paes; dos Santos Bersot, Luciano

    2016-01-01

    The aim of this study was to investigate the occurrence of multidrug-resistant, extended spectrum beta-lactamase (ESBL) producing Salmonella spp. isolated from conveyor belts of broiler cutting rooms in Brazilian broiler processing plants. Ninety-eight strains of Salmonella spp. were analyzed. Multidrug resistance was determined by the disk diffusion test and the susceptibility of the isolated bacteria was evaluated against 18 antimicrobials from seven different classes. The double disk diffusion test was used to evaluate ESBL production. Of the 98 strains tested, 84 were multidrug resistant. The highest rates of resistance were against nalidixic acid (95%), tetracycline (91%), and the beta-lactams: ampicillin and cefachlor (45%), followed by streptomycin and gentamicin with 19% and 15% of strain resistance, respectively. By contrast, 97% of the strains were sensitive to chloramphenicol. 45% of the strains were positive for the presence of ESBL activity. In this study, high rates of multidrug resistance and ESBL production were observed in Salmonella spp. PMID:26887244

  14. Multidrug resistance and ESBL-producing Salmonella spp. isolated from broiler processing plants

    Directory of Open Access Journals (Sweden)

    Rosangela Estel Ziech

    2016-03-01

    Full Text Available Abstract The aim of this study was to investigate the occurrence of multidrug-resistant, extended spectrum beta-lactamase (ESBL producing Salmonella spp. isolated from conveyor belts of broiler cutting rooms in Brazilian broiler processing plants. Ninety-eight strains of Salmonella spp. were analyzed. Multidrug resistance was determined by the disk diffusion test and the susceptibility of the isolated bacteria was evaluated against 18 antimicrobials from seven different classes. The double disk diffusion test was used to evaluate ESBL production. Of the 98 strains tested, 84 were multidrug resistant. The highest rates of resistance were against nalidixic acid (95%, tetracycline (91%, and the beta-lactams: ampicillin and cefachlor (45%, followed by streptomycin and gentamicin with 19% and 15% of strain resistance, respectively. By contrast, 97% of the strains were sensitive to chloramphenicol. 45% of the strains were positive for the presence of ESBL activity. In this study, high rates of multidrug resistance and ESBL production were observed in Salmonella spp.

  15. Multidrug resistant Acinetobacter baumannii: a descriptive study in a city hospital

    Directory of Open Access Journals (Sweden)

    Pratap Siddharth

    2010-07-01

    Full Text Available Abstract Background Multidrug resistant Acinetobacter baumannii, (MRAB is an important cause of hospital acquired infection. The purpose of this study is to determine the risk factors for MRAB in a city hospital patient population. Methods This study is a retrospective review of a city hospital epidemiology data base and includes 247 isolates of Acinetobacter baumannii (AB from 164 patients. Multidrug resistant Acinetobacter baumannii was defined as resistance to more than three classes of antibiotics. Using the non-MRAB isolates as the control group, the risk factors for the acquisition of MRAB were determined. Results Of the 247 AB isolates 72% (177 were multidrug resistant. Fifty-eight percent (143/247 of isolates were highly resistant (resistant to imipenem, amikacin, and ampicillin-sulbactam. Of the 37 patients who died with Acinetobacter colonization/infection, 32 (86% patients had the organism recovered from the respiratory tract. The factors which were found to be significantly associated (p ≤ 0.05 with multidrug resistance include the recovery of AB from multiple sites, mechanical ventilation, previous antibiotic exposure, and the presence of neurologic impairment. Multidrug resistant Acinetobacter was associated with significant mortality when compared with sensitive strains (p ≤ 0.01. When surgical patients (N = 75 were considered separately, mechanical ventilation and multiple isolates remained the factors significantly associated with the development of multidrug resistant Acinetobacter. Among surgical patients 46/75 (61% grew a multidrug resistant strain of AB and 37/75 (40% were resistant to all commonly used antibiotics including aminoglycosides, cephalosporins, carbepenems, extended spectrum penicillins, and quinolones. Thirty-five percent of the surgical patients had AB cultured from multiple sites and 57% of the Acinetobacter isolates were associated with a co-infecting organism, usually a Staphylococcus or Pseudomonas. As

  16. Differential expression of sphingolipids in P-glycoprotein or multidrug resistance-related protein 1 expressing human neuroblastoma cell lines

    NARCIS (Netherlands)

    Dijkhuis, AJ; Douwes, J; Kamps, W; Sietsma, H; Kok, JW

    2003-01-01

    The sphingolipid composition and multidrug resistance status of three human neuroblastoma cell lines were established. SK-N-FI cells displayed high expression and functional (efflux) activity of P-glycoprotein, while multidrug resistance-related protein 1 was relatively abundant and most active in S

  17. Expression and cellular distribution of multidrug resistance-related proteins in the hippocampus of patients with mesial temporal lobe epilepsy

    NARCIS (Netherlands)

    E. Aronica; J.A. Gorter; M. Ramkema; S. Redeker; F. Ozbas-Gercer; E.A. van Vliet; G.L. Scheffer; R.J. Scheper; P. van der Valk; J.C. Baayen; D. Troost

    2004-01-01

    Purpose: This study investigated the cellular distribution of different multidrug resistance (MDR)-related proteins such as P-glycoprotein (P-gp), the multidrug resistance-associated proteins (MRP) 1 and 2, and the major vault protein (MVP) in normal and sclerotic hippocampus of patients with medica

  18. Differential expression of sphingolipids in P-glycoprotein or multidrug resistance-related protein 1 expressing human neuroblastoma cell lines

    NARCIS (Netherlands)

    Dijkhuis, AJ; Douwes, J; Kamps, W; Sietsma, H; Kok, JW

    2003-01-01

    The sphingolipid composition and multidrug resistance status of three human neuroblastoma cell lines were established. SK-N-FI cells displayed high expression and functional (efflux) activity of P-glycoprotein, while multidrug resistance-related protein 1 was relatively abundant and most active in

  19. Multidrug-resistant Gram-negative bacteria-resistant infections: epidemiology, clinical issues and therapeutic options

    Directory of Open Access Journals (Sweden)

    Matteo Bassetti

    2016-12-01

    Full Text Available In the last decade, we have witnessed a dramatic increase in the number of multidrug resistant Gram-negative (MDRGN bacterial pathogens, both in Italy and worldwide, with Enterobacteriacae (mostly Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii being the major threats in clinical practice. Inadequate empirical antimicrobial therapy of severe infections caused by MDR Enterobacteriacae has been associated with an increased morbidity and mortality. However, a careful selection of patients who may receive empirical treatment covering MDR Enterobacteriacae is important to avoid the overuse of broad-spectrum antibiotics. The aim of this review is to describe the mechanism of resistance, epidemiology, risk factors, clinical issues, and therapeutic options for MDRGN pathogens.

  20. Molecular analysis of chloroquine and sulfadoxine-pyrimethamine resistance-associated alleles in Plasmodium falciparum isolates from Nicaragua.

    Science.gov (United States)

    Sridaran, Sankar; Rodriguez, Betzabe; Soto, Aida Mercedes; Macedo De Oliveira, Alexandre; Udhayakumar, Venkatachalam

    2014-05-01

    Chloroquine (CQ) is used as a first-line therapy for the treatment of Plasmodium falciparum malaria in Nicaragua. We investigated the prevalence of molecular markers associated with CQ and sulfadoxine-pyrimethamine (SP) resistance in P. falciparum isolates obtained from the North Atlantic Autonomous Region of Nicaragua. Blood spots for this study were made available from a CQ and SP drug efficacy trial conducted in 2005 and also from a surveillance study performed in 2011. Polymorphisms in P. falciparum CQ resistance transporter, dihydrofolate reductase, and dihydropteroate synthase gene loci that are associated with resistance to CQ, pyrimethamine, and sulfadoxine, respectively, were detected by DNA sequencing. In the 2005 dataset, only 2 of 53 isolates had a CQ resistance allele (CVIET), 2 of 52 had a pyrimethamine resistance allele, and 1 of 49 had a sulfadoxine resistance allele. In the 2011 dataset, none of 45 isolates analyzed had CQ or SP resistance alleles.

  1. [MOLECULAR CHARACTERISTICS OF THE MULTIDRUG-RESISTANT MYCOBACTERIUM TUBERCULOSIS STRAINS IN THE NORTHWEST RUSSIA].

    Science.gov (United States)

    Vyazovaya, A A; Mokrousov, I V; Zhuravlev, V Yu; Solovieva, N S; Otten, T F; Manicheva, O A; Vishnevsky, B I; Narvskaya, O V

    2016-01-01

    The goal of this work was to study the genotypic characteristics of the multidrug-resistant (MDR, i.e., resistant to at least rifampicine and isoniazid) Mycobacterium tuberculosis strains isolated in 2011-2012 from tuberculosis (TB) patients in the Northwest Russia. Spoligotyping of 195 M. tuberculosis isolates identified 14 different spoligotypes and assigned isolates to the genetic families Beijing (n = 162, 83%), LAM (n = 15), H3/URAL (n = 14), as well as T, Haarlem and X. Spoligotypes SIT1 (Beijing), SIT42 (LAM) and SIT262 (H3/URAL) were the most prevalent. Irrespective to the genotype, all the isolates were resistant to streptomycin. The multidrug resistance was accompanied by the resistance to ethionamide (56%), amikacin (31%), kanamycin (40%), and capreomycin (33%). The ethambutol resistance was found in 71% (n = 115) and 42% (n = 14) of the Beijing and non-Beijing strains, respectively (p Russia continues to be dominated by the Beijing family strains.

  2. Importance of inducible multidrug resistance 1 expression in HL-60 cells resistant to gemtuzumab ozogamicin.

    Science.gov (United States)

    Matsumoto, Taichi; Jimi, Shiro; Hara, Shuuji; Takamatsu, Yasushi; Suzumiya, Junji; Tamura, Kazuo

    2012-07-01

    Resistance to gemtuzumab ozogamicin (GO) hampers the effective treatment of refractory acute myeloid leukemia (AML). To clarify the mechanism of resistance to GO, HL-60 cells were persistently exposed to GO in order to establish GO-resistant HL-60 (HL-60/GOR) cells. Multidrug resistance 1 (MDR-1) was strongly expressed in HL-60/GOR cells, but not in HL-60 cells. Although withdrawal of GO after the chronic exposure of HL-60/GOR cells to this compound gradually decreased MDR-1 expression to trace levels, reintroducing GO restored high MDR-1 expression in HL-60/GOR cells, but not in HL-60 cells. These results indicate that HL-60/GOR cells acquired the ability to induce MDR-1 expression in response to GO. U0126, a MEK1/2 inhibitor, prevented GO-inducible MDR-1 expression and abrogated GO resistance in HL-60/GOR cells. These results suggest that in the clinical use of GO, inducible MDR-1 expression in tumor cells should be investigated before treatment with GO. If the cells are positive then MEK1/2 inhibitors may be effective in overcoming resistance to GO.

  3. [Multidrug-Resistant Tuberculosis by Strains of Beijing Family, in Patients from Lisbon, Portugal: Preliminary Report].

    Science.gov (United States)

    Maltez, Fernando; Martins, Teresa; Póvoas, Diana; Cabo, João; Peres, Helena; Antunes, Francisco; Perdigão, João; Portugal, Isabel

    2017-03-31

    Beijing family strains of Mycobacterium tuberculosis are associated with multidrug-resistance. Although strains of the Lisboa family are the most common among multidrug-resistant and extensively drug-resistant patients in the region, several studies have reported the presence of the Beijing family. However, the features of patients from whom they were isolated, are not yet known. Retrospective study involving 104 multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis, from the same number of patients, isolated and genotyped between 1993 and 2015 in Lisbon. We assessed the prevalence of strains of both families and the epidemiologic and clinical features of those infected with Beijing family strains. Seventy-four strains (71.2%) belonged to the Lisboa family, 25 (24.0%) showed a unique genotypic pattern and five (4.8%) belonged to the Beijing family, the latter identified after 2009. Those infected with Beijing family strains were angolan (n = 1), ukrainian (n = 2) and portuguese (n = 2), mainly young-aged and, four of five immunocompetent and with no past history of tuberculosis. All had multidrug-resistant tuberculosis. We did not find any distinctive clinical or radiological features, neither a predominant resistance pattern. Cure rate was high (four patients). Although the number of infected patients with Beijing strains was small, it suggests an important proportion of primary tuberculosis, a potential for transmission in the community but also a better clinical outcome when compared to other reported strains, such as W-Beijing and Lisboa. Although Lisboa family strains account for most of the multidrug and extensively drug-resistant tuberculosis cases in Lisbon area, Beijing strains are transmitted in the city and might change the local characteristics of the epidemics.

  4. Priorities in the prevention and control of multidrug-resistant Enterobacteriaceae in hospitals.

    LENUS (Irish Health Repository)

    Khan, A S

    2012-10-01

    Multidrug-resistant Enterobacteriaceae (MDE) are a major public health threat due to international spread and few options for treatment. Furthermore, unlike meticillin-resistant Staphylococcus aureus (MRSA), MDE encompass several genera and multiple resistance mechanisms, including extended-spectrum beta-lactamases and carbapenemases, which complicate detection in the routine diagnostic laboratory. Current measures to contain spread in many hospitals are somewhat ad hoc as there are no formal national or international guidelines.

  5. Household Risk Factors for Colonization with Multidrug-Resistant Staphylococcus aureus Isolates

    Science.gov (United States)

    Davis, Meghan F.; Peterson, Amy E.; Julian, Kathleen G.; Greene, Wallace H.; Price, Lance B.; Nelson, Kenrad; Whitener, Cynthia J.; Silbergeld, Ellen K.

    2013-01-01

    Antimicrobial resistance, particularly in pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), limits treatment options and increases healthcare costs. To understand patient risk factors, including household and animal contact, potentially associated with colonization with multidrug-resistant MRSA isolates, we performed a prospective study of case patients colonized with MRSA on admission to a rural tertiary care hospital. Patients were interviewed and antimicrobial resistance patterns were tested among isolates from admitted patients colonized with MRSA in 2009–10. Prevalence of resistance was compared by case-patient risk factors and length-of-stay outcome among 88 MRSA case patients. Results were compared to NHANES 2003–04. Overall prevalence of multidrug resistance (non-susceptibility to ≥four antimicrobial classes) in MRSA nasal isolates was high (73%) and was associated with a 1.5-day increase in subsequent length of stay (p = 0.008). History of hospitalization within the past six months, but not antimicrobial use in the same time period, was associated with resistance patterns. Within a subset of working-age case patients without recent history of hospitalization, animal contact was potentially associated with multidrug resistance. History of hospitalization, older age, and small household size were associated with multidrug resistance in NHANES data. In conclusion, recent hospitalization of case patients was predictive of antimicrobial resistance in MRSA isolates, but novel risk factors associated with the household may be emerging in CA-MRSA case patients. Understanding drivers of antimicrobial resistance in MRSA isolates is important to hospital infection control efforts, relevant to patient outcomes and to indicators of the economic burden of antimicrobial resistance. PMID:23359808

  6. INDUCTION OF DRUG RESISTANCE IN PLASMODIUM FALCIPARUM: AN INTERMITTENT DRUG EXPOSURE METHOD

    Directory of Open Access Journals (Sweden)

    M.Nateghpour

    1998-03-01

    Full Text Available The production of experimentally induced drug resistance in the laboratory provides valuable opportunities for investigators to study the nature and genetics of drug resistance mechanisms to a given agent, patterns of cross resistance and the mode of action of drugs. At the beginning the continuous drug exposure was chosen as a standard procedure to produce drug— resistant strains of P. falciparum,.but later on some other methods were also applied. An intermittent drug exposure method as a novel procedure has been introduced in this study. Intermittent exposure of chloroquine resistant Kl and chloroquine sensitive T9.96 strains of P. falciparum to halofantrine culminated in a relatively rapid reduction in sensitivity to the drug. The response of halofantrifle - resistnat K1HF and T9.96 strains and parent parasites to halofantrifle, inefloquine, quinine and chloroquine was determined. The results indicated that the effectiveness of halofantrine to K1HF and T9.96HF strains decreased 9 and 3 folds respectively, compared to the parent parasites. Cross -resistance occurred among halofantrine. mefloquine and quinine. Halofantrine resistance was associated with enhanced chloroquine sensitivity in the strain derived from chloroquine - resistant K1 strain, hut not in the strain derived from chloroquine - sensitive T9.96 parasites.

  7. Prevalence of multidrug resistant pathogens in children with urinary tract infection: a retrospective analysis

    Directory of Open Access Journals (Sweden)

    Srinivasan S, Madhusudhan NS

    2014-11-01

    Full Text Available Urinary tract infection (UTI is one of the commonest medical problems in children. It can distress the child and may cause kidney damage. Prompt diagnosis and effective treatment can prevent complications in the child. But treatment of UTI in children has now become a challenge due to the emergence of multidrug resistant bacteria. Aims & Objectives: To know the bacteriological profile and susceptibility pattern of urinary tract infections in children and to know the prevalence of multidrug resistant uropathogens. Materials & Methods: A retrospective analysis was done on all paediatric urine samples for a period of one year. A total of 1581 samples were included in the study. Antimicrobial susceptibility testing was done on samples showing significant growth by Kirby-Bauer disc diffusion method. Statistical analysis: Prevalence and pattern were analyzed using proportions and percentages. Results: E.coli was the most predominant organism (56% causing UTI in children followed by Klebsiella sp (17%. Fifty three percent of gram negative organisms isolated from children were found to be multidrug resistant. Majority of E. coli isolates were found to be highly resistant to Ampicillin (91% and Cotrimoxazole (82% and highly sensitive to Imipenem (99% and Amikacin (93%. Conclusion: Paediatric UTI was common in children less than 5 years of age. Gram negative bacteria (E. coli and Klebsiella sp were more common than gram positive bacteria. Our study revealed that multidrug resistance was higher in E.coli.

  8. Surveillance of multidrug resistant suppurative infection causing bacteria in hospitalized patients in an Indian tertiary care hospital

    Directory of Open Access Journals (Sweden)

    Nabakishore Nayak

    2014-01-01

    Conclusions: Of these S. aureus, particularly the methicillin resistant strain predominates, followed by strains of S. pyogenes and P. aeruginosa that were in the higher proportions of multidrug resistance.

  9. MUC1 induces drug resistance in pancreatic cancer cells via upregulation of multidrug resistance genes.

    Science.gov (United States)

    Nath, S; Daneshvar, K; Roy, L D; Grover, P; Kidiyoor, A; Mosley, L; Sahraei, M; Mukherjee, P

    2013-06-17

    MUC1 (CD227), a membrane tethered mucin glycoprotein, is overexpressed in >60% of human pancreatic cancers (PCs), and is associated with poor prognosis, enhanced metastasis and chemoresistance. The objective of this study was to delineate the mechanism by which MUC1 induces drug resistance in human (BxPC3 and Capan-1) and mouse (KCKO, KCM) PC cells. We report that PC cells that express high levels of MUC1 exhibit increased resistance to chemotherapeutic drugs (gemcitabine and etoposide) in comparison with cells that express low levels of MUC1. This chemo resistance was attributed to the enhanced expression of multidrug resistance (MDR) genes including ABCC1, ABCC3, ABCC5 and ABCB1. In particular, levels of MRP1 protein encoded by the ABCC1 gene were significantly higher in the MUC1-high PC cells. In BxPC3 and Capan-1 cells MUC1 upregulates MRP1 via an Akt-dependent pathway, whereas in KCM cells MUC1-mediated MRP1 upregulation is via an Akt-independent mechanism. In KCM, BxPC3 and Capan-1 cells, the cytoplasmic tail motif of MUC1 associates directly with the promoter region of the Abcc1/ABCC1 gene, indicating a possible role of MUC1 acting as a transcriptional regulator of this gene. This is the first report to show that MUC1 can directly regulate the expression of MDR genes in PC cells, and thus confer drug resistance.

  10. [Antimicrobial therapy in severe infections with multidrug-resistant Gram-negative bacterias].

    Science.gov (United States)

    Duszyńska, Wiesława

    2010-01-01

    Multidrug-resistant Gram-negative bacteria pose a serious and rapidly emerging threat to patients in healthcare settings, and are especially prevalent and problematic in intensive therapy units. Recently, the emergence of pandrug-resistance in Gram-negative bacteria poses additional concerns. This review examines the clinical impact and epidemiology of multidrug-resistant Gram-negative bacteria as a cause of increased morbidity and mortality among ITU patients. Beta-lactamases, cephalosporinases and carbapenemases play the most important role in resistance to antibiotics. Despite the tendency to increased resistance, carbapenems administered by continuous infusion remain the most effective drugs in severe sepsis. Drug concentration monitoring, albeit rarely used in practice, is necessary to ensure an effective therapeutic effect.

  11. Severe infection with multidrug-resistant Salmonella choleraesuis in a young patient with primary sclerosing cholangitis

    Science.gov (United States)

    Ferstl, Philip G; Reinheimer, Claudia; Jozsa, Katalin; Zeuzem, Stefan; Kempf, Volkhard AJ; Waidmann, Oliver; Grammatikos, Georgios

    2017-01-01

    Massive global spread of multidrug-resistant (MDR) Salmonella spp. expressing extended-spectrum beta-lactamase (ESBL) and additional resistance to fluoroquinolones has often been attributed to high international mobility as well as excessive use of oral antibiotics in livestock farming. However, MDR Salmonella spp. have not been mentioned as a widespread pathogen in clinical settings so far. We demonstrate the case of a 25-year-old male with primary sclerosing cholangitis who tested positive for MDR Salmonella enterica serotype Choleraesuis expressing ESBL and fluoroquinolone resistance. The pathogen was supposedly acquired during a trip to Thailand, causing severe fever, cholangitis and pancreatitis. To our knowledge, this is the first report of Salmonella enterica serotype Choleraesuis in Europe expressing such a multidrug resistance pattern. ESBL resistance of Salmonella enterica spp. should be considered in patients with obstructive biliary tract pathology and travel history in endemic countries. PMID:28373776

  12. Within-host competition and drug resistance in the human malaria parasite Plasmodium falciparum.

    Science.gov (United States)

    Bushman, Mary; Morton, Lindsay; Duah, Nancy; Quashie, Neils; Abuaku, Benjamin; Koram, Kwadwo A; Dimbu, Pedro Rafael; Plucinski, Mateusz; Gutman, Julie; Lyaruu, Peter; Kachur, S Patrick; de Roode, Jacobus C; Udhayakumar, Venkatachalam

    2016-03-16

    Infections with the malaria parasite Plasmodium falciparum typically comprise multiple strains, especially in high-transmission areas where infectious mosquito bites occur frequently. However, little is known about the dynamics of mixed-strain infections, particularly whether strains sharing a host compete or grow independently. Competition between drug-sensitive and drug-resistant strains, if it occurs, could be a crucial determinant of the spread of resistance. We analysed 1341 P. falciparum infections in children from Angola, Ghana and Tanzania and found compelling evidence for competition in mixed-strain infections: overall parasite density did not increase with additional strains, and densities of individual chloroquine-sensitive (CQS) and chloroquine-resistant (CQR) strains were reduced in the presence of competitors. We also found that CQR strains exhibited low densities compared with CQS strains (in the absence of chloroquine), which may underlie observed declines of chloroquine resistance in many countries following retirement of chloroquine as a first-line therapy. Our observations support a key role for within-host competition in the evolution of drug-resistant malaria. Malaria control and resistance-management efforts in high-transmission regions may be significantly aided or hindered by the effects of competition in mixed-strain infections. Consideration of within-host dynamics may spur development of novel strategies to minimize resistance while maximizing the benefits of control measures.

  13. Nonradioactive heteroduplex tracking assay for the detection of minority-variant chloroquine-resistant Plasmodium falciparum in Madagascar

    Directory of Open Access Journals (Sweden)

    Mwapasa Victor

    2009-03-01

    Full Text Available Abstract Background Strains of Plasmodium falciparum genetically resistant to chloroquine (CQ due to the presence of pfcrt 76T appear to have been recently introduced to the island of Madagascar. The prevalence of such resistant genotypes is reported to be low (P. falciparum isolates on the island. Previously, minority variant chloroquine resistant parasites were described in Malawian patients using an isotopic heteroduplex tracking assay (HTA, which can detect pfcrt 76T-bearing P. falciparum minority variants in individual patients that were undetectable by conventional PCR. However, as this assay required a radiolabeled probe, it could not be used in many resource-limited settings. Methods This study describes a digoxigenin (DIG-labeled chemiluminescent heteroduplex tracking assay (DIG-HTA to detect pfcrt 76T-bearing minority variant P. falciparum. This assay was compared to restriction fragment length polymorphism (RFLP analysis and to the isotopic HTA for detection of genetically CQ-resistant parasites in clinical samples. Results Thirty one clinical P. falciparum isolates (15 primary isolates and 16 recurrent isolates from 17 Malagasy children treated with CQ for uncomplicated malaria were genotyped for the pfcrt K76T mutation. Two (11.7% of 17 patients harboured genetically CQ-resistant P. falciparum strains after therapy as detected by HTA. RFLP analysis failed to detect any pfcrt K76T-bearing isolates. Conclusion These findings indicate that genetically CQ-resistant P. falciparum are more common than previously thought in Madagascar even though the fitness of the minority variant pfcrt 76T parasites remains unclear. In addition, HTAs for malaria drug resistance alleles are promising tools for the surveillance of anti-malarial resistance. The use of a non-radioactive label allows for the use of HTAs in malaria endemic countries.

  14. Treatment of complicated intra-abdominal infections in the era of multi-drug resistant Bacteria

    Directory of Open Access Journals (Sweden)

    Herzog T

    2010-11-01

    Full Text Available Abstract The management of severe intra-abdominal infections remains a major challenge facing surgeons and intensive care physicians, because of its association with high morbidity and mortality. Surgical management and intensive care medicine have constantly improved, but in the recent years a rapidly continuing emergence of resistant pathogens led to treatment failure secondary to infections with multi-drug resistant bacteria. In secondary peritonitis the rate of resistant germs at the initial operation is already 30%. The lack of effective antibiotics against these pathogens resulted in the development of new broad-spectrum compounds and antibiotics directed against resistant germs. But so far no "super-drug" with efficacy against all resistant bacteria exists. Even more, soon after their approval, reports on resistance against these novel drugs have been reported, or the drugs were withdrawn from the market due to severe side effects. Since pharmaceutical companies reduced their investigations on antibiotic research, only few new antimicrobial derivates are available. In abdominal surgery you may be in fear that in the future more and more patients with tertiary peritonitis secondary to multi-drug resistant species are seen with an increase of mortality after secondary peritonitis. This article reviews the current treatment modalities for complicated intra-abdominal infections with special reference to the antibiotic treatment of complicated intra-abdominal infections with multi-drug resistant species.

  15. The culturable soil antibiotic resistome: a community of multi-drug resistant bacteria.

    Directory of Open Access Journals (Sweden)

    Fiona Walsh

    Full Text Available Understanding the soil bacterial resistome is essential to understanding the evolution and development of antibiotic resistance, and its spread between species and biomes. We have identified and characterized multi-drug resistance (MDR mechanisms in the culturable soil antibiotic resistome and linked the resistance profiles to bacterial species. We isolated 412 antibiotic resistant bacteria from agricultural, urban and pristine soils. All isolates were multi-drug resistant, of which greater than 80% were resistant to 16-23 antibiotics, comprising almost all classes of antibiotic. The mobile resistance genes investigated, (ESBL, bla NDM-1, and plasmid mediated quinolone resistance (PMQR resistance genes were not responsible for the respective resistance phenotypes nor were they present in the extracted soil DNA. Efflux was demonstrated to play an important role in MDR and many resistance phenotypes. Clinically relevant Burkholderia species are intrinsically resistant to ciprofloxacin but the soil Burkholderia species were not intrinsically resistant to ciprofloxacin. Using a phenotypic enzyme assay we identified the antibiotic specific inactivation of trimethoprim in 21 bacteria from different soils. The results of this study identified the importance of the efflux mechanism in the soil resistome and variations between the intrinsic resistance profiles of clinical and soil bacteria of the same family.

  16. Molecular characterization of multidrug-resistant Shigella spp. of food origin.

    Science.gov (United States)

    Ahmed, Ashraf M; Shimamoto, Tadashi

    2015-02-02

    Shigella spp. are the causative agents of food-borne shigellosis, an acute enteric infection. The emergence of multidrug-resistant clinical isolates of Shigella presents an increasing challenge for clinicians in the treatment of shigellosis. Several studies worldwide have characterized the molecular basis of antibiotic resistance in clinical Shigella isolates of human origin, however, to date, no such characterization has been reported for Shigella spp. of food origin. In this study, we characterized the genetic basis of multidrug resistance in Shigella spp. isolated from 1600 food samples (800 meat products and 800 dairy products) collected from different street venders, butchers, retail markets, and slaughterhouses in Egypt. Twenty-four out of 27 Shigella isolates (88.9%) showed multidrug resistance phenotypes to at least three classes of antimicrobials. The multidrug-resistant Shigella spp. were as follows: Shigella flexneri (66.7%), Shigella sonnei (18.5%), and Shigella dysenteriae (3.7%). The highest resistance was to streptomycin (100.0%), then to kanamycin (95.8%), nalidixic acid (95.8%), tetracycline (95.8%), spectinomycin (93.6%), ampicillin (87.5%), and sulfamethoxazole/trimethoprim (87.5%). PCR and DNA sequencing were used to screen and characterize integrons and antibiotic resistance genes. Our results indicated that 11.1% and 74.1% of isolates were positive for class 1 and class 2 integrons, respectively. Beta-lactamase-encoding genes were identified in 77.8% of isolates, and plasmid-mediated quinolone resistance genes were identified in 44.4% of isolates. These data provide useful information to better understand the molecular basis of antimicrobial resistance in Shigella spp. To the best of our knowledge, this is the first report of the molecular characterization of antibiotic resistance in Shigella spp. isolated from food.

  17. Influence of multidrug resistance on {sup 18}F-FCH cellular uptake in a glioblastoma model

    Energy Technology Data Exchange (ETDEWEB)

    Vanpouille, Claire; Jeune, Nathalie le; Clotagatide, Anthony; Dubois, Francis [Universite de Lyon, Universite Jean Monnet-Cancer Research Group IFRESIS 143, Saint-Etienne (France); Kryza, David; Janier, Marc [Hospice Civils de Lyon, Quai Des Celestins, CREATIS, UMR CNRS, Lyon (France); Perek, Nathalie [Universite de Lyon, Universite Jean Monnet-Cancer Research Group IFRESIS 143, Saint-Etienne (France); Laboratoire de Biophysique, Faculte de Medecine, Saint-Etienne (France)

    2009-08-15

    Multidrug resistance, aggressiveness and accelerated choline metabolism are hallmarks of malignancy and have motivated the development of new PET tracers like {sup 18}F-FCH, an analogue of choline. Our aim was to study the relationship of multidrug resistance of cultured glioma cell lines and {sup 18}F-FCH tracer uptake. We used an in vitro multidrug-resistant (MDR) glioma model composed of sensitive parental U87MG and derived resistant cells U87MG-CIS and U87MG-DOX. Aggressiveness, choline metabolism and transport were studied, particularly the expression of choline kinase (CK) and high-affinity choline transporter (CHT1). FCH transport studies were assessed in our glioblastoma model. As expected, the resistant cell lines express P-glycoprotein (Pgp), multidrug resistance-associated protein isoform 1 (MRP1) and elevated glutathione (GSH) content and are also more mobile and more invasive than the sensitive U87MG cells. Our results show an overexpression of CK and CHT1 in the resistant cell lines compared to the sensitive cell lines. We found an increased uptake of FCH (in % of uptake per 200,000 cells) in the resistant cells compared to the sensitive ones (U87MG: 0.89{+-}0.14; U87MG-CIS: 1.27{+-}0.18; U87MG-DOX: 1.33{+-}0.13) in line with accelerated choline metabolism and aggressive phenotype. FCH uptake is not influenced by the two ATP-dependant efflux pumps: Pgp and MRP1. FCH would be an interesting probe for glioma imaging which would not be effluxed from the resistant cells by the classic MDR ABC transporters. Our results clearly show that FCH uptake reflects accelerated choline metabolism and is related to tumour aggressiveness and drug resistance. (orig.)

  18. Multidrug-Resistant Gram-Negative Bacterial and Carbapenem-Resistant Enterobacteriaceae Infections in the Department of the Navy: Annual Report 2013

    Science.gov (United States)

    2015-03-19

    nosocomial multidrug-resistant, gram - negative bacilli : A 9-year surveillance study. Infect Control Hosp Epidemiol. 2004; 25(10):842- 846. 8. Giske C...Monnet D, Cars O, Carmeli Y. Clinical and economic impact of common multidrug-resistant gram - negative bacilli . Antimicrob Agents Chemother. 2008... gram - negative bacilli . Clin Infect Dis. 2005; 41:848-854. 15. Cohen AL, Calfee D, Fridkin SK, et al. Recommendations for Metrics for Multidrug

  19. Multidrug-resistant gram-negative bacilli colonization risk factors among trauma patients.

    Science.gov (United States)

    Gilbert, Laura J; Li, Ping; Murray, Clinton K; Yun, Heather C; Aggarwal, Deepak; Weintrob, Amy C; Tribble, David R

    2016-04-01

    Prior studies have demonstrated high rates of colonization and infection with multidrug-resistant gram-negative bacilli (MDR-GNB) in injured military personnel. Our analysis shows that injuries inflicted during peak combat periods, massive blood transfusion requirement, and posttrauma cefazolin prophylaxis (additive effect with fluoroquinolones) were risk factors for MDR-GNB colonization. Published by Elsevier Inc.

  20. What do proton motive force driven multidrug resistance transporters have in common?

    NARCIS (Netherlands)

    Mazurkiewicz, P.; Driessen, A.J.M.; Konings, W.N

    2005-01-01

    The extensive progress of genome sequencing projects in recent years has demonstrated that multidrug resistance (MDR) transporters are widely spread among all domains of life. This indicates that they play crucial roles in the survival of organisms. Moreover, antibiotic and chemotherapeutic treatmen

  1. Multidrug resistant Acinetobacter baumannii reaches a new frontier: prosthetic hip joint infection.

    Science.gov (United States)

    Hischebeth, G T R; Wimmer, M D; Molitor, E; Seifert, H; Gravius, S; Bekeredjian-Ding, I

    2015-02-01

    Acinetobacter baumannii is an emerging nosocomial pathogen primarily in countries with a high prevalence of multidrug resistance. Here we report the detection of a bla OXA23 carbapenemase-producing A. baumannii strain in a German patient with prosthetic hip joint infection following several hip joint surgeries but no history of foreign travel.

