Venkatesan, Meera; Gadalla, Nahla B; Stepniewska, Kasia
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...
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.
Kavishe, Reginald A; Paulo, Petro; Kaaya, Robert D
falciparum positive dried blood spots on filter paper and rapid diagnostic test strips collected by finger pricks from patients attending health facilities in six regions of Tanzania mainland between June 2010 and August 2011 were used. Polymerase chain reaction-restriction fragment length polymorphism (PCR...... of common Pfmdr1 haplotypes reflecting strict implementation of ALu policy in Tanzania with overall prevalence of NFD haplotype ranging from 17 to 26% among other haplotypes. With continuation of ALu as first-line drug this haplotype is expected to keep rising, thus there is need for continued...
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
Thomsen, Thomas T; Madsen, Laura B; Hansson, Helle H
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...
OCT 2014 2. REPORT TYPE N/A 3. DATES COVERED - 4. TITLE AND SUBTITLE Ex Vivo Activity of Endoperoxide Antimalarials , Including Artemisone...Prescribed by ANSI Std Z39-18 Ex Vivo Activity of Endoperoxide Antimalarials , Including Artemisone and Arterolane, against Multidrug-Resistant...potent antimalarial activity (2, 3). Despite having a rapid mecha- nism of action, artemisinin resistance eventually emerged and was first detected
Happi, C. T.; Gbotosho, G. O.; Folarin, O. A.; Sowunmi, A.; Hudson, T.; O'Neil, M.; Milhous, W.; Wirth, D. F.; Oduola, A. M. J.
We assessed Plasmodium falciparum mdr1 (Pfmdr1) gene polymorphisms and copy numbers as well as P. falciparum Ca2+ ATPase (PfATPase6) gene polymorphisms in 90 Nigerian children presenting with uncomplicated falciparum malaria and enrolled in a study of the efficacy of artemether-lumefantrine (AL). The nested PCR-restriction fragment length polymorphism and the quantitative real-time PCR methodologies were used to determine the alleles of the Pfmdr1 and PfATPase6 genes and the Pfmdr1 copy numbe...
Price, Ric N.; Uhlemann, Anne-Catrin; van Vugt, Michele; Brockman, Al; Hutagalung, Robert; Nair, Shalini; Nash, Denae; Singhasivanon, Pratap; Anderson, Tim J. C.; Krishna, Sanjeev; White, Nicholas J.; Nosten, François
Our study examined the relative contributions of host, pharmacokinetic, and parasitological factors in determining the therapeutic response to artemether-lumefantrine (AL). On the northwest border of Thailand, patients with uncomplicated Plasmodium falciparum malaria were enrolled in prospective
Wangchuk, Phurpa; Phurpa, Wangchuk; Keller, Paul A; Pyne, Stephen G; Lie, Wilford; Willis, Anthony C; Rattanajak, Roonglawan; Kamchonwongpaisan, Sumalee
The aerial components of Meconopsis simplicifolia (D. Don) Walpers are indicated in Bhutanese traditional medicine for treating malaria, coughs and colds, and the infections of the liver, lung and blood. This study is to validate the ethnopharmacological uses of this plant and also identify potent antimalarial drug leads through bioassays of its crude extracts and phytochemical constituents. Meconopsis simplicifolia (D. Don) Walpers was collected from Bhutan and its crude MeOH extract was subjected to acid-base fractionation. Through repeated extractions, separations and spectroscopic analysis, the alkaloids obtained were identified and tested for their antimalarial and cytotoxicity activities. Phytochemical studies resulted in the isolation of one new protoberberine type alkaloid which we named as simplicifolianine and five known alkaloids: protopine, norsanguinarine, dihydrosanguinarine, 6-methoxydihydrosanguinarine and oxysanguinarine. Among the five of the alkaloids tested, simplicifolianine showed the most potent antiplasmodial activities against the Plasmodium falciparum strains, TM4/8.2 (chloroquine-antifolate sensitive strain) and K1CB1 (multidrug resistant strain) with IC50 values of 0.78 μg/mL and 1.29 μg/mL, respectively. The compounds tested did not show any significant cytotoxicity activities against human oral carcinoma KB cells and normal Vero cells of African kidney epithelial cells. This study validated the traditional uses of the plant for the treatment of malaria and identified a new alkaloid, simplicifolianine as a potential antimalarial drug lead. © 2013 Published by Elsevier Ireland Ltd.
Happi, C. T.; Gbotosho, G. O.; Folarin, O. A.; Sowunmi, A.; Hudson, T.; O'Neil, M.; Milhous, W.; Wirth, D. F.; Oduola, A. M. J.
We assessed Plasmodium falciparum mdr1 (Pfmdr1) gene polymorphisms and copy numbers as well as P. falciparum Ca2+ ATPase (PfATPase6) gene polymorphisms in 90 Nigerian children presenting with uncomplicated falciparum malaria and enrolled in a study of the efficacy of artemether-lumefantrine (AL). The nested PCR-restriction fragment length polymorphism and the quantitative real-time PCR methodologies were used to determine the alleles of the Pfmdr1 and PfATPase6 genes and the Pfmdr1 copy number variation, respectively, in patients samples collected prior to treatment and at the reoccurrence of parasites during a 42-day follow-up. The Pfmdr1 haplotype 86N-184F-1246D was significantly associated (P copy of the Pfmdr1 gene and the wild-type allele (L89) at codon 89 of the PfATPase6 gene. These findings suggest that polymorphisms in the Pfmdr1 gene are under AL selection pressure. Pfmdr1 polymorphisms may result in reduction in the therapeutic efficacy of this newly adopted combination treatment for uncomplicated falciparum malaria in Saharan countries of Africa. PMID:19075074
Happi, C T; Gbotosho, G O; Folarin, O A; Sowunmi, A; Hudson, T; O'Neil, M; Milhous, W; Wirth, D F; Oduola, A M J
We assessed Plasmodium falciparum mdr1 (Pfmdr1) gene polymorphisms and copy numbers as well as P. falciparum Ca(2+) ATPase (PfATPase6) gene polymorphisms in 90 Nigerian children presenting with uncomplicated falciparum malaria and enrolled in a study of the efficacy of artemether-lumefantrine (AL). The nested PCR-restriction fragment length polymorphism and the quantitative real-time PCR methodologies were used to determine the alleles of the Pfmdr1 and PfATPase6 genes and the Pfmdr1 copy number variation, respectively, in patients samples collected prior to treatment and at the reoccurrence of parasites during a 42-day follow-up. The Pfmdr1 haplotype 86N-184F-1246D was significantly associated (P copy of the Pfmdr1 gene and the wild-type allele (L89) at codon 89 of the PfATPase6 gene. These findings suggest that polymorphisms in the Pfmdr1 gene are under AL selection pressure. Pfmdr1 polymorphisms may result in reduction in the therapeutic efficacy of this newly adopted combination treatment for uncomplicated falciparum malaria in Saharan countries of Africa.
Arendrup, Maiken Cavling; Patterson, Thomas F
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...
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.
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.
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
Impact of treatment and re-treatment with artemether-lumefantrine and artesunate-amodiaquine on selection of Plasmodium falciparum multidrug resistance gene-1 polymorphisms in the Democratic Republic of Congo and Uganda.
Full Text Available The emergence of resistance against artemisinin combination treatment is a major concern for malaria control. ACTs are recommended as the rescue treatment, however, there is limited evidence as to whether treatment and re-treatment with ACTs select for drug-resistant P. falciparum parasites. Thus, the purpose of the present study is to investigate the impact of (re-treatment using artesunate-amodiaquine (ASAQ and artemether-lumefantrine (AL on the selection of P. falciparum multidrug resistance-1 (Pfmdr1 alleles in clinical settings.P. falciparum positive samples were collected from children aged 12-59 months in a clinical trial in DR Congo and Uganda. Pfmdr1 single nucleotide polymorphisms (SNPs analysis at codons N86Y, Y184F, and D1246Y were performed at baseline and post-treatment with either AL or ASAQ as a rescue treatment using nested PCR followed by restriction fragment length polymorphism (RFLP assays.The pre-treatment prevalence of Pfmdr1 N86 and D1246Y varied significantly between the sites, (p>0.001 and (p = 0.013, respectively. There was borderline significant directional selection for Pfmdr1 184F in recurrent malaria infections after treatment with AL in Uganda site (p = 0.05. Pfmdr1 NFD haplotype did not significantly change in post-treatment infections after re-treatment with either AL or ASAQ. Comparison between pre-treatment and post-treatment recurrences did not indicate directional selection of Pfmdr1 N86, D1246 alleles in the pre-RCT, RCT and post-RCT phases in both AL and ASAQ treatment arms. Pfmdr1 86Y was significantly associated with reduced risk of AL treatment failure (RR = 0.34, 95% CI:0.11-1.05, p = 0.04 while no evidence for D1246 allele (RR = 1.02; 95% CI: 0.42-2.47, p = 1.0. Survival estimates showed that the Pfmdr1 alleles had comparable mean-time to PCR-corrected recrudescence and new infections in both AL and ASAQ treatment arms.We found limited impact of (re-treatment with AL or ASAQ on selection for Pfmdr1
Ursing, Johan; Rombo, Lars; Bergqvist, Yngve
BACKGROUND: 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. METHODS: Standard or double-dose chloroquine was given to 892 children aged ...-up. The P. falciparum resistance-conferring genotype (pfcrt 76T) and day 7 chloroquine concentrations were determined. Data were divided into age groups (chloroquine is prescribed according to body weight. RESULTS: Adequate clinical...
Multidrug resistance (MDR) was initially recongnized as the major cause of the failure of the drug-based treatment of human cancers. It has become increasingly clear that MDR occurs in mammalian cells but also in lower eukaryotes and bacteria. The appearance of multiple antibiotic resistant
health, with the focus of DOTS programmes on cure of infectious TB patients and prevention of drug resistance. ... Despite highly effective drugs and disease control strategies, morbidity and mortality .... notification and registration system.
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.
Antequera, P; Garcia-Conca, V; Martín-González, C; Ortiz-de-la-Tabla, V
We report a case of keratitis in a female contact lens wearer, who developed a deep corneal abscess. The culture of a corneal biopsy scraping was positive for multiresistant Fusarium solani. The patient has a complicated clinical course and failed to respond to local and systemic antifungal treatment, requiring eye enucleation. Fusarium keratitis may progress to severe endophthalmitis. Clinical suspicion is paramount in order to start antifungal therapy without delay. Therapy is complex due to the high resistance of this organism to usual antifungal drugs. Copyright © 2014 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.
Nov 2, 2009 ... involvement during the transport of β - lactams in multidrug resistant Escherichia coli isolated from extra-intestinal infections. Also, the ... lactam resistance in multidrug resistant E. coli in ESBL and non-ESBL isolates. .... and decreased susceptibility to carbapenems, particularly ertapenem (Perez et al.,.
Bansal, Devendra; Sehgal, Rakesh; Chawla, Yogesh; Malla, Nancy; Mahajan, R C
Amoebiasis, caused by Entamoeba sp. a protozoan parasite, is a major public health problem in tropical and subtropical countries. The symptomatic patients are treated by specific chemotherapy. However, there are reports of treatment failure in some cases suggesting the possibility of drug resistance. The present study was therefore planned to assess the presence and expression of mRNA of multidrug resistance (MDR) gene in clinical isolates of Entamoeba histolytica and E. dispar. Forty five clinical isolates of Entamoeba sp. [E. histolytica (15) and E. dispar (30)] were maintained in polyxenic followed by monoxenic medium. DNA and total RNA were extracted from clinical isolates of Entamoeba sp. and from sensitive strain of E. histolytica (HM1: IMSS) and subjected to polymerase chain reaction (PCR) and multiplex reverse transcription (RT)-PCR techniques. The 344 bp segment of E. histolytica DNA was seen by PCR using primers specific to EhPgp1 in all clinical isolates and sensitive strain of E. histolytica. Over expression of EhPgp1 was observed only in resistant mutant of E. histolytica; however, transcription of EhPgp1 was not seen in any clinical isolates and sensitive strain of E. histolytica. The findings of the present study indicate that, so far, drug resistance in clinical isolates of E. histolytica does not seem to be a major problem in this country. However, susceptibility of clinical isolates of E. histolytica against various antiamoebic drugs needs to be investigated for better management.
Ursing, Johan; Kofoed, Poul-Erik; Rodrigues, Amabelia
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...... to become the dominant P.falciparum type in Guinea-Bissau. This is most likely due to the efficacy of high-dose chloroquine as used in Guinea-Bissau, combined with a loss of fitness associated with pfcrt 76T.......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...
Jovel, Irina T; Mejía, Rosa E; Banegas, Engels; Piedade, Rita; Alger, Jackeline; Fontecha, Gustavo; Ferreira, Pedro E; Veiga, Maria I; Enamorado, Irma G; Bjorkman, Anders; Ursing, Johan
In Honduras, chloroquine and primaquine are recommended and still appear to be effective for treatment of Plasmodium falciparum and Plasmodium vivax malaria. The aim of this study was to determine the proportion of resistance associated genetic polymorphisms in P. falciparum and P. vivax collected in Honduras. Blood samples were collected from patients seeking medical attention at the Hospital Escuela in Tegucigalpa from 2004 to 2006 as well as three regional hospitals, two health centres and one regional laboratory during 2009. Single nucleotide polymorphisms in P. falciparum chloroquine resistance transporter (pfcrt), multidrug resistance 1 (pfmdr1), dihydrofolate reductase (pfdhfr) and dihydropteroate synthase (pfdhps) genes and in P. vivax multidrug resistance 1 (pvmdr1) and dihydrofolate reductase (pvdhfr) genes were detected using PCR based methods. Thirty seven P. falciparum and 64 P. vivax samples were collected. All P. falciparum infections acquired in Honduras carried pfcrt, pfmdr1, pfdhps and pfdhfr alleles associated with chloroquine, amodiaquine and sulphadoxine-pyrimethamine sensitivity only. One patient with parasites acquired on a Pacific Island had pfcrt 76 T and pfmdr1 86Y alleles. That patient and a patient infected in West Africa had pfdhfr 51I, 59 R and 108 N alleles. Pvmdr1 976 F was found in 7/37 and two copies of pvmdr1 were found in 1/37 samples. Pvdhfr 57 L + 58 R was observed in 2/57 samples. The results indicate that P. falciparum from Honduras remain sensitive to chloroquine and sulphadoxine-pyrimethamine. This suggests that chloroquine and sulphadoxine-pyrimethamine should be efficacious for treatment of uncomplicated P. falciparum malaria, supporting current national treatment guidelines. However, genetic polymorphisms associated with chloroquine and sulphadoxine-pyrimethamine tolerance were detected in local P. vivax and imported P. falciparum infections. Continuous monitoring of the prevalence of drug resistant/tolerant P
Background: Multi-drug resistant Escherichia coli has become a major threat and cause of many urinary tract infections (UTIs) in Abeokuta, Nigeria. Objectives: This study was carried out to determine the resistant plasmids of multidrug resistant Escherichia coli isolated from (Urinary tract infections)UTIs in Abeokuta.
Gian Maria Pacifici
Full Text Available Bacterial infections may cause disease and death. Infants and children are often subject to bacterial infections. Antimicrobials kill bacteria protecting the infected patients andreducing the risk of morbidity and mortality caused by bacteria. The antibiotics may lose their antibacterial activity when they become resistant to a bacteria. The resistance to different antibiotics in a bacteria is named multidrug-resistance. Gram-negative bacilli, especially Escherichia coli, Klebsiella, Enterobacter, Salmonella, Shigella, Pseudomonas, Streptococcus, and Haemophilus influenzae type b, may become resistant. Amikacin ampicillin, amoxicillin, amoxiclav, cefuroxime, cefotaxime, ceftazidime, cefoperazone tetracycline, chloramphenicol, ciprofloxacin, and gentamicin may cause bacterial-resistance. Resistance to bacteria for several pathogens makes complications in the treatment of infections caused by them. Salmonella strains may become resistant to ampicillin, cephalotin, ceftriaxone, gentamicin, amikacin, trimethoprim-sulfamethoxazole, chloramphenicol, and tetracycline. Shigella strains may become resistant to ampicillin, cotrimoxazole, chloramphenicol, and streptomycin. Multidrug-resistance of Streptococcus pneumoniae may be due to β-lactams, macrolides, tetracycline, chloramphenicol, and trimethoprim-sulfamethoxazole. Multidrug-resistance of Pseudomonas aeruginosa may become resistant to β-lactams, chloramphenicol, trimethoprim-sulfamethoxazole, and tetracycline. The antibacterial activity against Haemophilus strains may occur with ampicillin, sulbactam-ampicillin, trimethoprim-sulfamethoxazole, gentamicin, chloramphenicol, and ciprofloxacin. Multidrug-resistance of the Klebsiella species may be due with ampicillin, cefotaxime, cefuroxime, co-amxilav, mezlocillin, chloramphenicol, gentamicin, and ceftazidime. Multidrug-resistance of Escherichia coli may be caused by ampicillin, cotrimoxazole, chloramphenicol, ceftriaxone, and ceftazidime. Vibrio
Price, Ric N; Uhlemann, Anne-Catrin; Brockman, Alan; McGready, Rose; Ashley, Elizabeth; Phaipun, Lucy; Patel, Rina; Laing, Kenneth; Looareesuwan, Sornchai; White, Nicholas J; Nosten, François; Krishna, Sanjeev
The borders of Thailand harbour the world's most multidrug resistant Plasmodium falciparum parasites. In 1984 mefloquine was introduced as treatment for uncomplicated falciparum malaria, but substantial resistance developed within 6 years. A combination of artesunate with mefloquine now cures more than 95% of acute infections. For both treatment regimens, the underlying mechanisms of resistance are not known. The relation between polymorphisms in the P falciparum multidrug resistant gene 1 (pfmdr1) and the in-vitro and in-vivo responses to mefloquine were assessed in 618 samples from patients with falciparum malaria studied prospectively over 12 years. pfmdr1 copy number was assessed by a robust real-time PCR assay. Single nucleotide polymorphisms of pfmdr1, P falciparum chloroquine resistance transporter gene (pfcrt) and P falciparum Ca2+ ATPase gene (pfATP6) were assessed by PCR-restriction fragment length polymorphism. Increased copy number of pfmdr1 was the most important determinant of in-vitro and in-vivo resistance to mefloquine, and also to reduced artesunate sensitivity in vitro. In a Cox regression model with control for known confounders, increased pfmdr1 copy number was associated with an attributable hazard ratio (AHR) for treatment failure of 6.3 (95% CI 2.9-13.8, p<0.001) after mefloquine monotherapy and 5.4 (2.0-14.6, p=0.001) after artesunate-mefloquine therapy. Single nucleotide polymorphisms in pfmdr1 were associated with increased mefloquine susceptibility in vitro, but not in vivo. Amplification in pfmdr1 is the main cause of resistance to mefloquine in falciparum malaria. Multidrug resistant P falciparum malaria is common in southeast Asia, but difficult to identify and treat. Genes that encode parasite transport proteins maybe involved in export of drugs and so cause resistance. In this study we show that increase in copy number of pfmdr1, a gene encoding a parasite transport protein, is the best overall predictor of treatment failure with
Full Text Available AIM: To elucidate the mechanism of multidrug resistance in retinoblastoma, and to acquire more insights into in vivo drug resistance. METHODS: Three anticancer drug resistant Y79 human RB cells were generated against vincristine, etoposide or carboplatin, which are used for conventional chemotherapy in RB. Primary cultures from enucleated eyes after chemotherapy (PCNC were also prepared. Their chemosensitivity to chemotherapeutic agents (vincristine, etoposide and carboplatin were measured using MTT assay. Western blot analysis was performed to evaluate the expression of p53, Bcl-2 and various multidrug resistant proteins in retinoblastoma cells. RESULTS: Following exposure to chemotherapeutic drugs, PCNC showed less sensitivity to drugs. No significant changes observed in the p53 expression, whereas Bcl-2 expression was found to be increased in the drug resistant cells as well as in PCNC. Increased expression of P-glycoprotein (P-gp was observed in drug resistant Y79 cells; however there was no significant change in the expression of P-gp found between primary cultures of primarily enucleated eyes and PCNC. Multidrug resistance protein 1 (Mrp-1 expression was found to be elevated in the drug resistant Y79 cells as well as in PCNC. No significant change in the expression of lung resistance associated protein (Lrp was observed in the drug resistant Y79 cells as well as in PCNC. CONCLUSION: Our results suggest that multidrug resistant proteins are intrinsically present in retinoblastoma which causes treatment failure in managing retinoblastoma with chemotherapy.
Shukla, Swati; Srivastava, Arpna; Kumar, Sunil; Singh, Usha; Goswami, Sandeep; Chawla, Bhavna; Bajaj, Mandeep Singh; Kashyap, Seema; Kaur, Jasbir
To elucidate the mechanism of multidrug resistance in retinoblastoma, and to acquire more insights into in vivo drug resistance. Three anticancer drug resistant Y79 human RB cells were generated against vincristine, etoposide or carboplatin, which are used for conventional chemotherapy in RB. Primary cultures from enucleated eyes after chemotherapy (PCNC) were also prepared. Their chemosensitivity to chemotherapeutic agents (vincristine, etoposide and carboplatin) were measured using MTT assay. Western blot analysis was performed to evaluate the expression of p53, Bcl-2 and various multidrug resistant proteins in retinoblastoma cells. Following exposure to chemotherapeutic drugs, PCNC showed less sensitivity to drugs. No significant changes observed in the p53 expression, whereas Bcl-2 expression was found to be increased in the drug resistant cells as well as in PCNC. Increased expression of P-glycoprotein (P-gp) was observed in drug resistant Y79 cells; however there was no significant change in the expression of P-gp found between primary cultures of primarily enucleated eyes and PCNC. Multidrug resistance protein 1 (Mrp-1) expression was found to be elevated in the drug resistant Y79 cells as well as in PCNC. No significant change in the expression of lung resistance associated protein (Lrp) was observed in the drug resistant Y79 cells as well as in PCNC. Our results suggest that multidrug resistant proteins are intrinsically present in retinoblastoma which causes treatment failure in managing retinoblastoma with chemotherapy.
Shukla, Swati; Srivastava, Arpna; Kumar, Sunil; Singh, Usha; Goswami, Sandeep; Chawla, Bhavna; Bajaj, Mandeep Singh; Kashyap, Seema; Kaur, Jasbir
AIM To elucidate the mechanism of multidrug resistance in retinoblastoma, and to acquire more insights into in vivo drug resistance. METHODS Three anticancer drug resistant Y79 human RB cells were generated against vincristine, etoposide or carboplatin, which are used for conventional chemotherapy in RB. Primary cultures from enucleated eyes after chemotherapy (PCNC) were also prepared. Their chemosensitivity to chemotherapeutic agents (vincristine, etoposide and carboplatin) were measured using MTT assay. Western blot analysis was performed to evaluate the expression of p53, Bcl-2 and various multidrug resistant proteins in retinoblastoma cells. RESULTS Following exposure to chemotherapeutic drugs, PCNC showed less sensitivity to drugs. No significant changes observed in the p53 expression, whereas Bcl-2 expression was found to be increased in the drug resistant cells as well as in PCNC. Increased expression of P-glycoprotein (P-gp) was observed in drug resistant Y79 cells; however there was no significant change in the expression of P-gp found between primary cultures of primarily enucleated eyes and PCNC. Multidrug resistance protein 1 (Mrp-1) expression was found to be elevated in the drug resistant Y79 cells as well as in PCNC. No significant change in the expression of lung resistance associated protein (Lrp) was observed in the drug resistant Y79 cells as well as in PCNC. CONCLUSION Our results suggest that multidrug resistant proteins are intrinsically present in retinoblastoma which causes treatment failure in managing retinoblastoma with chemotherapy. PMID:29181307
Inoue, Juliana; Silva, Miguel; Fofana, Bakary; Sanogo, Kassim; Mårtensson, Andreas; Sagara, Issaka; Björkman, Anders; Veiga, Maria Isabel; Ferreira, Pedro Eduardo; Djimde, Abdoulaye; Gil, José Pedro
Dihydroartemisinin/piperaquine (DHA/PPQ) is increasingly deployed as antimalaria drug in Africa. We report the detection in Mali of Plasmodium falciparum infections carrying plasmepsin 2 duplications (associated with piperaquine resistance) in 7/65 recurrent infections within 2 months after DHA/PPQ treatment. These findings raise concerns about the long-term efficacy of DHA/PPQ treatment in Africa.
Antimicrobial Activity of Actinomycetes Against Multidrug Resistant Staphylococcus aureus, E. coli and Various Other Pathogens. ... Purpose: The rapid emergence of drug resistance among pathogenic bacteria, especially multidrugresistant bacteria, underlines the need to look for new antibiotics. Methods: In the present ...
Multidrug resistance (MDR) is the condition where cancer cells or microorganisms cease to respond to multiple drugs. MDR conferred by efflux transporters, that deprive the bioavailability of drugs at their site of action, are a threat to cancer and malarial chemotherapy. Specifically, the mammalian ABC transporter Pglycoprotein (P-gp) has undermined many drugs in treatment of cancer and other disease states. Mutations in the parasitic transporter Plasmodium falciparum chloroquine resistance t...
Impact of treatment and re-treatment with artemether-lumefantrine and artesunate-amodiaquine on selection of Plasmodium falciparum multidrug resistance gene-1 polymorphisms in the Democratic Republic of Congo and Uganda
Baraka, Vito; Mavoko, Hypolite Muhindo; Nabasumba, Carolyn
fragment length polymorphism (RFLP) assays. RESULTS: The pre-treatment prevalence of Pfmdr1 N86 and D1246Y varied significantly between the sites, (p>0.001) and (p = 0.013), respectively. There was borderline significant directional selection for Pfmdr1 184F in recurrent malaria infections after treatment...... with AL in Uganda site (p = 0.05). Pfmdr1 NFD haplotype did not significantly change in post-treatment infections after re-treatment with either AL or ASAQ. Comparison between pre-treatment and post-treatment recurrences did not indicate directional selection of Pfmdr1 N86, D1246 alleles in the pre......BACKGROUND: The emergence of resistance against artemisinin combination treatment is a major concern for malaria control. ACTs are recommended as the rescue treatment, however, there is limited evidence as to whether treatment and re-treatment with ACTs select for drug-resistant P. falciparum...
The study was conducted with the objective of examining the outer membrane proteins and their involvement during the transport of β - lactams in multidrug resistant Escherichia coli isolated from extra-intestinal infections. Also, the response of gram negative bacterial biomembrane alteration was studied using extended ...
Background: Acinetobacter baumannii, a non-glucose fermenting Gram negative bacillus, has emerged in the last three decades as a major etiological agent of hospital-associated infections giving rise to significant morbidity and mortality particularly in immunocompromised patients. Multidrug resistant A. baumannii ...
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
Miotto, Olivo; Amato, Roberto; Ashley, Elizabeth A; MacInnis, Bronwyn; Almagro-Garcia, Jacob; Amaratunga, Chanaki; Lim, Pharath; Mead, Daniel; Oyola, Samuel O; Dhorda, Mehul; Imwong, Mallika; Woodrow, Charles; Manske, Magnus; Stalker, Jim; Drury, Eleanor; Campino, Susana; Amenga-Etego, Lucas; Thanh, Thuy-Nhien Nguyen; Tran, Hien Tinh; Ringwald, Pascal; Bethell, Delia; Nosten, Francois; Phyo, Aung Pyae; Pukrittayakamee, Sasithon; Chotivanich, Kesinee; Chuor, Char Meng; Nguon, Chea; Suon, Seila; Sreng, Sokunthea; Newton, Paul N; Mayxay, Mayfong; Khanthavong, Maniphone; Hongvanthong, Bouasy; Htut, Ye; Han, Kay Thwe; Kyaw, Myat Phone; Faiz, Md Abul; Fanello, Caterina I; Onyamboko, Marie; Mokuolu, Olugbenga A; Jacob, Christopher G; Takala-Harrison, Shannon; Plowe, Christopher V; Day, Nicholas P; Dondorp, Arjen M; Spencer, Chris C A; McVean, Gilean; Fairhurst, Rick M; White, Nicholas J; Kwiatkowski, Dominic P
We report a large multicenter genome-wide association study of Plasmodium falciparum resistance to artemisinin, the frontline antimalarial drug. Across 15 locations in Southeast Asia, we identified at least 20 mutations in kelch13 (PF3D7_1343700) affecting the encoded propeller and BTB/POZ domains, which were associated with a slow parasite clearance rate after treatment with artemisinin derivatives. Nonsynonymous polymorphisms in fd (ferredoxin), arps10 (apicoplast ribosomal protein S10), mdr2 (multidrug resistance protein 2) and crt (chloroquine resistance transporter) also showed strong associations with artemisinin resistance. Analysis of the fine structure of the parasite population showed that the fd, arps10, mdr2 and crt polymorphisms are markers of a genetic background on which kelch13 mutations are particularly likely to arise and that they correlate with the contemporary geographical boundaries and population frequencies of artemisinin resistance. These findings indicate that the risk of new resistance-causing mutations emerging is determined by specific predisposing genetic factors in the underlying parasite population. PMID:25599401
Gaspari, Romolo J; Dickson, Eric; Karlowsky, James; Doern, Gary
Urinary tract infections (UTIs) represent a common infection in the pediatric population. Escherichia coli is the most common uropathogen in children, and antimicrobial resistance in this species complicates the treatment of pediatric UTIs. Despite the impact of resistance on empiric antibiotic choice, there is little data on multidrug resistance in pediatric patients. In this paper, we describe characteristics of multidrug-resistant E. coli in pediatric patients using a large national database of uropathogens antimicrobial sensitivities. Antimicrobial susceptibility patterns to commonly prescribed antibiotics were performed on uropathogens isolated from children presenting to participating hospitals between 1999 and 2001. Data were analyzed separately for four pediatric age groups. Single and multidrug resistance to ampicillin, amoxicillin-clavulanate, cefazolin, ciprofloxacin, nitrofurantoin, and trimethoprim-sulfamethoxazole (TMP-SMX) were performed on all specimens. There were a total of 11,341 E. coli urine cultures from 343 infants (0-4 weeks), 1,801 toddlers (5 weeks-24 months), 6,742 preteens (2-12 years), and 2,455 teens (13-17 years). E. coli resistance to ampicillin peaked in toddlers (52.8%) but was high in preteens (52.1%), infants (50.4%), and teens (40.6%). Resistance to two or more antibiotics varied across age groups, with toddlers (27%) leading preteens (23.1%), infants (21%), and teens (15.9%). Resistance to three or more antibiotics was low in all age groups (range 3.1-5.2%). The most common co-resistance in all age groups was ampicillin/TMP-SMZ. In conclusion, less than half of all pediatric UTIs are susceptible to all commonly used antibiotics. In some age groups, there is a significant percentage of co-resistance between the two most commonly used antibiotics (ampicillin and TMP-SMZ).
Thita, Thunyapit; Jadsri, Pimrat; Thamkhantho, Jarupatr; Ruang-Areerate, Toon; Suwandittakul, Nantana; Sitthichot, Naruemon; Mahotorn, Kittiya; Tan-Ariya, Peerapan; Mungthin, Mathirut
In Thailand, artemisinin-based combination therapy (ACT) has been used to treat uncomplicated falciparum malaria since 1995. Unfortunately, artemisinin resistance has been reported from Thailand and other Southeast Asian countries since 2003. Malarone ® , a combination of atovaquone-proguanil (ATQ-PG), has been used to cease artemisinin pressure in some areas along Thai-Cambodia border, as part of an artemisinin resistance containment project since 2009. This study aimed to determine genotypes and phenotypes of Plasmodium falciparum isolates collected from the Thai-Cambodia border after the artemisinin resistance containment project compared with those collected before. One hundred and nine of P. falciparum isolates collected from Thai-Cambodia border from Chanthaburi and Trat provinces during 1988-2016 were used in this study. Of these, 58 isolates were collected after the containment. These parasite isolates were characterized for in vitro antimalarial sensitivities including chloroquine (CQ), quinine (QN), mefloquine (MQ), piperaquine (PPQ), artesunate (AS), dihydroartemisinin (DHA), ATQ and PG and genetic markers for drug resistance including the Kelch13 (k13), Plasmodium falciparum chloroquine resistance transporter (pfcrt), P. falciparum multidrug resistance 1 (pfmdr1) and cytochrome b (cytb) genes. Mean CQ, QN, MQ, PPQ and AS IC 50 s of the parasite isolates collected from 2009 to 2016 exhibited significantly higher than those of parasites collected before 2009. Approximately 57% exhibited in vitro MQ resistance. Approximately 94% of the isolates collected from 2009 to 2016 contained the pfmdr1 184F allele. Mutations of the k13 gene were detected in approximately 90% of the parasites collected from 2009 to 2016 which were significantly higher than the parasite isolates collected before. No ATQ-resistant genotype and phenotype of P. falciparum were found among the isolates collected after the containment project. Although the containment project had been
Bukhari, Syed Z.; Ashshi, Ahmad M.; Hussain, Waleed M.; Fatani, Mohammad I.
We report a case of pneumonia due to multi-drug resistant Ewingella Americana in a young patient admitted in the Intensive Care Unit of Hera General Hospital, Makkah, Saudi Arabia with severe head injury in a road traffic accident. He was an Indonesian pilgrim who had traveled to the Kingdom of Saudi Arabia to perform Hajj in December 2007. Ewingella Americana was identified to be the pathogen of pneumonia with clinical signs and symptoms along with positive radiological findings. (author)
Kang, Yoon Koo; Yoo, Young Do
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
PLASMID MEDIATED RESISTANCE IN MULTIDRUG RESISTANT BACTERIA. ISOLATED FROM CHILDREN WITH SUSPECTED SEPTICAEMIA IN ZARIA,. NIGERIA. AbdulAziz, Z. A.,1* Ehinmidu, J. O.,1 Adeshina, G. O.,1 Pala, Y. Y2., Yusuf, S. S2. and. Bugaje, M. A.3. 1Department of Pharmaceutics and Pharmaceutical ...
Artemisinin derivatives constitute a key component of the present-day treatment for Plasmodium falciparum malaria. Resistance with artemisinins is generally associated with S769N point mutation in the sarco-endoplasmic reticulumdependant ATPase6 (SERCA ATPase6) gene of Plasmodium falciparum, few studies have ...
Foumane Ngane, Vincent; Allico Djaman, Joseph; Culeux, Cécile; Piette, Nathalie; Carnevale, Pierre; Besnard, Patrick; Fortes, Filomeno; Basco, Leonardo K; Tahar, Rachida
The malaria situation has been worsening in Angola, partly due to armed conflict until the recent past and drug-resistant Plasmodium falciparum. Malaria transmission is heterogeneous within the country, and data on drug-resistant malaria in different parts of the country are incomplete. The aim of the present study was to evaluate resistance to 4-aminoquinolines and antifolate drugs in P. falciparum isolates collected in Benguela province, central Angola, using molecular markers. Fingerprick capillary blood was collected from asymptomatic children aged less than 15 years old during a household survey in and around Balombo town in 2010-2011. Samples were screened for P. falciparum by nested PCR. Molecular markers (P. falciparum dihydrofolate reductase [pfdhfr], P. falciparum dihydropteroate synthase [pfdhps], P. falciparum chloroquine resistance transporter [pfcrt], and P. falciparum multidrug-resistance gene 1 [pfmdr1]) were sequenced to determine the key codons associated with drug resistance. A total of 60 blood samples were positive for P. falciparum. Most isolates with successful PCR amplification had mutant pfdhfr alleles, with either double mutant AICNI (69%) or triple mutant AIRNI (21%) haplotypes. A16V, S108T, and I164L substitutions were not found. Many of the isolates were carriers of either SGKAA (60%) or AGKAA (27%) pfdhps haplotype. K540E substitution was absent. There were only two pfcrt haplotypes: wild-type CVMNK (11%) and mutant CVIET (89%). Wild-type pfmdr1 NYSND haplotype was found in 19% of the isolates, whereas single mutant pfmdr1 YYSND and NFSND haplotypes occurred in 48% and 11%, respectively. Double mutant pfmdr1 haplotypes (YFSND and YYSNY) occurred rarely. The results suggest that the high prevalence of mutant pfcrt CVIET haplotype is in agreement with low clinical efficacy of chloroquine observed in earlier studies and that the double pfdhfr mutant AICNI and single pfdhps mutant SGKAA are currently the predominant haplotypes associated
Woodcock, D. M.; Linsenmeyer, M. E.; Chojnowski, G.; Kriegler, A. B.; Nink, V.; Webster, L. K.; Sawyer, W. H.
Cremophor EL, a pharmacologically inactive solubilising agent, has been shown to reverse multidrug resistance (MDR). Using flow cytometric evaluation of equilibrium intracellular levels of daunorubicin (DNR), we found that eight other surface active agents will also reverse MDR. All the active detergents contain polyethoxylated moieties but have no similarities in their hydrophobic components. The properties of three polyethoxylated surfactants that showed the lowest toxicities, Cremophor, Tween 80 and Solutol HS15, were examined in more detail. The concentrations of Tween 80 and Solutol required to reverse DNR exclusion were 10-fold lower than for Cremophor. However while concentrations greater than or equal to 1:10(2) of the former two surfactants resulted in breakdown of cells, even 1:10 of Cremophor did not lyse cells. Studies of the effects of Cremophor on the uptake and efflux of DNR in normal and MDR cell types showed that Cremophor increases intracellular DNR primarily by locking the rapid efflux from the cells. This blockage of drug efflux may be mediated by a substantial alteration in the fluidity of cell membranes induced by Cremophor, as shown by decreased fluorescence anisotropy of a membrane probe. Consistent with these data, coinjection of adriamycin plus Cremophor into mice carrying a multidrug resistant P388 transplantable tumour significantly increased the survival time of the mice compared with adriamycin treatment alone. PMID:1637678
Raphael Silveira Vidal
Full Text Available Cancer outcome has improved since introduction of target therapy. However, treatment success is still impaired by the same drug resistance mechanism of classical chemotherapy, known as multidrug resistance (MDR phenotype. This phenotype promotes resistance to drugs with different structures and mechanism of action. Recent reports have shown that resistance acquisition is coupled to metabolic reprogramming. High-gene expression, increase of active transport, and conservation of redox status are one of the few examples that increase energy and substrate demands. It is not clear if the role of this metabolic shift in the MDR phenotype is related to its maintenance or to its induction. Apart from the nature of this relation, the metabolism may represent a new target to avoid or to block the mechanism that has been impairing treatment success. In this mini-review, we discuss the relation between metabolism and MDR resistance focusing on the multiple non-metabolic functions that enzymes of the glycolytic pathway are known to display, with emphasis with the diverse activities of glyceraldehyde-3-phosphate dehydrogenase.
Chim W Chan
Full Text Available Nearly one million deaths are attributed to malaria every year. Recent reports of multi-drug treatment failure of falciparum malaria underscore the need to understand the molecular basis of drug resistance. Multiple mutations in the Plasmodium falciparum chloroquine resistance transporter (pfcrt are involved in chloroquine resistance, but the evolution of complex haplotypes is not yet well understood. Using over 4,500 archival human serum specimens collected from 19 Pacific populations between 1959 and 1979, the period including and just prior to the appearance of chloroquine treatment failure in the Pacific, we PCR-amplified and sequenced a portion of the pfcrt exon 2 from 771 P. falciparum-infected individuals to explore the spatial and temporal variation in falciparum malaria prevalence and the evolution of chloroquine resistance. In the Pacific, the prevalence of P. falciparum varied considerably across ecological zones. On the island of New Guinea, the decreases in prevalence of P. falciparum in coastal, high-transmission areas over time were contrasted by the increase in prevalence during the same period in the highlands, where transmission was intermittent. We found 78 unique pfcrt haplotypes consisting of 34 amino acid substitutions and 28 synonymous mutations. More importantly, two pfcrt mutations (N75D and K76T implicated in chloroquine resistance were present in parasites from New Hebrides (now Vanuatu eight years before the first report of treatment failure. Our results also revealed unexpectedly high levels of genetic diversity in pfcrt exon 2 prior to the historical chloroquine resistance selective sweep, particularly in areas where disease burden was relatively low. In the Pacific, parasite genetic isolation, as well as host acquired immune status and genetic resistance to malaria, were important contributors to the evolution of chloroquine resistance in P. falciparum.
George, A M
In Gram-negative bacteria, multidrug resistance is a term that is used to describe mechanisms of resistance by chromosomal genes that are activated by induction or mutation caused by the stress of exposure to antibiotics in natural and clinical environments. Unlike plasmid-borne resistance genes, there is no alteration or degradation of drugs or need for genetic transfer. Exposure to a single drug leads to cross-resistance to many other structurally and functionally unrelated drugs. The only mechanism identified for multidrug resistance in bacteria is drug efflux by membrane transporters, even though many of these transporters remain to be identified. The enteric bacteria exhibit mostly complex multidrug resistance systems which are often regulated by operons or regulons. The purpose of this review is to survey molecular mechanisms of multidrug resistance in enteric and other Gram-negative bacteria, and to speculate on the origins and natural physiological functions of the genes involved.
Bhumiratana, Adisak; Intarapuk, Apiradee; Sorosjinda-Nunthawarasilp, Prapa; Maneekan, Pannamas; Koyadun, Surachart
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. PMID:23865048
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.
Dhingra, V.K.; Arora, V.K.; Rajpal, S.
This is a case report of 26 years old pregnant woman with multidrug-resistant tuberculosis (MDR TB), treated at outpatient department of New Delhi Tuberculosis (NDTB) Centre, India with second line agents. Before presentation at NDTB Centre, she had been treated with first line drugs for approximately one and-a-half-year, including category II re-treatment DOTS regimen under RNTCP. Patient conceived twice during her anti-TB treatment. The first one was during her category II treatment, when put on second line drugs. We describe congenital abnormalities documented in her second child exposed in-utero to second line anti-tubercular drugs with a brief review of treatment of MDR TB in pregnancy. (author)
Sá, Juliana Martha; Twu, Olivia; Hayton, Karen; Reyes, Sahily; Fay, Michael P.; Ringwald, Pascal; Wellems, Thomas E.
Chloroquine (CQ) resistance (CQR) in Plasmodium falciparum originated from at least six foci in South America, Asia, and Oceania. Malaria parasites from these locations exhibit contrasting resistance phenotypes that are distinguished by point mutations and microsatellite polymorphisms in and near the CQR transporter gene, pfcrt, and the multidrug resistance transporter gene, pfmdr1. Amodiaquine (AQ), a 4-aminoquinoline related to CQ, is recommended and often used successfully against CQ-resistant P. falciparum in Africa, but it is largely ineffective across large regions of South America. The relationship of different pfcrt and pfmdr1 combinations to these drug-resistant phenotypes has been unclear. In two P. falciparum genetic crosses, particular pfcrt and pfmdr1 alleles from South America interact to yield greater levels of resistance to monodesethylamodiaquine (MDAQ; the active metabolite of AQ) than to CQ, whereas a pfcrt allele from Southeast Asia and Africa is linked to greater CQ than MDAQ resistance with all partner pfmdr1 alleles. These results, together with (i) available haplotype data from other parasites; (ii) evidence for an emerging focus of AQ resistance in Tanzania; and (iii) the persistence of 4-aminoquinoline-resistant parasites in South America, where CQ and AQ use is largely discontinued, suggest that different histories of drug use on the two continents have driven the selection of distinct suites of pfcrt and pfmdr1 mutations. Increasing use of AQ in Africa poses the threat of a selective sweep of highly AQ-resistant, CQ-resistant parasites with pfcrt and pfmdr1 mutations that are as advantaged and persistent as in South America. PMID:19884511
VIVIAN M. RUMJANEK
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
Hendrikse, N.H.; Franssen, E.J.F.; Graaf, W.T.A. van der; Vries, E.G.E. de; Vaalburg, W.
Various mechanisms are involved in multidrug resistance (MDR) for chemotherapeutic drugs, such as the drug efflux pumps, P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP). In this review the mechanisms involved in MDR are described and results are reviewed with particular attention to the in vivo imaging of Pgp and MRP. Various detection assays provide information about the presence of drug efflux pumps at the mRNA and protein levels. However, these methods do not yield information about the dynamic function of Pgp and MRP in vivo. For the study of Pgp- and MRP-mediated transport, single-photon emission tomography (SPET) and positron emission tomography (PET) are available. Technetium-99m sestamibi is a substrate for Pgp and MRP, and has been used in clinical studies for tumour imaging, and to visualize blockade of Pgp-mediated transport after modulation of the Pgp pump. Other 99m Tc radiopharmaceuticals, such as 99m Tc-tetrofosmin and several 99 Tc-Q complexes, are also substrates for Pgp, but to date only results from in vitro and animal studies are available for these compounds. Several agents, including [ 11 C]colchicine, [ 11 C]verapamil and [ 11 C]daunorubicin, have been evaluated for the quantification of Pgp-mediated transport with PET in vivo. The results suggest that radiolabelled colchicine, verapamil and daunorubicin are feasible substrates with which to image Pgp function in tumours. Uptake of [ 11 C]colchicine and [ 11 C]verapamil is relatively high in the chest area, reducing the value of both tracers for monitoring Pgp-mediated drug transport in tumours located in this region. In addition, it has to be borne in mind that only comparison of Pgp-mediated transport of radioalabelled substrates in the absence and in the presence of Pgp blockade gives quantitative information on Pgp-mediated pharmacokinetics. Leukotrienes are specific substrates for MRP. Therefore, N-[ 11 C]acetyl-leukotriene E 4 provides an opportunity to study MRP
Risk factors for multidrug resistant tuberculosis patients in Amhara National ... risk factors of MDR-TB patients in Amhara National Regional State, Ethiopia. ... strict adherence to directly observed therapy, appropriate management of TB ...
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.
Yang Jun; Zhou Xinhua; Li Xi; Fu Yuhong; Zheng Suhua; Lv Pingxin; Ma Daqing
Objective: To evaluate the imaging features of multidrug-resistant tuberculosis by collecting multidrug-resistant tuberculosis verified by test of drug-sensitivity, which defined as resistance to three anti-tuberculosis drugs. Methods:Fifty-one cases of multidrug-resistant tuberculosis were categorized as group of observed, and 46 cases of drug sensitive tuberculosis were categorized as control. Cultures were positive for Mycobacterium tuberculosis in all cases with no other illness such as diabetes mellitus. All patients had chest radiographs available for review, while 64 cases had tomography and 30 cases had CT during the same time. All images were analyzed by three of the radiologists, disagreement among them was discussed and a consensus was reached. Results: There was no difference in the distribution of lesions between the multidrug-resistant tuberculosis group and control group. However, the radiological findings in the multidrug-resistant tuberculosis group were significantly more common than in control group, such as multiple nodules (10 cases), disseminated foci (23 cases), cavity (9 cases), and complications (10 cases). Comparing the dynamic cases, deteriorating cases were more commonly seen in observed group than in control group, while improved cases were less in observed group than in control group. Conclusion: Multidrug-resistant tuberculosis is the most serious tuberculosis, which is characterized with significant activity, more disseminated foci, cavity, and complications. The lesion deteriorated while correct anti-tuberculosis treatment is applied. (authors)
Mallick, Prashant K; Sutton, Patrick L; Singh, Ruchi; Singh, Om P; Dash, Aditya P; Singh, Ashok K; Carlton, Jane M; Bhasin, Virendra K
Efforts to control malignant malaria caused by Plasmodium falciparum are hampered by the parasite's acquisition of resistance to antimalarial drugs, e.g., chloroquine. This necessitates evaluating the spread of chloroquine resistance in any malaria-endemic area. India displays highly variable malaria epidemiology and also shares porous international borders with malaria-endemic Southeast Asian countries having multi-drug resistant malaria. Malaria epidemiology in India is believed to be affected by two major factors: high genetic diversity and evolving drug resistance in P. falciparum. How transmission intensity of malaria can influence the genetic structure of chloroquine-resistant P. falciparum population in India is unknown. Here, genetic diversity within and among P. falciparum populations is analyzed with respect to their prevalence and chloroquine resistance observed in 13 different locations in India. Microsatellites developed for P. falciparum, including three putatively neutral and seven microsatellites thought to be under a hitchhiking effect due to chloroquine selection were used. Genetic hitchhiking is observed in five of seven microsatellites flanking the gene responsible for chloroquine resistance. Genetic admixture analysis and F-statistics detected genetically distinct groups in accordance with transmission intensity of different locations and the probable use of chloroquine. A large genetic break between the chloroquine-resistant parasite of the Northeast-East-Island group and Southwest group (FST=0.253, Pstructure for Indian P. falciparum population. Overall, the study suggests that transmission intensity can be an efficient driver for genetic differentiation at both neutral and adaptive loci across India. Copyright © 2013 Elsevier B.V. All rights reserved.
Mallick, Prashant K.; Sutton, Patrick L.; Singh, Ruchi; Singh, Om P.; Dash, Aditya P.; Singh, Ashok K.; Carlton, Jane M.; Bhasin, Virendra K.
