Mungube Erick O
Full Text Available Abstract Background African animal trypanosomosis is a major constraint to the rearing of productive livestock in the sub-humid Sudan-Sahel zone of West Africa where cotton is grown. Trypanosomosis is mainly controlled using trypanocidal drugs, but the effective use of drugs is threatened by the development of widespread resistance. This study tested integrated best-bet strategies for containment and/ or reversal of trypanocide resistance in villages in south-east Mali where resistance has been reported. Methods Four sentinel villages each from an intervention area (along the road from Mali to Burkina Faso and a control area (along the road from Mali to Côte d’Ivoire were selected for the study. Tsetse control was based on deltamethrin-treated stationary attractive devices and targeted cattle spraying between March 2008 and November 2009. Trypanosome-positive cattle were selectively treated with 3.5 mg/kg diminazene aceturate. Strategic helminth control using 10 mg/kg albendazole was also undertaken. During the intervention, tsetse densities along drainage lines, trypanosome infections and faecal egg counts in risk cattle (3 to 12 months of age were monitored. Results Catch reductions of 66.5 % in Glossina palpalis gambiensis and 90 % in G. tachinoides were observed in the intervention area. Trypanosome prevalence was significantly (p 0.05. Further studies are required before confirming the existence of albendazole resistant strongyles in the study area. Conclusion Integration of best-bet strategies in areas of multiple drug-resistance is expected to reduce trypanosome infection risk thus contributing to containment of trypanocidal drug resistance. Integrated best-bet strategies could therefore be considered a viable trypanosomosis control option especially in areas where multiple drug-resistance has been reported.
Full Text Available Abstract Background Drug resistance has now posed more severe and emergent threats to human health and infectious disease treatment. However, wet-lab approaches alone to counter drug resistance have so far still achieved limited success due to less knowledge about the underlying mechanisms of drug resistance. Our approach apply a heuristic search algorithm in order to extract active network under drug treatment and use a random walk model to identify potential co-targets for effective antibacterial drugs. Results We use interactome network of Mycobacterium tuberculosis and gene expression data which are treated with two kinds of antibiotic, Isoniazid and Ethionamide as our test data. Our analysis shows that the active drug-treated networks are associated with the trigger of fatty acid metabolism and synthesis and nicotinamide adenine dinucleotide (NADH-related processes and those results are consistent with the recent experimental findings. Efflux pumps processes appear to be the major mechanisms of resistance but SOS response is significantly up-regulation under Isoniazid treatment. We also successfully identify the potential co-targets with literature confirmed evidences which are related to the glycine-rich membrane, adenosine triphosphate energy and cell wall processes. Conclusions With gene expression and interactome data supported, our study points out possible pathways leading to the emergence of drug resistance under drug treatment. We develop a computational workflow for giving new insights to bacterial drug resistance which can be gained by a systematic and global analysis of the bacterial regulation network. Our study also discovers the potential co-targets with good properties in biological and graph theory aspects to overcome the problem of drug resistance.
YAN Li-ping; QIN Lian-hua; ZHANG Qing; SUN Hua; HAN Min; XIAO He-ping
Background Diagnosis and appropriate treatment of multidrug-resistant tuberculosis (MDR-TB) remain major challenges.We sought to elucidate that persons who share a household with drug resistance tuberculosis patients are at high risk for primary drug resistance tuberculosis and how to prevent these outbreaks.Methods We used 12-locus mycobacterial interspersed repetitive unit and 7-locus variable-number tandem repeat to identify household transmission of extensively drug resistant and multiple drug resistant Mycobacterium tuberculosis in three families admitted in Shanghai Pulmonary Hospital affiliated with Tongji University.Drug susceptibility tests were done by the modified proportion method in the MGIT 960 system in the same time.Clinical data were also obtained from the subjects' medical records.Results All of the six strains were defined as Beijing genotype by the deletion-targeted multiplex PCR (DTM-PCR) identification on the genomic deletion RD105.Strains from family-1 had the same minisatellite interspersed repetitive unit (MIRU) pattem (232225172531) and the same MIRU pattern (3677235).Strains from family-2 had the same MIRU pattern (2212261553323) and the same MIRU pattern (3685134).Strains from family-3 did not have the same MIRU pattern and they differed at only one locus (223326173533,223325173533),and did not have the same VNTR pattern with two locus differed (3667233,3677234).Conclusions Household transmission exists in the three families.A clear chain of tuberculosis transmission within family exists.Tuberculosis susceptibility should be considered when there is more than one tuberculosis patients in a family.Household tuberculosis transmission could be prevented with adequate treatment of source patients.
HIV Treatment Drug Resistance (Last updated 3/2/2017; last reviewed 3/2/2017) Key Points As HIV multiplies in the ... the risk of drug resistance. What is HIV drug resistance? Once a person becomes infected with HIV, ...