  2. Utilization of Colistin for Treatment of Multidrug-Resistant Pseudomonas aeruginosa

    Directory of Open Access Journals (Sweden)

    Deana M Sabuda

    2008-01-01

    Full Text Available BACKGROUND: Colistin is uncommonly used in clinical practice; however, the emergence of multidrug-resistant organisms has rekindled interest in this potentially toxic therapeutic option. The present study describes the authors’ experience with colistin in the management of patients who were infected with metallo-beta-lactamase (MBL-producing Pseudomonas aeruginosa within the Calgary Health Region (Calgary, Alberta.

  3. Genome Resequencing of the Virulent and Multidrug-Resistant Reference Strain Clostridium difficile 630

    OpenAIRE

    Riedel, Thomas; Bunk, Boyke; Thürmer, Andrea; Spröer, Cathrin; Brzuszkiewicz, Elzbieta; Abt, Birte; Gronow, Sabine; Liesegang, Heiko; Daniel, Rolf; Overmann, Jörg

    2015-01-01

    We resequenced the complete genome of the virulent and multidrug-resistant pathogen Clostridium difficile strain 630. A combination of single-molecule real-time and Illumina sequencing technology revealed the presence of an additional rRNA gene cluster, additional tRNAs, and the absence of a transposon in comparison to the published and reannotated genome sequence.

  4. Genome Resequencing of the Virulent and Multidrug-Resistant Reference Strain Clostridium difficile 630

    Science.gov (United States)

    Bunk, Boyke; Thürmer, Andrea; Spröer, Cathrin; Brzuszkiewicz, Elzbieta; Abt, Birte; Gronow, Sabine; Liesegang, Heiko; Daniel, Rolf; Overmann, Jörg

    2015-01-01

    We resequenced the complete genome of the virulent and multidrug-resistant pathogen Clostridium difficile strain 630. A combination of single-molecule real-time and Illumina sequencing technology revealed the presence of an additional rRNA gene cluster, additional tRNAs, and the absence of a transposon in comparison to the published and reannotated genome sequence. PMID:25858846

  5. The wide spectrum of multidrug resistance 3 deficiency : From neonatal cholestasis to cirrhosis of adulthood

    NARCIS (Netherlands)

    Jacquemin, E; de Vree, JML; Cresteil, D; Sokal, EM; Sturm, E; Dumont, M; Scheffer, GL; Paul, M; Burdelski, M; Bernard, O; Hadchouel, M; Elferink, RPJO

    Background & Aims: We have specified the features of progressive familial intrahepatic cholestasis type 3 and investigated in 31 patients whether a defect of the multidrug resistance 3 gene (MDR3) underlies this phenotype. Methods: MDR3 sequencing liver MDR3 immunohistochemistry, and biliary

  6. Novel mechanism of bacteriocin secretion and immunity carried out by lactococcal multidrug resistance proteins

    NARCIS (Netherlands)

    Gajic, O; Buist, G; Kojic, M; Topisirovic, L; Kuipers, OP; Kok, J

    2003-01-01

    A natural isolate of Lactococcus lactis was shown to produce two narrow spectrum class II bacteriocins, designated LsbA and LsbB. The cognate genes are located on a 5.6-kb plasmid within a gene cluster specifying LmrB, an ATP-binding cassette-type multidrug resistance transporter protein. LsbA is a

  7. Recycling antibiotics into GUMBOS: A new combination strategy to combat multi-drug resistant bacteria

    Science.gov (United States)

    The emergence of multi-drug resistant bacteria, coupled with the lack of new antibiotics in development, is fast evolving into a global crisis. New strategies utilizing existing antibacterial agents are urgently needed. We propose one such strategy in which four outmoded ß-lactam antibiotics (amp...

  8. Intestinal Decontamination of Multidrug-resistant Klebsiella pneumoniae After Recurrent Infections in an Immunocompromised Host

    Science.gov (United States)

    Kronman, Matthew P.; Zerr, Danielle M.; Qin, Xuan; Englund, Janet; Cornell, Cathy; Sanders, Jean E.; Myers, Jeffrey; Rayar, Jaipreet; Berry, Jessica E.; Adler, Amanda L.; Weissman, Scott J.

    2014-01-01

    Multidrug-resistant (MDR) Enterobacteriaceae infections are associated with increased morbidity. We describe a 20-year-old hematopoietic cell transplantation recipient with recurrent MDR Klebsiella pneumoniae infection, prolonged intestinal colonization, and subsequent intestinal decontamination. Further study should evaluate stool surveillance, molecular typing, and fecal microbiota transplantation for patients with intestinal MDR Enterobacteriaceae carriage. PMID:25041704

  9. Antibacterial activities of ethanol extracts of Philippine medicinal plants against multidrug-resistant bacteria

    Directory of Open Access Journals (Sweden)

    Demetrio L. Valle Jr.

    2015-07-01

    Conclusions: P. betle had the greatest potential value against both Gram-negative and Gram-positive multidrug-resistant bacteria. Favorable antagonistic activities were also exhibited by the ethanol extracts of Psidium guajava, Phyllanthus niruri and Ehretia microphylla.

  10. [Psychological impacts of being a carrier of multi-drug resistant bacteria].

    Science.gov (United States)

    Pires, Elisabete; Frange, Pierre; Henry, Benoît; Lortholary, Olivier; Reichert, Catherine

    2015-01-01

    Learning that they are a carrier of multi-drug resistant bacteria and being placed in isolation to prevent transmission has significant psychological repercussions for the patient and their families. Through therapeutic education, caregivers adapt their support to the patient's experience, raising their awareness of prevention. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  11. Endothelin and calciotropic hormones share regulatory pathways in multidrug resistance protein 2-mediated transport

    NARCIS (Netherlands)

    Wever, K.E.; Masereeuw, R.; Miller, D.S.; Hang, X.M.; Flik, G.

    2006-01-01

    The kidney of vertebrates plays a key role in excretion of endogenous waste products and xenobiotics. Active secretion in the proximal nephron is at the basis of this excretion, mediated by carrier proteins including multidrug resistance protein 2 (Mrp2). We previously showed that Mrp2 function is

  12. Beauvericin counteracted multi-drug resistant Candida albicans by blocking ABC transporters

    DEFF Research Database (Denmark)

    Tong, Yaojun; Liu, Mei; Zhang, Yu

    2016-01-01

    screening and whole-cell based mechanism study, identified a natural product, beauvericin (BEA) as a drug efflux pump modulator, which can reverse the multi-drug resistant phenotype of Candida albicans by specifically blocking the ATP-binding cassette (ABC) transporters; meantime, BEA alone has fungicidal...

  13. Individualized treatment of multidrug-resistant tuberculosis using therapeutic drug monitoring

    NARCIS (Netherlands)

    Bolhuis, Mathieu S; Akkerman, Onno W; Sturkenboom, Marieke G G; de Lange, Wiel C M; van der Werf, Tjip S; Alffenaar, Jan-Willem C

    2016-01-01

    OBJECTIVE/BACKGROUND: Globally, approximately 50% of patients with multidrug-resistant tuberculosis (MDR-TB) experience treatment failure. MDR-TB treatment is hindered by adverse events, toxicity of the second-line anti-TB drugs, logistics and costs, especially in low-income countries, and problems

  14. A cohort study on the outcome of multidrug-resistant tuberculosis in elderly patients

    Institute of Scientific and Technical Information of China (English)

    郝晓晖

    2014-01-01

    Objective To investigate the clinical curative effect and outcomes of multidrug-resistant tuberculosis(MDRTB)in elderly patients.Methods Fifty-nine elderly patients with MDR-TB were enrolled from Shanghai Pulmonary Hospital from January 2007 to January 2010,and80 younger patients with MDR-TB during the same period served as the control group.Clinical characteristics,out-

  15. Targeting multidrug-resistant tuberculosis (MDR-TB) by therapeutic vaccines

    NARCIS (Netherlands)

    Prabowo, Satria A.; Groeschel, Matthias I.; Schmidt, Ed D. L.; Skrahina, Alena; Mihaescu, Traian; Hasturk, Serap; Mitrofanov, Rotislav; Pimkina, Edita; Visontai, Ildik; de Jong, Bouke; Stanford, John L.; Cardona, Pere-Joan; Kaufmann, Stefan H. E.; van der Werf, Tjipke

    2013-01-01

    Tuberculosis (TB) has scourged humankind for millennia, and latent infection affects nearly one-third of today's world population. The emergence of multidrug-resistant (MDR)-TB is a major global threat and reflects treatment failure of drug-sensitive disease. MDR-TB management is a burden for patien

  16. Potential antimicrobial agents for the treatment of multidrug-resistant tuberculosis

    NARCIS (Netherlands)

    Alsaad, Noor; Wilffert, Bob; van Altena, Richard; de Lange, Wiel C. M.; van der Werf, Tjip S.; Kosterink, Jos G. W.; Alffenaar, Jan-Willem C.

    2014-01-01

    Treatment of multidrug-resistant (MDR) tuberculosis (TB) is challenging because of the high toxicity of second-line drugs and the longer treatment duration than for drug-susceptible TB patients. In order to speed up novel treatment for MDR-TB, we suggest considering expanding the indications of alre

  17. Multidrug-resistant tuberculosis, People's Republic of China, 2007-2009.

    NARCIS (Netherlands)

    He, G.X.; Wang, H.Y.; Borgdorff, M.W.; Soolingen, D. van; Werf, M.J. van der; Liu, Z.M.; Li, X.Z.; Guo, H.; Zhao, Y.L.; Varma, J.K.; Tostado, C.P.; Hof, S. van den

    2011-01-01

    We conducted a case-control study to investigate risk factors for multidrug-resistant tuberculosis (MDR TB) in the People's Republic of China. Genotyping analysis was used to estimate the percentage of cases from recent transmission among 100 MDR TB case-patients hospitalized during April 2007-July

  18. Novel mechanism of bacteriocin secretion and immunity carried out by lactococcal multidrug resistance proteins

    NARCIS (Netherlands)

    Gajic, O; Buist, G; Kojic, M; Topisirovic, L; Kuipers, OP; Kok, J

    2003-01-01

    A natural isolate of Lactococcus lactis was shown to produce two narrow spectrum class II bacteriocins, designated LsbA and LsbB. The cognate genes are located on a 5.6-kb plasmid within a gene cluster specifying LmrB, an ATP-binding cassette-type multidrug resistance transporter protein. LsbA is a

  19. Identification of New Drug Targets in Multi-Drug Resistant Bacterial Infections

    Science.gov (United States)

    2012-10-01

    COVERED 26 September 2011 25 September 2012 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Identification of New Drug Targets in Multi-Drug Resistant...will be necessary for the fragment based screening and subsequent design of new drug lead compounds. To accompany and validate the structural studies

  20. Potential antimicrobial agents for the treatment of multidrug-resistant tuberculosis

    NARCIS (Netherlands)

    Alsaad, Noor; Wilffert, Bob; van Altena, Richard; de Lange, Wiel C. M.; van der Werf, Tjip S.; Kosterink, Jos G. W.; Alffenaar, Jan-Willem C.

    2014-01-01

    Treatment of multidrug-resistant (MDR) tuberculosis (TB) is challenging because of the high toxicity of second-line drugs and the longer treatment duration than for drug-susceptible TB patients. In order to speed up novel treatment for MDR-TB, we suggest considering expanding the indications of

  1. Distribution and physiology of ABC-Type transporters contributing to multidrug resistance in bacteria

    NARCIS (Netherlands)

    Lubelski, Jacek; Konings, Wil N.; Driessen, Arnold J. M.

    2007-01-01

    Membrane proteins responsible for the active efflux of structurally and functionally unrelated drugs were first characterized in higher eukalyotes. To date, a vast number of transporters contributing to multidrug resistance (MDR transporters) have been reported for a large variety of organisms. Pred

  2. Expression of multidrug resistance-associated proteins predicts prognosis in childhood and adult acute lymphoblastic leukemia

    NARCIS (Netherlands)

    Plasschaert, SLA; de Bont, ESJM; Boezen, M; vander Kolk, DM; Daenen, SMJG; Faber, KN; Kamps, WA; de Vries, EGE; Vellenga, E

    2005-01-01

    PURPOSE: Patients with acute lymphoblastic leukemia (ALL) are treated with a variety of chemotherapeutic drugs, which can be transported by six multidrug resistance-associated proteins (MRP). These MRPs have strongly overlapping functional activities. The aim of this study was to investigate the exp

  3. Evaluation of macrolides for possible use against multidrug-resistant Mycobacterium tuberculosis

    NARCIS (Netherlands)

    van der Paardt, Anne-Fleur; Wilffert, Bob; Akkerman, Onno W.; de Lange, Wiel C. M.; van Soolingen, Dick; Sinha, Bhanu; van der Werf, Tjip S.; Kosterink, Jos G. W.; Alffenaar, Jan-Willem C.

    2015-01-01

    Multidrug-resistant tuberculosis (MDR-TB) is a major global health problem. The loss of susceptibility to an increasing number of drugs behoves us to consider the evaluation of non-traditional anti-tuberculosis drugs. Clarithromycin, a macrolide antibiotic, is defined as a group 5 anti-tuberculosis

  4. Multidrug-resistant Bacteroides fragilis group on the rise in Europe?

    DEFF Research Database (Denmark)

    Hartmeyer, G N; Sóki, J; Nagy, E

    2012-01-01

    We report a case of multidrug-resistance (MDR) in a strain of Bacteroides fragilis from a blood culture and abdominal fluid in a Danish patient. The patient had not been travelling for several years and had not received antibiotics prior to the present case. We also summarize the cases that have...

  5. Capreomycin-induced optic neuritis in a case of multidrug resistant pulmonary tuberculosis

    Directory of Open Access Journals (Sweden)

    Magazine Rahul

    2010-01-01

    Full Text Available A patient of multidrug-resistant pulmonary tuberculosis was prescribed an anti-tubercular regimen containing capreomycin. Patient developed optic neuritis 3 months after starting treatment. Investigations did not reveal any specific cause for this ocular condition and on discontinuing capreomycin his vision recovered. We conclude that capreomycin is the cause of reversible optic neuritis in our case.

  6. Isolation and characterization of antimicrobial compounds in plant extracts against multidrug-resistant Acinetobacter baumannii.

    Directory of Open Access Journals (Sweden)

    Yoko Miyasaki

    Full Text Available The number of fully active antibiotic options that treat nosocomial infections due to multidrug-resistant Acinetobacter baumannii (A. baumannii is extremely limited. Magnolia officinalis, Mahonia bealei, Rabdosia rubescens, Rosa rugosa, Rubus chingii, Scutellaria baicalensis, and Terminalia chebula plant extracts were previously shown to have growth inhibitory activity against a multidrug-resistant clinical strain of A. baumannii. In this study, the compounds responsible for their antimicrobial activity were identified by fractionating each plant extract using high performance liquid chromatography, and determining the antimicrobial activity of each fraction against A. baumannii. The chemical structures of the fractions inhibiting >40% of the bacterial growth were elucidated by liquid chromatography/mass spectrometry analysis and nuclear magnetic resonance spectroscopy. The six most active compounds were identified as: ellagic acid in Rosa rugosa; norwogonin in Scutellaria baicalensis; and chebulagic acid, chebulinic acid, corilagin, and terchebulin in Terminalia chebula. The most potent compound was identified as norwogonin with a minimum inhibitory concentration of 128 µg/mL, and minimum bactericidal concentration of 256 µg/mL against clinically relevant strains of A. baumannii. Combination studies of norwogonin with ten anti-Gram negative bacterial agents demonstrated that norwogonin did not enhance the antimicrobial activity of the synthetic antibiotics chosen for this study. In conclusion, of all identified antimicrobial compounds, norwogonin was the most potent against multidrug-resistant A. baumannii strains. Further studies are warranted to ascertain the prophylactic and therapeutic potential of norwogonin for infections due to multidrug-resistant A. baumannii.

  7. Modulation of multidrug resistance by flavonoids. Inhibitors of glutathione conjugation and MRP-mediated transport

    NARCIS (Netherlands)

    Zanden, van J.J.

    2005-01-01

    In this thesis, the use of flavonoids for inhibition of two important players in the glutathione related biotransformation system involved in multidrug resistance was investigated using several in vitro model systems. The enzymes of interest included the phase II glutathione S-transferase enzyme

  8. The molecular basis of antifolate resistance in Plasmodium falciparum: looking beyond point mutations.

    Science.gov (United States)

    Heinberg, Adina; Kirkman, Laura

    2015-04-01

    Drugs that target the folate-synthesis pathway have a long history of effectiveness against a variety of pathogens. As antimalarials, the antifolates were safe and well tolerated, but resistance emerged quickly and has persisted even with decreased drug pressure. The primary determinants of resistance in Plasmodium falciparum are well-described point mutations in the enzymes dihydropteroate synthase and dihydrofolate reductase targeted by the combination sulfadoxine-pyrimethamine. Recent work has highlighted the contributions of additional parasite adaptation to antifolate resistance. In fact, the evolution of antifolate-resistant parasites is multifaceted and complex. Gene amplification of the first enzyme in the parasite folate synthesis pathway, GTP-cyclohydrolase, is strongly associated with resistant parasites and potentially contributes to persistence of resistant parasites. Further understanding of how parasites adjust flux through the folate pathway is important to the further development of alternative agents targeting this crucial synthesis pathway.

  9. Plasmodium falciparum field isolates from areas of repeated emergence of drug resistant malaria show no evidence of hypermutator phenotype.

    Science.gov (United States)

    Brown, Tyler S; Jacob, Christopher G; Silva, Joana C; Takala-Harrison, Shannon; Djimdé, Abdoulaye; Dondorp, Arjen M; Fukuda, Mark; Noedl, Harald; Nyunt, Myaing Myaing; Kyaw, Myat Phone; Mayxay, Mayfong; Hien, Tran Tinh; Plowe, Christopher V; Cummings, Michael P

    2015-03-01

    Multiple transcontinental waves of drug resistance in Plasmodium falciparum have originated in Southeast Asia before spreading westward, first into the rest of Asia and then to sub-Saharan Africa. In vitro studies have suggested that hypermutator P. falciparum parasites may exist in Southeast Asia and that an increased rate of acquisition of new mutations in these parasites may explain the repeated emergence of drug resistance in Southeast Asia. This study is the first to test the hypermutator hypothesis using field isolates. Using genome-wide SNP data from human P. falciparum infections in Southeast Asia and West Africa and a test for relative rate differences we found no evidence of increased relative substitution rates in P. falciparum isolates from Southeast Asia. Instead, we found significantly increased substitution rates in Mali and Bangladesh populations relative to those in populations from Southeast Asia. Additionally we found no association between increased relative substitution rates and parasite clearance following treatment with artemisinin derivatives.

  10. Multidrug and vancomycin resistance among clinical isolates of ...

    African Journals Online (AJOL)

    2017-09-03

    Sep 3, 2017 ... Keywords: Bacterial resistance, vancomycin resistant S. aureus, susceptibility studies, agar dilution. ..... therapy, a lack of sufficient knowledge on the danger of ... lin-resistant Staphylococcus aureus as a public-health threat.

  11. [Reversing effects of emodin on multidrug resistance in resistant HL-60/ADR cells].

    Science.gov (United States)

    Chen, Ying-Yu; Li, Jing; Hu, Jian-Da; Zheng, Jing; Zheng, Zhi-Hong; Zhu, Liang-Fang; Chen, Xin-Ji; Lin, Zhen-Xing

    2013-12-01

    This study was aimed to investigate the reversing effects of emodin on multidrug resistance (MDR) in resistant HL-60/ADR cells, and to explore the underlying mechanisms. The MTT assay was used to assess the chemoresistance of HL-60/ADR cells to emodin and 8 chemotherapeutic agents commonly used in clinic. The reversal effects of emodin on MDR of HL-60/ADR cells were also evaluated by MTT method. DNA ploidy analysis and DNA Ladder assay were used to detect apoptosis-induced effects on HL-60/ADR cells via the adriamycin (ADR) and emodin combination. The expression changes of the drug resistance-associated genes and proteins were detected by RT-PCR and Western Blot respectively. The intracellular accumulation and subcellular distribution of ADR and DNR were measured by flow cytometry and confocal laser scanning microscopy. The results showed that emodin inhibited HL-60/ADR cell proliferation with an average IC50 value of 24.09 ± 1.72 µmol/L, which was similar to that of the parental HL-60 cells (average IC50 = 23.18 ± 0.87 µmol/L). HL-60/ADR cells were resistant to a variety of chemotherapeutic agents, such as ADR, DNR, VP16, VCR,Ara-C, HHT, MTZ and THP. The reversal multiple were between 1.58 and 4.12 after the treatment with low concentration of emodin combined with the above mentioned different agents. The combination of ADR with emodin showed the best reversal effects, and the typical hypodiploid peak (apoptotic peak) and DNA ladder could be detected after the co-treatment.In addition, emodin down-regulated the mRNA and protein expression levels of MRP1, TOPOIIβ, GST π and BCL-2. Furthermore, the addition of emodin enhanced ADR and DNR intracellular accumulation and subcellular distribution in HL-60/ADR cells in dose-dependent manner. It is concluded that the emodin shows reversing effects on the multidrug resistant HL-60/ADR cells, possibly via decreasing the expression levels of drug resistance-associated genes, increasing the intracellular accumulation of

  12. Characterization of integrons and resistance genes in multidrug-resistant Salmonella enterica isolated from meat and dairy products in Egypt.

    Science.gov (United States)

    Ahmed, Ashraf M; Shimamoto, Toshi; Shimamoto, Tadashi

    2014-10-17

    Foodborne pathogens are a leading cause of illness and death, especially in developing countries. The problem is exacerbated if bacteria attain multidrug resistance. Little is currently known about the extent of antibiotic resistance in foodborne pathogens and the molecular mechanisms underlying this resistance in Africa. Therefore, the current study was carried out to characterize, at the molecular level, the mechanism of multidrug resistance in Salmonella enterica isolated from 1600 food samples (800 meat products and 800 dairy products) collected from different street venders, butchers, retail markets and slaughterhouses in Egypt. Forty-seven out of 69 isolates (68.1%) showed multidrug resistance phenotypes to at least three classes of antimicrobials. The incidence of multidrug-resistant isolates was higher in meat products (37, 69.8%) than in dairy products (10, 62.5%). The multidrug-resistant serovars included, S. enterica serovar Typhimurium (24 isolates, 34.8%), S. enterica serovar Enteritidis, (15 isolates, 21.8%), S. enterica serovar Infantis (7 isolates, 10.1%) and S. enterica non-typable serovar (1 isolate, 1.4%). The highest resistance was to ampicillin (95.7%), then to kanamycin (93.6%), spectinomycin (93.6%), streptomycin (91.5%) and sulfamethoxazole/trimethoprim (91.5%). PCR and DNA sequencing were used to screen and characterize integrons and antibiotic resistance genes and 39.1% and 8.7% of isolates were positive for class 1 and class 2 integrons, respectively. β-lactamase-encoding genes were identified in 75.4% of isolates and plasmid-mediated quinolone resistance genes were identified in 27.5% of isolates. Finally, the florphenicol resistance gene, floR, was identified in 18.8% of isolates. PCR screening identified S. enterica serovar Typhimurium DT104 in both meat and dairy products. This is the first study to report many of these resistance genes in dairy products. This study highlights the high incidence of multidrug-resistant S. enterica in

  13. Multidrug resistant bacteria in companion animals: impact on animal health and zoonotic aspects

    DEFF Research Database (Denmark)

    Damborg, Peter Panduro

    The role of companion animals as a source of antibiotic resistant bacteria has historically been given little emphasis when compared with that of food animals. However, various resistant bacteria may cause serious treatment problems in companion animal medicine. Some of the most important multidrug......-resistant bacteria include methicillin-resistant Staphylococcus pseudintermedius (MRSP), methicillin-resistant Staphylococcus aureus (MRSA) and extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. These bacteria will be described with focus on their prevalence across Europe, their impact on animal...

  14. Characterisation of multidrug-resistant Ehrlich ascites tumour cells selected in vivo for resistance to etoposide

    DEFF Research Database (Denmark)

    Nielsen, D; Maare, C; Eriksen, J

    2000-01-01

    -extractable immunoreactive topoisomerase IIalpha and beta in EHR2/VP16 was reduced by 30-40% relative to that in EHR2. The multidrug resistance-associated protein (MRP) mRNA was increased 20-fold in EHR2/VP16 as compared with EHR2, whereas the expression of P-glycoprotein was unchanged. In EHR2/VP16, the steady......-state accumulation of [(3)H]VP16 and daunorubicin was reduced by 64% and 17%, respectively, as compared with EHR2. Deprivation of energy by addition of sodium azide increased the accumulation of both drugs to the level of sensitive cells. When glycolysis was restored by the addition of glucose to EHR2/VP16 cells...

  15. Antimalarial drug resistance of Plasmodium falciparum in India: changes over time and space

    OpenAIRE

    Shah, Naman K.; Dhillon, Gajender P S; Dash, Adtiya P; Arora, Usha; Meshnick, Steven R.; Valecha, Neena

    2011-01-01

    After the launch of the National Malaria Control Programme in 1953, the number of malaria cases reported in India fell to an all-time low of 0·1 million in 1965. However, the initial success could not be maintained and a resurgence of malaria began in the late 1960s. Resistance of Plasmodium falciparum to chloroquine was first reported in 1973 and increases in antimalarial resistance, along with rapid urbanisation and labour migration, complicated the challenge that India’s large geographical...

  16. Evaluation of multidrug resistance-1 gene C>T polymorphism frequency in patients with asthma

    Directory of Open Access Journals (Sweden)

    Ümran Toru

    2015-10-01

    Full Text Available OBJECTIVES:Asthma is a chronic inflammatory lung disease characterized by bronchial hyperresponsiveness and airflow obstruction. Genetic and oxidative stress factors, in addition to pulmonary and systemic inflammatory processes, play a pivotal role in the pathogenesis of asthma. The products of the multidrug resistance-1 gene protect lung tissue from oxidative stress. Here, we aimed to evaluate the association between the multidrug resistance-1 gene C>T polymorphism and asthma with regard to oxidative stress-related parameters of asthmatic patients.METHODS:Forty-five patients with asthma and 27 healthy age-matched controls were included in this study. Blood samples were collected in tubes with ethylenediaminetetraacetic acid. DNA was extracted from the blood samples. The multidrug resistance-1 gene polymorphism was detected by polymerase chain reaction and a subsequent enzyme digestion technique. The serum levels of total oxidant status and total antioxidant status were determined by the colorimetric measurement method.RESULTS:The heterozygous polymorphic genotype was the most frequent in both groups. A significant difference in the multidrug resistance-1 genotype frequencies between groups indicated an association of asthma with the TT genotype. A significant difference between groups was found for wild type homozygous participants and carriers of polymorphic allele participants. The frequency of the T allele was significantly higher in asthmatic patients. The increase in the oxidative stress index parameter was significant in the asthma group compared with the control group.CONCLUSIONS:The multidrug resistance-1 gene C/T polymorphism may be an underlying genetic risk factor for the development of asthma via oxidant-antioxidant imbalance, leading to increased oxidative stress.

  17. Antimicrobial metallopolymers and their bioconjugates with conventional antibiotics against multidrug-resistant bacteria.

    Science.gov (United States)

    Zhang, Jiuyang; Chen, Yung Pin; Miller, Kristen P; Ganewatta, Mitra S; Bam, Marpe; Yan, Yi; Nagarkatti, Mitzi; Decho, Alan W; Tang, Chuanbing

    2014-04-02

    Bacteria are now becoming more resistant to most conventional antibiotics. Methicillin-resistant Staphylococcus aureus (MRSA), a complex of multidrug-resistant Gram-positive bacterial strains, has proven especially problematic in both hospital and community settings by deactivating conventional β-lactam antibiotics, including penicillins, cephalosporins, and carbapenems, through various mechanisms, resulting in increased mortality rates and hospitalization costs. Here we introduce a class of charged metallopolymers that exhibit synergistic effects against MRSA by efficiently inhibiting activity of β-lactamase and effectively lysing bacterial cells. Various conventional β-lactam antibiotics, including penicillin-G, amoxicillin, ampicillin, and cefazolin, are protected from β-lactamase hydrolysis via the formation of unique ion-pairs between their carboxylate anions and cationic cobaltocenium moieties. These discoveries could provide a new pathway for designing macromolecular scaffolds to regenerate vitality of conventional antibiotics to kill multidrug-resistant bacteria and superbugs.

  18. Multidrug and heavy metal-resistant Raoultella planticola isolated from surface water.

    Science.gov (United States)

    Koc, Serkan; Kabatas, Burak; Icgen, Bulent

    2013-08-01

    A surface water isolate of Raoultella sp. having both multidrug- and multimetal-resistant ability was isolated and identified as Raoultella planticola. R. planticola displayed resistance to 15 drugs like ampicillin, amoxicillin/clavulanic acid, aztreonam, erythromycin, imipenem, oxacillin, pefloxacin, penicillin, piperacillin, piperacillin/tazobactam, rifampin, sulbactam/cefoperazone, ticarsillin, ticarsillin/clavulanic acid, vancomycin, and to 11 heavy metals like aluminum, barium, copper, iron, lead, lithium, manganese, nickel, silver, strontium, and tin. The multidrug and multi-metal-resistant R. planticola may remain present in the environment for a long time. Due to a possible health risk of these pathogenic bacteria, a need exists for an accurate assessment of their acquired resistance to multiple drugs and metals.

  19. Cloning and characterization of the rat multidrug resistance-associated protein 1

    OpenAIRE

    Yang, Ziping; Li, Cheryl S. W.; Shen, Danny D.; Ho, Rodney J. Y.

    2002-01-01

    Multidrug resistance-associated protein 1 (MRP1) was originally shown to confer resistance of human tumor cells to a broad range of natural product anticancer drugs. MRP1 has also been shown to mediate efflux transport of glutathione and glucuronide conjugates of drugs and endogenous substrates. An ortholog of MRP1 in the mouse has been cloned and characterized. Significant functional differences between murine and human MRP1 have been noted. Since drug disposition and pharmacology studies of...

  20. Multidrug-resistant Acinetobacter Infection Mortality Rate and Length of Hospitalization

    OpenAIRE

    Sunenshine, Rebecca H.; Wright, Marc-Oliver; Maragakis, Lisa L.; Harris, Anthony D.; Song, Xiaoyan; Hebden, Joan; Cosgrove, Sara E.; Anderson, Ashley; Carnell, Jennifer; Jernigan, Daniel B.; Kleinbaum, David G.; Perl, Trish M.; Standiford, Harold C.; Srinivasan, Arjun

    2007-01-01

    Acinetobacter infections have increased and gained attention because of the organism’s prolonged environmental survival and propensity to develop antimicrobial drug resistance. The effect of multidrug-resistant (MDR) Acinetobacter infection on clinical outcomes has not been reported. A retrospective, matched cohort investigation was performed at 2 Baltimore hospitals to examine outcomes of patients with MDR Acinetobacter infection compared with patients with susceptible Acinetobacter infectio...

  1. Anthelmintic Avermectins Kill Mycobacterium tuberculosis, Including Multidrug-Resistant Clinical Strains

    OpenAIRE

    Lim, Leah E.; Vilchèze, Catherine; Ng, Carol; Jacobs, William R.; Ramón-García, Santiago; Thompson, Charles J

    2013-01-01

    Avermectins are a family of macrolides known for their anthelmintic activities and traditionally believed to be inactive against all bacteria. Here we report that members of the family, ivermectin, selamectin, and moxidectin, are bactericidal against mycobacterial species, including multidrug-resistant and extensively drug-resistant clinical strains of Mycobacterium tuberculosis. Avermectins are approved for clinical and veterinary uses and have documented pharmacokinetic and safety profiles....

  2. Whole genome sequencing of emerging multidrug resistant Candida auris isolates in India demonstrates low genetic variation

    OpenAIRE

    2016-01-01

    Candida auris is an emerging multidrug resistant yeast that causes nosocomial fungaemia and deep-seated infections. Notably, the emergence of this yeast is alarming as it exhibits resistance to azoles, amphotericin B and caspofungin, which may lead to clinical failure in patients. The multigene phylogeny and amplified fragment length polymorphism typing methods report the C. auris population as clonal. Here, using whole genome sequencing analysis, we decipher for the first time that C. auris ...

  3. Novel Bis-Indole Agents Active Against Multidrug-Resistant Acinetobacter baumannii

    Science.gov (United States)

    Jacobs, Michael R.; Bajaksouzian, Saralee; Good, Caryn E.; Butler, Michelle M.; Williams, John D.; Peet, Norton P.; Bowlin, Terry L.; Endimiani, Andrea; Bonomo, Robert A

    2013-01-01

    The in vitro activity of five novel Microbiotix bis-indole agents (MBXs) against 30 multidrug-resistant (MDR) A. baumannii (including 18 resistant to carbapenems) was evaluated. Overall, MIC90s ranged from 1-8 μg/ml, whereas those for imipenem were > 64 μg/ml. MBX 1196 was the most potent (MIC90 1 μg/ml). MBXs are compounds that are highly effective against MDR A. baumannii. PMID:21146724

  4. The burden of transmitted multi-drug resistance among epidemics of tuberculosis: A transmission model

    OpenAIRE

    Emily A Kendall; Fofana, Mariam O.; Dowdy, David W.

    2015-01-01

    Background Multidrug-resistant tuberculosis (MDR-TB) can be acquired through de novo mutation during TB treatment or through transmission from other individuals with active MDR-TB. Understanding the balance between these two mechanisms is essential when allocating resources for MDR-TB. Methods We constructed a dynamic transmission model of an MDR-TB epidemic, allowing for both treatment-related acquisition and person-to-person transmission of resistance. We used national TB notification data ...

  5. In vitro antimicrobial activity of five essential oils on multidrug resistant Gram-negative clinical isolates

    OpenAIRE

    Sakkas, Hercules; Gousia, Panagiota; Economou, Vangelis; Sakkas, Vassilios; Petsios, Stefanos; Papadopoulou, Chrissanthy

    2016-01-01

    Aim/Background: The emergence of drug-resistant pathogens has drawn attention on medicinal plants for potential antimicrobial properties. The objective of the present study was the investigation of the antimicrobial activity of five plant essential oils on multidrug resistant Gram-negative bacteria. Materials and Methods: Basil, chamomile blue, origanum, thyme, and tea tree oil were tested against clinical isolates of Acinetobacter baumannii (n = 6), Escherichia coli (n = 4), Klebsiella pneum...

  6. Regulation of Multidrug Resistance Proteins by Genistein in a Hepatocarcinoma Cell Line: Impact on Sorafenib Cytotoxicity

    OpenAIRE

    2015-01-01

    Hepatocellular carcinoma (HCC) is the fifth most frequent cancer worldwide. Sorafenib is the only drug available that improves the overall survival of HCC patients. P-glycoprotein (P-gp), Multidrug resistance-associated proteins 2 and 3 (MRP2 and 3) and Breast cancer resistance protein (BCRP) are efflux pumps that play a key role in cancer chemoresistance. Their modulation by dietary compounds may affect the intracellular accumulation and therapeutic efficacy of drugs that are substrates of t...