Efforts to control malignant malaria caused by Plasmodium falciparum are hampered by the parasite’s acquisition of resistance to antimalarial drugs, e.g., chloroquine. This necessitates evaluating the spread of chloroquine resistance in any malaria-endemic area. India displays highly variable malaria epidemiology and also shares porous international borders with malaria-endemic Southeast Asian countries having multi-drug resistant malaria. Malaria epidemiology in India is believed to be affected by two major factors: high genetic diversity and evolving drug resistance in P. falciparum. How transmission intensity of malaria can influence the genetic structure of chloroquine-resistant P. falciparum population in India is unknown. Here, genetic diversity within and among P. falciparum populations is analyzed with respect to their prevalence and chloroquine resistance observed in 13 different locations in India. Microsatellites developed for P. falciparum, including three putatively neutral and seven microsatellites thought to be under a hitchhiking effect due to chloroquine selection were used. Genetic hitchhiking is observed in five of seven microsatellites flanking the gene responsible for chloroquine resistance. Genetic admixture analysis and F-statistics detected genetically distinct groups in accordance with transmission intensity of different locations and the probable use of chloroquine. A large genetic break between the chloroquine-resistant parasite of the Northeast-East-Island group and Southwest group (FST = 0.253, P<0.001) suggests a long period of isolation or a possibility of different origin between them. A pattern of significant isolation by distance was observed in low transmission areas (r = 0.49, P=0.003, N = 83, Mantel test). An unanticipated pattern of spread of hitchhiking suggests genetic structure for Indian P. falciparum population. Overall, the study suggests that transmission intensity can be an efficient driver for genetic differentiation
Full Text Available This case control study was conducted between January to June 2010 to determine the relationship between substance abuse and multidrug- resistant tuberculosis. A total of 73 cases were selected purposively, from culture- positive multidrug- resistant tuberculosis patients admitted in the National Institute of Diseases of the Chest and Hospital, Dhaka and compared with 81 un-matched controls, recruited from the cured patients of pulmonary tuberculosis who attended several DOTS centers of ‘Nagar Shastho Kendra’ under Urban Primary Health Care Project in Dhaka city. Data were collected by face to face interview and documents’ review, using a pre- tested structured questionnaire and a checklist. Multidrug- resistance was found to be associated with smoking status (χ2 = 11.76; p = 0.01 and panmasala use (χ2 = 8.28; p = 0.004. The study also revealed that alcohol consumption and other substance abuse such as jarda, sadapata, gul, snuff, heroine, cannabis, injectable drugs was not associated with the development of multidrug- resistant tuberculosis. Relationship between substance abuse and multidrug- resistant tuberculosis are more or less similar in the developing countries. Bangladesh is not out of this trend. The present study revealed the same fact, which warrants actions targeting specific factors. Further study is recommended to assess the magnitude and these factors related to the development of multidrug- resistant tuberculosis in different settings in our country. Ibrahim Med. Coll. J. 2012; 6(2: 50-54
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.
Gatton, Michelle L.; Martin, Laura B; Cheng, Qin
The development of resistance to sulfadoxine-pyrimethamine by Plasmodium parasites is a major problem for the effective treatment of malaria, especially P. falciparum malaria. Although the molecular basis for parasite resistance is known, the factors promoting the development and transmission of these resistant parasites are less clear. This paper reports the results of a quantitative comparison of factors previously hypothesized as important for the development of drug resistance, drug dosag...
Günther, G.; van Leth, F.; Altet, N.; Dedicoat, M.; Duarte, R.; Gualano, G.; Kunst, H.; Muylle, I.; Spinu, V.; Tiberi, S.; Viiklepp, P.; Lange, C.; Alexandru, S.; Cernenco, I.; Ciobanu, A.; Donica, A.; Cayla, J.; Fina, L.; Galvao, M. L. de Souza; Maldonado, J.; Avsar, K.; Bang, D.; Andersen, A. B.; Barbuta, R.; Dubceac, V.; Bothamley, G.; Crudu, V.; Davilovits, M.; Atunes, A.; de Lange, W.; Leimane, V.; Rusmane, L.; de Lorenzo, S.; Cuppen, F.; de Guchtenaire, I.; Magis-Escurra, C.; McLaughlin, A.-M.; Meesters, R.; te Pas, M.; Prins, B.; Mütterlein, R.; Kotrbova, J.; Polcová, V.; Vasakova, M.; Pontali, E.; Rumetshofer, R.; Rowhani, M.; Skrahina, A.; Avchinko, V.; Katovich, D.
The emergence of drug-resistant tuberculosis (TB) is a challenge to TB control in Europe. We evaluated second-line drug susceptibility testing in Mycobacterium tuberculosis isolates from patients with multidrug-resistant, pre-extensively drug-resistant (pre-XDR-TB) and XDR-TB at 23 TBNET sites in 16
Infections of methicillin-resistant Staphylococcus aureus (MRSA) are becoming an increasingly concerning clinical problem. The aim of this study was to assess the development of multidrug resistant strains of MRSA from clinical samples andpossibilities for reducing resistance. This study included a total of seventy-five (75) ...
Bassetti, Matteo; Peghin, Maddalena; Pecori, Davide
Multidrug-resistant (MDR) Enterobacteriaceae are often related to the production of extended-spectrum b-lactamases (ESBLs) and carbapenemase-producing Enterobacteriaceae (CRE), and represent an increasing global threat. Recommendations for the therapeutic management of MDR-related infections, however, are mainly derived from retrospective and nonrandomized prospective studies. The aim of this review is to discuss the challenges in the treatment of patients with infections because of MDR Enterobacteriaceae and provide an expert opinion while awaiting for more definitive data. To avoid the selection of carbapenemase-producing Enterobacteriaceae, carbapenem-sparing strategies should be considered. B-lactams/b-lactamase inhibitors, mainly piperacillin-tazobactam, minimum inhibitory concentration (MIC) 16/4mg/ml or less represents the best alternative to carbapenems for the treatment of ESBL-producing strains. Overall, combination therapy may be preferred over monotherapy for CRE. The combination of a carbapenem-containing regimen with colistin or high-dose tigecycline or aminoglycoside can be administered at high-dose prolonged infusion with therapeutic drug monitoring for the treatment of CRE with MIC for meropenem 8-16 mg/l or less. For MIC higher than 8-16 mg/l, the use of meropenem should be avoided and various combination therapies based on the in-vitro susceptibility of antimicrobials (e.g., colistin, high-dose tigecycline, fosfomycin, and aminoglycosides) should be selected. Carbapenem-sparing strategies should be used, when feasible, for ESBL infections. The majority of available nonrandomized studies highlight that combination for CRE seem to offer some therapeutic advantage over monotherapy. Strict infection control measures toward MDR Gram-negative pathogens remain necessary while awaiting for new treatment options.
Sindani, Ireneaus; Fitzpatrick, Christopher; Falzon, Dennis; Suleiman, Bashir; Arube, Peter; Adam, Ismail; Baghdadi, Samiha; Bassili, Amal; Zignol, Matteo
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.
Sindani, Ireneaus; Fitzpatrick, Christopher; Falzon, Dennis; Suleiman, Bashir; Arube, Peter; Adam, Ismail; Baghdadi, Samiha; Bassili, Amal
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. PMID:23621911
Background: Drug resistant Tuberculosis is well documented worldwide and is associated with increasing morbidity and mortality complicating Tuberculosis control with increasing costs of managing the disease. Broad. Objective: To describe clinical and laboratory characteristics of multi-drug resistant Tuberculosis ...
Chemotherapy is a main treatment for cancer, while multidrug-resistance is the main reason for chemotherapy failure, and tumor relapse and metastasis. Cancer stem cells or cancer stem-like cells (CSCs) are a small subset of cancer cells, which may be inherently resistant to the cytotoxic effect of chemotherapy.
The ability of Escherichia coli and Klebsiella aerogenes to form biofilms was most affected. There was little inhibition of biofilm formation by the biocides on Staphylococcus aureus. This study has shown a relationship between biocide and multidrug resistance. Keywords: Biocides, Multi drug resistance, sodium hypochlorite, ...
Duru, Valentine; Witkowski, Benoit; Ménard, Didier
Artemisinin-based combination therapies (ACTs) are the cornerstone of current strategies for fighting malaria. Over the last decade, ACTs have played a major role in decreasing malaria burden. However, this progress is being jeopardized by the emergence of artemisinin-resistant Plasmodium falciparum parasites. Artemisinin resistance was first detected in western Cambodia in 2008 and has since been observed in neighboring countries in southeast Asia. The problem of antimalarial drug resistance has recently worsened in Cambodia, with reports of parasites resistant to piperaquine, the latest generation of partner drug used in combination with dihydroartemisinin, leading to worrying rates of clinical treatment failure. The monitoring and the comprehension of both types of resistance are crucial to prevent the spread of multidrug-resistant parasites outside southeast Asia, and particularly to Africa, where the public health consequences would be catastrophic. To this end, new tools are required for studying the biological and molecular mechanisms underlying resistance to antimalarial drugs and for monitoring the geographic distribution of the resistant parasites. In this review, we detail the major advances in our understanding of resistance to artemisinin and piperaquine and define the challenges that the malaria community will have to face in the coming years. PMID:27928074
Full Text Available Shigella enteritis remains an important cause of mortality and morbidity in all age groups, in developing as well as developed countries. Owing to the emerging resistance to multiple antibiotics among Shigella spp., it has been recognized as a major global public health concern and warrants constant monitoring of its resistance pattern. We report a case of segmental ileitis caused by non.-ESBL producing multidrug resistant Shigella flexneri in an infant clinically mimicking intussusception, which was effectively treated by ceftriaxone.
Arendrup, Maiken Cavling; Patterson, Thomas F
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: email@example.com.
Blanco, Paula; Hernando-Amado, Sara; Reales-Calderon, Jose Antonio; Corona, Fernando; Lira, Felipe; Alcalde-Rico, Manuel; Bernardini, Alejandra; Sanchez, Maria Blanca; Martinez, Jose Luis
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.
Jahnsen, Rasmus D; Sandberg-Schaal, Anne; Vissing, Karina Juul
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 peptidomimetics...... cells. Thus, lead compounds with a high selectivity toward killing of clinically important multidrug-resistant E. coli were identified....
Jailton Lobo da Costa Lima
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.
Background: Multidrug-resistant Escherichia coli (MDR E. coli) has become a major public health concern in Sudan and many countries, causing failure in treatment with consequent huge health burden. Objectives: To determine the prevalence and susceptibility of MDR E. coli isolated from patients in hospitals at Khartoum ...
Bolhuis, Mathieu S.; van Altena, Richard; van Soolingen, Dick; de Lange, Wiel C. M.; Uges, Donald R. A.; van der Werf, Tjip S.; Kosterink, Jos G. W.; Alffenaar, Jan-Willem C.
The use of linezolid for the treatment of multidrug-resistant tuberculosis is limited by dose-and time-dependent toxicity. Recently, we reported a case of pharmacokinetic drug drug interaction between linezolid and clarithromycin that resulted in increased linezolid exposure. The aim of this
The iron metabolism plays a key role in the progression of active Tuberculosis. Several studies have shown a link between iron metabolism disorders an active tuberculosis. The aim of this study was to explore the iron metabolism of 100 patients with multidrug-resistant tuberculosis. (MDR-TB) treated with second ...
Jahnsen, Rasmus D; Frimodt-Møller, Niels; Franzyk, Henrik
Novel remedies in the battle against multidrug-resistant bacterial strains are urgently needed, and one obvious approach involves antimicrobial peptides and mimics hereof. The impact of a- and ß-peptoid as well as ß(3)-amino acid modifications on the activity profile against ß-lactamase-producing...
Diacon, Andreas H.; Pym, Alexander; Grobusch, Martin P.; de Los Rios, Jorge M.; Gotuzzo, Eduardo; Vasilyeva, Irina; Leimane, Vaira; Andries, Koen; Bakare, Nyasha; de Marez, Tine; Haxaire-Theeuwes, Myriam; Lounis, Nacer; Meyvisch, Paul; de Paepe, Els; van Heeswijk, Rolf P. G.; Dannemann, Brian; Rolla, Valeria; Dalcomo, Margreth; Gripp, Karla; Escada, Rodrigo; Tavares, Isabel; Borga, Liamar; Thomas, Aleyamma; Rekha, Banu; Nair, Dina; Chandrasekar, Chockalingam; Parthasarathy, Ramavaran Thiruvengadaraj; Sekhar, Gomathi; Ganesh, Krishnamoorthy; Rajagopalan, Krishnakumar; Rajapandian, Gangadevi; Dorairajalu, Rajendran; Sharma, Surendra Kumar; Banavaliker, Jayant; Kadhiravan, Tamilarasu; Gulati, Vinay; Mahmud, Hanif; Gupta, Arvind; Bhatnagar, Anuj; Jain, Vipin; Hari, Smriti; Gupta, Yogesh Kumar; Vaid, Ashok; Cirule, Andra; Dravniece, Gunta; Skripconoka, Vija; Kuksa, Liga; Kreigere, Edite; Ramos, Carlos Rafael Seas; Amat y Leon, Ivan Arapovic
BACKGROUND Bedaquiline (Sirturo, TMC207), a diarylquinoline that inhibits mycobacterial ATP synthase, has been associated with accelerated sputum-culture conversion in patients with multidrug-resistant tuberculosis, when added to a preferred background regimen for 8 weeks. METHODS In this phase 2b
Background: Multidrug resistant tuberculosis (MDR-TB) remains is an important public health problem in developing world. We conducted this study to determine risk factors associated with MDR-TB and drug susceptibility pattern to second line drug among MDR TB patients in Tanzania. Methods: Unmatched case control ...
The iron metabolism plays a key role in the progression of active Tuberculosis. Several studies have shown a link between iron metabolism disorders an active tuberculosis. The aim of this study was to explore the iron metabolism of 100 patients with multidrug-resistant tuberculosis (MDR-TB) treated with second generation ...
Kunjachan, S.; Blauz, A.; Möckel, D.; Theek, B.; Kiessling, F.; Etrych, Tomáš; Ulbrich, K.; van Bloois, L.; Storm, G.; Bartosz, G.; Rychlik, B.; Lammers, T.
Roč. 45, č. 4 (2012), s. 421-428 ISSN 0928-0987 R&D Projects: GA AV ČR IAA400500806 Institutional research plan: CEZ:AV0Z40500505 Keywords : cancer * nanomedicine * multidrug resistance Subject RIV: CD - Macromolecular Chemistry Impact factor: 2.987, year: 2012
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.
Hargreaves, S.; Lönnroth, K.; Nellums, L. B.
Multidrug-resistant tuberculosis (MDR-TB) in low-incidence countries in Europe is more prevalent among migrants than the native population. The impact of the recent increase in migration to EU and EEA countries with a low incidence of TB (
Nseir, S; Ader, F; Marquette, C-H; Durocher, A
During the last two decades, fluoroquinolone use has significantly increased in Europe and in the USA. This could be explained by the arrival of newer fluoroquinolones with antipneumoccal activity. Increased use of fluoroquinolones is associated with higher rates of bacterial resistance to these antibiotics. Resistance of Gram-negative bacilli to fluoroquinolones is increasing in industrialized countries. In addition, fluoroquinolone use has been identified as a risk factor for colonization and infection to methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumanni, extending-spectrum beta-lactamase producing Gram negative bacilli, and multidrug-resistant bacteria. Nosocomial infections due to multidrug-resistant bacteria are associated with higher mortality and morbidity rates. This could be related to more frequent inappropriate initial antibiotic treatment in these patients. Limiting the use of fluoroquinolones, limiting the duration of treatment with fluoroquinolones, and using appropriate dosage of these antibiotics could be suggested to reduce resistance to these antibiotics and to reduce the emergence of multidrug-resistant bacteria.
Ayesh, S; Litman, Thomas; Stein, W D
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...
Griffing, Sean; Syphard, Luke; Sridaran, Sankar; McCollum, Andrea M.; Mixson-Hayden, Tonya; Vinayak, Sumiti; Villegas, Leopoldo; Barnwell, John W.; Escalante, Ananias A.; Udhayakumar, Venkatachalam
Molecular tools are valuable for determining evolutionary history and the prevalence of drug-resistant malaria parasites. These tools have helped to predict decreased sensitivity to antimalarials and fixation of multidrug resistance genotypes in some regions. In order to assess how historical drug policies impacted Plasmodium falciparum in Venezuela, we examined molecular changes in genes associated with drug resistance. We examined pfmdr1 and pfcrt in samples from Sifontes, Venezuela, and integrated our findings with earlier work describing dhfr and dhps in these samples. We characterized pfmdr1 genotypes and copy number variation, pfcrt genotypes, and proximal microsatellites in 93 samples originating from surveillance from 2003 to 2004. Multicopy pfmdr1 was found in 12% of the samples. Two pfmdr1 alleles, Y184F/N1042D/D1246Y (37%) and Y184F/S1034C/N1042D/D1246Y (63%), were found. These alleles share ancestry, and no evidence of strong selective pressure on mutations was found. pfcrt chloroquine resistance alleles are fixed with two alleles: StctVMNT (91%) and SagtVMNT (9%). These alleles are associated with strong selection. There was also an association between pfcrt, pfmdr1, dhfr, and dhps genotypes/haplotypes. Duplication of pfmdr1 suggests a potential shift in mefloquine sensitivity in this region, which warrants further study. A bottleneck occurred in P. falciparum in Sifontes, Venezuela, and multidrug resistance genotypes are present. This population could be targeted for malaria elimination programs to prevent the possible spread of multidrug-resistant parasites. PMID:20145087
Full Text Available Candida aurisis an emerging multidrug-resistant pathogen that can be difficult to identify using traditional biochemical methods. C. auris is capable of causing invasive fungal infections, particularly among hospitalized patients with significant medical comorbidities. Echinocandins are the empiric drugs of choice for C. auris, although not all isolates are susceptible and resistance may develop on therapy. Nosocomial C. auris outbreaks have been reported in a number of countries and aggressive infection control measures are paramount to stopping transmission.
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.
Walther, Birgit; Tedin, Karsten; Lübke-Becker, Antina
Although the problems associated with healthcare-associated infections (HAI) and the emergence of zoonotic and multidrug-resistant pathogens in companion animal (dogs, cats and horses) medicine have been well-known for decades, current progress with respect to practical implementation of infection control programs in veterinary clinics has been limited. Clinical outbreak events reported for methicillin-resistant Staphylooccus aureus (MRSA) and Staphylococcus pseudintermedius (MRSP), extended spectrum beta-lactamase (ESBL)-producing Escherichia coli and multidrug-resistant (MDR) Salmonella Serovars indicate the necessity of infection control strategies for protecting animal patients at risk as well as veterinary personnel. The close bond between humans and their companion animals provides opportunities for exchange of microorganisms, including MDR pathogens. This particular aspect of the "One Health" idea requires more representative surveillance efforts and infection control strategies with respect to animal-species specific characters. Copyright © 2016 Elsevier B.V. All rights reserved.
Peek, Ron; van Gool, Tom; Panchoe, Daynand; Greve, Sophie; Bus, Ellen; Resida, Lesley
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
Fançony, Cláudia; Brito, Miguel; Gil, Jose Pedro
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.
Boyanova, Lyudmila; Evstatiev, Ivailo; Gergova, Galina; Yaneva, Penka; Mitov, Ivan
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. Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
Rijpma, Sanna R; van der Velden, Maarten; Annoura, Takeshi; Matz, Joachim M; Kenthirapalan, Sanketha; Kooij, Taco W A; Matuschewski, Kai; van Gemert, Geert-Jan; van de Vegte-Bolmer, Marga; Siebelink-Stoter, Rianne; Graumans, Wouter; Ramesar, Jai; Klop, Onny; Russel, Frans G M; Sauerwein, Robert W; Janse, Chris J; Franke-Fayard, Blandine M; Koenderink, Jan B
Multidrug resistance (MDR) proteins belong to the B subfamily of the ATP Binding Cassette (ABC) transporters, which export a wide range of compounds including pharmaceuticals. In this study, we used reverse genetics to study the role of all seven Plasmodium MDR proteins during the life cycle of malaria parasites. Four P. berghei genes (encoding MDR1, 4, 6 and 7) were refractory to deletion, indicating a vital role during blood stage multiplication and validating them as potential targets for antimalarial drugs. Mutants lacking expression of MDR2, MDR3 and MDR5 were generated in both P. berghei and P. falciparum, indicating a dispensable role for blood stage development. Whereas P. berghei mutants lacking MDR3 and MDR5 had a reduced blood stage multiplication in vivo, blood stage growth of P. falciparum mutants in vitro was not significantly different. Oocyst maturation and sporozoite formation in Plasmodium mutants lacking MDR2 or MDR5 was reduced. Sporozoites of these P. berghei mutants were capable of infecting mice and life cycle completion, indicating the absence of vital roles during liver stage development. Our results demonstrate vital and dispensable roles of MDR proteins during blood stages and an important function in sporogony for MDR2 and MDR5 in both Plasmodium species. © 2016 John Wiley & Sons Ltd.
Bamaga, Omar A A; Mahdy, Mohammed A K; Lim, Yvonne A L
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. Copyright © 2015 Elsevier B.V. All rights reserved.
Günther, Gunar; van Leth, Frank; Alexandru, Sofia
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 non-MDR TB were enrolled at 23 centers in 16 countries in Europe during 2010-2011. A total of 52.4% of MDR TB patients had never been treated for TB, which suggests primary transmission of MDR M. tuberculosis. At initiation of treatment for MDR TB, 59.7% of M. tuberculosis strains tested were...
Jana, Bimal; Cain, Amy K; Doerrler, William T; Boinett, Christine J; Fookes, Maria C; Parkhill, Julian; Guardabassi, Luca
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.
Amato, Roberto; Pearson, Richard D; Almagro-Garcia, Jacob; Amaratunga, Chanaki; Lim, Pharath; Suon, Seila; Sreng, Sokunthea; Drury, Eleanor; Stalker, Jim; Miotto, Olivo; Fairhurst, Rick M; Kwiatkowski, Dominic P
Antimalarial resistance is rapidly spreading across parts of southeast Asia where dihydroartemisinin-piperaquine is used as first-line treatment for Plasmodium falciparum malaria. The first published reports about resistance to antimalarial drugs came from western Cambodia in 2013. Here, we analyse genetic changes in the P falciparum population of western Cambodia in the 6 years before those reports. We analysed genome sequence data on 1492 P falciparum samples from 11 locations across southeast Asia, including 464 samples collected in western Cambodia between 2007 and 2013. Different epidemiological origins of resistance were identified by haplotypic analysis of the kelch13 artemisinin resistance locus and the plasmepsin 2-3 piperaquine resistance locus. We identified more than 30 independent origins of artemisinin resistance, of which the KEL1 lineage accounted for 140 (91%) of 154 parasites resistant to dihydroartemisinin-piperaquine. In 2008, KEL1 combined with PLA1, the major lineage associated with piperaquine resistance. By 2013, the KEL1/PLA1 co-lineage had reached a frequency of 63% (24/38) in western Cambodia and had spread to northern Cambodia. The KEL1/PLA1 co-lineage emerged in the same year that dihydroartemisinin-piperaquine became the first-line antimalarial drug in western Cambodia and spread rapidly thereafter, displacing other artemisinin-resistant parasite lineages. These findings have important implications for management of the global health risk associated with the current outbreak of multidrug-resistant malaria in southeast Asia. Wellcome Trust, Bill & Melinda Gates Foundation, Medical Research Council, UK Department for International Development, and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Miotto, Olivo; Almagro-Garcia, Jacob; Manske, Magnus; MacInnis, Bronwyn; Campino, Susana; Rockett, Kirk A; Amaratunga, Chanaki; Lim, Pharath; Suon, Seila; Sreng, Sokunthea; Anderson, Jennifer M; Duong, Socheat; Nguon, Chea; Chuor, Char Meng; Saunders, David; Se, Youry; Lon, Chantap; Fukuda, Mark M; Amenga-Etego, Lucas; Hodgson, Abraham VO; Asoala, Victor; Imwong, Mallika; Takala-Harrison, Shannon; Nosten, Francois; Su, Xin-zhuan; Ringwald, Pascal; Ariey, Frédéric; Dolecek, Christiane; Hien, Tran Tinh; Boni, Maciej F; Thai, Cao Quang; Amambua-Ngwa, Alfred; Conway, David J; Djimdé, Abdoulaye A; Doumbo, Ogobara K; Zongo, Issaka; Ouedraogo, Jean-Bosco; Alcock, Daniel; Drury, Eleanor; Auburn, Sarah; Koch, Oliver; Sanders, Mandy; Hubbart, Christina; Maslen, Gareth; Ruano-Rubio, Valentin; Jyothi, Dushyanth; Miles, Alistair; O’Brien, John; Gamble, Chris; Oyola, Samuel O; Rayner, Julian C; Newbold, Chris I; Berriman, Matthew; Spencer, Chris CA; McVean, Gilean; Day, Nicholas P; White, Nicholas J; Bethell, Delia; Dondorp, Arjen M; Plowe, Christopher V; Fairhurst, Rick M; Kwiatkowski, Dominic P
We describe an analysis of genome variation in 825 Plasmodium falciparum samples from Asia and Africa that reveals an unusual pattern of parasite population structure at the epicentre of artemisinin resistance in western Cambodia. Within this relatively small geographical area we have discovered several distinct but apparently sympatric parasite subpopulations with extremely high levels of genetic differentiation. Of particular interest are three subpopulations, all associated with clinical resistance to artemisinin, which have skewed allele frequency spectra and remarkably high levels of haplotype homozygosity, indicative of founder effects and recent population expansion. We provide a catalogue of SNPs that show high levels of differentiation in the artemisinin-resistant subpopulations, including codon variants in various transporter proteins and DNA mismatch repair proteins. These data provide a population genetic framework for investigating the biological origins of artemisinin resistance and for defining molecular markers to assist its elimination. PMID:23624527
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
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
Shankar Thangamani; Waleed Younis; Mohamed N. Seleem
Novel antimicrobials and new approaches to developing them are urgently needed. Repurposing already-approved drugs with well-characterized toxicology and pharmacology is a novel way to reduce the time, cost, and risk associated with antibiotic innovation. Ebselen, an organoselenium compound, is known to be clinically safe and has a well-known pharmacology profile. It has shown potent bactericidal activity against multidrug-resistant clinical isolates of staphylococcus aureus, including methic...
Mercado-Lubo, Regino; Zhang, Yuanwei; Zhao, Liang; Rossi, Kyle; Wu, Xiang; Zou, Yekui; Castillo, Antonio; Leonard, Jack; Bortell, Rita; Greiner, Dale L; Shultz, Leonard D; Han, Gang; McCormick, Beth A
Salmonella enterica serotype Typhimurium is a food-borne pathogen that also selectively grows in tumours and functionally decreases P-glycoprotein (P-gp), a multidrug resistance transporter. Here we report that the Salmonella type III secretion effector, SipA, is responsible for P-gp modulation through a pathway involving caspase-3. Mimicking the ability of Salmonella to reverse multidrug resistance, we constructed a gold nanoparticle system packaged with a SipA corona, and found this bacterial mimic not only accumulates in tumours but also reduces P-gp at a SipA dose significantly lower than free SipA. Moreover, the Salmonella nanoparticle mimic suppresses tumour growth with a concomitant reduction in P-gp when used with an existing chemotherapeutic drug (that is, doxorubicin). On the basis of our finding that the SipA Salmonella effector is fundamental for functionally decreasing P-gp, we engineered a nanoparticle mimic that both overcomes multidrug resistance in cancer cells and increases tumour sensitivity to conventional chemotherapeutics.
Tuberculose is een potentieel dodelijke infectieziekte die wordt veroorzaakt door de bacterie Mycobacterium tuberculosis. Een deel van de tuberculosepatiënten is besmet met multiresistente tuberculose. In het geval van multiresistente tuberculose is de bacterie resistent tegen de twee belangrijkste
Falzon, Dennis; Gandhi, Neel; Migliori, Giovanni B.; Sotgiu, Giovanni; Cox, Helen S.; Holtz, Timothy H.; Hollm-Delgado, Maria-Graciela; Keshavjee, Salmaan; Deriemer, Kathryn; Centis, Rosella; D'Ambrosio, Lia; Lange, Christoph G.; Bauer, Melissa; Menzies, Dick; Ahuja, S. D.; Ashkin, D.; Avendaño, M.; Banerjee, R.; Bauer, M.; Becerra, M. C.; Benedetti, A.; Burgos, M.; Centis, R.; Chan, E. D.; Chiang, C. Y.; Cobelens, F.; Cox, H.; D'Ambrosio, L.; de Lange, W. C. M.; DeRiemer, K.; Enarson, D.; Falzon, D.; Flanagan, K. L.; Flood, J.; Gandhi, N.; Garcia-Garcia, M. L.; Granich, R. M.; Hollm-Delgado, M. G.; Holtz, T. H.; Hopewell, P.; Iseman, M. D.; Jarlsberg, L. G.; Keshavjee, S.; Kim, H. R.; Koh, W. J.; Lancaster, J. L.; Lange, C.; Leimane, V.; Leung, C. C.; Li, J.
A meta-analysis for response to treatment was undertaken using individual data of multidrug-resistant tuberculosis (MDR-TB) (resistance to isoniazid and rifampicin) patients from 26 centres. The analysis assessed the impact of additional resistance to fluoroquinolones and/or second-line injectable
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.
Cleopas Martin Rumende
Diabetes mellitus has been a well-known risk factor for TB in the past. The global convergence of the accelerating type 2 DM pandemic, high TB prevalence and drug-resistant TB during the past couple of decades has become a serious challenge to clinicians worldwide. Over the past few years, some studies have shown that the treatment failure rate is higher in TB patients with DM as comorbidity. Moreover, there is significant association between DM an MDR-TB. There is higher chance of TB bacilli persistence to be present in sputum of pulmonary TB patient with DM than TB-only patient after 5 months treatment, and this persistence made it necessary for more longer treatment. Presence of DM in TB patients cause a longer period for sputum conversion, therefore it may become a major cause of poor treatment outcome in TB patients. Previous studies showed that a major mechanism for the emergence of drugs resistance in TB bacilli is random mutation in the bacterial genome and the pressure of selection by anti-TB drugs. Pulmonary TB in diabetic patients usually show higher mycobacterial loads at the initiation of treatment, hence they may have higher chance of bacillary mutation and the emergence of MDR-TB with the presenting of higher bacterial loads, longer treatment is needed to clear the bacteria. Therefore, it is not suprising that a higher chance of MDR-TB patients could be find in those patients. A pharmacokinetic study noted that plasma levels of rifampicin were 53% lower in TB patients with diabetes, which might affect treatment outcomes. Inadequate immune respons of the host may also be important in this negative effect of diabetes. Depressed production of IFN-γ in diabetic patients is related to decreasing immune response to TB infection. Reduction of IL-12 response to mycobacterial stimulation in leukocytes from TB with diabetic patients suggest a compromise of innate immune response.
More, Arun Punaji; Nagdawane, Ramkrishna Panchamrao; Gangurde, Aniket K
Objective: In India, increasing prevalence of multi-drug resistant tuberculosis (MDR) has aggravated the control oftuberculosis problem. In many urban and semi-urban regions of India, no surveillance data of multidrug resistance inMycobacterium tuberculosisis available.Methods: A surveillance study on multidrug resistance was carried out in semi-urban and rural regions in and aroundNashik City of Maharashtra, India. The surveillance study was conducted in this region found that the prevalence...
Mitchell, J.B.; Gamson, J.; Russo, A.; Friedman, N.; DeGraff, W.; Carmichael, J.; Glatstein, E.
The inherent cellular radiosensitivity of a Chinese hamster ovary pleiotropic cell line that is multidrug resistant (CHRC5) was compared to that of its parental cell line (AuxB1). Radiation survival curve parameters n and D0 were 4.5 and 1.1 Gy, respectively, for the CHRC5 line and 5.0 and 1.2 Gy, respectively, for the parental line. Thus, the inherent radiosensitivity of the two lines was similar even though key intracellular free radical scavenging and detoxifying systems employing glutathione, glutathione transferase, and catalase produced enzyme levels that were 2.0-, 1.9-, and 1.9-fold higher, respectively, in the drug-resistant cell line. Glutathione depletion by buthionine sulfoximine resulted in the same extent of aerobic radiosensitization in both lines (approximately 10%). Incorporation of iododeoxyuridine into cellular DNA sensitized both cell lines to radiation. These studies indicate that pleiotropic drug resistance does not necessarily confer radiation resistance
Costa, E M; Silva, S; Vicente, S; Veiga, M; Tavaria, F; Pintado, M M
Over the last two decades worldwide levels of antibiotic resistance have risen leading to the appearance of multidrug resistant microorganisms. Acinetobacter baumannii is a known skin pathogen which has emerged as a major cause of nosocomial outbreaks due to its capacity to colonize indwelling medical devices and natural antibiotic resistance. With chitosan being an effective antimicrobial agent against antibiotic resistant microorganisms, the aim of this work was to access its potential as an alternative to traditional antimicrobials in the management of A. baumannii growth. What the results showed was that both chitosan MW's tested were active upon A. baumannii's planktonic and sessile growth. For planktonic growth MICs and MBCs were obtained at relatively low concentrations (0.5-2mg/mL) while for sessile growth chitosan proved to be an effective inhibitor of A. baumannii's adhesion and biofilm formation. Considering these results chitosan shows a high potential for control of A. baumannii infections. Copyright © 2017 Elsevier Ltd. All rights reserved.
Courtney, Colleen M.; Goodman, Samuel M.; McDaniel, Jessica A.; Madinger, Nancy E.; Chatterjee, Anushree; Nagpal, Prashant
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.
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.
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.
Thangamani, Shankar; Younis, Waleed; Seleem, Mohamed N
Novel antimicrobials and new approaches to developing them are urgently needed. Repurposing already-approved drugs with well-characterized toxicology and pharmacology is a novel way to reduce the time, cost, and risk associated with antibiotic innovation. Ebselen, an organoselenium compound, is known to be clinically safe and has a well-known pharmacology profile. It has shown potent bactericidal activity against multidrug-resistant clinical isolates of staphylococcus aureus, including methicillin- and vancomycin-resistant S. aureus (MRSA and VRSA). We demonstrated that ebselen acts through inhibition of protein synthesis and subsequently inhibited toxin production in MRSA. Additionally, ebselen was remarkably active and significantly reduced established staphylococcal biofilms. The therapeutic efficacy of ebselen was evaluated in a mouse model of staphylococcal skin infections. Ebselen 1% and 2% significantly reduced the bacterial load and the levels of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and monocyte chemo attractant protein-1 (MCP-1) in MRSA USA300 skin lesions. Furthermore, it acts synergistically with traditional antimicrobials. This study provides evidence that ebselen has great potential for topical treatment of MRSA skin infections and lays the foundation for further analysis and development of ebselen as a potential treatment for multidrug-resistant staphylococcal infections.
Hooijberg, J. H.; Broxterman, H. J.; Kool, M.; Assaraf, Y. G.; Peters, G. J.; Noordhuis, P.; Scheper, R. J.; Borst, P.; Pinedo, H. M.; Jansen, G.
Transfection of multidrug resistance proteins (MRPs) MRP1 and MRP2 in human ovarian carcinoma 2008 cells conferred a marked level of resistance to short-term (1-4 h) exposure to the polyglutamatable antifolates methotrexate (MTX; 21-74-fold), ZD1694 (4-138-fold), and GW1843 (101-156-fold). Evidence
Full Text Available Abstract 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 assessed. Results P. falciparum and P. vivax were observed in 69% and 31% of the patients, respectively. Pfdhfr triple mutations and pfdhfr/pfdhps quintuple mutations occurred in 87% and 86% of P. falciparum isolates, respectively. Pfcrt T76 was seen in all and pfmdr1 Y86 in 81% of P. falciparum. The P. vivax dhfr core mutations N117 and R58 were present in 94% and 74%, respectively. Conclusion These data point to an extraordinarily high frequency of drug-resistance mutations in both P. falciparum and P. vivax in southern Ethiopia, and strongly support that both SP and CQ are inadequate drugs for this region.
Doyle, Marjorie E
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
Lee, Jae Tae
Although diverse mechanisms are involved in multidrug resistance for chemotherapeutic drugs, the development of cellular P-glycoprotein(Pgp) and multidrug-resistance associated protein (MRP) are improtant factors in the chemotherapy failure to cancer. Various detection assays provide information about the presence of drug efflux pumps at the mRNA and protein levels. However these methods do not yield information about dynamic function of Pgp and MRP in vivo. Single photon emission tomograpy (SPECT) and positron emission tomograpy (PET) are available for the detection of Pgp and MRP-mediated transport. 99m Tc-sestaMIBI and other 99m Tc-radiopharmaceuticals are substrates for Pgp and MRP, and have been used in clinical studies of tumor imaging, and to visualize blockade of Pgp-mediated transport after modulation of Pgp pump. Colchicine, verapamil and daunorubicin labeled with 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- (11 C]acetyl-leukotriene E4 provides an opportunity to study MRP function non-invasively in vivo. Results obtained from recent publications are reviewed to confirm the feasibility of using SPECT and PET to study the functionality of MDR transportes in vivo
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.
Putman, M; van Veen, HW; Degener, JE; Konings, WN
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
Butin, Marine; Martins-Simões, Patricia; Rasigade, Jean-Philippe; Picaud, Jean-Charles; Laurent, Frédéric
A multidrug-resistant Staphylococcus capitis clone, NRCS-A, has been isolated from neonatal intensive care units in 17 countries throughout the world. S. capitis NRCS-A prevalence is high in some neonatal intensive care units in France. These data highlight the worldwide endemicity and epidemiologic relevance of this multidrug-resistant, coagulase-negative staphylococci clone.
Full Text Available Acinetobacter baumannii is a species of nonfermentative gram-negative bacteria commonly found in water and soil. This organism was susceptible to most antibiotics in the 1970s. It has now become a major cause of hospital-acquired infections worldwide due to its remarkable propensity to rapidly acquire resistance determinants to a wide range of antibacterial agents. Here we use a comparative genomic approach to identify the complete repertoire of resistance genes exhibited by the multidrug-resistant A. baumannii strain AYE, which is epidemic in France, as well as to investigate the mechanisms of their acquisition by comparison with the fully susceptible A. baumannii strain SDF, which is associated with human body lice. The assembly of the whole shotgun genome sequences of the strains AYE and SDF gave an estimated size of 3.9 and 3.2 Mb, respectively. A. baumannii strain AYE exhibits an 86-kb genomic region termed a resistance island--the largest identified to date--in which 45 resistance genes are clustered. At the homologous location, the SDF strain exhibits a 20 kb-genomic island flanked by transposases but devoid of resistance markers. Such a switching genomic structure might be a hotspot that could explain the rapid acquisition of resistance markers under antimicrobial pressure. Sequence similarity and phylogenetic analyses confirm that most of the resistance genes found in the A. baumannii strain AYE have been recently acquired from bacteria of the genera Pseudomonas, Salmonella, or Escherichia. This study also resulted in the discovery of 19 new putative resistance genes. Whole-genome sequencing appears to be a fast and efficient approach to the exhaustive identification of resistance genes in epidemic infectious agents of clinical significance.
Full Text Available Acinetobacter baumannii is a species of nonfermentative gram-negative bacteria commonly found in water and soil. This organism was susceptible to most antibiotics in the 1970s. It has now become a major cause of hospital-acquired infections worldwide due to its remarkable propensity to rapidly acquire resistance determinants to a wide range of antibacterial agents. Here we use a comparative genomic approach to identify the complete repertoire of resistance genes exhibited by the multidrug-resistant A. baumannii strain AYE, which is epidemic in France, as well as to investigate the mechanisms of their acquisition by comparison with the fully susceptible A. baumannii strain SDF, which is associated with human body lice. The assembly of the whole shotgun genome sequences of the strains AYE and SDF gave an estimated size of 3.9 and 3.2 Mb, respectively. A. baumannii strain AYE exhibits an 86-kb genomic region termed a resistance island-the largest identified to date-in which 45 resistance genes are clustered. At the homologous location, the SDF strain exhibits a 20 kb-genomic island flanked by transposases but devoid of resistance markers. Such a switching genomic structure might be a hotspot that could explain the rapid acquisition of resistance markers under antimicrobial pressure. Sequence similarity and phylogenetic analyses confirm that most of the resistance genes found in the A. baumannii strain AYE have been recently acquired from bacteria of the genera Pseudomonas, Salmonella, or Escherichia. This study also resulted in the discovery of 19 new putative resistance genes. Whole-genome sequencing appears to be a fast and efficient approach to the exhaustive identification of resistance genes in epidemic infectious agents of clinical significance.
Multiple drug resistance isolates causing UTI has seri- ous implications for the empiric therapy against patho- genic isolates and for the possible co-selection of antimicrobial resistant mediated by multi drug resistant plasmids21,22. E. coli from clinical isolates are known to harbour plasmids of different molecular sizes23.
Chinappi, Mauro; Via, Allegra; Marcatili, Paolo; Tramontano, Anna
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.
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.
Marcatili, Paolo; Tramontano, Anna
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. PMID:21124966
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
Porse, Andreas; Schønning, Kristian; Munck, Christian
Large conjugative plasmids are important drivers of bacterial evolution and contribute significantly to the dissemination of antibiotic resistance. Although plasmid borne multidrug resistance is recognized as one of the main challenges in modern medicine, the adaptive forces shaping the evolution...
Paganelli, Fernanda L.; van de Kamer, Tim; Brouwer, Ellen C.; Leavis, Helen L.; Woodford, Neil; Bonten, Marc J M; Willems, Rob J L; Hendrickx, Antoni P A
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)
Yılmaz, Çiğdem; Özcengiz, Gülay
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.
Kamela O. Alegre
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.
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
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: firstname.lastname@example.org.
Chen, Hua; Shen, Jacson; Choy, Edwin; Hornicek, Francis J; Duan, Zhenfeng
Sarcomas are a group of cancers that arise from transformed cells of mesenchymal origin. They can be classified into over 50 subtypes, accounting for approximately 1% of adult and 15% of pediatric cancers. Wide surgical resection, radiotherapy, and chemotherapy are the most common treatments for the majority of sarcomas. Among these therapies, chemotherapy can palliate symptoms and prolong life for some sarcoma patients. However, sarcoma cells can have intrinsic or acquired resistance after treatment with chemotherapeutics drugs, leading to the development of multidrug resistance (MDR). MDR attenuates the efficacy of anticancer drugs and results in treatment failure for sarcomas. Therefore, overcoming MDR is an unmet need for sarcoma therapy. Certain protein kinases demonstrate aberrant expression and/or activity in sarcoma cells, which have been found to be involved in the regulation of sarcoma cell progression, such as cell cycle, apoptosis, and survival. Inhibiting these protein kinases may not only decrease the proliferation and growth of sarcoma cells, but also reverse their resistance to chemotherapeutic drugs to subsequently reduce the doses of anticancer drugs and decrease drug side-effects. The discovery of novel strategies targeting protein kinases opens a door to a new area of sarcoma research and provides insight into the mechanisms of MDR in chemotherapy. This review will focus on the recent studies in targeting protein kinase to reverse chemotherapeutic drug resistance in sarcoma. Copyright © 2015 Elsevier Ltd. All rights reserved.
Full Text Available This report describes an unusual case of multidrug resistant tuberculosis (MDR-TB, involving the right clavicle and multicentric aytpical spine involvement without any neurological deficit. The female patient presented with acute onset of right clavicular pain associated with a one-month history of lower backache with constitutional symptoms. The clavicular lesion and MRI spine findings were highly suggestive of TB. Anti TB drugs (ATD were started empirically as Sabah, Malaysia the patient’s home, is an endemic area for TB. Despite, 2 months of ATD administration, the patient did not respond well clinically and developed left sided chest wall abscesses arising from the left 3rd and 6th ribs. She was then treated for MDR-TB infection and has responded well to this treatment.
Kremer, Kristin; Heersma, Herre; Van Soolingen, Dick
Molecular surveillance of multidrug-resistant tuberculosis (MDR TB) was implemented in Europe as case reporting in 2005. For all new MDR TB cases detected from January 2003 through June 2007, countries reported case-based epidemiologic data and DNA fingerprint patterns of MDR TB strains when available. International clusters were detected and analyzed. From 2003 through mid-2007 in Europe, 2,494 cases of MDR TB were reported from 24 European countries. Epidemiologic and molecular data were linked for 593 (39%) cases, and 672 insertion sequence 6110 DNA fingerprint patterns were reported from 19 countries. Of these patterns, 288 (43%) belonged to 18 European clusters; 7 clusters (242/288 cases, 84%) were characterized by strains of the Beijing genotype family, including the largest cluster (175/288 cases, 61%). Both clustering and the Beijing genotype were associated with strains originating in eastern European countries. Molecular cluster detection contributes to identification of transmission profile, risk factors, and control measures. PMID:19624920
Lee, Jae Tae; Ahn, Byeong Cheol
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. 99 m-Tc-MIBI and other 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 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-( 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
The modern, ... World Health Organization is based on a four-drug regimen ... Better management and control of tuberculosis specially drug resistant TB by experienced and qualified .... a comprehensive approach including the major DOTS.
Boutonnat, J; Bonnefoix, T; Mousseau, M; Seigneurin, D; Ronot, X
Cross resistance to multiple natural cytotoxic products represents a major obstacle in myeloblastic acute leukaemia (AML). Multidrug resistance (MDR) often involves overexpression of plasma membrane drug transporter P-glycoprotein (PGP) or the resistance associated protein (MRP). Recently, a protein overexpressed in a non-PGP MDR lung cancer cell line and termed lung resistance related protein (LRP) was identified. These proteins are known to be associated with a bad prognosis in AML. We have developed a triple indirect labelling analysed by flow cytometry to detect the coexpression of these proteins. Since no cell line expressing all three antigens is known, we mixed K562 cells (resistant to Adriblastine, PGP+, MRP-, LRP-) with GLC4 cells (resistant to Adriblastine, PGP-, MRP+, LRP+) to create a model system to test the method. The antibodies used were UIC2 for PGP, MRPm6 for MRP and LRP56 for LRP. They were revealed by Fab'2 coupled with Fluoresceine-isothiocyanate, Phycoerythrin or Tricolor with isotype specificity. Cells were fixed and permeabilized after PGP labelling because MRPm6 and LRP56 recognize intracellular epitopes. PGP and LRP were easily detected. MRP is expressed at relatively low levels and was more difficult to detect because in the triple labelling the non specific staining was higher than in a single labelling. Despite the increased background in the triple labelling we were able to detect coexpression of PGP, MRP, LRP by flow cytometry. This method appears to be very useful to detect coexpression of markers in AML. Such coexpression could modify the therapeutic approach with revertants.
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.
Zahirifard, S.; Amiri, M.V.; Bakhshayesh Karam, M.; Mirsaeidi, S.M.; Ehsanpour, A.; Masjedi, M.R.
Background: Multidrug-resistant tuberculosis is a major worldwide health problem. In countries where tuberculosis is of moderate to high prevalence, the issue of Multidrug-resistant tuberculosis carries significant importance. Multidrug-resistant tuberculosis, similar to drug-sensitive tuberculosis, is contagious. Meanwhile its treatment is not only more difficult but also more expensive with lower success rates. Regarding clinical findings, there is no significant difference between Multidrug-resistant tuberculosis and drug-sensitive tuberculosis. Therefore determination of characteristic radiological findings in cases of Multidrug-resistant tuberculosis might be of help in early detection, and hence appropriate management of this disease condition. Objective: To explain the radiological spectrum of pulmonary Multidrug-resistant tuberculosis. Patients and methods: We retrospectively evaluated the radiographic images of 35 patients with clinically-and microbiologically- proven Multidrug-resistant tuberculosis admitted to our tertiary-care tuberculosis unit over a period of 13 months. The latest chest x-ray of all patients and the conventional chest CT scan without contrast of 15 patients were reviewed by three expert radiologists who rendered consensus opinion. Results: Of the 35 patients with imaging studies, 23 (66%) were male and 12 (34%) were female. The mean±SD age of participants was 38.2±17.3 (range: 16-20) years. 33 patients were known as secondary and only 2 had primary Multidrug-resistant tuberculosis. Chest radiography revealed cavitary lesion in 80% pulmonary infiltration in 89% and nodules in 80% of the cases. Pleurisy was the rarest finding observed in only 5 (14%) patients. All of 15 chest CT scans revealed cavitation, 93% of which were bilateral and multiple. Pleural involvement was seen in 93% of patients. Conclusion: Presence of multiple cavities, especially in both lungs, nodular and infiltrative lesions, and pleural effusion are main features
The antibiotic susceptibility testing of isolated bacteria associated with septicaemia in children were carried out using standard microbiological protocol. The MAR index for the test bacterial isolates was determined and the bacterial isolates that displayed multiple antibiotic resistance were investigated for the presence of ...
Full Text Available Fen Pan,1 Hong Zhang,1 Xiaoyan Dong,2 Weixing Ye,3 Ping He,4 Shulin Zhang,4 Jeff Xianchao Zhu,5 Nanbert Zhong1,2,6 1Department of Clinical Laboratory, Shanghai Children’s Hospital, Shanghai Jiaotong University, Shanghai, China; 2Department of Respiratory, Shanghai Children’s Hospital, Shanghai Jiaotong University, Shanghai, China; 3Shanghai Personal Biotechnology Co., Ltd, Shanghai, China; 4Department of Medical Microbiology and Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; 5Zhejiang Bioruida Biotechnology co. Ltd, Zhejiang, China; 6New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA Introduction: Multidrug resistance in Streptococcus pneumoniae has emerged as a serious problem to public health. A further understanding of the genetic diversity in antibiotic-resistant S. pneumoniae isolates is needed. Methods: We conducted whole-genome resequencing for 25 pneumococcal strains isolated from children with different antimicrobial resistance profiles. Comparative analysis focus on detection of single-nucleotide polymorphisms (SNPs and insertions and deletions (indels was conducted. Moreover, phylogenetic analysis was applied to investigate the genetic relationship among these strains. Results: The genome size of the isolates was ~2.1 Mbp, covering >90% of the total estimated size of the reference genome. The overall G+C% content was ~39.5%, and there were 2,200–2,400 open reading frames. All isolates with different drug resistance profiles harbored many indels (range 131–171 and SNPs (range 16,103–28,128. Genetic diversity analysis showed that the variation of different genes were associated with specific antibiotic resistance. Known antibiotic resistance genes (pbps, murMN, ciaH, rplD, sulA, and dpr were identified, and new genes (regR, argH, trkH, and PTS-EII closely related with antibiotic resistance were found, although these genes were primarily annotated
Ladislau C. Kovari
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.