Zhang, Hong-Jie; Rumschlag-Booms, Emily; Guan, Yi-Fu; Wang, Dong-Ying; Liu, Kang-Lun; Li, Wan-Fei; Nguyen, Van H; Cuong, Nguyen M; Soejarto, Djaja D; Fong, Harry H S; Rong, Lijun
Justicia gendarussa, a medicinal plant collected in Vietnam, was identified as a potent anti-HIV-1 active lead from the evaluation of over 4500 plant extracts. Bioassay-guided separation of the extracts of the stems and roots of this plant led to the isolation of an anti-HIV arylnaphthalene lignan (ANL) glycoside, patentiflorin A (1). Evaluation of the compound against both the M- and T-tropic HIV-1 isolates showed it to possess a significantly higher inhibition effect than the clinically used anti-HIV drug AZT. Patentiflorin A and two congeners were synthesized, de novo, as an efficient strategy for resupply as well as for further structural modification of the anti-HIV ANL glycosides in the search for drug leads. Subsequently, it was determined that the presence of a quinovopyranosyloxy group in the structure is likely essential to retain the high degree of anti-HIV activity of this type of compounds. Patentiflorin A was further investigated against the HIV-1 gene expression of the R/U5 and U5/gag transcripts, and the data showed that the compound acts as a potential inhibitor of HIV-1 reverse transcription. Importantly, the compound displayed potent inhibitory activity against drug-resistant HIV-1 isolates of both the nucleotide analogue (AZT) and non-nucleotide analogue (nevaripine). Thus, the ANL glycosides have the potential to be developed as novel anti-HIV drugs.
Medina, Noraine P; Mingala, Claro N
Trypanosoma infection is one of the most important infections in livestock and humans. One of the main problems of its therapeutic control and treatment is the resurgence of drug resistance. One of the most studied causes of such resistance is the function of its adenosine transporter gene. A trypanosomal gene TbAT1 from Trypanosoma brucei has been cloned in yeast to demonstrate its function in the transport of adenosine and trypanocidal agents. Drug resistant trypanosomes showed a defective TbAT1 variant; furthermore, deletion of the gene and set point mutations in the transporter gene has been demonstrated from isolates from relapse patients. The molecular understanding of the mechanism of action trypanocidal agents and function of transporter gene can lead to control of drug resistance of Trypanosomes.
Tong, Mengsha; Zheng, Weicheng; Lu, Xingrong; Ao, Lu; Li, Xiangyu; Guan, Qingzhou; Cai, Hao; Li, Mengyao; Yan, Haidan; Guo, You; Chi, Pan; Guo, Zheng
Until recently, few molecular signatures of drug resistance identified in drug-induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5-fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens.
Gorter, J.A.; Potschka, H.; Noebels, J.L.; Avoli, M.; Rogawski, M.A.; Olsen, R.W.; Delgado-Escueta, A.V.
Drug resistance remains to be one of the major challenges in epilepsy therapy. Identification of factors that contribute to therapeutic failure is crucial for future development of novel therapeutic strategies for difficult-to-treat epilepsies. Several clinical studies have shown that high seizure f
Balko, Justin M; Cook, Rebecca S; Vaught, David B; Kuba, María G; Miller, Todd W; Bhola, Neil E; Sanders, Melinda E; Granja-Ingram, Nara M; Smith, J Joshua; Meszoely, Ingrid M; Salter, Janine; Dowsett, Mitch; Stemke-Hale, Katherine; González-Angulo, Ana M; Mills, Gordon B; Pinto, Joseph A; Gómez, Henry L; Arteaga, Carlos L
Neoadjuvant chemotherapy (NAC) induces a pathological complete response (pCR) in ~30% of patients with breast cancer. However, many patients have residual cancer after chemotherapy, which correlates with a higher risk of metastatic recurrence and poorer outcome than those who achieve a pCR. We hypothesized that molecular profiling of tumors after NAC would identify genes associated with drug resistance. Digital transcript counting was used to profile surgically resected breast cancers after NAC. Low concentrations of dual specificity protein phosphatase 4 (DUSP4), an ERK phosphatase, correlated with high post-NAC tumor cell proliferation and with basal-like breast cancer (BLBC) status. BLBC had higher DUSP4 promoter methylation and gene expression patterns of Ras-ERK pathway activation relative to other breast cancer subtypes. DUSP4 overexpression increased chemotherapy-induced apoptosis, whereas DUSP4 depletion dampened the response to chemotherapy. Reduced DUSP4 expression in primary tumors after NAC was associated with treatment-refractory high Ki-67 scores and shorter recurrence-free survival. Finally, inhibition of mitogen-activated protein kinase kinase (MEK) synergized with docetaxel treatment in BLBC xenografts. Thus, DUSP4 downregulation activates the Ras-ERK pathway in BLBC, resulting in an attenuated response to anti-cancer chemotherapy. PMID:22683778