  7. Diverse and Abundant Multi-Drug Resistant E. coli in Matang Mangrove Estuaries, Malaysia

    Directory of Open Access Journals (Sweden)

    Aziz eGhaderpour

    2015-09-01

    Full Text Available E. coli, an important vector distributing antimicrobial resistance in the environment, was found to be multi-drug resistant, abundant and genetically diverse in the Matang mangrove estuaries, Malaysia. One-third (34% of the estuarine E. coli was multi-drug resistant. The highest antibiotic resistance prevalence was observed for aminoglycosides (83% and beta-lactams (37%. Phylogenetic groups A and B1, being the most predominant E. coli, demonstrated the highest antibiotic resistant level and prevalence of integrons (integron I, 21%; integron II, 3%. Detection of phylogenetic group B23 downstream of fishing villages indicates human fecal contamination as a source of E. coli pollution. Enteroaggregative E. coli (1% were also detected immediately downstream of the fishing village. The results indicated multi-drug resistance among E. coli circulating in Matang estuaries, which could be reflective of anthropogenic activities and aggravated by bacterial and antibiotic discharges from village lack of a sewerage system, aquaculture farms and upstream animal husbandry.

  8. Bactericidal Efficacy of Allium sativum (garlic Against Multidrug Resistant Vibrio cholerae O1 Epidemic Strains

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    Pramod Kumar

    2016-09-01

    Full Text Available In recent years, emerging trend of antibiotic resistance in Vibrio cholerae associated with cholera epidemics is a matter of serious concern for the management of the disease. Indiscriminate use of antibiotics generally results in selection of antibiotic resistant strains. Introduction of newer antibiotics is a challenging task for the researchers as bacteria soon attain resistance. Therefore, identifying natural compounds of medicinal importance for control of cholera would be the best alternative. Garlic (Allium sativum was recognised for many centuries in early Chinese, Egyptian and Indian civilisations as an herbal or traditional medicine. In present study, garlic was selected for screening of antimicrobial efficacy against V. cholerae. A total of 55 V. cholerae strains isolated from various outbreaks/epidemics were subjected to antimicrobial testing as per CLSI, USA 2010 guidelines. Antimicrobial screening of garlic extract was performed against all the multidrug resistant strains of V. cholerae. The garlic extracts showed antibacterial activity against all the V. cholerae strains tested, irrespective of their origin, multidrug resistance and virulence. Antibacterial efficacy of garlic on V. cholerae was also evident from in vivo study on sealed adult mice model. Thus, the Garlic extract harnesses the potential to control infection of multidrug resistant V. cholerae, especially in outbreak like situations in remote and under developed areas where drug supply itself is a challenge

  9. New Roads Leading to Old Destinations: Efflux Pumps as Targets to Reverse Multidrug Resistance in Bacteria

    Directory of Open Access Journals (Sweden)

    Gabriella Spengler

    2017-03-01

    Full Text Available Multidrug resistance (MDR has appeared in response to selective pressures resulting from the incorrect use of antibiotics and other antimicrobials. This inappropriate application and mismanagement of antibiotics have led to serious problems in the therapy of infectious diseases. Bacteria can develop resistance by various mechanisms and one of the most important factors resulting in MDR is efflux pump-mediated resistance. Because of the importance of the efflux-related multidrug resistance the development of new therapeutic approaches aiming to inhibit bacterial efflux pumps is a promising way to combat bacteria having over-expressed MDR efflux systems. The definition of an efflux pump inhibitor (EPI includes the ability to render the bacterium increasingly more sensitive to a given antibiotic or even reverse the multidrug resistant phenotype. In the recent years numerous EPIs have been developed, although so far their clinical application has not yet been achieved due to their in vivo toxicity and side effects. In this review, we aim to give a short overview of efflux mediated resistance in bacteria, EPI compounds of plant and synthetic origin, and the possible methods to investigate and screen EPI compounds in bacterial systems.

  10. Molecular surveillance for drug-resistant Plasmodium falciparum in clinical and subclinical populations from three border regions of Burma/Myanmar: cross-sectional data and a systematic review of resistance studies

    Science.gov (United States)

    2012-01-01

    Background Confirmation of artemisinin-delayed parasite clearance in Plasmodium falciparum along the Thai-Myanmar border has inspired a global response to contain and monitor drug resistance to avert the disastrous consequences of a potential spread to Africa. However, resistance data from Myanmar are sparse, particularly from high-risk areas where limited health services and decades of displacement create conditions for resistance to spread. Subclinical infections may represent an important reservoir for resistance genes that confer a fitness disadvantage relative to wild-type alleles. This study estimates the prevalence of resistance genotypes in three previously unstudied remote populations in Myanmar and tests the a priori hypothesis that resistance gene prevalence would be higher among isolates collected from subclinical infections than isolates collected from febrile clinical patients. A systematic review of resistance studies is provided for context. Methods Community health workers in Karen and Kachin States and an area spanning the Indo-Myanmar border collected dried blood spots from 988 febrile clinical patients and 4,591 villagers with subclinical infection participating in routine prevalence surveys. Samples positive for P. falciparum 18 s ribosomal RNA by real-time PCR were genotyped for P. falciparum multidrug resistance protein (pfmdr1) copy number and the pfcrt K76T polymorphism using multiplex real-time PCR. Results Pfmdr1 copy number increase and the pfcrt K76 polymorphism were determined for 173 and 269 isolates, respectively. Mean pfmdr1 copy number was 1.2 (range: 0.7 to 3.7). Pfmdr1 copy number increase was present in 17.5%, 9.6% and 11.1% of isolates from Karen and Kachin States and the Indo-Myanmar border, respectively. Pfmdr1 amplification was more prevalent in subclinical isolates (20.3%) than clinical isolates (6.4%, odds ratio 3.7, 95% confidence interval 1.1 - 12.5). Pfcrt K76T prevalence ranged from 90-100%. Conclusions Community

  11. Intraventricular ciprofloxacin usage in treatment of multidrug-resistant central nervous system infections: report of four cases.

    Science.gov (United States)

    Karaaslan, Ayşe; Kadayifçi, Eda Kepenekli; Turel, Ozden; Toprak, Demet Gedikbaşi; Soysal, Ahmet; Bakir, Mustafa

    2014-08-12

    In recent years, multidrug-resistant microorganisms appear as important nosocomial pathogens which treatment is quite difficult. As sufficient drug levels could not be achieved in cerebrospinal fluid during intravenous antibiotic therapy for central nervous system infections and due to multidrug-resistance treatment alternatives are limited. In this study, four cases of central nervous system infections due to multidrug-resistant microorganisms who were successfully treated with removal of the devices and intraventricular ciprofloxacin are presented. In conclusion, intraventricular ciprofloxacin can be used for treatment of central nervous system infections if the causative microorganism is sensitive to the drug and no other alternative therapy is available.

  12. Intraventricular ciprofloxacin usage in treatment of multidrug-resistant central nervous system infections: report of four cases

    Directory of Open Access Journals (Sweden)

    Ayse Karaaslan

    2014-12-01

    Full Text Available In recent years, multidrug-resistant microorganisms appear as important nosocomial pathogens which treatment is quite difficult. As sufficient drug levels could not be achieved in cerebrospinal fluid during intravenous antibiotic therapy for central nervous system infections and due to multidrug-resistance treatment alternatives are limited. In this study, four cases of central nervous system infections due to multidrug-resistant microorganisms who were successfully treated with removal of the devices and intraventricular ciprofloxacin are presented. In conclusion, intraventricular ciprofloxacin can be used for treatment of central nervous system infections if the causative microorganism is sensitive to the drug and no other alternative therapy is available.

  13. Historical shifts in Brazilian P. falciparum population structure and drug resistance alleles.

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    Sean M Griffing

    Full Text Available Previous work suggests that Brazilian Plasmodium falciparum has limited genetic diversity and a history of bottlenecks, multiple reintroductions due to human migration, and clonal expansions. We hypothesized that Brazilian P. falciparum would exhibit clonal structure. We examined isolates collected across two decades from Amapá, Rondônia, and Pará state (n = 190. By examining more microsatellites markers on more chromosomes than previous studies, we hoped to define the extent of low diversity, linkage disequilibrium, bottlenecks, population structure, and parasite migration within Brazil. We used retrospective genotyping of samples from the 1980s and 1990s to explore the population genetics of SP resistant dhfr and dhps alleles. We tested an existing hypothesis that the triple mutant dhfr mutations 50R/51I/108N and 51I/108N/164L developed in southern Amazon from a single origin of common or similar parasites. We found that Brazilian P. falciparum had limited genetic diversity and isolation by distance was rejected, which suggests it underwent bottlenecks followed by migration between sites. Unlike Peru, there appeared to be gene flow across the Brazilian Amazon basin. We were unable to divide parasite populations by clonal lineages and pairwise FST were common. Most parasite diversity was found within sites in the Brazilian Amazon, according to AMOVA. Our results challenge the hypothesis that triple mutant alleles arose from a single lineage in the Southern Amazon. SP resistance, at both the double and triple mutant stages, developed twice and potentially in different regions of the Brazilian Amazon. We would have required samples from before the 1980s to describe how SP resistance spread across the basin or describe the complex internal migration of Brazilian parasites after the colonization efforts of past decades. The Brazilian Amazon basin may have sufficient internal migration for drug resistance reported in any particular region to

  14. Genetic polymorphisms in Plasmodium falciparum chloroquine resistance genes, pfcrt and pfmdr1, in North Sulawesi, Indonesia.

    Science.gov (United States)

    Reteng, Patrick; Vrisca, Visia; Sukarno, Inka; Djarkoni, Ilham Habib; Kalangi, Jane Angela; Jacobs, George Eduardo; Runtuwene, Lucky Ronald; Eshita, Yuki; Maeda, Ryuichiro; Suzuki, Yutaka; Mongan, Arthur Elia; Warouw, Sarah Maria; Yamagishi, Junya; Tuda, Josef

    2017-04-04

    Malaria still poses one of the major threats to human health. Development of effective antimalarial drugs has decreased this threat; however, the emergence of drug-resistant Plasmodium falciparum, a cause of Malaria, is disconcerting. The antimalarial drug chloroquine has been effectively used, but resistant parasites have spread worldwide. Interestingly, the withdrawal of the drug reportedly leads to an increased population of susceptible parasites in some cases. We examined the prevalence of genomic polymorphisms in a malaria parasite P. falciparum, associated with resistance to an antimalarial drug chloroquine, after the withdrawal of the drug from Indonesia. Blood samples were collected from 95 malaria patients in North Sulawesi, Indonesia, in 2010. Parasite DNA was extracted and analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for pfcrt and pfmdr1. In parallel, multiplex amplicon sequencing for the same genes was carried out with Illumina MiSeq. Of the 59 cases diagnosed as P. falciparum infection by microscopy, PCR-RFLP analysis clearly identified the genotype 76T in pfcrt in 44 cases. Sequencing analysis validated the identified genotypes in the 44 cases and demonstrated that the haplotype in the surrounding genomic region was exclusively SVMNT. Results of pfmdr1 were successfully obtained for 51 samples, where the genotyping results obtained by the two methods were completely consistent. In pfmdr1, the 86Y mutant genotype was observed in 45 cases (88.2%). Our results suggest that the prevalence of the mutated genotypes remained dominant even 6 years after the withdrawal of chloroquine from this region. Diversified haplotype of the resistance-related locus, potentially involved in fitness costs, unauthorized usage of chloroquine, and/or a short post-withdrawal period may account for the observed high persistence of prevalence.

  15. Transmission of extensively drug-resistant and multidrug resistant Mycobacterium tuberculosis in families identified by genotyping

    Institute of Scientific and Technical Information of China (English)

    YAN Li-ping; QIN Lian-hua; ZHANG Qing; SUN Hua; HAN Min; XIAO He-ping

    2013-01-01

    Background Diagnosis and appropriate treatment of multidrug-resistant tuberculosis (MDR-TB) remain major challenges.We sought to elucidate that persons who share a household with drug resistance tuberculosis patients are at high risk for primary drug resistance tuberculosis and how to prevent these outbreaks.Methods We used 12-locus mycobacterial interspersed repetitive unit and 7-locus variable-number tandem repeat to identify household transmission of extensively drug resistant and multiple drug resistant Mycobacterium tuberculosis in three families admitted in Shanghai Pulmonary Hospital affiliated with Tongji University.Drug susceptibility tests were done by the modified proportion method in the MGIT 960 system in the same time.Clinical data were also obtained from the subjects' medical records.Results All of the six strains were defined as Beijing genotype by the deletion-targeted multiplex PCR (DTM-PCR) identification on the genomic deletion RD105.Strains from family-1 had the same minisatellite interspersed repetitive unit (MIRU) pattem (232225172531) and the same MIRU pattern (3677235).Strains from family-2 had the same MIRU pattern (2212261553323) and the same MIRU pattern (3685134).Strains from family-3 did not have the same MIRU pattern and they differed at only one locus (223326173533,223325173533),and did not have the same VNTR pattern with two locus differed (3667233,3677234).Conclusions Household transmission exists in the three families.A clear chain of tuberculosis transmission within family exists.Tuberculosis susceptibility should be considered when there is more than one tuberculosis patients in a family.Household tuberculosis transmission could be prevented with adequate treatment of source patients.

  16. Positive epistasis drives the acquisition of multidrug resistance.

    Directory of Open Access Journals (Sweden)

    Sandra Trindade

    2009-07-01

    Full Text Available The evolution of multiple antibiotic resistance is an increasing global problem. Resistance mutations are known to impair fitness, and the evolution of resistance to multiple drugs depends both on their costs individually and on how they interact--epistasis. Information on the level of epistasis between antibiotic resistance mutations is of key importance to understanding epistasis amongst deleterious alleles, a key theoretical question, and to improving public health measures. Here we show that in an antibiotic-free environment the cost of multiple resistance is smaller than expected, a signature of pervasive positive epistasis among alleles that confer resistance to antibiotics. Competition assays reveal that the cost of resistance to a given antibiotic is dependent on the presence of resistance alleles for other antibiotics. Surprisingly we find that a significant fraction of resistant mutations can be beneficial in certain resistant genetic backgrounds, that some double resistances entail no measurable cost, and that some allelic combinations are hotspots for rapid compensation. These results provide additional insight as to why multi-resistant bacteria are so prevalent and reveal an extra layer of complexity on epistatic patterns previously unrecognized, since it is hidden in genome-wide studies of genetic interactions using gene knockouts.

  17. Targeting Plasmodium falciparum Hsp90: Towards Reversing Antimalarial Resistance

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    Dea Shahinas

    2013-02-01

    Full Text Available Malaria continues to exact a great human toll in tropical settings. Antimalarial resistance is rife and the parasite inexorably develops mechanisms to outwit our best drugs, including the now first-line choice, artesunate. Novel strategies to circumvent resistance are needed. Here we detail drug development focusing on heat shock protein 90 and its central role as a chaperone. A growing body of evidence supports the role for Hsp90 inhibitors as adjunctive drugs able to restore susceptibility to traditionally efficacious compounds like chloroquine.

  18. The Role of Antimicrobial Peptides in Preventing Multidrug-Resistant Bacterial Infections and Biofilm Formation

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    Kyung-Soo Hahm

    2011-09-01

    Full Text Available Over the last decade, decreasing effectiveness of conventional antimicrobial-drugs has caused serious problems due to the rapid emergence of multidrug-resistant pathogens. Furthermore, biofilms, which are microbial communities that cause serious chronic infections and dental plaque, form environments that enhance antimicrobial resistance. As a result, there is a continuous search to overcome or control such problems, which has resulted in antimicrobial peptides being considered as an alternative to conventional drugs. Antimicrobial peptides are ancient host defense effector molecules in living organisms. These peptides have been identified in diverse organisms and synthetically developed by using peptidomimic techniques. This review was conducted to demonstrate the mode of action by which antimicrobial peptides combat multidrug-resistant bacteria and prevent biofilm formation and to introduce clinical uses of these compounds for chronic disease, medical devices, and oral health. In addition, combinations of antimicrobial peptides and conventional drugs were considered due to their synergetic effects and low cost for therapeutic treatment.

  19. Antibiotic Synergy Interaction against Multidrug-Resistant Pseudomonas aeruginosa Isolated from an Abattoir Effluent Environment

    Directory of Open Access Journals (Sweden)

    Etinosa O. Igbinosa

    2012-01-01

    Full Text Available Pseudomonas aeruginosa is an opportunistic pathogen in environmental waters with a high prevalence of multidrug resistance. In this study the synergistic efficacy of synergy antibiotic combinations in multidrug-resistant P. aeruginosa strains isolated from an abattoir effluent was investigated. Water samples were processed using membrane filtration; Pseudomonas was isolated with Pseudomonas Isolation Agar and confirmed using polymerase chain reaction with specie-specific primer. Susceptibility studies and in vitro synergy interaction testing were carried out, employing agar dilution and Etest procedure, respectively. Resistance was noted for clinically relevant antipseudomonal agents tested. Finding from antibiotic synergy interaction studies revealed that cefepime, imipenem, and meropenem combined with amikacin resulted in statistically significant (P<0.0001 in vitro antibiotics synergy interaction, indicating the possible use of this regimen in treatment of pseudomonal infections.

  20. Targeting the cell stress response of Plasmodium falciparum to overcome artemisinin resistance.

    Science.gov (United States)

    Dogovski, Con; Xie, Stanley C; Burgio, Gaetan; Bridgford, Jess; Mok, Sachel; McCaw, James M; Chotivanich, Kesinee; Kenny, Shannon; Gnädig, Nina; Straimer, Judith; Bozdech, Zbynek; Fidock, David A; Simpson, Julie A; Dondorp, Arjen M; Foote, Simon; Klonis, Nectarios; Tilley, Leann

    2015-04-01

    Successful control of falciparum malaria depends greatly on treatment with artemisinin combination therapies. Thus, reports that resistance to artemisinins (ARTs) has emerged, and that the prevalence of this resistance is increasing, are alarming. ART resistance has recently been linked to mutations in the K13 propeller protein. We undertook a detailed kinetic analysis of the drug responses of K13 wild-type and mutant isolates of Plasmodium falciparum sourced from a region in Cambodia (Pailin). We demonstrate that ART treatment induces growth retardation and an accumulation of ubiquitinated proteins, indicative of a cellular stress response that engages the ubiquitin/proteasome system. We show that resistant parasites exhibit lower levels of ubiquitinated proteins and delayed onset of cell death, indicating an enhanced cell stress response. We found that the stress response can be targeted by inhibiting the proteasome. Accordingly, clinically used proteasome inhibitors strongly synergize ART activity against both sensitive and resistant parasites, including isogenic lines expressing mutant or wild-type K13. Synergy is also observed against Plasmodium berghei in vivo. We developed a detailed model of parasite responses that enables us to infer, for the first time, in vivo parasite clearance profiles from in vitro assessments of ART sensitivity. We provide evidence that the clinical marker of resistance (delayed parasite clearance) is an indirect measure of drug efficacy because of the persistence of unviable parasites with unchanged morphology in the circulation, and we suggest alternative approaches for the direct measurement of viability. Our model predicts that extending current three-day ART treatment courses to four days, or splitting the doses, will efficiently clear resistant parasite infections. This work provides a rationale for improving the detection of ART resistance in the field and for treatment strategies that can be employed in areas with ART

  1. Emergence of a Potent Multidrug Efflux Pump Variant That Enhances Campylobacter Resistance to Multiple Antibiotics

    Directory of Open Access Journals (Sweden)

    Hong Yao

    2016-09-01

    Full Text Available Bacterial antibiotic efflux pumps are key players in antibiotic resistance. Although their role in conferring multidrug resistance is well documented, the emergence of “super” efflux pump variants that enhance bacterial resistance to multiple drugs has not been reported. Here, we describe the emergence of a resistance-enhancing variant (named RE-CmeABC of the predominant efflux pump CmeABC in Campylobacter, a major zoonotic pathogen whose resistance to antibiotics is considered a serious antibiotic resistance threat in the United States. Compared to the previously characterized CmeABC transporters, RE-CmeABC is much more potent in conferring Campylobacter resistance to antibiotics, which was shown by increased MICs and reduced intracellular accumulation of antibiotics. Structural modeling suggests that sequence variations in the drug-binding pocket of CmeB possibly contribute to the enhanced efflux function. Additionally, RE-CmeABC expands the mutant selection window of ciprofloxacin, enhances the emergence of antibiotic-resistant mutants, and confers exceedingly high-level resistance to fluoroquinolones, an important class of antibiotics for clinical therapy of campylobacteriosis. Furthermore, RE-CmeABC is horizontally transferable, shifts antibiotic MIC distribution among clinical isolates, and is increasingly prevalent in Campylobacter jejuni isolates, suggesting that it confers a fitness advantage under antimicrobial selection. These findings reveal a new mechanism for enhanced multidrug resistance and an effective strategy utilized by bacteria for adaptation to selection from multiple antibiotics.

  2. Many chromosomal genes modulate MarA-mediated multidrug resistance in Escherichia coli.

    Science.gov (United States)

    Ruiz, Cristian; Levy, Stuart B

    2010-05-01

    Multidrug resistance (MDR) in clinical isolates of Escherichia coli can be associated with overexpression of marA, a transcription factor that upregulates multidrug efflux and downregulates membrane permeability. Using random transposome mutagenesis, we found that many chromosomal genes and environmental stimuli affected MarA-mediated antibiotic resistance. Seven genes affected resistance mediated by MarA in an antibiotic-specific way; these were mostly genes encoding unrelated enzymes, transporters, and unknown proteins. Other genes affected MarA-mediated resistance to all antibiotics tested. These genes were acrA, acrB, and tolC (which encode the major MarA-regulated multidrug efflux pump AcrAB-TolC), crp, cyaA, hns, and pcnB (four genes involved in global regulation of gene expression), and the unknown gene damX. The last five genes affected MarA-mediated MDR by altering marA expression or MarA function specifically on acrA. These findings demonstrate that MarA-mediated MDR is regulated at multiple levels by different genes and stimuli, which makes it both complex and fine-tuned and interconnects it with global cell regulation and metabolism. Such a regulation could contribute to the adaptation and spread of MDR strains and may be targeted to treat antibiotic-resistant E. coli and related pathogens.

  3. Overcoming of multidrug resistance by introducing the apoptosis gene, bcl-Xs, into MRP-overexpressing drug resistant cells.

    Science.gov (United States)

    Ohi, Y; Kim, R; Toge, T

    2000-05-01

    Multidrug resistance associated protein (MRP) is one of drug transport membranes that confer multidrug resistance in cancer cells. Multidrug resistance has been known to be associated with resistance to apoptosis. In this study, using MRP overexpressing multidrug resistant nasopharyngeal cancer cells, we examined the expression of apoptosis related genes including p53, p21WAF1, bax and bcl-Xs between drug sensitive KB and its resistant KB/7D cells. We also examined whether the introduction of apoptosis related gene could increase the sensitivity to anticancer drugs in association with apoptotic cell death. The relative resistances to anticancer drugs in KB/7D cells evaluated by IC50 values were 3.6, 61.3, 10.4 and 10.5 to adriamycin (ADM), etoposide (VP-16), vincristine (VCR) and vindesine (VDS), respectively. The resistance to anticancer drugs in KB/7D cells was associated with the attenuation of internucleosomal DNA ladder formation in apoptosis. Of important, the mRNA expression of bcl-Xs gene in KB/7D cells was decreased in one-fourth as compared to that of KB cells among the apoptosis genes. The mRNA expression of bcl-Xs gene in a bcl-Xs transfected clone (KB/7Dbcl-Xs) was increased about 2-fold compared to that of KB/7Dneo cells, while the mRNA expression of MRP gene was not significantly different in KB/7bcl-Xs and KB/7Dneo cells. The sensitivities to anticancer drugs including ADM, VCR and VDS except VP-16 were increased in KB/7Dbcl-Xs cells, in turn, the relative resistance in KB/7Dbcl-Xs cells was decreased to 1.4, 4.0, and 3.0 in ADM, VCR and VDS, respectively, as compared to those of KB/7Dneo cells. Of interest, the studies on the accumulation of [3H]VCR showed that the decrease of [3H]VCR accumulation in KB/7Dbcl-Xs was not significantly different from that of KB/7Dneo cells. Collectively, these results indicated that the mechanism(s) of drug resistance in KB/7D cells could be explained at least by two factors: a) reduced drug accumulation mediated by

  4. Current understanding of the molecular basis of chloroquine-resistance in Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Jiang H

    2006-01-01

    Full Text Available Chloroquine (CQ is the most successful antimalarial drug ever discovered. Unfortunately, parasites resistant to the drug eventually emerged after its large scale use and are now widespread. Although great progress in our understanding of the mechanisms of CQ action and CQ resistance (CQR has been achieved over the past two decades, including the identification of the molecules responsible for CQR (e.g., Plasmodium falciparum chloroquine resistant transporter, PfCRT many questions remain unanswered. Here we highlight recent advances in our understanding of the genetics and molecular mechanisms of CQR, with particular emphasis on the role of genes such as pfcrt and pfmdr1 in the resistance to CQ and other drugs. New drug development and applications will undoubtedly benefit from a better understanding of CQR, eventually leading to more effective malaria control measures.

  5. Confirmation of Plasmodium falciparum in vitro resistance to monodesethylamodiaquine and chloroquine in Dakar, Senegal, in 2015.

    Science.gov (United States)

    Diawara, Silman; Madamet, Marylin; Kounta, Mame Bou; Lo, Gora; Wade, Khalifa Ababacar; Nakoulima, Aminata; Bercion, Raymond; Amalvict, Rémy; Gueye, Mamadou Wague; Fall, Bécaye; Diatta, Bakary; Pradines, Bruno

    2017-03-16

    In response to increasing resistance to anti-malarial drugs, Senegal adopted artemisinin-based combination therapy (ACT) as the first-line treatment for uncomplicated malaria in 2006. However, resistance of Plasmodium falciparum parasites to artemisinin derivatives, characterized by delayed parasite clearance after treatment with ACT or artesunate monotherapy, has recently emerged and rapidly spread in Southeast Asia. After 10 years of stability with rates ranging from 5.6 to 11.8%, the prevalence of parasites with reduced susceptibility in vitro to monodesethylamodiaquine, the active metabolite of an ACT partner drug, increased to 30.6% in 2014 in Dakar. Additionally, after a decrease of the in vitro chloroquine resistance in Dakar in 2009-2011, the prevalence of parasites that showed in vitro chloroquine resistance increased again to approximately 50% in Dakar since 2013. The aim of this study was to follow the evolution of the susceptibility to ACT partners and other anti-malarial drugs in 2015 in Dakar. An in vitro test is the only method currently available to provide an early indication of resistance to ACT partners. Thirty-two P. falciparum isolates collected in 2015 in Dakar were analysed using a standard ex vivo assay based on an HRP2 ELISA. The prevalence of P. falciparum parasites with reduced susceptibility in vitro to monodesethylamodiaquine, chloroquine, mefloquine, doxycycline and quinine was 28.1, 46.9, 45.2, 31.2 and 9.7%, respectively. None of the parasites were resistant to lumefantrine, piperaquine, pyronaridine, dihydroartemisinin and artesunate. These results confirm an increase in the reduced susceptibility to monodesethylamodiaquine observed in 2014 in Dakar and the chloroquine resistance observed in 2013. The in vitro resistance seems to be established in Dakar. Additionally, the prevalence of parasites with reduced susceptibility to doxycycline has increased two-fold compared to 2014. The establishment of a reduced susceptibility to

  6. Artemisinin Resistance-Associated Polymorphisms at the K13-Propeller Locus Are Absent in Plasmodium falciparum Isolates from Haiti

    Science.gov (United States)

    Carter, Tamar E.; Boulter, Alexis; Existe, Alexandre; Romain, Jean R.; St. Victor, Jean Yves; Mulligan, Connie J.; Okech, Bernard A.

    2015-01-01

    Antimalarial drugs are a key tool in malaria elimination programs. With the emergence of artemisinin resistance in southeast Asia, an effort to identify molecular markers for surveillance of resistant malaria parasites is underway. Non-synonymous mutations in the kelch propeller domain (K13-propeller) in Plasmodium falciparum have been associated with artemisinin resistance in samples from southeast Asia, but additional studies are needed to characterize this locus in other P. falciparum populations with different levels of artemisinin use. Here, we sequenced the K13-propeller locus in 82 samples from Haiti, where limited government oversight of non-governmental organizations may have resulted in low-level use of artemisinin-based combination therapies. We detected a single-nucleotide polymorphism (SNP) at nucleotide 1,359 in a single isolate. Our results contribute to our understanding of the global genomic diversity of the K13-propeller locus in P. falciparum populations. PMID:25646258

  7. 2-Pyrrolinodoxorubicin and its peptide-vectorized form bypass multidrug resistance.

    Science.gov (United States)

    Castex, Cédric; Merida, Peggy; Blanc, Emmanuelle; Clair, Philippe; Rees, Anthony R; Temsamani, Jamal

    2004-07-01

    A well-known mechanism leading to the emergence of multidrug-resistant tumor cells is the overexpression of P-glycoprotein, which is capable of lowering intracellular drug concentrations. In the present study, we tested the capability of 2-pyrrolinodoxorubicin (p-DOX), a highly potent derivative of DOX, to bypass multidrug resistance. The accumulation, intracellular distribution and cytotoxicity of p-DOX were tested in two cell lines (K562 and A2780) and their DOX-resistant counterparts (K562/ADR and A2780/ADR). Cellular accumulation and cytotoxicity were dramatically lowered for DOX in resistant cell lines, in comparison with non-resistant cells. In contrast, cellular accumulation, intracellular distribution and cytotoxicity of p-DOX were independent of the nature of the cell lines. The p-DOX showed potent dose-dependent inhibition of cell growth against resistant cells as compared with DOX. After treatment of resistant cells with verapamil, the intracellular levels of DOX were markedly increased and consequent cytotoxicity improved. In contrast, treatment of resistant cells with verapamil did not cause any further enhancement of cell uptake or an increase in the cytotoxic effect of the derivative p-DOX, indicating that the compound bypasses the P-glycoprotein. Finally, we show that vectorization of p-DOX by a peptide vector (SynB3) which has been shown to enhance the brain uptake of DOX and to decrease its heart accumulation does not affect this property. These results indicate that p-DOX and its vectorized form are potent and effective in overcoming multidrug resistance.

  8. Transcriptional and proteomic analyses of two-component response regulators in multidrug-resistant Mycobacterium tuberculosis.

    Science.gov (United States)

    Zhou, Lei; Yang, Liu; Zeng, Xianfei; Danzheng, Jiacuo; Zheng, Qing; Liu, Jiayun; Liu, Feng; Xin, Yijuan; Cheng, Xiaodong; Su, Mingquan; Ma, Yueyun; Hao, Xiaoke

    2015-07-01

    Two-component systems (TCSs) have been reported to exhibit a sensing and responding role under drug stress that induces drug resistance in several bacterial species. However, the relationship between TCSs and multidrug resistance in Mycobacterium tuberculosis has not been comprehensively analysed to date. In this study, 90 M. tuberculosis clinical isolates were analysed using 15-loci mycobacterial interspersed repetitive unit (MIRU)-variable number tandem repeat (VNTR) typing and repetitive extragenic palindromic (rep)-PCR-based DNA fingerprinting. The results showed that all of the isolates were of the Beijing lineage, and strains with a drug-susceptible phenotype had not diverged into similar genotype clusters. Expression analysis of 13 response regulators of TCSs using real-time PCR and tandem mass spectrometry (MS/MS) proteomic analysis demonstrated that four response regulator genes (devR, mtrA, regX3 and Rv3143) were significantly upregulated in multidrug-resistant (MDR) strains compared with the laboratory strain H37Rv as well as drug-susceptible and isoniazid-monoresistant strains (PMycobacterium bovis BCG did not alter its sensitivity to the four antitubercular drugs. This suggests that upregulation of devR, which is common in MDR-TB strains, might be induced by drug stress and hypoxic adaptation following the acquisition of multidrug resistance.

  9. Multi-drug resistant gram negative bacilli causing early neonatal sepsis in India.

    Science.gov (United States)

    Viswanathan, Rajlakshmi; Singh, Arun Kumarendu; Basu, Sulagna; Chatterjee, Suparna; Sardar, Syamal; Isaacs, David

    2012-05-01

    To study the organisms causing early and late onset neonatal sepsis, with special reference to multi-drug resistant gram negative bacilli, at two neonatal units (one urban, one rural) in India. Prospective surveillance study. There were 159 episodes of sepsis (81 urban and 77 rural) affecting 158 babies. Gram negative bacilli caused 117 infections (68%) and predominated at both centres in both early and late sepsis. Klebsiella pneumoniae was the commonest organism, causing 61 infections (38.3%). In early sepsis (0-2 days), non-fermenting gram negative bacilli caused 42.1% of infections at the urban centre; there were no cases of early Group B Streptococcus sepsis. Late onset sepsis was mainly caused by gram negative bacilli at both centres. Multi-drug resistance of over 80% of early-onset gram negative organisms to ampicillin, third generation cephalosporins and gentamicin indicates that these multi-resistant organisms are almost certainly circulating widely in the community. The overall mortality from early sepsis was 27.3% (9 of 33) and from late sepsis was 26.2% (33 of 126). Gram negative bacilli caused all deaths from early sepsis and 87.5% of deaths from late sepsis. This study shows that multi-drug resistant gram negative bacilli are a major cause of early and late neonatal sepsis in India and are almost certainly widespread in the community.

  10. Characterization of putative multidrug resistance transporters of the major facilitator-superfamily expressed in Salmonella Typhi.

    Science.gov (United States)

    Shaheen, Aqsa; Ismat, Fouzia; Iqbal, Mazhar; Haque, Abdul; De Zorzi, Rita; Mirza, Osman; Walz, Thomas; Rahman, Moazur

    2015-05-01

    Multidrug resistance mediated by efflux pumps is a well-known phenomenon in infectious bacteria. Although much work has been carried out to characterize multidrug efflux pumps in Gram-negative and Gram-positive bacteria, such information is still lacking for many deadly pathogens. The aim of this study was to gain insight into the substrate specificity of previously uncharacterized transporters of Salmonella Typhi to identify their role in the development of multidrug resistance. S. Typhi genes encoding putative members of the major facilitator superfamily were cloned and expressed in the drug-hypersensitive Escherichia coli strain KAM42, and tested for transport of 25 antibacterial compounds, including representative antibiotics of various classes, antiseptics, dyes and detergents. Of the 15 tested putative transporters, STY0901, STY2458 and STY4874 exhibited a drug-resistance phenotype. Among these, STY4874 conferred resistance to at least ten of the tested antimicrobials: ciprofloxacin, norfloxacin, levofloxacin, kanamycin, streptomycin, gentamycin, nalidixic acid, chloramphenicol, ethidium bromide, and acriflavine, including fluoroquinolone antibiotics, which were drugs of choice to treat S. Typhi infections. Cell-based functional studies using ethidium bromide and acriflavine showed that STY4874 functions as a H(+)-dependent exporter. These results suggest that STY4874 may be an important drug target, which can now be tested by studying the susceptibility of a STY4874-deficient S. Typhi strain to antimicrobials.