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
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
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.
Ouji, Manel; Augereau, Jean-Michel; Paloque, Lucie; Benoit-Vical, Françoise
The use of artemisinin-based combination therapies (ACTs), which combine an artemisinin derivative with a partner drug, in the treatment of uncomplicated malaria has largely been responsible for the significant reduction in malaria-related mortality in tropical and subtropical regions. ACTs have also played a significant role in the 18% decline in the incidence of malaria cases from 2010 to 2016. However, this progress is seriously threatened by the reduced clinical efficacy of artemisinins, which is characterised by delayed parasitic clearance and a high rate of recrudescence, as reported in 2008 in Western Cambodia. Resistance to artemisinins has already spread to several countries in Southeast Asia. Furthermore, resistance to partner drugs has been shown in some instances to be facilitated by pre-existing decreased susceptibility to the artemisinin component of the ACT. A major concern is not only the spread of these multidrug-resistant parasites to the rest of Asia but also their possible appearance in Sub-Saharan Africa, the continent most affected by malaria, as has been the case in the past with parasite resistance to other antimalarial treatments. It is therefore essential to understand the acquisition of resistance to artemisinins by Plasmodium falciparum to adapt malaria treatment policies and to propose new therapeutic solutions. © M. Ouji et al., published by EDP Sciences, 2018.
Full Text Available The use of artemisinin-based combination therapies (ACTs, which combine an artemisinin derivative with a partner drug, in the treatment of uncomplicated malaria has largely been responsible for the significant reduction in malaria-related mortality in tropical and subtropical regions. ACTs have also played a significant role in the 18% decline in the incidence of malaria cases from 2010 to 2016. However, this progress is seriously threatened by the reduced clinical efficacy of artemisinins, which is characterised by delayed parasitic clearance and a high rate of recrudescence, as reported in 2008 in Western Cambodia. Resistance to artemisinins has already spread to several countries in Southeast Asia. Furthermore, resistance to partner drugs has been shown in some instances to be facilitated by pre-existing decreased susceptibility to the artemisinin component of the ACT. A major concern is not only the spread of these multidrug-resistant parasites to the rest of Asia but also their possible appearance in Sub-Saharan Africa, the continent most affected by malaria, as has been the case in the past with parasite resistance to other antimalarial treatments. It is therefore essential to understand the acquisition of resistance to artemisinins by Plasmodium falciparum to adapt malaria treatment policies and to propose new therapeutic solutions.
Bryant, Josephine M; Grogono, Dorothy M; Rodriguez-Rincon, Daniela
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....
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.
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.
Morales, Eva; Cots, Francesc; Sala, Maria; Comas, Mercè; Belvis, Francesc; Riu, Marta; Salvadó, Margarita; Grau, Santiago; Horcajada, Juan P; Montero, Maria Milagro; Castells, Xavier
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.
Brügger, D; Herbart, H; Gekeler, V; Seitz, G; Liu, C; Klingebiel, T; Orlikowsky, T; Einsele, H; Denzlinger, C; Bader, P; Niethammer, D; Beck, J F
Despite the high effectiveness of various P-glycoprotein (P-gp) modulating substances in vitro their clinical value e.g. for combination treatment of acute myelogenous leukemias (AML) remains still unclear. This might be explainable by recent findings that other factors than P-gp (e.g. the multidrug resistance associated protein (MRP)) may also be involved in clinical occurring drug resistance. To study P-gp and MRP mediated MDR in AML blasts from patients with relapses at the functional level we measured rhodamine 123 (RHO) efflux in combination with a P-gp specific (SDZ PSC 833) or a MRP specific (MK571) modulator, respectively. Furthermore, direct antineoplastic drug action was monitored by determination of damaged cell fraction of a blast population using flow cytometry. We generally found strongly modulated RHO efflux by SDZ PSC 833 but slight RHO-efflux modulation by MK571 in blasts from relapsed states of AML expressing MDR1 or MRP mRNA at various levels. We could not demonstrate, though, significant PSC 833 or MK571 mediated modulation of the cytotoxic effects of etoposide. The results point to the possibility that combination of etoposide and a modulator might not improve responses to chemotherapy by targeting P-gp or MRP exclusively.
Korytny, Alexander; Riesenberg, Klaris; Saidel-Odes, Lisa; Schlaeffer, Fransisc; Borer, Abraham
The prevalence of antimicrobial co-resistance among ESBL-producing Enterobactereaceae is extremely high in Israel. Multidrug-resistant Proteus mirabilis strains (MDR-PM), resistant to almost all antibiotic classes have been described. The aim was to determine the risk factors for bloodstream infections caused by MDR-PM and clinical outcomes. A retrospective case-control study. Adult patients with PM bacteremia during 7 years were identified retrospectively and their files reviewed for demographics, underlying diseases, Charlson Comorbidity Index, treatment and outcome. One hundred and eighty patients with PM-bloodstream infection (BSI) were included; 90 cases with MDR-PM and 90 controls with sensitive PM (S-PM). Compared to controls, cases more frequently were from nursing homes, had recurrent hospital admissions in the past year and received antibiotic therapy in the previous 3 months, were bedridden and suffered from peripheral vascular disease and peptic ulcer disease (p < 0.001). Two-thirds of the MDR-PM isolates were ESBL-producers vs 4.4% of S-PM isolates (p < 0.001, OR = 47.6, 95% CI = 15.9-142.6). In-hospital crude mortality rate of patients with MDR-PM BSI was 37.7% vs 23.3% in those with S-PM BSI (p = 0.0359, OR = 2, 95% CI = 1.4-3.81). PM bacteremia in elderly and functionally-dependent patients is likely to be caused by nearly pan-resistant PM strains in the institution; 51.8% of the patients received inappropriate empiric antibiotic treatment. The crude mortality rate of patients with MDR-PM BSI was significantly higher than that of patients with S-PM BSI.
Miravet Sorribes, Luis; Arnedo Pena, Alberto; Bellido Blasco, Juan B; Romeu García, María Angeles; Gil Fortuño, María; García Sidro, Patricia; Cortés Miró, Pascual
To describe an outbreak of multidrug-resistant tuberculosis (MDR-TB) in two schools This was a prospective, observational study of an outbreak of MDR-TB in 2 schools located in the towns of Onda and Nules, in the Spanish province of Castellon, from the moment of detection in November 2008 until November 2014, including patient follow-up and contact tracing. Five cases of MDR-TB were diagnosed. Overall attack rate was 0.9%, and among the contacts traced, 66 had latent tuberculous infection, with an infection rate of 14.4%. Molecular characterization of the 5M. tuberculosis isolates was performed by restriction fragment length polymorphism (RFLP) analysis of the IS6110 sequence. In all 5 patients, cultures were negative at 4-month follow-up, showing the efficacy of the treatment given. No recurrence has been reported to date. In the context of globalization and the increased prevalence of MDR-TB, outbreaks such as the one presented here are only to be expected. Contact tracing, strict follow-up of confirmed cases, the availability of fast diagnostic techniques to avoid treatment delay, and chemoprophylaxis, together with the molecular characterization of strains, are still essential. Copyright © 2015 SEPAR. Published by Elsevier Espana. All rights reserved.
Full Text Available 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.
Seddon, James A; Thee, Stephanie; Jacobs, Kayleen; Ebrahim, Adam; Hesseling, Anneke C; Schaaf, H Simon
The aminoglycosides and polypeptides are vital drugs for the management of multidrug-resistant (MDR) tuberculosis (TB). Both classes of drug cause hearing loss. We aimed to determine the extent of hearing loss in children treated for MDR-TB. In this retrospective study, children (Hearing was assessed and classified using audiometry and otoacoustic emissions. Ninety-four children were included (median age: 43 months). Of 93 tested, 28 (30%) were HIV-infected. Twenty-three (24%) children had hearing loss. Culture-confirmed, as opposed to presumed, diagnosis of TB was a risk factor for hearing loss (OR: 4.12; 95% CI: 1.13-15.0; p = 0.02). Seven of 11 (64%) children classified as having hearing loss using audiometry had progression of hearing loss after finishing the injectable drug. Hearing loss is common in children treated for MDR-TB. Alternative drugs are required for the treatment of paediatric MDR-TB. Copyright © 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
Xu, Ze-Qi; Flavin, Michael T; Flavin, John
Multidrug-resistant (MDR) bacterial infections, especially those caused by Gram-negative pathogens, have emerged as one of the world's greatest health threats. The development of novel antibiotics to treat MDR Gram-negative bacteria has, however, stagnated over the last half century. This review provides an overview of recent R&D activities in the search for novel antibiotics against MDR Gram-negatives. It provides emphasis in three key areas. First, the article looks at new analogs of existing antibiotic molecules such as β-lactams, tetracyclines, and aminoglycoside as well as agents against novel bacterial targets such as aminoacyl-tRNA synthetase and peptide deformylase. Second, it also examines alternative strategies to conventional approaches including cationic antimicrobial peptides, siderophores, efflux pump inhibitors, therapeutic antibodies, and renewed interest in abandoned treatments or those with limited indications. Third, the authors aim to provide an update on the current clinical development status for each drug candidate. The traditional analog approach is insufficient to meet the formidable challenge brought forth by MDR superbugs. With the disappointing results of the genomics approach for delivering novel targets and drug candidates, alternative strategies to permeate the bacterial cell membrane, enhance influx, disrupt efflux, and target specific pathogens via therapeutic antibodies are attractive and promising. Coupled with incentivized business models, governmental policies, and a clarified regulatory pathway, it is hoped that the antibiotic pipeline will be filled with an effective armamentarium to safeguard global health.
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
Yan, Meiying; Li, Xinlan; Liao, Qiaohong; Li, Fang; Zhang, Jing; Kan, Biao
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.
Fleming, Erin; Heil, Emily L; Hynicka, Lauren M
To describe the management strategy for a multidrug-resistant (MDR) Klebsiella urinary tract infection (UTI). A 69-year-old Caucasian woman with a past medical history of recurrent UTIs and a right-lung transplant presented with fever to 101.4°F, chills, malaise, and cloudy, foul-smelling urine for approximately 1 week. She was found to have a MDR Klebsiella UTI that was sensitive to tigecycline and cefepime. To further evaluate the degree of resistance Etest minimum inhibitory concentrations were requested for cefepime, amikacin, meropenem, and ertapenem. The patient received a 14-day course of amikacin, which resulted in resolution of her symptoms. One month later, the patient's UTI symptoms returned. The urine culture again grew MDR Klebsiella, sensitive only to tigecycline. Fosfomycin was initiated and resulted in limited resolution of her symptoms. Colistin was started, however, therapy was discontinued on day 5 secondary to the development of acute kidney injury. Despite the short course of therapy, the patient's symptoms resolved. The case presented lends itself well to numerous discussion items that are important to consider when determining optimal treatment for MDR Gram-negative bacilli (GNBs). Susceptibility testing is an important tool for optimizing antibiotic therapy, however, automated systems may overestimate the susceptibility profile for a MDR GNB. Treatment strategies evaluated to treat MDR GNB, include combination therapy with a carbepenem and synergy using polymyxin. We have described the management strategy for a MDR Klebsiella UTI, the consequences of the initial management strategy, and potential strategies to manage these types of infections in future patients.
Bowers Jolene R
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.
Background Plasmodium falciparum malaria remains a leading health problem in Africa and its control is seriously challenged by drug resistance. Although resistance to the sulphadoxine-pyrimethamine (SP) is widespread, this combination remains an important component of malaria control programmes as intermittent preventive therapy (IPT) for pregnant women and children. In Angola, resistance patterns have been poorly characterized, and IPT has been employed for pregnant women since 2006. The aim of this study was to assess the prevalence of key antifolate resistance mediating polymorphisms in the pfdhfr and pfdhps genes in P. falciparum samples from Angola. Methods Plasmodium falciparum samples collected in Luanda, in 2007, were genotyped by amplification and DNA forward and reverse sequencing of the pfdhfr and pfdhps genes. Results The most prevalent polymorphisms identified were pfdhfr 108N (100%), 51I (93%), 59R (57%) and pfdhps 437G (93%). Resistance-mediating polymorphisms in pfdhps less commonly observed in West Africa were also identified (540E in 10%, 581G in 7% of samples). Conclusion This study documents an important prevalence of 4 P. falciparum polymorphisms that predicts an antifolate resistance in Luanda. Further, some samples presented additional mutations associated to high-level resistance. These results suggest that the use of SP for IPT may no longer be warranted in Angola. PMID:21864379
Ma, Sheng-lin; Feng, Jian-guo; Gu, Lin-hui; Ling, Yu-tian
To establish human multidrug-resistant lung carcinoma cell line (D6/MVP) with its characteristics studied. Intermittent administration of high-dose MMC, VDS and DDP (MVP) was used to induce human lung carcinoma cell line (D6) to a multidrug-resistant variety (D6/MVP). MTT assay was used to study the multidrug resistance of D6/MVP to multianticarcinogen. Flow cytometry was used to study the cell cycle distribution and the expression of P-gp, multidrug resistance-associated protein (MRP) and GSH/GST. 1. D6/MVP was resistant to many anti-tumor agents, with the IC(50) 13.3 times higher and the drug resistance 2 - 6 times higher than D6, 2. The multiplication time of D6/MVP was prolonged and the cell number of S-phase decreased while that of G1- and G(2)-phase increased and 3. The expression of P-gp and MRP was enhanced significantly (96.2% vs 51.7%), but the expression of GSH/GST kept stable. D6/MVP is a multidrug-resistant cell line possessing the basic characteristics of drug-resistance.
Zaman, G. J.; Flens, M. J.; van Leusden, M. R.; de Haas, M.; Mülder, H. S.; Lankelma, J.; Pinedo, H. M.; Scheper, R. J.; Baas, F.; Broxterman, H. J.
The multidrug-resistance associated protein MRP is a 180- to 195-kDa membrane protein associated with resistance of human tumor cells to cytotoxic drugs. We have investigated how MRP confers drug resistance in SW-1573 human lung carcinoma cells by generating a subline stably transfected with an
Stocks, Paul A; Raynes, Kaylene J; Bray, Patrick G; Park, B Kevin; O'Neill, Paul M; Ward, Stephen A
A series of short chain chloroquine (CQ) derivatives have been synthesized in one step from readily available starting materials. The diethylamine function of CQ is replaced by shorter alkylamine groups (4-9) containing secondary or tertiary terminal nitrogens. Some of these derivatives are significantly more potent than CQ against a CQ resistant strain of Plasmodium falciparum in vitro. We conclude that the ability to accumulate at higher concentrations within the food vacuole of the parasite is an important parameter that dictates their potency against CQ sensitive and the chloroquine resistant K1 P. falciparum.
Full Text Available A total of 312 sputum samples from pediatric patients presumptive of multidrug resistant tuberculosis were tested for the detection of drug resistance using the GenoTypeMTBDRplus assay. A total of 193 (61.8% patients were smear positive and 119 (38.1% were smear negative by Ziehl–Neelsen staining. Line probe assay (LPA was performed for 208 samples/cultures (193 smear positive samples and 15 cultures from smear negative samples. Valid results were obtained from 198 tests. Of these, 125/198 (63.1% were sensitive to both rifampicin (RIF and isoniazid (INH. 73/198 (36.9% were resistant to at least INH/RIF, out of which 49 (24.7% were resistant to both INH and RIF (multidrug resistant. Children with tuberculosis are often infected by someone close to them, so strengthening of contact tracing in the program may help in early diagnosis to identify additional cases within the household. There is a need to evaluate newer diagnostic assays which have a high sensitivity in the case of smear negative samples, additional samples other than sputum among young children not able to expectorate, and also to fill the gap between estimated and reported cases under the program.
Choo Yee Yu
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. Keywords: Chryseobacterium indologenes, Genome, Multi-drug resistant, blaIND, Next generation sequencing
Huwaitat, Rawan; McCloskey, Alice P; Gilmore, Brendan F; Laverty, Garry
Antimicrobial resistance is one of the leading threats to society. The increasing burden of multidrug-resistant Gram-negative infection is particularly concerning as such bacteria are demonstrating resistance to nearly all currently licensed therapies. Various strategies have been hypothesized to treat multidrug-resistant Gram-negative infections including: targeting the Gram-negative outer membrane; neutralization of lipopolysaccharide; inhibition of bacterial efflux pumps and prevention of protein folding. Silver and silver nanoparticles, fusogenic liposomes and nanotubes are potential strategies for extending the activity of licensed, Gram-positive selective, antibiotics to Gram-negatives. This may serve as a strategy to fill the current void in pharmaceutical development in the short term. This review outlines the most promising strategies that could be implemented to solve the threat of multidrug-resistant Gram-negative infections.
Franke, Molly F.; Appleton, Sasha C.; Mitnick, Carole D.; Furin, Jennifer J.; Bayona, Jaime; Chalco, Katiuska; Shin, Sonya; Murray, Megan; Becerra, Mercedes C.
Background. 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. Methods. 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. Results. 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). Conclusions. 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. PMID:23223591
One focus area of DOE Office of Science was the Imaging of Gene Expression in Health and Disease in real time in tissue culture, whole animals and ultimately patients. Investigators of the Molecular Imaging Group, Washington University Medical School, ascribed to this objective and a major focus of this group directly tied into the DOE program through their efforts targeting the multidrug resistance gene (MDR1). Our plans for continuation of the program were to extend and build on this line of investigation, incorporating new molecular tools into our methodology to selectively inhibit MDR1 gene expression with novel modulation strategies. Two approaches were to be pursued: (1) high throughput screening of compounds that disrupted mutant p53 transactivation of the MDR1 promoter, and (2) knockdown of MDR1 messenger RNA with retroviral-mediated delivery of small interfering RNA constructs. These would be combined with our continuing effort to synthesize ligands and examine structure-activity relationships of bis-salicylaldehydes labeled with gallium-68 to generate PET agents for imaging MDR1 P-glycoprotein function. We would be uniquely positioned to correlate therapeutic modulation of MDR1 gene expression and protein function in the same systems in vivo using PET and bioluminescence reporters. Use of animal models such as the mdr1a/1b(-/-) gene deleted mice would also have enabled refined analysis of modulation and tracer pharmacokinetics in vivo. Overall, this DOE program and resultant tools would enable direct monitoring of novel therapeutic strategies and the MDR phenotype in relation to gene expression and protein function in vivo.
Happi, Christian T; Gbotosho, Grace O; Folarin, Onikepe A; Milner, Danny; Sarr, Ousmane; Sowunmi, Akintunde; Kyle, Dennis E; Milhous, Wilbur K; Wirth, Dyann F; Oduola, Ayoade MJ
Abstract Background In vitro and in vivo resistance of Plasmodium falciparum to atovaquone or atovaquone-proguanil hydrochloride combination has been associated to two point mutations in the parasite cytochrome b (cytb) gene (Tyr268Ser and Tyr268Asn). However, little is known about the prevalence of codon-268 mutations in natural populations of P. falciparum without previous exposure to the drug in Africa. Methods The prevalence of codon-268 mutations in the cytb gene of African P. falciparum...
van Veen, HW; Callaghan, R; Soceneantu, L; Sardini, A; Konings, WN; Higgins, CF
Bacteria have developed many fascinating antibiotic-resistance mechanisms(1,2). A protein in Lactococcus lactis, LmrA, mediates antibiotic resistance by extruding amphiphilic compounds from the inner leaflet of the cytoplasmic membrane(3,4). Unlike other known bacterial multidrug-resistance
Ana Teresa P. Carvalho
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
Wang, Xin; Liu, Ying; Wang, Shouju; Shi, Donghong; Zhou, Xianguang; Wang, Chunyan; Wu, Jiang; Zeng, Zhiyong; Li, Yanjun; Sun, Jing; Wang, Jiandong; Zhang, Longjiang; Teng, Zhaogang; Lu, Guangming
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
Ravi, Anuradha; Avershina, Ekaterina; Foley, Steven L; Ludvigsen, Jane; Storrø, Ola; Øien, Torbjørn; Johnsen, Roar; McCartney, Anne L; L'Abée-Lund, Trine M; Rudi, Knut
Despite the accumulating knowledge on the development and establishment of the gut microbiota, its role as a reservoir for multidrug resistance is not well understood. This study investigated the prevalence and persistence patterns of an integrase gene (int1), used as a proxy for integrons (which often carry multiple antimicrobial resistance genes), in the fecal microbiota of 147 mothers and their children sampled longitudinally from birth to 2 years. The study showed the int1 gene was detected in 15% of the study population, and apparently more persistent than the microbial community structure itself. We found int1 to be persistent throughout the first two years of life, as well as between mothers and their 2-year-old children. Metagenome sequencing revealed integrons in the gut meta-mobilome that were associated with plasmids and multidrug resistance. In conclusion, the persistent nature of integrons in the infant gut microbiota makes it a potential reservoir of mobile multidrug resistance.
Mahfoud, Maysa; Al Najjar, Mona; Hamzeh, Abdul Rezzak
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.
Udani, Rupa A; Levy, Stuart B
MarA47(Yp) from Yersinia pestis, showing 47% identity to Escherichia coli MarA in its N terminus, caused resistance to antibiotics and to organic solvents when expressed in both E. coli and Y. pestis. Resistance was linked to increased expression of the AcrAB multidrug efflux pump. In four of five spontaneous multidrug-resistant mutants of Y. pestis independently selected by growth on tetracycline, the marA47(Yp) gene was overexpressed. The findings suggest that marA47(Yp) is a marA ortholog in Y. pestis.
Rønn, A M; Msangeni, H A; Mhina, J
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...
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.
Sydenham, Thomas Vognbjerg; Sóki, József; Hasman, Henrik
Bacteroides fragilis constitutes the most frequent anaerobic bacterium causing bacteremia in humans. The genetic background for antimicrobial resistance in B. fragilis is diverse with some genes requiring insertion sequence (IS) elements inserted upstream for increased expression. To evaluate whole...... genome shotgun sequencing as a method for predicting antimicrobial resistance properties, one meropenem resistant and five multidrug-resistant blood culture isolates were sequenced and antimicrobial resistance genes and IS elements identified using ResFinder 2.1 (http...
Gebreyes, Wondwossen A.; Thakur, Siddhartha
Salmonella serovars are important reservoirs of antimicrobial resistance. Recently, we reported on multidrug-resistant (MDR) Salmonella enterica serovar Typhimurium strains among pigs with resistance to ampicillin, kanamycin, streptomycin, sulfamethoxazole, and tetracycline (resistance [R] type AKSSuT) and resistance to amoxicillin-clavulanic acid, ampicillin, chloramphenicol, streptomycin, sulfamethoxazole, and tetracycline (R type AxACSSuT). In the present study, 67 isolates (39 from humans...
Shaheen, Aqsa; Iqbal, Mazhar; Mirza, Osman
. Research on the underlying causes of multidrug resistance in cancerous cells and later on in infectious bacteria revealed the involvement of integral membrane transporters, capable of recognizing a broad range of structurally different molecules as substrates and exporting them from the cell using cellular...... superfamilies, viz., ATP-binding cassette superfamily, major facilitator superfamily and resistance nodulation division superfamily are presented. Further, the future role of structural biology in improving our understanding of drug-transporter interactions and in designing novel inhibitors against MDR pump...... century, mankind has become aware and confronted with the emergence of antibiotic-resistant pathogens. In parallel to the failure of antibiotic therapy against infectious pathogens, there had been continuous reports of cancerous cells not responding to chemotherapy with increase in the duration of therapy...
Müller, M.; de Vries, E. G.; Jansen, P. L.
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
Muller, M; deVries, EGE; Jansen, PLM
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
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.
Martins , A.; Spengler , G.; Martins , M.; Rodrigues , L.; Viveiros , M.; Davin-Regli , A.; Chevalier , J.; Couto , I.; Pagès , J.M.; Amaral , L.
Abstract Enterobacter aerogenes predominates among Enterobacteriaceae species that are increasingly reported as producers of extended-spectrum ?-lactamases. Although this mechanism of resistance to ?-lactams is important, other mechanisms bestowing a multidrug-resistant (MDR) phenotype in this species are now well documented. Among these mechanisms is the overexpression of efflux pumps that extrude structurally unrelated antibiotics prior to their reaching their targets. Interestin...
Drug-resistant tuberculosis poses a serious challenge to global control of TB. These forms of TB do not respond to the standard six-month treatment; it can take two years or more to treat with category IV drugs that are less potent, more toxic and much more expensive. Treatment of multi-drug resistant tuberculosis is still ...
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.
Dinio, Theresa; Gorka, Alexander P; McGinniss, Andrew; Roepe, Paul D; Morgan, Jeremy B
Plasmodium falciparum, the deadliest malarial parasite species, has developed resistance against nearly all man-made antimalarial drugs within the past century. However, quinine (QN), the first antimalarial drug, remains efficacious worldwide. Some chloroquine resistant (CQR) P. falciparum strains or isolates show mild cross resistance to QN, but many do not. Further optimization of QN may provide a well-tolerated therapy with improved activity versus CQR malaria. Thus, using the Heck reaction, we have pursued a structure-activity relationship study, including vinyl group modifications of QN. Certain derivatives show good antiplasmodial activity in QN-resistant and QN-sensitive strains, with lower IC(50) values relative to QN. Copyright © 2012 Elsevier Ltd. All rights reserved.
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
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.
Shaheen, Aqsa; Ismat, Fouzia; Iqbal, Mazhar
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...
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.
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
Background 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 p...
Nasser, Kother; Mustafa, Abu Salim; Khan, Mohd Wasif; Purohit, Prashant; Al-Obaid, Inaam; Dhar, Rita; Al-Fouzan, Wadha
Acinetobacter baumannii is an important opportunistic pathogen in global health care settings. Its dissemination and multidrug resistance pose an issue with treatment and outbreak control. Here, we present draft genome assemblies of six multidrug-resistant clinical strains of A. baumannii isolated from patients admitted to one of two major hospitals in Kuwait. Copyright © 2018 Nasser et al.
Mirza, S H; Khan, M A [Armed Forces Inst. of Pathology, Rawalpindi (Pakistan). Dept. of Microbiolgy
To find out the frequency of low-level quinolone-resistance in Multi-Drug Resistant (MDR) typhoid using nalidixic acid screening disc. Blood was obtained from suspected cases of typhoid fever and cultured in to BacT/ALERT. The positive blood cultures bottles were subcultured. The isolates were identified by colony morphology and biochemical tests using API-20E galleries. Susceptibility testing of isolates was done by modified Kirby-Bauer disc diffusion method on Muellar Hinton Agar. For the isolates, which were resistant to nalidixic acid by disc diffusion method, Minimal Inhibitory Concentrations (MICs) of ciprofloxacin and nalidixic acid were determined by using the E-test strips. Disc diffusion susceptibility tests and MICs were interpreted according to the guidelines provided by National Committee for Control Laboratory Standard (NCCLS). A total of 21(65.5%) out of 32 isolates of Salmonellae were nalidixic acid-resistant by disk diffusion method. All the nalidixic acid-resistant isolates by disc diffusion method were confirmed by MICs for both ciprofloxacin and nalidixic acid. All the nalidixic acid-resistant isolates had a ciprofloxacin MIC of 0.25-1 microg/ml (reduced susceptibility) and nalidixic acid MICs > 32 microg (resistant). Out of all Salmonella isolates, 24 (75%) were found to be MDR, and all were S. typbi. Low-level quinolone-resistance in typhoid was high in this small series. Screening for nalidixic acid resistance with a 30 microg nalidixic acid disk is a reliable and cost-effective method to detect low-level fluoroquinolone resistance, especially in the developing countries. (author)
Mirza, S.H.; Khan, M.A.
To find out the frequency of low-level quinolone-resistance in Multi-Drug Resistant (MDR) typhoid using nalidixic acid screening disc. Blood was obtained from suspected cases of typhoid fever and cultured in to BacT/ALERT. The positive blood cultures bottles were subcultured. The isolates were identified by colony morphology and biochemical tests using API-20E galleries. Susceptibility testing of isolates was done by modified Kirby-Bauer disc diffusion method on Muellar Hinton Agar. For the isolates, which were resistant to nalidixic acid by disc diffusion method, Minimal Inhibitory Concentrations (MICs) of ciprofloxacin and nalidixic acid were determined by using the E-test strips. Disc diffusion susceptibility tests and MICs were interpreted according to the guidelines provided by National Committee for Control Laboratory Standard (NCCLS). A total of 21(65.5%) out of 32 isolates of Salmonellae were nalidixic acid-resistant by disk diffusion method. All the nalidixic acid-resistant isolates by disc diffusion method were confirmed by MICs for both ciprofloxacin and nalidixic acid. All the nalidixic acid-resistant isolates had a ciprofloxacin MIC of 0.25-1 microg/ml (reduced susceptibility) and nalidixic acid MICs > 32 microg (resistant). Out of all Salmonella isolates, 24 (75%) were found to be MDR, and all were S. typbi. Low-level quinolone-resistance in typhoid was high in this small series. Screening for nalidixic acid resistance with a 30 microg nalidixic acid disk is a reliable and cost-effective method to detect low-level fluoroquinolone resistance, especially in the developing countries. (author)
Khan, A S
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.
Gustavo A Fontecha
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.
Fontecha, Gustavo A; Sanchez, Ana L; Mendoza, Meisy; Banegas, Engels; Mejía-Torres, Rosa E
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.
Srinivasan S, Madhusudhan NS
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.
Wu, Long; Xu, Jun; Yuan, Weiqi; Wu, Baojian; Wang, Hao; Liu, Guangquan; Wang, Xiaoxiong; Du, Jun; Cai, Shaohui
Purpose P-glycoprotein mediated efflux is one of the main mechanisms for multidrug resistance in cancers, and 3-Bromopyruvate acts as a promising multidrug resistance reversal compound in our study. To test the ability of 3-Bromopyruvate to overcome P-glycoprotein-mediated multidrug resistance and to explore its mechanisms of multidrug resistance reversal in MCF-7/ADR cells, we evaluate the in vitro and in vivo modulatory activity of this compound. Methods The in vitro and in vivo activity wa...
Richard J Pearce
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.
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.
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.
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
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.
Vanpouille, Claire; Jeune, Nathalie le; Clotagatide, Anthony; Dubois, Francis; Kryza, David; Janier, Marc; Perek, Nathalie
Multidrug resistance, aggressiveness and accelerated choline metabolism are hallmarks of malignancy and have motivated the development of new PET tracers like 18 F-FCH, an analogue of choline. Our aim was to study the relationship of multidrug resistance of cultured glioma cell lines and 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.)
Ahmed, Ashraf M; Shimamoto, Tadashi
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. Copyright © 2014 Elsevier B.V. All rights reserved.
Walsh, Fiona; Duffy, Brion
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.
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.
Tutuncu, E Ediz; Kuscu, Ferit; Gurbuz, Yunus; Ozturk, Baris; Haykir, Asli; Sencan, Irfan
The treatment of post-surgical meningitis due to multidrug-resistant (MDR) Acinetobacter baumannii is a therapeutic dilemma. The cases of two patients with MDR A. baumannii meningitis secondary to surgical site infections, successfully treated with combination regimens including tigecycline, are presented. Copyright © 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Arceci, R. J.; Baas, F.; Raponi, R.; Horwitz, S. B.; Housman, D.; Croop, J. M.
The multidrug resistance (mdr) gene family has been shown to encode a membrane glycoprotein, termed the P-glycoprotein, which functions as a drug efflux pump with broad substrate specificity. This multigene family is expressed in a tissue-specific fashion in a wide variety of normal and neoplastic
Demetrio L. Valle Jr.
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.
Rijpma, S.R.; Velden, M. van der; Annoura, T.; Matz, J.M.; Kenthirapalan, S.; Kooij, T.W.; Matuschewski, K.; Gemert, G.J.A. van; Vegte-Bolmer, M.G. van de; Siebelink-Stoter, R.; Graumans, W.; Ramesar, J.; Klop, O.; Russel, F.G.; Sauerwein, R.W.; Janse, C.J.; Franke-Fayard, B.M.; Koenderink, J.B.
Multidrug resistance (MDR) proteins belong to the B subfamily of the ATP Binding Cassette (ABC) transporters, which export a wide range of compounds including pharmaceuticals. In this study, we used reverse genetics to study the role of all seven Plasmodium MDR proteins during the life cycle of
Alffenaar, Jan-Willem C.; Kosterink, Jos G. W.; van Altena, Richard; van der Werf, Tjip S.; Uges, Donald R. A.; Proost, Johannes H.
Introduction: Linezolid is a potential drug for the treatment of multidrug-resistant tuberculosis but its use is limited because of severe adverse effects such as anemia, thrombocytopenia, and peripheral neuropathy. This study aimed to develop a model for the prediction of linezolid area. under the
Hedt, Bethany Lynn; van Leth, Frank; Zignol, Matteo; Cobelens, Frank; van Gemert, Wayne; Nhung, Nguyen Viet; Lyepshina, Svitlana; Egwaga, Saidi; Cohen, Ted
Background: Current methodology for multidrug-resistant tuberculosis (MDR TB) surveys endorsed by the World Health Organization provides estimates of MDR TB prevalence among new cases at the national level. On the aggregate, local variation in the burden of MDR TB may be masked. This paper
Fox, Gregory J.; Mitnick, Carole D.; Benedetti, Andrea; Chan, Edward D.; Becerra, Mercedes; Chiang, Chen-Yuan; Keshavjee, Salmaan; Koh, Won-Jung; Shiraishi, Yuji; Viiklepp, Piret; Yim, Jae-Joon; Pasvol, Geoffrey; Robert, Jerome; Shim, Tae Sun; Shin, Sonya S.; Menzies, Dick; van der Werf, Tjip S.
Background. Medical treatment for multidrug-resistant (MDR)-tuberculosis is complex, toxic, and associated with poor outcomes. Surgical lung resection may be used as an adjunct to medical therapy, with the intent of reducing bacterial burden and improving cure rates. We conducted an individual
Biliński, Jarosław; Grzesiowski, Paweł; Muszyński, Jacek; Wróblewska, Marta; Mądry, Krzysztof; Robak, Katarzyna; Dzieciątkowski, Tomasz; Wiktor-Jedrzejczak, Wiesław; Basak, Grzegorz W
Colonization of the gastrointestinal tract with multidrug-resistant (MDR) bacteria is a consequence of gut dysbiosis. We describe the successful utilization of fecal microbiota transplantation to inhibit Klebsiella pneumoniae MBL(+) and Escherichia coli ESBL(+) gut colonization in the immunocompromised host as a novel tool in the battle against MDR microorganisms. ClinicalTrials.gov identifier NCT02461199.
Pattern of intensive phase treatment outcomes of multi-drug resistant tuberculosis in University of Port Harcourt Treatment Centre: a review of records from ... Data on patients' age, sex, HIV status, treatment outcomes were extracted from the hospital book records into a computer data sheet at the UPTH treatment centre.
Sun, Ju-Feng; Hou, Gui-Ge; Zhao, Feng; Cong, Wei; Li, Hong-Juan; Liu, Wen-Shuai; Wang, Chunhua
A series of heterocyclic α,β-unsaturated carbonyl compounds (1a-1d, 2a-2d, 3a-3d, 4a-3d, and 5a-5d) with 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore were synthesized for the development of anticancer and multidrug resistance reverting agents. The antiproliferative activities were tested against nine human cancer cell lines. Approximately 73% of the IC50 values were below 5 μm, while 35% of these figures were submicromolar, and compounds 3a-3d with 4-trifluoro methyl in the arylidene benzene rings were the most potent, since their IC50 values are between 0.06 and 3.09 μm against all cancer cell lines employed. Meanwhile, their multidrug resistance reversal properties and cellular uptake were further examined. The data displayed that all of these compounds could reverse multidrug resistance, particularly, compounds 3a and 4a demonstrated both potent multidrug resistance reverting properties and strong antiproliferative activities, which can be taken as leading molecules for further research of dual effect agents in tumor chemotherapy. © 2016 John Wiley & Sons A/S.
Introduction: Multidrug-resistant tuberculosis (MDR-TB), a growing global menace, is seriously undermining the previous successes made in the elimination of TB. MDR-TB treatment takes a long time, is complex, and is frequently associated with the occurrence of adverse drug reactions, some of which
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.
Lorenzi, Vannina; Muselli, Alain; Bernardini, Antoine François; Berti, Liliane; Pagès, Jean-Marie; Amaral, Leonard; Bolla, Jean-Michel
The essential oil of Helichrysum italicum significantly reduces the multidrug resistance of Enterobacter aerogenes, Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii. Combinations of the two most active fractions of the essential oil with each other or with phenylalanine arginine β-naphthylamide yield synergistic activity. Geraniol, a component of one fraction, significantly increased the efficacy of β-lactams, quinolones, and chloramphenicol. PMID:19258278
Lubelski, Jacek; Konings, Wil N.; Driessen, Arnold J. M.
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.
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.
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
van den Hof, Susan; Collins, David; Hafidz, Firdaus; Beyene, Demissew; Tursynbayeva, Aigul; Tiemersma, Edine
One of the main goals of the post-2015 global tuberculosis (TB) strategy is that no families affected by TB face catastrophic costs. We revised an existing TB patient cost measurement tool to specifically also measure multi-drug resistant (MDR) TB patients' costs and applied it in Ethiopia,
Fivelman, Quinton L; Butcher, Geoffrey A; Adagu, Ipemida S; Warhurst, David C; Pasvol, Geoffrey
Abstract We report the first in vitro and genetic confirmation of Malarone® (GlaxoSmithKline; atovaquone and proguanil hydrochloride) resistance in Plasmodium falciparum acquired in Africa. On presenting with malaria two weeks after returning from a 4-week visit to Lagos, Nigeria without prophylaxis, a male patient was given a standard 3-day treatment course of Malarone®. Twenty-eight days later the parasitaemia recrudesced. Parasites were cultured from the blood and the isolate (NGATV01) was...
Benoit-Vical, Françoise; Robert, Anne; Meunier, Bernard
The influence of different metalloporphyrin derivatives on the antimalarial activity of artemisinin was studied with two chloroquine-resistant strains of Plasmodium falciparum (FcB1-Colombia and FcM29-Cameroon) cultured in human erythrocytes. This potentiation study indicates that the manganese complex of meso-tetrakis(4-sulfonatophenyl)porphyrin has a significant synergistic effect on the activity of artemisinin against both Plasmodium strains. PMID:10508044
Alcalde-Rico, Manuel; Hernando-Amado, Sara; Blanco, Paula; Martínez, José L
Multidrug efflux pumps can be involved in bacterial resistance to antibiotics at different levels. Some efflux pumps are constitutively expressed at low levels and contribute to intrinsic resistance. In addition, their overexpression may allow higher levels of resistance. This overexpression can be transient, in the presence of an effector (phenotypic resistance), or constitutive when mutants in the regulatory elements of the expression of efflux pumps are selected (acquired resistance). Efflux pumps are present in all cells, from human to bacteria and are highly conserved, which indicates that they are ancient elements in the evolution of different organisms. Consequently, it has been suggested that, besides antibiotic resistance, bacterial multidrug efflux pumps would likely contribute to other relevant processes of the microbial physiology. In the current article, we discuss some specific examples of the role that efflux pumps may have in the bacterial virulence of animals' and plants' pathogens, including the processes of intercellular communication. Based in these evidences, we propose that efflux pumps are at the crossroad between resistance and virulence of bacterial pathogens. Consequently, the comprehensive study of multidrug efflux pumps requires addressing these functions, which are of relevance for the bacterial-host interactions during infection.
Full Text Available Multidrug efflux pumps can be involved in bacterial resistance to antibiotics at different levels. Some efflux pumps are constitutively expressed at low levels and contribute to intrinsic resistance. In addition, their overexpression may allow higher levels of resistance. This overexpression can be transient, in the presence of an effector (phenotypic resistance, or constitutive when mutants in the regulatory elements of the expression of efflux pumps are selected (acquired resistance. Efflux pumps are present in all cells, from human to bacteria and are highly conserved, which indicates that they are ancient elements in the evolution of different organisms. Consequently, it has been suggested that, besides antibiotic resistance, bacterial multidrug efflux pumps would likely contribute to other relevant process of the microbial physiology. In the current article, we discuss some specific examples of the role that efflux pumps may have in the bacterial virulence of animals' and plants' pathogens, including the processes of intercellular communication. Based in these evidences, we propose that efflux pumps are at the crossroad between resistance and virulence of bacterial pathogens. Consequently, the comprehensive study of multidrug efflux pumps requires addressing these functions, which are of relevance for the bacterial-host interactions during infection.
The appearance and dissemination of penicillin resistant and macrolide resistant Streptococcus pneumoniae strains has caused increasing concern worldwide. The aim of this study was to survey drug resistance and genetic characteristics of macrolide and penicillin resistance in S. pneumoniae. This is a cross-sectional ...
Dalal, Alpa; Pawaskar, Akshay; Das, Mrinalini; Desai, Ranjan; Prabhudesai, Pralhad; Chhajed, Prashant; Rajan, Sujeet; Reddy, Deepesh; Babu, Sajit; Jayalakshmi, T K; Saranchuk, Peter; Rodrigues, Camilla; Isaakidis, Petros
While the high burden of multidrug-resistant tuberculosis (MDR-TB) itself is a matter of great concern, the emergence and rise of advanced forms of drug-resistance such as extensively drug-resistant TB (XDR-TB) and extremely drug-resistant TB (XXDR-TB) is more troubling. The aim of this study was to investigate the trends over time of patterns of drug resistance in a sample of MDR-TB patients in greater metropolitan Mumbai, India. This was a retrospective, observational study of drug susceptibility testing (DST) results among MDR-TB patients from eight health care facilities in greater Mumbai between 2005 and 2013. We classified resistance patterns into four categories: MDR-TB, pre-XDR-TB, XDR-TB and XXDR-TB. A total of 340 MDR-TB patients were included in the study. Pre-XDR-TB was the most common form of drug-resistant TB observed overall in this Mumbai population at 56.8% compared to 29.4% for MDR-TB. The proportion of patients with MDR-TB was 39.4% in the period 2005-2007 and 27.8% in 2011-2013, while the proportion of those with XDR-TB and XXDR-TB was changed from 6.1% and 0% respectively to 10.6% and 5.6% during the same time period. During the same periods, the proportions of patients with ofloxacin, moxifloxacin and ethionamide resistance significantly increased from 57.6% to 75.3%, from 60.0% to 69.5% and from 24.2% to 52.5% respectively (pMumbai highlight the need for individualized drug regimens, designed on the basis of DST results involving first- and second-line anti-TB drugs and treatment history of the patient. A drug-resistant TB case-finding strategy based on molecular techniques that identify only rifampicin resistance will lead to initiation of suboptimal treatment regimens for a significant number of patients, which may in turn contribute to amplification of resistance and transmission of strains with increasingly advanced resistance within the community.
Decristophoris, Paola Maria Aurelia
Background: The human relationship with cats and dogs has been suggested to be of potential concern to public health because of the possible role of pets as reservoir of antibiotic resistant microorganisms. Here I suggest the “One Health” interdisciplinary approach to be helpful towards the understanding of the role of pets in antibiotic resistance spreading, considering also the socio-emotional context of the human-pet relationship. Methods: I investigated the presence of multi-drug resis...
Kalle, Arunasree M; Rizvi, Arshad
Multidrug resistance (MDR) is a major problem in the treatment of infectious diseases and cancer. Accumulating evidence suggests that the cyclooxygenase-2 (COX-2)-specific inhibitor celecoxib would not only inhibit COX-2 but also help in the reversal of drug resistance in cancers by inhibiting the MDR1 efflux pump. Here, we demonstrate that celecoxib increases the sensitivity of bacteria to the antibiotics ampicillin, kanamycin, chloramphenicol, and ciprofloxacin by accumulating the drugs inside the cell, thus reversing MDR in bacteria.
Anuradha Ravi; Ekaterina Avershina; Steven L. Foley; Jane Ludvigsen; Ola Storrø; Torbjørn Øien; Roar Johnsen; Anne L. McCartney; Trine M. L’Abée-Lund; Knut Rudi
Despite the accumulating knowledge on the development and establishment of the gut microbiota, its role as a reservoir for multidrug resistance is not well understood. This study investigated the prevalence and persistence patterns of an integrase gene (int1), used as a proxy for integrons (which often carry multiple antimicrobial resistance genes), in the fecal microbiota of 147 mothers and their children sampled longitudinally from birth to 2 years. The study showed the int1 gene was detect...
Falcone, Marco; Russo, Alessandro; Giannella, Maddalena; Cangemi, Roberto; Scarpellini, Maria Gabriella; Bertazzoni, Giuliano; Alarc?n, Jos? Mart?nez; Taliani, Gloria; Palange, Paolo; Farcomeni, Alessio; Vestri, Annarita; Bouza, Emilio; Violi, Francesco; Venditti, Mario
Introduction The diffusion of multidrug-resistant (MDR) bacteria has created the need to identify risk factors for acquiring resistant pathogens in patients living in the community. Objective To analyze clinical features of patients with community-onset pneumonia due to MDR pathogens, to evaluate performance of existing scoring tools and to develop a bedside risk score for an early identification of these patients in the Emergency Department. Patients and Methods This was an open, observation...
Rigalli, Juan Pablo; Ciriaci, Nadia; Arias, Agostina; Ceballos, Mar?a Paula; Villanueva, Silvina Stella Maris; Luquita, Marcelo Gabriel; Mottino, Aldo Domingo; Ghanem, Carolina In?s; Catania, Viviana Alicia; Ruiz, Mar?a Laura
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...
Hare Krishna Tiwari
Full Text Available Hare Krishna Tiwari1, Darshan Sapkota2, Malaya Ranjan Sen11Department of Microbiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India; 2Department of Microbiology, Universal College of Medical Sciences, Bhairahawa, NepalAbstract: Methicillin-resistant Staphylococcus aureus (MRSA is an important nosocomial and community pathogen. The objectives of this study were to estimate the prevalence of multidrug-resistant MRSA strains in clinical specimens and to investigate the sensitivity pattern of these strains against various antibiotics used for treating hospitalized and out patients. Strains were identified using standard procedures, and their sensitivity pattern was investigated using such techniques as disc diffusion, minimum inhibitory concentration (MIC, and the mecA gene PCR. Among 783 isolates of S. aureus, 301 (38.44% were methicillin-resistant, of which 217 (72.1% were found to be multidrug-resistant. Almost all MRSA strains were resistant to penicillin, 95.68% were resistant to cotrimoxazole, 92.36% were resistant to chloramphenicol, 90.7% were resistant to norfloxacin, 76.1% were resistant to tetracycline, and 75.75% were resistant to ciprofloxacin. Vancomycin was the most effective drug, with only 0.33% of MRSA strains being resistant to it. It is concluded that antibiotics other than vancomycin can be used as anti-MRSA agents after a sensitivity test so as to preclude the emergence of resistance to it and that prevailing problems in chemotherapy will escalate unless indiscriminate and irrational usage of antibiotics is checked.Keywords: multidrug-resistant MRSA, prevalence, India
Zaidi, Arsalan Haseeb; Bakkes, Patrick J.; Lubelski, Jacek; Agustiandari, Herfita; Kuipers, Oscar P.; Driessen, Arnold J. M.
Upon prolonged exposure to cholate and other toxic compounds, Lactococcus lactis develops a multidrug resistance phenotype that has been attributed to an elevated expression of the heterodimeric ABC-type multidrug transporter LmrCD. To investigate the molecular basis of bile acid resistance in L.
Nielsen, D; Maare, C; Eriksen, J
-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......M. ATPase activity was slightly stimulated by daunorubicin, whereas vinblastine, verapamil, and cyclosporin A had no effect. In conclusion, development of resistance to VP16 in EHR2 is accompanied by a significant reduction in topoisomerase II (alpha and beta) and by increased expression of MRP mRNA (20......-fold). MRP displays several points of resemblance to P-glycoprotein in its mode of action: 1) like P-glycoprotein, MRP causes resistance to a range of hydrophobic drugs; 2) MRP decreases drug accumulation in the cells and this decrease is abolished by omission of energy; and 3) MRP increases efflux...
Motile bacteria utilize one or more strategies for movement, such as darting, gliding, sliding, swarming, swimming, and twitching. The ability to move is considered a virulence factor in many pathogenic bacteria, including Salmonella. Multidrug-resistant (MDR) Salmonella encodes acquired factors t...
Koziolová, Eva; Chytil, Petr; Etrych, Tomáš; Janoušková, Olga
Roč. 28, č. 10 (2017), s. 1126-1130 ISSN 0959-4973 R&D Projects: GA MŠk(CZ) LO1507 Institutional support: RVO:61389013 Keywords : drug-delivery polymers * multidrug resistance * N-(2-hydroxypropyl) methacrylamide Subject RIV: CD - Macromolecular Chemistry OBOR OECD: Polymer science Impact factor: 2.320, year: 2016
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.
Arun P. More
Full Text Available Objective: In India, increasing prevalence of multi-drug resistant tuberculosis (MDR has aggravated the control oftuberculosis problem. In many urban and semi-urban regions of India, no surveillance data of multidrug resistance inMycobacterium tuberculosisis available.Methods: A surveillance study on multidrug resistance was carried out in semi-urban and rural regions in and aroundNashik City of Maharashtra, India. The surveillance study was conducted in this region found that the prevalence ofcombined resistance to first and second-line anti-tuberculosis drugs is remarkably high. The isolates of M. tuberculosiswas identified and subjected to drug susceptibility testing. The patterns of drug susceptibility of isolates of M. tuberculosisduring the periods 2000 and 2004 were compared with drug susceptibility patterns of the organisms during theperiod 2008 to 2011.Results: The 260 isolates identified as M. tuberculosis show mean drug resistance prevalence of 45.6% for more than anytwo drugs and the MDR rate as 37% in the years 2000 to 2004 whereas 305 isolates of the organism show mean drugresistance prevalence of 30.2% and the MDR rate as 25% in the years 2008 to 2011.Conclusion: The researcher found that, though the prevalence of multidrug resistance to the drugs tested is remarkablyhigh, it has come down noticeably during the past seven years due to efforts of State Government and strict implementationof treatment guidelines of WHO by the physicians. J Microbiol Infect Dis 2013; 3(1: 12-17Key words: MDR-TB, XDR-TB, DOTS, drug-resistance prevalence rate.