Armas-López, Leonel; Piña-Sánchez, Patricia; Arrieta, Oscar; de Alba, Enrique Guzman; Ortiz-Quintero, Blanca; Santillán-Doherty, Patricio; Christiani, David C.; Zúñiga, Joaquín; Ávila-Moreno, Federico
Several homeobox-related gene (HOX) transcription factors such as mesenchyme HOX-2 (MEOX2) have previously been associated with cancer drug resistance, malignant progression and/or clinical prognostic responses in lung cancer patients; however, the mechanisms involved in these responses have yet to be elucidated. Here, an epigenomic strategy was implemented to identify novel MEOX2 gene promoter transcription targets and propose a new molecular mechanism underlying lung cancer drug resistance and poor clinical prognosis. Chromatin immunoprecipitation (ChIP) assays derived from non-small cell lung carcinomas (NSCLC) hybridized on gene promoter tiling arrays and bioinformatics analyses were performed, and quantitative, functional and clinical validation were also carried out. We statistically identified a common profile consisting of 78 gene promoter targets, including Hedgehog-GLI1 gene promoter sequences (FDR≤0.1 and FDR≤0.2). The GLI-1 gene promoter region from −2,192 to −109 was occupied by MEOX2, accompanied by transcriptionally active RNA Pol II and was epigenetically linked to the active histones H3K27Ac and H3K4me3; these associations were quantitatively validated. Moreover, siRNA genetic silencing assays identified a MEOX2-GLI1 axis involved in cellular cytotoxic resistance to cisplatinum in a dose-dependent manner, as well as cellular migration and proliferation. Finally, Kaplan-Maier survival analyses identified significant MEOX2-dependent GLI-1 protein expression associated with clinical progression and poorer overall survival using an independent cohort of NSCLC patients undergoing platinum-based oncological therapy with both epidermal growth factor receptor (EGFR)-non-mutated and EGFR-mutated status. In conclusion, this is the first study to investigate epigenome-wide MEOX2-transcription factor occupation identifying a novel overexpressed MEOX2-GLI1 axis and its clinical association with platinum-based cancer drug resistance and EGFR
Gordon F. Bennett
Full Text Available Linear measurements and derived indices of trypanosomes from species of Fennoscandian birds were compared to those reported form Trypanosoma avium, T. everetti, T. ontarioensis and T. paddae. The trypanosomes encountered in the Fennoscandian birds were identified as T. avium from Tengmalm's owl Aegolius funereus and the pied flycatcher Ficedula hypoleuca, T. everetti from the great tit Parus major and collared flycatcher F. albicollis and T. ontarioensis from the collared flycatcher; T. paddae was not seen.
... the past 70 years, antimicrobial drugs, such as antibiotics, have been successfully used to treat patients with bacterial and infectious diseases. Why Is the Study of Antimicrobial (Drug) Resistance a Priority for NIAID? Over time, many infectious ...
Velikova, Nadya; Fulle, Simone; Manso, Ana Sousa; Mechkarska, Milena; Finn, Paul; Conlon, J. Michael; Oggioni, Marco Rinaldo; Wells, Jerry M.; Marina, Alberto
Novel antibacterials are urgently needed to address the growing problem of bacterial resistance to conventional antibiotics. Two-component systems (TCS) are widely used by bacteria to regulate gene expression in response to various environmental stimuli and physiological stress and have been previously proposed as promising antibacterial targets. TCS consist of a sensor histidine kinase (HK) and an effector response regulator. The HK component contains a highly conserved ATP-binding site that is considered to be a promising target for broad-spectrum antibacterial drugs. Here, we describe the identification of putative HK autophosphorylation inhibitors following two independent experimental approaches: in vitro fragment-based screen via differential scanning fluorimetry and in silico structure-based screening, each followed up by the exploration of analogue compounds as identified by ligand-based similarity searches. Nine of the tested compounds showed antibacterial effect against multi-drug resistant clinical isolates of bacterial pathogens and include three novel scaffolds, which have not been explored so far in other antibacterial compounds. Overall, putative HK autophosphorylation inhibitors were found that together provide a promising starting point for further optimization as antibacterials.
Extensively drug-resistant tuberculosis (XDR TB) outbreaks have been reported in South Africa, and strains have been identified on 6 continents. Dr. Peter Cegielski, team leader for drug-resistant TB with the Division of Tuberculosis Elimination at CDC, comments on a multinational team's report on this emerging global public health threat. Created: 3/1/2007 by Emerging Infectious Diseases. Date Released: 3/26/2007.