  11. Biofilm formation in clinical isolates of nosocomial Acinetobacter baumannii and its relationship with multidrug resistance

    Institute of Scientific and Technical Information of China (English)

    Ebrahim Babapour; Azam Haddadi; Reza Mirnejad; Seyed-Abdolhamid Angaji; Nour Amirmozafari

    2016-01-01

    Objective: To check biofilm formation by Acinetobacter baumannii(A. baumannii)clinical isolates and show their susceptibility to different antibiotics and investigate a possible link between establishment of biofilm and multidrug resistance.Methods: This study was performed on clinical samples collected from patients with nosocomial infections in three hospitals of Tehran. Samples were initially screened by culture and biochemical tests for the presence of different species of Acinetobacter. Identifications were further confirmed by PCR assays. Their susceptibilities to 11 antibiotics of different classes were determined by disc diffusion method according to Clinical and Laboratory Standards Institute guidelines. The ability to produce biofilm was investigated using methods: culture on Congo red agar, microtiter plate, and test tube method.Results: From the overall clinical samples, 156 specimens were confirmed to contain A. baumannii. The bacteria were highly resistant to most antibiotics except polymyxin B.Of these isolates, 10.26% were able to produce biofilms as shown on Congo red agar.However, the percentage of bacteria with positive biofilm in test tube, standard microtiter plate, and modified microtiter plate assays were 48.72%, 66.66%, and 73.72%, respectively. At least 92% of the biofilm forming isolates were multidrug resistant.Conclusions: Since most of the multidrug resistant strains produce biofilm, it seems necessary to provide continuous monitoring and determination of antibiotic susceptibility of clinical A. baumannii. This would help to select the most appropriate antibiotic for treatment.

  12. Biofilm formation in clinical isolates of nosocomial Acinetobacter baumannii and its relationship with multidrug resistance

    Institute of Scientific and Technical Information of China (English)

    Ebrahim Babapour; Azam Haddadi; Reza Mirnejad; Seyed-Abdolhamid Angaji; Nour Amirmozafari

    2016-01-01

    Objective: To check biofilm formation by Acinetobacter baumannii (A. baumannii) clinical isolates and show their susceptibility to different antibiotics and investigate a possible link between establishment of biofilm and multidrug resistance. Methods: This study was performed on clinical samples collected from patients with nosocomial infections in three hospitals of Tehran. Samples were initially screened by culture and biochemical tests for the presence of different species of Acinetobacter. Iden-tifications were further confirmed by PCR assays. Their susceptibilities to 11 antibiotics of different classes were determined by disc diffusion method according to Clinical and Laboratory Standards Institute guidelines. The ability to produce biofilm was investigated using methods:culture on Congo red agar, microtiter plate, and test tube method. Results: From the overall clinical samples, 156 specimens were confirmed to contain A. baumannii. The bacteria were highly resistant to most antibiotics except polymyxin B. Of these isolates, 10.26% were able to produce biofilms as shown on Congo red agar. However, the percentage of bacteria with positive biofilm in test tube, standard microtiter plate, and modified microtiter plate assays were 48.72%, 66.66%, and 73.72%, respec-tively. At least 92%of the biofilm forming isolates were multidrug resistant. Conclusions: Since most of the multidrug resistant strains produce biofilm, it seems necessary to provide continuous monitoring and determination of antibiotic susceptibility of clinical A. baumannii. This would help to select the most appropriate antibiotic for treatment.

  13. Silver Nanocomposite Biosynthesis: Antibacterial Activity against Multidrug-Resistant Strains of Pseudomonas aeruginosa and Acinetobacter baumannii

    Directory of Open Access Journals (Sweden)

    Klebson Silva Santos

    2016-09-01

    Full Text Available Bacterial resistance is an emerging public health issue that is disseminated worldwide. Silver nanocomposite can be an alternative strategy to avoid Gram-positive and Gram-negative bacteria growth, including multidrug-resistant strains. In the present study a silver nanocomposite was synthesized, using a new green chemistry process, by the addition of silver nitrate (1.10−3 mol·L−1 into a fermentative medium of Xanthomonas spp. to produce a xanthan gum polymer. Transmission electron microscopy (TEM was used to evaluate the shape and size of the silver nanoparticles obtained. The silver ions in the nanocomposite were quantified by flame atomic absorption spectrometry (FAAS. The antibacterial activity of the nanomaterial against Escherichia coli (ATCC 22652, Enterococcus faecalis (ATCC 29282, Pseudomonas aeruginosa (ATCC 27853 and Staphylococcus aureus (ATCC 25923 was carried out using 500 mg of silver nanocomposite. Pseudomonas aeruginosa and Acinetobacter baumannii multidrug-resistant strains, isolated from hospitalized patients were also included in the study. The biosynthesized silver nanocomposite showed spherical nanoparticles with sizes smaller than 10 nm; 1 g of nanocomposite contained 49.24 µg of silver. Multidrug-resistant strains of Pseudomonas aeruginosa and Acinetobacter baumannii, and the other Gram-positive and Gram-negative bacteria tested, were sensitive to the silver nanocomposite (10–12.9 mm of inhibition zone. The biosynthesized silver nanocomposite seems to be a promising antibacterial agent for different applications, namely biomedical devices or topical wound coatings.

  14. The cmbT gene encodes a novel major facilitator multidrug resistance transporter in Lactococcus lactis.

    Science.gov (United States)

    Filipic, Brankica; Golic, Natasa; Jovcic, Branko; Tolinacki, Maja; Bay, Denice C; Turner, Raymond J; Antic-Stankovic, Jelena; Kojic, Milan; Topisirovic, Ljubisa

    2013-01-01

    Functional characterization of the multidrug resistance CmbT transporter was performed in Lactococcus lactis. The cmbT gene is predicted to encode an efflux protein homologous to the multidrug resistance major facilitator superfamily. The cmbT gene (1377 bp) was cloned and overexpressed in L. lactis NZ9000. Results from cell growth studies revealed that the CmbT protein has an effect on host cell resistance to lincomycin, cholate, sulbactam, ethidium bromide, Hoechst 33342, sulfadiazine, streptomycin, rifampicin, puromycin and sulfametoxazole. Moreover, in vivo transport assays showed that overexpressed CmbT-mediated extrusion of ethidium bromide and Hoechst 33342 was higher than in the control L. lactis NZ9000 strain. CmbT-mediated extrusion of Hoechst 33342 was inhibited by the ionophores nigericin and valinomycin known to dissipate proton motive force. This indicates that CmbT-mediated extrusion is based on a drug-proton antiport mechanism. Taking together results obtained in this study, it can be concluded that CmbT is a novel major facilitator multidrug resistance transporter candidate in L. lactis, with a possible signaling role in sulfur metabolism.

  15. Emergence of Multidrug Resistance and Metallo‑beta‑lactamase ...

    African Journals Online (AJOL)

    resistance mechanisms against carbapenems in some bacteria including Acinetobacterbaumannii. Aims: This study was aimed to ... of MβL among carbapenem‑resistant isolates of A. baumannii. Materials and ... A. baumannii using Microgen™ kits and confirmed by molecular method. ... at − 70°C until for long preservation.

  16. Multiple origins of Plasmodium falciparum dihydropteroate synthetase mutant alleles associated with sulfadoxine resistance in India.

    Science.gov (United States)

    Lumb, Vanshika; Das, Manoj K; Singh, Neeru; Dev, Vas; Khan, Wajihullah; Sharma, Yagya D

    2011-06-01

    With the spread of chloroquine (CQ)-resistant malaria in India, sulfadoxine-pyrimethamine (SP) alone or in combination with artesunate is used as an alternative antimalarial drug. Due to continuous drug pressure, the Plasmodium falciparum parasite is exhibiting resistance to antifolates because of mutations in candidate genes dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps). Our earlier study on flanking microsatellite markers of dhfr mutant alleles from India had shown a single origin of the pyrimethamine resistance and some minor haplotypes which shared haplotypes with Southeast Asian (Thailand) strains. In the present study, we have analyzed 193 of these Indian P. falciparum isolates for 15 microsatellite loci around dhps to investigate the genetic lineages of the mutant dhps alleles in different parts of the country. Eighty-one of these samples had mutant dhps alleles, of which 62 were from Andaman and Nicobar Islands and the remaining 19 were from mainland India. Of 112 isolates with a wild-type dhps allele, 109 were from mainland India and only 3 were from Andaman and Nicobar Islands. Consistent with the model of selection, the mean expected heterozygosity (H(e)) around mutant dhps alleles (H(e) = 0.55; n = 81) associated with sulfadoxine resistance was lower (P ≤ 0.05) than the mean H(e) around the wild-type dhps allele (H(e) = 0.80; n = 112). There was more genetic diversity in flanking microsatellites of dhps than dhfr among these isolates, which confirms the assertion that dhps mutations are at a very early stage of fixation in the parasite population. Microsatellite haplotypes around various mutant dhps alleles suggest that the resistant dhps alleles have multiple independent origins in India, especially in Andaman and Nicobar Islands. Determining the genetic lineages of the resistant dhps alleles on Andaman and Nicobar Islands and mainland India is significant, given the role of Asia in the intercontinental spread of chloroquine

  17. Synergistic effect of Thymbra spicata L. extracts with antibiotics against multidrug- resistant Staphylococcus aureus and Klebsiella pneumoniae strains

    Directory of Open Access Journals (Sweden)

    Mohammad F Haroun

    2016-11-01

    Conclusion: These results may indicate that T. spicata extracts potentiates the antimicrobial action of antibiotics, suggesting a possible utilization of this herb in combination therapy against emerging multidrug-resistance S. aureus and K. pneumoniae.

  18. Intraventricular ciprofloxacin usage in treatment of multidrug-resistant central nervous system infections: report of four cases

    National Research Council Canada - National Science Library

    Karaaslan, Ayşe; Kadayifçi, Eda Kepenekli; Turel, Ozden; Toprak, Demet Gedikbaşi; Soysal, Ahmet; Bakir, Mustafa

    2014-01-01

    .... In this study, four cases of central nervous system infections due to multidrug-resistant microorganisms who were successfully treated with removal of the devices and intraventricular ciprofloxacin are presented...

  19. RISK FACTORS FOR INEFFECTIVE CHEMOTHERAPY IN PATIENTS WITH MULTIDRUG-RESISTANT TUBERCULOSIS

    Directory of Open Access Journals (Sweden)

    O. V. Filinyuk

    2014-01-01

    Full Text Available The social, clinical, radiological, and bacteriological causes of DOTS-PLUS failure were analyzed. According to the findings, diagnosis at the early stage of fibrocavernous tuberculosis, respiratory failure, or hemoptysis in the presence of chronic bronchitis, gastrointestinal and urinary tract diseases, as well as in prison increased the risk of poor therapy outcome. Massive bacterial excretion, high rate of secondary resistance development in Mycobacterium tuberculosis, and its drug resistance to five agents or more are maximally associated with treatment failure in patients with multidrug-resistant tuberculosis.

  20. Multidrug-resistant Streptococcus pneumoniae isolates from healthy Ghanaian preschool children

    DEFF Research Database (Denmark)

    Dayie, Nicholas Tete Kwaku Dzifa; Arhin, Reuben E.; Newman, Mercy J.

    2015-01-01

    Streptococcus pneumoniae is the cause of high mortality among children worldwide. Antimicrobial treatment and vaccination are used to control pneumococcal infections. In Ghana, data on antimicrobial resistance and the prevalence of multidrug-resistant pneumococcal clones are scarce; hence, the aim...... of this study was to determine the antibiogram of S. pneumoniae recovered from Ghanaian children younger than six years of age and to what extent resistances were due to the spread of certain sero- and multilocus sequence typing (MLST) types. The susceptibility of 115 pneumococcal isolates, recovered...

  1. Whole genome sequencing of emerging multidrug resistant Candida auris isolates in India demonstrates low genetic variation.

    Science.gov (United States)

    Sharma, C; Kumar, N; Pandey, R; Meis, J F; Chowdhary, A

    2016-09-01

    Candida auris is an emerging multidrug resistant yeast that causes nosocomial fungaemia and deep-seated infections. Notably, the emergence of this yeast is alarming as it exhibits resistance to azoles, amphotericin B and caspofungin, which may lead to clinical failure in patients. The multigene phylogeny and amplified fragment length polymorphism typing methods report the C. auris population as clonal. Here, using whole genome sequencing analysis, we decipher for the first time that C. auris strains from four Indian hospitals were highly related, suggesting clonal transmission. Further, all C. auris isolates originated from cases of fungaemia and were resistant to fluconazole (MIC >64 mg/L).

  2. Characterization of an IncA/C Multidrug Resistance Plasmid in Vibrio alginolyticus.

    Science.gov (United States)

    Ye, Lianwei; Li, Ruichao; Lin, Dachuan; Zhou, Yuanjie; Fu, Aisi; Ding, Qiong; Chan, Edward Wai Chi; Yao, Wen; Chen, Sheng

    2016-05-01

    Cephalosporin-resistant Vibrio alginolyticus was first isolated from food products, with β-lactamases encoded by blaPER-1, blaVEB-1, and blaCMY-2 being the major mechanisms mediating their cephalosporin resistance. The complete sequence of a multidrug resistance plasmid, pVAS3-1, harboring the blaCMY-2 and qnrVC4 genes was decoded in this study. Its backbone exhibited genetic homology to known IncA/C plasmids recoverable from members of the family Enterobacteriaceae, suggesting its possible origin in Enterobacteriaceae. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  3. Pneumocephalus as a complication of multidrug-resistant Klebsiella pneumoniae meningitis.

    Science.gov (United States)

    Sreejith, P; Vishad, V; Pappachan, Joseph M; Laly, D C; Jayaprakash, R; Ranjith, V T

    2008-03-01

    Pneumocephalus implies air inside the cranial vault, which usually results from cranio-facial trauma. Occasionally, meningitis caused by gas-forming organisms can result in pneumocephalus. Klebsiella pneumoniae meningitis can, on rare occasions, cause pneumocephalus as a complication. The drug of choice for K. pneumoniae meningitis is a third-generation cephalosporin, and resistance to these drugs is unusual. We report a case of multidrug-resistant K. pneumoniae meningitis resulting from chronic suppurative otitis media, which was later complicated by pneumocephalus. The patient was successfully managed with meropenam and amikacin, the only antibiotics to which these bacilli showed no resistance.

  4. Multidrug efflux pumps in Gram-negative bacteria and their role in antibiotic resistance.

    Science.gov (United States)

    Blair, Jessica M A; Richmond, Grace E; Piddock, Laura J V

    2014-01-01

    Gram-negative bacteria express a plethora of efflux pumps that are capable of transporting structurally varied molecules, including antibiotics, out of the bacterial cell. This efflux lowers the intracellular antibiotic concentration, allowing bacteria to survive at higher antibiotic concentrations. Overexpression of some efflux pumps can cause clinically relevant levels of antibiotic resistance in Gram-negative pathogens. This review discusses the role of efflux in resistance of clinical isolates of Gram-negative bacteria, the regulatory mechanisms that control efflux pump expression, the recent advances in our understanding of efflux pump structure and how inhibition of efflux is a promising future strategy for tackling multidrug resistance in Gram-negative pathogens.

  5. Establishment of a human hepatoma multidrug resistant cell line in vitro

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    AIM:To establish a multidrug-resistant hepatoma cell line(SK-Hep-1),and to investigate its biological characteristics.METHODS:A highly invasive SK-Hep-1 cell line of human hepatocellular carcinoma,also known as malignant hepatoma was incubated with a high concentration of cisplatin(CDDP) to establish a CDDP-resistant cell subline(SK-Hep-1/CDDP).The 50% inhibitory dose(IC50) values and the resistance indexes [(IC50 SK-Hep-1/CDDP)/(IC50 SK-Hep-1)] for other chemotherapeutic agents and the growth curve of cell...

  6. Clinical Management of an Increasing Threat: Outpatient Urinary Tract Infections Due to Multidrug-Resistant Uropathogens.

    Science.gov (United States)

    Walker, Emily; Lyman, Alessandra; Gupta, Kalpana; Mahoney, Monica V; Snyder, Graham M; Hirsch, Elizabeth B

    2016-10-01

    Urinary tract infections (UTIs) are among the most commonly treated bacterial infections. Over the past decade, antimicrobial resistance has become an increasingly common factor in the management of outpatient UTIs. As treatment options for multidrug-resistant (MDR) uropathogens are limited, clinicians need to be aware of specific clinical and epidemiological risk factors for these infections. Based on available literature, the activity of fosfomycin and nitrofurantoin remain high for most cases of MDR Escherichia coli UTIs. Trimethoprim-sulfamethoxazole retains clinical efficacy, but resistance rates are increasing internationally. Beta-lactam agents have the highest rates of resistance and lowest rates of clinical success. Fluoroquinolones have high resistance rates among MDR uropathogens and are being strongly discouraged as first-line agents for UTIs. In addition to accounting for local resistance rates, consideration of patient risk factors for resistance and pharmacological principles will help guide optimal empiric treatment of outpatient UTIs.

  7. Antibacterial activities of ethanol extracts of Philippine medicinal plants against multidrug-resistant bacteria

    Institute of Scientific and Technical Information of China (English)

    Demetrio L Valle Jr; Jeannie I Andrade; Juliana Janet M Puzon; Esperanza C Cabrera; Windell L Rivera

    2015-01-01

    Objective:To investigate the antibacterial activities of crude ethanol extracts of 12 Philippine medicinal plants. Methods:Crude ethanol extracts from 12 Philippine medicinal plants were evaluated for their antibacterial activity against methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, extended spectrum β-lactamase-producing, carbapenem-resistant Enterobacteriaceae and metallo-β-lactamase-producing Pseudomonas aeruginosa and Acinetobacter baumannii. Results:The leaf extracts of Psidium guajava, Phyllanthus niruri, Ehretia microphylla and Piper betle (P. betle) showed antibacterial activity against the Gram-positive methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. P. betle showed the highest antibacterial activity for these bacteria in the disk diffusion (16-33 mm inhibition diameter), minimum inhibitory concentration (19-156 μg/mL) and minimum bactericidal concentration (312μg/mL) assays. P. betle leaf extracts only showed remarkable antibacterial activity for all the Gram-negative multidrug-resistant bacteria (extended spectrumβ-lactamase-producing, carbapenem-resistant Enterobacteriaceae and metallo-β-lactamase-producing) in the disk diffusion (17-21 mm inhibition diameter), minimum inhibitory concentration (312-625μg/mL) and minimum bactericidal concentration (312-625μg/mL) assays. Conclusions:P. betle had the greatest potential value against both Gram-negative and Gram-positive multidrug-resistant bacteria. Favorable antagonistic activities were also exhibited by the ethanol extracts of Psidium guajava, Phyllanthus niruri and Ehretia microphylla.

  8. Multidrug-Resistant Salmonella Isolates from Swine in the Eastern Cape Province, South Africa.

    Science.gov (United States)

    Iwu, Chinwe Juliana; Iweriebor, Benson Chuks; Obi, Larry Chikwelu; Basson, Albertus Kotze; Okoh, Anthony Ifeanyi

    2016-07-01

    The exposure of farm animals to antimicrobials for treatment, prophylaxis, or growth promotion can select for resistant bacteria that can be transmitted to humans, and Salmonella as an important zoonotic pathogen can act as a potential reservoir of antimicrobial resistance determinants. We assessed the antibiogram profiles of Salmonella species isolated from pig herds in two commercial farms in South Africa. Two hundred fifty-eight presumptive Salmonella isolates were recovered from the fecal samples of 500 adult pigs. Specific primers targeting Salmonella serogroups A, B, C1, C2, and D were used to determine the prevalence of different serogroups. Only serogroup A (n = 48) was detected, while others were not. Antimicrobial susceptibility of the confirmed Salmonella serogroup A isolates was performed by using the disk diffusion method against a panel of 18 antibiotics. All the 48 isolates were resistant to tetracycline and oxytetracycline, while 75% were resistant to ampicillin, sulphamethoxazole-trimethoprim, nalidixic acid, and streptomycin. All the isolates exhibited multidrug resistance, with the predominant phenotype being against 11 antibiotics, and multiple antibiotic resistance index ranged between 0.3 and 0.6. The incidence of genes encoding resistance against ampicillin (ampC), tetracycline (tetA), and streptomycin (strA) were 54, 61, and 44%, respectively. We conclude that healthy pigs are potential reservoirs of multidrug-resistant Salmonella that could be transmitted to humans through the food chain and, hence, a significant public health threat.

  9. Expression of Survivin Gene and Its Relationship with Clinical Multidrug Resistance in Osteosarcoma

    Institute of Scientific and Technical Information of China (English)

    NIETao; DAIMin; ZONGShizhang

    2005-01-01

    Objective: To study the expression of survivin and its relationship with clinical multidrug resistance in osteosarcoma. Methods: By using immunohistochemistry (S-P) method, the expression of Survivin in osteosarcoma, osteochondroma and normal osseous tissue, and the expression of P-glycoprotein in osteosarcoma was detected. Results: Survivin positive expression rate was 65.71% in osteosarcoma, but no expression of Survivin was detectable in osteochondroma and normal osseous tissue. The positive expression rate of Survivin was significantly associated with Enneking clinical stages and histological typing (WHO), but no relationship was found among Survivin expression and age, sex and tumor location. The positive expression rate of P-glycoprotein was 45.71%. There was a significant correlation between Survivin and p-glycoprotein. Conclusion: Survivin overexpression was significantly associated with clinical multidrug resistance in osteosarcoma. It could be a potential target for treatment of osteosarcoma.

  10. Isolation and characterization of a bacteriophage phiEap-2 infecting multidrug resistant Enterobacter aerogenes.

    Science.gov (United States)

    Li, Erna; Wei, Xiao; Ma, Yanyan; Yin, Zhe; Li, Huan; Lin, Weishi; Wang, Xuesong; Li, Chao; Shen, Zhiqiang; Zhao, Ruixiang; Yang, Huiying; Jiang, Aimin; Yang, Wenhui; Yuan, Jing; Zhao, Xiangna

    2016-06-20

    Enterobacter aerogenes (Enterobacteriaceae) is an important opportunistic pathogen that causes hospital-acquired pneumonia, bacteremia, and urinary tract infections. Recently, multidrug-resistant E. aerogenes have been a public health problem. To develop an effective antimicrobial agent, bacteriophage phiEap-2 was isolated from sewage and its genome was sequenced because of its ability to lyse the multidrug-resistant clinical E. aerogenes strain 3-SP. Morphological observations suggested that the phage belongs to the Siphoviridae family. Comparative genome analysis revealed that phage phiEap-2 is related to the Salmonella phage FSL SP-031 (KC139518). All of the structural gene products (except capsid protein) encoded by phiEap-2 had orthologous gene products in FSL SP-031 and Serratia phage Eta (KC460990). Here, we report the complete genome sequence of phiEap-2 and major findings from the genomic analysis. Knowledge of this phage might be helpful for developing therapeutic strategies against E. aerogenes.

  11. Multidrug-Resistant Gram-Negative Bacteria Colonization of Healthy US Military Personnel in the US and Afghanistan

    Science.gov (United States)

    2013-02-05

    Randrianirina F, Ratovoson R, et al: Rectal carriage of extended- spectrum beta-lactamase-producing gram - negative bacilli in community settings in...FEB 2013 2. REPORT TYPE N/A 3. DATES COVERED - 4. TITLE AND SUBTITLE Multidrug-resistant gram - negative bacteria colonization of healthy US...98) Prescribed by ANSI Std Z39-18 Multidrug-resistant gram - negative bacteria colonization of healthy US military personnel in the US and

  12. The role of ATP-binding cassette transporter A2 in childhood acute lymphoblastic leukemia multidrug resistance

    OpenAIRE

    Aberuyi, N; Rahgozar, S; Moafi, A

    2014-01-01

    Acute lymphoblastic leukemia (ALL) is one of the most prevalent hematologic malignancies in children. Although the cure rate of ALL has improved over the past decades, the most important reason for ALL treatment failure is multidrug resistance (MDR) phenomenon. The current study aims to explain the mechanisms involved in multidrug resistance of childhood ALL, and introduces ATP-binding cassette transporterA2 (ABCA2) as an ABC transporter gene which may have a high impact on MDR. Benefiting fr...

  13. Genetic diversity of Plasmodium falciparum and distribution of drug resistance haplotypes in Yemen

    Science.gov (United States)

    2013-01-01

    Background Despite evident success of malaria control in many sites in the Arabian Peninsula, malaria remains endemic in a few spots, in Yemen and south-west of Saudi Arabia. In addition to local transmission, imported malaria sustains an extra source of parasites that can challenge the strengths of local control strategies. This study examined the genetic diversity of Plasmodium falciparum in Yemen and mutations of drug resistant genes, to elucidate parasite structure and distribution of drug resistance genotypes in the region. Methods Five polymorphic loci (MSP-2, Pfg377 and three microsatellites on chromosome 8) not involved in anti-malarial drug resistance, and four drug resistant genes (pfcrt, pfmdr1, dhfr and dhps) were genotyped in 108 P. falciparum isolates collected in three sites in Yemen: Dhamar, Hodeidah and Taiz. Results High diversity was seen in non-drug genes, pfg377 (He = 0.66), msp-2 (He = 0.80) and three microsatellites on chr 8, 7.7 kb (He = 0.88), 4.3 kb (He = 0.77) and 0.8 kb (He = 0.71). There was a high level of mixed-genotype infections (57%), with an average 1.8 genotypes per patient. No linkage disequilibrium was seen between drug resistant genes and the non-drug markers (p < 0.05). Genetic differentiation between populations was low (most pair-wise FST values <0.03), indicating extensive gene flow between the parasites in the three sites. There was a high prevalence of mutations in pfmdr1, pfcrt and dhfr; with four mutant pfmdr1 genotypes (NFCDD[57%], NFSND[21%], YFCDD[13%] and YFSND[8% ]), two mutant pfcrt genotypes (CVIET[89%] and SVMNT[4%]) and one mutant dhfr genotype (ICNI[53.7%]). However, no dhps mutations were detected. Conclusion The high diversity of P. falciparum in Yemen is indicative of a large parasite reservoir, which represents a challenge to control efforts. The presence of two distinct pfcrt genotype, CVIET and SVMNT, suggests that chloroquine resistance can possibly be related to a migratory

  14. ANTIMICROBIAL SENSITIVITY OF MULTIDRUG-RESISTANT ACINETOBACTER BAUMANNII IN A TERTIARY CARE HOSPITAL OF PATNA

    Directory of Open Access Journals (Sweden)

    Keshav Kumar Bimal

    2017-06-01

    Full Text Available BACKGROUND Acinetobacter spp. has emerged as an important nosocomial pathogen especially in ICU settings. Acinetobacter baumannii is the most commonly isolated species among different Acinetobacters and is associated with variety of human infections. A. baumannii exhibits resistance not only to beta-lactams and cephalosporins, but also to other groups of antibiotics including carbapenems and this has resulted in the emergence of multidrug-resistance A. baumannii species, which is now widespread. To know the prevalence and antimicrobial susceptibility pattern of A. baumannii is crucial for the optimal antimicrobial therapy and to resist the spread of MDR Acinetobacter spp. The aim of the study is to study the antimicrobial susceptibility pattern of A. baumannii isolated from various clinical specimens and to explore the risk factors for multidrug-resistant A. baumannii infections. MATERIALS AND METHODS The present study was conducted from August 2015 to July 2016 at Indira Gandhi Institute of Medical Sciences, Patna. Antimicrobial susceptibility testing was done by Kirby-Bauer’s disc diffusion method. The zones of inhibition were interpreted for antibiotic sensitivity as per the CLSI guidelines 2014. Data regarding patients demographic and clinical status was obtained from medical records and possible risk factors for multidrug-resistant A. baumannii infections was evaluated for their statistical significance. Statistical analysis used- Microsoft excel sheet 2007 and Epi Info software (version 7.2.0.1 was used for different statistical analysis including Pearson’s x 2 test and simple logistic regression. RESULTS A. baumannii was isolated predominantly from respiratory samples (35.3%. Majority of the isolates were from different inpatient departments (59.1%, followed by different ICUs (40.9%. The A. baumannii isolates showed most sensitivity to colistin (100% followed by polymyxin B (90.20% and least sensitive to ampicillin (5.19%. Most of the

  15. Overcoming drug resistance in multi-drug resistant cancers and microorganisms: a conceptual framework.

    Science.gov (United States)

    Avner, Benjamin S; Fialho, Arsenio M; Chakrabarty, Ananda M

    2012-01-01

    Resistance development against multiple drugs is a common feature among many pathogens--including bacteria such as Pseudomonas aeruginosa, viruses, and parasites--and also among cancers. The reasons are two-fold. Most commonly-used rationally-designed small molecule drugs or monoclonal antibodies, as well as antibiotics, strongly inhibit a key single step in the growth and proliferation of the pathogen or cancer cells. The disease agents quickly change or switch off this single target, or activate the efflux mechanisms to pump out the drug, thereby becoming resistant to the drug. A second problem is the way drugs are designed. The pharmaceutical industry chooses to use, by high-throughput screening, compounds that are maximally inhibitory to the key single step in the growth of the pathogen or cancer, thereby promoting selective pressure. An ideal drug would be one that inhibits multiple steps in the disease progression pathways with less stringency in these steps. Low levels of inhibition at multiple steps provide cumulative strong inhibitory effect, but little incentives or ability on the part of the pathogen/cancer to develop resistance. Such intelligent drug design involving multiple less stringent inhibitory steps is beyond the scope of the drug industry and requires evolutionary wisdom commonly possessed by bacteria. This review surveys assessments of the current clinical situation with regard to drug resistance in P. aeruginosa, and examines tools currently employed to limit this trend. We then provide a conceptual framework in which we explore the similarities between multi-drug resistance in pathogens and in cancers. We summarize promising work on anti-cancer drugs derived from the evolutionary wisdom of bacteria such as P. aeruginosa, and how such strategies can be the basis for how to look for candidate protein/peptide antibiotic drugs from bioengineered bugs. Such multi-domain proteins, unlike diffusible antibiotics, are not diffusible because of their

  16. Effect of curcumin on multidrug resistance in resistant human gastric carcinoma cell line SGC7901/VCR

    Institute of Scientific and Technical Information of China (English)

    Xiao-qing TANG; Hu BI; Jian-qiang FENG; Jian-guo CAO

    2005-01-01

    Aim: To investigate the reversal effects of curcumin on multidrug resistance (MDR)in a resistant human gastric carcinoma cell line. Methods: The cytotoxic effect of vincristine (VCR) was evaluated by MTT assay. The cell apoptosis induced by VCR was determined by propidium iodide (PI)-stained flow cytometry (FCM) and a morphological assay using acridine orange (AO)/ethidium bromide (EB) dual staining. P-glycoprotein (P-gp) function was demonstrated by the accumulation and efflux of rhodamine123 (Rh123) using FCM. The expression of P-gp and the activation of caspase-3 were measured by FCM using fluorescein isothiocyanate (FITC)-conjugated anti-P-gp and anti-cleaved caspase-3 antibodies, respectively.Results: Curcumin, at concentrations of 5 μmol/L, 10 μmol/L, or 20 μmol/L, had no cytotoxic effect on a parent human gastric carcinoma cell line (SGC7901) or its VCR-resistant variant cell line (SGC7901/VCR). The VCR-IC50 value of the SGC7901/VCR cells was 45 times more than that of the SGC7901cells and the SGC7901/VCR cells showed apoptotic resistance to VCR. SGC7901/VCR cells treated with 5μmol/L, 10 μmol/L, or 20 μmol/L curcumin decreased the IC50 value of VCR and promoted VCR-mediated apoptosis in a dose-dependent manner. Curcumin (10μmol/L) increased Rh 123 accumulation and inhibited the efflux of Rh 123 in S GC7901/VCR cells, but did not change the accumulation and efflux of Rh123 in SGC7901cells. P-gp was overexpressed in SGC7901/VCR cells, whereas it was downregulated after a 24-h treatment with curcumin (10 μmol/L). Resistant cells treated with 1μmol/L VCR alone showed 77% lower levels of caspase-3 activation relative to SGC7901 cells, but the activation of caspase-3 in the resistant cell line increased by 44% when cells were treated with VCR in combination with curcumin.Conclusion: Curcumin can reverse the MDR of the human gastric carcinoma SGC7901/VCR cell line. This might be associated with decreased P-gp function and expression, and the promotion of

  17. Multi-drug resistant Staphylococcus aureus isolated from emergency ...

    African Journals Online (AJOL)

    various equipment of an Iranian hospital emergency ward. Methods: Two hundred swab ... resistance pattern was analyzed using disk diffusion method. Results: Nine of 200 ..... Dehkordi, Department of Food Hygiene and. Quality Control ...

  18. Multidrug resistance and retroviral transduction potential in human small cell lung cancer cell lines

    DEFF Research Database (Denmark)

    Theilade, M D; Gram, G J; Jensen, P B;

    1999-01-01

    Multidrug resistance (MDR) remains a major problem in the successful treatment of small cell lung cancer (SCLC). New treatment strategies are needed, such as gene therapy specifically targeting the MDR cells in the tumor. Retroviral LacZ gene-containing vectors that were either pseudotyped...... cells, and that MLV-A as well as GALV-1 retroviral vectors are suitable for further development of gene therapy in SCLC....

  19. Vinblastine and sulfinpyrazone export by the multidrug resistance protein MRP2 is associated with glutathione export

    OpenAIRE

    Evers, R.; Haas, M; Sparidans, R; Beijnen, J.; Wielinga, P R; Lankelma, J.; Borst, P

    2000-01-01

    The multidrug resistance proteins MRP1 and MRP2 are members of the same subfamily of ATP-binding cassette transporters. Besides organic molecules conjugated to negatively charged ligands, these proteins also transport cytotoxic drugs for which no negatively charged conjugates are known to exist. In polarized MDCKII cells, MRP1 routes to the lateral plasma membrane, and MRP2 to the apical plasma membrane. In these cells MRP1 transports daunorubicin, and MRP2 vinblastine; both transporters expo...

  20. In-vitro antimicrobial activity of marine actinobacteria against multidrug resistance Staphylococcus aureus

    OpenAIRE

    Sathish Kumar SR; Kokati Venkata Bhaskara Rao

    2012-01-01

    Objective: To investigate the antibacterial activity of marine actinobacteria against multidrug resistance Staphylococcus aureus (MDRSA). Methods: Fifty one actinobacterial strains were isolated from salt pans soil, costal area in Kothapattanam, Ongole, Andhra Pradesh. Primary screening was done using cross-streak method against MDRSA. The bioactive compounds are extracted from efficient actinobacteria using solvent extraction. The antimicrobial activity of crude and solvent extracts was p...