Hedt, Bethany Lynn; van Leth, Frank; Zignol, Matteo; Cobelens, Frank; van Gemert, Wayne; Nhung, Nguyen Viet; Lyepshina, Svitlana; Egwaga, Saidi; Cohen, Ted
Current methodology for multidrug-resistant tuberculosis (MDR TB) surveys endorsed by the World Health Organization provides estimates of MDR TB prevalence among new cases at the national level. On the aggregate, local variation in the burden of MDR TB may be masked. This paper investigates the utility of applying lot quality-assurance sampling to identify geographic heterogeneity in the proportion of new cases with multidrug resistance. We simulated the performance of lot quality-assurance sampling by applying these classification-based approaches to data collected in the most recent TB drug-resistance surveys in Ukraine, Vietnam, and Tanzania. We explored 3 classification systems- two-way static, three-way static, and three-way truncated sequential sampling-at 2 sets of thresholds: low MDR TB = 2%, high MDR TB = 10%, and low MDR TB = 5%, high MDR TB = 20%. The lot quality-assurance sampling systems identified local variability in the prevalence of multidrug resistance in both high-resistance (Ukraine) and low-resistance settings (Vietnam). In Tanzania, prevalence was uniformly low, and the lot quality-assurance sampling approach did not reveal variability. The three-way classification systems provide additional information, but sample sizes may not be obtainable in some settings. New rapid drug-sensitivity testing methods may allow truncated sequential sampling designs and early stopping within static designs, producing even greater efficiency gains. Lot quality-assurance sampling study designs may offer an efficient approach for collecting critical information on local variability in the burden of multidrug-resistant TB. Before this methodology is adopted, programs must determine appropriate classification thresholds, the most useful classification system, and appropriate weighting if unbiased national estimates are also desired.
Lauderdale, T. L.; Aarestrup, Frank Møller; Chen, P. C.
(41%) and was highly prevalent in Salmonella enterica serotype Typhimurium (72.7%, 176/242) the most common serotype. Additional resistance to trimethoprim was present in 155 (19.4% overall) of the ACSSuT R-type isolates from several serotypes. Reduced susceptibility to fluoroquinolone (FQ...... multiresistant to other antimicrobials. Studies are needed to determine the sources of different multidrug-resistant serotypes. Continued national surveillance is underway to monitor changes in resistance trends and to detect further emergence of resistant Salmonella serotypes in Taiwan. (c) 2006 Elsevier Inc...
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.
Vidya P Narayanaswamy
Full Text Available The incidence of multidrug-resistant (MDR organisms, including methicillin-resistant Staphylococcus aureus (MRSA, is a serious threat to public health. Progress in developing new therapeutics is being outpaced by antibiotic resistance development, and alternative agents that rapidly permeabilize bacteria hold tremendous potential for treating MDR infections. A new class of glycopolymers includes polycationic poly-N (acetyl, arginyl glucosamine (PAAG is under development as an alternative to traditional antibiotic strategies to treat MRSA infections. This study demonstrates the antibacterial activity of PAAG against clinical isolates of methicillin and mupirocin-resistant Staphylococcus aureus. Multidrug-resistant S. aureus was rapidly killed by PAAG, which completely eradicated 88% (15/17 of all tested strains (6-log reduction in CFU in ≤ 12-hours at doses that are non-toxic to mammalian cells. PAAG also sensitized all the clinical MRSA strains (17/17 to oxacillin as demonstrated by the observed reduction in the oxacillin MIC to below the antibiotic resistance breakpoint. The effect of PAAG and standard antibiotics including vancomycin, oxacillin, mupirocin and bacitracin on MRSA permeability was studied by measuring propidium iodide (PI uptake by bacterial cells. Antimicrobial resistance studies showed that S. aureus developed resistance to PAAG at a rate slower than to mupirocin but similar to bacitracin. PAAG was observed to resensitize drug-resistant S. aureus strains sampled from passage 13 and 20 of the multi-passage resistance study, reducing MICs of mupirocin and bacitracin below their clinical sensitivity breakpoints. This class of bacterial permeabilizing glycopolymers may provide a new tool in the battle against multidrug-resistant bacteria.
Narayanaswamy, Vidya P; Giatpaiboon, Scott A; Uhrig, John; Orwin, Paul; Wiesmann, William; Baker, Shenda M; Townsend, Stacy M
The incidence of multidrug-resistant (MDR) organisms, including methicillin-resistant Staphylococcus aureus (MRSA), is a serious threat to public health. Progress in developing new therapeutics is being outpaced by antibiotic resistance development, and alternative agents that rapidly permeabilize bacteria hold tremendous potential for treating MDR infections. A new class of glycopolymers includes polycationic poly-N (acetyl, arginyl) glucosamine (PAAG) is under development as an alternative to traditional antibiotic strategies to treat MRSA infections. This study demonstrates the antibacterial activity of PAAG against clinical isolates of methicillin and mupirocin-resistant Staphylococcus aureus. Multidrug-resistant S. aureus was rapidly killed by PAAG, which completely eradicated 88% (15/17) of all tested strains (6-log reduction in CFU) in ≤ 12-hours at doses that are non-toxic to mammalian cells. PAAG also sensitized all the clinical MRSA strains (17/17) to oxacillin as demonstrated by the observed reduction in the oxacillin MIC to below the antibiotic resistance breakpoint. The effect of PAAG and standard antibiotics including vancomycin, oxacillin, mupirocin and bacitracin on MRSA permeability was studied by measuring propidium iodide (PI) uptake by bacterial cells. Antimicrobial resistance studies showed that S. aureus developed resistance to PAAG at a rate slower than to mupirocin but similar to bacitracin. PAAG was observed to resensitize drug-resistant S. aureus strains sampled from passage 13 and 20 of the multi-passage resistance study, reducing MICs of mupirocin and bacitracin below their clinical sensitivity breakpoints. This class of bacterial permeabilizing glycopolymers may provide a new tool in the battle against multidrug-resistant bacteria.
Mukherjee, Angana; Bopp, Selina; Magistrado, Pamela; Wong, Wesley; Daniels, Rachel; Demas, Allison; Schaffner, Stephen; Amaratunga, Chanaki; Lim, Pharath; Dhorda, Mehul; Miotto, Olivo; Woodrow, Charles; Ashley, Elizabeth A; Dondorp, Arjen M; White, Nicholas J; Wirth, Dyann; Fairhurst, Rick; Volkman, Sarah K
Artemisinin resistance is associated with delayed parasite clearance half-life in vivo and correlates with ring-stage survival under dihydroartemisinin in vitro. Both phenotypes are associated with mutations in the PF3D7_1343700 pfkelch13 gene. Recent spread of artemisinin resistance and emerging piperaquine resistance in Southeast Asia show that artemisinin combination therapy, such as dihydroartemisinin-piperaquine, are losing clinical effectiveness, prompting investigation of drug resistance mechanisms and development of strategies to surmount emerging anti-malarial resistance. Sixty-eight parasites isolates with in vivo clearance data were obtained from two Tracking Resistance to Artemisinin Collaboration study sites in Cambodia, culture-adapted, and genotyped for pfkelch13 and other mutations including pfmdr1 copy number; and the RSA 0-3h survival rates and response to antimalarial drugs in vitro were measured for 36 of these isolates. Among these 36 parasites one isolate demonstrated increased ring-stage survival for a PfKelch13 mutation (D584V, RSA 0-3h = 8%), previously associated with slow clearance but not yet tested in vitro. Several parasites exhibited increased ring-stage survival, yet lack pfkelch13 mutations, and one isolate showed evidence for piperaquine resistance. This study of 68 culture-adapted Plasmodium falciparum clinical isolates from Cambodia with known clearance values, associated the D584V PfKelch13 mutation with increased ring-stage survival and identified parasites that lack pfkelch13 mutations yet exhibit increased ring-stage survival. These data suggest mutations other than those found in pfkelch13 may be involved in conferring artemisinin resistance in P. falciparum. Piperaquine resistance was also detected among the same Cambodian samples, consistent with reports of emerging piperaquine resistance in the field. These culture-adapted parasites permit further investigation of mechanisms of both artemisinin and piperaquine
Microtubules are highly dynamic structures that form spindle fibres during mitosis and are one of the most validated cancer targets. The success of drugs targeting microtubules, however, is often limited by the development of multidrug resistance. Here we describe the discovery and characterization of SSE15206, a pyrazolinethioamide derivative [3-phenyl-5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide] that has potent antiproliferative activities in cancer cell lines of different origins and overcomes resistance to microtubule-targeting agents. Treatment of cells with SSE15206 causes aberrant mitosis resulting in G2/M arrest due to incomplete spindle formation, a phenotype often associated with drugs that interfere with microtubule dynamics. SSE15206 inhibits microtubule polymerization both in biochemical and cellular assays by binding to colchicine site in tubulin as shown by docking and competition studies. Prolonged treatment of cells with the compound results in apoptotic cell death [increased Poly (ADP-ribose) polymerase cleavage and Annexin V/PI staining] accompanied by p53 induction. More importantly, we demonstrate that SSE15206 is able to overcome resistance to chemotherapeutic drugs in different cancer cell lines including multidrug-resistant KB-V1 and A2780-Pac-Res cell lines overexpressing MDR-1, making it a promising hit for the lead optimization studies to target multidrug resistance.
Jamil, K. F.
Tuberculosis (TB) is a chronic infectious disease mainly caused by Mycobacterium tuberculosis(MTB). 10.4 million new TB cases will appear in 2015 worldwide. There were an estimated 1.4 million TB deaths in 2015, and an additional 0.4 million deaths resulting from TB disease among people living with human immunodeficiency virus (HIV). Multidrug- resistant and extensively drug-resistant tuberculosis (MDR and XDR-TB) are major public health concerns worldwide. 480.000 new cases of MDR-TB will appear in 2015 and an additional 100,000 people with rifampicin-resistant TB (RR-TB) who were also newly eligible for MDR-TB treatment. Their association with HIV infection has contributed to the slowing down of TB incidence decline over the last two decades, therefore representing one important barrier to reach TB elimination. Patients infected with MDR-TB require more expensive treatment regimens than drug-susceptible TB, with poor treatment.Patients with multidrug- resistant tuberculosis do not receive rifampin; drug interactions risk is markedly reduced. However, overlapping toxicities may limit options for co-treatment of HIV and multidrug- resistant tuberculosis.
Fivelman, Quinton L; Butcher, Geoffrey A; Adagu, Ipemida S; Warhurst, David C; Pasvol, Geoffrey
We report the first in vitro and genetic confirmation of Malarone (GlaxoSmithKline; atovaquone and proguanil hydrochloride) resistance in Plasmodium falciparum acquired in Africa. On presenting with malaria two weeks after returning from a 4-week visit to Lagos, Nigeria without prophylaxis, a male patient was given a standard 3-day treatment course of Malarone. Twenty-eight days later the parasitaemia recrudesced. Parasites were cultured from the blood and the isolate (NGATV01) was shown to be resistant to atovaquone and the antifolate pyrimethamine. The cytochrome b gene of isolate NGATV01 showed a single mutation, Tyr268Asn which has not been seen previously.
Munro-Rojas, Daniela; Fernandez-Morales, Esdras; Zarrabal-Meza, José; Martínez-Cazares, Ma. Teresa; Parissi-Crivelli, Aurora; Fuentes-Domínguez, Javier; Séraphin, Marie Nancy; Lauzardo, Michael; González-y-Merchand, Jorge Alberto; Rivera-Gutierrez, Sandra
Background Mexico is one of the most important contributors of drug and multidrug-resistant tuberculosis in Latin America; however, knowledge of the genetic diversity of drug-resistant tuberculosis isolates is limited. Methods In this study, the genetic structure of 112 Mycobacterium tuberculosis strains from the southeastern Mexico was determined by spoligotyping and 24-loci MIRU-VNTRs. Findings The results show eight major lineages, the most of which was T1 (24%), followed by LAM (16%) and H (15%). A total of 29 (25%) isolates were identified as orphan. The most abundant SITs were SIT53/T1 and SIT42/LAM9 with 10 isolates each and SIT50/H3 with eight isolates. Fifty-two spoligotype patterns, twenty-seven clusters and ten clonal complexes were observed, demonstrating an important genetic diversity of drug and multidrug-resistant tuberculosis isolates in circulation and transmission level of these aggravated forms of tuberculosis. Being defined as orphan or as part of an orphan cluster, was a risk factor for multidrug resistant-tuberculosis (OR 2.5, IC 1.05–5.86 and OR 3.3, IC 1–11.03, respectively). Multiple correspondence analyses showed association of some clusters and SITs with specific geographical locations. Conclusions Our study provides one of the most detailed description of the genetic structure of drug and multidrug-resistant tuberculosis strains in southeast Mexico, establishing for the first time a baseline of the genotypes observed in resistant isolates circulating, however further studies are required to better elucidate the genetic structure of tuberculosis in region and the factors that could be participating in their dispersion. PMID:29543819
Kyle Dennis E
Full Text Available Abstract Background In vitro and in vivo resistance of Plasmodium falciparum to atovaquone or atovaquone-proguanil hydrochloride combination has been associated to two point mutations in the parasite cytochrome b (cytb gene (Tyr268Ser and Tyr268Asn. However, little is known about the prevalence of codon-268 mutations in natural populations of P. falciparum without previous exposure to the drug in Africa. Methods The prevalence of codon-268 mutations in the cytb gene of African P. falciparum isolates from Nigeria, Malawi and Senegal, where atovaquone-proguanil has not been introduced for treatment of malaria was assessed. Genotyping of the cytb gene in isolates of P. falciparum was performed by PCR-restriction fragment length polymorphism and confirmed by sequencing. Results 295 samples from Nigeria (111, Malawi (91 and Senegal (93 were successfully analyzed for detection of either mutant Tyr268Ser or Tyr268Asn. No case of Ser268 or Asn268 was detected in cytb gene of parasites from Malawi or Senegal. However, Asn268 was detected in five out of 111 (4.5% unexposed P. falciparum isolates from Nigeria. In addition, one out of these five mutant Asn268 isolates showed an additional cytb mutation leading to a Pro266Thr substitution inside the ubiquinone reduction site. Conclusion No Tyr268Ser mutation is found in cytb of P. falciparum isolates from Nigeria, Malawi or Senegal. This study reports for the first time cytb Tyr268Asn mutation in unexposed P. falciparum isolates from Nigeria. The emergence in Africa of P. falciparum isolates with cytb Tyr268Asn mutation is a matter of serious concern. Continuous monitoring of atovaquone-proguanil resistant P. falciparum in Africa is warranted for the rational use of this new antimalarial drug, especially in non-immune travelers.
Happi, Christian T; Gbotosho, Grace O; Folarin, Onikepe A; Milner, Danny; Sarr, Ousmane; Sowunmi, Akintunde; Kyle, Dennis E; Milhous, Wilbur K; Wirth, Dyann F; Oduola, Ayoade M J
In vitro and in vivo resistance of Plasmodium falciparum to atovaquone or atovaquone-proguanil hydrochloride combination has been associated to two point mutations in the parasite cytochrome b (cytb) gene (Tyr268Ser and Tyr268Asn). However, little is known about the prevalence of codon-268 mutations in natural populations of P. falciparum without previous exposure to the drug in Africa. The prevalence of codon-268 mutations in the cytb gene of African P. falciparum isolates from Nigeria, Malawi and Senegal, where atovaquone-proguanil has not been introduced for treatment of malaria was assessed. Genotyping of the cytb gene in isolates of P. falciparum was performed by PCR-restriction fragment length polymorphism and confirmed by sequencing. 295 samples from Nigeria (111), Malawi (91) and Senegal (93) were successfully analyzed for detection of either mutant Tyr268Ser or Tyr268Asn. No case of Ser268 or Asn268 was detected in cytb gene of parasites from Malawi or Senegal. However, Asn268 was detected in five out of 111 (4.5%) unexposed P. falciparum isolates from Nigeria. In addition, one out of these five mutant Asn268 isolates showed an additional cytb mutation leading to a Pro266Thr substitution inside the ubiquinone reduction site. No Tyr268Ser mutation is found in cytb of P. falciparum isolates from Nigeria, Malawi or Senegal. This study reports for the first time cytb Tyr268Asn mutation in unexposed P. falciparum isolates from Nigeria. The emergence in Africa of P. falciparum isolates with cytb Tyr268Asn mutation is a matter of serious concern. Continuous monitoring of atovaquone-proguanil resistant P. falciparum in Africa is warranted for the rational use of this new antimalarial drug, especially in non-immune travelers.
Bates, S E; Robey, R; Miyake, K
in the role of drug transporters in clinical drug resistance. These newly identified transporters include additional members of the MRP family, ABC2, and a new half-transporter, MXR/BCRP/ABCP1. This half-transporter confers high levels of resistance to mitoxantrone, anthracyclines, and the camptothecins SN-38...
and 4 were deemed to be contaminants, leaving 35 specimens for analysis of DST. DST was performed in 32 of the 35 isolates; 10 (31%) were resistant to at least one of .... (PCR) technologies that are emerging elsewhere. Future studies should investigate if extensively drug resistant TB (XDR-TB) strains are also affecting.
Regmi, A; Singh, P; Harford, A
Tuberculosis (TB) is a common opportunistic infection after renal transplantation. The risk of TB in renal transplant recipients is reported to be 20 to 74 times higher than in the general population. Although extrapulmonary TB occurs frequently, isolated ankle joint TB is a rare form of extrapulmonary TB infection. It is often difficult to diagnose because of its atypical presentation; management is complex, especially with multidrug-resistant TB, the need for a prolonged course of therapy, and the risks of drug interactions and drug toxicity. We report herein a case of a 60-year-old female renal allograft recipient who developed multidrug-resistant ankle joint TB 11 months after her deceased donor renal transplantation. She presented to the emergency department with escalating pain and swelling of the left ankle, difficulty in ambulation, and a low-grade fever. An x-ray of the ankle revealed an effusion and soft tissue swelling. A synovial fluid culture was performed which tested positive for acid fast bacilli which grew a multidrug-resistant form of Mycobacterium tuberculosis. She was initially treated with isoniazid, rifampin, ethambutol, and pyrazinamide; then therapy was tailored secondary to the resistant nature of the organism. She received a combination of extensive debridement of the joint and institution of second-line anti-TB therapy with pyrazinamide, ethambutol, moxifloxacin, and ethionamide. To our knowledge, no other cases of multidrug-resistant TB have been reported in the literature after renal transplantation. This case shows both an atypical presentation of TB and the difficulties in managing a transplant patient with this disease. Copyright © 2014 Elsevier Inc. All rights reserved.
Yurtsev, Eugene; Dai, Lei; Gore, Jeff
The emergence of antibiotic resistance in bacteria is a significant health concern. A frequent mechanism of antibiotic resistance involves the production of an enzyme which inactivates the antibiotic. By inactivating the antibiotic, resistant cells can ``share'' their resistance with other cells in the bacterial population, suggesting that it may be possible to observe cooperation between strains that inactivate different antibiotics. Here, we experimentally track the population dynamics of two E. coli strains in the presence of two different antibiotics. We find that together the strains are able to grow in antibiotic concentrations that inhibit growth of either of the strains individually. We observe that even when there is stable coexistence between the two strains, the population size of each strain can undergo large oscillations. We expect that our results will provide insight into the evolution of antibiotic resistance and the evolutionary origin of phenotypic diversity and cooperative behaviors.
Rao, Srinivasa P S; Lakshminarayana, Suresh B; Kondreddi, Ravinder R; Herve, Maxime; Camacho, Luis R; Bifani, Pablo; Kalapala, Sarath K; Jiricek, Jan; Ma, Ng L; Tan, Bee H; Ng, Seow H; Nanjundappa, Mahesh; Ravindran, Sindhu; Seah, Peck G; Thayalan, Pamela; Lim, Siao H; Lee, Boon H; Goh, Anne; Barnes, Whitney S; Chen, Zhong; Gagaring, Kerstin; Chatterjee, Arnab K; Pethe, Kevin; Kuhen, Kelli; Walker, John; Feng, Gu; Babu, Sreehari; Zhang, Lijun; Blasco, Francesca; Beer, David; Weaver, Margaret; Dartois, Veronique; Glynne, Richard; Dick, Thomas; Smith, Paul W; Diagana, Thierry T; Manjunatha, Ujjini H
New chemotherapeutic compounds against multidrug-resistant Mycobacterium tuberculosis (Mtb) are urgently needed to combat drug resistance in tuberculosis (TB). We have identified and characterized the indolcarboxamides as a new class of antitubercular bactericidal agent. Genetic and lipid profiling studies identified the likely molecular target of indolcarboxamides as MmpL3, a transporter of trehalose monomycolate that is essential for mycobacterial cell wall biosynthesis. Two lead candidates, NITD-304 and NITD-349, showed potent activity against both drug-sensitive and multidrug-resistant clinical isolates of Mtb. Promising pharmacokinetic profiles of both compounds after oral dosing in several species enabled further evaluation for efficacy and safety. NITD-304 and NITD-349 were efficacious in treating both acute and chronic Mtb infections in mouse efficacy models. Furthermore, dosing of NITD-304 and NITD-349 for 2 weeks in exploratory rat toxicology studies revealed a promising safety margin. Finally, neither compound inhibited the activity of major cytochrome P-450 enzymes or the hERG (human ether-a-go-go related gene) channel. These results suggest that NITD-304 and NITD-349 should undergo further development as a potential treatment for multidrug-resistant TB.
Park, Jin-Hyeong; Kim, Young-Ji; Binn-Kim; Seo, Kun-Ho
Wastewater treatment plants (WWTPs) that release treated wastewater into the environment have emerged as a major threat to public health. In this study, we investigated Escherichia coli load and antibiotic-resistance profiles across different treatment processes at a swine farm WWTP. The frequency of the detection of class 1 and 2 integrons, and their association with antibiotic resistance, were also analyzed. Samples were obtained at each of five sampling sites that represented each processing step within the WWTP. The largest decrease in E. coli load was observed during the anaerobic digestion step (from 4.86 to 2.89log CFU/mL). Isolates resistant to β-lactam antibiotics were efficiently removed after a series of treatment steps, whereas the proportions of isolates resistant to non-β-lactam antibiotics and multidrug-resistant strains were maintained across treatments. The occurrence of integron-positive strains was not significantly different at the various sampling sites (43.4-70%; p>0.05). Of the class 1 integron-positive isolates, 17.9% harbored the integron-associated gene cassettes aadA2, aadA12, aadA22, and dfrA15. To the best of our knowledge, this is the first description of a class 1 integron containing the aadA12 gene cassette from a swine farm and the presence of a class 1 integron containing dfrA15 in E. coli. This suggests that novel antibiotic-resistance gene cassette arrays could be generated in swine farm WWTPs. Moreover, 75% of integron-positive strains were categorized as multidrug resistant, whereas only 15.4% of integron-negative strains were multidrug resistant (pswine farm WWTPs in terms of the spread of antibiotic-resistant bacteria to the aquatic environment. Copyright © 2017 Elsevier Inc. All rights reserved.
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.
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
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
Ye, Lianwei; Li, Ruichao; Lin, Dachuan; Zhou, Yuanjie; Fu, Aisi; Ding, Qiong; Chan, Edward Wai Chi; Yao, Wen; Chen, Sheng
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.
Neyfakh, A A; Borsch, C M; Kaatz, G W
The gene of the Staphylococcus aureus fluoroquinolone efflux transporter protein NorA confers resistance to a number of structurally dissimilar drugs, not just to fluoroquinolones, when it is expressed in Bacillus subtilis. NorA provides B. subtilis with resistance to the same drugs and to a similar extent as the B. subtilis multidrug transporter protein Bmr does. NorA and Bmr share 44% sequence similarity. Both the NorA- and Bmr-conferred resistances can be completely reversed by reserpine.
Conclusions. Comprehensive assessment of integral indices of endogenous intoxication and level of certain pro- and anti-inflammatory cytokines in the blood plasma of patients with MDR TB shows a moderate endogenous intoxication, break down of the cellular component of the immune reactivity due to the formation of conditions for the development of Mycobacterium tuberculosis resistance, with further growth of cytotoxic hypoxia and activation of systemic inflammatory response syndrome. Analysis of plasma concentration of IL-6, IL-10 and IL-18 in patients with multidrug-resistance proved, that their level depends on the nature of Mycobacterium tuberculosis resistance.
Full Text Available Infections caused by antibiotic resistant pathogens are of significant concern and are associated with higher mortality and morbidity. Nitrofurantoin is a broad-spectrum bactericidal antibiotic and is effectively used to treat urinary tract infections (UTIs caused by E. coli, Klebsiella sp., Enterobacter sp., Enterococcus sp. and Staphylococcus aureus. It interfere with the synthesis of cell wall, bacterial proteins and DNA of both Gram positive and Gram negative pathogens. Nitrofurantoin has been used successfully for treatment and prophylaxis of acute lower urinary tract infections. With the emergence of antibiotic resistance, nitrofurantoin has become the choice of agent for treating UTIs caused by multi-drug resistant pathogens.
Naha, Sowjanya; Naha, Kushal; Acharya, Vasudev; Hande, H Manjunath; Vivek, G
We describe two cases of bacterial endocarditis secondary to multidrug-resistant Gram-negative organisms. In both cases, the diagnosis was made in accordance with the modified Duke's criteria and confirmed by histopathological analysis. Furthermore, in both instances there were no identifiable sources of bacteraemia and no history of contact with hospital or other medical services prior to the onset of symptoms. The patients were managed in similar fashion with prolonged broad-spectrum antibiotic therapy and surgical intervention and made complete recoveries. These cases highlight Gram-negative organisms as potential agents for endocarditis, as well as expose the dissemination of such multidrug-resistant bacteria into the community. The application of an integrated medical and surgical approach and therapeutic dilemmas encountered in managing these cases are described. 2014 BMJ Publishing Group Ltd.
Full Text Available Context: Possible linkage between biocide and antibiotic resistance in bacteria is a major area of concern. Aim: To evaluate the susceptibility of multidrug-resistant (MDR bacteria to four commonly used biocides. Settings and Design: A pilot study was conducted in a tertiary care hospital from April to November 2017. Materials and Methods: Fifty-four MDR bacterial isolates, namely Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus, were obtained from various clinical samples of inpatients. These isolates were subjected to tube dilution method for determining minimum inhibitory concentration (MIC of four commonly used biocides in our hospital, namely 5% w/v povidone iodine, absolute ethanol (99.9%, sodium hypochlorite (4% available chlorine, and quaternary ammonium compounds (QACs (3.39%. Minimum bactericidal concentration (MBC of these biocides was determined as per standard guidelines. Similar tests were also performed on corresponding American Type Culture Collection (ATCC bacterial strains. Statistical Analysis: The Fisher exact test. Results: Twenty-two MDR bacterial isolates had higher MIC values for QACs than their corresponding ATCC strains. Statistically significant difference in proportion of test isolates exhibiting higher MIC values for QACs and absolute ethanol was observed (P-value = 0.02. Twenty-four MDR bacterial isolates exhibited higher MBC values for sodium hypochlorite than their corresponding ATCC strains. The difference in proportion of test isolates exhibiting higher MBC values for sodium hypochlorite and absolute ethanol, respectively, was statistically significant (P-value <0.0001. The difference in proportion of test isolates exhibiting higher MBC values for absolute ethanol versus QACs and povidone iodine, respectively, was statistically significant (P-values = 0.0003 and 0.0076. Statistically significant differences in susceptibility to biocides among test isolates were also
This study aimed at determining anti-microbial resistance pattern of food borne illness ... bial drugs in the pharmaceutical pipeline.2 The effective- ness of ... Materials and methods ... selected based on local availability, clinical efficiency, liter-.
Bhatta, Dharm R.; Cavaco, Lina; Nath, Gopal
antibiotic susceptibility testing in developing countries like Nepal. Hospital acquired infections including prevalence of MRSA can be minimized by appropriate hygienic measures in patient care and management and by antibiotic stewardship. Screening of erythromycin resistant isolates would minimize clinical...
van Harten, Roel M; Willems, Rob J L; Martin, Nathaniel I; Hendrickx, Antoni P A
Over the past two decades infections due to antibiotic-resistant bacteria have escalated world-wide, affecting patient morbidity, mortality, and health care costs. Among these bacteria, Enterococcus faecium and Enterococcus faecalis represent opportunistic nosocomial pathogens that cause
Coon, J S; Knudson, W; Clodfelter, K; Lu, B; Weinstein, R S
A recently developed non-ionic surfactant called Solutol HS 15 (poly-oxyethylene esters of 12-hydroxystearic acid), with low toxicity in vivo, was shown to reverse completely the multidrug resistance of KB 8-5 and KB 8-5-11 human epidermoid carcinoma cells in vitro but did not potentiate drug toxicity in drug-sensitive KB 3-1 cells. At a concentration of 10% of its own IC50 (mean concentration of drug that causes 50% inhibition of cell growth compared to controls), Solutol HS 15 produced a 35-, 28-, and 42-fold reduction in the resistance of KB 8-5-11 cells to colchicine, vinblastine, and doxorubicin, respectively. Solutol HS 15 was relatively much more potent than the prototypic reversing agent, verapamil, for reversing colchicine resistance, compared to the ability of each agent to reverse colchicine resistance, compared to the ability of each agent to reverse vinblastine resistance. Like verapamil, Solutol HS 15 promoted a 50-fold accumulation of rhodamine 123 in KB 8-5-11 cells, as measured by flow cytometry. Also, Solutol HS 15 and verapamil reduced the efflux of rhodamine 123 from KB 8-5-11 cells previously loaded with rhodamine 123 to a similar low rate. Solutol HS 15 did not affect the transport of alanine or glucose into KB 8-5-11 cells, indicating that its effect upon membrane active transport is not entirely nonspecific. Considering their different structure and different relative potency for reversing colchicine resistance, Solutol HS 15 and verapamil probably reverse multidrug resistance by different mechanisms. Solutol HS 15 merits consideration as a potential therapeutic agent because of its effectiveness for reversing multidrug resistance in vitro and its low toxicity in vivo.
Full Text Available Abstract Background Over the last decade, nosocomial infections due to Acinetobacter baumannii have been described with an increasing trend towards multidrug resistance, mostly in intensive care units. The aim of the present study was to determine the clonal relatedness of clinical isolates and to elucidate the genetic basis of imipenem resistance. Methods A. baumannii isolates (n = 83 originated from two hospital settings in central Ohio were used in this study. Pulsed-field gel electrophoresis genotyping and antimicrobial susceptibility testing for clinically relevant antimicrobials were performed. Resistance determinants were characterized by using different phenotypic (accumulation assay for efflux and genotypic (PCR, DNA sequencing, plasmid analysis and electroporation approaches. Results The isolates were predominantly multidrug resistant (>79.5% and comprised of thirteen unique pulsotypes, with genotype VII circulating in both hospitals. The presence of blaOXA-23 in 13% (11/83 and ISAba1 linked blaOXA-66 in 79.5% (66/83 of clinical isolates was associated with high level imipenem resistance. In this set of OXA producing isolates, multidrug resistance was bestowed by blaADC-25, class 1 integron-borne aminoglycoside modifying enzymes, presence of sense mutations in gyrA/parC and involvement of active efflux (with evidence for the presence of adeB efflux gene. Conclusion This study underscores the major role of carbapenem-hydrolyzing class D β-lactamases, and in particular the acquired OXA-23, in the dissemination of imipenem-resistant A. baumannii. The co-occurrence of additional resistance determinant could also be a significant threat.
Full Text Available 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
Heckel, Maria; Herbst, Franziska A; Adelhardt, Thomas; Tiedtke, Johanna M; Sturm, Alexander; Stiel, Stephanie; Ostgathe, Christoph
Background Information lacks about institutional stakeholders’ perspectives on management approaches of multidrug-resistant bacterial organism in end-of-life situations. The term “institutional stakeholder” includes persons in leading positions with responsibility in hospitals’ multidrug-resistant bacterial organism management. They have great influence on how strategies on multidrug-resistant bacterial organism management approaches in institutions of the public health system are designed. This study targeted institutional stakeholders’ individual perspectives on multidrug-resistant bacterial organism colonization or infection and isolation measures at the end of life. Methods Between March and December 2014, institutional stakeholders of two study centers, a German palliative care unit and a geriatric ward, were queried in semistructured interviews. Interviews were audiotaped, transcribed verbatim, and analyzed qualitatively with the aid of the software MAXQDA for qualitative data analysis using principles of Grounded Theory. In addition, two external stakeholders were interviewed to enrich data. Results Key issues addressed by institutional stakeholders (N=18) were the relevance of multidrug-resistant bacterial organism in palliative and geriatric care, contradictions between hygiene principles and patients’ and family caregivers’ needs and divergence from standards, frame conditions, and reflections on standardization of multidrug-resistant bacterial organism end-of-life care procedures. Results show that institutional stakeholders face a dilemma between their responsibility in protecting third persons and ensuring patients’ quality of life. Until further empirical evidence establishes a clear multidrug-resistant bacterial organism management approach in end-of-life care, stakeholders suggest a case-based approach. Conclusion The institutional stakeholders’ perspectives and their suggestion of a case-based approach advance the development
Heckel, Maria; Herbst, Franziska A; Adelhardt, Thomas; Tiedtke, Johanna M; Sturm, Alexander; Stiel, Stephanie; Ostgathe, Christoph
Information lacks about institutional stakeholders' perspectives on management approaches of multidrug-resistant bacterial organism in end-of-life situations. The term "institutional stakeholder" includes persons in leading positions with responsibility in hospitals' multidrug-resistant bacterial organism management. They have great influence on how strategies on multidrug-resistant bacterial organism management approaches in institutions of the public health system are designed. This study targeted institutional stakeholders' individual perspectives on multidrug-resistant bacterial organism colonization or infection and isolation measures at the end of life. Between March and December 2014, institutional stakeholders of two study centers, a German palliative care unit and a geriatric ward, were queried in semistructured interviews. Interviews were audiotaped, transcribed verbatim, and analyzed qualitatively with the aid of the software MAXQDA for qualitative data analysis using principles of Grounded Theory. In addition, two external stakeholders were interviewed to enrich data. Key issues addressed by institutional stakeholders (N=18) were the relevance of multidrug-resistant bacterial organism in palliative and geriatric care, contradictions between hygiene principles and patients' and family caregivers' needs and divergence from standards, frame conditions, and reflections on standardization of multidrug-resistant bacterial organism end-of-life care procedures. Results show that institutional stakeholders face a dilemma between their responsibility in protecting third persons and ensuring patients' quality of life. Until further empirical evidence establishes a clear multidrug-resistant bacterial organism management approach in end-of-life care, stakeholders suggest a case-based approach. The institutional stakeholders' perspectives and their suggestion of a case-based approach advance the development process of a patient-, family-, staff-, and institutional
Hartmeyer, G N; Sóki, J; Nagy, E
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...... been reported to date of MDR B. fragilis group in Europe. As far as we know, a case like this with MDR B. fragilis has not been described in Scandinavia before....
Ben-Ami, Ronen; Berman, Judith; Novikov, Ana; Bash, Edna; Shachor-Meyouhas, Yael; Zakin, Shiri; Maor, Yasmin; Tarabia, Jalal; Schechner, Vered; Adler, Amos; Finn, Talya
Candida auris and C. haemulonii are closely related, multidrug-resistant emerging fungal pathogens that are not readily distinguishable with phenotypic assays. We studied C. auris and C. haemulonii clinical isolates from 2 hospitals in central Israel. C. auris was isolated in 5 patients with nosocomial bloodstream infection, and C. haemulonii was found as a colonizer of leg wounds at a peripheral vascular disease clinic. Liberal use of topical miconazole and close contact among patients were ...
Asgedom, Solomon Weldegebreal; Teweldemedhin, Mebrahtu; Gebreyesus, Hailay
Background. Multidrug-resistant tuberculosis (MDR-TB) has continued to be a challenge for tuberculosis (TB) control globally. Ethiopia is one of the countries with high MDR-TB burden. Objective. The main purpose of this study was to determine the prevalence of MDR-TB and associated factors in Ethiopia. Methods. A systematic review of the literatures on prevalence of MDR-TB and associated factors was conducted in the country. Results. In our electronic search, 546 citations were depicted. Amon...
Porse, Andreas; Schønning, Kristian; Munck, Christian
sequencing to show that the long-term persistence and molecular integrity of the plasmid is highly influenced by multiple factors within a 25 kb plasmid region constituting a host-dependent burden. In the E. coli hosts investigated here, improved plasmid stability readily evolves via IS26 mediated deletions...... consistently followed by all evolved E. coli lineages exposes a trade-off between horizontal and vertical transmission that may ultimately limit the dissemination potential of clinical multidrug resistance plasmids in these hosts....
Adigbli, D. K.; Wilson, D. G. G.; Farooqui, N.; Sousi, E.; Risley, P.; Taylor, I.; MacRobert, A. J.; Loizidou, M.
Multidrug resistance (MDR) is the major confounding factor in adjuvant solid tumour chemotherapy. Increasing intracellular amounts of chemotherapeutics to circumvent MDR may be achieved by a novel delivery method, photochemical internalisation (PCI). PCI consists of the co-administration of drug and photosensitiser; upon light activation the latter induces intracellular release of organelle-bound drug. We investigated whether co-administration of hypericin ( photosensitiser) with mitoxantrone...
Adigbli, D K; Wilson, D G G; Farooqui, N; Sousi, E; Risley, P; Taylor, I; MacRobert, A J; Loizidou, M
Multidrug resistance (MDR) is the major confounding factor in adjuvant solid tumour chemotherapy. Increasing intracellular amounts of chemotherapeutics to circumvent MDR may be achieved by a novel delivery method, photochemical internalisation (PCI). PCI consists of the co-administration of drug and photosensitiser; upon light activation the latter induces intracellular release of organelle-bound drug. We investigated whether co-administration of hypericin (photosensitiser) with mitoxantrone ...
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.
DIDEUTERO AND DITRITIOISOTOPOMERS OF THE MULTIDRUG RESISTANCE MODULATOR LY335979 WERE PREPARED BY INITIAL BROMINATION OF 5-HYDROXYQUINOLINE UNDER ACIDIC CONDITIONS FOLLOWED BY MITSUNOBU COUPLING OF 6,8-DIBROMO-5-HYDROXYQUINOLINE WITH (S)-GLYCIDOL. OPENING OF THE RESULTING EPOXIDE WITH DIBENZOSUBERYLPIPERAZINE LY335995 RESULTED IN DIBROMOANALOG OF LY335979, WHICH WAS FINALLY REDUCTIVELY DEBROMINATED WITH DEUTERIUM OR TRITIUM IN THE PRESENCE OF PALLADIUM ON CARBON. (AUTHOR)
Juliano, Jonathan J; Randrianarivelojosia, Milijaona; Ramarosandratana, Benjamin; Ariey, Frédéric; Mwapasa, Victor; Meshnick, Steven R
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 (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. PMID:19291288
Cheng, Tangjian; Liu, Jinjian; Ren, Jie; Huang, Fan; Ou, Hanlin; Ding, Yuxun; Zhang, Yumin; Ma, Rujiang; An, Yingli; Liu, Jianfeng; Shi, Linqi
Chemotherapy for cancer treatment has been demonstrated to cause some side effects on healthy tissues and multidrug resistance of the tumor cells, which greatly limits therapeutic efficacy. To address these limitations and achieve better therapeutic efficacy, combination therapy based on nanoparticle platforms provides a promising approach through delivering different agents simultaneously to the same destination with synergistic effect. In this study, a novel green tea catechin-based polyion complex (PIC) micelle loaded with doxorubicin (DOX) and (-)-Epigallocatechin-3-O-gallate (EGCG) was constructed through electrostatic interaction and phenylboronic acid-catechol interaction between poly(ethylene glycol)-block-poly(lysine-co-lysine-phenylboronic acid) (PEG-PLys/PBA) and EGCG. DOX was co-loaded in the PIC micelles through π-π stacking interaction with EGCG. The phenylboronic acid-catechol interaction endowed the PIC micelles with high stability under physiological condition. Moreover, acid cleavability of phenylboronic acid-catechol interaction in the micelle core has significant benefits for delivering EGCG and DOX to same destination with synergistic effects. In addition, benefiting from the oxygen free radicals scavenging activity of EGCG, combination therapy with EGCG and DOX in the micelle core could protect the cardiomyocytes from DOX-mediated cardiotoxicity according to the histopathologic analysis of hearts. Attributed to modulation of EGCG on P-glycoprotein (P-gp) activity, this kind of PIC micelles could effectively reverse multidrug resistance of cancer cells. These results suggested that EGCG based PIC micelles could effectively overcome DOX induced cardiotoxicity and multidrug resistance. PMID:27375779
Weber, J M; Sircar, S; Horvath, J; Dion, P
Three independent variants (G2, G4, G5), resistant to methylglyoxal bis(guanylhydrazone), an anticancer drug, have been isolated by single step selection from an adenovirus-transformed rat brain cell line (1). These variants display selective cross-resistance to several natural product drugs of dissimilar structure and action. Multidrug resistance has recently been shown to be caused by overexpression of the membrane-associated p-glycoprotein, most often caused by amplification of the mdr gene. Several types of experiments were conducted to determine whether the observed drug resistance in our cell lines could be due to changes at the mdr locus. The following results were obtained: (a) the mdr locus was not amplified; (b) transcription of the mdr gene and p-glycoprotein synthesis were not increased; (c) multidrug resistance cell lines, which carry an amplified mdr locus, were not cross-resistant to methylglyoxal bis(guanylhydrazone); (d) verapamil did not reverse the resistance of G cells or mdr cells to methylglyoxal bis(guanylhydrazone), nor that of G cells to vincristine; and (e) methylglyoxal bis(guanylhydrazone) resistance was recessive and depended on a block to drug uptake, as opposed to mdr cells which are dominant and express increased drug efflux. The results obtained suggest that the drug resistance in the G2, G4, and G5 cells was atypical and may be due to a mechanism distinct from that mediated by the mdr locus.
S F Swedan
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.
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
Hashem, Hany; Hanora, Amro; Abdalla, Salah; Shawky, Alaa; Saad, Alaa
Resistant Pseudomonas aeruginosa is a serious concern for antimicrobial therapy, as the common isolates exhibit variable grades of resistance, involving beta-lactamase enzymes, beside native defense mechanisms. The present study was designed to determine the occurrence of Metallo-β- Lactamases (MBL) and Amp C harboring P. aeruginosa isolates from Suez Canal university hospital in Ismailia, Egypt. A total of 147 P. aeruginosa isolates, recovered from 311 patients during a 10-month period, were collected between May 2013 and February 2014; the isolates were collected from urine, wound and sputum. Minimum inhibitory concentration (MIC) determined by agar dilution methods was ≥2 μg/mL for meropenem and imipenem. Identification of P. aeruginosa was confirmed using API 20NE. Metallo-β- Lactamases and Amp C were detected based on different phenotypic methods. Overall, 26.5% of P. aeruginosa isolates (39/147) were carbapenem resistant isolates. Furthermore, 64.1% (25/39) were MBL producers, these isolates were screened by the combined disc and disc diffusion methods to determine the ability of MBL production. Both MBL and Amp C harbored P. aeruginosa isolates were 28% (7/25). Sixty-four percent of P. aeruginosa isolates were multidrug resistant (MDR) (16/25). The sensitivity toward polymyxin, imipenem, norfloxacin, piperacillin-tazobactam and gentamicin was 99%, 91%, 88%, 82% and 78%, respectively. The resistance rate towards cefotaxime, ceftazidime, cefepime, aztreonam and meropenem was 98.6%, 86%, 71.4%, 34% and 30%, respectively. Multidrug resistance was significantly associated with MBL production in P. aeruginosa . Early detection of MBL-producing P. aeruginosa and hospital antibiotic policy prescription helps proper antimicrobial therapy and avoidance of dissemination of these multidrug resistance isolates.
Mohd Abd Razak, Mohd Ridzuan; Afzan, Adlin; Ali, Rosnani; Amir Jalaluddin, Nur Fasihah; Wasiman, Mohd Isa; Shiekh Zahari, Siti Habsah; Abdullah, Noor Rain; Ismail, Zakiah
The development of resistant to current antimalarial drugs is a major challenge in achieving malaria elimination status in many countries. Therefore there is a need for new antimalarial drugs. Medicinal plants have always been the major source for the search of new antimalarial drugs. The aim of this study was to screen selected Malaysian medicinal plants for their antiplasmodial properties. Each part of the plants were processed, defatted by hexane and sequentially extracted with dichloromethane, methanol and water. The antiplasmodial activities of 54 plant extracts from 14 species were determined by Plasmodium falciparum Histidine Rich Protein II ELISA technique. In order to determine the selectivity index (SI), all plant extracts demonstrating a good antiplasmodial activity were tested for their cytotoxicity activity against normal Madin-Darby Bovine Kidney (MDBK) cell lines by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Twenty three extracts derived from Curcuma zedoaria (rhizome), Curcuma aeruginosa (rhizome), Alpinia galanga (rhizome), Morinda elliptica (leaf), Curcuma mangga (rhizome), Elephantopus scaber (leaf), Vitex negundo (leaf), Brucea javanica (leaf, root and seed), Annona muricata (leaf), Cinnamomun iners (leaf) and Vernonia amygdalina (leaf) showed promising antiplasmodial activities against the blood stage chloroquine resistant P. falciparum (EC50 toxicity effect to MDBK cells in vitro (SI ≥10). The extracts belonging to eleven plant species were able to perturb the growth of chloroquine resistant P. falciparum effectively. The findings justified the bioassay guided fractionation on these plants for the search of potent antimalarial compounds or formulation of standardized extracts which may enhance the antimalarial effect in vitro and in vivo.
Background: Nasal Staphylococcus aureus is a major source of community and hospital associated staphylococcal infections. This study determined the prevalence of nasal S. aureus isolates and investigated their antimicrobial resistance profile in healthy volunteers. Methods: Nasal specimens of healthy volunteers in ...
Purpose: To study the prevalence of resistant strains of S. aureus isolated from surfaces, beds and various equipment of an Iranian hospital emergency ward. Methods: Two hundred swab samples were collected from the surfaces, beds, trolleys, surgical equipment and diagnostic medical devices in emergency ward.
Diacon, Andreas H.; Pym, Alexander; Grobusch, Martin; Patientia, Ramonde; Rustomjee, Roxana; Page-Shipp, Liesl; Pistorius, Christoffel; Krause, Rene; Bogoshi, Mampedi; Churchyard, Gavin; Venter, Amour; Allen, Jenny; Palomino, Juan Carlos; de Marez, Tine; van Heeswijk, Rolf P. G.; Lounis, Nacer; Meyvisch, Paul; Verbeeck, Johan; Parys, Wim; de Beule, Karel; Andries, Koen; Mc Neeley, David F.
BACKGROUND: The diarylquinoline TMC207 offers a new mechanism of antituberculosis action by inhibiting mycobacterial ATP synthase. TMC207 potently inhibits drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro and shows bactericidal activity in patients who have drug-susceptible
Aims: This study was aimed to determine the antimicrobial susceptibility and the prevalence of MβL among carbapenem‑resistant isolates of A. baumannii. Materials and Methods: In this cross‑sectional study from October 2012 to April 2013, 98 isolates were identified as A. baumannii using Microgen™ kits and confirmed by ...
Wittekamp, Bastiaan H J; Bonten, Marc J M
The prophylactic use of antibiotics can only be justified when clinical benefits on relevant patient outcomes, such as morbidity or mortality, cost-effectiveness, and absence of immediate emergence of antibiotic resistance have been unequivocally demonstrated. In some intensive care unit (ICU) patients, antibiotic prophylaxis is used as part of selective digestive tract decontamination (SDD) and selective oropharyngeal decontamination (SOD). Recent trials in ICUs with low levels of antibiotic resistance strongly suggest that both regimens reduce the incidence of ICU-acquired infections and improve patient survival. Naturally, the unique microbial ecology of such settings reduce generalizability of results. Therefore, the routine use of SOD and SDD remains highly controversial, especially in ICUs with higher levels of antibiotic resistance. Moreover, convincing evidence is still missing on several important aspects related to efficacy and safety. Despite numerous trials, effects of SDD and SOD on antibiotic resistance during and after decolonization treatment have still been insufficiently investigated, and existing results are contradicting. Furthermore, the effects of both regimens on the non-culturable part of the intestinal flora remain unknown. Finally, cost-effectiveness has not been thoroughly investigated, and prices of the antimicrobial agents that have been used have increased dramatically in recent years. In this review, important knowledge gaps that so far prevent the widespread use of SDD and SOD will be addressed.
The SP cells showed high resistance to drugs such as 5-fluorouracil, cisplatin, paclitaxel (2 μmol/L) and oxaliplatin. The survival rate of SP cells after treatment with these drugs was significantly higher (p < 0.01) than that of non-SP cells. Furthermore, the number of spheres generated in serumfree medium was significantly ...
Virology, School of Medicine, Shiraz ... carbapenem‑resistant isolates, 43 were phenotypically positive for MβL; out of 43 isolates, 37 .... of Iran) was used as the positive control. ..... Coexistence of blaNDM‑1 with the prevalent blaOXA23 and.
Results: SP cells in the prostate cancer samples constituted 2.8 %, but fell to 0.6 % after treatment with ... tumor. Keywords: Side population cells, ABC transporters, Cancer stem cells, Chemotherapy, Prostate treatment failure, Tumor recurrence, Drug resistance ..... Identification of human brain tumour initiating cells.
Carey, Maureen A; Papin, Jason A; Guler, Jennifer L
Malaria remains a major public health burden and resistance has emerged to every antimalarial on the market, including the frontline drug, artemisinin. Our limited understanding of Plasmodium biology hinders the elucidation of resistance mechanisms. In this regard, systems biology approaches can facilitate the integration of existing experimental knowledge and further understanding of these mechanisms. Here, we developed a novel genome-scale metabolic network reconstruction, iPfal17, of the asexual blood-stage P. falciparum parasite to expand our understanding of metabolic changes that support resistance. We identified 11 metabolic tasks to evaluate iPfal17 performance. Flux balance analysis and simulation of gene knockouts and enzyme inhibition predict candidate drug targets unique to resistant parasites. Moreover, integration of clinical parasite transcriptomes into the iPfal17 reconstruction reveals patterns associated with antimalarial resistance. These results predict that artemisinin sensitive and resistant parasites differentially utilize scavenging and biosynthetic pathways for multiple essential metabolites, including folate and polyamines. Our findings are consistent with experimental literature, while generating novel hypotheses about artemisinin resistance and parasite biology. We detect evidence that resistant parasites maintain greater metabolic flexibility, perhaps representing an incomplete transition to the metabolic state most appropriate for nutrient-rich blood. Using this systems biology approach, we identify metabolic shifts that arise with or in support of the resistant phenotype. This perspective allows us to more productively analyze and interpret clinical expression data for the identification of candidate drug targets for the treatment of resistant parasites.
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
Carter, Tamar E.; Boulter, Alexis; Existe, Alexandre; Romain, Jean R.; St. Victor, Jean Yves; Mulligan, Connie J.; Okech, Bernard A.
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
Full Text Available Plasmodium falciparum sensitivity to chloroquine (CHL, amodiaquine (AMO and sulfadoxine/pyrimethamine (SDX/PYR was assessed in vivo and in vitro in a representative sample from the population of Zaragoza in El Bajo Cauca region (Antioquia-Colombia. There were 94 patients with P. falciparum evaluated. For the in vivo test the patients were followed by clinical examination and microscopy, during 7 days. The in vitro test was performed following the recommendations of the World Health Organization. The in vivo prevalence of resistance to CHL was 67%, to AMO 3% and to SDX/PYR 9%. The in vitro test showed sensitivity to all antimalarials evaluated. Concordance for CHL between the in vivo and in vitro tests was 33%. For AMO and SDX/PYR, the concordance was 100%. We conclude that a high percentage of patients are resistant to CHL (in vivo. A high rate of intestinal parasitism might explain in part, the differences observed between the in vivo and the in vitro results. Therefore, new policies and treatment regimens should be proposed for the treatment of the infection in the region. Nationwide studies assessing the degree of resistance are needed.
Newton Paul N
Full Text Available Abstract Background Artemisinin resistance in Plasmodium falciparum malaria has emerged in Western Cambodia. This is a major threat to global plans to control and eliminate malaria as the artemisinins are a key component of antimalarial treatment throughout the world. To identify key features associated with the delayed parasite clearance phenotype, we employed DNA microarrays to profile the physiological gene expression pattern of the resistant isolates. Results In the ring and trophozoite stages, we observed reduced expression of many basic metabolic and cellular pathways which suggests a slower growth and maturation of these parasites during the first half of the asexual intraerythrocytic developmental cycle (IDC. In the schizont stage, there is an increased expression of essentially all functionalities associated with protein metabolism which indicates the prolonged and thus increased capacity of protein synthesis during the second half of the resistant parasite IDC. This modulation of the P. falciparum intraerythrocytic transcriptome may result from differential expression of regulatory proteins such as transcription factors or chromatin remodeling associated proteins. In addition, there is a unique and uniform copy number variation pattern in the Cambodian parasites which may represent an underlying genetic background that contributes to the resistance phenotype. Conclusions The decreased metabolic activities in the ring stages are consistent with previous suggestions of higher resilience of the early developmental stages to artemisinin. Moreover, the increased capacity of protein synthesis and protein turnover in the schizont stage may contribute to artemisinin resistance by counteracting the protein damage caused by the oxidative stress and/or protein alkylation effect of this drug. This study reports the first global transcriptional survey of artemisinin resistant parasites and provides insight to the complexities of the molecular basis
Conclusions: Beta-lactamase mediated resistance mechanisms are accounting very high in the multidrug resistant isolates of E. coli. Therefore, early detection of beta lactamase mediated resistant strains and their current antibiotic susceptibility pattern is necessary to avoid treatment failure and prevent the spread of MDR. Keywords: e. coli; extended-spectrum-β-lactamase; metallo-β-lactamase; multidrug-resistance.
Full Text Available Cancer multidrug resistance (MDR occurs when cancer cells evade the cytotoxic actions of chemotherapeutics through the active efflux of drugs from within the cells. Our group have previously demonstrated that multidrug-resistant breast cancer cells spontaneously shed microparticles (MPs and that these MPs can transfer resistance to drug-responsive cells and confer MDR on those cells in as little as 4 h. Furthermore, we also showed that, unlike MPs derived from leukaemia cells, breast cancer–derived MPs display a tissue selectivity in the transfer of P-glycoprotein (P-gp, transferring the resistance protein only to malignant breast cells. This study aims to define the proteome of breast cancer–derived MPs in order to understand the differences in protein profiles between those shed from drug-resistant versus drug-sensitive breast cancer cells. In doing so, we detail the protein cargo required for the intercellular transfer of MDR to drug-sensitive recipient cells and the factors governing the transfer selectivity to malignant breast cells. We describe the first proteomic analysis of MPs derived from human breast cancer cells using SDS PAGE and liquid chromatography–tandem mass spectrometry (LC/MS/MS, in which we identify 120 unique proteins found only in drug-resistant, breast cancer–derived MPs. Our results demonstrate that the MP-mediated transfer of P-gp to recipient cells occurs alongside CD44; the Ezrin, Radixin and Moesin protein family (ERM; and cytoskeleton motor proteins within the MP cargo.
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
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. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
Nishikawa, Joy L; Boeszoermenyi, Andras; Vale-Silva, Luis A; Torelli, Riccardo; Posteraro, Brunella; Sohn, Yoo-Jin; Ji, Fei; Gelev, Vladimir; Sanglard, Dominique; Sanguinetti, Maurizio; Sadreyev, Ruslan I; Mukherjee, Goutam; Bhyravabhotla, Jayaram; Buhrlage, Sara J; Gray, Nathanael S; Wagner, Gerhard; Näär, Anders M; Arthanari, Haribabu
Eukaryotic transcription activators stimulate the expression of specific sets of target genes through recruitment of co-activators such as the RNA polymerase II-interacting Mediator complex. Aberrant function of transcription activators has been implicated in several diseases. However, therapeutic targeting efforts have been hampered by a lack of detailed molecular knowledge of the mechanisms of gene activation by disease-associated transcription activators. We previously identified an activator-targeted three-helix bundle KIX domain in the human MED15 Mediator subunit that is structurally conserved in Gal11/Med15 Mediator subunits in fungi. The Gal11/Med15 KIX domain engages pleiotropic drug resistance transcription factor (Pdr1) orthologues, which are key regulators of the multidrug resistance pathway in Saccharomyces cerevisiae and in the clinically important human pathogen Candida glabrata. The prevalence of C. glabrata is rising, partly owing to its low intrinsic susceptibility to azoles, the most widely used antifungal agent. Drug-resistant clinical isolates of C. glabrata most commonly contain point mutations in Pdr1 that render it constitutively active, suggesting that this transcriptional activation pathway represents a linchpin in C. glabrata multidrug resistance. Here we perform sequential biochemical and in vivo high-throughput screens to identify small-molecule inhibitors of the interaction of the C. glabrata Pdr1 activation domain with the C. glabrata Gal11A KIX domain. The lead compound (iKIX1) inhibits Pdr1-dependent gene activation and re-sensitizes drug-resistant C. glabrata to azole antifungals in vitro and in animal models for disseminated and urinary tract C. glabrata infection. Determining the NMR structure of the C. glabrata Gal11A KIX domain provides a detailed understanding of the molecular mechanism of Pdr1 gene activation and multidrug resistance inhibition by iKIX1. We have demonstrated the feasibility of small-molecule targeting of a
Kristiansen, Jette E; Dastidar, Sujata G; Palchoudhuri, Shauroseni
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]....
Full Text Available Background: Biofilm formation plays an important role in resistance of Staphylococcus aureus isolates; especially multidrug-resistant isolates are a threat to healthcare settings. Objectives: The aims of this study were to detect biofilm formation and presence of several related genes among multidrug-resistant (MDR isolates of Staphylococcus aureus. Patients and Methods: A total Of 209 S. aureus strains were isolated from patients and identified by conventional diagnostic tests. The multidrug-resistant MRSA isolates were detected by antibiotic susceptibility test. The phenotypic biofilm formation was detected by micro-titre tissue plate assay. The polymerase chain reaction (PCR was performed to detect the mecA, Staphylococcal Cassette Chromosome mec (SCCmec types, accessory gene regulatory (agr genes, the icaADBC and several genes encoding staphylococcal surface proteins including clfAB, fnbAB, fib, eno, can, ebps and bbp genes with specific primers. Results: Sixty-four (30.6% isolates were methicillin-resistant, among which thirty-six (56.2% were MDR. These isolates were resistant to amoxicillin, tetracycline, ciprofloxacin, gentamicin, erythromycin and trimethoprim-sulfamethoxazole (except to 6 isolates. All the isolates were susceptible to vancomycin and linezolid. All the MDR-MRSA harbored SCCmec type III. All the MDR- MRSA isolates were strong biofilm producers in the phenotypic test. The majority of MDR- MRSA was belonged to agrI (67%, n = 24, followed by agr II (17%, n = 6, agrIV (11%, n = 4 and agrIII (5.5%, n = 2. The frequency of icaADBC genes were 75% (n = 27, 61% (n = 22, 72% (n = 26 and 72% (n = 26, respectively. Furthermore, the prevalence of clfA, clfB, fnbA, fnbB, fib, can, eno, ebps and bbp genes was 100%, 100%, 67%, 56%, 80%, 63%, 78%, 7% and 0%, respectively. Furthermore, approximately all the MRSA was strong biofilm producers. Conclusions: Multidrug-resistant isolates produced biofilm strongly and the majority harbored most
Cochrane, Stephen A; Lohans, Christopher T; van Belkum, Marco J; Bels, Manon A; Vederas, John C
Previously other groups had reported that Paenibacillus polymyxa NRRL B-30507 produces SRCAM 37, a type IIA bacteriocin with antimicrobial activity against Campylobacter jejuni. Genome sequencing and isolation of antimicrobial compounds from this P. polymyxa strain show that the antimicrobial activity is due to polymyxins and tridecaptin B1. The complete structural assignment, synthesis, and antimicrobial profile of tridecaptin B1 is reported, as well as the putative gene cluster responsible for its biosynthesis. This peptide displays strong activity against multidrug resistant Gram-negative bacteria, a finding that is timely to the current problem of antibiotic resistance.
The author discussed the main mechanism of multidrug resistance of breast cancer tissues, and the correlation between technetium-99m sestamibi ( 99 Tc m -MIBI) breast imaging results, with the expression of drug resistance proteins P-glycoprotein and glutathione-S-transferase-π in human breast cancer. Through not all the results reported before matched each other, as a kind of a noninvasive simple functional test imaging technology in vitro, SPECT can be used to diagnose P-glycoprotein expression in breast cancer, and can be used to predict chemotherapy response
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.
Schuster, Sabine; Vavra, Martina; Schweigger, Tobias M.; Rossen, John W. A.; Matsumura, Yasufumi; Kern, Winfried V.
Drug efflux by resistance-nodulation-cell division (RND)-type transporters, such as AcrAB-ToIC of Escherichia can, is an important resistance mechanism in Gram-negative bacteria; however, its contribution to multidrug resistance (MDR) in clinical isolates is poorly defined. We inactivated acrB of a
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.
Kaingona-Daniel, Elsa P S; Gomes, Larissa Rodrigues; Gama, Bianca E; Almeida-de-Oliveira, Natália K; Fortes, Filomeno; Ménard, Didier; Daniel-Ribeiro, Cláudio Tadeu; Ferreira-da-Cruz, Maria de Fátima
Malaria is a major parasitic disease, affecting millions of people in endemic areas. Plasmodium falciparum parasites are responsible for the most severe cases and its resistance to anti-malarial drugs is notorious. This is a possible obstacle to the effectiveness of intermittent preventive treatment (IPT) based on sulfadoxine-pyrimethamine (SP) cures administrated to pregnant women (IPTp) during their pregnancy. As this intervention is recommended in Angola since 2006, it has assessed, in this country, the molecular profiles in P. falciparum dhfr and dhps, two polymorphic genes associated to pyrimethamine and sulfadoxine resistance, respectively. Blood samples from 52 falciparum patients were collected in Lubango, Angola and pfdhfr and pfdhps polymorphisms were analysed using nested-PCR and DNA sequencing. In the pfdhfr gene, the 108N mutation was almost fixed (98 %), followed by 59R (63 %), 51I (46 %), 50R and 164L (2 %, respectively). No 16V/S mutations were found. The most common double mutant genotype was CNRN (59 + 108; 46 %), followed by CICN (51 + 108; 29 %) whereas IRN (51 + 59 + 108; 15 %), CNRNVL (59 + 108 + 164; 2 %) and RICN (50 + 51 + 108; 2 %) triple mutant genotypes were detected. Investigations of the pfdhps gene showed that the 437G mutation was the most prevalent (97 %). Only two and one samples disclosed the 540E (7 %) and the 436A (3 %), respectively. Single mutant SGKAA (437; 86 %) was higher than SGEAA (437 + 540; 7 %) or AGKAA (436 + 437; 3 %) double mutants genotypes. No polymorphism was detected at codons 581G and 613T/S. Combining pfdhfr and pfdhps alleles two triple mutant haplotypes (double mutant in dhfr and single mutant in dhps) were observed: the ACICNVI/SGKAA in 14 (56 %) samples and the ACNRNVI/SGKAA in five (20 %) samples. One quadruple mutant haplotype was detected (ACIRNVI/SGKAA) in six (24 %) P. falciparum samples. No quintuple pfdhfr-pfdhps mutant was noted. pfdhfr and pfdhps gene
REN, NA; GAO, GUIJU; SUN, YUE; ZHANG, LING; WANG, HUIZHU; HUA, WENHAO; WAN, KANGLIN; LI, XINGWANG
Tuberculosis (TB) infections, caused by multi-drug-resistant Mycobacterium tuberculosis (MDR MTB), remain a significant public health concern worldwide. The regulatory mechanisms underlying the emergence of MDR MTB strains remain to be fully elucidated, and further investigation is required in order to develop better strategies for TB control. The present study investigated the expression profile of microRNA (miRNA) in MTB strains, and examined the differences between sensitive MTB and MDR MTB using next generation sequencing (NGS) with Illumina Deep Sequencing technology to better understand the mechanisms of resistance in MDR MTB, A total of 5, 785 and 195, and 6, 290 and 595 qualified Illumina reads were obtained from two MDR MTB strains, and 6, 673 and 665, and 7, 210 and 217 qualified Illumina reads were obtained from two sensitive MTB strains. The overall de novo assembly of miRNA sequence data generated 62 and 62, and 95 and 112 miRNAs between the 18 and 30 bp long from sensitive MTB strains and MDR MTB strains, respectively. Comparative miRNA analysis revealed that 142 miRNAs were differentially expressed in the MDR MTB strain, compared with the sensitive MTB strain, of which 48 were upregulated and 94 were downregulated. There were six similarly expressed miRNAs between the MDR and sensitive MTB strains, and 108 miRNAs were expressed only in the MDR MTB strain. The present study acquired miRNA data from sensitive MTB and MDR MTB strains using NGS techniques, and this identification miRNAs may serve as an invaluable resource for revealing the molecular basis of the regulation of expression associated with the mechanism of drug-resistance in MTB. PMID:26324150
Jana, Bimal; Cain, Amy K.; Doerrler, William T.
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...
Gerard de Vries
Full Text Available Abstract Background In the European Union and European Economic Area only 38% of multidrug-resistant tuberculosis patients notified in 2011 completed treatment successfully at 24 months’ evaluation. Socio-economic factors and patient factors such as demographic characteristics, behaviour and attitudes are associated with treatment outcomes. Characteristics of healthcare systems also affect health outcomes. This study was conducted to identify and better understand the contribution of health system components to successful treatment of multidrug-resistant tuberculosis. Methods We selected four European Union countries to provide for a broad range of geographical locations and levels of treatment success rates of the multidrug-resistant tuberculosis cohort in 2009. We conducted semi-structured interviews following a conceptual framework with representatives from policy and planning authorities, healthcare providers and civil society organisations. Responses were organised according to the six building blocks of the World Health Organization health systems framework. Results In the four included countries, Austria, Bulgaria, Spain, and the United Kingdom, the following healthcare system factors were perceived as key to achieving good treatment results for patients with multidrug-resistant tuberculosis: timely diagnosis of drug-resistant tuberculosis; financial systems that ensure access to a full course of treatment and support for multidrug-resistant tuberculosis patients; patient-centred approaches with strong intersectoral collaboration that address patients’ emotional and social needs; motivated and dedicated healthcare workers with sufficient mandate and means to support patients; and cross-border management of multidrug-resistant tuberculosis to secure continuum of care between countries. Conclusion We suggest that the following actions may improve the success of treatment for multidrug-resistant tuberculosis patients: deployment of
Nandi, Shuvro Prokash; Sultana, Munawar; Hossain, M Anwar
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.
Vercauteren, Jurgen; Theys, Kristof; Carvalho, Ana Patricia; Valadas, Emília; Duque, Luis Miguel; Teófilo, Eugénio; Faria, Telo; Faria, Domitília; Vera, José; Aguas, Maria João; Peres, Susana; Mansinho, Kamal; Vandamme, Anne-Mieke; Camacho, Ricardo Jorge
Despite a decreasing mortality and morbidity in treated HIV-1 patients, highly active antiretroviral treatment (HAART) can still fail due to the development of drug resistance. Especially, multidrug-resistant viruses pose a threat to efficient therapy. We studied the changing prevalence of multidrug resistance (MDR) over time in a cohort of HIV-1-infected patients in Portugal. We used data of 8065 HIV-1-infected patients followed from July 2001 up to April 2012 in 22 hospitals located in Portugal. MDR at a specific date of sampling was defined as no more than one fully active drug (excluding integrase and entry inhibitors) at that time authorized by the Portuguese National Authority of Medicines and Health Products (INFARMED), as interpreted with the Rega algorithm version 8.0.2. A generalized linear mixed model was used to study the time trend of the prevalence of MDR. We observed a statistically significant decrease in the prevalence of MDR over the last decade, from 6.9% (95% CI: 5.7-8.4) in 2001-03, 6.0% (95% CI: 4.9-7.2) in 2003-05, 3.7% (95% CI: 2.8-4.8) in 2005-07 and 1.6% (95% CI: 1.1-2.2) in 2007-09 down to 0.6% (95% CI: 0.3-0.9) in 2009-12 [OR=0.80 (95% CI: 0.75-0.86); P<0.001]. In July 2011 the last new case of MDR was seen. The prevalence of multidrug-resistant HIV-1 is decreasing over time in Portugal, reflecting the increasing efficiency of HAART and the availability of new drugs. Therefore, in designing a new drug, safety and practical aspects, e.g. less toxicity and ease of use, may need more attention than focusing mainly on efficacy against resistant strains.
van Harten, Roel M; Willems, Rob J L; Martin, Nathaniel I; Hendrickx, Antoni P A
Over the past two decades infections due to antibiotic-resistant bacteria have escalated world-wide, affecting patient morbidity, mortality, and health care costs. Among these bacteria, Enterococcus faecium and Enterococcus faecalis represent opportunistic nosocomial pathogens that cause difficult-to-treat infections because of intrinsic and acquired resistance to a plethora of antibiotics. In recent years, a number of novel antimicrobial compound classes have been discovered and developed that target Gram-positive bacteria, including E. faecium and E. faecalis. These new antibacterial agents include teixobactin (targeting lipid II and lipid III), lipopeptides derived from nisin (targeting lipid II), dimeric vancomycin analogues (targeting lipid II), sortase transpeptidase inhibitors (targeting the sortase enzyme), alanine racemase inhibitors, lipoteichoic acid synthesis inhibitors (targeting LtaS), various oxazolidinones (targeting the bacterial ribosome), and tarocins (interfering with teichoic acid biosynthesis). The targets of these novel compounds and mode of action make them very promising for further antimicrobial drug development and future treatment of Gram-positive bacterial infections. Here we review current knowledge of the most favorable anti-enterococcal compounds along with their implicated modes of action and efficacy in animal models to project their possible future use in the clinical setting. Copyright © 2017 Elsevier Ltd. All rights reserved.
Wang, Xiaohong; Xu, Chengfeng; Hua, Yitong; Sun, Leitao; Cheng, Kai; Jia, Zhongming; Han, Yong; Dong, Jianli; Cui, Yuzhen; Yang, Zhenlin
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.
Lavania, Mallika; Singh, Itu; Turankar, Ravindra P; Ahuja, Madhvi; Pathak, Vinay; Sengupta, Utpal; Das, Loretta; Kumar, Archana; Darlong, Joydeepa; Nathan, Rajeev; Maseey, Asha
The emergence of multidrug-resistant (MDR) organisms for any infectious disease is a public health concern. Global efforts to control leprosy by intensive chemotherapy have led to a significant decrease in the number of registered patients. Currently recommended control measures for treating leprosy with multidrug therapy (MDT) were designed to prevent the spread of dapsone-resistant Mycobacterium leprae strains. Here we report the identification of MDR M. leprae from relapse leprosy patients from endemic regions in India. Resistance profiles to rifampicin, dapsone and ofloxacin of the isolated strains were confirmed by identification of mutations in genes previously shown to be associated with resistance to each drug. Between 2009-2016, slit-skin smear samples were collected from 239 relapse and 11 new leprosy cases from hospitals of The Leprosy Mission across India. DNA was extracted from the samples and was analysed by PCR targeting the rpoB, folP and gyrA genes associated with resistance to rifampicin, dapsone and ofloxacin, respectively, in M. leprae. M. leprae Thai-53 (wild-type) and Zensho-4 (MDR) were used as reference strains. Fifteen strains showed representative mutations in at least two resistance genes. Two strains showed mutations in all three genes responsible for drug resistance. Seven, seven and one strain, respectively, showed mutations in genes responsible for rifampicin and dapsone resistance, for dapsone and ofloxacin resistance and for rifampicin and ofloxacin resistance. This study showed the emergence of MDR M. leprae in MDT-treated leprosy patients from endemic regions of India. Copyright © 2017 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.
Ayman A. Elshayeb
Full Text Available Abstract Background Enteric fever has persistence of great impact in Sudanese public health especially during rainy season when the causative agent Salmonella enterica serovar Typhi possesses pan endemic patterns in most regions of Sudan - Khartoum. Objectives The present study aims to assess the recent state of antibiotics susceptibility of Salmonella Typhi with special concern to multidrug resistance strains and predict the emergence of new resistant patterns and outbreaks. Methods Salmonella Typhi strains were isolated and identified according to the guidelines of the International Standardization Organization and the World Health Organization. The antibiotics susceptibilities were tested using the recommendations of the Clinical Laboratories Standards Institute. Predictions of emerging resistant bacteria patterns and outbreaks in Sudan were done using logistic regression, forecasting linear equations and in silico simulations models. Results A total of 124 antibiotics resistant Salmonella Typhi strains categorized in 12 average groups were isolated, different patterns of resistance statistically calculated by (y = ax − b. Minimum bactericidal concentration’s predication of resistance was given the exponential trend (y = n ex and the predictive coefficient R2 > 0 < 1 are approximately alike. It was assumed that resistant bacteria occurred with a constant rate of antibiotic doses during the whole experimental period. Thus, the number of sensitive bacteria decreases at the same rate as resistant occur following term to the modified predictive model which solved computationally. Conclusion This study assesses the prediction of multi-drug resistance among S. Typhi isolates by applying low cost materials and simple statistical methods suitable for the most frequently used antibiotics as typhoid empirical therapy. Therefore, bacterial surveillance systems should be implemented to present data on the aetiology and current
Liew, Siew Mun; Rajasekaram, Ganeswrei; Puthucheary, Savithri D; Chua, Kek Heng
The increasing incidence of carbapenem-resistant Pseudomonas aeruginosa along with the discovery of novel metallo-β-lactamases (MBLs) is of concern. In this study, the isolation of Malaysian MBL-producing P. aeruginosa clinical strains was investigated. Fifty-three P. aeruginosa clinical strains were isolated from different patients in Sultanah Aminah Hospital, Johor Bahru, Malaysia in 2015. Antimicrobial susceptibility test was conducted. Minimum inhibitory concentrations (MICs) of imipenem and meropenem were determined by Etest. The carbapenem-resistant strains were screened for MBL production by IMP-EDTA double disk synergy test (DDST), MBL imipenem/imipenem-inhibitor (IP/IPI) Etest and polymerase chain reaction (PCR). Genotyping was performed by multilocus sequence typing (MLST) analysis. Three (5.7%) clinical strains were identified as MBL producers. Multidrug resistance was observed in the three strains, and two were resistant to all the antimicrobials tested. Sequencing analysis confirmed the three strains to harbour carbapenemase genes: one with bla IMP-1 , one with bla VIM-2 and the other with bla NDM-1 genes. These multidrug resistant strains were identified as sequence type (ST) 235 and ST308. None of the bla IMP-1 and bla NDM-1 genes have been reported in Malaysian P. aeruginosa. The emergence of imipenemase 1 (IMP-1)- and New Delhi metallo-β-lactamase 1 (NDM-1)-producing P. aeruginosa in Malaysia maybe travel-associated. Copyright © 2018. Published by Elsevier Ltd.
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.
Full Text Available OBJECTIVE: To characterize time to sputum conversion among patients with multidrug resistant tuberculosis who were enrolled into second-line tuberculosis treatment program; to identify risk factors for delayed sputum conversion. DESIGN: Retrospective cohort study designed to identify the factors associated with sputum conversion. Survival analysis was performed using Kaplan-Meier estimator to compute estimates for median time to sputum conversion and Cox proportional hazards model to compute hazard ratios (HR. RESULTS: Sputum conversion from positive to negative was observed in 134 out of 195 cases (69%. Among these who converted the median time to conversion was 3.7 months. Factors independently associated with time to sputum conversion in the proportional hazards model were: male sex (HR=0.51, 95% CI 0.32-0.81, ofloxacin-resistant tuberculosis (HR = 0.45, 95% CI 0.26-0.78 and first period of recruitment into second-line treatment (HR= 0.69, 95% CI 0.47-1.01. CONCLUSION: Time to sputum conversion in patients with multidrug-resistant tuberculosis in Armenia was 5.8 months (range 0.5-17.0 months. High level of ofloxacin resistance was the main reason for compromised response to treatment. Patients with a poor resistance profile and males should be targeted with more aggressive initial therapy.
Full Text Available OBJECTIVE: To characterize time to sputum conversion among patients with multidrug resistant tuberculosis who were enrolled into second-line tuberculosis treatment program; to identify risk factors for delayed sputum conversion. DESIGN: Retrospective cohort study designed to identify the factors associated with sputum conversion. Survival analysis was performed using Kaplan-Meier estimator to compute estimates for median time to sputum conversion and Cox proportional hazards model to compute hazard ratios (HR. RESULTS: Sputum conversion from positive to negative was observed in 134 out of 195 cases (69%. Among these who converted the median time to conversion was 3.7 months. Factors independently associated with time to sputum conversion in the proportional hazards model were: male sex (HR=0.51, 95% CI 0.32-0.81, ofloxacin-resistant tuberculosis (HR = 0.45, 95% CI 0.26-0.78 and first period of recruitment into second-line treatment (HR= 0.69, 95% CI 0.47-1.01. CONCLUSION: Time to sputum conversion in patients with multidrug-resistant tuberculosis in Armenia was 5.8 months (range 0.5- 17.0 months. High level of ofloxacin resistance was the main reason for compromised response to treatment. Patients with a poor resistance profile and males should be targeted with more aggressive initial therapy.
Sevgen Tanır Basaranoglu
Full Text Available Optimal therapy for infections with carbapenem resistant GNB is not well established due to the weakness of data. Patients presenting with bloodstream infections caused by multidrug resistant Klebsiella pneumoniae were treated with a combination treatment. Optimal therapy for infections with carbapenem resistant Gram-negative bacteria is a serious problem in pediatric patients. We presented three cases who were successfully treated with addition of ertapenem to the combination treatment for bacteremia with multidrug resistant Klebsiella pneumoniae. Dual carbapenem treatment approach is a new approach for these infections and requires more data in children.
Taha, Adham Abu; Daoud, Ayman; Zaid, Sawsan; Sammour, Sajida; Belleh, Maram; Daifi, Refqa
Active surveillance is important in infection control programmes, allowing the detection of patients colonised with multi-drug resistant organisms and preventing the spread of multi-drug resistant organisms. The aim of this study was to determine the rate of asymptomatic colonisation with multi-drug resistant organisms and the prevalence of each organism in patients transferred to An-Najah National University Hospital, Nablus, occupied Palestinian territory. Patients transferred from other hospitals between January and December, 2015, were screened at time of admission by taking nasal, groin, and axillary swabs. Swabs were cultured and assessed for the presence of multi-drug resistant organisms (extended spectrum β-lactamase producers, Pseudomonas aeroginosae, Acinetobacter baumannii, methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococcus, and carbapenem-resistant enterobacteriaceae. Of the 822 screened patients, 265 (32%) had infections with multi-drug resistant organisms. 394 isolates of multi-drug resistant organisms were obtained: 131 (33%) isolates were extended spectrum β-lactamase producers, 119 (30%) isolates were P aeroginosae, 26 (9%) isolates were A baumannii, 94 (24%) isolates were methicillin-resistant S aureus, 13 (3%) isolates were vancomycin-resistant enterococci, and one (<1%) isolate was carbapenem-resistant enterobacteriaceae. We identified a high prevalence of asymptomatic colonisation with multidrug-resistant bacteria in transferred patients. These findings emphasise the need for a national strategy to combat the spread of multi-drug resistant organisms in the occupied Palestinian territory. An-Najah National University. Copyright © 2018 Elsevier Ltd. All rights reserved.
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.
Bashir A Akhoon
Full Text Available The rapid appearance of resistant malarial parasites after introduction of atovaquone (ATQ drug has prompted the search for new drugs as even single point mutations in the active site of Cytochrome b protein can rapidly render ATQ ineffective. The presence of Y268 mutations in the Cytochrome b (Cyt b protein is previously suggested to be responsible for the ATQ resistance in Plasmodium falciparum (P. falciparum. In this study, we examined the resistance mechanism against ATQ in P. falciparum through computational methods. Here, we reported a reliable protein model of Cyt bc1 complex containing Cyt b and the Iron-Sulphur Protein (ISP of P. falciparum using composite modeling method by combining threading, ab initio modeling and atomic-level structure refinement approaches. The molecular dynamics simulations suggest that Y268S mutation causes ATQ resistance by reducing hydrophobic interactions between Cyt bc1 protein complex and ATQ. Moreover, the important histidine contact of ATQ with the ISP chain is also lost due to Y268S mutation. We noticed the induced mutation alters the arrangement of active site residues in a fashion that enforces ATQ to find its new stable binding site far away from the wild-type binding pocket. The MM-PBSA calculations also shows that the binding affinity of ATQ with Cyt bc1 complex is enough to hold it at this new site that ultimately leads to the ATQ resistance.
Ahmad, Amais; Zachariasen, Camilla; Christiansen, Lasse Engbo
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.......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...
Kupsakova, I.; Drobna, Z.; Breier, A.
In this paper study of multidrug resistance (MDR) antitumor agents - P-glycoprotein (PGP) is presented. The ability of pentoxifylline (PTX) to depress resistance mediated by overexpression of PGP in mouse leukemic cell line L 121 ONCR resistant to vincristine (VCR) was described earlier. PTX depressed the resistance of these cells in a dose and time dependent manner. This effect was accompanied by increased level of [ 3 H]-vincristine accumulation by these cells. The methylxanthines with different length of this aliphatic side chain were synthesized and their capability to depress MDR was tested. The results indicated that the position of carbonyl group plays a crucial role for the ability of the derivative to depress MDR of L 121 ONCR cells. (authors)
Singh, P; Benjak, A; Carat, S; Kai, M; Busso, P; Avanzi, C; Paniz-Mondolfi, A; Peter, C; Harshman, K; Rougemont, J; Matsuoka, M; Cole, S T
Genotyping and molecular characterization of drug resistance mechanisms in Mycobacterium leprae enables disease transmission and drug resistance trends to be monitored. In the present study, we performed genome-wide analysis of Airaku-3, a multidrug-resistant strain with an unknown mechanism of resistance to rifampicin. We identified 12 unique non-synonymous single-nucleotide polymorphisms (SNPs) including two in the transporter-encoding ctpC and ctpI genes. In addition, two SNPs were found that improve the resolution of SNP-based genotyping, particularly for Venezuelan and South East Asian strains of M. leprae. © 2014 The Authors Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases.
Gupta, Akash; Saleh, Neveen M.; Das, Riddha; Landis, Ryan F.; Bigdeli, Arafeh; Motamedchaboki, Khatereh; Rosa Campos, Alexandre; Pomeroy, Kenneth; Mahmoudi, Morteza; Rotello, Vincent M.
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.
Walter, R D; Seth, M; Bhaduri, A P
The spreading of resistance towards chloroquine has diminished its value as a potent and safe drug in malaria endemic areas. Recent reports on the reversal of chloroquine resistance in the malaria parasite Plasmodium falciparum in vitro and in vivo by verapamil, desipramine and other Ca(2+)-channel blockers and antidepressants has initiated a strategy for chemotherapy by treatment with chloroquine in combination with a drug resistance modulator. Described here is a class of modulators of distinct structure which reverse chloroquine resistance in a different manner. Contrary to verapamil and desipramine, CDRI 87/209, the most potent compound of this new class and used as a chemical lead, did not restore chloroquine accumulation in the resistant parasites, thereby indicating that besides the proposed blockade of drug efflux other mechanisms are vulnerable targets for a chemotherapeutic approach towards drug resistance. Similar to the former modulators, CDRI 87/209 showed only weak intrinsic plasmodicidal activity and the increase of drug susceptibility was restricted to resistant plasmodia.
Romina Belén Parada
Full Text Available Two hundred and thirty four actinobacteria strains were isolated from Argentinian and Peruvian soil in order to evaluate the antimicrobial activity against multidrug resistant bacteria On the basis of their antagonist activity against methicillin-resistant Staphylococcus aureus (MRSA and two vancomycin-resistant Enterococcus (EVR-Van A and EVR Van B,13 strains were selected. The presence of NRPS, PKS-I and PKS-II genes were also investigated by PCR techniques. Among the 13 selected actinobacteria, strain AC69C displayed the higher activity in diffusion tests in solid medium and was further evaluated for the production of antagonist metabolites in liquid media. The best results were obtained using fermentation broth with carbohydrates, when starch and glucose were used in combination. Antimicrobial activities of 640 arbitrary units (AU, 320 AU, 320 AU and 80 AU were obtained against EVR-Van A, EVR-Van B, Listeria monocytogenes ATCC7644 and MRSA, respectively. PCR amplification of 16S rRNA gene and subsequent phylogenetic analysis of AC69C strain displayed a 100 % homology with Streptomyces antibioticus NRRL B-1701. It was not possible to establish a correlation between the amplified genes and antimicrobial activity of the 13 selected strains. The results of this work show the wide distribution of actinobacteria in soil and the importance of the isolation of strain to screen novel active metabolites against multidrug resistant bacteria of clinical origin.
Sakkas, Hercules; Gousia, Panagiota; Economou, Vangelis; Sakkas, Vassilios; Petsios, Stefanos; Papadopoulou, Chrissanthy
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. Basil, chamomile blue, origanum, thyme, and tea tree oil were tested against clinical isolates of Acinetobacter baumannii (n = 6), Escherichia coli (n = 4), Klebsiella pneumoniae (n = 7), and Pseudomonas aeruginosa (n = 5) using the broth macrodilution method. The tested essential oils produced variable antibacterial effect, while Chamomile blue oil demonstrated no antibacterial activity. Origanum, Thyme, and Basil oils were ineffective on P. aeruginosa isolates. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration values ranged from 0.12% to 1.50% (v/v) for tea tree oil, 0.25-4% (v/v) for origanum and thyme oil, 0.50% to >4% for basil oil and >4% for chamomile blue oil. Compared to literature data on reference strains, the reported MIC values were different by 2SD, denoting less successful antimicrobial activity against multidrug resistant isolates. The antimicrobial activities of the essential oils are influenced by the strain origin (wild, reference, drug sensitive, or resistant) and it should be taken into consideration whenever investigating the plants' potential for developing new antimicrobials.
Tipsuwan, Wachiraporn; Srichairatanakool, Somdet; Kamchonwongpaisan, Sumalee; Yuthavong, Yongyuth; Uthaipibull, Chairat
Abstract Background The prevalence of drug resistance amongst the human malaria Plasmodium species has most commonly been associated with genomic mutation within the parasites. This phenomenon necessitates evolutionary predictive studies of possible resistance mutations, which may occur when a new drug is introduced. Therefore, identification of possible new Plasmodium falciparum dihydrofolate reductase (PfDHFR) mutants that confer resistance to antifolate drugs is essential in the process of...
Zakai, Haytham A; Khan, Wajihullah; Asma, Umme
Therapeutic efficacy of sulfadoxine-pyrimethamine (SP), which is commonly used to treat falciparum malaria, was assessed in isolates of Plasmodium falciparum (Welch, 1897) and Plasmodium vivax (Grassi et Feletti, 1890) ofAligarh, Uttar Pradesh, North India and Taif, Saudi Arabia during 2011-2012. Both the species showed mutations in dihydrofolate reductase (DHFR) enzyme as they have common biochemical drug targets. Mutation rate for pfdhfr was higher compared to pvdhfr because the drug was mainly given to treat falciparum malaria. Since both the species coexist, P. vivax was also exposed to SP due to faulty species diagnosis or medication without specific diagnosis. Low level of mutations against SP in P. falciparum of Saudi isolates indicates that the SP combination is still effective for the treatment of falciparum malaria. Since SP is used as first-line of treatment because of high level of resistance against chloroquine (CQ), it may result in spread of higher level of mutations resulting in drug resistance and treatment failure in near future. Therefore, to avoid further higher mutations in the parasite, use of better treatment regimens such as artesunate combination therapy must be introduced against SP combination.
Folster, Jason P; Campbell, Davina; Grass, Julian; Brown, Allison C; Bicknese, Amelia; Tolar, Beth; Joseph, Lavin A; Plumblee, Jodie R; Walker, Carrie; Fedorka-Cray, Paula J; Whichard, Jean M
Salmonella enterica is one of the most common causes of bacterial foodborne illness in the United States. Although most Salmonella infections are self-limiting, antimicrobial treatment of invasive salmonellosis is critical. The primary antimicrobial treatment options include fluoroquinolones or extended-spectrum cephalosporins, and resistance to these antimicrobial drugs may complicate treatment. At present, S. enterica is composed of more than 2,600 unique serotypes, which vary greatly in geographic prevalence, ecological niche, and the ability to cause human disease, and it is important to understand and mitigate the source of human infection, particularly when antimicrobial resistance is found. In this study, we identified and characterized 19 S. enterica serotype Albert isolates collected from food animals, retail meat, and humans in the United States during 2005 to 2013. All five isolates from nonhuman sources were obtained from turkeys or ground turkey, and epidemiologic data suggest poultry consumption or live-poultry exposure as the probable source of infection. S. enterica serotype Albert also appears to be geographically localized to the midwestern United States. All 19 isolates displayed multidrug resistance, including decreased susceptibility to fluoroquinolones and resistance to extended-spectrum cephalosporins. Turkeys are a likely source of multidrug-resistant S. enterica serotype Albert, and circulation of resistance plasmids, as opposed to the expansion of a single resistant strain, is playing a role. More work is needed to understand why these resistance plasmids spread and how their presence and the serotype they reside in contribute to human disease. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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.
Warhurst David C
Full Text Available Abstract We report the first in vitro and genetic confirmation of Malarone® (GlaxoSmithKline; atovaquone and proguanil hydrochloride resistance in Plasmodium falciparum acquired in Africa. On presenting with malaria two weeks after returning from a 4-week visit to Lagos, Nigeria without prophylaxis, a male patient was given a standard 3-day treatment course of Malarone®. Twenty-eight days later the parasitaemia recrudesced. Parasites were cultured from the blood and the isolate (NGATV01 was shown to be resistant to atovaquone and the antifolate pyrimethamine. The cytochrome b gene of isolate NGATV01 showed a single mutation, Tyr268Asn which has not been seen previously.
Ursing, Johan; Kofoed, Poul-Erik; Rodrigues, Amabelia
Chloroquine is the most commonly used antimalarial in Guinea-Bissau and high doses are routinely prescribed. Blood from 497 patients treated with different doses of chloroquine or amodiaquine were genotyped. Pfcrt and pfmdr1 polymorphisms were identified. Pfmsp2 analysis identified recrudescent...... infections. The pfcrt 72-76 haplotypes were CVIET and CVMNK. The pfcrt 76T prevalence was 23% at day 0 and 96%, 83% and 100% at recrudescence following treatment with 25 mg/kg and 50 mg/kg of chloroquine and 15 mg/kg of amodiaquine respectively. When treating pfcrt 76T carrying P. falciparum the efficacy...... of 50 mg/kg and 25 mg/kg of chloroquine was 78% and 34% respectively (P = 0.007). The genetic basis of chloroquine resistance is probably the same in Guinea-Bissau as in the rest of Africa. The low pfcrt 76T prevalence suggests that resistance to normal dose chloroquine does not confer a major advantage...
Anthony D. Kappell
Full Text Available Urban waterways represent a natural reservoir of antibiotic resistance which may provide a source of transferable genetic elements to human commensal bacteria and pathogens. The objective of this study was to evaluate antibiotic resistance of Escherichia coli isolated from the urban waterways of Milwaukee, WI compared to those from Milwaukee sewage and a clinical setting in Milwaukee. Antibiotics covering 10 different families were utilized to determine the phenotypic antibiotic resistance for all 259 E. coli isolates. All obtained isolates were determined to be multi-drug resistant. The E. coli isolates were also screened for the presence of the genetic determinants of resistance including ermB (macrolide resistance, tet(M (tetracycline resistance, and β-lactamases (blaOXA, blaSHV, and blaPSE. E. coli from urban waterways showed a greater incidence of antibiotic resistance to 8 of 17 antibiotics tested compared to human derived sources. These E. coli isolates also demonstrated a greater incidence of resistance to higher numbers of antibiotics compared to the human derived isolates. The urban waterways demonstrated a greater abundance of isolates with co-occurrence of antibiotic resistance than human derived sources. When screened for 5 different antibiotic resistance genes conferring macrolide, tetracycline, and β-lactam resistance, clinical E. coli isolates were more likely to harbor ermB and blaOXA than isolates from urban waterway. These results indicate that Milwaukee’s urban waterways may select for a greater incidence of multiple antibiotic resistance organisms and likely harbor a different antibiotic resistance gene pool than clinical sources. The implications of this study are significant to understanding the presence of resistance in urban freshwater environments by supporting the idea that sediment from urban waterways serves as a reservoir of antibiotic resistance.
Saeed, Mohamed E M; Meyer, Marion; Hussein, Ahmed; Efferth, Thomas
Traditional medicine plays a major role for primary health care worldwide. Cancer belongs to the leading disease burden in industrialized and developing countries. Successful cancer therapy is hampered by the development of resistance towards established anticancer drugs. In the present study, we investigated the cytotoxicity of 29 extracts from 26 medicinal plants of South-Africa against leukemia cell lines, most of which are used traditionally to treat cancer and related symptoms. We have investigated the plant extracts for their cytotoxic activity towards drug-sensitive parental CCRF-CEM leukemia cells and their multidrug-resistant P-glycoprotein-overexpressing subline, CEM/ADR5000 by means of the resazurin assay. A panel of 60 NCI tumor cell lines have been investigated for correlations between selected phytochemicals from medicinal plants and the expression of resistance-conferring genes (ABC-transporters, oncogenes, tumor suppressor genes). Seven extracts inhibited both cell lines (Acokanthera oppositifolia, Hypoestes aristata, Laurus nobilis, Leonotis leonurus, Plectranthus barbatus, Plectranthus ciliates, Salvia apiana). CEM/ADR5000 cells exhibited a low degree of cross-resistance (3.35-fold) towards the L. leonurus extract, while no cross-resistance was observed to other plant extracts, although CEM/ADR5000 cells were highly resistant to clinically established drugs. The log10IC50 values for two out of 14 selected phytochemicals from these plants (acovenoside A and ouabain) of 60 tumor cell lines were correlated to the expression of ABC-transporters (ABCB1, ABCB5, ABCC1, ABCG2), oncogenes (EGFR, RAS) and tumor suppressors (TP53). Sensitivity or resistance of the cell lines were not statistically associated with the expression of these genes, indicating that multidrug-resistant, refractory tumors expressing these genes may still respond to acovenoside A and ouabain. The bioactivity of South African medicinal plants may represent a basis for the development
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
Rahman, Hazir; Khan, Ilyas; Hussain, Anwar; Shahat, Abdelaaty Abdelaziz; Tawab, Abdul; Qasim, Muhammad; Adnan, Muhammad; Al-Said, Mansour S; Ullah, Riaz; Khan, Shahid Niaz
Medicinal plants have been founded as traditional herbal medicine worldwide. Most of the plant's therapeutic properties are due to the presence of secondary metabolites such as alkaloids, glycosides, tannins and volatile oil. The present investigation analyzed the High-Pressure Liquid Chromatography (HPLC) fractions of Glycyrrhiza glabra (Aqueous, Chloroform, Ethanol and Hexane) against multidrug resistant human bacterial pathogens (Escherichia coli, Acinetobacter baumannii, Staphylococcus aureus and Pseudomonas aeruginosa). All the fractions showed antibacterial activity, were subjected to LC MS/MS analysis for identification of bioactive compounds. Among total HPLC fractions of G. glabra (n = 20), three HPLC fractions showed potential activity against multidrug resistant (MDR) bacterial isolates. Fraction 1 (F1) of aqueous extracts, showed activity against A. baumannii (15 ± 0.5 mm). F4 from hexane extract of G. glabra showed activity against S. aureus (10 ± 0.2 mm). However, F2 from ethanol extract exhibited activity against S. aureus (10 ± 0.3 mm). These active fractions were further processed by LC MS/MS analysis for the identification of compounds. Ellagic acid was identified in the F1 of aqueous extract while 6-aldehydo-isoophiopogonone was present in F4 of hexane extract. Similarly, Liquirtigenin was identified in F2 of ethanol. Glycyrrhiza glabra extracts HPLC fractions showed anti-MDR activity. Three bioactive compounds were identified in the study. 6-aldehydo-isoophiopogonone and Liquirtigenin were for the first time reported in G. glabra. Further characterization of the identified compounds will be helpful for possible therapeutic uses against infectious diseases caused by multidrug resistant bacteria.
Modongo, Chawangwa; Pasipanodya, Jotam G; Zetola, Nicola M; Williams, Scott M; Sirugo, Giorgio; Gumbo, Tawanda
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.
Marna S Costanzo
Full Text Available 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.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.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.
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.
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
Abdullah Al Faruq
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.
Phan, Minh-Duy; Peters, Kate M; Sarkar, Sohinee; Lukowski, Samuel W; Allsopp, Luke P; Gomes Moriel, Danilo; Achard, Maud E S; Totsika, Makrina; Marshall, Vikki M; Upton, Mathew; Beatson, Scott A; Schembri, Mark A
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 cause disease.
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
ter Kuile, F. O.; Nosten, F.; Luxemburger, C.; Kyle, D.; Teja-Isavatharm, P.; Phaipun, L.; Price, R.; Chongsuphajaisiddhi, T.; White, N. J.
Between 1990 and 1994, a series of prospective studies were conducted to optimize the treatment of multidrug-resistant falciparum malaria on the borders of Thailand. The tolerance of various treatment regimens containing either mefloquine 15 mg/kg (M15) or 25 mg/kg (M25) was evaluated in 3673
Nag, Sidsel; Dalgaard, Marlene Danner; Kofoed, Poul-Erik
Genetic polymorphisms in P. falciparum can be used to indicate the parasite's susceptibility to antimalarial drugs as well as its geographical origin. Both of these factors are key to monitoring development and spread of antimalarial drug resistance. In this study, we combine multiplex PCR, custo...