  1. Glutathione depletion regulates both extrinsic and intrinsic apoptotic signaling cascades independent from multidrug resistance protein 1

    OpenAIRE

    2014-01-01

    Glutathione (GSH) depletion is an important hallmark of apoptosis. We previously demonstrated that GSH depletion, by its efflux, regulates apoptosis by modulation of executioner caspase activity. However, both the molecular identity of the GSH transporter(s) involved and the signaling cascades regulating GSH loss remain obscure. We sought to determine the role of multidrug resistance protein 1 (MRP1) in GSH depletion and its regulatory role on extrinsic and intrinsic pathways of apoptosis. In...

  2. Draft genome of a commonly misdiagnosed multidrug resistant pathogen Candida auris

    OpenAIRE

    2015-01-01

    Background Candida auris is a multidrug resistant, emerging agent of fungemia in humans. Its actual global distribution remains obscure as the current commercial methods of clinical diagnosis misidentify it as C. haemulonii. Here we report the first draft genome of C. auris to explore the genomic basis of virulence and unique differences that could be employed for differential diagnosis. Results More than 99.5 % of the C. auris genomic reads did not align to the current whole (or draft) genom...

  3. Combination antibiotic therapy for multidrug-resistant Gram-negative bacteria

    OpenAIRE

    Tängdén, Thomas

    2014-01-01

    Combination antibiotic therapy for Gram-negative sepsis is controversial. The present review provides a brief summary of the existing knowledge on combination therapy for severe infections with multidrug-resistant Pseudomonas spp., Acinetobacter spp., and Enterobacteriaceae. Empirical combination antibiotic therapy is recommended for severe sepsis and septic shock to reduce mortality related to inappropriate antibiotic treatment. Because definitive combination therapy has not been proven supe...

  4. Multidrug-resistant Achromobacter animicus causing wound infection in a street child in Mwanza, Tanzania.

    Science.gov (United States)

    Moremi, Nyambura; Claus, Heike; Hingi, Marko; Vogel, Ulrich; Mshana, Stephen E

    2017-02-10

    Achromobacter animicus (A. animicus) is an aerobic, motile, gram-negative, non-fermenting small bacillus that can also grow anaerobically with potassium nitrate. It has been isolated from sputum of humans suffering from respiratory infections. Literature regarding the role of A. animicus in wound infections is limited. We report a first case of a chronic post-traumatic wound infection caused by a multidrug-resistant A. animicus in a street child from Africa and accompanied diagnostic challenges.

  5. Experience with Fosfomycin for Treatment of Urinary Tract Infections Due to Multidrug-Resistant Organisms

    OpenAIRE

    Neuner, Elizabeth A.; Sekeres, Jennifer; Hall, Gerri S.; van Duin, David

    2012-01-01

    Fosfomycin has shown promising in vitro activity against multidrug-resistant (MDR) urinary pathogens; however, clinical data are lacking. We conducted a retrospective chart review to describe the microbiological and clinical outcomes of urinary tract infections (UTIs) with MDR pathogens treated with fosfomycin tromethamine. Charts for 41 hospitalized patients with a urine culture for an MDR pathogen who received fosfomycin tromethamine from 2006 to 2010 were reviewed. Forty-one patients had 4...

  6. Disease Control Implications of India's Changing Multi-Drug Resistant Tuberculosis Epidemic

    OpenAIRE

    Sze-Chuan Suen; Eran Bendavid; Goldhaber-Fiebert, Jeremy D.

    2014-01-01

    BACKGROUND: Multi-drug resistant tuberculosis (MDR TB) is a major health challenge in India that is gaining increasing public attention, but the implications of India's evolving MDR TB epidemic are poorly understood. As India's MDR TB epidemic is transitioning from a treatment-generated to transmission-generated epidemic, we sought to evaluate the potential effectiveness of the following two disease control strategies on reducing the prevalence of MDR TB: a) improving treatment of non-MDR TB;...

  7. Enterobacter cloacae multidrug-resistant: a case report of nosocomial urinary catheter-associated infection

    Directory of Open Access Journals (Sweden)

    Dino De Conno

    2008-12-01

    Full Text Available Enterobacter species, particularly E. cloacae and E. aerogenes, are important nosocomial pathogenes responsible for various infections.We report a 70-y-old patient with catheter-associated urinary tract infection (UTI caused by a nosocomial Enterobacter cloacae with multidrug-resistance.The identification of isolates from clinical culture and the study of pattern antimicrobial susceptibility were performed to the clinical risolution of the patient’s disease.The initial empirical antimicrobial therapy resulted ineffective.

  8. A case of acute postoperative keratitis after deep anterior lamellar keratoplasty by multidrug resistant Klebsiella

    Directory of Open Access Journals (Sweden)

    Leena Bajracharya

    2015-01-01

    Full Text Available A healthy lady of 42 years underwent deep anterior lamellar keratoplasty for granular dystrophy. The very next day, it was complicated by development of infectious keratitis. The organism was identified as multidrug resistant Klebsiella pneumoniae. Donor corneal button may be implicated in the transmission of infection in an otherwise uneventful surgery and follow-up. Nosocomial infections are usually severe, rapidly progressive and difficult to treat. Finally, the lady had to undergo therapeutic penetrating keratoplasty for complete resolution of infection.

  9. Left-Sided Endocarditis Associated with Multi-Drug Resistance Acinetobacter Lwoffii

    Directory of Open Access Journals (Sweden)

    Naghmeh Moshtaghi

    2009-09-01

    Full Text Available Acinetobacter lwoffii, an important nosocomial pathogen, is a gram-negative aerobic bacillus that is a component of the normal flora on the skin, oropharynx, and perineum of about 20-25% of healthy individuals. We herein present a case of a 66-year-old man with combined mitral and aortic valve endocarditis associated with multi-drug resistance acinetobacter lowffii bacteremia.

  10. Multidrug Resistance 1 Gene Variants, Pesticide Exposure, and Increased Risk of DNA Damage

    OpenAIRE

    Chun-Chieh Chen; Chun-Huang Huang; Man-Tzu Marcie Wu; Chia-Hsuan Chou; Chia-Chen Huang; Tzu-Yen Tseng; Fang-Yu Chang; Ying-Ti Li; Chun-Cheng Tsai; Tsung-Shing Wang; Ruey-Hong Wong

    2014-01-01

    The P-glycoprotein, encoded by the multidrug resistance (MDR)1 gene, extrudes fat-soluble compounds to the extracellular environment. However, the DNA damage of pesticides in subjects with genetic variation in MDR1 has not been investigated. In this study, the comet assay was applied to examine the extent of DNA damage in the peripheral blood of 195 fruit growers who had been exposed to pesticides and 141 unexposed controls. The MDR1 polymorphisms were identified. Questionnaires were administ...

  11. Antibacterial activity of some natural products against bacteria expressing a multidrug-resistant phenotype

    OpenAIRE

    2011-01-01

    Abstract The present study assessed the antimicrobial activities of various natural products belonging to the terpenoids, alkaloids and phenolics against a collection of Gram-negative multidrug-resistant (MDR) bacteria. The results demonstrated that most of the compounds were extruded by bacterial efflux pumps. In the presence of the efflux pump inhibitor phenylalanine arginine ?-naphthylamide (PA?N), the activities of laurentixanthone B (xanthone), plumbagin (naphthoquinone), 4-hy...

  12. Multidrug-Resistant Tuberculosis: Long Term Follow-Up of 40 Non-HIV-Infected Patients

    Directory of Open Access Journals (Sweden)

    Monica Avendaño

    2000-01-01

    Full Text Available BACKGROUND: There has been a steady increase in referrals of patients with multidrug-resistant tuberculosis (MDR-TB who are human immunodeficiency virus (HIV negative. Between 1986 and 1999, 40 patients were admitted to the authors' institution, eight of whom were admitted between January and June 1999. The management of such individuals is difficult. Although they are a clinically and epidemiologically important group of patients, few reports detail their management.

  13. Modulation of function of multidrug resistance associated-proteins by Kaempferia parviflora extracts and their components

    OpenAIRE

    Patanasethanont, Denpong; NAGAI, Junya; Matsuura, Chie; Fukui, Kyoko; Sutthanut, Khaetthareeya; Sripanidkulchai, Bung-Orn; Yumoto, Ryoko; Takano, Mikihisa

    2007-01-01

    In this study, the effects of extracts and flavone derivatives from the rhizome of Kaempferia parviflora on multidrug resistance associated-proteins (MRP)-mediated transport in A549 cells were examined. The cells employed express MRP1 and MRP2, but not P-glycoprotein. The cellular accumulation of calcein, an MRP substrate, was significantly increased by various MRP inhibitors without being affected by verapamil, a typical P-glycoprotein inhibitor. Ethanol and aqueous extracts from Kaempferia ...

  14. Reducing the price of treatment for multidrug-resistant tuberculosis through the Global Drug Facility.

    Science.gov (United States)

    Lunte, Kaspars; Cordier-Lassalle, Thierry; Keravec, Joel

    2015-04-01

    Many countries have limited experience of securing the best prices for drugs and have little negotiating power. This is particularly true for the complex, lengthy and expensive regimens used to treat multidrug-resistant tuberculosis. The Stop TB Partnership's Global Drug Facility is dedicated to improving worldwide access to antituberculosis medicines and diagnostic techniques that meet international quality standards. The Global Drug Facility is able to secure price reductions through competitive tendering among prequalified drug manufacturers and by consolidating orders to achieve large purchase volumes. Consolidating the market in this way increases the incentives for suppliers of quality-assured medicines. In 2013 the Global Drug Facility reduced the price of the second-line drugs it supplies for multidrug-resistant tuberculosis: the overall cost of the longest and most expensive treatment regimen for a patient decreased by 26% - from 7890 United States dollars (US$) in 2011 to US$ 5822 in 2013. The price of treatment for multidrug-resistant tuberculosis supplied by the Global Drug Facility was reduced by consolidating orders to achieve large purchase volumes, by international, competitive bidding and by the existence of donor-funded medicine stockpiles. The rise in the number of suppliers of internationally quality-assured drugs was also important. The savings achieved from lower drug costs could be used to increase the number of patients on high-quality treatment.

  15. Resin glycosides from Ipomoea wolcottiana as modulators of the multidrug resistance phenotype in vitro.

    Science.gov (United States)

    Corona-Castañeda, Berenice; Rosas-Ramírez, Daniel; Castañeda-Gómez, Jhon; Aparicio-Cuevas, Manuel Alejandro; Fragoso-Serrano, Mabel; Figueroa-González, Gabriela; Pereda-Miranda, Rogelio

    2016-03-01

    Recycling liquid chromatography was used for the isolation and purification of resin glycosides from the CHCl3-soluble extracts prepared using flowers of Ipomoea wolcottiana Rose var. wolcottiana. Bioassay-guided fractionation, using modulation of both antibiotic activity against multidrug-resistant strains of Gram-negative bacteria and vinblastine susceptibility in breast carcinoma cells, was used to isolate the active glycolipids as modulators of the multidrug resistance phenotype. An ester-type dimer, wolcottine I, one tetra- and three pentasaccharides, wolcottinosides I-IV, in addition to the known intrapilosin VII, were characterized by NMR spectroscopy and mass spectrometry. In vitro assays established that none of these metabolites displayed antibacterial activity (MIC>512 μg/mL) against multidrug-resistant strains of Escherichia coli, and two nosocomial pathogens: Salmonella enterica serovar Typhi and Shigella flexneri; however, when tested (25 μg/mL) in combination with tetracycline, kanamycin or chloramphenicol, they exerted a potentiation effect of the antibiotic susceptibility up to eightfold (64 μg/mL from 512 μg/mL). It was also determined that these non-cytotoxic (CI50>8.68 μM) agents modulated vinblastine susceptibility at 25 μg/mL in MFC-7/Vin(+) cells with a reversal factor (RFMCF-7/Vin(+)) of 2-130 fold.

  16. An international multicenter retrospective study of Pseudomonas aeruginosa nosocomial pneumonia: impact of multidrug resistance.

    Science.gov (United States)

    Micek, Scott T; Wunderink, Richard G; Kollef, Marin H; Chen, Catherine; Rello, Jordi; Chastre, Jean; Antonelli, Massimo; Welte, Tobias; Clair, Bernard; Ostermann, Helmut; Calbo, Esther; Torres, Antoni; Menichetti, Francesco; Schramm, Garrett E; Menon, Vandana

    2015-05-06

    Pseudomonas aeruginosa nosocomial pneumonia (Pa-NP) is associated with considerable morbidity, prolonged hospitalization, increased costs, and mortality. We conducted a retrospective cohort study of adult patients with Pa-NP to determine 1) risk factors for multidrug-resistant (MDR) strains and 2) whether MDR increases the risk for hospital death. Twelve hospitals in 5 countries (United States, n = 3; France, n = 2; Germany, n = 2; Italy, n = 2; and Spain, n = 3) participated. We compared characteristics of patients who had MDR strains to those who did not and derived regression models to identify predictors of MDR and hospital mortality. Of 740 patients with Pa-NP, 226 patients (30.5%) were infected with MDR strains. In multivariable analyses, independent predictors of multidrug-resistance included decreasing age (adjusted odds ratio [AOR] 0.91, 95% confidence interval [CI] 0.96-0.98), diabetes mellitus (AOR 1.90, 95% CI 1.21-3.00) and ICU admission (AOR 1.73, 95% CI 1.06-2.81). Multidrug-resistance, heart failure, increasing age, mechanical ventilation, and bacteremia were independently associated with in-hospital mortality in the Cox Proportional Hazards Model analysis. Among patients with Pa-NP the presence of infection with a MDR strain is associated with increased in-hospital mortality. Identification of patients at risk of MDR Pa-NP could facilitate appropriate empiric antibiotic decisions that in turn could lead to improved hospital survival.

  17. Noma Neonatorum From Multidrug-Resistant Pseudomonas aeruginosa: An Underestimated Threat?

    Science.gov (United States)

    Raimondi, Francesco; Veropalumbo, Claudio; Coppola, Clara; Maddaluno, Sergio; Ferrara, Teresa; Cangiano, Giancarlo; Capasso, Letizia

    2015-09-01

    We present the case of an extremely low birth weight infant with diffuse gingival noma, initially misdiagnosed as thrush. Multidrug-resistant Pseudomonas aeruginosa strain was cultured and treated with systemic and local colistin with complete healing. Noma neonatorum from multidrug-resistant pathogens may appear in neonatal intensive care units. Old antibiotics may help.Noma (cancrum oris) is a devastating gangrenous disease that leads to destruction of facial tissue with significant morbidity and mortality in children and young adults. Noma has virtually disappeared from Europe and North America, but it is still common among children and young adults in India, Africa, and South America. Noma is a polymicrobial opportunistic infection related to malnutrition and immune dysfunction. In the neonate, a similar but distinct condition, known as "noma neonatorum" was described in 1977, in which gangrenous lesions involve the mucocutaneous junctions of oral, nasal, and anal area, and, occasionally, the eyelids and the scrotum. The neonatal disease has been linked to Pseudomonas aeruginosa, prematurity, and low birth weight. There is no established treatment, and mortality is almost inevitable in the few reported cases. In this study, we present the first European case of noma neonatorum from a multidrug-resistant strain of P aeruginosa.

  18. Phenotypic and molecular characterization of multidrug resistant Klebsiella pneumoniae isolated from a university teaching hospital, China.

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    Jikun Du

    Full Text Available The multidrug-resistant rate of Klebsiella pneumoniae has risen rapidly worldwide. To better understand the multidrug resistance situation and molecular characterization of Klebsiella pneumoniae, a total of 153 Klebsiella pneumoniae isolates were collected, and drug susceptibility test was performed to detect its susceptibility patterns to 13 kinds of antibiotics. Phenotypic tests for carbapenemases ESBLs and AmpC enzyme-producing strains were performed to detect the resistance phenotype of the isolates. Then PCR amplification and sequencing analysis were performed for the drug resistance determinants. The results showed that 63 strains harbored bla CTX-M gene, and 14 strains harbored bla DHA gene. Moreover, there were 5 strains carrying bla KPC gene, among which 4 strains carried bla CTX-M, bla DHA and bla KPC genes, and these 4 strains were also resistant to imipenem. Our data indicated that drug-resistant Klebsiella pneumoniae were highly prevalent in the hospital. Thus it is warranted that surveillance of epidemiology of those resistant isolates should be a cause for concern, and appropriate drugs should be chosen.

  19. Phenotypic and molecular characterization of multidrug resistant Klebsiella pneumoniae isolated from a university teaching hospital, China.

    Science.gov (United States)

    Du, Jikun; Li, Peipei; Liu, Helu; Lü, Dongyue; Liang, Hong; Dou, Yuhong

    2014-01-01

    The multidrug-resistant rate of Klebsiella pneumoniae has risen rapidly worldwide. To better understand the multidrug resistance situation and molecular characterization of Klebsiella pneumoniae, a total of 153 Klebsiella pneumoniae isolates were collected, and drug susceptibility test was performed to detect its susceptibility patterns to 13 kinds of antibiotics. Phenotypic tests for carbapenemases ESBLs and AmpC enzyme-producing strains were performed to detect the resistance phenotype of the isolates. Then PCR amplification and sequencing analysis were performed for the drug resistance determinants. The results showed that 63 strains harbored bla CTX-M gene, and 14 strains harbored bla DHA gene. Moreover, there were 5 strains carrying bla KPC gene, among which 4 strains carried bla CTX-M, bla DHA and bla KPC genes, and these 4 strains were also resistant to imipenem. Our data indicated that drug-resistant Klebsiella pneumoniae were highly prevalent in the hospital. Thus it is warranted that surveillance of epidemiology of those resistant isolates should be a cause for concern, and appropriate drugs should be chosen.

  20. In Vitro Antibacterial Properties of Aqueous Garlic Extract (AEG Against Multidrug-Resistant Enterococci

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    Mohammad Bokaeian

    2013-06-01

    Full Text Available Background: As relatively avirulent enteric bacteria, enterococci usually cause infections in immune-compromised patients. The antimicrobial treatment, however, is quite challenging, since enterococci are intrinsically resistant to many antibiotics. Objective of the present study was to examine the antibacterial activity of aqueous garlic extract on isolates of enterococci.Materials and Methods: In this descriptive research, a total of 120 enterococcus isolates including 70 multidrug-resistant isolates causing different infections were collected from three hospitals in Zahedan. The susceptibility of isolates to different antibiotics was measured by agar diffusion test and antibacterial activity of garlic extract was measured using disc-diffusion and microbroth dilution methods.Results: Among 120 enterococcus samples, 95 (79.2% and 25 (20.8% isolates were E. faecalis and E. faecium respectively. The highest resistance was observed in erythromycin (95.8% and the lowest resistance (6.7% in chloramphenicol, while 88.3% and 65.8% of the isolates were resistant to tetracycline and ampicillin respectively. Moreover, 58% of the isolates were Multi-Drug Resistant (MDR and showed resistance to at least three antibiotics. Antibacterial activity of AGE was characterized by inhibition zones of 16.8±1.8 mm and Minimum Inhibitory Concentration (MIC ranged from 4 to 32 mg/ml. Conclusion: The present study suggests that AGE has a significant anti-enterococcal effect and therefore, supports the use of garlic as an herbal remedy in Zahedan.

  1. Genotyping and serotyping of macrolide and multidrug resistant Streptococcus pneumoniae isolated from carrier children

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    S F Swedan

    2016-01-01

    Full Text Available Aims: Streptococcus pneumoniae, an opportunistic pathogen commonly carried asymptomatically in the nasopharynx of children, is associated with increasing rates of treatment failures due to a worldwide increase in drug resistance. We investigated the carriage of S. pneumoniae in children 5 years or younger, the identity of prevalent serotypes, the rates of resistance to macrolides and other antimicrobial agents and the genotypes responsible for macrolide resistance. Materials and Methods: Nasopharyngeal swabs were collected from 157 children under 5 years for cultural isolation of S. pneumoniae. Antibiogram of isolates  was determined using the disk diffusion test, and the minimal inhibitory concentration to macrolides was determined using the E-test. Isolate serotypes and macrolide resistance genes, erm(B and mef(E, were identified using multiplex polymerase chain reactions. Results: S. pneumoniae was recovered from 33.8% of children; 41.9% among males and 21.9% among females (P = 0.009. The highest carriage rate occurred among age groups 7-12 months and 49-60 months. Most frequent serotypes were 19F, 6A/B, 11A, 19A, 14 and 15B/C.  Resistance to macrolides was 60.4%. Resistance to oxacillin, trimethoprim/sulfamethoxazole and clindamycin was present among 90.6%, 54.7% and 32.1% of isolates, respectively. All isolates were susceptible to chloramphenicol, levofloxacin and vancomycin. Isolates resistant to one or more macrolide drugs were more likely to be multidrug resistant. Resistance to clindamycin or oxacillin coexisted with macrolide resistance. Among the erythromycin-resistant isolates, erm(B, mef(E and erm(B and mef(E genes were present at rates of 43.8%, 37.5% and 6.3%, respectively. Erm(B and mef(E were associated with very high level and moderate-to-high level resistance to macrolides, respectively. Conclusion: A significant proportion of children harboured macrolide and multidrug-resistant S. pneumoniae.

  2. Hypoxia-inducible factor-1α induces multidrug resistance protein in colon cancer

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    Lv Y

    2015-07-01

    Full Text Available Yingqian Lv, Shan Zhao, Jinzhu Han, Likang Zheng, Zixin Yang, Li Zhao Department of Oncology, The Second Hospital, Hebei Medical University, Shijiazhuang, Hebei Province, People’s Republic of China Abstract: Multidrug resistance is the major cause of chemotherapy failure in many solid tumors, including colon cancer. Hypoxic environment is a feature for all solid tumors and is important for the development of tumor resistance to chemotherapy. Hypoxia-inducible factor (HIF-1α is the key transcription factor that mediates cellular response to hypoxia. HIF-1α has been shown to play an important role in tumor resistance; however, the mechanism is still not fully understood. Here, we found that HIF-1α and the drug resistance-associated gene multidrug resistance associated protein 1 (MRP1 were induced by treatment of colon cancer cells with the hypoxia-mimetic agent cobalt chloride. Inhibition of HIF-1α by RNA interference and dominant-negative protein can significantly reduce the induction of MRP1 by hypoxia. Bioinformatics analysis showed that a hypoxia response element is located at -378 to -373 bp upstream of the transcription start site of MRP1 gene. Luciferase reporter assay combined with mutation analysis confirmed that this element is essential for hypoxia-mediated activation of MRP gene. Furthermore, RNA interference revealed that HIF-1α is necessary for this hypoxia-driven activation of MRP1 promoter. Importantly, chromatin immunoprecipitation analysis demonstrated that HIF-1α could directly bind to this HRE site in vivo. Together, these data suggest that MRP1 is a downstream target gene of HIF-1α, which provides a potential novel mechanism for HIF-1α-mediated drug resistance in colon cancer and maybe other solid tumors as well. Keywords: hypoxia, hypoxia-inducible factor-1α, multidrug resistance associated protein, transcriptional regulation, chemotherapy tolerance

  3. Epidemic and nonepidemic multidrug-resistant Enterococcus faecium.

    Science.gov (United States)

    Leavis, Helen L; Willems, Rob J L; Top, Janetta; Spalburg, Emile; Mascini, Ellen M; Fluit, Ad C; Hoepelman, Andy; de Neeling, Albert J; Bonten, Marc J M

    2003-09-01

    The epidemiology of vancomycin-resistant Entero- coccus faecium (VREF) in Europe is characterized by a large community reservoir. In contrast, nosocomial outbreaks and infections (without a community reservoir) characterize VREF in the United States. Previous studies demonstrated host-specific genogroups and a distinct genetic lineage of VREF associated with hospital outbreaks, characterized by the variant esp-gene and a specific allele-type of the purK housekeeping gene (purK1). We investigated the genetic relatedness of vanA VREF (n=108) and vancomycin-susceptible E. faecium (VSEF) (n=92) from different epidemiologic sources by genotyping, susceptibility testing for ampicillin, sequencing of purK1, and testing for presence of esp. Clusters of VSEF fit well into previously described VREF genogroups, and strong associations were found between VSEF and VREF isolates with resistance to ampicillin, presence of esp, and purK1. Genotypes characterized by presence of esp, purK1, and ampicillin resistance were most frequent among outbreak-associated isolates and almost absent among community surveillance isolates. Vancomycin-resistance was not specifically linked to genogroups. VREF and VSEF from different epidemiologic sources are genetically related; evidence exists for nosocomial selection of a subtype of E. faecium, which has acquired vancomycin-resistance through horizontal transfer.

  4. Phenothiazines as a solution for multidrug resistant tuberculosis

    DEFF Research Database (Denmark)

    Kristiansen, Jette E.; Dastidar, Sujata G.; Palchoudhuri, Shauroseni;

    2015-01-01

    . The phenothiazines were first recognised for their antipsychotic properties, but soon after their antimicrobial functions came to be known and then such compounds were designated as non-antibiotics. The emergence of highly drug-resistant bacteria had initiated an urgent need to search for novel affordable compounds...... thioridazine and its (-) form to be combined with other antitubercular drugs to treat infections by drug-resistant strains of Mycobacterium tuberculosis and try to eradicate this deadly disease. [Int Microbiol 2015; 18(1):1-12]....

  5. Prevalence of molecular markers of anti-malarial drug resistance in Plasmodium vivax and Plasmodium falciparum in two districts of Nepal

    DEFF Research Database (Denmark)

    Ranjitkar, Samir; Schousboe, Mette L; Thomsen, Thomas

    2011-01-01

    ABSTRACT: BACKGROUND: Sulphadoxine-pyrimethamine (SP) and chloroquine (CQ) have been used in treatment of falciparum and vivax malaria in Nepal. Recently, resistance to both drugs have necessitated a change towards artemisinin combination therapy (ACT) against Plasmodium falciparum in highly...... endemic areas. However, SP is still used against P. falciparum infections in low endemic areas while CQ is used in suspected cases in areas with lack of diagnostic facilities. This study examines the prevalence of molecular markers of P. falciparum and Plasmodium vivax CQ and SP resistance to determine...... if high levels of in vivo resistance are reflected at molecular level as well. METHODS: Finger prick blood samples (n=189) were collected from malaria positive patients from two high endemic districts and analysed for single nucleotide polymorphisms (SNPs) in the resistance related genes of P. falciparum...

  6. The Relationship between Extensively Drug-Resistant Tuberculosis and Multidrug-Resistant Gram-Negative Bacilli.

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    Jiang-Nan Zhao

    Full Text Available The relationship between extensively drug-resistant tuberculosis (XDR-TB and multidrug-resistant Gram-negative bacilli (MDR-GNB is unclear. Identification of the relationship between XDR-TB and MDR-GNB would have important implications for patient care.We conducted a retrospective study reviewing the records of patients admitted with a confirmed pulmonary TB from 2011 to 2014. To identify the relationship between XDR-TB and MDR-GNB, univariable comparison and multivariable logistic regression were performed.Among 2962 pulmonary TB patients, 45(1.5% patients had a diagnosis of XDR-TB. A total of 165 MDR-GNB strains were detected in 143 (4.8% pulmonary TB patients. XDR-TB patients had a significantly higher occurrence of MDR-GNB than non-XDR-TB patients (24.4% vs. 4.5%; P<0.001. Age (OR 1.02, 95% CI 1.01-1.03, hypoalbuminemia (OR 1.48, 95% CI 1.18-1.85, chronic renal failure (OR 6.67, 95% CI 1.42-31.47, chronic hepatic insufficiency (OR 1.99, 95% CI 1.15-3.43, presence of XDR-TB (OR 6.56, 95% CI 1.61-26.69, and duration of TB diagnostic delay (OR 1.01, 95% CI 1.00-1.02 were the independent risk factors for MDR-GNB infection.Patients with XDR-TB have a significantly higher risk of being affected by MDR-GNB pathogen. The underlying mechanism association warrant further studies.

  7. Utility of lytic bacteriophage in the treatment of multidrug-resistant Pseudomonas aeruginosa septicemia in mice

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    Vinodkumar C

    2008-07-01

    Full Text Available Drug resistance is the major cause of increase in morbidity and mortality in neonates. One thousand six hundred forty-seven suspected septicemic neonates were subjected for microbiological analysis over a period of 5 years. Forty-two P. aeruginosa were isolated and the antibiogram revealed that 28 P. aeruginosa were resistant to almost all the common drugs used (multidrug-resistant. The emergence of antibiotic-resistant bacterial strains is one of the most critical problems of modern medicine. As a result, a novel and most effective approaches for treating infection caused by multidrug-resistant bacteria are urgently required. In this context, one intriguing approach is to use bacteriophages (viruses that kill bacteria in the treatment of infection caused by drug-resistant bacteria. In the present study, the utility of lytic bacteriophages to rescue septicemic mice with multidrug-resistant (MDR P. aeruginosa infection was evaluated. MDR P. aeruginosa was used to induce septicemia in mice by intraperitoneal (i.p. injection of 10 7 CFU. The resulting bacteremia was fatal within 48 hrs. The phage strain used in this study had lytic activity against a wide range of clinical isolates of MDR P. aeruginosa. A single i.p. injection of 3 x 10 9 PFU of the phage strain, administered 45 min after the bacterial challenge, was sufficient to rescue 100% of the animals. Even when treatment was delayed to the point where all animals were moribund, approximately 50% of them were rescued by a single injection of this phage preparation. The ability of this phage to rescue septicemic mice was demonstrated to be due to the functional capabilities of the phage and not to a nonspecific immune effect. The rescue of septicemic mice could be affected only by phage strains able to grow in vitro on the bacterial host used to infect the animals and when such strains are heat-inactivated, they lose their ability to rescue the infected mice. Multidrug-resistant bacteria have

  8. Molecular patterns of multidrug resistance of Mycobacterium tuberculosis in Georgia

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    N Shubladze

    2013-01-01

    Conclusions: A great majority of the Georgian MDR MTB strains have a strong preference for the drug resistance mutations carrying no or low fitness cost. Thus, it can be suggested that MDR MTB strains with such mutations will continue to arise in Georgia at a high frequency even in the absence of antibiotic pressure.

  9. Poly (l-γ-glutamylglutamine Polymer Enhances Doxorubicin Accumulation in Multidrug Resistant Breast Cancer Cells

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    Ting Peng

    2016-06-01

    Full Text Available Background: Drug resistance is one of the bottlenecks of cancer chemotherapy in the clinic. Polymeric nanomedicine is one of the most promising strategies for overcoming poor chemotherapy responses due to the multidrug resistance (MDR. Methods: In this study, a new polymer-based drug delivery system, poly (l-γ-glutamylglutamine-doxorubicin (PGG-Dox conjugate, was studied in both drug-induced resistant human breast cancer MDA-MB-231/MDR cells and their parent human breast cancer MDA-MB-231 cells. The effect of PGG on facilitating the growth inhibition of Dox against multidrug resistant cells were investigated by evaluating the cytotoxicity of PGG-Dox conjugate, PGG/Dox unconjugated complex and free Dox on both cells. The underlying mechanisms in resistant cells were further studied via the intracellular traffic studies. Results: Both conjugated and unconjugated PGG significantly increased Dox uptake, prolonged Dox retention and reduced Dox efflux in the MDA-MB-231/MDR cells. The PGG-Dox conjugate is taken up by tumor cells mainly by pinocytosis pathway, in which PGG-Dox conjugate-containing vesicles are formed and enter the cells. Conclusions: This study indicated that both polymer-drug conjugate and unconjugated complex are promising strategies of overcoming resistance of anti-tumor drugs.

  10. Antibacterial activities of ethanol extracts of Philippine medicinal plants against multidrug-resistant bacteria

    Institute of Scientific and Technical Information of China (English)

    Demetrio; L.Valle; Jr.; Jeannie; I.Andrade; Juliana; Janet; M.Puzon; Esperanza; C.Cabrera; Windell; L.Rivera

    2015-01-01

    Objective: To investigate the antibacterial activities of crude ethanol extracts of 12 Philippine medicinal plants.Methods: Crude ethanol extracts from 12 Philippine medicinal plants were evaluated for their antibacterial activity against methicillin-resistant Staphylococcus aureus, vancomycinresistant Enterococcus, extended spectrum β-lactamase-producing, carbapenem-resistant Enterobacteriaceae and metallo-β-lactamase-producing Pseudomonas aeruginosa and Acinetobacter baumannii. Results: The leaf extracts of Psidium guajava, Phyllanthus niruri, Ehretia microphylla and Piper betle(P. betle) showed antibacterial activity against the Gram-positive methicillinresistant Staphylococcus aureus and vancomycin-resistant Enterococcus. P. betle showed the highest antibacterial activity for these bacteria in the disk diffusion(16-33 mm inhibition diameter), minimum inhibitory concentration(19-156 μg/m L) and minimum bactericidal concentration(312 μg/m L) assays. P. betle leaf extracts only showed remarkable antibacterial activity for all the Gram-negative multidrug-resistant bacteria(extended spectrum β-lactamaseproducing, carbapenem-resistant Enterobacteriaceae and metallo-β-lactamase-producing) in the disk diffusion(17-21 mm inhibition diameter), minimum inhibitory concentration(312-625 μg/m L) and minimum bactericidal concentration(312-625 μg/m L) assays. Conclusions: P. betle had the greatest potential value against both Gram-negative and Grampositive multidrug-resistant bacteria. Favorable antagonistic activities were also exhibited by the ethanol extracts of Psidium guajava, Phyllanthus niruri and Ehretia microphylla.

  11. Antisense RNA regulation and application in the development of novel antibiotics to combat multidrug resistant bacteria.

    Science.gov (United States)

    Ji, Yinduo; Lei, Ting

    2013-01-01

    Despite the availability of antibiotics and vaccines, infectious diseases remain one of most dangerous threats to humans and animals. The overuse and misuse of antibacterial agents have led to the emergence of multidrug resistant bacterial pathogens. Bacterial cells are often resilient enough to survive in even the most extreme environments. To do so, the organisms have evolved different mechanisms, including a variety of two-component signal transduction systems, which allow the bacteria to sense the surrounding environment and regulate gene expression in order to adapt and respond to environmental stimuli. In addition, some bacteria evolve resistance to antibacterial agents while many bacterial cells are able to acquire resistance genes from other bacterial species to enable them to survive in the presence of toxic antimicrobial agents. The crisis of antimicrobial resistance is an unremitting menace to human health and a burden on public health. The rapid increase in antimicrobial resistant organisms and limited options for development of new classes of antibiotics heighten the urgent need to develop novel potent antibacterial therapeutics in order to combat multidrug resistant infections. In this review, we introduce the regulatory mechanisms of antisense RNA and significant applications of regulated antisense RNA interference technology in early drug discovery. This includes the identification and evaluation of drug targets in vitro and in vivo, the determination of mode of action for antibiotics and new antibacterial agents, as well as the development of peptide-nucleic acid conjugates as novel antibacterials.

  12. Overcoming ABC transporter-mediated multidrug resistance: Molecular mechanisms and novel therapeutic drug strategies.

    Science.gov (United States)

    Li, Wen; Zhang, Han; Assaraf, Yehuda G; Zhao, Kun; Xu, Xiaojun; Xie, Jinbing; Yang, Dong-Hua; Chen, Zhe-Sheng

    2016-07-01

    Multidrug resistance is a key determinant of cancer chemotherapy failure. One of the major causes of multidrug resistance is the enhanced efflux of drugs by membrane ABC transporters. Targeting ABC transporters projects a promising approach to eliminating or suppressing drug resistance in cancer treatment. To reveal the functional mechanisms of ABC transporters in drug resistance, extensive studies have been conducted from identifying drug binding sites to elucidating structural dynamics. In this review article, we examined the recent crystal structures of ABC proteins to depict the functionally important structural elements, such as domains, conserved motifs, and critical amino acids that are involved in ATP-binding and drug efflux. We inspected the drug-binding sites on ABC proteins and the molecular mechanisms of various substrate interactions with the drug binding pocket. While our continuous battle against drug resistance is far from over, new approaches and technologies have emerged to push forward our frontier. Most recent developments in anti-MDR strategies include P-gp inhibitors, RNA-interference, nano-medicines, and delivering combination strategies. With the advent of the 'Omics' era - genomics, epigenomics, transcriptomics, proteomics, and metabolomics - these disciplines play an important role in fighting the battle against chemoresistance by further unraveling the molecular mechanisms of drug resistance and shed light on medical therapies that specifically target MDR. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Isolation and molecular characterization of multidrug-resistant Gram-negative bacteria from imported flamingos in Japan

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    Fukumoto Yukio

    2009-11-01

    Full Text Available Abstract Imported animals, especially those from developing countries, may constitute a potential hazard to native animals and to public health. In this study, a new flock of lesser flamingos imported from Tanzania to Hiroshima Zoological Park were screened for multidrug-resistant Gram-negative bacteria, integrons and antimicrobial resistance genes. Thirty-seven Gram-negative bacterial isolates were obtained from the flamingos. Seven isolates (18.9% showed multidrug resistance phenotypes, the most common being against: ampicillin, streptomycin, tetracycline, trimethoprim/sulfamethoxazole and nalidixic acid. Molecular analyses identified class 1 and class 2 integrons, β-lactamase-encoding genes, blaTEM-1 and blaCTX-M-2 and the plasmid-mediated quinolone resistance genes, qnrS and qnrB. This study highlights the role of animal importation in the dissemination of multidrug-resistant bacteria, integrons and antimicrobial resistance genes from one country to another.

  14. Jurkat/A4 cells with multidrug resistance exhibit reduced sensitivity to quercetin.

    Science.gov (United States)

    Philchenkov, A; Zavelevich, M; Savinska, L; Blokhin, D

    2010-07-01

    While multidrug resistance of cancer cells is a well-known phenomenon, little is known on the cross resistance between cytotoxic chemotherapeutical agents and unrelated substances such as natural flavonoids. To compare the effects of cytotoxic drug, vepeside and natural flavonoid, quercetin in Jurkat cells and their multidrug-resistant subline Jurkat/A4, in particular to analyze the effector mechanisms of apoptosis and the profiles of several pro- and antiapoptotic proteins in these cells upon exposure to vepeside or quercetin. Apoptosis and poly (ADP-ribose) polymerase cleavage were assessed by flow cytometry. Expression of apoptosis-related proteins was analyzed by Western blotting. Jurkat/A4 cells are less sensitive to antiproliferative effects of quercetin as compared with the parental Jurkat cell line. While vepeside as well as quercetin initially induces apoptosis in both cell lines, the following survival of the exposed cells is essentially different. In resistant Jurkat/A4 cells, vepeside or quercetin treatment activates significantly less caspase-9 and -3 as compared with that in the parental cells. The expression of Bad and BNip1 proteins in Jurkat/A4 cells is lower than in the parental cell line. At the same time, XIAP and CAS levels in Jurkat/A4 cells increase. Upon apoptosis induction, XIAP and CAS levels in Jurkat cells decrease, this effect being negligible in resistant cells. Multidrug-resistant Jurkat/A4 cells exhibit reduced sensitivity to cytotoxic effects of quercetin. The expression profile of Jurkat/A4 cells is characterized by the increased levels of XIAP and CAS representing the endogenous inhibitors of apoptosis.

  15. A Novel SERCA Inhibitor Demonstrates Synergy with Classic SERCA Inhibitors and Targets Multidrug-Resistant AML

    Science.gov (United States)

    Bleeker, Nicholas P.; Cornea, Razvan L.; Thomas, David D.; Xing, Chengguo

    2013-01-01

    Drug resistance exists as a major obstacle in the treatment of cancer and drug molecules that retain effectiveness against resistant cancers are a high clinical priority. Ethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (CXL017) was recently identified as a promising lead for the treatment of multidrug-resistant leukemia, which elicits its cytotoxic effect, in part, through inhibition of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). Herein initial experiments with SERCA1a, CXL017 demonstrated no significant effect on calcium affinity, competed with ATP, and induced a dose-dependent decrease in ATPase activity. Among all CXLs tested, (−)-CXL017 exhibited the greatest SERCA inhibition with an IC50 = 13.5 ± 0.5 μM. Inhibitor combination studies were used to assess potential interactions between (−)-CXL017 and well-known SERCA inhibitors: thapsigargin, cyclopiazonic acid, and 2, 5-di-tert-butylhydroquinone. Surprisingly, (−)-CXL017 exhibited marked synergy with each of the known SERCA inhibitors whereas all combinations of the known inhibitors yielded additive effects, indicating that (−)-CXL017 may bind at a unique allosteric site. Treatment of parental (HL60) and multidrug-resistant (HL60/MX2) acute myeloid leukemia cells with the known SERCA inhibitors revealed that all of these inhibitors demonstrate selective cytotoxicity (7.7 to 400 fold) for the resistant cell line. Within the CXL series, a positive correlation exists between SERCA inhibition and cytotoxicity in HL60/MX2 but not HL60. (−)-CXL017 was also shown to enhance the cytotoxicity of thapsigargin in HL60/MX2 cells. Given the elevated SERCA levels and ER calcium content in HL60/MX2, SERCA likely plays a significant role in the collateral sensitivity of this multidrug-resistance cell line to CXL molecules as well as known SERCA inhibitors. PMID:24079514

  16. Genome evolution and plasticity of Serratia marcescens, an important multidrug-resistant nosocomial pathogen.

    Science.gov (United States)

    Iguchi, Atsushi; Nagaya, Yutaka; Pradel, Elizabeth; Ooka, Tadasuke; Ogura, Yoshitoshi; Katsura, Keisuke; Kurokawa, Ken; Oshima, Kenshiro; Hattori, Masahira; Parkhill, Julian; Sebaihia, Mohamed; Coulthurst, Sarah J; Gotoh, Naomasa; Thomson, Nicholas R; Ewbank, Jonathan J; Hayashi, Tetsuya

    2014-08-01

    Serratia marcescens is an important nosocomial pathogen that can cause an array of infections, most notably of the urinary tract and bloodstream. Naturally, it is found in many environmental niches, and is capable of infecting plants and animals. The emergence and spread of multidrug-resistant strains producing extended-spectrum or metallo beta-lactamases now pose a threat to public health worldwide. Here we report the complete genome sequences of two carefully selected S. marcescens strains, a multidrug-resistant clinical isolate (strain SM39) and an insect isolate (strain Db11). Our comparative analyses reveal the core genome of S. marcescens and define the potential metabolic capacity, virulence, and multidrug resistance of this species. We show a remarkable intraspecies genetic diversity, both at the sequence level and with regards genome flexibility, which may reflect the diversity of niches inhabited by members of this species. A broader analysis with other Serratia species identifies a set of approximately 3,000 genes that characterize the genus. Within this apparent genetic diversity, we identified many genes implicated in the high virulence potential and antibiotic resistance of SM39, including the metallo beta-lactamase and multiple other drug resistance determinants carried on plasmid pSMC1. We further show that pSMC1 is most closely related to plasmids circulating in Pseudomonas species. Our data will provide a valuable basis for future studies on S. marcescens and new insights into the genetic mechanisms that underlie the emergence of pathogens highly resistant to multiple antimicrobial agents.

  17. A better resolution for integrating methods for monitoring Plasmodium falciparum resistance to antimalarial drugs.

    Science.gov (United States)

    Abdul-Ghani, Rashad; Al-Maktari, Mohamed T; Al-Shibani, Latifa A; Allam, Amal F

    2014-09-01

    Effective chemotherapy is the mainstay of malaria control. However, resistance of falciparum malaria to antimalarial drugs compromised the efforts to eliminate the disease and led to the resurgence of malaria epidemics. Three main approaches are used to monitor antimalarial drug efficacy and drug resistance; namely, in vivo trials, in vitro/ex vivo assays and molecular markers of drug resistance. Each approach has its implications of use as well as its advantages and drawbacks. Therefore, there is a need to use an integrated approach that would give the utmost effect to detect resistance as early as its emergence and to track it once spread. Such integration becomes increasingly needed in the era of artemisinin-based combination therapy as a forward action to deter resistance. The existence of regional and global networks for the standardization of methodology, provision of high quality reagents for the assessment of antimalarial drug resistance and dissemination of open-access data would help in approaching an integrated resistance surveillance system on a global scale.

  18. Relationship between Methylation Status of Multi-drug Resistance Protein(MRP) and Multi-drug Resistance in Lung Cancer Cell Lines

    Institute of Scientific and Technical Information of China (English)

    LIU Rui-jun; ZHONG Hong

    2007-01-01

    Objective: To study the relationship between the methylation status of multi-drug resistance protein (MRP) gene and the expression of its mRNA and protein in lung cancer cell lines. Methods: Human embryo lung cell line WI-38, lung adenocarcinoma cell line SPCA-1 and its drug-resistant cells induced by different concentrations of doxorubicin were treated with restriction endonuclease Eco47Ⅲ. The methylation status of MRP was examined by PCR, and the expressions of its mRNA and protein were evaluated by in situ hybridization and immunohistochemistry. Results: MRP gene promoter region of WI-38 cells was in hypermethylation status, but the promoter region of MRP in SPCA-1 cells and their resistant derivatives induced by different concentrations of doxorubicin were in hypomethylation status. There were significant differences in the expression of MRP mRNA among WI-38 cell line, SPCA-1 cells and their drug-resistant derivatives induced by different concentration of doxorubicin. Consistently, MRP immunostaining presented similar significant differences. Conclusion: The promoter region of MRP in SPCA-1 lung adenocarcinoma cells was in hypomethylation status. The hypomethylation status of 5' regulatory region of MRP promoter is an important structural basis that can increase the activity of transcription and results in the development of drug resistance in lung cancer.

  19. Iodination increases the activity of verapamil derivatives in reversing PGP multidrug resistance.

    Science.gov (United States)

    Barattin, Regis; Gerby, Bastien; Bourges, Kevin; Hardy, Gaëlle; Olivares, Jose; Boutonnat, Jean; Arnoult, Christophe; D'Hardemare, Amaury D U Moulinet; Ronot, Xavier

    2010-07-01

    Iodinated derivatives of verapamil were synthesized and tested as P-glycoprotein (Pgp)-mediated multidrug resistance (MDR) reversal agents. The ability of these compounds to revert MDR was evaluated on daunorubicin-resistant K562 cells, by measuring the intracellular accumulation of rhodamine 123, a fluorescent probe of Pgp transport activity. One of the investigated compounds (16c) was found to be a more potent MDR reversal agent than verapamil and cyclosporin A, used as reference molecules. Further in vitro studies showed that compound 16c restored daunorubicin activity and, when used alone, did not induce cell death, cell cycle perturbation and modification of calcium channel activity in comparison with verapamil.

  20. Phenothiazines as a solution for multidrug resistant tuberculosis

    DEFF Research Database (Denmark)

    Kristiansen, Jette E.; Dastidar, Sujata G.; Palchoudhuri, Shauroseni

    2015-01-01

    Historically, multiplicity of actions in synthetic compounds is a rule rather than exception. The science of non-antibiotics evolved in this background. From the antimalarial and antitrypanosomial dye methylene blue, chemically similar compounds, the phenothiazines, were developed. The phenothiaz...... thioridazine and its (-) form to be combined with other antitubercular drugs to treat infections by drug-resistant strains of Mycobacterium tuberculosis and try to eradicate this deadly disease. [Int Microbiol 2015; 18(1):1-12]....

  1. Multidrug-resistant Gram-negative bacteria: a product of globalization.

    Science.gov (United States)

    Hawkey, P M

    2015-04-01

    Global trade and mobility of people has increased rapidly over the last 20 years. This has had profound consequences for the evolution and the movement of antibiotic resistance genes. There is increasing exposure of populations all around the world to resistant bacteria arising in the emerging economies. Arguably the most important development of the last two decades in the field of antibiotic resistance is the emergence and spread of extended-spectrum β-lactamases (ESBLs) of the CTX-M group. A consequence of the very high rates of ESBL production among Enterobacteriaceae in Asian countries is that there is a substantial use of carbapenem antibiotics, resulting in the emergence of plasmid-mediated resistance to carbapenems. This article reviews the emergence and spread of multidrug-resistant Gram-negative bacteria, focuses on three particular carbapenemases--imipenem carbapenemases, Klebsiella pneumoniae carbapenemase, and New Delhi metallo-β-lactamase--and highlights the importance of control of antibiotic use.

  2. ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal

    Directory of Open Access Journals (Sweden)

    Choi Cheol-Hee

    2005-10-01

    Full Text Available Abstract One of the major problems related with anticancer chemotherapy is resistance against anticancer drugs. The ATP-binding cassette (ABC transporters are a family of transporter proteins that are responsible for drug resistance and a low bioavailability of drugs by pumping a variety of drugs out cells at the expense of ATP hydrolysis. One strategy for reversal of the resistance of tumor cells expressing ABC transporters is combined use of anticancer drugs with chemosensitizers. In this review, the physiological functions and structures of ABC transporters, and the development of chemosensitizers are described focusing on well-known proteins including P-glycoprotein, multidrug resistance associated protein, and breast cancer resistance protein.

  3. Establishment and biological characteristics of a multi-drug resistant cell line A549/Gem

    Directory of Open Access Journals (Sweden)

    Yunfeng ZHU

    2008-02-01

    Full Text Available Background and objective Multi-drug resistance is one of the most important reason why the survival time of non-small cell lung cancer patients is so short. The aim of this study is to establish multi-drug resistant cell line A549/Gem and discuss its biological characters so as to elaborate the possible mechanisms of gemcitabine resistance. Methods Human gemcitabine-resistant non-small cell lung cancer cell line A549/Gem was established by repeated clinical serous peak concentration then low but gradually increasing concentration of gemcitabine from its parental cell human lung adenocarcinoma cell line A549 which is sensitive to gemcitabine. During the course of inducement, monitored its morphology, checked its resistance index and resistant pedigree by MTT method, gathered its growth curve and calculated its doubling time, examined its DNA contents and cell cycles by flow cytometry; at the same time, measured its expression of P53, EGFR, c-erb-B-2, PTEN, PCNA, c-myc, VEGF, MDR-1, Bcl-2, nm23, MMP-9, TIMP-1, CD44v6 Proteins, and RRM1 mRNA. Results The resistance index of A549/Gem?to gemcitabine was 163.228, and the cell line also exhibited cross-resistance to vinorelbine, taxotere, fluorouraci, etoposide and cisplatin, but kept sensitivity to paclitaxol and oxaliplatin. The doubling time of it was shorter and figures in G0-G1 phase were increased than A549. Compared with A549, A549/Gem?achieved EGFR and c-myc protein expression, nm23 protein expression enhanced, p53, Cerb-B-2 and bcl-2 protein expression reduced, PTEN, PCNA and MDR-1 protein expression vanished, but that of MMP-9, VEGF, CD44v6 and TIMP-1 protein changed trivially. Meanwhile, the expression of RRM1 mRNA was augmented markedly. The resistance index of A549/Gem to gemcitabine was 129.783, and the cell line also held cross-resistance to vinorelbine, taxotere, etoposide, cisplatin and sensitivity to paclitaxol. But the resistance to fluorouracil and sensitivity to oxaliplatin

  4. What do proton motive force driven multidrug resistance transporters have in common?

    Science.gov (United States)

    Mazurkiewicz, Piotr; Driessen, Arnold J M; Konings, Wil N

    2005-01-01

    The extensive progress of genome sequencing projects in recent years has demonstrated that multidrug resistance (MDR) transporters are widely spread among all domains of life. This indicates that they play crucial roles in the survival of organisms. Moreover, antibiotic and chemotherapeutic treatments have revealed that microorganisms and cancer cells may use MDR transporters to fight the cytotoxic action of drugs. Currently, several MDR extrusion systems are being investigated in detail. It is expected that understanding of the molecular basis of multidrug recognition and the transport mechanisms will allow a more rational design of new drugs which either will not be recognized and expelled by or will efficiently inhibit the activity of the MDR transporters. MDR transporters either utilize ATP hydrolysis or an ion motive force as an energy source to drive drugs out of the cell. This review summarizes the recent progress in the field of bacterial proton motive force driven MDR transporters.

  5. Large-scale survey for novel genotypes of Plasmodium falciparum chloroquine-resistance gene pfcrt

    Directory of Open Access Journals (Sweden)

    Takahashi Nobuyuki

    2012-03-01

    Full Text Available Abstract Background In Plasmodium falciparum, resistance to chloroquine (CQ is conferred by a K to T mutation at amino acid position 76 (K76T in the P. falciparum CQ transporter (PfCRT. To date, at least 15 pfcrt genotypes, which are represented by combinations of five amino acids at positions 72-76, have been described in field isolates from various endemic regions. To identify novel mutant pfcrt genotypes and to reveal the genetic relatedness of pfcrt genotypes, a large-scale survey over a wide geographic area was performed. Methods Sequences for exon 2 in pfcrt, including known polymorphic sites at amino acid positions 72, 74, 75 and 76, were obtained from 256 P. falciparum isolates collected from eight endemic countries in Asia (Bangladesh, Cambodia, Lao P.D.R., the Philippines and Thailand, Melanesia (Papua New Guinea and Vanuatu and Africa (Ghana. A haplotype network was constructed based on six microsatellite markers located -29 kb to 24 kb from pfcrt in order to examine the genetic relatedness among mutant pfcrt genotypes. Results In addition to wild type (CVMNK at positions 72-76, four mutant pfcrt were identified; CVIET, CVIDT, SVMNT and CVMNT (mutated amino acids underlined. Haplotype network revealed that there were only three mutant pfcrt lineages, originating in Indochina, Philippines and Melanesia. Importantly, the Indochina lineage contained two mutant pfcrt genotypes, CVIET (n = 95 and CVIDT (n = 14, indicating that CVIDT shares a common origin with CVIET. Similarly, one major haplotype in the Melanesian lineage contained two pfcrt genotypes; SVMNT (n = 71 and CVMNT (n = 3. In Africa, all mutant pfcrt genotypes were the CVIET of the Indochina lineage, probably resulting from the intercontinental migration of CQ resistance from Southeast Asia. Conclusions The number of CQ-mutant lineages observed in this study was identical to that found in previous studies. This supports the hypothesis that the emergence of novel CQ resistance

  6. Exosomes play an important role in the process of psoralen reverse multidrug resistance of breast cancer.

    Science.gov (United States)

    Wang, Xiaohong; Xu, Chengfeng; Hua, Yitong; Sun, Leitao; Cheng, Kai; Jia, Zhongming; Han, Yong; Dong, Jianli; Cui, Yuzhen; Yang, Zhenlin

    2016-12-01

    Release of exosomes have been shown to play critical roles in drug resistance by delivering cargo. Targeting the transfer of exosomes from resistant cells to sensitive cells may be an approach to overcome some cases of drug resistance. In this study, we investigated the potential role of exosomes in the process of psoralen reverse multidrug resistance of MCF-7/ADR cells. Exosomes were isolated by differential centrifugation of culture media from MCF-7/ADR cells (ADR/exo) and MCF-7 parental cells (S/exo). Exosomes were characterized by morphology, exosomal markers and size distribution. The ability of ADR/exo to transfer multidrug resistance was assessed by MTT and real-time quantitative PCR. The different formation and secretion of exosomes were detected by immunofluorescence and transmission electron microscopy. Then we performed comparative transcriptomic analysis using RNA-Seq technology and real-time quantitative PCR to better understand the gene expression regulation in exosmes formation and release after psoralen treatment. Our data showed that exosomes derived from MCF-7/ADR cells were able to promote active sequestration of drugs and could induce a drug resistance phenotype by transferring drug-resistance-related gene MDR-1 and P-glycoprotein protein. Psoralen could reduce the formation and secretion of exosomes to overcome drug resistance. There were 21 differentially expressed genes. Gene ontology (GO) pathway analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the most significantly expressed genes were linked to PPAR and P53 signaling pathways which were related to exosomes formation, secretion and cargo sorting. Psoralen can affect the exosomes and induce the reduction of resistance transmission via exosomes might through PPAR and P53 signaling pathways, which might provide a novel strategy for breast cancer resistance to chemotherapy in the future.

  7. Prevalence and characterization of multidrug-resistant zoonotic Enterobacter spp. in poultry of Bangladesh.

    Science.gov (United States)

    Nandi, Shuvro Prokash; Sultana, Munawar; Hossain, M Anwar

    2013-05-01

    Poultry and poultry products are major contributors of zoonotic pathogens. Limited data are available on Enterobacter spp. as a potent zoonotic pathogen in poultry. The present study is a first endeavor on the emergence of multidrug-resistant zoonotic Enterobacter spp. and its prevalence arising from poultry in Bangladesh. Cloacal swabs from poultry samples of five different farms at Savar, Dhaka, Bangladesh were collected and from 106 isolates, 18 presumptive Enterobacter spp. were obtained. Antibiogram using 19 used antibiotics belonging to 15 major groups revealed that all of the 18 isolates were completely resistant to penicillin and rifampicin, but differed in their drug resistance pattern against ampicillin (94.4%), clindamycin (94.4%), erythromycin (94.4%), vancomycin (88.9%), sulfonamides (72.2%), imipenem (66.6%), streptomycin (55.6%), nitrofurantoin (33.3%), doxycycline (33.3%), tetracyclines (33.3%), cefepime (11.1%), and gentamicin (5.6%). All Enterobacter spp. were found to be plasmid free, implying that multidrug-resistant properties are chromosomal borne. The vanA and sulI were detected by polymerase chain reaction assay in 17 and 13 isolates, respectively. Amplified ribosomal DNA restriction analysis and randomly amplified polymorphic DNA distributed the 18 multidrug-resistant Enterobacter spp. into three genotypes. Phylogenetic analysis of the representatives of the three genotypes using partial 16S rRNA gene sequence (approximately 900 bp) showed that the genotypically diverse groups belonged to Enterobacter hormaechei, E. cloacae, and E. cancerogenus, respectively. The clinical significance of the close relative Enterobacter spp. is indicative of their zoonotic potential. Therefore, urgent intervention is required to limit the emergence and spread of these bacteria in poultry feed as well as prudent use of antibiotics among poultry farmers in Bangladesh.

  8. Multidrug resistance to Mycobacterium tuberculosis in a tertiary hospital.

    Science.gov (United States)

    Kehinde, Aderemi Oludiran; Obaseki, Felix Ariebuwa; Ishola, Oluponle Christiana; Ibrahim, Kolo Doko

    2007-01-01

    OBJECTIVE: The magnitude of drug-resistant Mycobacterium tuberculosis infection (MDR-TB) in Nigeria, the most populous country in sub-Saharan Africa, is largely unknown. This information would assist policymakers to develop intervention strategies against tuberculosis (TB) in the country. MATERIALS AND METHODS: This is a one-year laboratory-based study. Specimens from suspected new TB patients sent to the TB laboratory of the Department of Medical Microbiology, University College Hospital Ibadan, Nigeria from May 1, 2005 to April 27, 2006 were processed and analyzed. The specimens were stained with Ziehl-Neelsen (Z-N) reagents and cultured on Lowenstein-Jensen medium, incubated at 37 degrees C for 6-8 weeks. Isolates were confirmed as MDR-TB by Z-N reactions and biochemical methods. Drug susceptibility to streptomycin, ethambutol, rifampicin and isoniazid was done using Bactec 460 TB radiometric method. RESULTS: Of the 1,120 specimens processed, 80 (7.1%) were smear positive, while 56 (5.0%) were culture positive, even though the association was not statistically significant (p > 0.05). Culture contamination rate was 8.8%. Thirty (53.6%) of the culture positive isolates were resistant to both isoniazid and rifampicin, while 26 (46.4%) were susceptible. About half--53.3%--of the resistant isolates were from the antiretroviral clinic, while 10 (33.4%) were from peripheral centers. CONCLUSION: This study shows that MDR-TB is emerging in Nigeria. Further studies on MDR-TB are urgently needed in the country to ascertain the magnitude of the problem and to proffer solutions to it. PMID:17987922

  9. Molecular Genetic Analysis of Multi-drug Resistance in Indian Isolates of Mycobacterium tuberculosis

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    Noman Siddiqi

    1998-09-01

    Full Text Available A total of 116 isolates from patients attending the out-patient department at the All India Institute of Medical Sciences, New Delhi and the New Delhi Tuberculosis Centre, New Delhi, India were collected. They were analyzed for resistance to drugs prescribed in the treatment for tuberculosis. The drug resistance was initially determined by microbiological techniques. The Bactec 460TB system was employed to determine the type and level of resistance in each isolate. The isolates were further characterized at molecular level. The multi-drug loci corresponding to rpo b, gyr A, kat G were studied for mutation(s by the polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP technique. The SSCP positive samples were sequenced to characterize the mutations in rpo b, and gyr A loci. While previously reported mutations in the gyr A and rpo b loci were found to be present, several novel mutations were also scored in the rpo b locus. Interestingly, analysis of the gyr A locus showed the presence of point mutation(s that could not be detected by PCR-SSCP. Furthermore, rifampicin resistance was found to be an important marker for checking multi-drug resistance (MDR in clinical isolates of Mycobacterium tuberculosis. This is the first report on molecular genetic analysis of MDR tuberculosis one from India, highlights the increasing incidence of MDR in the Indian isolates of M. tuberculosis.

  10. Antimicrobial potential of Pakistani medicinal plants against multi-drug resistance Staphylococcus aureus

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    Rahat Ejaz

    2014-09-01

    Full Text Available Objective: To determine resistance patterns of Staphylococcus aureus (S. aureus isolated from different areas of Pakistan and to identify antimicrobial agents against multi-drug resistant S. aureus strains. Methods: A total of 67 samples (sewerage, nasal and milk were collected from different farm areas of Pakistan to identify local strains of S. aureus. Sixteen out of 67 samples were positive for S. aureus. Only 6 out of 16 S. aureus strains showed resistance to antibiotics. Then the antibacterial effect of 29 medicinal plants was evaluated on these S. aureus isolates and a standard S. aureus strain ATCC 25923. The solvents used for the extraction of plants were acetone, dimethyl sulfoxide and methanol. The in vitro antibacterial activity was performed using agar disc diffusion method. Moreover, minimum inhibitory concentration of effective medicinal plant extracts was identified through micro-dilution method to find out their 50% inhibitory concentration. Results: Plant extracts of 5 medicinal plants (Psidium guajava, Nigella sativa, Piper nigrum, Valeriana jatamansi, and Cucurbita pepo exhibited antibacterial activity against locally isolated multidrug resistant strains of S. aureus. The minimum inhibitory concentration of these extracts was ranged from 0.328 to 5.000 mg/mL. Conclusions: Plant extracts of Psidium guajava, Piper nigrum seed, Valeriana jatamansi, Cucurbita pepo and Nigella sativa showed significant in vitro antibacterial activity and thus, such findings may serve as valuable contribution in the treatment of infection and may contribute to the development of potential antimicrobial agents against multi drug resistant strains of S. aureus

  11. High prevalence of multi-drug resistant Streptococcus pneumoniae among healthy children in Thailand.

    Science.gov (United States)

    Thummeepak, Rapee; Leerach, Nontapat; Kunthalert, Duangkamol; Tangchaisuriya, Udomsak; Thanwisai, Aunchalee; Sitthisak, Sutthirat

    2015-01-01

    Antibiotic resistance in Streptococcus pneumoniae is an emerging health problem worldwide. The incidence of antimicrobial-resistant S. pneumoniae is increasing, and nasal colonization of S. pneumoniae in children increases the risk of pneumococcal infection. In this study, the prevalence of S. pneumoniae nasal colonization was studied in Thai children from three different districts. S. pneumoniae nasal colonization was found in 38 of 237 subjects (16.0%). The carriage rate indicated higher rates in two rural districts (18.2% and 29.8%) than in the urban district (2.8%). The antibiotic susceptibility pattern was determined using the disk diffusion method. Prevalence of multi-drug resistance S. pneumoniae (MDR-SP) was 31.6%. Resistance to commonly prescribed antibiotics was found for ampicillin (5.3%), azithromycin (26.3%), cefepime (2.6%), chloramphenicol (18.4%), clindamycin (18.4%), erythromycin (21.1%), oxacillin (44.7%), trimethoprim/sulfamethoxazole (78.9%) and tetracycline (15.8%). All isolates were sensitive to ceftriaxone. The pulsed-field gel electrophoresis pattern was used to compare genetic diversity of the S. pneumoniae isolates. PFGE demonstrated the variation in genotypes of S. pneumoniae from different areas. High prevalence of multi-drug resistance S. pneumoniae nasal colonization in healthy Thai children was indicated. Effective strategies for appropriate use of antibiotics are therefore needed in the community.

  12. Ribosomal mutations promote the evolution of antibiotic resistance in a multidrug environment

    Science.gov (United States)

    Gomez, James E; Kaufmann-Malaga, Benjamin B; Wivagg, Carl N; Kim, Peter B; Silvis, Melanie R; Renedo, Nikolai; Ioerger, Thomas R; Ahmad, Rushdy; Livny, Jonathan; Fishbein, Skye; Sacchettini, James C; Carr, Steven A; Hung, Deborah T

    2017-01-01

    Antibiotic resistance arising via chromosomal mutations is typically specific to a particular antibiotic or class of antibiotics. We have identified mutations in genes encoding ribosomal components in Mycobacterium smegmatis that confer resistance to several structurally and mechanistically unrelated classes of antibiotics and enhance survival following heat shock and membrane stress. These mutations affect ribosome assembly and cause large-scale transcriptomic and proteomic changes, including the downregulation of the catalase KatG, an activating enzyme required for isoniazid sensitivity, and upregulation of WhiB7, a transcription factor involved in innate antibiotic resistance. Importantly, while these ribosomal mutations have a fitness cost in antibiotic-free medium, in a multidrug environment they promote the evolution of high-level, target-based resistance. Further, suppressor mutations can then be easily acquired to restore wild-type growth. Thus, ribosomal mutations can serve as stepping-stones in an evolutionary path leading to the emergence of high-level, multidrug resistance. DOI: http://dx.doi.org/10.7554/eLife.20420.001 PMID:28220755

  13. Multidrug-resistant Salmonellae isolated in Japanese quails reared in Abeokuta, Nigeria.

    Science.gov (United States)

    Omoshaba, Ezekiel O; Olufemi, F O; Ojo, O E; Sonibare, A O; Agbaje, M

    2017-07-17

    Salmonellosis is a major bacterial disease causing huge economic losses in the poultry industry worldwide. This study was carried out to determine the period prevalence and antimicrobial susceptibility of Salmonella enterica in Japanese quails in Abeokuta, Nigeria. Four hundred cloacal swabs of quail birds were collected from 4 locations within Abeokuta. Salmonella was isolated from the samples using conventional methods for selective isolation of Salmonella and biochemical identification. Isolates were confirmed by polymerase chain reaction assays for the amplification and detection of Salmonella-associated virulence genes (invA and stn) using specific primers. Antimicrobial susceptibility testing was done using the Kirby-Bauer disk diffusion method. In all, Salmonella was isolated from 14 (3.5%) cloacal swabs. All 14 isolates possessed invA and stn genes. The Salmonella isolates showed resistance to tetracycline (100%), doxycycline (100%), ampicillin (100%), sulphamethoxazole (92.9%), nalidixic acid (85.8%), ceftazidime (78.6%), neomycin (64.3%), streptomycin (50%) and gentamycin (28.6%) but all the isolates were susceptible to ciprofloxacin. The isolates were resistant to at least three antimicrobials indicating multidrug resistance. The results concluded that Japanese quails harbour multidrug-resistant Salmonella which could be transmitted to humans through consumption of contaminated food or by direct and indirect contact with the carrier birds. Antimicrobial resistance could be due to overdependence on antimicrobials. Ciprofloxacin could be considered in the treatment of zoonotic Salmonellosis in humans.

  14. OAK-based cochleates as a novel approach to overcome multidrug resistance in bacteria.

    Science.gov (United States)

    Livne, L; Epand, R F; Papahadjopoulos-Sternberg, B; Epand, R M; Mor, A

    2010-12-01

    Antibiotic resistance has become a worldwide medical problem. To find new ways of overcoming this phenomenon, we investigated the role of the membrane-active oligo-acyl-lysyl (OAK) sequence C(12)K-7α(8), in combination with essentially ineffective antibiotics. Determination of minimal inhibitory concentration (MIC) against gram-negative multidrug-resistant strains of Escherichia coli revealed combinations with sub-MIC OAK levels that acted synergistically with several antibiotics, thus lowering their MICs by several orders of magnitude. To shed light into the molecular basis for this synergism, we used both mutant strains and biochemical assays. Our results suggest that bacterial sensitization to antibiotics was derived mainly from the OAK's capacity to overcome the efflux-enhanced resistance mechanism, by promoting backdoor entry of otherwise excluded antibiotics. To facilitate simultaneous delivery of the pooled drugs to an infection site, we developed a novel OAK-based cochleate system with demonstrable stability in whole blood. To assess the potential therapeutic use of such cochleates, we performed preliminary experiments that imitate systemic treatment of neutropenic mice infected with lethal inoculums of multidrug resistance E. coli. Single-dose administration of erythromycin coencapsulated in OAK-based cochleates has decreased drug toxicity and increased therapeutic efficacy in a dose-dependent manner. Collectively, our findings suggest a potentially useful approach for fighting efflux-enhanced resistance mechanisms.