Rahmat Sayyid Zharfan
Full Text Available Pseudomonas aeruginosa is the main cause of nosocomial infection which is responsible for 10% of hospital-acquired infection. Pseudomonas aeruginosa tends to mutate and displays potential for development of antibiotic resistance. Approximately, 10% of global bacterial isolates are found as Multidrug-resistant Pseudomonas aeruginosa. Pseudomonas aeruginosa have a quite tremendous severity index, especially on pneumonia and urinary tract infections, even sepsis, which 50% mortality rate. Pineapple (Ananas comosus L. Merr has antimicrobial properties. The active antimicrobial compounds in Ananas comosus L. Merr include saponin and bromelain. This research aims to find the potency of antimicrobial effect of pineapple (Ananas comosus L. Merr extract towards Multidrug-resistant Pseudomonas aeruginosa. Multidrug-resistant Pseudomonas aeruginosa specimen is obtained from patient’s pus in orthopaedic department, Dr Soetomo Public Hospital, Surabaya. Multidrug-resistant Pseudomonas aeruginosa specimen is resistant to all antibiotic agents except cefoperazone-sulbactam. This research is conducted by measuring the Minimum Inhibitory Concentration (MIC through dilution test with Mueller-Hinton broth medium. Pineapple extract (Ananas comosus L. Merr. is dissolved in aquadest, then poured into test tube at varying concentrations (6 g/ml; 3 g/ml; 1.5 g/ml; 0.75 g/ml, 0.375 g/ml; and 0.1875 g/ml. After 24 hours’ incubation, samples are plated onto nutrient agar plate, to determine the Minimum Bactericidal Concentration (MBC. The extract of pineapple (Ananas comosus L. Merr has antimicrobial activities against Multidrug-resistant Pseudomonas aeruginosa. Minimum Inhibitory Concentration (MIC could not be determined, because turbidity changes were not seen. The Minimum Bactericidal Concentration (MBC of pineapple extract (Ananas comosus L. Merr to Multidrug-resistant Pseudomonas aeruginosa is 0.75 g/ml. Further study of in vivo is needed.
Zhang, Xuejun C; Liu, Min; Lu, Guangyuan; Heng, Jie
Multidrug resistance (MDR) presents a growing challenge to global public health. Drug extrusion transporters play a critical part in MDR; thus, their mechanisms of substrate recognition are being studied in great detail. In this work, we review common structural features of key transporters involved in MDR. Based on our membrane potential-driving hypothesis, we propose a general energy-coupling mechanism for secondary-active antiporters. This putative mechanism provides a common framework for understanding poly-specificity of most-if not all-MDR transporters. © 2017 The Protein Society.
Glatzel, Stefan; Hezwani, Mohammed; Kitson, Philip J.; Gromski, Piotr S.; Schürer, Sophie; Cronin, Leroy
Summary: Multidrug-resistant bacteria are a major threat to human health, but broad-spectrum\\ud antibiotics are losing efficacy. There is a need to screen a given drug against\\ud a bacterial infection outside of the laboratory. To address this need, we have designed\\ud and built an inexpensive and easy-to-use 3D-printer-based system that\\ud allows easily readable quantitative tests for the performance of antibacterial\\ud drugs. The platform creates a sterile diagnostic device by using 3D prin...
Braunová, Alena; Kostka, Libor; Sivák, Ladislav; Cuchalová, Lucie; Hvězdová, Zuzana; Laga, Richard; Filippov, Sergey K.; Černoch, Peter; Pechar, Michal; Janoušková, Olga; Šírová, Milada; Etrych, Tomáš
Roč. 245, 10 January (2017), s. 41-51 ISSN 0168-3659 R&D Projects: GA MZd(CZ) NV16-28600A; GA MŠk(CZ) LO1507; GA MŠk(CZ) LQ1604; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61389013 ; RVO:61388971 Keywords : multidrug resistance * P-glycoprotein inhibitor * EPR effect Subject RIV: CD - Macromolecular Chemistry; EE - Microbiology, Virology (MBU-M) OBOR OECD: Polymer science; Microbiology (MBU-M) Impact factor: 7.786, year: 2016
Mohd Zakihalani A. Halim
Full Text Available Here, we report the draft genome sequence and annotation of a multidrug resistant Mycobacterium tuberculosis strain PR10 (MDR-TB PR10 isolated from a patient diagnosed with tuberculosis. The size of the draft genome MDR-TB PR10 is 4.34 Mbp with 65.6% of G + C content and consists of 4637 predicted genes. The determinants were categorized by RAST into 400 subsystems with 4286 coding sequences and 50 RNAs. The whole genome shotgun project has been deposited at DDBJ/EMBL/GenBank under the accession number CP010968. Keywords: Mycobacterium tuberculosis, Genome, MDR, Extrapulmonary
Polypharmacy is a growing problem nowadays, which can increase the risk of potential drug interactions, and result in a loss of effectiveness. This is particularly relevant to the anti-infective therapy, especially when infection is produced by resistant bacteria, because therapeutic options are limited and interactions can cause treatment failure. All antimicrobial prescriptions were retrospectively reviewed during a week in the Pharmacy Department, in order to detect potential drug-interactions and analysing their clinical significance. A total of 314 antimicrobial prescriptions from 151 patients were checked. There was at least one potential interaction detected in 40% of patients, being more frequent and severe in those infected with multidrug-resistant microorganisms. Drugs most commonly involved were quinolones, azoles, linezolid and vancomycin. Potential drug interactions with antimicrobial agents are a frequent problem that can result in a loss of effectiveness. This is why they should be detected and avoided when possible, in order to optimize antimicrobial therapy, especially in case of multidrug resistant infections.
Roundhill, E A; Burchill, S A
Overexpression of plasma membrane multi-drug resistance protein 1 (MRP-1) can lead to multidrug resistance. In this study, we describe for the first time the expression of mitochondrial MRP-1 in untreated human normal and cancer cells and tissues. MRP-1 expression and subcellular localisation in normal and cancer cells and tissues was examined by differential centrifugation and western blotting, and immunofluorescence microscopy. Viable mitochondria were isolated and MRP-1 efflux activity measured using the calcein-AM functional assay. MRP-1 expression was increased using retroviral infection and specific overexpression confirmed by RNA array. Cell viability was determined by trypan blue exclusion and annexin V-propidium iodide labelling of cells. MRP-1 was detected in the mitochondria of cancer and normal cells and tissues. The efflux activity of mitochondrial MRP-1 was more efficient (55-64%) than that of plasma membrane MRP-1 (11-22%; PMRP-1 expression resulted in a preferential increase in mitochondrial MRP-1, suggesting selective targeting to this organelle. Treatment with a non-lethal concentration of doxorubicin (0.85 nM, 8 h) increased mitochondrial and plasma membrane MRP-1, increasing resistance to MRP-1 substrates. For the first time, we have identified MRP-1 with efflux activity in human mitochondria. Mitochondrial MRP-1 may be an exciting new therapeutic target where historically MRP-1 inhibitor strategies have limited clinical success.
Liu, Junhua; Wang, Xu; Liu, Peng; Deng, Rongxin; Lei, Min; Chen, Wantao; Hu, Lihong
Novel 20(S)-protopanoxadiol (PPD) analogues were designed, synthesized, and evaluated for the chemosensitizing activity against a multidrug resistant (MDR) cell line (KBvcr) overexpressing P-glycoprotein (P-gp). Structure-activity relationship analysis showed that aromatic substituted aliphatic amine at the 24-positions (groups V) effectively and significantly sensitized P-gp overexpressing multidrug resistant (MDR) cells to anticancer drugs, such as docetaxel (DOC), vincristine (VCR), and adriamycin (ADM). PPD derivatives 12 and 18 showed 1.3-2.6 times more effective reversal ability than verapamil (VER) for DOC and VCR. Importantly, no cytotoxicity was observed by the active PPD analogues (5μM) against both non-MDR and MDR cells, suggesting that PPD analogues serve as novel lead compounds toward a potent and safe resistance modulator. Moreover, a preliminary mechanism study demonstrated that the chemosensitizing activity of PPD analogues results from inhibition of P-glycoprotein (P-gp) overexpressed in MDR cancer cells. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.
Wahaab, Femina; Subramaniam, Kalidass
A potent Streptomyces bacillaris strain RAM25C4 was isolated for controlling methicillin-resistant Staphylococcus aureus and multidrug-resistant bacteria such as Staphylococcus aureus, Acinetobacter baumannii, and Pseudomonas aeruginosa. A total of 131 actinomycetes were isolated from the Rameswaram coastal region, Tamil Nadu, India. Among 131 actinomycetes, maximum number of actinomycetes (55%) isolated at the distance of 3-6 m from seashore. Out of 131 actinomycetes, 85% of the actinomycetes exhibited different degree of antagonistic activity against test pathogens. The antagonistic activity evaluated using actinomycetes direct culture filtrate and culture filtrate extracts. Among these culture filtrate, extracts had supreme antagonistic activity against multidrug-resistant bacteria and the solvent ethyl acetate was the best for extracting secondary metabolites from actinomycetes. In HPTLC analysis, the presence of macrolides, terpenoids, and quinolones was identified in RAM25C4 extract. In GC-MS analysis, various potent compounds such as phenolic compound-2,6-di-tert-butylphenol, alkaloid compound-1H, 5H, pyrrolo (1' 2':3, 4) imidazo, and quinolone compound-1,4-benzenediol, 2,5-bis(1,1-dimethylethyl) were identified in the ethyl acetate extract of RAM25C4. The phylogenetic analysis of 16S rRNA gene sequence of RAM25C4 isolate was deposited in NCBI with name Streptomyces bacillaris strain RAM25C4 and accession number KM513543.
Full Text Available The emergence and spread of antibiotic-resistant Neisseria gonorrhoeae has led to difficulties in treating patients, and novel strategies to prevent and treat this infection are urgently needed. Here, we examined 21 different nanomaterials for their potential activity against N. gonorrhoeae (ATCC 49226. Silver nanoparticles (Ag NPs, 120 nm showed the greatest potency for reducing N. gonorrhoeae colony formation (MIC: 12.5 µg/ml and possessed the dominant influence on the antibacterial activity with their properties of the nanoparticles within a concentration range that did not induce cytotoxicity in human fibroblasts or epithelial cells. Electron microscopy revealed that the Ag NPs significantly reduced bacterial cell membrane integrity. Furthermore, the use of clinical isolates of multidrug-resistant N. gonorrhoeae showed that combined treatment with 120 nm Ag NPs and cefmetazole produced additive effects. This is the first report to screen the effectiveness of nanomaterials against N. gonorrhoeae, and our results indicate that 120 nm Ag NPs deliver low levels of toxicity to human epithelial cells and could be used as an adjuvant with antibiotic therapy, either for topical use or as a coating for biomaterials, to prevent or treat multidrug-resistant N. gonorrhoeae.
Alya Putri Khairani
Full Text Available Objective: To determine the risk factors that played roles in the incidence of multidrug-resistant tuberculosis (MDR-TB in such patients. Multidrug-Resistant Tuberculosis is a form of tuberculosis caused by Mycobacterium tuberculosis that is resistant to at least isoniazid and rifampicin. Methods: This was a case control study to compare MDR-TB to non-MDR-TB pulmonary tuberculosis outpatients in Dr. Hasan Sadikin General Hospital, Bandung on August–September 2014. Fifty MDR-TB outpatients were included as the cases and 50 non-MDR-TB outpatients as controls. Data was collected by questionnaires and patient’s registration forms. Bivariate and multivariate analyses were performed using chi-square test and multiple logistic regression test, with p<0.05 considered significant. Results: From bivariate analysis, number of previous tuberculosis treatments, regularity of previous treatment, and burden of cost were significant risk factors for developing MDR-TB (p<0.05; while from multivariate analysis, number of previous TB treatments was the only risk factor that played a significant role in the incidence of MDR-TB (OR 24.128 95% CI 6.771-85,976. Conclusions: Patients and medication factors are risk factors that play roles in the incidence of MDR-TB. The significant risk factor is the number of previous TB treatment.
Mariana Lima Prata-Rocha
Full Text Available Multidrug-resistant (MDR Acinetobacter baumannii (Acb is a rapidly emerging pathogen in healthcare settings. The aim of this study was to evaluate the predictors of poor outcome in patients with MDR Acb. This is the first report documenting factors influencing survival in patients with MDR Acb in this tertiary hospital. This study is a prospective of the hospital epidemiology database. A total of 73 patients with 84 Acb isolates were obtained between August 2009 and October 2010 in this hospital. In the present study, the 30-day mortality rate was 39.7%. Of 84 Acb isolates, 50 (59% were MDR, nine (11% were pan-resistant, and 25 (30% were non-MDR. The non-MDR isolates were used as the control group. The factors significantly associated with multidrug resistance included previous surgeries, presence of comorbidity (renal disease, use of more than two devices, parenteral nutrition, and inappropriate antimicrobial therapy. Significant predictors of 30-day mortality in the univariate analysis included pneumonia, diabetes mellitus, renal disease, use of more than two devices, and inappropriate antimicrobial therapy administered within two days of the onset of infection. The factors associated with mortality in patients with MDR Acb infection in this study were: age > 60 years, pneumonia, diabetes mellitus, renal disease, use of more than two invasive procedures, and inappropriate antimicrobial therapy. Vigilance is needed to prevent outbreaks of this opportunistic and deadly pathogen.
Wang, Jia; Wu, Lei; Kou, Longfa; Xu, Meng; Sun, Jin; Wang, Yongjun; Fu, Qiang; Zhang, Peng; He, Zhonggui
Novel enoxaparin sodium-PLGA hybrid nanocarries (EPNs) were successfully designed for sustained delivery of hydrophilic cationic doxorubicin hydrochloride (DOX) and to overcome multidrug resistance (MDR). By incorporation of the negative polymer of enoxaparin sodium (ES), DOX was highly encapsulated into EPNs with an encapsulation efficiency of 92.49%, and ES effectively inhibited the proliferation of HUVEC cell lines. The in vivo pharmacokinetics study after intravenous injection indicated that DOX-loaded EPNs (DOX-EPNs) exhibited a higher area under the curve (AUC) and a longer half-life (t 1/2 ) in comparison with DOX solution (DOX-Sol). The biodistribution study demonstrated that DOX-EPNs increased the DOX level in plasma and decreased the accumulation of DOX in liver and spleen. Compared with DOX-Sol, DOX-EPNs increased the cytotoxicity in P-gp over-expressing MCF-7/Adr cells, attributed to the higher intracellular efficiency of DOX produced by the EPNs. DOX-EPNs entered into resistant tumor cells by multiple endocytosis pathways, which resulted in overcoming the multidrug resistance of MCF-7/Adr cells by escaping the efflux induced by P-gp transporters. Copyright © 2016 Elsevier B.V. All rights reserved.
Full Text Available Abstract Background Military members, injured in Afghanistan or Iraq, have returned home with multi-drug resistant Acinetobacter baumannii infections. The source of these infections is unknown. Methods Retrospective study of all Canadian soldiers who were injured in Afghanistan and who required mechanical ventilation from January 1 2006 to September 1 2006. Patients who developed A. baumannii ventilator associated pneumonia (VAP were identified. All A. baumannii isolates were retrieved for study patients and compared with A. baumannii isolates from environmental sources from the Kandahar military hospital using pulsed-field gel electrophoresis (PFGE. Results During the study period, six Canadian Forces (CF soldiers were injured in Afghanistan, required mechanical ventilation and were repatriated to Canadian hospitals. Four of these patients developed A. baumannii VAP. A. baumannii was also isolated from one environmental source in Kandahar – a ventilator air intake filter. Patient isolates were genetically indistinguishable from each other and from the isolates cultured from the ventilator filter. These isolates were resistant to numerous classes of antimicrobials including the carbapenems. Conclusion These results suggest that the source of A. baumannii infection for these four patients was an environmental source in the military field hospital in Kandahar. A causal linkage, however, was not established with the ventilator. This study suggests that infection control efforts and further research should be focused on the military field hospital environment to prevent further multi-drug resistant A. baumannii infections in injured soldiers.
Mikolajczyk, Rafael T; Kauermann, Göran; Sagel, Ulrich; Kretzschmar, Mirjam
Creation of a mixture model based on Poisson processes for assessment of the extent of cross-transmission of multidrug-resistant pathogens in the hospital. We propose a 2-component mixture of Poisson processes to describe the time series of detected cases of colonization. The first component describes the admission process of patients with colonization, and the second describes the cross-transmission. The data set used to illustrate the method consists of the routinely collected records for methicillin-resistant Staphylococcus aureus (MRSA), imipenem-resistant Pseudomonas aeruginosa, and multidrug-resistant Acinetobacter baumannii over a period of 3 years in a German tertiary care hospital. For MRSA and multidrug-resistant A. baumannii, cross-transmission was estimated to be responsible for more than 80% of cases; for imipenem-resistant P. aeruginosa, cross-transmission was estimated to be responsible for 59% of cases. For new cases observed within a window of less than 28 days for MRSA and multidrug-resistant A. baumannii or 40 days for imipenem-resistant P. aeruginosa, there was a 50% or greater probability that the cause was cross-transmission. The proposed method offers a solution to assessing of the extent of cross-transmission, which can be of clinical use. The method can be applied using freely available software (the package FlexMix in R) and it requires relatively little data.
Jeganathan, Lakshmi Priya
Pseudomonas aeruginosa infections are difficult to treat due to the presence of a multitude of virulence factors and antibiotic resistance. Here, we report the draft genome sequence of P. aeruginosa BK1, an invasive and multidrug-resistant strain, isolated from a bacterial keratitis patient in southern India.
Full Text Available Treatment of Acinetobacter baumannii meningitis is an important challenge due to the accumulation of resistance of this bacteria and low meningeal diffusion of several antimicrobial requiring use of an antimicrobial effective combination to eradicate these species. We report a case of Acinetobacter baumannii multidrug-resistant nosocomial meningitis which was successfully treated with intravenous and intrathecal colistin associated with rifampicin.
Oh, Won Keun; Cho, Kyoung Bin; Hien, Tran Thi
The transition from a chemotherapy-responsive cancer to a chemotherapy-resistant one is accompanied by increased expression of multidrug resistance 1 (MDR1, p-glycoprotein), which plays an important role in the efflux from the target cell of many anticancer agents. We recently showed that a Forkh...
Jeganathan, Lakshmi Priya; Prakash, Logambiga; Neelamegam, Sivakumar; Antony, Aju; Alqarawi, Sami; Prajna, Lalitha; Devarajan, Bharanidharan; Mohankumar, Vidyarani
Pseudomonas aeruginosa infections are difficult to treat due to the presence of a multitude of virulence factors and antibiotic resistance. Here, we report the draft genome sequence of P. aeruginosa BK1, an invasive and multidrug-resistant strain
de Vries, EGE; van Putten, WLJ; Verdonck, LF; Ossenkoppele, GJ; Verhoef, GEG; Vellenga, E
Despite treatment with intensive chemotherapy, a considerable number of patients with acute myeloid leukemia (AML) die from their disease due to the occurrence of resistance. Overexpression of the transporter proteins P-glycoprotein (P-gp) and multidrug resistance protein (MRP) 1 has been identified
Iacono, M.; Villa, L.; Fortini, D.
The whole-genome sequence of an epidemic, multidrug-resistant Acinetobacter baumannii strain (strain ACICU) belonging to the European clone II group and carrying the plasmid-mediated bla(OXA-58) carbapenem resistance gene was determined. The A. baumannii ACICU genome was compared with the genomes...
Aarestrup, Frank Møller; Hendriksen, Rene S.; Lockett, Jana
We compared 581 Salmonella enterica serotype Schwarzengrund isolates from persons, food, and food animals in Denmark, Thailand, and the United States by antimicrobial drug susceptibility and pulsed-field gel electrophoresis (PFGE) typing. Resistance, including resistance to nalidixic acid......, was frequent among isolates from persons and chickens in Thailand, persons in the United States, and food imported from Thailand to Denmark and the United States. A total of 183 PFGE patterns were observed, and 136 (23.4%) isolates had the 3 most common patterns. Seven of 14 isolates from persons in Denmark...... had patterns found in persons and chicken meat in Thailand; 22 of 390 human isolates from the United States had patterns found in Denmark and Thailand. This study suggests spread of multidrug-resistant S. Schwarzengrund from chickens to persons in Thailand, and from imported Thai food products...
Boyer-Cazajous, Géraldine; Martinaud, Christophe; Déhan, Céline; Hassan, Mohammed Osman; Gaas, Yassin; Chenilleau-Vidal, Marie-Caroline; Soler, Charles
The Republic of Djibouti is an African country that exhibits one of the highest incidence rate of tuberculosis in the world. The aim of this study was to evaluate the prevalence of multidrug-resistant tuberculosis among new cases. We studied retrospectively every tuberculosis case diagnosed over a 12-month period in patients hospitalized at the French Military Hospital of Bouffard. During this period, 1,274 samples from 675 patients were tested. We isolated 266 mycobacteria corresponding to 180 cases of tuberculosis. Thirty-three were fully susceptible and 57% met the tuberculosis criteria, with 46% primary resistance. No extensively-drug-resistant tuberculosis was found. Our results highlight a major concern about the situation in this part of the world.
Full Text Available Healthcare professionals (HCP might be at increased risk of acquisition of multidrug-resistant bacteria (MDRB, i.e., methillicin-resistant (MRSA, vancomycin-resistant enterococci (VRE, and multidrug-resistant gram-negative bacteria (MDRGN and could be an unidentified source of MDRB transmission.The aim of this study was to determine the prevalence as well as risk factors of MDRB colonization among HCP.HCP (n=107 taking part in an antibiotic stewardship program, were voluntarily recruited to perform a rectal swab and to fill in a questionnaire to identify risk factors of MDRB carriage, i.e. being physician, gender, travel abroad within the previous 12 months, vegetarianism, regular consumption of raw meat, contact to domestic animals, household members with contact to livestock, work or fellowship abroad, as well as medical treatment abroad and antibiotic therapy within the previous 12 months. Selective solid media were used to determine the colonization rate with MRSA, VRE and MDRGN. MDRGN were further characterized by molecular analysis of underlying β-lactamases. None of the participants had an intestinal colonization with MRSA or VRE. 3.7% of the participants were colonized with extended-spectrum beta-lactamase (ESBL-producing , predominantly type. Neither additional flouroquinolone resistance nor carbapenem resistance was detected in any of these isolates. No risk factors were identified to have a significant impact of MDRB carriage among HCP.A colonization rate of 3.7% with ESBL-producing is of interest, but comparing it to previously published data with similar colonization rates in the healthy population in the same geographic area, it is probably less an occupational risk.
Full Text Available A total of 310 Salmonella isolates were isolated from 6 broiler farms in Eastern China, serotyped according to the Kauffmann-White classification. All isolates were examined for susceptibility to 17 commonly used antimicrobial agents, representative isolates were examined for resistance genes and class I integrons using PCR technology. Clonality was determined by pulsed-field gel electrophoresis (PFGE. There were two serotypes detected in the 310 Salmonella strains, which included 133 Salmonella enterica serovar Indiana isolates and 177 Salmonella enterica serovar Enteritidis isolates. Antimicrobial sensitivity results showed that the isolates were generally resistant to sulfamethoxazole, ampicillin, tetracycline, doxycycline and trimethoprim, and 95% of the isolates sensitive to amikacin and polymyxin. Among all Salmonella enterica serovar Indiana isolates, 108 (81.2% possessed the blaTEM, floR, tetA, strA and aac (6'-Ib-cr resistance genes. The detected carriage rate of class 1 integrons was 66.5% (206/310, with 6 strains carrying gene integron cassette dfr17-aadA5. The increasing frequency of multidrug resistance rate in Salmonella was associated with increasing prevalence of int1 genes (rs = 0.938, P = 0.00039. The int1, blaTEM, floR, tetA, strA and aac (6'-Ib-cr positive Salmonella enterica serovar Indiana isolates showed five major patterns as determined by PFGE. Most isolates exhibited the common PFGE patterns found from the chicken farms, suggesting that many multidrug-resistant isolates of Salmonella enterica serovar Indiana prevailed in these sources. Some isolates with similar antimicrobial resistance patterns represented a variety of Salmonella enterica serovar Indiana genotypes, and were derived from a different clone.
Full Text Available Drug resistant tuberculosis continues to increase and new approaches for its treatment are necessary. The identification of M. tuberculosis clinical isolates presenting efflux as part of their resistant phenotype has a major impact in tuberculosis treatment. In this work, we used a checkerboard procedure combined with the tetrazolium microplate-based assay (TEMA to study single combinations between antituberculosis drugs and efflux inhibitors (EIs against multidrug resistant M. tuberculosis clinical isolates using the fully susceptible strain H37Rv as reference. Efflux activity was studied on a real-time basis by a fluorometric method that uses ethidium bromide as efflux substrate. Quantification of efflux pump genes mRNA transcriptional levels were performed by RT-qPCR. The fractional inhibitory concentrations (FIC indicated synergistic activity for the interactions between isoniazid, rifampicin, amikacin, ofloxacin, and ethidium bromide plus the EIs verapamil, thioridazine and chlorpromazine. The FICs ranged from 0.25, indicating a four-fold reduction on the MICs, to 0.015, 64-fold reduction. The detection of active efflux by real-time fluorometry showed that all strains presented intrinsic efflux activity that contributes to the overall resistance which can be inhibited in the presence of the EIs. The quantification of the mRNA levels of the most important efflux pump genes on these strains shows that they are intrinsically predisposed to expel toxic compounds as the exposure to subinhibitory concentrations of antibiotics were not necessary to increase the pump mRNA levels when compared with the non-exposed counterpart. The results obtained in this study confirm that the intrinsic efflux activity contributes to the overall resistance in multidrug resistant clinical isolates of M. tuberculosis and that the inhibition of efflux pumps by the EIs can enhance the clinical effect of antibiotics that are their substrates.
Full Text Available Background: Food-borne diseases pose serious health problems, affecting public health and economic development worldwide. Methods: Salmonella was isolated from samples of chicken parts, skin samples of whole chicken carcasses, raw egg yolks, eggshells and chicken faeces. Resulting isolates were characterised by serogrouping, serotyping, antimicrobial susceptibility testing and detection of extended-spectrum β-lactamase (ESBL production. Antibiotic resistance genes and integrons were identified by polymerase chain reaction (PCR. Results: The detection rates of Salmonella were 60%, 64% and 62% in chicken parts, skin, and faeces, respectively, whereas the egg yolks and eggshells were uniformly negative. Salmonella Kentucky and S. Enteritidis serotypes comprised 43.6% and 2.6% of the isolates, respectively, whilst S. Typhimurium was absent. Variable resistance rates were observed against 16 antibiotics; 97% were resistant to sulfamethoxazole, 96% to nalidixic acid and tetracycline and 76% to ampicillin. Multidrug resistance was detected in 82% (64/78 of the isolates and ESBL production was detected in 8% (6/78. The β-lactamase blaTEM-1 gene was detected in 57.6% and blaSHV-1 in 6.8% of the isolates, whilst the blaOXA gene was absent. The sul1gene was detected in 97.3% and the sul2 gene in 5.3% of the isolates. Sixty-four of the 78 isolates (82% were positive for the integrase gene (int I from class 1 integrons, whilst int II was absent. Conclusion: This study reveals the presence of an alarming number of multidrug-resistant Salmonella isolates in the local poultry markets in Cairo. The high levels of drug resistance suggest an emerging problem that could impact negatively on efforts to prevent and treat poultry and poultry-transmitted human diseases in Egypt.
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
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
Al-Shamahy, H.; Al-Harazy, Abdulilah Hussein; Harmal, Nabil S.; Al-Kabsi, Abdulgudos N.
Unpublished studies on antimalarial drug efficacy have found low levels of chloroquine resistance in Yemen. This study was carried out to determine the current prevalence of drug resistance in Plasmodium falciparum in Yemen to the main anti-malarial drugs and to determine the effective concentration (EC) values. The WHO standard protocol was used for the selection of subjects, collection of blood samples, culture techniques, examination of post-culture blood slides and interpretation of results. The in vitro micro-test Mark III was used for assessing susceptibility of P. falciparum isolates. The criteria for blood parasite density was met by 219 P. falciparum malaria patients. Chloroquine resistance was found in 47% of isolated P. falciparum schizonts. Mefloquine resistance was found in 5.2%. In addition, the EC50 and EC95 values in blood that inhibited schizont maturation in resistant isolates were higher than the normal therapeutic level for mefloquine. No resistance occurred against quinine or artemisinin, with no growth at the cut off level for quinine and inhibition at low concentrations of artemisinin. Our study confirmed the occurrence of chloroquine-resistant P. falciparum and a slow increase in the rate of this resistance will increase further and spread over all the foci of malaria in Yemen. The low rate of chloroquine-resistant P. falciparum was lower than that reported in Africa or Southeast Asia, but is the first report of the mefloquine resistance in Yemen. Finally, the isolates were sensitive to low concentrations of quinine and artemisinin. (author)
Al-Hamidhi, Salama; Mahdy, Mohammed A K; Al-Hashami, Zainab; Al-Farsi, Hissa; Al-mekhlafi, Abdulsalam M; Idris, Mohamed A; Beja-Pereira, Albano; Babiker, Hamza A
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. 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. 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 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 path from Africa and Asia. The absence of the triple mutant dhfr genotype (IRN) and dhps mutations supports the use of artesunate + sulphadoxine-pyrimethamine as first-line therapy. However, the prevalent pfmdr1 genotype NFSND [21%] has previously been associated with tolerance/resistance response to artemisinin combination therapy (ACT). Regular surveys are, therefore, important to monitor spread of pfmdr1 and dhfr mutations and response to ACT.
Full Text Available Most of the substances used as fluorescent probes to study drug transport and the effect of efflux blockers in multidrug resistant cells have many drawbacks, such as toxicity, unspecific background, accumulation in mitochondria. New fluorescent compounds, among which Bodipy‐FL‐verapamil (BV, have been therefore proposed as more useful tools. The uptake of BV has been evaluated by cytofluorimetry and fluorescence microscopy using cell lines that overexpress P‐glycoprotein (P388/ADR and LLC‐PK1/ADR or MRP (multidrug resistance‐related protein (PANC‐1 and clinical specimens from patients. The effect of specific inhibitors for P‐glycoprotein (verapamil and vinblastine or MRP (MK571 and probenecid has been also studied. BV intracellular concentrations were significantly lower in the two P‐glycoprotein overexpressing cell lines in comparison with the parental lines. In addition, verapamil and vinblastine increased the intracellular concentrations of the dye; MK571 and probenecid, two MRP inhibitors, increased BV levels in PANC‐1 cells, that express this protein. These findings were confirmed in clinical specimens from patients. Fluorescence microscopy revealed a faint fluorescence emission in P‐glycoprotein or MRP expressing cell lines; however, treatment with specific inhibitors significantly increased the fluorescence. BV is a useful tool for studying multidrug resistance proteins with different techniques such as cytofluorimetry and fluorescence microscopy, but does not discriminate between P‐glycoprotein and MRP. In comparison with other classic fluorescent probes, the assay with this dye is extremely rapid, simple, not toxic for cells, devoid of fluorescent background, and can be useful in the clinical settings.
Regula, Gertraud; Petrini, Orlando; Zinsstag, Jakob; Schelling, Esther
We investigated the distribution of commensal staphylococcal species and determined the prevalence of multi-drug resistance in healthy cats and dogs. Risk factors associated with the carriage of multi-drug resistant strains were explored. Isolates from 256 dogs and 277 cats were identified at the species level using matrix-assisted laser desorption ionisation-time of flight mass spectrometry. The diversity of coagulase-negative Staphylococci (CNS) was high, with 22 species in dogs and 24 in cats. Multi-drug resistance was frequent (17%) and not always associated with the presence of the mecA gene. A stay in a veterinary clinic in the last year was associated with an increased risk of colonisation by multi-drug resistant Staphylococci (OR = 2.4, 95% CI: 1.1~5.2, p value LRT = 0.04). When identifying efficient control strategies against antibiotic resistance, the presence of mechanisms other than methicillin resistance and the possible role of CNS in the spread of resistance determinants should be considered. PMID:23820161
Alam, Mohammad Shafiul; Ley, Benedikt; Nima, Maisha Khair; Johora, Fatema Tuj; Hossain, Mohammad Enayet; Thriemer, Kamala; Auburn, Sarah; Marfurt, Jutta; Price, Ric N; Khan, Wasif A
Artemisinin resistance is present in the Greater Mekong region and poses a significant threat for current anti-malarial treatment guidelines in Bangladesh. The aim of this molecular study was to assess the current status of drug resistance in the Chittagong Hill Tracts of Bangladesh near the Myanmar border. Samples were obtained from patients enrolled into a Clinical Trial (NCT02389374) conducted in Alikadam, Bandarban between August 2014 and January 2015. Plasmodium falciparum infections were confirmed by PCR and all P. falciparum positive isolates genotyped for the pfcrt K76T and pfmdr1 N86Y markers. The propeller region of the kelch 13 (k13) gene was sequenced from isolates from patients with delayed parasite clearance. In total, 130 P. falciparum isolates were available for analysis. The pfcrt mutation K76T, associated with chloroquine resistance was found in 81.5% (106/130) of cases and the pfmdr1 mutation N86Y in 13.9% (18/130) cases. No single nucleotide polymorphisms were observed in the k13 propeller region. This study provides molecular evidence for the ongoing presence of chloroquine resistant P. falciparum in Bangladesh, but no evidence of mutations in the k13 propeller domain associated with artemisinin resistance. Monitoring for artemisinin susceptibility in Bangladesh is needed to ensure early detection and containment emerging anti-malarial resistance.
Ershova, Julia; Vlasova, Natalia; Nikishova, Elena; Tarasova, Irina; Eliseev, Platon; Maryandyshev, Andrey O.; Shemyakin, Igor G.; Kurbatova, Ekaterina; Cegielski, J. Peter
Acquired resistance to antituberculosis drugs decreases effective treatment options and the likelihood of treatment success. We identified risk factors for acquisition of drug resistance during treatment for multidrug-resistant tuberculosis (MDR TB) and evaluated the effect on treatment outcomes. Data were collected prospectively from adults from Arkhangelsk Oblast, Russia, who had pulmonary MDR TB during 2005–2008. Acquisition of resistance to capreomycin and of extensively drug-resistant TB were more likely among patients who received 3 effective drugs (9.4% vs. 0% and 8.6% vs. 0.8%, respectively). Poor outcomes were more likely among patients with acquired capreomycin resistance (100% vs. 25.9%), acquired ofloxacin resistance (83.6% vs. 22.7%), or acquired extensive drug resistance (100% vs. 24.4%). To prevent acquired drug resistance and poor outcomes, baseline susceptibility to first- and second-line drugs should be determined quickly, and treatment should be adjusted to contain >3 effective drugs. PMID:25988954
Shen, Jianan; He, Qianjun; Gao, Yu; Shi, Jianlin; Li, Yaping
Multidrug resistance (MDR) is one of the major obstacles for successful chemotherapy in cancer. One of the effective approaches to overcome MDR is to use nanoparticle-mediated drug delivery to increase drug accumulation in drug resistant cancer cells. In this work, we first report that the performance and mechanism of an inorganic engineered delivery system based on mesoporous silica nanoparticles (MSNs) loading doxorubicin (DMNs) to overcome the MDR of MCF-7/ADR (a DOX-resistant and P-glycoprotein (P-gp) over-expression cancer cell line). The experimental results showed that DMNs could enhance the cellular uptake of doxorubicin (DOX) and increase the cell proliferation suppression effect of DOX against MCF-7/ADR cells. The IC50 of DMNs against MCF-7/ADR cells was 8-fold lower than that of free DOX. However, an improved effect of DOX in DMNs against MCF-7 cells (a DOX-sensitive cancer cell line) was not found. The increased cellular uptake and nuclear accumulation of DOX delivered by DMNs in MCF-7/ADR cells was confirmed by confocal laser scanning microscopy, and could result from the down-regulation of P-gp and bypassing the efflux action by MSNs themselves. The cellular uptake mechanism of DMNs indicated that the macropinocytosis was one of the pathways for the uptake of DMNs by MCF-7/ADR cells. The in vivo biodistribution showed that DMNs induced a higher accumulation of DOX in drug resistant tumors than free DOX. These results suggested that MSNs could be an effective delivery system to overcome multidrug resistance.
Clyde, D F; McCarthy, V C; Miller, R M; Hornick, R B
A strain of Plasmodium falciparum, transmitted in Irian Jaya (Indonesian New Guinea) was isolated in 1974 and sent to the University of Maryland for characterization in nonimmune volunteers. At Maryland the Indonesia (Whit.) strain, as it has been designated, was transmitted to colonized Anopheles stephensi. Prophylactically, it was not suppressed by proguanil hydrochloride 100 mg. daily. Curatively, parasitaemia was not cleared by treatment with 1-5 g. (base) in three days of chloroquine or amodiaquine (RII responses), nor by treatment with 150 mg. of pyrimethamine in three days (RIII), and some resistance was also shown to quinine. A single dose of 1-5 g. of mefloquine (WR 142,490) produced radical cure in the two patients treated with this new 4-quinolinemethanol compound.
Godfred Ngu Tanih
Full Text Available Objective: To evaluate the prevalence of Enterococcus species in cattle faeces, their corresponding drug resistant patterns as well as the genes coding for resistance in the isolates. Methods: Two hundred and ninety rectal swabs were cultured for the isolation of Enterococcus. Presumptive isolates were confirmed by PCR, targeting the tuf gene, and confirmed isolates were identified to species level, using species-specific primers aimed at targeting six different species. Additionally, antibiogram was performed by disc diffusion and genes implicated in resistance were evaluated using molecular methods. Results: All presumptive isolates were confirmed as Enterococcus and speciated as: Enterococcus hirae (82%, Enterococcus faecium (5%, Enterococcus durans (5%, Enterococcus faecalis (2% and 6% of unidentified species. Resistance to various antimicrobials ranged from 16.4% for penicillin to 69.6% for erythromycin. Among the tetracycline and erythromycin-resistant isolates, tet M (100% and erm B (29% were the only amplified genes known to mediate resistance respectively. Other detected genes included van B (25%, van C1 (21% and bla Z (11%. Conclusions: A high prevalence of multidrug resistant Enterococcus species was observed in this study, accentuating the need to improve on animal farming practices to prevent the dissemination of this microorganism to the environment.
Coban, Ahmet Yilmaz; Uzun, Meltem
Early detection of drug resistance in Mycobacterium tuberculosis isolates allows for earlier and more effective treatment of patients. The aim of this study was to investigate the performance of the malachite green decolourisation assay (MGDA) in detecting isoniazid (INH) and rifampicin (RIF) resistance in M. tuberculosis clinical isolates. Fifty M. tuberculosis isolates, including 19 multidrug-resistant, eight INH-resistant and 23 INH and RIF-susceptible samples, were tested. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and agreement of the assay for INH were 92.5%, 91.3%, 92.5%, 91.3% and 92%, respectively. Similarly, the sensitivity, specificity, PPV, NPV and agreement of the assay for RIF were 94.7%, 100%, 100%, 96.8% and 98%, respectively. There was a major discrepancy in the tests of two isolates, as they were sensitive to INH by the MGDA test, but resistant by the reference method. There was a minor discrepancy in the tests of two additional isolates, as they were sensitive to INH by the reference method, but resistant by the MGDA test. The drug susceptibility test results were obtained within eight-nine days. In conclusion, the MGDA test is a reliable and accurate method for the rapid detection of INH and RIF resistance compared with the reference method and the MGDA test additionally requires less time to obtain results. PMID:24402143
Ahmet Yilmaz Coban
Full Text Available Early detection of drug resistance in Mycobacterium tuberculosis isolates allows for earlier and more effective treatment of patients. The aim of this study was to investigate the performance of the malachite green decolourisation assay (MGDA in detecting isoniazid (INH and rifampicin (RIF resistance in M. tuberculosis clinical isolates. Fifty M. tuberculosis isolates, including 19 multidrug-resistant, eight INH-resistant and 23 INH and RIF-susceptible samples, were tested. The sensitivity, specificity, positive predictive value (PPV, negative predictive value (NPV and agreement of the assay for INH were 92.5%, 91.3%, 92.5%, 91.3% and 92%, respectively. Similarly, the sensitivity, specificity, PPV, NPV and agreement of the assay for RIF were 94.7%, 100%, 100%, 96.8% and 98%, respectively. There was a major discrepancy in the tests of two isolates, as they were sensitive to INH by the MGDA test, but resistant by the reference method. There was a minor discrepancy in the tests of two additional isolates, as they were sensitive to INH by the reference method, but resistant by the MGDA test. The drug susceptibility test results were obtained within eight-nine days. In conclusion, the MGDA test is a reliable and accurate method for the rapid detection of INH and RIF resistance compared with the reference method and the MGDA test additionally requires less time to obtain results.
Callaghan, Richard; Luk, Frederick; Bebawy, Mary
P-glycoprotein (P-gp) is a key player in the multidrug-resistant phenotype in cancer. The protein confers resistance by mediating the ATP-dependent efflux of an astonishing array of anticancer drugs. Its broad specificity has been the subject of numerous attempts to inhibit the protein and restore the efficacy of anticancer drugs. The general strategy has been to develop compounds that either compete with anticancer drugs for transport or act as direct inhibitors of P-gp. Despite considerable in vitro success, there are no compounds currently available to "block" P-gp-mediated resistance in the clinic. The failure may be attributed to toxicity, adverse drug interaction, and numerous pharmacokinetic issues. This review provides a description of several alternative approaches to overcome the activity of P-gp in drug-resistant cells. These include 1) drugs that specifically target resistant cells, 2) novel nanotechnologies to provide high-dose, targeted delivery of anticancer drugs, 3) compounds that interfere with nongenomic transfer of resistance, and 4) approaches to reduce the expression of P-gp within tumors. Such approaches have been developed through the pursuit of greater understanding of resistance mediators such as P-gp, and they show considerable potential for further application.
Elshayeb, Ayman A; Ahmed, Abdelazim A; El Siddig, Marmar A; El Hussien, Adil A
Enteric fever has persistence of great impact in Sudanese public health especially during rainy season when the causative agent Salmonella enterica serovar Typhi possesses pan endemic patterns in most regions of Sudan - Khartoum. The present study aims to assess the recent state of antibiotics susceptibility of Salmonella Typhi with special concern to multidrug resistance strains and predict the emergence of new resistant patterns and outbreaks. Salmonella Typhi strains were isolated and identified according to the guidelines of the International Standardization Organization and the World Health Organization. The antibiotics susceptibilities were tested using the recommendations of the Clinical Laboratories Standards Institute. Predictions of emerging resistant bacteria patterns and outbreaks in Sudan were done using logistic regression, forecasting linear equations and in silico simulations models. A total of 124 antibiotics resistant Salmonella Typhi strains categorized in 12 average groups were isolated, different patterns of resistance statistically calculated by (y = ax - b). Minimum bactericidal concentration's predication of resistance was given the exponential trend (y = n e x ) and the predictive coefficient R 2 > 0 current antimicrobial drug resistance patterns of community-acquired agents causing outbreaks.
Currie, Erin; King, Brian; Lawrenson, Andrea L; Schroeder, Lena K; Kershner, Aaron M; Hermann, Greg J
Caenorhabditis elegans gut granules are lysosome-related organelles with birefringent contents. mrp-4, which encodes an ATP-binding cassette (ABC) transporter homologous to mammalian multidrug resistance proteins, functions in the formation of gut granule birefringence. mrp-4(-) embryos show a delayed appearance of birefringent material in the gut granule but otherwise appear to form gut granules properly. mrp-4(+) activity is required for the extracellular mislocalization of birefringent material, body-length retraction, and NaCl sensitivity, phenotypes associated with defective gut granule biogenesis exhibited by embryos lacking the activity of GLO-1/Rab38, a putative GLO-1 guanine nucleotide exchange factor GLO-4, and the AP-3 complex. Multidrug resistance protein (MRP)-4 localizes to the gut granule membrane, consistent with it playing a direct role in the transport of molecules that compose and/or facilitate the formation of birefringent crystals within the gut granule. However, MRP-4 is also present in oocytes and early embryos, and our genetic analyses indicate that its site of action in the formation of birefringent material may not be limited to just the gut granule in embryos. In a search for genes that function similarly to mrp-4(+), we identified WHT-2, another ABC transporter that acts in parallel to MRP-4 for the formation of birefringent material in the gut granule.
Wang, W.; Takezawa, D.; Poovaiah, B. W.
A homologue of the multidrug resistance (MDR) gene was obtained while screening a potato stolon tip cDNA expression library with S-15-labeled calmodulin. The mammalian MDR gene codes for a membrane-bound P-glycoprotein (170-180 kDa) which imparts multidrug resistance to cancerous cells. The potato cDNA (PMDR1) codes for a polypeptide of 1313 amino acid residues (ca. 144 kDa) and its structural features are very similar to the MDR P-glycoprotein. The N-terminal half of the PMDR1-encoded protein shares striking homology with its C-terminal half, and each half contains a conserved ATP-binding site and six putative transmembrane domains. Southern blot analysis indicated that potato has one or two MDR-like genes. PMDR1 mRNA is constitutively expressed in all organs studied with higher expression in the stem and stolon tip. The PMDR1 expression was highest during tuber initiation and decreased during tuber development.
Richeldi, Luca; Ewer, Katie; Losi, Monica; Bergamini, Barbara M; Roversi, Pietro; Deeks, Jonathan; Fabbri, Leonardo M; Lalvani, Ajit
Molecular epidemiology indicates significant transmission of Mycobacterium tuberculosis after casual contact with infectious tuberculosis cases. We investigated M. tuberculosis transmission after brief exposure using a T cell-based assay, the enzyme-linked-immunospot (ELISPOT) for IFN-gamma. After childbirth, a mother was diagnosed with sputum smear-positive multidrug-resistant tuberculosis. Forty-one neonates and 47 adults were present during her admission on the maternity unit; 11 weeks later, all underwent tuberculin skin testing (TST) and ELISPOT. We correlated test results with markers of exposure to the index case. The participants, who were asymptomatic and predominantly had no prior tuberculosis exposure, had 6.05 hours mean exposure (range: 0-65 hours) to the index case. Seventeen individuals, including two newborns, were ELISPOT-positive, and ELISPOT results correlated significantly with three of four predefined measures of tuberculosis exposure. For each hour sharing room air with the index case, the odds of a positive ELISPOT result increased by 1.05 (95% CI: 1.02-1.09, p = 0.003). Only four adults were TST-positive and TST results did not correlate with exposure. Thus, ELISPOT, but not TST, suggested quite extensive nosocomial transmission of multidrug-resistant M. tuberculosis after brief exposure. These results help to explain the apparent importance of casual contact for tuberculosis transmission, and may have implications for prevention.
S. L. Matveyeva
Full Text Available Abstract Background Multidrug-resistant tuberculosis (MDRTB remains a health problem for many countries in the world. The share of MDRTB is 10–30% among newly diagnosed cases and 20–70% among relapses and treatment failure. The aim of the study is to define the side effects of second line drugs used in the treatment of MDRTB on thyroid function. Methods In 30 patients with multidrug resistant tuberculosis, echostructure of thyroid was studied by ultrasound imaging method. Indices of thyroid function: plasma levels of free thyroxin, thyroid stimulating hormone were studied before chemotherapy initiated, at the end of intensive phase and after the treatment finished. Results Decreasing of thyroid function under antituberculosis chemotherapy was approved. Monitoring and correction of thyroid function during antituberculosis chemotherapy was suggested. Conclusion Patients with MDRTB taking ethionamide and PAS are at increased risk for hypothyroidism and goiter, and therefore require monitoring of thyroid function at all stages of antituberculosis chemotherapy for its timely correction.
Tri Yudani Mardining Raras
Full Text Available The soluble urokinase plasminogen activator receptor (suPAR has been shown to be a strong prognostic biomarker for tuberculosis (TB. In the present study, the profiles of plasma suPAR levels in pulmonary TB patients at high risk for multidrug resistance were analyzed and compared with those in multidrug resistant (MDR-TB patients. Forty patients were prospectively included, consisting of 10 MDR-TB patients and 30 TB patients at high risk for MDR, underwent clinical assesment. Plasma suPAR levels were measured using ELISA (SUPARnostic, Denmark and bacterial cultures were performed in addition to drug susceptibility tests. All patients of suspected MDR-TB group demonstrated significantly higher suPAR levels compared with the healthy TB-negative group (1.79 ng/mL. Among the three groups at high risk for MDR-TB, only the relapse group (7.87 ng/mL demonstrated suPAR levels comparable with those of MDR-TB patients (7.67 ng/mL. suPAR levels in the two-month negative acid-fast bacilli conversion group (9.29 ng/mL were higher than positive control, whereas levels in the group consisting of therapy failure patients (5.32 ng/mL were lower. Our results strongly suggest that suPAR levels enable rapid screening of suspected MDR-TB patients, but cannot differentiate between groups.
Mohd, N.M.D.; Nurnajwa, M.H.; Lay, J.; Teoh, J.C.; Syafinaz, A.N.; Niazlin, M.T.
A case-control study was conducted based on medical cases of 100 hospitalized patients with Pseudomonas aeruginosa-isolation at a Malaysian hospital. Cases with 50 multidrug-resistant P. aeruginosa MDRPA and 50 non-multidrug-resistant P. aeruginosa (NMDRPA) were randomly included and compared with socio-demographic and clinical data of the patients, using Chi-square and Fisher's exact tests as the statistical tool. Analysis found no significant association between MDRPA with ages, gender and ethnicity of patients (p>0.050). Other risk factors being investigated were invasive procedure, immunosuppression, bedridden and clinical diagnosis such as central nervous- and respiratory-system disorder, as well as antibiotic exposure during hospitalization and duration of hospital stay with only the last two were found to have significant association (p=0.035 and 0.019, respectively). Some other studies also reported a similar association indicating that the two factors could serve as an important predictive tool for isolation of MDRPA. More studies involving a larger sampling size are warranted to establish the association. (author)
Brotfain, Evgeni; Borer, Abraham; Koyfman, Leonid; Saidel-Odes, Lisa; Frenkel, Amit; Gruenbaum, Shaun E; Rosenzweig, Vsevolod; Zlotnik, Alexander; Klein, Moti
Acinetobacter baumannii is a multidrug resistant (MDR), gram-negative bacterium commonly implicated in ventilator-associated pneumonia (VAP) in critically ill patients. Patients in the intensive care unit (ICU) with VAP often subsequently develop A baumannii bacteremia, which may significantly worsen outcomes. In this study, we retrospectively reviewed the clinical and laboratory records of 129 ICU patients spanning 6 years with MDR A baumannii VAP; 46 (35%) of these patients had concomitant MDR A baumannii bacteremia. The ICU mortality rate was higher in patients with VAP having A baumannii bacteremia compared to nonbacteremic patients (32.4% vs 9.6% respectively, P 65 years, an Acute Physiology and Chronic Health Evaluation II (APACHE-II) score higher than 20, a Sequential Organ Failure Assessment (SOFA) score higher than 7 on the day of bacteremia, and the presence of comorbid disease (chronic obstructive pulmonary disease [COPD] and chronic renal failure) were found to be independent risk factors for in-hospital mortality in this population. Multidrug resistant A baumannii was not an independent risk factor for mortality. Although the presence of comorbid diseases (COPD and chronic renal failure) and severity of disease (APACHE > 20 and SOFA >7) were found to be independent risk factors for ICU mortality, MDR A baumannii bacteremia was not an independent risk factor for mortality in our critically ill population.