  15. Antimicrobial potential of Pakistani medicinal plants against multi-drug resistance Staphylococcus aureus

    Institute of Scientific and Technical Information of China (English)

    Rahat Ejaz; Usman A Ashfaq; Sobia Idrees

    2014-01-01

    Objective: To determine resistance patterns of Staphylococcus aureus (S. aureus) isolated from different areas of Pakistan and to identify antimicrobial agents against multi-drug resistant S.aureus strains. Methods: A total of 67 samples (sewerage, nasal and milk) were collected from different farm areas of Pakistan to identify local strains of S. aureus. Sixteen out of 67 samples were positive for S.aureus. Only 6 out of 16 S. aureus strains showed resistance to antibiotics. Then the antibacterial effect of 29 medicinal plants was evaluated on these S. aureus isolates and a standard S. aureus strain ATCC 25923. The solvents used for the extraction of plants were acetone, dimethyl sulfoxide and methanol. The in vitro antibacterial activity was performed using agar disc diffusion method. Moreover, minimum inhibitory concentration of effective medicinal plant extracts was identified through micro-dilution method to find out their 50% inhibitory concentration.Results:Plant extracts of 5 medicinal plants (Psidium guajava, Nigella sativa, Piper nigrum, Valeriana jatamansi, and Cucurbita pepo) exhibited antibacterial activity against locally isolated multidrug resistant strains of S. aureus. The minimum inhibitory concentration of these extracts was ranged from 0.328 to 5.000 mg/mL. Conclusions: Plant extracts of Psidium guajava, Piper nigrum seed, Valeriana jatamansi, Cucurbita pepo and Nigella sativa showed significant in vitro antibacterial activity and thus, such findings may serve as valuable contribution in the treatment of infection and may contribute to the development of potential antimicrobial agents against multi drug resistant strains of S. aureus.

  16. Genomic definition of hypervirulent and multidrug-resistant Klebsiella pneumoniae clonal groups.

    Science.gov (United States)

    Bialek-Davenet, Suzanne; Criscuolo, Alexis; Ailloud, Florent; Passet, Virginie; Jones, Louis; Delannoy-Vieillard, Anne-Sophie; Garin, Benoit; Le Hello, Simon; Arlet, Guillaume; Nicolas-Chanoine, Marie-Hélène; Decré, Dominique; Brisse, Sylvain

    2014-11-01

    Multidrug-resistant and highly virulent Klebsiella pneumoniae isolates are emerging, but the clonal groups (CGs) corresponding to these high-risk strains have remained imprecisely defined. We aimed to identify K. pneumoniae CGs on the basis of genome-wide sequence variation and to provide a simple bioinformatics tool to extract virulence and resistance gene data from genomic data. We sequenced 48 K. pneumoniae isolates, mostly of serotypes K1 and K2, and compared the genomes with 119 publicly available genomes. A total of 694 highly conserved genes were included in a core-genome multilocus sequence typing scheme, and cluster analysis of the data enabled precise definition of globally distributed hypervirulent and multidrug-resistant CGs. In addition, we created a freely accessible database, BIGSdb-Kp, to enable rapid extraction of medically and epidemiologically relevant information from genomic sequences of K. pneumoniae. Although drug-resistant and virulent K. pneumoniae populations were largely nonoverlapping, isolates with combined virulence and resistance features were detected.

  17. Intracellular targeted co-delivery of shMDR1 and gefitinib with chitosan nanoparticles for overcoming multidrug resistance

    Science.gov (United States)

    Yu, Xiwei; Yang, Guang; Shi, Yijie; Su, Chang; Liu, Ming; Feng, Bo; Zhao, Liang

    2015-01-01

    Nowadays, multidrug resistance and side effects of drugs limit the effectiveness of chemotherapies in clinics. P-glycoprotein (P-gp) (MDR1), as a member of the ATP-binding cassette family, acts on transporting drugs into cell plasma across the membrane of cancer cells and leads to the occurrence of multidrug resistance, thus resulting in the failure of chemotherapy in cancer. The main aims of this research were to design a nanodelivery system for accomplishing the effective co-delivery of gene and antitumor drug and overcoming multidrug resistance effect. In this study, shMDR1 and gefitinib-encapsulating chitosan nanoparticles with sustained release, small particle size, and high encapsulation efficiency were prepared. The serum stability, protection from nuclease, and transfection efficiency of gene in vitro were investigated. The effects of co-delivery of shMDR1 and gefitinib in nanoparticles on reversing multidrug resistance were also evaluated by investigating the cytotoxicity, cellular uptake mechanism, and cell apoptosis on established gefitinib-resistant cells. The results demonstrated that chitosan nanoparticles entrapping gefitinib and shMDR1 had the potential to overcome the multidrug resistance and improve cancer treatment efficacy, especially toward resistant cells. PMID:26648717

  18. The secondary resistome of multidrug-resistant Klebsiella pneumoniae

    DEFF Research Database (Denmark)

    Jana, Bimal; Cain, Amy K.; Doerrler, William T.

    2017-01-01

    insertions and measured mutant depletion upon exposure to three clinically relevant antimicrobials (colistin, imipenem or ciprofloxacin) by Transposon Directed Insertion-site Sequencing (TraDIS). Using this high-throughput approach, we defined three sets of chromosomal non-essential genes essential...... for growth during exposure to colistin (n = 35), imipenem (n = 1) or ciprofloxacin (n = 1) in addition to known resistance determinants, collectively termed the “secondary resistome”. As proof of principle, we demonstrated that inactivation of a non-essential gene not previously found linked to colistin...

  19. Threat of multidrug resistant Staphylococcus aureus in Western Nepal

    DEFF Research Database (Denmark)

    Bhatta, Dharm R.; Cavaco, Lina; Nath, Gopal

    2015-01-01

    ObjectiveTo determine the prevalence of methicillin resistant Staphylococcus aureus (MRSA) and antimicrobial susceptibility patterns of the isolates from Manipal Teaching Hospital, Pokhara, Nepal. MethodsThis study was conducted over a period of 11 months (September 2012–August 2013) at the Manipal...... using disc diffusion test by cefoxitin (30 μg) and oxacillin (1 μg) disc, further confirmation was done by detection of mecA gene using PCR. ResultsOut of 400 Staphylococcus aureus strains, 139 (34.75%) were found to be MRSA. Among the MRSA isolates, 74 (53.2%) were from inpatient departments, 58 (41...

  20. Plasmodium falciparum Drug-Resistant Haplotypes and Population Structure in Postearthquake Haiti, 2010.

    Science.gov (United States)

    Morton, Lindsay Carol; Huber, Curtis; Okoth, Sheila Akinyi; Griffing, Sean; Lucchi, Naomi; Ljolje, Dragan; Boncy, Jacques; Oscar, Roland; Townes, David; McMorrow, Meredith; Chang, Michelle A; Udhayakumar, Venkatachalam; Barnwell, John W

    2016-10-05

    Chloroquine (CQ) remains the first-line treatment of malaria in Haiti. Given the challenges of conducting in vivo drug efficacy trials in low-endemic settings like Haiti, molecular surveillance for drug resistance markers is a reasonable approach for detecting resistant parasites. In this study, 349 blood spots were collected from suspected malaria cases in areas in and around Port-au-Prince from March to July 2010. Among them, 121 samples that were Plasmodium falciparum positive by polymerase chain reaction were genotyped for drug-resistant pfcrt, pfdhfr, pfdhps, and pfmdr1 alleles. Among the 108 samples that were successfully sequenced for CQ resistant markers in pfcrt, 107 were wild type (CVMNK), whereas one sample carried a CQ-resistant allele (CVIET). Neutral microsatellite genotyping revealed that the CQ-resistant isolate was distinct from all other samples in this study. Furthermore, the remaining parasite specimens appeared to be genetically distinct from other reported Central and South American populations. © The American Society of Tropical Medicine and Hygiene.

  1. Fitness trade-offs in the evolution of dihydrofolate reductase and drug resistance in Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Marna S Costanzo

    Full Text Available BACKGROUND: Patterns of emerging drug resistance reflect the underlying adaptive landscapes for specific drugs. In Plasmodium falciparum, the parasite that causes the most serious form of malaria, antifolate drugs inhibit the function of essential enzymes in the folate pathway. However, a handful of mutations in the gene coding for one such enzyme, dihydrofolate reductase, confer drug resistance. Understanding how evolution proceeds from drug susceptibility to drug resistance is critical if new antifolate treatments are to have sustained usefulness. METHODOLOGY/PRINCIPAL FINDINGS: We use a transgenic yeast expression system to build on previous studies that described the adaptive landscape for the antifolate drug pyrimethamine, and we describe the most likely evolutionary trajectories for the evolution of drug resistance to the antifolate chlorcycloguanil. We find that the adaptive landscape for chlorcycloguanil is multi-peaked, not all highly resistant alleles are equally accessible by evolution, and there are both commonalities and differences in adaptive landscapes for chlorcycloguanil and pyrimethamine. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that cross-resistance between drugs targeting the same enzyme reflect the fitness landscapes associated with each particular drug and the position of the genotype on both landscapes. The possible public health implications of these findings are discussed.

  2. Management of multidrug-resistant tuberculosis and patients in retreatment.

    Science.gov (United States)

    Caminero, J A

    2005-05-01

    Retreatment of tuberculosis involves the management of entities as diverse as relapse, failure, treatment after default, and poor patient adherence to the previous treatment. The emergence of conditions for selection of resistance (failure and partial abandonment) is a matter of great concern. The development of a retreatment regimen for tuberculosis requires consideration of certain basic premises. The importance of a comprehensive and directed history of drugs taken in the past, and the limited reliability of susceptibility tests to many of these drugs, should be kept in mind. Taking this into account, and possessing a thorough knowledge of all anti-tuberculosis medications, it is possible to cure almost all patients with an appropriate retreatment regimen including a minimum of three or four drugs not previously used. Nonetheless, the treatment of these patients is so complex that it should only be carried out by experienced staff. Concern about treating tuberculosis patients with drug resistance varies greatly depending on the available resources. High-income countries should provide individual treatment regimens adapted to each patient; however, in other settings, restricted resources could justify the implementation of standardised therapeutic guidelines with second-line drugs in order to facilitate management and reduce costs.

  3. Evaluation of dihydrofolate reductase and dihydropteroate synthetase genotypes that confer resistance to sulphadoxine-pyrimethamine in Plasmodium falciparum in Haiti.

    Science.gov (United States)

    Carter, Tamar E; Warner, Megan; Mulligan, Connie J; Existe, Alexander; Victor, Yves S; Memnon, Gladys; Boncy, Jacques; Oscar, Roland; Fukuda, Mark M; Okech, Bernard A

    2012-08-13

    Malaria caused by Plasmodium falciparum infects roughly 30,000 individuals in Haiti each year. Haiti has used chloroquine (CQ) as a first-line treatment for malaria for many years and as a result there are concerns that malaria parasites may develop resistance to CQ over time. Therefore it is important to prepare for alternative malaria treatment options should CQ resistance develop. In many other malaria-endemic regions, antifolates, particularly pyrimethamine (PYR) and sulphadoxine (SDX) treatment combination (SP), have been used as an alternative when CQ resistance has developed. This study evaluated mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) genes that confer PYR and SDX resistance, respectively, in P. falciparum to provide baseline data in Haiti. This study is the first comprehensive study to examine PYR and SDX resistance genotypes in P. falciparum in Haiti. DNA was extracted from dried blood spots and genotyped for PYR and SDX resistance mutations in P. falciparum using PCR and DNA sequencing methods. Sixty-one samples were genotyped for PYR resistance in codons 51, 59, 108 and 164 of the dhfr gene and 58 samples were genotyped for SDX resistance codons 436, 437, 540 of the dhps gene in P. falciparum. Thirty-three percent (20/61) of the samples carried a mutation at codon 108 (S108N) of the dhfr gene. No mutations in dhfr at codons 51, 59, 164 were observed in any of the samples. In addition, no mutations were observed in dhps at the three codons (436, 437, 540) examined. No significant difference was observed between samples collected in urban vs rural sites (Welch's T-test p-value = 0.53 and permutations p-value = 0.59). This study has shown the presence of the S108N mutation in P. falciparum that confers low-level PYR resistance in Haiti. However, the absence of SDX resistance mutations suggests that SP resistance may not be present in Haiti. These results have important implications for ongoing discussions on

  4. Evaluation of dihydrofolate reductase and dihydropteroate synthetase genotypes that confer resistance to sulphadoxine-pyrimethamine in Plasmodium falciparum in Haiti

    Directory of Open Access Journals (Sweden)

    Carter Tamar E

    2012-08-01

    Full Text Available Abstract Background Malaria caused by Plasmodium falciparum infects roughly 30,000 individuals in Haiti each year. Haiti has used chloroquine (CQ as a first-line treatment for malaria for many years and as a result there are concerns that malaria parasites may develop resistance to CQ over time. Therefore it is important to prepare for alternative malaria treatment options should CQ resistance develop. In many other malaria-endemic regions, antifolates, particularly pyrimethamine (PYR and sulphadoxine (SDX treatment combination (SP, have been used as an alternative when CQ resistance has developed. This study evaluated mutations in the dihydrofolate reductase (dhfr and dihydropteroate synthetase (dhps genes that confer PYR and SDX resistance, respectively, in P. falciparum to provide baseline data in Haiti. This study is the first comprehensive study to examine PYR and SDX resistance genotypes in P. falciparum in Haiti. Methods DNA was extracted from dried blood spots and genotyped for PYR and SDX resistance mutations in P. falciparum using PCR and DNA sequencing methods. Sixty-one samples were genotyped for PYR resistance in codons 51, 59, 108 and 164 of the dhfr gene and 58 samples were genotyped for SDX resistance codons 436, 437, 540 of the dhps gene in P. falciparum. Results Thirty-three percent (20/61 of the samples carried a mutation at codon 108 (S108N of the dhfr gene. No mutations in dhfr at codons 51, 59, 164 were observed in any of the samples. In addition, no mutations were observed in dhps at the three codons (436, 437, 540 examined. No significant difference was observed between samples collected in urban vs rural sites (Welch’s T-test p-value = 0.53 and permutations p-value = 0.59. Conclusion This study has shown the presence of the S108N mutation in P. falciparum that confers low-level PYR resistance in Haiti. However, the absence of SDX resistance mutations suggests that SP resistance may not be present in Haiti. These

  5. Expression of multidrug resistance-associated proteins in rhabdomyosarcomas before and after chemotherapy : The relationship between lung resistance-related protein (LRP) and differentiation

    NARCIS (Netherlands)

    Klunder, JW; Komdeur, R; van der Graaf, WTA; de Bont, EJSM; Hoekstra, HJ; van den Berg, E; Molenaar, WM

    Rhabdomyosarcomas generally respond well to chemotherapy, and the residual lesions often are better differentiated than their primaries. This phenomenon may be explained by selective multidrug resistance (MDR) of differentiated tumor cell populations. We assess the role of MDR proteins in

  6. Assessment of Plasmodium falciparum resistance to ferroquine (SSR97193 in field isolates and in W2 strain under pressure

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    Pradines Bruno

    2006-02-01

    Full Text Available Abstract Background Ferroquine (FQ, or SSR97193, is a novel antimalarial drug currently in phase I clinical trials. FQ is a unique organometallic compound designed to overcome the chloroquine (CQ resistance problem. FQ revealed to be equally active on CQ-sensitive and CQ-resistant Plasmodium falciparum laboratory strains and field isolates. FQ is also curative on rodent malaria parasites. As FQ will be tested in patients, the potential for resistance to this drug was evaluated. Methods The relationship between CQ-resistant transporter gene genotype and susceptibility to FQ were studied in 33 Cambodian P. falciparum field isolates previously studied for their in vitro response to CQ. In parallel, the ability of the CQ-resistant strain W2, to become resistant to FQ under drug pressure was assessed. Results The IC50 values for FQ in field isolates were found to be unrelated to mutations occurring in the P. falciparum chloroquine resistance transporter (PfCRT or to the level of expression of the corresponding mRNA. In vitro, under a drug pressure of 100 nM of FQ, transient survival was observed in only one of two experiments. Conclusion Field isolates studies and experimental drug pressure experiments showed that FQ overcomes CQ resistance, which reinforces the potential of this compound as a new antimalarial drug.

  7. Strategies for decreasing multidrug antibiotic resistance: role of ototopical agents for treatment of middle ear infections.

    Science.gov (United States)

    Klein, Jerome O

    2002-10-01

    Change in the susceptibility of bacterial pathogens to antimicrobial agents is constant. The efficacy of a new drug may change as it is used in clinical settings, and resistant bacterial clones result from the encounter of drug and organism. Soon after the introduction of the sulfonamides in the mid-1930s, the first effective agents of the antimicrobial era, resistance of pneumococci and group A streptococci was evident. In each of the following decades, a different problem in multidrug resistance occurred among common bacterial pathogens: beta-lactamase-producing staphylococci in the 1950s; highly resistant gram-negative enteric bacteria in the 1960s; beta-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis in the 1970s; and multidrug-resistant pneumococci in the 1980s. Antimicrobial resistance among respiratory pathogens is now a common clinical problem throughout the world, and its management is a part of routine office practice. Currently in the United States, about 25% of pneumococci are resistant to penicillin, and 25% of H influenzae and 90% of M catarrhalis produce beta-lactamase and would be inactivated by organisms producing the enzyme. The emergence of penicillin and multidrug-resistant pneumococci and beta-lactamase-producing strains of H influenzae and M catarrhalis have special importance for the management of infections of the middle ear. The widespread use of oral and parenteral antimicrobial drugs for appropriate and inappropriate uses has driven the emergence and spread of resistant organisms. This article discusses current susceptibility patterns of organisms involved in middle ear infections, risk factors associated with development of resistant strains, strategies for limiting the incidence and spread of resistant organisms and, as part of the strategy, use of ototopical rather than systemic antimicrobial drugs for chronic suppurative otitis media (CSOM) and acute otitis media (AOM) in children with tympanostomy tubes. Although

  8. Polymorphisms in the dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) genes of Plasmodium falciparum and in vivo resistance to sulphadoxine/pyrimethamine in isolates from Tanzania

    DEFF Research Database (Denmark)

    Jelinek, T; Rønn, A M; Lemnge, M M

    1998-01-01

    The efficacy of sulphadoxine/pyrimethamine (S/P) in treatment of uncomplicated falciparum malaria in Africa is increasingly compromised by development of resistance. The occurrence of mutations associated with the active site sequence in the Plasmodium falciparum genes coding for dihydrofolate...

  9. Antibiotic combination therapy can select for broad-spectrum multidrug resistance in Pseudomonas aeruginosa.

    Science.gov (United States)

    Vestergaard, Martin; Paulander, Wilhelm; Marvig, Rasmus L; Clasen, Julie; Jochumsen, Nicholas; Molin, Søren; Jelsbak, Lars; Ingmer, Hanne; Folkesson, Anders

    2016-01-01

    Combination therapy with several antibiotics is one strategy that has been applied in order to limit the spread of antimicrobial resistance. We compared the de novo evolution of resistance during combination therapy with the β-lactam ceftazidime and the fluoroquinolone ciprofloxacin with the resistance evolved after single-drug exposure. Combination therapy selected for mutants that displayed broad-spectrum resistance, and a major resistance mechanism was mutational inactivation of the repressor gene mexR that regulates the multidrug efflux operon mexAB-oprM. Deregulation of this operon led to a broad-spectrum resistance phenotype that decreased susceptibility to the combination of drugs applied during selection as well as to unrelated antibiotic classes. Mutants isolated after single-drug exposure displayed narrow-spectrum resistance and carried mutations in the MexCD-OprJ efflux pump regulator gene nfxB conferring ciprofloxacin resistance, or in the gene encoding the non-essential penicillin-binding protein DacB conferring ceftazidime resistance. Reconstruction of resistance mutations by allelic replacement and in vitro fitness assays revealed that in contrast to single antibiotic use, combination therapy consistently selected for mutants with enhanced fitness expressing broad-spectrum resistance mechanisms.

  10. DNA sequence analysis of plasmids from multidrug resistant Salmonella enterica serotype Heidelberg isolates.

    Directory of Open Access Journals (Sweden)

    Jing Han

    Full Text Available Salmonella enterica serovar Heidelberg is among the most detected serovars in swine and poultry, ranks among the top five serotypes associated with human salmonellosis and is disproportionately associated with invasive infections and mortality in humans. Salmonella are known to carry plasmids associated with antimicrobial resistance and virulence. To identify plasmid-associated genes in multidrug resistant S. enterica serovar Heidelberg, antimicrobial resistance plasmids from five isolates were sequenced using the 454 LifeSciences pyrosequencing technology. Four of the isolates contained incompatibility group (Inc A/C multidrug resistance plasmids harboring at least eight antimicrobial resistance genes. Each of these strains also carried a second resistance plasmid including two IncFIB, an IncHI2 and a plasmid lacking an identified Inc group. The fifth isolate contained an IncI1 plasmid, encoding resistance to gentamicin, streptomycin and sulfonamides. Some of the IncA/C plasmids lacked the full concert of transfer genes and yet were able to be conjugally transferred, likely due to the transfer genes carried on the companion plasmids in the strains. Several non-IncA/C resistance plasmids also carried putative virulence genes. When the sequences were compared to previously sequenced plasmids, it was found that while all plasmids demonstrated some similarity to other plasmids, they were unique, often due to differences in mobile genetic elements in the plasmids. Our study suggests that Salmonella Heidelberg isolates harbor plasmids that co-select for antimicrobial resistance and virulence, along with genes that can mediate the transfer of plasmids within and among other bacterial isolates. Prevalence of such plasmids can complicate efforts to control the spread of S. enterica serovar Heidelberg in food animal and human populations.

  11. Phenothiazines as a solution for multidrug resistant tuberculosis

    DEFF Research Database (Denmark)

    Kristiansen, Jette E; Dastidar, Sujata G; Palchoudhuri, Shauroseni;

    2015-01-01

    . The phenothiazines were first recognised for their antipsychotic properties, but soon after their antimicrobial functions came to be known and then such compounds were designated as non-antibiotics. The emergence of highly drug-resistant bacteria had initiated an urgent need to search for novel affordable compounds......Historically, multiplicity of actions in synthetic compounds is a rule rather than exception. The science of non-antibiotics evolved in this background. From the antimalarial and antitrypanosomial dye methylene blue, chemically similar compounds, the phenothiazines, were developed...... try to remain and multiply silently. Such a small dose is devoid of its adverse side-effects. Recent studies have shown that the (-) thioridazine is a more active antimicrobial agent and devoid of the toxic side effects normally encountered. This review describes the possibilities of bringing down...

  12. High prevalence of multidrug resistance in bacterial uropathogens from Kathmandu, Nepal

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    Baral Pankaj

    2012-01-01

    Full Text Available Abstract Background Urinary Tract Infection (UTI is one of the most common infectious diseases and people of all age-groups and geographical locations are affected. The impact of disease is even worst in low-resource developing countries due to unaware of the UTIs caused by multidrug-resistant (MDR pathogens and the possibility of transfer of MDR traits between them. The present study aimed to determine the prevalence of MDR bacterial isolates from UTI patients, the antibiotic resistance pattern and the conjugational transfer of multidrug resistance phenotypes in Escherichia coli (E. coli. Results Two hundred and nineteen bacterial isolates were recovered from 710 urine samples at Kathmandu Model hospital during the study period. All samples and isolates were investigated by standard laboratory procedures. Among the significant bacterial growth (30.8%, 219 isolates, 41.1% isolates were MDR. The most prevailing organism, E. coli (81.3%, 178 isolates was 38.2% MDR, whereas second most common organism, Citrobacter spp. (5%, 11 isolates was found 72.7% MDR. Extended-spectrum β-lactamase (ESBL production was detected in 55.2% of a subset of MDR E. coli isolates. Among the 29 MDR E. coli isolates, plasmids of size ranging 2-51 kb were obtained with different 15 profiles. The most common plasmid of size 32 kb was detected in all of the plasmid-harbored E. coli strains. The majority of E. coli isolates investigated for the multidrug resistance transfer were able to transfer plasmid-mediated MDR phenotypes along with ESBL pattern with a frequency ranging from 0.3 × 10-7 to 1.5 × 10-7 to an E. coli HB101 recipient strain by conjugation. Most of the donor and recipient strain showed high levels of minimum inhibitory concentration (MIC values for commonly-used antibiotics. Conclusions The high prevalence of multidrug resistance in bacterial uropathogens was observed. Particularly, resistance patterns were alarmingly higher for amoxycillin, co

  13. Multidrug-resistant Plasmodium vivax associated with severe and fatal malaria: a prospective study in Papua, Indonesia.

    Directory of Open Access Journals (Sweden)

    Emiliana Tjitra

    2008-06-01

    Full Text Available Multidrug-resistant Plasmodium vivax (Pv is widespread in eastern Indonesia, and emerging elsewhere in Asia-Pacific and South America, but is generally regarded as a benign disease. The aim of the study was to review the spectrum of disease associated with malaria due to Pv and P. falciparum (Pf in patients presenting to a hospital in Timika, southern Papua, Indonesia.Data were prospectively collected from all patients attending the outpatient and inpatient departments of the only hospital in the region using systematic data forms and hospital computerised records. Between January 2004 and December 2007, clinical malaria was present in 16% (60,226/373,450 of hospital outpatients and 32% (12,171/37,800 of inpatients. Among patients admitted with slide-confirmed malaria, 64% of patients had Pf, 24% Pv, and 10.5% mixed infections. The proportion of malarial admissions attributable to Pv rose to 47% (415/887 in children under 1 y of age. Severe disease was present in 2,634 (22% inpatients with malaria, with the risk greater among Pv (23% [675/2,937] infections compared to Pf (20% [1,570/7,817]; odds ratio [OR] = 1.19 [95% confidence interval (CI 1.08-1.32], p = 0.001, and greatest in patients with mixed infections (31% [389/1,273]; overall p < 0.0001. Severe anaemia (haemoglobin < 5 g/dl was the major complication associated with Pv, accounting for 87% (589/675 of severe disease compared to 73% (1,144/1,570 of severe manifestations with Pf (p < 0.001. Pure Pv infection was also present in 78 patients with respiratory distress and 42 patients with coma. In total 242 (2.0% patients with malaria died during admission: 2.2% (167/7,722 with Pf, 1.6% (46/2,916 with Pv, and 2.3% (29/1260 with mixed infections (p = 0.126.In this region with established high-grade chloroquine resistance to both Pv and Pf, Pv is associated with severe and fatal malaria particularly in young children. The epidemiology of P. vivax needs to be re-examined elsewhere where

  14. Multidrug-resistant Plasmodium vivax associated with severe and fatal malaria: a prospective study in Papua, Indonesia.

    Science.gov (United States)

    Tjitra, Emiliana; Anstey, Nicholas M; Sugiarto, Paulus; Warikar, Noah; Kenangalem, Enny; Karyana, Muhammad; Lampah, Daniel A; Price, Ric N

    2008-06-17

    Multidrug-resistant Plasmodium vivax (Pv) is widespread in eastern Indonesia, and emerging elsewhere in Asia-Pacific and South America, but is generally regarded as a benign disease. The aim of the study was to review the spectrum of disease associated with malaria due to Pv and P. falciparum (Pf) in patients presenting to a hospital in Timika, southern Papua, Indonesia. Data were prospectively collected from all patients attending the outpatient and inpatient departments of the only hospital in the region using systematic data forms and hospital computerised records. Between January 2004 and December 2007, clinical malaria was present in 16% (60,226/373,450) of hospital outpatients and 32% (12,171/37,800) of inpatients. Among patients admitted with slide-confirmed malaria, 64% of patients had Pf, 24% Pv, and 10.5% mixed infections. The proportion of malarial admissions attributable to Pv rose to 47% (415/887) in children under 1 y of age. Severe disease was present in 2,634 (22%) inpatients with malaria, with the risk greater among Pv (23% [675/2,937]) infections compared to Pf (20% [1,570/7,817]; odds ratio [OR] = 1.19 [95% confidence interval (CI) 1.08-1.32], p = 0.001), and greatest in patients with mixed infections (31% [389/1,273]); overall p accounting for 87% (589/675) of severe disease compared to 73% (1,144/1,570) of severe manifestations with Pf (p < 0.001). Pure Pv infection was also present in 78 patients with respiratory distress and 42 patients with coma. In total 242 (2.0%) patients with malaria died during admission: 2.2% (167/7,722) with Pf, 1.6% (46/2,916) with Pv, and 2.3% (29/1260) with mixed infections (p = 0.126). In this region with established high-grade chloroquine resistance to both Pv and Pf, Pv is associated with severe and fatal malaria particularly in young children. The epidemiology of P. vivax needs to be re-examined elsewhere where chloroquine resistance is increasing.

  15. Spread of artemisinin-resistant Plasmodium falciparum in Myanmar: a cross-sectional survey of the K13 molecular marker.

    Science.gov (United States)

    Tun, Kyaw M; Imwong, Mallika; Lwin, Khin M; Win, Aye A; Hlaing, Tin M; Hlaing, Thaung; Lin, Khin; Kyaw, Myat P; Plewes, Katherine; Faiz, M Abul; Dhorda, Mehul; Cheah, Phaik Yeong; Pukrittayakamee, Sasithon; Ashley, Elizabeth A; Anderson, Tim J C; Nair, Shalini; McDew-White, Marina; Flegg, Jennifer A; Grist, Eric P M; Guerin, Philippe; Maude, Richard J; Smithuis, Frank; Dondorp, Arjen M; Day, Nicholas P J; Nosten, François; White, Nicholas J; Woodrow, Charles J

    2015-04-01

    Emergence of artemisinin resistance in southeast Asia poses a serious threat to the global control of Plasmodium falciparum malaria. Discovery of the K13 marker has transformed approaches to the monitoring of artemisinin resistance, allowing introduction of molecular surveillance in remote areas through analysis of DNA. We aimed to assess the spread of artemisinin-resistant P falciparum in Myanmar by determining the relative prevalence of P falciparum parasites carrying K13-propeller mutations. We did this cross-sectional survey at malaria treatment centres at 55 sites in ten administrative regions in Myanmar, and in relevant border regions in Thailand and Bangladesh, between January, 2013, and September, 2014. K13 sequences from P falciparum infections were obtained mainly by passive case detection. We entered data into two geostatistical models to produce predictive maps of the estimated prevalence of mutations of the K13 propeller region across Myanmar. Overall, 371 (39%) of 940 samples carried a K13-propeller mutation. We recorded 26 different mutations, including nine mutations not described previously in southeast Asia. In seven (70%) of the ten administrative regions of Myanmar, the combined K13-mutation prevalence was more than 20%. Geospatial mapping showed that the overall prevalence of K13 mutations exceeded 10% in much of the east and north of the country. In Homalin, Sagaing Region, 25 km from the Indian border, 21 (47%) of 45 parasite samples carried K13-propeller mutations. Artemisinin resistance extends across much of Myanmar. We recorded P falciparum parasites carrying K13-propeller mutations at high prevalence next to the northwestern border with India. Appropriate therapeutic regimens should be tested urgently and implemented comprehensively if spread of artemisinin resistance to other regions is to be avoided. Wellcome Trust-Mahidol University-Oxford Tropical Medicine Research Programme and the Bill & Melinda Gates Foundation. Copyright © 2015

  16. Selection of a multidrug resistance plasmid by sublethal levels of antibiotics and heavy metals.

    Science.gov (United States)

    Gullberg, Erik; Albrecht, Lisa M; Karlsson, Christoffer; Sandegren, Linus; Andersson, Dan I

    2014-10-07

    How sublethal levels of antibiotics and heavy metals select for clinically important multidrug resistance plasmids is largely unknown. Carriage of plasmids generally confers substantial fitness costs, implying that for the plasmid-carrying bacteria to be maintained in the population, the plasmid cost needs to be balanced by a selective pressure conferred by, for example, antibiotics or heavy metals. We studied the effects of low levels of antibiotics and heavy metals on the selective maintenance of a 220-kbp extended-spectrum β-lactamase (ESBL) plasmid identified in a hospital outbreak of Klebsiella pneumoniae and Escherichia coli. The concentrations of antibiotics and heavy metals required to maintain plasmid-carrying bacteria, the minimal selective concentrations (MSCs), were in all cases below (almost up to 140-fold) the MIC of the plasmid-free susceptible bacteria. This finding indicates that the very low antibiotic and heavy metal levels found in polluted environments and in treated humans and animals might be sufficiently high to maintain multiresistance plasmids. When resistance genes were moved from the plasmid to the chromosome, the MSC decreased, showing that MSC for a specific resistance conditionally depends on genetic context. This finding suggests that a cost-free resistance could be maintained in a population by an infinitesimally low concentration of antibiotic. By studying the effect of combinations of several compounds, it was observed that for certain combinations of drugs each new compound added lowered the minimal selective concentration of the others. This combination effect could be a significant factor in the selection of multidrug resistance plasmids/bacterial clones in complex multidrug environments. Importance: Antibiotic resistance is in many pathogenic bacteria caused by genes that are carried on large conjugative plasmids. These plasmids typically contain multiple antibiotic resistance genes as well as genes that confer resistance to

  17. Multistrain models predict sequential multidrug treatment strategies to result in less antimicrobial resistance than combination treatment

    DEFF Research Database (Denmark)

    Ahmad, Amais; Zachariasen, Camilla; Christiansen, Lasse Engbo;

    2016-01-01

    Background: Combination treatment is increasingly used to fight infections caused by bacteria resistant to two or more antimicrobials. While multiple studies have evaluated treatment strategies to minimize the emergence of resistant strains for single antimicrobial treatment, fewer studies have...... generated by a mathematical model of the competitive growth of multiple strains of Escherichia coli.Results: Simulation studies showed that sequential use of tetracycline and ampicillin reduced the level of double resistance, when compared to the combination treatment. The effect of the cycling frequency...... frequency did not play a role in suppressing the growth of resistant strains, but the specific order of the two antimicrobials did. Predictions made from the study could be used to redesign multidrug treatment strategies not only for intramuscular treatment in pigs, but also for other dosing routes....

  18. Synergistic antimicrobial therapy using nanoparticles and antibiotics for the treatment of multidrug-resistant bacterial infection

    Science.gov (United States)

    Gupta, Akash; Saleh, Neveen M.; Das, Riddha; Landis, Ryan F.; Bigdeli, Arafeh; Motamedchaboki, Khatereh; Rosa Campos, Alexandre; Pomeroy, Kenneth; Mahmoudi, Morteza; Rotello, Vincent M.

    2017-06-01

    Infections caused by multidrug-resistant (MDR) bacteria pose a serious global burden of mortality, causing thousands of deaths each year. Antibiotic treatment of resistant infections further contributes to the rapidly increasing number of antibiotic-resistant species and strains. Synthetic macromolecules such as nanoparticles (NPs) exhibit broad-spectrum activity against MDR species, however lack of specificity towards bacteria relative to their mammalian hosts limits their widespread therapeutic application. Here, we demonstrate synergistic antimicrobial therapy using hydrophobically functionalized NPs and fluoroquinolone antibiotics for treatment of MDR bacterial strains. An 8-16-fold decrease in antibiotic dosage is achieved in presence of engineered NPs to combat MDR strains. This strategy demonstrates the potential of using NPs to ‘revive’ antibiotics that have been rendered ineffective due to the development of resistance by pathogenic bacteria.

  19. DbMDR: a relational database for multidrug resistance genes as potential drug targets.

    Science.gov (United States)

    Gupta, Sanchita; Mishra, Manoj; Sen, Naresh; Parihar, Rashi; Dwivedi, Gaurav Raj; Khan, Feroz; Sharma, Ashok

    2011-10-01

    DbMDR is non-redundant reference database of multidrug resistance (MDR) genes and their orthologs acting as potential drug targets. Drug resistance is a common phenomenon of pathogens, creating a serious problem of inactivation of drugs and antibiotics resulting in occurrence of diseases. Apart from other factors, the MDR genes present in pathogens are shown to be responsible for multidrug resistance. Much of the unorganized information on MDR genes is scattered across the literature and other web resources. Thus, consolidation of such knowledge about MDR genes into one database will make the drug discovery research more efficient. Mining of text for MDR genes has resulted into a large number of publications but in scattered and unorganized form. This information was compiled into a database, which enables a user not only to look at a particular MDR gene but also to find out putative homologs based on sequence similarity, conserved domains, and motifs in proteins encoded by MDR genes more efficiently. At present, DbMDR database contains 2843 MDR genes characterized experimentally as well as functionally annotated with cross-referencing search support. The DbMDR database (http://203.190.147.116/dbmdr/) is a comprehensive resource for comparative study focused on MDR genes and metabolic pathway efflux pumps and intended to provide a platform for researchers for further research in drug resistance.

  20. Toxicological relevance of the multidrug resistance protein 1, MRP1 (ABCC1) and related transporters.

    Science.gov (United States)

    Leslie, E M; Deeley, R G; Cole, S P

    2001-10-05

    The 190 kDa multidrug resistance protein 1 (MRP1/ABCC1) is a founding member of a subfamily of the ATP binding cassette (ABC) superfamily of transport proteins and was originally identified on the basis of its elevated expression in multidrug resistant lung cancer cells. In addition to its ability to confer resistance in tumour cells, MRP1 is ubiquitously expressed in normal tissues and is a primary active transporter of GSH, glucuronate and sulfate conjugated and unconjugated organic anions of toxicological relevance. Substrates include lipid peroxidation products, herbicides, tobacco specific nitrosamines, mycotoxins, heavy metals, and natural product and antifolate anti-cancer agents. MRP1 also transports unmodified xenobiotics but often requires GSH to do so. Active efflux is generally an important aspect of cellular detoxification since it prevents the accumulation of conjugated and unconjugated compounds that have the potential to be directly toxic. The related transporters MRP2 and MRP3 have overlapping substrate specificities with MRP1 but different tissue distributions, and evidence that they also have chemoprotective functions are discussed. Finally, MRP homologues have been described in other species including yeast and nematodes. Those isolated from the vascular plant Arabidopsis thaliana (AtMRPs) decrease the cytoplasmic concentration of conjugated toxins through sequestration in vacuoles and are implicated in providing herbicide resistance to plants.

  1. Functional Comparison of 45 Naturally Occurring Isoforms of the Plasmodium falciparum Chloroquine Resistance Transporter (PfCRT).

    Science.gov (United States)

    Callaghan, Paul S; Hassett, Matthew R; Roepe, Paul D

    2015-08-18

    At least 53 distinct isoforms of Plasmodium falciparum chloroquine resistance transporter (PfCRT) protein are expressed in strains or isolates of P. falciparum malarial parasites from around the globe. These parasites exhibit a range of sensitivities to chloroquine (CQ) and other drugs. Mutant PfCRT is believed to confer cytostatic CQ resistance (CQR(CS)) by transporting CQ away from its DV target (free heme released upon hemoglobin digestion). One theory is that variable CQ transport catalyzed by these different PfCRT isoforms is responsible for the range of CQ sensitivities now found for P. falciparum. Alternatively, additional mutations in drug-selected parasites, or additional functions of PfCRT, might complement PfCRT-mediated CQ transport in conferring the range of observed resistance phenotypes. To distinguish between these possibilities, we recently optimized a convenient method for measuring PfCRT-mediated CQ transport, involving heterologous expression in Saccharomyces cerevisiae. Here, we use this method to quantify drug transport activity for 45 of 53 of the naturally occurring PfCRT isoforms. Data show that variable levels of CQR likely depend upon either additional PfCRT functions or additional genetic events, including perhaps changes that influence DV membrane potential. The data also suggest that the common K76T PfCRT mutation that is often used to distinguish a P. falciparum CQR phenotype is not, in and of itself, a fully reliable indicator of CQR status.

  2. Antibiotic Restriction Might Facilitate the Emergence of Multi-drug Resistance

    Science.gov (United States)

    Obolski, Uri; Stein, Gideon Y.; Hadany, Lilach

    2015-01-01

    High antibiotic resistance frequencies have become a major public health issue. The decrease in new antibiotics' production, combined with increasing frequencies of multi-drug resistant (MDR) bacteria, cause substantial limitations in treatment options for some bacterial infections. To diminish overall resistance, and especially the occurrence of bacteria that are resistant to all antibiotics, certain drugs are deliberately scarcely used—mainly when other options are exhausted. We use a mathematical model to explore the efficiency of such antibiotic restrictions. We assume two commonly used drugs and one restricted drug. The model is examined for the mixing strategy of antibiotic prescription, in which one of the drugs is randomly assigned to each incoming patient. Data obtained from Rabin medical center, Israel, is used to estimate realistic single and double antibiotic resistance frequencies in incoming patients. We find that broad usage of the hitherto restricted drug can reduce the number of incorrectly treated patients, and reduce the spread of bacteria resistant to both common antibiotics. Such double resistant infections are often eventually treated with the restricted drug, and therefore are prone to become resistant to all three antibiotics. Thus, counterintuitively, a broader usage of a formerly restricted drug can sometimes lead to a decrease in the emergence of bacteria resistant to all drugs. We recommend re-examining restriction of specific drugs, when multiple resistance to the relevant alternative drugs already exists. PMID:26110266

  3. Antibiotic Restriction Might Facilitate the Emergence of Multi-drug Resistance.

    Science.gov (United States)

    Obolski, Uri; Stein, Gideon Y; Hadany, Lilach

    2015-06-01

    High antibiotic resistance frequencies have become a major public health issue. The decrease in new antibiotics' production, combined with increasing frequencies of multi-drug resistant (MDR) bacteria, cause substantial limitations in treatment options for some bacterial infections. To diminish overall resistance, and especially the occurrence of bacteria that are resistant to all antibiotics, certain drugs are deliberately scarcely used--mainly when other options are exhausted. We use a mathematical model to explore the efficiency of such antibiotic restrictions. We assume two commonly used drugs and one restricted drug. The model is examined for the mixing strategy of antibiotic prescription, in which one of the drugs is randomly assigned to each incoming patient. Data obtained from Rabin medical center, Israel, is used to estimate realistic single and double antibiotic resistance frequencies in incoming patients. We find that broad usage of the hitherto restricted drug can reduce the number of incorrectly treated patients, and reduce the spread of bacteria resistant to both common antibiotics. Such double resistant infections are often eventually treated with the restricted drug, and therefore are prone to become resistant to all three antibiotics. Thus, counterintuitively, a broader usage of a formerly restricted drug can sometimes lead to a decrease in the emergence of bacteria resistant to all drugs. We recommend re-examining restriction of specific drugs, when multiple resistance to the relevant alternative drugs already exists.

  4. Chloroquine resistant P. falciparum prevalence is low and unchanged between 1990 and 2005 in Guinea-Bissau

    DEFF Research Database (Denmark)

    Ursing, Johan; Schmidt, Berit Aydin; Lebbad, Marianne;

    2007-01-01

    and other genetic polymorphisms in samples from 1992, 1993, 1995, 2004 and 2005. We have also monitored drug prescriptions for febrile illnesses. The mean proportion of in vitro tests indicating chloroquine resistance was 33% (range 14-54%) with the exception of an outlying value year 2000. The proportion...... of chloroquine resistant P. falciparum detected by in vitro testing did not increase over time. Pfcrt 76T was associated with chloroquine resistance but pfmdr1 86Y was not. The mean pfcrt 76T prevalence varied between 13% and 38%. The prevalence of SNPs at Pfcrt positions 76, 271, 326 and pfmdr1 position 86 did...... of chloroquine resistant P. falciparum has not gradually increased between 1990 and 2005 in Guinea-Bissau. Chloroquine is commonly prescribed at more than double the normal dose in Guinea Bissau. It has previously been hypothesized that treatment with high doses of chloroquine may be effective. We discuss...

  5. Control of multidrug resistant bacteria in a tertiary care hospital in India

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    Jaggi Namita

    2012-06-01

    Full Text Available Abstract Background The objective of this study was to assess the impact of antimicrobial stewardship programs on the multidrug resistance patterns of bacterial isolates. The study comprised an initial retrospective analysis of multidrug resistance in bacterial isolates for one year (July 2007-June 2008 followed by prospective evaluation of the impact of Antimicrobial Stewardship programs on resistance for two years and nine months (July 2008-March 2011. Setting A 300-bed tertiary care private hospital in Gurgaon, Haryana (India Findings Methods Study Design • July 2007 to June 2008: Resistance patterns of bacterial isolates were studied. • July 2008: Phase I intervention programme Implementation of an antibiotic policy in the hospital. • July 2008 to June 2010: Assessment of the impact of the Phase I intervention programme. • July 2010 to March 2011: Phase II intervention programme: Formation and effective functioning of the antimicrobial stewardship committee. Statistical correlation of the Defined daily dose (DDD for prescribed drugs with the antimicrobial resistance of Gram negatives. Results Phase I intervention programme (July 2008 resulted in a decrease of 4.47% in ESBLs (E.coli and Klebsiella and a significant decrease of 40.8% in carbapenem-resistant Pseudomonas. Phase II intervention (July 2010 brought a significant reduction (24.7% in carbapenem-resistant Pseudomonas. However, the resistance in the other Gram negatives (E.coli, Klebsiella, and Acinetobacter rose and then stabilized. A positive correlation was observed in Pseudomonas and Acinetobacter with carbapenems and cefoperazone-sulbactam. Piperacillin-tazobactam showed a positive correlation with Acinetobacter only. E.coli and Klebsiella showed positive correlation with cefoparazone-sulbactam and piperacillin-tazobactam. Conclusion An antimicrobial stewardship programme with sustained and multifaceted efforts is essential to promote the judicious use of antibiotics.

  6. Autophagy facilitates multidrug resistance development through inhibition of apoptosis in breast cancer cells.

    Science.gov (United States)

    Sun, W L; Lan, D; Gan, T Q; Cai, Z W

    2015-01-01

    Acquired multidrug resistance (MDR) is the main mechanism of chemotherapeutic drugs resistance. Nevertheless, the mechanisms of MDR are complex and still not very clear. Recently, including our previous study, several studies have revealed that macroautophagy (here referred to as autophagy) induced by anti-cancer drugs in breast cancer cells may facilitate the development of resistance to epirubicin (EPI), paclitaxel (PTX), tamoxifen or herceptin. Whereas there are a few studies on the relationship between autophagy and MDR, especially the studies designed directly employing induced resistant breast cancer cells. Based on previous study, we explored the relationship between autophagy and MDR. The results showed that induced EPI-resistant MCF-7er and SK-BR-3er cells were simultaneously resistant to PTX and vinorelbine (NVB), which demonstrated that the cells obtained MDR phenotype. Furthermore, PTX and NVB could also induce autophagy in MCF-7er and SK-BR-3er cells, and the induced autophagy protected the cells from apoptosis, which facilitated the development of resistance to PTX and NVB. Thus, autophagy promoted the development of MDR in breast cancer cells through inhibition of apoptosis. In addition, we found that P-glycoprotein (Pgp) was overexpressed in MCF-7er and SK-Br-3er cells. And we preliminarily investigated the relationship between autophagy and P-glycoprotein (Pgp). The results showed that the expression of the protein did not obviously change despite the inhibition of autophagy. Therefore, the role of Pgp in the development of MDR might be independent of autophahy. Also this finding implies that autophagy might be a target to overcome MDR in breast cancer cells, and clinical use autophagy inhibitors might be one of the important strategies for overcoming MDR in breast cancer therapy. Autophagy, apoptosis, multidrug resistance, breast cancer, chemotherapy.

  7. Characteristics of multidrug-resistant Mycobacterium tuberculosis in southern Brazil.

    Science.gov (United States)

    Perizzolo, Paulo F; Dalla Costa, Elis R; Ribeiro, Andrezza W; Spies, Fernanda S; Ribeiro, Marta O; Dias, Cláudia F; Unis, Gisela; Almeida da Silva, Pedro; Gomes, Harrison M; Suffys, Philip N; Rossetti, Maria Lucia R

    2012-01-01

    A major threat to tuberculosis (TB) control programs is the emergence of drug resistant Mycobacterium tuberculosis strains that cause TB that cannot be cured by standard anti-TB drug regimens. Because few data exist on MDR-TB in this region of the country, we performed an epidemiologic study that combined conventional and molecular analysis of MDR-TB cases from Rio Grande do Sul (RS) that were diagnosed in this period and included cases that were under treatment with second line drug schemes. Included were 121 MDR cases and sequencing of rpoB and katG showed that 106 (87.6%) strains were mutated in rpoB and 97 (80.2%) in katG. Spoligotyping demonstrated that the LAM genotype was predominant (n = 70, 57.8%) and included the largest group composed by 22 (18.1%) strains with the LAM5 ST93 genotype. Other main genotypes belonged to the families T (n = 22, 18.2%), U family (n = 16, 13.2%), Haarlem (n = 5, 4.1%) and X (n = 1, 0.8%). Genotyping by IS6110-RFLP analysis showed 51 distinct fingerprints, 38 (31.4%) of these observed only once and the other 13 patterns being shared among the rest of the isolates (n = 83, 68.6%). Among the 22 strains that were LAM5 ST93, only two had different IS6110-RFLP genotypes. In conclusion, there exists a high degree of M. Tuberculosis genotype clustering among MDR-TB cases in Rio Grande do Sul. Moreover, we observed a large MDR-TB outbreak.

  8. Identification of multi-drug resistant Pseudomonas aeruginosa clinical isolates that are highly disruptive to the intestinal epithelial barrier

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    Shevchenko Olga

    2006-06-01

    Full Text Available Abstract Background Multi-drug resistant Pseudomonas aeruginosa nosocomial infections are increasingly recognized worldwide. In this study, we focused on the virulence of multi-drug resistant clinical strains P. aeruginosa against the intestinal epithelial barrier, since P. aeruginosa can cause lethal sepsis from within the intestinal tract of critically ill and immuno-compromised patients via mechanisms involving disruption of epithelial barrier function. Methods We screened consecutively isolated multi-drug resistant P. aeruginosa clinical strains for their ability to disrupt the integrity of human cultured intestinal epithelial cells (Caco-2 and correlated these finding to related virulence phenotypes such as adhesiveness, motility, biofilm formation, and cytotoxicity. Results Results demonstrated that the majority of the multi-drug resistant P. aeruginosa clinical strains were attenuated in their ability to disrupt the barrier function of cultured intestinal epithelial cells. Three distinct genotypes were found that displayed an extreme epithelial barrier-disrupting phenotype. These strains were characterized and found to harbor the exoU gene and to display high swimming motility and adhesiveness. Conclusion These data suggest that detailed phenotypic analysis of the behavior of multi-drug resistant P. aeruginosa against the intestinal epithelium has the potential to identify strains most likely to place patients at risk for lethal gut-derived sepsis. Surveillance of colonizing strains of P. aeruginosa in critically ill patients beyond antibiotic sensitivity is warranted.

  9. Amikacin Concentrations Predictive of Ototoxicity in Multidrug-Resistant Tuberculosis Patients.

    Science.gov (United States)

    Modongo, Chawangwa; Pasipanodya, Jotam G; Zetola, Nicola M; Williams, Scott M; Sirugo, Giorgio; Gumbo, Tawanda

    2015-10-01

    Aminoglycosides, such as amikacin, are used to treat multidrug-resistant tuberculosis. However, ototoxicity is a common problem and is monitored using peak and trough amikacin concentrations based on World Health Organization recommendations. Our objective was to identify clinical factors predictive of ototoxicity using an agnostic machine learning method. We used classification and regression tree (CART) analyses to identify clinical factors, including amikacin concentration thresholds that predicted audiometry-confirmed ototoxicity among 28 multidrug-resistant pulmonary tuberculosis patients in Botswana. Amikacin concentrations were measured for all patients. The quantitative relationship between predictive factors and the probability of ototoxicity were then identified using probit analyses. The primary predictors of ototoxicity on CART analyses were cumulative days of therapy, followed by cumulative area under the concentration-time curve (AUC), which improved on the primary predictor by 87%. The area under the receiver operating curve was 0.97 on the test set. Peak and trough were not predictors in any tree. When algorithms were forced to pick peak and trough as primary predictors, the area under the receiver operating curve fell to 0.46. Probit analysis revealed that the probability of ototoxicity increased sharply starting after 6 months of therapy to near maximum at 9 months. A 10% probability of ototoxicity occurred with a threshold cumulative AUC of 87,232 days · mg · h/liter, while that of 20% occurred at 120,000 days · mg · h/liter. Thus, cumulative amikacin AUC and duration of therapy, and not peak and trough concentrations, should be used as the primary decision-making parameters to minimize the likelihood of ototoxicity in multidrug-resistant tuberculosis. Copyright © 2015, Modongo et al.

  10. In vitro antimicrobial potential of Terminalia chebula fruit extracts against multidrug-resistant uropathogens

    Institute of Scientific and Technical Information of China (English)

    Anwesa Bag; Subir Kumar Bhattacharyya; Nishith Kumar Pal; Rabi Ranjan Chattopadhyay

    2012-01-01

    Objective: Terminalia chebula Retz. (combretaceae) is called the “King of Medicine” in Tibet and is always listed at the top of the list of “Ayurvedic Materia Medica” because of its extraordinary power of healing. The present study was carried out to evaluate the possible in vitro antibacterial potential of different solvent extracts of T. chebula fruit against multidrug-resistant uropathogens. Methods: A total of 52 multidrug-resistant uropathogenic bacteria were used in this study. Successive extractions of T. chebula fruits were performed with solvents of different polarities. Agar well diffusion and microbroth dilution assay methods were used for antibacterial susceptibility testing. Kill-kinetics study was done to know the rate and extent of bacterial killing. Qualitative phytochemical screening was done to know the major phytoconstituents present in the plant material. Acute oral toxicity study in mice was performed to evaluate the toxic potential of the plant material, if any. Results:The ethanol extract of T. chebula fruits demonstrated a strong antimicrobial activity against all the test isolates and found to be most effective over others. Kill-kinetics study showed dose and time dependent antibacterial activity of ethanol extract. Phytochemical analysis revealed the presence of high concentration of phenolics and low concentration of flavonoids and terpenoids. In acute oral toxicity study, no gross behavioral changes were observed in mice at recommended dosage level and 24 h LD50 of ethanol extract was found to be >4 g/kg, p.o. in mice. Conclusions: The results provide justification for the use of Terminalia chebula fruit in folk medicine to treat various infectious diseases and could be useful for the development of alternative/ complementary medicine for multidrug-resistant uropathogens.

  11. Curative effect of transbronchoscopic perfusion combined with conventional chemotherapy on multi-drug resistant tuberculosis

    Institute of Scientific and Technical Information of China (English)

    Yang Li

    2016-01-01

    Objective:To analyze the curative effect of transbronchoscopic perfusion combined with conventional chemotherapy on multi-drug resistant tuberculosis.Methods: A total of 70 patients with multi-drug resistant tuberculosis treated in our hospital between April 2012 and April 2015 were selected and randomly divided into two groups, control group received conventional chemotherapy and observation group received transbronchoscopic perfusion + conventional chemotherapy. After treatment, negative conversion ratio of sputum mycobacterium tuberculosis, immune function, disease-specific indexes, oxidative stress indexes and liver function indexes were compared between two groups of patients. Results: After 6 months and 12 months of treatment, negative conversion ratio of sputum mycobacterium tuberculosis of observation group were significantly higher than those of control group; after 12 months of treatment, CD3+, CD4+, CD4+/CD8+, IgA, IgM and IgG levels in peripheral blood of observation group were significantly higher than those of control group while disease-specific indexes ADA and LDH content in serum were lower than those of control group; oxidative stress indexes TOS, MAOA and OSI content in serum were lower than those of control group while TAS and GSH-Px content were higher than those of control group; liver function indexes STB, ALP, ALT and AST content in serum were lower than those of control group while TP content was higher than that of control group.Conclusions:Transbronchoscopic perfusion combined with conventional chemotherapy can improve the treatment effectiveness, improve immune function as well as reduce oxidative stress and liver damage in patients with multi-drug resistant tuberculosis, and is advantageous in optimizing long-term treatment outcome.

  12. Undomesticated animals as a reservoir of multidrug-resistant Enterococcus in eastern Poland.

    Science.gov (United States)

    Nowakiewicz, Aneta; Ziółkowska, Grażyna; Zięba, Przemysław; Kostruba, Anna

    2014-07-01

    To assess implications for public health we compared the resistance of Enterococcus spp. strains to antibacterial drugs in wild and exotic animals with strains originating in domesticated animals and characterized correlations between Enterococcus species, the source of the isolate, and the degree of resistance to selected antibiotics. All strains, regardless of source, were susceptible to β-lactams, gentamicin, linezolid, and teicoplanin; the highest resistance was to kanamycin, quinupristin, and rifampicin. Thirteen strains from undomesticated animals were resistant to vancomycin, and one strain, from a fox, was resistant to streptomycin (high-dose). Multidrug-resistant strains accounted for 46% of the strains from wild animals and 59% of the strains from an exotic animal (the Russian tortoise; Testudo horsfieldii). Despite the relatively low level of resistance in the strains isolated from wild and exotic animals, the large number of intermediately susceptible strains in these groups is an indication of the evolutionary character of the development of resistance, suggesting that these animals may be potential reservoirs of Enterococcus strains resistant to a wide panel of currently used antibiotics.

  13. The serum resistome of a globally disseminated multidrug resistant uropathogenic Escherichia coli clone.

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    Minh-Duy Phan

    Full Text Available Escherichia coli ST131 is a globally disseminated, multidrug resistant clone responsible for a high proportion of urinary tract and bloodstream infections. The rapid emergence and successful spread of E. coli ST131 is strongly associated with antibiotic resistance; however, this phenotype alone is unlikely to explain its dominance amongst multidrug resistant uropathogens circulating worldwide in hospitals and the community. Thus, a greater understanding of the molecular mechanisms that underpin the fitness of E. coli ST131 is required. In this study, we employed hyper-saturated transposon mutagenesis in combination with multiplexed transposon directed insertion-site sequencing to define the essential genes required for in vitro growth and the serum resistome (i.e. genes required for resistance to human serum of E. coli EC958, a representative of the predominant E. coli ST131 clonal lineage. We identified 315 essential genes in E. coli EC958, 231 (73% of which were also essential in E. coli K-12. The serum resistome comprised 56 genes, the majority of which encode membrane proteins or factors involved in lipopolysaccharide (LPS biosynthesis. Targeted mutagenesis confirmed a role in serum resistance for 46 (82% of these genes. The murein lipoprotein Lpp, along with two lipid A-core biosynthesis enzymes WaaP and WaaG, were most strongly associated with serum resistance. While LPS was the main resistance mechanism defined for E. coli EC958 in serum, the enterobacterial common antigen and colanic acid also impacted on this phenotype. Our analysis also identified a novel function for two genes, hyxA and hyxR, as minor regulators of O-antigen chain length. This study offers novel insight into the genetic make-up of E. coli ST131, and provides a framework for future research on E. coli and other Gram-negative pathogens to define their essential gene repertoire and to dissect the molecular mechanisms that enable them to survive in the bloodstream and

  14. Prevalence and multidrug resistance pattern of Salmonella isolated from resident wild birds of Bangladesh

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    Abdullah Al Faruq

    2016-10-01

    Full Text Available Aim: Salmonellosis is one of the most common zoonotic diseases, and the presence of antimicrobial resistant Salmonella in wild birds is global public health threat. Throughout the last decades, multidrug resistance of Salmonella spp. has increased, particularly in developing countries. Therefore, a cross-sectional study was conducted to investigate the prevalence of Salmonella spp. and antimicrobial resistance pattern against Salmonella spp. from two species of resident wild birds namely house crow (Corvus splendens and Asian pied starling (Gracupica contra. Materials and Methods: Samples were collected from cloacal swabs of house crows and Asian pied starling for isolating Salmonella spp. (bacteriological culture methods followed by antimicrobial susceptibility testing (disk diffusion method against Salmonella spp. isolates during March to December 2014. Results: The prevalence of Salmonella in Asian pied starling and house crows were 67% and 65%, respectively. Within the category of samples from different species, the variation in prevalence was not varied significantly (p>0.05. Isolated Salmonella spp. was tested for resistance to six different antimicrobial agents. Among six antimicrobial tested, 100% resistance were found to penicillin, oxacillin, and clindamycin followed by erythromycin (50-93%, kanamycin (7-20%, and cephalothin (30-67% from both species of birds. Kanamycin remained sensitive in (70-73%, cephalothin (26-70%, and erythromycin appeared to be (0-30% sensitive against Salmonella spp. isolates. Isolated Salmonella spp. was multidrug resistant up to three of the six antimicrobials tested. Conclusion: It can be said that the rational use of antimicrobials needs to be adopted in the treatment of disease for livestock, poultry, and human of Bangladesh to limit the emergence of drug resistance to Salmonella spp.

  15. Role of serum interleukin-6 in deciding therapy for multidrug resistant oral lichen planus

    Science.gov (United States)

    Marwah, Akanksha; Kaushik, Smita; Garg, Vijay K.; Gupta, Sunita

    2015-01-01

    Background Oral lichen planus (OLP) is a T cell mediated immune response. T cells locally present in the involved tissues release cytokines like interleukin-6 (IL-6), which contributes to pathogenesis of OLP. Also IL-6 has been associated with multidrug resistance protein (MRP) expression by keratinocytes. Correspondingly, upregulation of MRP was found in OLP. We conducted this study to evaluate the effects of various drugs on serum IL-6 in OLP; and correlation of these effects with the nature of clinical response and resistance pattern seen in OLP lesions with various therapeutic modalities. Thus we evaluated the role of serum IL-6 in deciding therapy for multidrug resistant OLP. Material and Methods Serum IL-6 was evaluated in 42 erosive OLP (EOLP) patients and 10 normal mucosa and 10 oral squamous cell carcinoma cases using ELISA technique. OLP patients were randomly divided into 3 groups of 14 patients each and were subjected to Pimecrolimus local application, oral Mycophenolate Mofetil (MMF) and Methotrexate (MTX) alongwith Pimecrolimus local application. IL-6 levels were evaluated before and after treatment. Results Serum IL-6 levels were raised above 3pg/ml in 26.19% erosive OLP (EOLP) cases (mean- 3.72±8.14). EOLP (5%) cases with IL-6 levels above 5pg/ml were resistant in MTX group. However significant decrease in serum IL-6 corresponding with the clinical resolution was seen in MMF group. Conclusions Significantly raised IL-6 levels in EOLP reflect the chronic inflammatory nature of the disease. As serum IL-6 levels significantly decreased in MMF group, correspondingly no resistance to treatment was noted. However with MTX there was no significant decrease in IL-6 and resistance to treatment was noted in some, especially plaque type lesions. Thus IL-6 can be a possible biomarker in deciding the best possible therapy for treatment resistant OLP. Key words:Lichen planus, biological markers, cytokines, enzyme-linked immunosorbent assay, immunosuppressive

  16. Epidemiology and molecular characterization of multidrug-resistant Gram-negative bacteria in Southeast Asia

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    Nuntra Suwantarat

    2016-05-01

    Full Text Available Abstract Background Multidrug-resistant Gram-negative bacteria (MDRGN, including extended-spectrum β-lactamases (ESBLs and multidrug-resistant glucose-nonfermenting Gram-negative bacilli (nonfermenters, have emerged and spread throughout Southeast Asia. Methods We reviewed and summarized current critical knowledge on the epidemiology and molecular characterization of MDRGN in Southeast Asia by PubMed searches for publications prior to 10 March 2016 with the term related to “MDRGN definition” combined with specific Southeast Asian country names (Thailand, Singapore, Malaysia, Vietnam, Indonesia, Philippines, Laos, Cambodia, Myanmar, Brunei. Results There were a total of 175 publications from the following countries: Thailand (77, Singapore (35, Malaysia (32, Vietnam (23, Indonesia (6, Philippines (1, Laos (1, and Brunei (1. We did not find any publications on MDRGN from Myanmar and Cambodia. We did not include publications related to Shigella spp., Salmonella spp., and Vibrio spp. and non-human related studies in our review. English language articles and abstracts were included for analysis. After the abstracts were reviewed, data on MDRGN in Southeast Asia from 54 publications were further reviewed and included in this study. Conclusions MDRGNs are a major contributor of antimicrobial-resistant bacteria in Southeast Asia. The high prevalence of ESBLs has been a major problem since 2005 and is possibly related to the development of carbapenem resistant organisms in this region due to the overuse of carbapenem therapy. Carbapenem–resistant Acinetobacter baumannii is the most common pathogen associated with nosocomial infections in this region followed by carbapenem-resistant Pseudomonas aeruginosa. Although Southeast Asia is not an endemic area for carbapenem-resistant Enterobacteriaceae (CRE, recently, the rate of CRE detection has been increasing. Limited infection control measures, lack of antimicrobial control, such as the presence of

  17. New drugs to treat multidrug-resistant tuberculosis: the case for bedaquiline.

    Science.gov (United States)

    Leibert, Eric; Danckers, Mauricio; Rom, William N

    2014-01-01

    Mycobacterium tuberculosis develops spontaneous resistance mutants to virtually every drug in use. Courses of therapy select for these mutants and drug-resistant organisms emerge. The development of drug-resistant organisms has reached the point that drug resistance now threatens to undermine global success against tuberculosis (TB). New drugs are needed. The last new class of drugs specifically developed for treatment of TB was the rifamycins over 40 years ago. New funding sources and the development of product development partnerships have energized the TB drug development effort. There are now more TB drugs in development than at any time in the past. The first of these drugs to be developed and marketed was bedaquiline. Bedaquiline has an entirely novel mechanism of action and so should be active against otherwise highly resistant organisms. It acts on the transmembrane component of adenosine triphosphate synthase and acts by preventing electron transport. This raises the exciting possibility that bedaquiline may be active against less metabolically active organisms. Drug-drug interactions between rifamycins and the cytochrome P450-3A system will limit bedaquiline's utility and create complexity in treatment regimens. In clinical trials, treatment with bedaquiline added to a background multidrug-resistant TB regimen was associated with earlier culture conversion and higher cure rates, but there were unexplained excess deaths in the bedaquiline arms of these trials. Food and Drug Administration approved bedaquiline for the treatment of multidrug-resistant TB when an effective treatment regimen cannot otherwise be provided. They required a black box warning about excess deaths and require that a phase III trial be completed. A planned Phase III trial is being reorganized. While bedaquiline is an exciting drug and marks a dramatic moment in the history of TB treatment, its ultimate place in the anti-TB drug armamentarium is unclear pending the Phase III trial and

  18. Risk of drug resistance in Plasmodium falciparum malaria therapy-a systematic review and meta-analysis.

    Science.gov (United States)

    Zhou, Li-Juan; Xia, Jing; Wei, Hai-Xia; Liu, Xiao-Jun; Peng, Hong-Juan

    2017-02-01

    Plasmodium falciparum is responsible for the vast majority of the morbidity and mortality associated with malaria infection globally. Although a number of studies have reported the emergence of drug resistance in different therapies for P. falciparum infection, the degree of the drug resistance in different antimalarials is still unclear. This research investigated the risk of drug resistance in the therapies with different medications based on meta-analyses. Relevant original randomized control trials (RCTs) were searched in all available electronic databases. Pooled relative risks (RRs) with 95% confidence intervals (95% CIs) were used to evaluate the risk of drug resistance resulting from different treatments. Seventy-eight studies were included in the meta-analysis to compare drug resistance in the treatment of P. falciparum infections and yielded the following results: chloroquine (CQ) > sulfadoxine-pyrimethamine (SP) (RR = 3.67, p  artemether + lumefantrine (AL) (RR = 2.94, p  artemisinin-based combination therapies (ACTs) (RR = 1.93, p < 0.001); no significant difference was found in amodiaquine (AQ) vs. SP, AS + AQ vs. AS + SP, AS + AQ vs. AL, or AS + MQ vs. AL. These results presented a global view for the current status of antimalarial drug resistance and provided a guidance for choice of antimalarials for efficient treatment and prolonging the life span of the current effective antimalarial drugs.

  19. New drugs to treat multidrug-resistant tuberculosis: the case for bedaquiline

    Directory of Open Access Journals (Sweden)

    Leibert E

    2014-07-01

    Full Text Available Eric Leibert, Mauricio Danckers, William N Rom Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, New York University School of Medicine, New York, NY, USA Abstract: Mycobacterium tuberculosis develops spontaneous resistance mutants to virtually every drug in use. Courses of therapy select for these mutants and drug-resistant organisms emerge. The development of drug-resistant organisms has reached the point that drug resistance now threatens to undermine global success against tuberculosis (TB. New drugs are needed. The last new class of drugs specifically developed for treatment of TB was the rifamycins over 40 years ago. New funding sources and the development of product development partnerships have energized the TB drug development effort. There are now more TB drugs in development than at any time in the past. The first of these drugs to be developed and marketed was bedaquiline. Bedaquiline has an entirely novel mechanism of action and so should be active against otherwise highly resistant organisms. It acts on the transmembrane component of adenosine triphosphate synthase and acts by preventing electron transport. This raises the exciting possibility that bedaquiline may be active against less metabolically active organisms. Drug–drug interactions between rifamycins and the cytochrome P450-3A system will limit bedaquiline's utility and create complexity in treatment regimens. In clinical trials, treatment with bedaquiline added to a background multidrug-resistant TB regimen was associated with earlier culture conversion and higher cure rates, but there were unexplained excess deaths in the bedaquiline arms of these trials. Food and Drug Administration approved bedaquiline for the treatment of multidrug-resistant TB when an effective treatment regimen cannot otherwise be provided. They required a black box warning about excess deaths and require that a phase III trial be completed. A planned Phase

  20. Characteristics of human tumour cell lines after induction of multidrug resistance.

    Science.gov (United States)

    Nouri, A; Sharghi, S; Symes, M; Paris, A; Oliver, R

    1996-06-01

    A colorimetric technique was used to investigate some aspects of multidrug resistant (MDR)-induced cell lines. Continuous contact of the inducing agent with cells was necessary for MDR induction and this was followed by a series of phases i.e., a selection phase (ESP) lasted up to 6 days, a conditioning phase (CP) lasted up to 14 days and an expansion phase (EP) lasted up to 7 days. Gene transfection to correct missing MHC class I antigens on the Fen cell line did not affect cell behaviour. Of particular interest was the finding that the withdrawal of the MDR inducing agent did not reverse MDR phenotype immediately.