Morsy, Reda; Ali, Sameh S.; El-Shetehy, Mohamed
The several harmful effects on infected human skin resulting from exposure to the sun's UV radiation generate an interest in the development of a multifunctional hydroxyapatite-chitosan (HAp-chitosan) gel that works as an antibacterial sunscreen agent for skin care. In this work, HAp-chitosan gel was synthesized via coprecipitation method by dissolving chitosan in phosphoric acid and adding HAp. The characteristics of HAp-chitosan composite were investigated by conventional techniques, such as XRD, FTIR, and SEM techniques, while its sunscreen property was investigated by UV-spectroscopy. In addition to the influence of the gel on bacterial cell morphology, the antibacterial activity of HAp-chitosan gel against clinical multidrug resistant skin pathogens, such as Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa has been studied. The results revealed the formation of HAp-chitosan gel having nanosized particles, which confers protection against UV-radiation. The antibacterial activity records showed that chitosan-HAp gel exhibits a significant effect on the growth and ultrastructure of multi-drug resistant bacterial activities. Therefore, the chitosan-HAp gel is promising for skin health care as an antibacterial sunscreen.
Full Text Available Abstract Background To detect the expression of multidrug resistance molecules P-glycoprotein (P-gp, Lung resistnce protein (LRP and Multidrug resistance-associated protein (MRP and analyze the relationship between them and the clinico-pathological features. Methods The expressions of P-gp, LRP and MRP in formalin-fixed paraffin-embedded tissue sections from 59 gastric cancer patients were determined by a labbelled Streptavidin-Peroxidase (SP immunohistochemical technique, and the results were analyzed in correlation with clinicopathological data. None of these patients received chemotherapy prior to surgery. Results The positive rates of P-gp, LRP, MRP were 86.4%, 84.7% and 27.1%, respectively. The difference between the positive rate of P-gp and MRP was significant statistically, as well as the difference between the expression of MRP and LRP. No significant difference was observed between P-gp and LRP, but the positively correlation between the expression of P-gp and LRP had been found. No significant correlation between the expression of P-gp, LRP, MRP and the grade of differentiation were observed. The expression of P-gp was correlated with clinical stages positively (r = 0.742, but the difference with the expression of P-gp in different stages was not significant. Conclusion The expressions of P-gp, LRP and MRP in patients with gastric cancer without prior chemotherapy are high, indicating that innate drug resistance may exist in gastric cancer.
Vercauteren, Jurgen; Theys, Kristof; Carvalho, Ana Patricia; Valadas, Emília; Duque, Luis Miguel; Teófilo, Eugénio; Faria, Telo; Faria, Domitília; Vera, José; Águas, Maria João; Peres, Susana; Mansinho, Kamal; Vandamme, Anne-Mieke; Camacho, Ricardo Jorge; Mansinho, Kamal; Cláudia Miranda, Ana; Aldir, Isabel; Ventura, Fernando; Nina, Jaime; Borges, Fernando; Valadas, Emília; Doroana, Manuela; Antunes, Francisco; João Aleixo, Maria; João Águas, Maria; Botas, Júlio; Branco, Teresa; Vera, José; Vaz Pinto, Inês; Poças, José; Sá, Joana; Duque, Luis; Diniz, António; Mineiro, Ana; Gomes, Flora; Santos, Carlos; Faria, Domitília; Fonseca, Paula; Proença, Paula; Tavares, Luís; Guerreiro, Cristina; Narciso, Jorge; Faria, Telo; Teófilo, Eugénio; Pinheiro, Sofia; Germano, Isabel; Caixas, Umbelina; Faria, Nancy; Paula Reis, Ana; Bentes Jesus, Margarida; Amaro, Graça; Roxo, Fausto; Abreu, Ricardo; Neves, Isabel
Objectives Despite a decreasing mortality and morbidity in treated HIV-1 patients, highly active antiretroviral treatment (HAART) can still fail due to the development of drug resistance. Especially, multidrug-resistant viruses pose a threat to efficient therapy. We studied the changing prevalence of multidrug resistance (MDR) over time in a cohort of HIV-1-infected patients in Portugal. Patients and methods We used data of 8065 HIV-1-infected patients followed from July 2001 up to April 2012 in 22 hospitals located in Portugal. MDR at a specific date of sampling was defined as no more than one fully active drug (excluding integrase and entry inhibitors) at that time authorized by the Portuguese National Authority of Medicines and Health Products (INFARMED), as interpreted with the Rega algorithm version 8.0.2. A generalized linear mixed model was used to study the time trend of the prevalence of MDR. Results We observed a statistically significant decrease in the prevalence of MDR over the last decade, from 6.9% (95% CI: 5.7–8.4) in 2001–03, 6.0% (95% CI: 4.9–7.2) in 2003–05, 3.7% (95% CI: 2.8–4.8) in 2005–07 and 1.6% (95% CI: 1.1–2.2) in 2007–09 down to 0.6% (95% CI: 0.3–0.9) in 2009–12 [OR = 0.80 (95% CI: 0.75–0.86); P < 0.001]. In July 2011 the last new case of MDR was seen. Conclusions The prevalence of multidrug-resistant HIV-1 is decreasing over time in Portugal, reflecting the increasing efficiency of HAART and the availability of new drugs. Therefore, in designing a new drug, safety and practical aspects, e.g. less toxicity and ease of use, may need more attention than focusing mainly on efficacy against resistant strains. PMID:23228933
Tafsina Haque Aurin
Full Text Available The principal obstacles in the treatment of tuberculosis (TB are delayed and inaccurate diagnosis which often leads to the onset of the drug resistant TB cases. To avail the appropriate treatment of the patients and to hinder the transmission of drug-resistant TB, accurate and rapid detection of resistant isolates is critical. Present study was designed to demonstrate the efficacy of molecular techniques inclusive of line probe assay (LPA and GeneXpert MTB/RIF methods for the detection of multi-drug resistant (MDR TB. Sputum samples from 300 different categories of treated and new TB cases were tested for the detection of possible mutation in the resistance specific genes (rpoB, inhA and katG through Genotype MTBDRplus assay or LPA and GeneXpert MTB/RIF tests. Culture based conventional drug susceptibility test (DST was also carried out to measure the efficacy of the molecular methods employed. Among 300 samples, 191 (63.7% and 193 (64.3% cases were found to be resistant against rifampicin in LPA and GeneXpert methods, respectively; while 189 (63% cases of rifampicin resistance were detected by conventional DST methods. On the other hand, 196 (65.3% and 191 (63.7% isolates showed isoniazid resistance as detected by LPA and conventional drug susceptibility test (DST, respectively. Among the drug resistant isolates (collectively 198 in LPA and 193 in conventional DST, 189 (95.6% and 187 (96.9% were considered to be MDR as examined by LPA and conventional DST, respectively. Category-II and -IV patients encountered higher frequency of drug resistance compared to those from category-I and new cases. Considering the higher sensitivity, specificity and accuracy along with the required time to results significantly shorter, our study supports the adoption of LPA and GeneXpert assay as efficient tools in detecting drug resistant TB in Bangladesh.
Yuan, Hongyu; Li, Xun; Wu, Jifeng; Li, Jinpei; Qu, Xianjun; Xu, Wenfang; Tang, Wei
Cancer patients who receive chemotherapy often experience intrinsic or acquired resistance to a broad spectrum of chemotherapeutic agents. The phenomenon, termed multidrug resistance (MDR), is often associated with the over-expression of P-glycoprotein, a transmembrane protein pump, which can enhance efflux of a various chemicals structurally unrelated at the expense of ATP depletion, resulting in decrease of the intracellular cytotoxic drug accumulation. The MDR has been a big threaten to the human health and the war fight for it continues. Although several other mechanisms for MDR are elucidated in recent years, considerable efforts attempting to inverse MDR are involved in exploring P-glycoprotein modulators and suppressing P-glycoprotein expression. In this review, we will report on the recent advances in various strategies for overcoming or circumventing MDR mediated by P-glycoprotein.
Torres, Julio; Sardón, Victoria; Soto, Mirtha G; Anicama, Rolado; Arroyo-Hernández, Hugo; Munayco, César V
We describe the evolution and features of a cluster of Multidrug-resistant tuberculosis (MDR TB) cases that occurred in 2001, in a school located in a sub-urban area of the district of Ica, Peru. We identified 15 students related before becoming infected with tuberculosis. The mean age of the cluster was 15 years. A total of 12 students were MDR-TB cases and 7 were drug-resistant to 5 first-line drugs (RHEZS). Five out of the 15 cases received at least 3 different anti-tuberculosis treatment schemes. The average treatment duration was 37 months (minimum 21 and maximum 59 months). A total of 13 cases recovered and 2 died. This study describes a cluster of MDR -TB cases in an educational facility, which due to the epidemiological link and time presentation, is probably an outbreak of MDR TB with a satisfactory outcome after prolonged treatment.
Kibria, Golam; Hatakeyama, Hiroto; Harashima, Hideyoshi
Multidrug resistance (MDR), the principal mechanism by which many cancers develop resistance to chemotherapy, is one of the major obstacles to the successful clinical treatment of various types of cancer. Several key regulators are responsible for mediating MDR, a process that renders chemotherapeutic drugs ineffective in the internal organelles of target cells. A nanoparticulate drug delivery system (DDS) is a potentially promising tool for circumventing such MDR, which can be achieved by targeting tumor cells themselves or tumor endothelial cells that support the survival of MDR cancer cells. The present article discusses key factors that are responsible for MDR in cancer cells, with a specific focus on the application of DDS to overcome MDR via the use of chemotherapy or macromolecules.
Shuaizhang, L I; Zhang, Wen; Yin, Xuejiao; Xing, Shilai; Xie, Qunhui; Cao, Zhengyu; Zhao, Bin
The ABC (ATP-binding cassette) transporter is one of the largest and most ancient protein families with members functioning from protozoa to human. The resistance of cancer and tumor cells to anticancer drugs is due to the over-expression of some ABC transporters, which may finally lead to chemotherapy failure. The mouse ABC transporters are classified into seven subfamilies by phylogenetic analysis. The mouse ABC transporter gene, alias, chromosomal location and function have been determined. Within the ABC super-family, the MDR transporters (Abcb1, Abcc1, Abcg2) in mouse models have been proved to be valuable to investigate the biochemistry and physiological functions. This review concentrates on the multidrug resistance of mouse ABC transporters in cancer and tumor cells.
Golberg, Alexander; Broelsch, G. Felix; Vecchio, Daniela; Khan, Saiqa; Hamblin, Michael R.; Austen, William G.; Sheridan, Robert L.; Yarmush, Martin L.
Emerging bacterial resistance to multiple drugs is an increasing problem in burn wound management. New non-pharmacologic interventions are needed for burn wound disinfection. Here we report on a novel physical method for disinfection: antiseptic pulsed electric field (PEF) applied externally to the infected burns. In a mice model, we show that PEF can reduce the load of multidrug resistant Acinetobacter baumannii present in a full thickness burn wound by more than four orders of magnitude, as detected by bioluminescence imaging. Furthermore, using a finite element numerical model, we demonstrate that PEF provides non-thermal, homogeneous, full thickness treatment for the burn wound, thus, overcoming the limitation of treatment depth for many topical antimicrobials. These modeling tools and our in vivo results will be extremely useful for further translation of the PEF technology to the clinical setting, as they provide the essential elements for planning of electrode design and treatment protocol. PMID:25089285
Natan, Michal; Banin, Ehud
The spread of antibiotic resistance and increasing prevalence of biofilm-associated infections is driving demand for new means to treat bacterial infection. Nanotechnology provides an innovative platform for addressing this challenge, with potential to manage even infections involving multidrug-resistant (MDR) bacteria. The current review summarizes recent progress over the last 2 years in the field of antibacterial nanodrugs, and describes their unique properties, mode of action and activity against MDR bacteria and biofilms. Biocompatibility and commercialization are also discussed. As opposed to the more common division of nanoparticles (NPs) into organic- and inorganic-based materials, this review classifies NPs into two functional categories. The first includes NPs exhibiting intrinsic antibacterial properties and the second is devoted to NPs serving as a cargo for delivering antibacterial agents. Antibacterial nanomaterials used to decorate medical devices and implants are reviewed here as well. © FEMS 2017. All rights reserved. For permissions, please e-mail: email@example.com.
Wang, Tieshan; Su, Jianrong
Exploring novel antibiotics is necessary for multidrug-resistant pathogenic bacteria. Because the probiotics in soybean food have antimicrobial activities, we investigated their effects on multidrug-resistant Acinetobacter baumannii . Nineteen multidrug-resistant A. baumannii strains were clinifcally isolated as an experimental group and 11 multidrug-sensitive strains as controls. The growth rates of all bacteria were determined by using the analysis for xCELLigence Real-Time Cell. The combination of antibiotics showed synergistic effects on the strains in the control group but no effect on the strains in the experimental group. Efflux pump gene adeS was absent in all the strains from the control group, whereas it exists in all the strains from the experimental group. Furthermore, all the strains lost multidrug resistance when an adeS inhibitor was used. One strain of probiotics isolated from soybean food showed high antimicrobial activity for multidrug-resistant A. baumannii . The isolated strain belongs to Bacillus subtilis according to 16S RNA analysis. Furthermore, E. coli showed multidrug resistance when it was transformed with the adeS gene from A. baumannii whereas the resistant bacteria could be inhibited completely by isolated Bacillus subtilis . Thus, probiotics from soybean food provide potential antibiotics against multidrug-resistant pathogenic bacteria.
Hu, Yi-Fan; Liu, Chang-Pan; Wang, Nai-Yu; Shih, Shou-Chuan
Multidrug-resistant Pseudomonas aeruginosa has emerged as one of the most important healthcare-associated pathogens. Colistin is regarded as the last-resort antibiotic for multidrug-resistant Gram-negative bacteria, but is associated with high rates of acute kidney injury. The aim of this in vitro study is to search for an alternative treatment to colistin for multidrug-resistant P. aeruginosa infections. Multidrug and carbapenem-resistant P. aeruginosa isolates were collected between January 2009 and December 2012 at MacKay Memorial Hospital. Minimal inhibitory concentrations (MICs) were determined for various antibiotic combinations. Carbapenemase-producing genes including bla VIM, other β-lactamase genes and porin mutations were screened by PCR and sequencing. The efficacy of carbapenems (imipenem, meropenem, doripenem) with or without rifampicin was correlated with the type of porin mutation (frameshift mutation, premature stop codon mutation) in multidrug-resistant P. aeruginosa isolates without carbapenemase-producing genes. Of the 71 multidrug-resistant clinical P. aeruginosa isolates, only six harboured the bla VIM gene. Imipenem, meropenem and doripenem were significantly more effective (reduced fold-change of MICs) when combined with rifampicin in bla VIM-negative isolates, especially in isolates with porin frameshift mutation. Imipenem + rifampicin combination has a low MIC against multidrug-resistant P. aeruginosa, especially in isolates with porin frameshift mutation. The imipenem + rifampicin combination may provide an alternative treatment to colistin for multidrug -resistant P. aeruginosa infections, especially for patients with renal insufficiency.
Full Text Available Doxorubicin (Adriamycin, ADM is an antimitotic drug used in the treatment of a wide range of malignant tumors, including acute leukemia, lymphoma, osteosarcoma, breast cancer, and lung cancer. Multidrug resistance-associated proteins (MRPs are members of a superfamily of ATP-binding cassette (ABC transporters, which can transport various molecules across extra- and intra-cellular membranes. The aim of this study was to investigate whether there was a correlation between MRP4 and primary ADM resistance in osteosarcoma cells. In this paper, we chose the human osteosarcoma cell line MG63, ADM resistant cell line MG63/DOX, and the patient′s primary cell GSF-0686. We checked the ADM sensitivity and cytotoxicity of all the three cells by cell proliferation assay. The intracellular drug concentrations were measured by using LC-MS/MS. We also examined MRP4 gene expression by RT-PCR and Western Blot. We found that the intracellular ADM concentration of the parent osteosarcoma cell line MG63 was higher than the ADM resistant osteosarcoma MG63/DOX cell line or the GSF-0686 cell after ADM treatment (P < 0.05. In addition, MRP4 mRNA and protein levels in ADM resistant osteosarcoma cells were higher than in MG63 cell (P < 0.05. Taking together, this work suggests that overexpression of MRP4 may confer ADM resistance in osteosarcoma cells.
Full Text Available Objectives: We described the clinical outcomes of the diabetic patients who had foot infections with multidrug resistant organisms. Methods: We included the patients with diabetic foot infections (DFI from 19 centers, between May 2011 and December 2015. Infection was defined according to IDSA DFI guidelines. Patients with severe infection, complicated moderate infection were hospitalized. The patients were followed-up for 6 months after discharge. Results: In total, 791 patients with DFI were included, 531(67% were male, median age was 62 (19–90. Severe infection was diagnosed in 85 (11% patients. Osteomyelitis was diagnosed in 291(36.8% patients. 536 microorganisms were isolated, the most common microorganisms were S. aureus (20%, P. aeruginosa (19% and E. coli (12%. Methicillin resistance (MR rate among Staphylococcus aureus isolates was 31%. Multidrug resistant bacteria were detected in 21% of P. aeruginosa isolates. ESBL (+ Gram negative bacteria (GNB was detected in 38% of E. coli and Klebsiella isolates. Sixty three patients (8% were re-hospitalized. Of the 791 patiens, 127 (16% had major amputation, and 24 (3% patients died. In multivariate analysis, significant predictors for fatality were; dialysis (OR: 8.3, CI: 1.82–38.15, p = 0.006, isolation of Klebsiella spp. (OR:7.7, CI: 1.24–47.96, p = 0.028, and chronic heart failure (OR: 3, CI: 1.01–9.04, p = 0.05. MR Staphylococcus was detected in 21% of the rehospitalized patients, as the most common microorganism (p < 0.001. Conclusion: Among rehospitalized patients, methicillin resistant Staphylococcus infections was detected as the most common agent, and Klebsiella spp. infections were found to be significantly associated with fatality. Keywords: Diabetic foot infection, MRSA, Klebsiella, Fatality
Nairoukh, Yacoub R; Mahafzah, Azmi M; Irshaid, Amal; Shehabi, Asem A
Emergence of multi-drug resistant uropathogenic E. coli strains is an increasing problem to empirical treatment of urinary tract infections in many countries. This study investigated the magnitude of this problem in Jordan. A total of 262 E. coli isolates were recovered from urine samples of Jordanian patients which were suspected to have urinary tract infections (UTIs). All isolates were primarily identified by routine biochemical tests and tested for antimicrobial susceptibility by disc diffusion method. Fifty representative Multidrug Resistance (MDR) E. coli isolates to 3 or more antibiotic classes were tested for the presence of resistance genes of blaCTX-M- 1, 9 and 15, carbapenemase ( blaIMP, blaVIM, blaNDM-1, blaOXA-48 ), fluoroquinolones mutated genes ( parC and gyrA ) and clone of ST131 type using PCR methods. A total of 150/262 (57.3%) of E. coli isolates were MDR. Urine samples of hospitalized patients showed significantly more MDR isolates than outpatients. Fifty representative MDR E. coli isolates indicated the following molecular characteristics: All were positive for mutated parC gene and gyrA and for ST131 clone, and 78% were positive for genes of CTX-M-15 , 76% for CTX-M-I and for 8% CTX-M-9 , respectively. Additionally, all 50 MDR E. coli isolates were negative for carbapenemase genes ( blaIMP, blaVIM, blaNDM-1, blaOXA-48 ), except of one isolate was positive for blaKPC-2 . This study indicates alarming high rates recovery of MDR uropathogenic E. coli from Jordanian patients associated with high rates of positive ST131 clone, fluoroquinolone resistant and important types of blaCTX-M.
Khan, Usman Ali; Rahman, Hazir; Qasim, Muhammad; Hussain, Anwar; Azizllah, Azizullah; Murad, Waheed; Khan, Zakir; Anees, Muhammad; Adnan, Muhammad
Plants are rich source of chemical compounds that are used to accomplish biological activity. Indigenously crude extracts of plants are widely used as herbal medicine for the treatment of infections by people of different ethnic groups. The present investigation was carried out to evaluate the biological potential of Alkanna tinctoria leaves extract from district Charsadda, Pakistan against multidrug resistant human pathogenic bacteria including Acinetobacter baumannii, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. Anti-multi-drug resistant bacterial activity of aqueous, chloroform, ethanol and hexane extracts of Alkanna tinctoria leaves were evaluated by well diffusion method. Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of different extracts were determined. Moreover qualitative phytochemicals screening of the studied extracts was performed. All four selected bacteria including A. baumannii, E. coli, P. aeruginosa and S. aureus were categorized as multi-drug resistant (MDR) as they were found to be resistant to 13, 10, 19 and 22 antibiotics belonging to different groups respectively. All the four extract showed potential activity against S. aureus as compare to positive control antibiotic (Imipenem). Similarly among the four extracts of Alkanna tinctoria leaves, aqueous extract showed best activity against A. baumannii (10±03 mm), P. aeruginosa (12±0.5 mm), and S. aureus (14±0.5 mm) as compare to Imipenem. The MICs and MBCs results also showed quantitative concentration of plant extracts to inhibit or kill MDR bacteria. When phytochemicals analysis was performed it was observed that aqueous and ethanol extracts showed phytochemicals with large number as well as volume, especially Alkaloides, Flavonoides and Charbohydrates. The undertaken study demonstrated that all the four extracts of Alkanna tinctoria leaves exhibited considerable antibacterial activity against MDR isolates. Finding from the
Saltoglu, Nese; Ergonul, Onder; Tulek, Necla; Yemisen, Mucahit; Kadanali, Ayten; Karagoz, Gul; Batirel, Ayse; Ak, Oznur; Sonmezer, Cagla; Eraksoy, Haluk; Cagatay, Atahan; Surme, Serkan; Nemli, Salih A; Demirdal, Tuna; Coskun, Omer; Ozturk, Derya; Ceran, Nurgul; Pehlivanoglu, Filiz; Sengoz, Gonul; Aslan, Turan; Akkoyunlu, Yasemin; Oncul, Oral; Ay, Hakan; Mulazımoglu, Lutfiye; Erturk, Buket; Yilmaz, Fatma; Yoruk, Gulsen; Uzun, Nuray; Simsek, Funda; Yildirmak, Taner; Yaşar, Kadriye Kart; Sonmezoglu, Meral; Küçükardali, Yasar; Tuna, Nazan; Karabay, Oguz; Ozgunes, Nail; Sargın, Fatma
We described the clinical outcomes of the diabetic patients who had foot infections with multidrug resistant organisms. We included the patients with diabetic foot infections (DFI) from 19 centers, between May 2011 and December 2015. Infection was defined according to IDSA DFI guidelines. Patients with severe infection, complicated moderate infection were hospitalized. The patients were followed-up for 6 months after discharge. In total, 791 patients with DFI were included, 531(67%) were male, median age was 62 (19-90). Severe infection was diagnosed in 85 (11%) patients. Osteomyelitis was diagnosed in 291(36.8%) patients. 536 microorganisms were isolated, the most common microorganisms were S. aureus (20%), P. aeruginosa (19%) and E. coli (12%). Methicillin resistance (MR) rate among Staphylococcus aureus isolates was 31%. Multidrug resistant bacteria were detected in 21% of P. aeruginosa isolates. ESBL (+) Gram negative bacteria (GNB) was detected in 38% of E. coli and Klebsiella isolates. Sixty three patients (8%) were re-hospitalized. Of the 791 patiens, 127 (16%) had major amputation, and 24 (3%) patients died. In multivariate analysis, significant predictors for fatality were; dialysis (OR: 8.3, CI: 1.82-38.15, p=0.006), isolation of Klebsiella spp. (OR:7.7, CI: 1.24-47.96, p=0.028), and chronic heart failure (OR: 3, CI: 1.01-9.04, p=0.05). MR Staphylococcus was detected in 21% of the rehospitalized patients, as the most common microorganism (p<0.001). Among rehospitalized patients, methicillin resistant Staphylococcus infections was detected as the most common agent, and Klebsiella spp. infections were found to be significantly associated with fatality. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.
Full Text Available Bo Li1, Hui Xu2, Zhen Li1, Mingfei Yao1, Meng Xie1, Haijun Shen1, Song Shen1, Xinshi Wang1, Yi Jin11College of Pharmaceutical sciences, Zhejiang University, Hangzhou, 2No. 202 Hospital of People's Liberation Army, Shenyang, ChinaBackground: Multidrug resistance (MDR mediated by the overexpression of adenosine triphosphate (ATP-binding cassette (ABC transporters, such as P-glycoprotein (P-gp, remains one of the major obstacles to effective cancer chemotherapy. In this study, lipid/particle assemblies named LipoParticles (LNPs, consisting of a dimethyldidodecylammonium bromide (DMAB-modified poly(lactic-co-glycolic acid (PLGA nanoparticle core surrounded by a 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC shell, were specially designed for anticancer drugs to bypass MDR in human breast cancer cells that overexpress P-gp.Methods: Doxorubicin (DOX, a chemotherapy drug that is a P-gp substrate, was conjugated to PLGA and encapsulated in the self-assembled LNP structure. Physiochemical properties of the DOX-loaded LNPs were characterized in vitro. Cellular uptake, intracellular accumulation, and cytotoxicity were compared in parental Michigan Cancer Foundation (MCF-7 cells and P-gp-overexpressing, resistant MCF-7/adriamycin (MCF-7/ADR cells.Results: This study found that the DOX formulated in LNPs showed a significantly increased accumulation in the nuclei of drug-resistant cells relative to the free drug, indicating that LNPs could alter intracellular traffic and bypass drug efflux. The cytotoxicity of DOX loaded-LNPs had a 30-fold lower half maximal inhibitory concentration (IC50 value than free DOX in MCF-7/ADR, measured by the colorimetric cell viability (MTT assay, correlated with the strong nuclear retention of the drug.Conclusion: The results show that this core-shell lipid/particle structure could be a promising strategy to bypass MDR.Keywords: chemotherapy, drug delivery, polymeric nanoparticles, multidrug resistance
A simple, high-throughput method to detect Plasmodium falciparum single nucleotide polymorphisms in the dihydrofolate reductase, dihydropteroate synthase, and P. falciparum chloroquine resistance transporter genes using polymerase chain reaction- and enzyme-linked immunosorbent
Alifrangis, Michael; Enosse, Sonia; Pearce, Richard
Single nucleotide polymorphisms (SNPs) in the Plasmodium falciparum dihydrofolate reductase (dhfr), and dihydropteroate synthetase (dhps), and chloroquine resistance transporter (Pfcrt) genes are used as molecular markers of P. falciparum resistance to sulfadoxine/pyrimethamine and chloroquine....... However, to be a practical tool in the surveillance of drug resistance, simpler methods for high-throughput haplotyping are warranted. Here we describe a quick and simple technique that detects dhfr, dhps, and Pfcrt SNPs using polymerase chain reaction (PCR)- and enzyme-linked immunosorbent assay (ELISA...
Full Text Available After the era of plentiful antibiotics we are alarmed by the increasing number of antibiotic resistant strains. The genetic flexibility and adaptability of E. coli to constantly changing environments allows to acquire a great number of antimicrobial resistance mechanisms. Commensal strains of E. coli as versatile residents of the lower intestine are also repeatedly challenged by antimicrobial pressures during the lifetime of their host. As a consequence, commensal strains acquire the respective resistance genes, and/or develop resistant mutants in order to survive and maintain microbial homeostasis in the lower intestinal tract. Thus, commensal E. coli strains are regarded as indicators of antimicrobial load on their hosts. This chapter provides a short historic background of the appearance and presumed origin and transfer of antimicrobial resistance genes in commensal intestinal E. coli of animals with comparative information on their pathogenic counterparts. The dynamics, development and ways of evolution of resistance in the E. coli populations differ according to hosts, resistance mechanisms and antimicrobial classes used. The most frequent tools of E. coli against a variety of antimicrobials are the efflux pumps and mobile resistance mechanisms carried by plasmids and/or other transferable elements. The emergence of hybrid plasmids (both resistance and virulence among E. coli is of further concern. Co-existence and co-transfer of these bad genes in this huge and most versatile in vivo compartment may represent an increased public health risk in the future. Significance of multidrug resistant (MDR commensal E. coli seem to be highest in the food animal industry, acting as reservoir for intra- and interspecific exchange and a source for spread of MDR determinants through contaminated food to humans. Thus, public health potential of MDR commensal E. coli of food animals can be a concern and needs monitoring and more molecular analysis in the
Aluisio Augusto Cotrim SEGURADO
Full Text Available In order to study the chemoresistance of Plasmodium falciparum to commonly used antimalarial drugs in Brazil the authors have studied ten patients with falciparum malaria, acquired in the Brazilian Amazon region. Patients were submitted to in vivo study of drug sensitivity, after chemotherapy with either 4-aminoquinolines (chloroquine or amodiaquine or quinine. Adequate drug absorption was confirmed by standard urine excretion tests for antimalarials. Eight patients could be followed up to 28 days. Among these in vivo resistance (R I and R II responses was seen in all patients who received 4-amino-quinolines. One patient treated with quinine exhibited a R III response. Peripheral blood samples of the same patients were submitted to in vitro microtests for sensitivity to antimalarials. Out of nine successful tests, resistance to chloroquine and amodiaquine was found in 100% and resistance to quinine in 11.11% of isolates. Probit analysis of log dose-response was used to determine effective concentrations EC50, EC90 and EC99 to the studied drugs. Good correlation between in vivo and in vitro results was seen in six patients. The results emphasize high levels of P. falciparum resistance to 4- aminoquinolines and suggest an increase in resistance to quinine in the Brazilian Amazon region, reinforcing the need for continuous monitoring of drug sensitivity to adequate chemotherapy according to the most efficacious drug regimensResistência in vivo e in vitro do Plasmodium falciparum à cloroquina, amodiaquina e quinino na Amazônia Brasileira. Com o propósito de avaliar a resistência do Plasmodium falciparum às drogas antimaláricas, rotineiramente empregadas no Brasil, os autores acompanharam dez pacientes com malária falciparum adquirida na Amazônia brasileira. Os pacientes foram submetidos a estudo in vivo de sensibilidade a drogas, após tratamento com derivados 4-aminoquinoleínicos (cloroquina e amodiaquina ou quinino. A absorção das
T. V. Chernenkaya
Full Text Available ABSTRACT. Changes in the structure of the main causative agents of nosocomial infections and significant spread of multidrugresistant strains of bacteria are a natural biological response for antibiotics that selectively inhibit pathogens and contribute to selection, survival and growth of drug resistant strains of bacteria. In this literature review we present the change of structure of the major causative microorganisms of nosocomial septic infections and theirs resistance to antibiotics for the last 70 years.
Nyunt, Myat Htut; Soe, Myat Thu; Myint, Hla Win; Oo, Htet Wai; Aye, Moe Moe; Han, Soe Soe; Zaw, Ni Ni; Cho, Cho; Aung, Phyo Zaw; Kyaw, Khin Thiri; Aye, Thin Thin; San, Naychi Aung; Ortega, Leonard; Thimasarn, Krongthong; Bustos, Maria Dorina G; Galit, Sherwin; Hoque, Mohammad Rafiul; Ringwald, Pascal; Han, Eun-Taek; Kyaw, Myat Phone
Emergence of artemisinin-resistant malaria in Southeast Asian countries threatens the global control of malaria. Although K13 kelch propeller has been assessed for artemisinin resistance molecular marker, most of the mutations need to be validated. In this study, artemisinin resistance was assessed by clinical and molecular analysis, including k13 and recently reported markers, pfarps10, pffd and pfmdr2. A prospective cohort study in 1160 uncomplicated falciparum patients was conducted after treatment with artemisinin-based combination therapy (ACT), in 6 sentinel sites in Myanmar from 2009 to 2013. Therapeutic efficacy of ACT was assessed by longitudinal follow ups. Molecular markers analysis was done on all available day 0 samples. True recrudescence treatment failures cases and day 3 parasite positivity were detected at only the southern Myanmar sites. Day 3 positive and k13 mutants with higher prevalence of underlying genetic foci predisposing to become k13 mutant were detected only in southern Myanmar since 2009 and comparatively fewer mutations of pfarps10, pffd, and pfmdr2 were observed in western Myanmar. K13 mutations, V127M of pfarps10, D193Y of pffd, and T448I of pfmdr2 were significantly associated with day 3 positivity (OR: 6.48, 3.88, 2.88, and 2.52, respectively). Apart from k13, pfarps10, pffd and pfmdr2 are also useful for molecular surveillance of artemisinin resistance especially where k13 mutation has not been reported. Appropriate action to eliminate the resistant parasites and surveillance on artemisinin resistance should be strengthened in Myanmar. Trial registration This study was registered with ClinicalTrials.gov, identifier NCT02792816.
Full Text Available ABSTRACT OBJECTIVE To analyze the prevalence and factors associated with multidrug-resistant tuberculosis in Espírito Santo, Brazil. METHODS This is a cross-sectional study of cases of tuberculosis tested for first-line drugs (isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin in Espírito Santo between 2002 and 2012. We have used laboratory data and registration of cases of tuberculosis – from the Sistema Nacional de Agravos de Notificação and Sistema para Tratamentos Especiais de Tuberculose. Individuals have been classified as resistant and non-resistant and compared in relation to the sociodemographic, clinical, and epidemiological variables. Some variables have been included in a logistic regression model to establish the factors associated with resistance. RESULTS In the study period, 1,669 individuals underwent anti-tuberculosis drug susceptibility testing. Of these individuals, 10.6% showed resistance to any anti-tuberculosis drug. The rate of multidrug resistance observed, that is, to rifampicin and isoniazid, has been 5%. After multiple analysis, we have identified as independent factors associated with resistant tuberculosis: history of previous treatment of tuberculosis [recurrence (OR = 7.72; 95%CI 4.24–14.05 and re-entry after abandonment (OR = 3.91; 95%CI 1.81–8.43], smoking (OR = 3.93; 95%CI 1.98–7.79, and positive culture for Mycobacterium tuberculosis at the time of notification of the case (OR = 3.22; 95%CI 1.15–8.99. CONCLUSIONS The partnership between tuberculosis control programs and health teams working in the network of Primary Health Care needs to be strengthened. This would allow the identification and monitoring of individuals with a history of previous treatment of tuberculosis and smoking. Moreover, the expansion of the offer of the culture of tuberculosis and anti-tuberculosis drug susceptibility testing would provide greater diagnostic capacity for the resistant types in Espírito Santo.
Poudel, Ajay; Nakajima, Chie; Fukushima, Yukari; Suzuki, Haruka; Pandey, Basu Dev; Maharjan, Bhagwan; Suzuki, Yasuhiko
Despite the fact that Nepal is one of the first countries globally to introduce multidrug-resistant tuberculosis (MDR-TB) case management, the number of MDR-TB cases is continuing to rise in Nepal. Rapid molecular tests applicable in this setting to identify resistant organisms would be an effective tool in reversing this trend. To develop such tools, information about the frequency and distribution of mutations that are associated with phenotypic drug resistance in Mycobacterium tuberculosis is required. In the present study, we investigated the prevalence of mutations in rpoB and katG genes and the inhA promoter region in 158 M. tuberculosis isolates (109 phenotypically MDR and 49 non-MDR isolates collected in Nepal) by DNA sequencing. Mutations affecting the 81-bp rifampin (RIF) resistance-determining region (RRDR) of rpoB were identified in 106 of 109 (97.3%) RIF-resistant isolates. Codons 531, 526, and 516 were the most commonly affected, at percentages of 58.7, 15.6, and 15.6%, respectively. Of 113 isoniazid (INH)-resistant isolates, 99 (87.6%) had mutations in the katG gene, with Ser315Thr being the most prevalent (81.4%) substitution. Mutations in the inhA promoter region were detected in 14 (12.4%) INH-resistant isolates. The results from this study provide an overview of the current situation of RIF and INH resistance in M. tuberculosis in Nepal and can serve as a basis for developing or improving rapid molecular tests to monitor drug-resistant strains in this country.
Full Text Available Abstract Background The recent dramatic decline in dihydroartemisinin-piperaquine (DHA-PPQ efficacy in northwestern Cambodia has raised concerns about the rapid spread of piperaquine resistance just as DHA-PPQ is being introduced as first-line therapy in neighbouring countries. Methods Ex vivo parasite susceptibilities were tracked to determine the rate of progression of DHA, PPQ and mefloquine (MQ resistance from sentinel sites on the Thai–Cambodian and Thai–Myanmar borders from 2010 to 2015. Immediate ex vivo (IEV histidine-rich protein 2 (HRP-2 assays were used on fresh patient Plasmodium falciparum isolates to determine drug susceptibility profiles. Results IEV HRP-2 assays detected the precipitous emergence of PPQ resistance in Cambodia beginning in 2013 when 40 % of isolates had an IC90 greater than the upper limit of prior years, and this rate doubled to 80 % by 2015. In contrast, Thai–Myanmar isolates from 2013 to 14 remained PPQ-sensitive, while northeastern Thai isolates appeared to have an intermediate resistance profile. The opposite trend was observed for MQ where Cambodian isolates appeared to have a modest increase in overall sensitivity during the same period, with IC50 declining to median levels comparable to those found in Thailand. A significant association between increased PPQ IC50 and IC90 among Cambodian isolates with DHA-PPQ treatment failure was observed. Nearly all Cambodian and Thai isolates were deemed artemisinin resistant with a >1 % survival rate for DHA in the ring-stage assay (RSA, though there was no correlation among isolates to indicate cross-resistance between PPQ and artemisinins. Conclusions Clinical DHA-PPQ failures appear to be associated with declines in the long-acting partner drug PPQ, though sensitivity appears to remain largely intact for now in western Thailand. Rapid progression of PPQ resistance associated with DHA-PPQ treatment failures in northern Cambodia limits drugs of choice in
Full Text Available Virulent and resistant strains Pseudomonas aeruginosa (P. aeruginosa is one of the most important cause of UTIs in pediatrics. The present study was carried to investigate the frequency of virulence factors in the multi-drug resistant strains of P. aeruginosa isolated from pediatrics hospitalized due to the UTIs. One - hundred and forty three urine samples were collected from pediatric patients suffered from UTIs. Samples were cultured and those that were P. aeruginosa positive were analyzed for the presence of putative virulence genes. Seventy one out of 143 samples (49.65% were positive for P. aeruginosa. Monthly, sex and age-dependent prevalence were seen for P. aeruginosa. Bacterial strains had the highest levels of resistance against ampicillin (95.77%, gentamicin (92.95% and ciprofloxacin (81.69%. Of 71 P. aeruginosa isolates, 12 strains were resistant to more than 9 antibiotics (16.90%. The most commonly detected virulence factors in the cases of urethral infections were exoU and plcH while those of pyelonephritis and cystitis were were exoS and lasB. Our findings should raise awareness about antibiotic resistance in hospitalized pediatrics with UTIs in Iran. Clinicians should exercise caution in prescribing antibiotics, especially in cases of UTIs. Such information can help in identifying these virulence genes as useful diagnostic markers for clinical P. aeruginosa strains isolated from UTIs.
Full Text Available A cross-sectional study was carried out to determine antimicrobial drug resistance patterns of E. coli O157:H7 isolates and estimate the level of the pathogen. A total of 194 cloacae swab samples were collected randomly in two poultry farms. Standard cultural, biochemical, and serological (latex agglutination methods were used to isolate E. coli O157:H7. The isolates were subjected to antimicrobial susceptibility testing using disc diffusion method. Out of 194 cloacae samples examined, 13.4% (n=26 were found to be positive for E. coli O157:H7. The finding indicated differences in E. coli O157:H7 infection among the different risk factors. Chicken from Adele Poultry Farm showed higher E. coli O157:H7 infection (OR = 3.89 than Haramaya University poultry farm and young birds had more infection (OR = 4.62 than adult birds. Of the total 14 antimicrobials included in the panel of study, the susceptibility results were varied with 96.15% and 0% E. coli O157:H7 isolates expressing resistance to erythromycin, clindamycin, spectinomycin, and ciprofloxacin, respectively. Multidrug resistance to more than two antimicrobial agents was detected in 24 (92.30% of the isolates. The study showed high presence of antimicrobial resistant isolates of E. coli O157:H7. Further study is required to better understand the ecology and evolution of bacterial resistance to antimicrobial agents.
Resende, Juliana Alves; Silva, Vânia L.; Fontes, Cláudia Oliveira; Souza-Filho, Job Alves; de Oliveira, Tamara Lopes Rocha; Coelho, Cíntia Marques; César, Dionéia Evangelista; Diniz, Cláudio Galuppo
The use of antimicrobials and toxic metals should be considered carefully in aquaculture and surrounding environments. We aimed to evaluate medically relevant bacteria in an aquaculture system and their susceptibility to antimicrobials and toxic metals. Selective cultures for enterobacteria (ENT), non-fermenting Gram-negative rods (NFR) and Gram-positive cocci (GPC) were obtained from water samples collected in two different year seasons. The isolated bacteria were biochemically identified and antimicrobial and toxic metal susceptibility patterns were determined. Overall, 407 representative strains were recovered. In general, bacteria isolated from fish ponds showed higher multiple antibiotic resistance indices when compared to those isolated from a water-fed canal. Resistance to penicillin and azithromycin was observed more frequently in the GPC group, whereas resistance to ampicillin and ampicillin/sulbactam or gentamicin was observed more frequently in the ENT and NFR groups, respectively. All the isolated bacteria were tolerant to nickel, zinc, chromium and copper at high levels (≥1,024 μg mL−1), whereas tolerance to cadmium and mercury varied among the isolated bacteria (2–1,024 μg mL−1). Multidrug-resistant bacteria were more frequent and diverse in fish ponds than in the water-fed canal. A positive correlation was observed between antimicrobial resistance and metal tolerance. The data point out the need for water treatment associated with the aquaculture system. PMID:22972388
Shecho, Mude; Thomas, Naod; Kemal, Jelalu; Muktar, Yimer
A cross-sectional study was carried out to determine antimicrobial drug resistance patterns of E. coli O157:H7 isolates and estimate the level of the pathogen. A total of 194 cloacae swab samples were collected randomly in two poultry farms. Standard cultural, biochemical, and serological (latex agglutination) methods were used to isolate E. coli O157:H7. The isolates were subjected to antimicrobial susceptibility testing using disc diffusion method. Out of 194 cloacae samples examined, 13.4% ( n = 26) were found to be positive for E. coli O157:H7. The finding indicated differences in E. coli O157:H7 infection among the different risk factors. Chicken from Adele Poultry Farm showed higher E. coli O157:H7 infection (OR = 3.89) than Haramaya University poultry farm and young birds had more infection (OR = 4.62) than adult birds. Of the total 14 antimicrobials included in the panel of study, the susceptibility results were varied with 96.15% and 0% E. coli O157:H7 isolates expressing resistance to erythromycin, clindamycin, spectinomycin, and ciprofloxacin, respectively. Multidrug resistance to more than two antimicrobial agents was detected in 24 (92.30%) of the isolates. The study showed high presence of antimicrobial resistant isolates of E. coli O157:H7. Further study is required to better understand the ecology and evolution of bacterial resistance to antimicrobial agents.
Hawkey, P M
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. Copyright © 2015. Published by Elsevier Ltd.
The objective of this study was to evaluate conjugative transfer of cephalosporin resistance among (n=100) strains of multi-drug resistant Escherichia coli (MDRE) to Salmonella Newport and E. coli DH5-alpha recipients. To accomplish this, phenotypic and genotypic profiles were determined for MDRE, ...
Alffenaar, J.W.C.; Altena, R. van; Harmelink, I.M.; Filguera, P.; Molenaar, E.; Wessels, A.M.; Soolingen, D. van; Kosterink, J.G.W.; Uges, D.R.A.; Werf, T.S. van der
BACKGROUND AND OBJECTIVES: For the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB), potent new drugs are urgently needed. Linezolid is a promising drug, but its use is limited by adverse effects with prolonged administration of 600 mg twice daily. In
Alffenaar, Jan-Willem C.; van Altena, Richard; Harmelink, Ilse M.; Filguera, Patricia; Molenaar, Esther; Wessels, A. Mireille A.; van Soolingen, Dick; Kosterink, Jos G. W.; Uges, Donald R. A.; van der Werf, Tjip S.
Background and Objectives: For the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB), potent new drugs are urgently needed. Linezolid is a promising drug, but its use is limited by adverse effects with prolonged administration of 600 mg twice daily. In
Full Text Available Abstract Background Multidrug resistance (MDR is a phenomenon that is often associated with decreased intracellular drug accumulation in patient's tumor cells resulting from enhanced drug efflux. It is related to the overexpression of a membrane protein, P-glycoprotein (Pgp-170, thereby reducing drug cytotoxicity. A variety of studies have tried to find MDR modulators which increase drug accumulation in cancer cells. Methods In this study, natural curcuminoids, pure curcumin, demethoxycurcumin and bisdemethoxycurcumin, isolated from turmeric (Curcuma longa Linn, were compared for their potential ability to modulate the human MDR-1 gene expression in multidrug resistant human cervical carcinoma cell line, KB-V1 by Western blot analysis and RT-PCR. Results Western blot analysis and RT-PCR showed that all the three curcuminoids inhibited MDR-1 gene expression, and bisdemethoxycurcumin produced maximum effect. In additional studies we found that commercial grade curcuminoid (approximately 77% curcumin, 17% demethoxycurcumin and 3% bisdemthoxycurcumin decreased MDR-1 gene expression in a dose dependent manner and had about the same potent inhibitory effect on MDR-1 gene expression as our natural curcuminoid mixtures. Conclusion These results indicate that bisdemethoxycurcumin is the most active of the curcuminoids present in turmeric for modulation of MDR-1 gene. Treatment of drug resistant KB-V1 cells with curcumin increased their sensitivity to vinblastine, which was consistent with a decreased MDR-1 gene product, a P-glycoprotein, on the cell plasma membrane. Although many drugs that prevent the P-glycoprotein function have been reported, this report describes the inhibition of MDR-1 expression by a phytochemical. The modulation of MDR-1 expression may be an attractive target for new chemosensitizing agents.
Full Text Available The growing need of antimicrobial agent for novel therapies against multi-drug resistant bacteria has drawn researchers to green nanotechnology. Especially, eco-friendly biosynthesis of silver nanoparticles (Ag NPs has shown its interesting impact against bacterial infection in laboratory research. In this study, a simple method was developed to form Ag NPs at room temperature, bio-reduction of silver ions from silver nitrate salt by leaf extract from Ocimum gratissimum. The Ag NPs appear to be capped with plant proteins, but are otherwise highly crystalline and pure. The Ag NPs have a zeta potential of −15 mV, a hydrodynamic diameter of 31 nm with polydispersity index of 0.65, and dry sizes of 18 ± 3 nm and 16 ± 2 nm, based on scanning and transmission electron microscopy respectively. The minimum inhibitory concentration (MIC of the Ag NPs against a multi-drug resistant Escherichia coli was 4 μg/mL and the minimum bactericidal concentration (MBC was 8 μg/mL, while the MIC and MBC against a resistant strain of Staphylococcus aureus were slightly higher at 8 μg/mL and 16 μg/mL respectively. Further, the Ag NPs inhibited biofilm formation by both Escherichia coli and S. aureus at concentrations similar to the MIC for each strain. Treatment of E. coli and S. aureus with Ag NPs resulted in damage to the surface of the cells and the production of reactive oxygen species. Both mechanisms likely contribute to bacterial cell death. In summary, this new method appears promising for green biosynthesis of pure Ag NPs with potent antimicrobial activity.
Moradzadeh, Maliheh; Tabarraei, Alijan; Sadeghnia, Hamid Reza; Ghorbani, Ahmad; Mohamadkhani, Ashraf; Erfanian, Saiedeh; Sahebkar, Amirhossein
Acute promyelocytic leukemia (APL) is one of the most life-threatening hematological malignancies. Defects in the cell growth and apoptotic pathways are responsible for both disease pathogenesis and treatment resistance. Therefore, pro-apoptotic agents are potential candidates for APL treatment. Kaempferol is a flavonoid with antioxidant and anti-tumor properties. This study was designed to investigate the cytotoxic, pro-apoptotic, and differentiation-inducing effects of kaempferol on HL-60 and NB4 leukemia cells. Resazurin assay was used to determine cell viability following treatment with kaempferol (12.5-100 μM) and all-trans retinoic acid (ATRA; 10 μM; used as a positive control). Apoptosis and differentiation were also detected using propidium iodide and NBT staining techniques, respectively. Furthermore, the expression levels of genes involved in apoptosis (PI3 K, AKT, BCL2, BAX, p53, p21, PTEN, CASP3, CASP8, and CASP9), differentiation (PML-RAR and HDAC1), and multi-drug resistance (ABCB1 and ABCC1) were determined using quantitative real-time PCR. The protein expressions of Bax/Bcl2 and casp3 were confirmed using Western blot. The results showed that kaempferol decreased cell viability and increased subG1 population in the tested leukemic cells. This effect was associated with decreased expression of Akt, BCL2, ABCB1, and ABCC1 genes, while the expression of CASP3 and BAX/BCL-2 ratio were significantly increased at both gene and protein levels. Kaempferol promoted apoptosis and inhibited multidrug resistance in a concentration-dependent manner, without any differential effect on leukemic cells. In conclusion, this study suggested that kaempferol may be utilized as an appropriate alternative for ATRA in APL patients. © 2017 Wiley Periodicals, Inc.
Limtrakul, Pornngarm; Anuchapreeda, Songyot; Buddhasukh, Duang
Multidrug resistance (MDR) is a phenomenon that is often associated with decreased intracellular drug accumulation in patient's tumor cells resulting from enhanced drug efflux. It is related to the overexpression of a membrane protein, P-glycoprotein (Pgp-170), thereby reducing drug cytotoxicity. A variety of studies have tried to find MDR modulators which increase drug accumulation in cancer cells. In this study, natural curcuminoids, pure curcumin, demethoxycurcumin and bisdemethoxycurcumin, isolated from turmeric (Curcuma longa Linn), were compared for their potential ability to modulate the human MDR-1 gene expression in multidrug resistant human cervical carcinoma cell line, KB-V1 by Western blot analysis and RT-PCR. Western blot analysis and RT-PCR showed that all the three curcuminoids inhibited MDR-1 gene expression, and bisdemethoxycurcumin produced maximum effect. In additional studies we found that commercial grade curcuminoid (approximately 77% curcumin, 17% demethoxycurcumin and 3% bisdemthoxycurcumin) decreased MDR-1 gene expression in a dose dependent manner and had about the same potent inhibitory effect on MDR-1 gene expression as our natural curcuminoid mixtures. These results indicate that bisdemethoxycurcumin is the most active of the curcuminoids present in turmeric for modulation of MDR-1 gene. Treatment of drug resistant KB-V1 cells with curcumin increased their sensitivity to vinblastine, which was consistent with a decreased MDR-1 gene product, a P-glycoprotein, on the cell plasma membrane. Although many drugs that prevent the P-glycoprotein function have been reported, this report describes the inhibition of MDR-1 expression by a phytochemical. The modulation of MDR-1 expression may be an attractive target for new chemosensitizing agents
Disratthakit, Areeya; Meada, Shinji; Prammananan, Therdsak; Thaipisuttikul, Iyarit; Doi, Norio; Chaiprasert, Angkana
Drug-resistant tuberculosis (TB), which includes multidrug-resistant (MDR-TB), quinolone-resistant (QR-TB) and extensively drug-resistant tuberculosis (XDR-TB), is a serious threat to TB control. We aimed to characterize the genotypic diversity of drug-resistant TB clinical isolates collected in Thailand to establish whether the emergence of drug-resistant TB is attributable to transmitted resistance or acquired resistance. We constructed the first molecular phylogeny of MDR-TB (n=95), QR-TB (n=69) and XDR-TB (n=28) in Thailand based on spoligotyping and proposed 24-locus multilocus variable-number of tandem repeat analysis (MLVA). Clustering analysis was performed using the unweighted pair group method with arithmetic mean. Spoligotyping identified the Beijing strain (SIT1) as the most predominant genotype (n=139; 72.4%). The discriminatory power of 0.9235 Hunter-Gaston Discriminatory Index (HGDI) with the 15-locus variable-number tandem repeats of mycobacterial interspersed repetitive units typing was improved to a 0.9574 HGDI with proposed 24-locus MLVA, thereby resulting in the subdivision of a large cluster of Beijing strains (SIT1) into 17 subclusters. We identified the spread of drug-resistant TB clones caused by three different MLVA types in the Beijing strain (SIT1) and a specific clone of XDR-TB caused by a rare genotype, the Manu-ancestor strain (SIT523). Overall, 49.5% of all isolates were clustered. These findings suggest that a remarkable transmission of drug-resistant TB occurred in Thailand. The remaining 50% of drug-resistant TB isolates were unique genotypes, which may have arisen from the individual acquisition of drug resistance. Our results suggest that transmitted and acquired resistance have played an equal role in the emergence of drug-resistant TB. Further characterization of whole genome sequences of clonal strains could help to elucidate the mycobacterial genetic factors relevant for drug resistance, transmissibility and virulence
Richard J Maude
Full Text Available Malaria elimination requires a variety of approaches individually optimized for different transmission settings. A recent field study in an area of low seasonal transmission in South West Cambodia demonstrated dramatic reductions in malaria parasite prevalence following both mass drug administration (MDA and high treatment coverage of symptomatic patients with artemisinin-piperaquine plus primaquine. This study employed multiple combined strategies and it was unclear what contribution each made to the reductions in malaria.A mathematical model fitted to the trial results was used to assess the effects of the various components of these interventions, design optimal elimination strategies, and explore their interactions with artemisinin resistance, which has recently been discovered in Western Cambodia. The modelling indicated that most of the initial reduction of P. falciparum malaria resulted from MDA with artemisinin-piperaquine. The subsequent continued decline and near elimination resulted mainly from high coverage with artemisinin-piperaquine treatment. Both these strategies were more effective with the addition of primaquine. MDA with artemisinin combination therapy (ACT increased the proportion of artemisinin resistant infections, although much less than treatment of symptomatic cases with ACT, and this increase was slowed by adding primaquine. Artemisinin resistance reduced the effectiveness of interventions using ACT when the prevalence of resistance was very high. The main results were robust to assumptions about primaquine action, and immunity.The key messages of these modelling results for policy makers were: high coverage with ACT treatment can produce a long-term reduction in malaria whereas the impact of MDA is generally only short-term; primaquine enhances the effect of ACT in eliminating malaria and reduces the increase in proportion of artemisinin resistant infections; parasite prevalence is a better surveillance measure for
The management of epidemics of multi-drug and highly resistant bacteria must be based on a structured organisation. Within each region it requires the expertise of centres for the interregional coordination of nosocomial infection control (CCLINs) and their regional branches of nosocomial infection control (Arlin) which support hospitals in reporting these types of epidemics. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
Wang, Xia; Chen, Yong; Zhao, Wei; Wang, Yan; Song, Qing; Liu, Hui; Zhao, Jingya; Han, Xuelin; Hu, Xiaohua; Grundmann, Hajo; Xiao, Yanni; Han, Li
Major challenges remain when attempting to quantify and evaluate the impacts of contaminated environments and heterogeneity in the cohorting of health care workers (HCWs) on hospital infections. Data on the detection rate of multidrug-resistant Acinetobacter baumannii (MRAB) in a Chinese intensive
Background Multidrug-resistant (MDR) Salmonella enterica serovar Typhimurium (S. Typhimurium) is a serious public health threat as infections caused by these strains are more difficult and expensive to treat. Livestock serve as a reservoir for MDR Salmonella, and the antibiotics chlortetracycline an...
Vu, D H; Bolhuis, M S; Koster, R A; Greijdanus, B; de Lange, W C M; van Altena, R; Brouwers, J R B J; Uges, D R A; Alffenaar, J W C
Linezolid is a promising antimicrobial agent for the treatment of multidrug-resistant tuberculosis (MDR-TB), but its use is limited by toxicity. Therapeutic drug monitoring (TDM) may help to minimize toxicity while adequate drug exposure is maintained. Conventional plasma sampling and monitoring
Paulusma, C. C.; Kothe, M. J.; Bakker, C. T.; Bosma, P. J.; van Bokhoven, I.; van Marle, J.; Bolder, U.; Tytgat, G. N.; Oude Elferink, R. P.
We have studied regulation of the multidrug resistance protein 2 (mrp2) during bile duct ligation (BDL) in the rat. In hepatocytes isolated after 16, 48, and 72 hours of BDL, mrp2-mediated dinitrophenyl-glutathione (DNP-GS) transport was decreased to 65%, 33%, and 33% of control values,
Köck, Robin; Siemer, Philipp; Esser, Jutta; Kampmeier, Stefanie; Berends, Matthijs S; Glasner, Corinna; Arends, Jan P; Becker, Karsten; Friedrich, Alexander W
Preventing the spread of multidrug-resistant Gram-negative bacteria (MDRGNB) is a public health priority. However, the definition of MDRGNB applied for planning infection prevention measures such as barrier precautions differs depending on national guidelines. This is particularly relevant in the
Lockhart, S.R.; Etienne, K.A.; Vallabhaneni, S.; Farooqi, J.; Chowdhary, A.; Govender, N.P.; Colombo, A.L.; Calvo, B.; Cuomo, C.A.; Desjardins, C.A.; Berkow, E.L.; Castanheira, M.; Magobo, R.E.; Jabeen, K.; Asghar, R.J.; Meis, J.F.G.M.; Jackson, B.; Chiller, T.; Litvintseva, A.P.
BACKGROUND: Candida auris, a multidrug-resistant yeast that causes invasive infections, was first described in 2009 in Japan and has since been reported from several countries. METHODS: To understand the global emergence and epidemiology of C. auris, we obtained isolates from 54 patients with C.
Masereeuw, R.; Notenboom, S.; Smeets, P.H.E.; Wouterse, A.C.; Russel, F.G.M.
Previous studies with mutant transport-deficient rats (TR(-)), in which the multidrug resistance protein 2 (Mrp2) is lacking, have emphasized the importance of this transport protein in the biliary excretion of a wide variety of glutathione conjugates, glucuronides, and other organic anions. Mrp2 is
Janssen, Saskia; Padanilam, Xavier; Louw, Rianna; Mahanyele, Russel; Coetzee, Gerrit; Hänscheid, Thomas; Leenstra, Tjalling; Grobusch, Martin P.
Discharge of a hospital patient after a single negative sputum culture may save money when treating multidrug-resistant tuberculosis. However, after initial sputum conversion in 336 South Africans, 11.6% and 5.4% reconverted after 1 and 2 months, respectively. These findings endorse the WHO
Giacometti, Andrea; Cirioni, Oscar; Kamysz, Wojciech; D'Amato, Giuseppina; Silvestri, Carmela; Prete, Maria Simona Del; Licci, Alberto; Riva, Alessandra; Łukasiak, Jerzy; Scalise, Giorgio
The in vitro activity of the histatin derivative P-113, alone or combined with eight antibiotics, was investigated against multidrug-resistant strains isolated from clinical specimens of immunocompromised patients with pneumonia. The gram-negative isolates were susceptible to P-113. S. aureus showed less susceptibility. Synergy was demonstrated when P-113 was combined with beta-lactams against gram-negative organisms.
Tedim, Ana P.; Lanza, Val F.; Manrique, Marina; Pareja, Eduardo; Ruiz-Garbajosa, Patricia; Cantón, Rafael; Baquero, Fernando; Tobes, Raquel
ABSTRACT The emergence of nosocomial infections by multidrug-resistant sequence type 117 (ST117) Enterococcus faecium has been reported in several European countries. ST117 has been detected in Spanish hospitals as one of the main causes of bloodstream infections. We analyzed genome variations of ST117 strains isolated in Madrid and describe the first ST117 closed genome sequences. PMID:28360174
Vellenga, E; van der Veen, AY; Noordhoek, L; Timmer-Bosscha, H; Ossenkoppele, GJ; Raymakers, RA; Muller, M; van den Berg, E; de Vries, EGE
Deletion of the multidrug resistance gene MRP1 has been demonstrated in acute myeloid leukemia (AML) patients with inversion of chromosome 16 (inv), These AML patients are known to have a relatively favorable prognosis, which suggests that MRP1 might play an important role In determining
Zanden, J.J. van; Wortelboer, H.M.; Bijlsma, S.; Punt, A.; Usta, M.; Bladeren, P.J.V.; Rietjens, I.M.C.M.; Cnubben, N.H.P.
In the present study, the effects of a large series of flavonoids on multidrug resistance proteins (MRPs) were studied in MRP1 and MRP2 transfected MDCKII cells. The results were used to define the structural requirements of flavonoids necessary for potent inhibition of MRP1- and MRP2-mediated
Bolhuis, M. S.; van Altena, R.; van Hateren, K.; de Lange, W. C. M.; Greijdanus, B.; Uges, D. R. A.; Kosterink, J. G. W.; van der Werf, T. S.; Alffenaar, J. W. C.
Linezolid plays an increasingly important role in the treatment of multidrug-resistant tuberculosis (MDR-TB). However, patients should be carefully monitored due to time-and dose-dependent toxicity. Clarithromycin plays a more modest role. Therapeutic drug monitoring may contribute to assessment of
Stalenhoef, Janneke E; Terveer, Elisabeth M; Knetsch, Cornelis W; Van't Hof, Peter J; Vlasveld, Imro N; Keller, Josbert J; Visser, Leo G; Kuijper, Eduard J
Combined fecal microbiota transfer and antibiotic treatment prevented recurrences of urinary tract infections with multidrug-resistant (MDR) Pseudomonas aeruginosa , but it failed to eradicate intestinal colonization with MDR Escherichia coli . Based on microbiota analysis, failure was not associated with distinct diminished microbiota diversity.
Halaby, Teysir; Al Naiemi, Nashwan; Beishuizen, Bert; Verkooijen, Roel; Ferreira, José A; Klont, Rob; Vandenbroucke-Grauls, Christina
Cross-transmission of nosocomial pathogens occurs frequently in intensive care units (ICU). The aim of this study was to investigate whether the introduction of a single room policy resulted in a decrease in transmission of multidrug-resistant (MDR) bacteria in an ICU.
Background Artesunate plus sulphadoxine-pyrimethamine (AS+SP) is now first-line treatment for Plasmodium falciparum infection in several south Asian countries, including Afghanistan. Molecular studies provide a sensitive means to investigate the current state of drug susceptibility to the SP component, and can also provide information on the likely efficacy of other potential forms of artemisinin-combination therapy. Methods During the years 2007 to 2010, 120 blood spots from patients with P. falciparum malaria were obtained in four provinces of Afghanistan. PCR-based methods were used to detect drug-resistance mutations in dhfr, dhps, pfcrt and pfmdr1, as well as to determine copy number of pfmdr1. Results The majority (95.5%) of infections had a double mutation in the dhfr gene (C59R, S108N); no mutations at dhfr positions 16, 51 or 164 were seen. Most isolates were wild type across the dhps gene, but five isolates from the provinces of Kunar and Nangarhar in eastern Afghanistan had the triple mutation A437G / K540E / A581G; all five cases were successfully treated with three receiving AS+SP and two receiving dihydroartemisinin-piperaquine. All isolates showed the pfcrt SVNMT chloroquine resistance haplotype. Five of 79 isolates had the pfmdr1 N86Y mutation, while 52 had pfmdr1 Y184F; positions 1034, 1042 and 1246 were wild type in all isolates. The pfmdr1 gene was not amplified in any sample. Conclusions This study indicates that shortly after the adoption of AS+SP as first-line treatment in Afghanistan, most parasites had a double mutation haplotype in dhfr, and a small number of isolates from eastern Afghanistan harboured a triple mutation haplotype in dhps. The impact of these mutations on the efficacy of AS+SP remains to be assessed in significant numbers of patients, but these results are clearly concerning since they suggest a higher degree of SP resistance than previously detected. Further focused molecular and clinical studies in this region are urgently
Mohamed Khaled Ibrahim
Full Text Available Antibiotic resistance in bacteria is becoming a serious problem, especially after the emergence of multidrug-resistant strains. To overcome this problem, new and effective antibacterials or resistance modulators are highly needed and plant kingdom represents a valuable source of these compounds. In this study we investigated the antibacterial and resistance modulatory activity of Aniseeds waste Residue Extract (ASWRE and Star Anise Waste Residue Extract (SAWRE (post-distillation against 100 isolates belonging to two Gram positive (Streptococcus pneumoniae and Staphylococcus aureus and four Gram negative bacteria (Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii and Pseudomonas aeruginosa. Phenolic compounds of anise wastes were determined by HPLC. The antibacterial activity of anise waste extracts assays were performed by using inhibition zone diameters, MIC and MBC. Evaluation of synergy interaction between anise waste extracts and certain known antibacterial drugs like Cephradine, Chloramphenicol, Tetracycline and Amoxicillin was carried out using disc diffusion method, MIC and the fractional inhibitory concentrations (FIC. The results showed that HPLC method has been developed for the determination of 25 phenolic compounds from waste extracts. Both ASWRE and SAWRE have significant antibacterial activity against all of the test bacteria. SAWRE was found to have higher amounts of phenolic compounds contents that might be responsible for their comparatively higher antibacteria activity than ASWRE. Irradiation at 10 and 30 kGy did not significantly affect the antibacterial activity of both ASWRE and SAWRE. The combination of anise waste extracts and the tested antibiotics mostly showed synergistic effect. Synergistic interaction was most expressed against Streptococcus pneumoniae (Sp1 and Staphylococcus aureus (Sa1 by Tetracycline and chloramphenicol; Pseudomonas aeruginosa (P2, Klebsiella pneumoniae (K3, Acinetobacter baumannii
Ndiaye, Magatte; Faye, Babacar; Tine, Roger
Abstract. As a result of widespread antimalarial drug resistance, all African countries with endemic malaria have, in recent years, changed their malaria treatment policy. In Senegal, the health authorities changed from chloroquine (CQ) to a combination of sulfadoxine-pyrimethamine (SP) plus...... at the molecular level in selected sites in Senegal, because the scientific community is interested in using CQ again. Finger prick blood samples were collected from Plasmodium falciparum-positive children below the age of 10 years (N = 474) during cross-sectional surveys conducted in two study sites in Senegal...... with different malaria transmission levels. One site is in central Senegal, and the other site is in the southern part of the country. All samples were analyzed for single nucleotide polymorphisms (SNPs) in the P. falciparum CQ resistance transporter gene (Pfcrt; codons 72-76) using polymerase chain reaction...
Avery, Lindsay M; Nicolau, David P
Infections caused by multidrug-resistant Gram-negative bacteria (MDR-GNB) are associated with significant mortality and costs. New drugs in development to combat these difficult-to-treat infections primarily target carbapenem-resistant Enterobacteriaceae, MDR Pseudomonas aeruginosa, and MDR Acinetobacter baumannii. Areas covered: The authors summarize in vitro and in vivo efficacy studies, as well as available clinical trial findings, for new agents in development for treatment of infection caused by MDR-GNB. Information regarding dosage regimens utilized in clinical trials and key pharmacokinetic and pharmacodynamic considerations are provided if available. A summary of recently approved agents, delafloxacin and meropenem/vaborbactam, is also included. Expert opinion: The development of multiple novel agents to fight MDR-GNB is promising to help save the lives of patients who acquire infection, and judicious use of these agents is imperative once they come to market to prevent the development of resistance. The other component paramount to this field of research is implementation of effective infection control policies and carbapenem-resistant Enterobacteriaceae (CRE) carrier screening protocols to mitigate the worldwide spread of MDR-GNB. Further investigation of anti-infective synergistic combinations will also be important, as well as support for economic research to reveal the true cost-benefit of utilization of the new agents discussed herein.
Chung, Pooi Yin; Khanum, Ramona
Bacterial resistance to commonly used drugs has become a global health problem, causing increased infection cases and mortality rate. One of the main virulence determinants in many bacterial infections is biofilm formation, which significantly increases bacterial resistance to antibiotics and innate host defence. In the search to address the chronic infections caused by biofilms, antimicrobial peptides (AMP) have been considered as potential alternative agents to conventional antibiotics. Although AMPs are commonly considered as the primitive mechanism of immunity and has been extensively studied in insects and non-vertebrate organisms, there is now increasing evidence that AMPs also play a crucial role in human immunity. AMPs have exhibited broad-spectrum activity against many strains of Gram-positive and Gram-negative bacteria, including drug-resistant strains, and fungi. In addition, AMPs also showed synergy with classical antibiotics, neutralize toxins and are active in animal models. In this review, the important mechanisms of action and potential of AMPs in the eradication of biofilm formation in multidrug-resistant pathogen, with the goal of designing novel antimicrobial therapeutics, are discussed. Copyright © 2017. Published by Elsevier B.V.
Full Text Available Salmonella enterica is recognized as one of the major food-borne pathogens with more than 2,500 serotypes worldwide. The present study addresses antimicrobial resistance of Salmonella enterica serovar Enteritidis isolates in Iran. A collection of 151 Salmonella spp. isolates collected from poultry were serotyped to identify Salmonella Enteritidis. Sixty-one Salmonella Enteritidis were subsequently tested against 30 antimicrobials. A high frequency of antimicrobial resistance was observed against nitrofurantoin (n=55, 90.2% followed by nalidixic acid (n=41, 67.2%, and cephalexin (n=23, 37.7%. Multi-drug resistance were observed in 35 (57.4% out of 61 isolates. Twenty-six antimicrobial resistance patterns were observed among the 61 Salmonella Enteritidis. All isolates were susceptible to ofloxacin, imipenem, enrofloxacin, chloramphenicol, gentamicin, and 3rd and 4th generation cephalosporins. In conclusion, our results revealed that implementing new policies toward overuse of antimicrobial drugs in Iranian poultry industry are of great importance.
Full Text Available The emergence of Escherichia coli that produce extended spectrum β-lactamases (ESBLs and are multidrug resistant (MDR poses antibiotic management problems. Forty-seven E. coli isolates from various public hospitals in Malaysia were studied. All isolates were sensitive to imipenem whereas 36 were MDR (resistant to 2 or more classes of antibiotics. PCR detection using gene-specific primers showed that 87.5% of the ESBL-producing E. coli harbored the blaTEM gene. Other ESBL-encoding genes detected were blaOXA, blaSHV, and blaCTX-M. Integron-encoded integrases were detected in 55.3% of isolates, with class 1 integron-encoded intI1 integrase being the majority. Amplification and sequence analysis of the 5′CS region of the integrons showed known antibiotic resistance-encoding gene cassettes of various sizes that were inserted within the respective integrons. Conjugation and transformation experiments indicated that some of the antibiotic resistance genes were likely plasmid-encoded and transmissible. All 47 isolates were subtyped by PFGE and PCR-based fingerprinting using random amplified polymorphic DNA (RAPD, repetitive extragenic palindromes (REPs, and enterobacterial repetitive intergenic consensus (ERIC. These isolates were very diverse and heterogeneous. PFGE, ERIC, and REP-PCR methods were more discriminative than RAPD in subtyping the E. coli isolates.
Harasym, Troy O; Liboiron, Barry D; Mayer, Lawrence D
A newly identified form of multidrug resistance (MDR) in tumor cells is presented, pertaining to the commonly encountered resistance of cancer cells to anticancer drug combinations at discrete drug:drug ratios. In vitro studies have revealed that whether anticancer drug combinations interact synergistically or antagonistically can depend on the ratio of the combined agents. Failure to control drug ratios in vivo due to uncoordinated pharmacokinetics could therefore lead to drug resistance if tumor cells are exposed to antagonistic drug ratios. Consequently, the most efficacious drug combination may not occur at the typically employed maximum tolerated doses of the combined drugs if this leads to antagonistic ratios in vivo after administration and resistance to therapeutic effects of the drug combination. Our approach to systematically screen a wide range of drug ratios and concentrations and encapsulate the drug combination in a liposomal delivery vehicle at identified synergistic ratios represents a means to mitigate this drug ratio-dependent MDR mechanism. The in vivo efficacy of the improved agents (CombiPlex formulations) is demonstrated and contrasted with the decreased efficacy when drug combinations are exposed to tumor cells in vivo at antagonistic ratios.
Pesavento, Giovanna; Maggini, Valentina; Maida, Isabel; Lo Nostro, Antonella; Calonico, Carmela; Sassoli, Chiara; Perrin, Elena; Fondi, Marco; Mengoni, Alessio; Chiellini, Carolina; Vannacci, Alfredo; Gallo, Eugenia; Gori, Luigi; Bogani, Patrizia; Bilia, Anna Rita; Campana, Silvia; Ravenni, Novella; Dolce, Daniela; Firenzuoli, Fabio; Fani, Renato
Essential oils (EOs) are known to inhibit the growth of a wide range of microorganisms. Particularly interesting is the possible use of EOs to treat multidrug-resistant cystic fibrosis (CF) pathogens. We tested the essential oil (EO) from Origanum vulgare for in vitro antimicrobial activity, against three of the major human opportunistic pathogens responsible for respiratory infections in CF patients; these are methicillin-resistant Staphylococcus aureus, Stenotrophomonas maltophilia and Achromobacter xylosoxidans. Antibiotic susceptibility of each strain was previously tested by the standard disk diffusion method. Most strains were resistant to multiple antibiotics and could be defined as multi-drug-resistant (MDR). The antibacterial activity of O. vulgare EO (OEO) against a panel of 59 bacterial strains was evaluated, with MIC and MBC determined at 24, 48 and 72 hours by a microdilution method. The OEO was effective against all tested strains, although to a different extent. The MBC and MIC of OEO for S. aureus strains were either lower or equal to 0.50%, v/v, for A. xylosoxidans strains were lower or equal to 1% and 0.50%, v/v, respectively; and for S. maltophilia strains were lower or equal to 0.25%, v/v. The results from this study suggest that OEO might exert a role as an antimicrobial in the treatment of CF infections.
Full Text Available In spite of the recent introduction of two new drugs (delamanid and bedaquiline and a few repurposed compounds to treat multidrug-resistant and extensively drug-resistant tuberculosis (MDR- and XDR-TB, clinicians are facing increasing problems in designing effective regimens in severe cases. Recently a 9 to 12-month regimen (known as the ‘Bangladesh regimen’ proved to be effective in treating MDR-TB cases. It included an initial phase of 4 to 6 months of kanamycin, moxifloxacin, prothionamide, clofazimine, pyrazinamide, high-dose isoniazid, and ethambutol, followed by 5 months of moxifloxacin, clofazimine, pyrazinamide, and ethambutol. However, recent evidence from Europe and Latin America identified prevalences of resistance to the first-line drugs in this regimen (ethambutol and pyrazinamide exceeding 60%, and of prothionamide exceeding 50%. Furthermore, the proportions of resistance to the two most important pillars of the regimen – quinolones and kanamycin – were higher than 40%. Overall, only 14 out of 348 adult patients (4.0% were susceptible to all of the drugs composing the regimen, and were therefore potentially suitable for the ‘shorter regimen’. A shorter, cheaper, and well-tolerated MDR-TB regimen is likely to impact the number of patients treated and improve adherence if prescribed to the right patients through the systematic use of rapid MTBDRsl testing.
Sanjay M. Wavare
Full Text Available Background: Pyoderma is common in India and other tropical countries. Staphylococcus aureus is the commonest causative agent ofpyoderma. Aims and Objectives: To know the antibiotic susceptibility and bacteriophage pattern of Staphylococcus aureus isolated from pyoderma infection. Materials and Methods: One hundred clinically diagnosed pyoderma cases were investigated bacteriologically. A total of 59 isolates of S. aureus were subjected to antibioticsusceptibility testing by Kirby Bauers disk diffusion method and phage typing by routine test dilution X 100 bacteriophages. Results: Most of the strains were resistant to penicillin, ampicillin and were susceptible to gentamicin, streptomycin and erythromycin. Multidrug resistance was also high among these strains. Regarding the phage types, Phage type 52 (15 strains, 96 (8 strains and 71(16strains were predominant among the typed strains (55.95% of S. aureus. The most common group was mixed phage group (17% followed by phage group I (13.55%. Conclusion: Knowledge of antibioticsusceptibility pattern is essential to give proper antibiotic therapy and avoid unnecessary medication with non-effective drugs, which may increase resistance. Gentamicin, streptomycin and erythromycin are the drugs of choice in that order. Association of phage typing and antibiotic sensitivity of S. aureus showed the predominance of phage group III with greater frequency of penicillin resistance.
Ji, Xiufeng; Gao, Yu; Chen, Lingli; Zhang, Zhiwen; Deng, Yihui; Li, Yaping
Three new nanohybrid systems of non-ionic surfactant inserting liposomes loading paclitaxel (PTX) (NLPs) were prepared to overcome multidrug resistance (MDR) in PTX-resistance human lung cancer cell line. Three non-ionic surfactants, Solutol HS 15 (HS-15), pluronic F68 (PF-68) and cremophor EL (CrEL) were inserted into liposomes by film hydration method to form NLPs with an average size of around 110, 180 and 110 nm, respectively. There was an obvious increase of rhodamin 123 (Rh123) accumulation in A549/T cells after treated with nanohybrid systems loading Rh123 (NLRs) when compared with free Rh123 or liposomes loading Rh123 without surfactants (LRs), which indicated the significant inhibition effects of NLRs on drug efflux. The P-gp detection and ATP determination demonstrated that BNLs could not only interfere P-gp expression on the membrane of drug resistant cells, but also decrease ATP level in the cells. The cytotoxicity of NLPs against A549/T cells was higher than PTX loaded liposomes without surfactants (LPs), and the best result was achieved after treated with NLPs2. The apoptotic assay and the cell cycle analysis showed that NLPs could induce more apoptotic cells in drug resistant cells when compared with LPs. These results suggested that NLPs could overcome MDR by combination of drug delivery, P-gp inhibition and ATP depletion, and showed potential for treatment of MDR. Copyright © 2011 Elsevier B.V. All rights reserved.
Ajibade, V.A.; Famurewa, O.
Escherichia coli were isolated from 140 samples of blood, urine, stool and water made up of 15.7%, 42.9% and 30.0% and 25.7% respectively. From the samples, 71.9% enterotoxigenic E. coli (ETEC), 14.3% enteropathogenic E. coli (EPEC), 7.1% enterohemorrhagic E. coil (EHEC) and 7.1% enteroinvasive E. coli (EIEC) occurred as diarrheagenic E. coli. Of the ETEC (240) isolates tested for susceptibility to eight conventional antibiotics. 110 (46.0%) showed resistance to all the tested antimicrobial agents. However, of the resistant strains; 24 (22.0%) were multidrug resistant. These were tested against 3.0 mg/mL of saponin extract from phyllanthus niruri and 13 (55.0%) of these were susceptible to the saponin. The antimicrobial activities of saponin from P. niruri are of interest since the crude extract was effective at concentration of 3.0 mg/ml to multiple resistant isolates of EEC. (author)
Kong Dejuan; Liu Xiaodong; Liang Bing; Jia Lili; Ma Shumei
Objective: To investigate the effect of different subtypes of fractionated doses on multidrug resistance in ovarian cancer cells. Methods: The human ovarian cancer cell lines SKOV3 and its drug-resistant subtype SKVCR were divided into four groups i.e., sham-irradiated, single dose (10 Gy), fractionated dose (2 Gy × 5) and multi-fractionated dose (1 Gy × 2 × 5). Cell sensitivity to vincristine (VCR), etoposide (VP-16), pirarubicin (THP) and cisplatin (DDP) was measured by MTT assay. Western blot was applied to detect the expression of P-gp after irradiation. Results: The doubling time of SKVCR was about 1.8-fold of that of SKOV3 cells. P-gp was expressed in SKVCR but not in SKOV3. IC 50 values of SKVCR were higher than those of SKOV3. To SKOV3 cells, single dose irradiation decreased cell sensitivity to THP and DDP and fractionated irradiation decreased cell sensitivity to VCR, THP and VP-16. Multi-fractionated irradiation decreased cell sensitivity to VP-16. In SKVCR cells, all these irradiation treatments increased cell sensitivity to VCR and VP-16 but not to DDP. In addition, single and fractionated irradiation decreased P-gp expression in SKVCR cells. Conclusions: Single, fractionated and multi-fractionated radiation induced chemotherapy resistance in SKOV3 cells, while reversed drug resistance to VCR and VP-16 in SKVCR cells. (authors)
Noonan, K.E.; Beck, C.; Holzmayer, T.A.; Chin, J.E.; Roninson, I.B.; Wunder, J.S.; Andrulis, I.L.; Gazdar, A.F.; Willman, C.L.; Griffith, B.; Von Hoff, D.D.
The resistance of tumor cells ot chemotheraprutic drugs is a major obstacle to successful cancer chemotherapy. In human cells, expression of the MDR1 gene, encoding a transmembrane efflux pump (P-glycoprotein), leads to decreased intracellular accumulation and resistance to a variety of lipophilic drugs (multidrug resistance; MDR). The levels of MDR in cell lines selected in bitro have been shown to correlate with the steady-state levels of MDR1 mRNA and P-glycoprotein. In cells with a severalfold increase in cellular drug resistance, MDR1 expression levels are close to the limits of detection by conventional assays. MDR1 expression has been frequently observed in human tumors after chemotherapy and in some but not all types of clinically refactory tumors untreated with chemotherapeutic drugs. The authors have devised a highly sensitive, specific, and quantitative protocol for measuring the levels of MDR1 mRNA in clincal samples, based on the polymerase chain reaction. They have used this assay to measure MDR1 gene expression in MDR cell lines and >300 normal tissues, tumor-derived cell lines, and clinical specimens of untreated tumors of the types in which MDR1 expression was rarely observed by standard assays. Low levels of MDR1 expression were found by polymerase chain reaction in most solid tumors and leukemias tested. The frequency of samples without detectable MDR1 expression varied among different types of tumors; MDR1-negative samples were ost common among tumor types known to be relatively responsive to chemotherapy
Rante, H.; Yulianty, R.; Usmar; Djide, N.; Subehan; Burhamzah, R.; Prasad, M. B.
The increasing case of antibiotic resistence has become an important problem to be faced in treating the infection diseases. The diversities of microbia, especially actinomycetes bacteria which originated from rizosphere soil of medicinal plant, has opened a chance for discovering the metabolites which can be used in solving the antibiotic resistant pathogenic bacteria problems. The aim of this research was to isolate the actinobacteria originated from medicinal plant rizosphere of Orthosipon stamineus as the producer of anti-multidrug resistances bacteria compounds. Three isolates of actinomycetes has been isolated from Orthosipon stamineus rhizosphere named KC3-1, KC3-2 and KC3-3. One isolate (KC3-3) showed big activity in inhibiting the test microbes by antagonistic test of actinomycetes isolates against Staphylococcus aureus and Eschericia coli antibiotic resistant bacteria. Furthermore, the KC3-3 isolate was fermented in Starch Nitrate Broth (SNB) medium for 14 days. The supernatant and the biomass of the fermentation yield were separated. The supernatant were extracted using ethyl acetate as the solvent and the biomass were extracted using methanol. The antibacterial activity test of ethyl acetate and methanol extract revealed that the extracts can inhibit the bacteria test up to 5% concentration. The ethyl acetate and methanol extracts can inhibit the bacteria test up to 5% concentration.
Theilade, M D; Gram, G J; Jensen, P B
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...... for the gibbon ape leukemia virus (GALV-1) receptor or had specificity for the amphotropic murine leukemia virus (MLV-A) receptor were used for transduction of five SCLC cell lines differing by a range of MDR mechanisms. Transduction efficiencies in these cell lines were compared by calculating the percentage...... of blue colonies after X-Gal staining of the cells grown in soft agar. All examined SCLC cell lines were transducible with either vector. Transduction efficiencies varied from 5.7% to 33.5% independent of the presence of MDR. These results indicate that MDR does not severely impair transduction of SCLC...
de Sousa, Oscarina Viana; Hofer, Ernesto; Mafezoli, Jair; Barbosa, Francisco Geraldo
Prospect of antibacterial agents may provide an alternative therapy for diseases caused by multidrug-resistant bacteria. This study aimed to evaluate the in vitro bioactivity of Moringa oleifera seed extracts against 100 vibrios isolated from the marine shrimp Litopenaeus vannamei. Ethanol extracts at low (MOS-E) and hot (MOS-ES) temperature are shown to be bioactive against 92% and 90% of the strains, respectively. The most efficient Minimum Inhibitory Concentration (MIC) levels of MOS-E and MOS-ES against a high percentage of strains were 32 µg mL−1. Bioguided screening of bioactive compounds showed that the ethyl acetate fraction from both extracts was the only one that showed antibacterial activity. Vibriocidal substances, niazirine and niazimicine, were isolated from the aforementioned fraction through chromatographic fractionation. PMID:28770224
Full Text Available Abstract Multi-drug resistance (MDR of cancer cells severely limits therapeutic outcomes. A proposed mechanism for MDR involves the efflux of anti-cancer drugs from cancer cells, primarily mediated by ATP-binding cassette (ABC membrane transporters including P-glycoprotein. This article reviews the recent progress of using active ingredients, extracts and formulae from Chinese medicine (CM in circumventing ABC transporters-mediated MDR. Among the ABC transporters, Pgp is the most extensively studied for its role in MDR reversal effects. While other MDR reversal mechanisms remain unclear, Pgp inhibition is a criterion for further mechanistic study. More mechanistic studies are needed to fully establish the pharmacological effects of potential MDR reversing agents.
Full Text Available A systematic literature review was performed to investigate the occurrence of multidrug-resistant tuberculosis (MDR TB in prisons located in countries formerly part of the Soviet Union.A systematic search of published studies reporting MDR TB occurrence in prisons located in former Soviet countries was conducted by probing PubMed and Cumulative Index Nursing and Allied Health Literature for articles that met predetermined inclusion criteria.Seventeen studies were identified for systematic review. Studies were conducted in six different countries. Overall, prevalence of MDR TB among prisoners varied greatly between studies. Our findings suggest a high prevalence of MDR TB in prisons of Post-Soviet states with percentages as high as 16 times more than the worldwide prevalence estimated by the WHO in 2014.All studies suggested a high prevalence of MDR TB in prison populations in Post-Soviet states.
Sujay Kumar Bhunia
Full Text Available The re-emergence of multidrug-resistant tuberculosis (MDR-TB has brought to light the importance of screening effective novel drugs. In the present study, in vitro activities of different snake (Naja naja, Bungarus fasciatus, Daboia russelli russelli, Naja kaouthia venoms have been investigated against clinical isolate of MDR-TB strains. The treatment with all the venoms inhibited the mycobacterial growth for at least a week in common and two of them (Naja naja and Naja kaouthia showed significantly longer inhibition up to two weeks against the MDR-TB strain with single dose and a repetition of those two venoms exhibited inhibition up to more than four weeks.
Chai, Stella; To, Kenneth Kw; Lin, Ge
Multi-drug resistance (MDR) of cancer cells severely limits therapeutic outcomes. A proposed mechanism for MDR involves the efflux of anti-cancer drugs from cancer cells, primarily mediated by ATP-binding cassette (ABC) membrane transporters including P-glycoprotein. This article reviews the recent progress of using active ingredients, extracts and formulae from Chinese medicine (CM) in circumventing ABC transporters-mediated MDR. Among the ABC transporters, Pgp is the most extensively studied for its role in MDR reversal effects. While other MDR reversal mechanisms remain unclear, Pgp inhibition is a criterion for further mechanistic study. More mechanistic studies are needed to fully establish the pharmacological effects of potential MDR reversing agents.
Full Text Available Mycotic pseudoaneurysm of aorta following cardiac surgery is rare but is highly fatal if it is unrecognized and untreated. Here, we report a case of a 45-year-old male patient who presented with rapidly progressive multiple pseudoaneurysms of the ascending aorta infected with multidrug resistant (MDR Pseudomonas aeruginosa at 5 weeks after cardiac transplantation, on a background of prior bridging therapy with left ventricular assistant device (LVAD. The patient was successfully treated with the newer cephalosporin, Ceftolozane/Tazobactam, in combination with surgery. This is the first reported case of mycotic pseudoaneurysm infected with MDR Pseudomonas. This case also highlights the importance of high vigilance and timely multimodality treatment in the diagnosis and management of mycotic pseudoaneurysm following cardiac transplant, especially in patients who had LVAD.
Wang, Qiwen; Ma, Chenyao; Ma, Yun; Li, Xiang; Chen, Yong; Chen, Jianwei
Thirteen xanthones were isolated naturally from the stem of Securidaca inappendiculata Hassk, and structure-activity relationships (SARs) of these compounds were comparatively predicted for their cytotoxic activity against three human multidrug resistant (MDR) cell lines MCF-7/ADR, SMMC-7721/Taxol, and A549/Taxol cells. The results showed that the selected xanthones exhibited different potent cytotoxic activity against the growth of different human tumor cell lines, and most of the xanthones exhibited selective cytotoxicity against SMMC-7721/Taxol cells. Furthermore, some tested xanthones showed stronger cytotoxicity than Cisplatin, which has been used in clinical application extensively. The SARs analysis revealed that the cytotoxic activities of diverse xanthones were affected mostly by the number and position of methoxyl and hydroxyl groups. Xanthones with more free hydroxyl and methoxyl groups increased the cytotoxic activity significantly, especially for those with the presence of C-3 hydroxyl and C-4 methoxyl groups. Copyright © 2016 Elsevier Ltd. All rights reserved.
Full Text Available Despite the recent advances in the diagnosis of tuberculosis, treatment of the disease, for the most part, remains the same as it was half a century ago. In recent years only two new anti-tuberculosis drugs have been approved by the European Medicines Agency and Food and Drug Administration. Though the prevalence of this disease is slowly decreasing all over Europe, new challenges appear. One of them is multidrug-resistant tuberculosis (MDR-TB. This problem is especially prominent in Lithuania, which is one of the 27 high MDR-TB burden countries in the world and falls behind neighboring countries in terms of the prevalence of the disease. The objective of this paper was to review the situation of tuberculosis and MDR-TB in Lithuania, and current available methods of treatment, control and diagnosis of this disease.
Kordalewska, Milena; Zhao, Yanan; Lockhart, Shawn R; Chowdhary, Anuradha; Berrio, Indira; Perlin, David S
Candida auris is an emerging multidrug-resistant fungal pathogen causing nosocomial and invasive infections associated with high mortality. C. auris is commonly misidentified as several different yeast species by commercially available phenotypic identification platforms. Thus, there is an urgent need for a reliable diagnostic method. In this paper, we present fast, robust, easy-to-perform and interpret PCR and real-time PCR assays to identify C. auris and related species: Candida duobushaemulonii , Candida haemulonii , and Candida lusitaniae Targeting rDNA region nucleotide sequences, primers specific for C. auris only or C. auris and related species were designed. A panel of 140 clinical fungal isolates was used in both PCR and real-time PCR assays followed by electrophoresis or melting temperature analysis, respectively. The identification results from the assays were 100% concordant with DNA sequencing results. These molecular assays overcome the deficiencies of existing phenotypic tests to identify C. auris and related species. Copyright © 2017 Kordalewska et al.
Herlina, N.; Sinaga, B. Y. M.; Siagian, P.; Mutiara, E.
Low levels of vitamin D is a predisposing factor for Multidrug-resistant tuberculosis. Family members in contact with the patient are also at risk of infection. Currently, there is no study that compares vitamin D levels between MDR-TB patients and household contact. This study aims to identify the association between level vitamin D within MDR-TB occurrence. This was a case-control study, with the number of samples in each group (MDR-TB) patients and household contactswere40 people. Each member of each group was checked for vitamin D levels using enzyme-linked immunosorbent assay (ELISA) technique. Statistical analysis was by using Chi-Square analysis using SPSS. Mean levels of vitamin D in MDR-TB patients were 32.21, household contact 31.7. There was anosignificant association between vitamin D levels and MDR-TB occurrence (p=1.0).No significant associationbetween vitamin D level with theMDR-TB occurrence.
Dumyati, Ghinwa; Stone, Nimalie D; Nace, David A; Crnich, Christopher J; Jump, Robin L P
Nursing home residents are at high risk for colonization and infection with bacterial pathogens that are multidrug-resistant organisms (MDROs). We discuss challenges and potential solutions to support implementing effective infection prevention and control practices in nursing homes. Challenges include a paucity of evidence that addresses MDRO transmission during the care of nursing home residents, limited staff resources in nursing homes, insufficient infection prevention education in nursing homes, and perceptions by nursing home staff that isolation and contact precautions negatively influence the well being of their residents. A small number of studies provide evidence that specifically address these challenges. Their outcomes support a paradigm shift that moves infection prevention and control practices away from a pathogen-specific approach and toward one that focuses on resident risk factors.
Ayres, Janelle S.; Trinidad, Norver J.; Vance, Russell E.
The mammalian intestine harbors a complex microbial community that provides numerous benefits to its host. However, the microbiota can also include potentially virulent species, termed pathobionts, which can cause disease when intestinal homeostasis is disrupted. The molecular mechanisms by which pathobionts cause disease remain poorly understood. Here we describe a sepsis-like disease that occurs upon gut injury in antibiotic-treated mice. Sepsis was associated with the systemic spread of a specific multidrug-resistant E. coli pathobiont that expanded dramatically in the microbiota of antibiotic-treated mice. Rapid sepsis-like death required a component of the innate immune system, the Naip5-Nlrc4 inflammasome. In accordance with Koch's postulates, we found the E. coli pathobiont was sufficient to activate Naip5-Nlrc4 and cause disease when injected intravenously into unmanipulated mice. These findings reveal how sepsis-like disease can result from recognition of pathobionts by the innate immune system. PMID:22522562
Wind, N.S.; Holen, I.
The development of multidrug resistance (MDR) and subsequent relapse on therapy is a widespread problem in breast cancer, but our understanding of the underlying molecular mechanisms is incomplete. Numerous studies have aimed to establish the role of drug transporter pumps in MDR and to link their expression to response to chemotherapy. The ATP-binding cassette (ABC) transporters are central to breast cancer MDR, and increases in ABC expression levels have been shown to correlate with decreases in response to various chemotherapy drugs and a reduction in overall survival. But as there is a large degree of redundancy between different ABC transporters, this correlation has not been seen in all studies. This paper provides an introduction to the key molecules associated with breast cancer MDR and summarises evidence of their potential roles reported from model systems and clinical studies. We provide possible explanations for why despite several decades of research, the precise role of ABC transporters in breast cancer MDR remains elusive
Lhadon, Tenzin; Jullien, Sophie
Multidrug-resistant tuberculosis (MDR-TB) is a well-identified raising public health concern worldwide. However, the data available on MDR-TB in children and particularly in the neonate age group are limited. Congenital tuberculosis (TB) is rare, and its diagnosis is challenging because of non-specific manifestations. The choice of anti-tubercular drugs is difficult because of the lack of international consensus as a consequence of the scarcity of evidence-based data on this age group. We hereby present a case from Bhutan of a 23-day-old male neonate with congenital MDR-TB. His mother was diagnosed with disseminated TB, and treatment was commenced 11 days post-partum. Congenital transmission of TB was suspected, as direct postnatal transmission was unlikely and thorough screening of contacts for TB was negative. In this case, the mother's MDR-TB status was revealed only after her newborn's MDR-TB diagnosis.
Full Text Available Xiaozhe Wu,1 Zhan Li,1 Xiaolu Li,2,3 Yaomei Tian,1 Yingzi Fan,1 Chaoheng Yu,1 Bailing Zhou,1 Yi Liu,4 Rong Xiang,5 Li Yang1 1State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, 2International Center for Translational Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu, 3Department of Plastic and Burn Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, 4Department of Microbial Examination, Sichuan Center for Disease Control and Prevention, Chengdu, 5Nankai University School of Medicine, Tianjin, People’s Republic of China Abstract: Antibiotic-resistant bacteria present a great threat to public health. In this study, the synergistic effects of antimicrobial peptides (AMPs and antibiotics on several multidrug-resistant bacterial strains were studied, and their synergistic effects on azithromycin (AZT-resistance genes were analyzed to determine the relationships between antimicrobial resistance and these synergistic effects. A checkerboard method was used to evaluate the synergistic effects of AMPs (DP7 and CLS001 and several antibiotics (gentamicin, vancomycin [VAN], AZT, and amoxicillin on clinical bacterial strains (Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, and Escherichia coli. The AZT-resistance genes (ermA, ermB, ermC, mefA, and msrA were identified in the resistant strains using quantitative polymerase chain reaction. For all the clinical isolates tested that were resistant to different antibiotics, DP7 had high antimicrobial activity (≤32 mg/L. When DP7 was combined with VAN or AZT, the effect was most frequently synergistic. When we studied the resistance genes of the AZT-resistant isolates, the synergistic effect of DP7–AZT occurred most frequently in highly resistant strains or strains carrying more than two AZT-resistance genes. A transmission electron microscopic analysis of the S. aureus
Udwadia, Zarir F; Mullerpattan, Jai Bharat; Shah, Kushal D; Rodrigues, Camilla S
Treatment of multidrug-resistant tuberculosis (MDR-TB) in the Programmatic Management of Drug-resistant TB program involves a standard regimen with a 6-month intensive phase and an 18-month continuation phase. However, the local drug resistance patterns in high MDR regions such as Mumbai may not be adequately reflected in the design of the regimen for that particular area. The study was carried out at a private Tertiary Level Hospital in Mumbai in a mycobacteriology laboratory equipped to perform the second-line drug susceptibility testing (DST). We attempted to analyze the impact of prescribing the standardized Category IV regimen to all patients receiving a DST at our mycobacteriology laboratory. All samples confirmed to be MDR-TB and tested for the second-line drugs at Hinduja Hospital's Mycobacteriology Laboratory in the year 2012 were analyzed. A total of 1539 samples were analyzed. Of these, 464 (30.14%) were MDR-TB, 867 (56.33%) were MDR with fluoroquinolone resistance, and 198 (12.8%) were extensively drug-resistant TB. The average number of susceptible drugs per sample was 3.07 ± 1.29 (assuming 100% cycloserine susceptibility). Taking 4 effective drugs to be the cut or an effective regimen, the number of patients receiving 4 or more effective drugs from the standardized directly observed treatment, short-course plus regimen would be 516 (33.5%) while 66.5% of cases would receive 3 or less effective drugs. Our study shows that a high proportion of patients will have resistance to a number of the first- and second-line drugs. Local epidemiology must be factored in to avoid amplification of resistance.