Krüger, Timothy; Engstler, Markus
Evolution has generated a plethora of flagellate microswimmers. They populate all natural waters, from the deep sea to the ponds in our neighbourhood. But flagellates also thrive in the bodies of higher organisms, where they mostly remain undetected, but can also become pathogenic. Trypanosomes comprise a large group of mostly parasitic flagellates that cause many diseases, such as human sleeping sickness or the cattle plague nagana. We consider African trypanosomes as extremely versatile microswimmers, as they have to adapt to very diverse microenvironments. They swim efficiently in the blood of their mammalian hosts, but also in various tissue spaces and even in the human brain. Furthermore, in the transmitting tsetse fly, trypanosomes undergo characteristic morphological changes that are accompanied by amazing transitions between solitary and collective types of motion. In this review, we provide a basic introduction to trypanosome biology and then focus on the complex type of rotational movement that trypanosomes display. We relate their swimming performance to morphological parameters and the respective microenvironment, developing a contemporary view on the physics of trypanosome motility. The genetically programmed successions of life style-dependent motion patterns provide challenges and opportunities for interdisciplinary studies of microswimmers.
Ruef, B J; Hecht, J H; Manning, J E
A chimeric oligonucleotide was constructed using DNA sequences from two distal regions of a cDNA which encodes a major surface antigen (TSA-1) of Trypanosoma cruzi. Conditions were found that allowed the chimeric oligonucleotide to hybridize only to a 5.4 kb EcoRI fragment in a Southern blot of total genomic DNA. The 5.4 kb EcoRI genomic DNA fragment has previously been shown to be located at a telomeric site, thus the studies described here directly demonstrate that the TSA-1 gene is telomeric in location. It is also shown that the chimeric oligonucleotide can be used to selectively identify recombinant lambda phage which harbor the TSA-1 gene using standard library screening procedures. Since these studies demonstrate that a chimeric oligonucleotide can be used to identify in both Southern blots and library screens a single member among the more than sixty members of the TSA-1 gene family, it seems likely that chimeric oligonucleotides may be of general use in studies involving repetitive DNA sequence families.
Garg, Ravindra K; Jain, Amita; Malhotra, Hardeep S; Agrawal, Avinash; Garg, Rajiv
Drug-resistant tuberculosis, including drug-resistant tuberculous meningitis, is an emerging health problem in many countries. An association with Beijing strains and drug resistance-related mutations, such as mutations in katG and rpoB genes, has been found. The pathology, clinical features and neuroimaging characteristics of drug-resistant tuberculous meningitis are similar to drug-responsive tuberculous meningitis. Detection of mycobacteria in cerebrospinal fluid (CSF) by conventional methods (smear examination or culture) is often difficult. Nucleic acid amplification assays are better methods owing to their rapidity and high sensitivity. The Xpert MTB/RIF assay (Cepheid, CA, USA) is a fully-automated test that has also been found to be effective for CSF samples. Treatment of multidrug-resistant tuberculous meningitis depends on the drug susceptibility pattern of the isolate and/or the previous treatment history of the patient. Second-line drugs with good penetration of the CSF should be preferred. Isoniazid monoresistant disease requires addition of another drug with better CSF penetration. Drug-resistant tuberculous meningitis is associated with a high mortality. HIV infected patients with drug-resistant tuberculous meningitis have severe clinical manifestations with exceptionally high mortality. Prevention of tuberculosis is the key to reduce drug-resistant tuberculous meningitis.
Nim, Shweta; Lobato, Lucia Gonzalez; Moreno, Alexis; Chaptal, Vincent; Rawal, Manpreet Kaur; Falson, Pierre; Prasad, Rajendra
The ABC (ATP-Binding Cassette) transporter Cdr1 (Candida drug resistance 1) protein (Cdr1p) of Candida albicans, shows promiscuity towards the substrate it exports and plays a major role in antifungal resistance. It has two transmembrane domains (TMDs) comprising of six transmembrane helices (TMH) that envisage and confer the substrate specificity and two nucleotide binding domains (NBDs), interconnected by extracellular loops (ECLs) and intracellular loops (ICLs) Cdr1p. This study explores the diverse substrate specificity spectrum to get a deeper insight into the structural and functional features of Cdr1p. By screening with the variety of compounds towards an in-house TMH 252 mutant library of Cdr1p, we establish new substrates of Cdr1p. The localization of substrate-susceptible mutants in an ABCG5/G8 homology model highlights the common and specific binding pockets inside the membrane domain, where rhodamines and tetrazoliums mainly engage the N-moiety of Cdr1p, binding between TMH 2, 11 and surrounded by TMH 1, 5. Whereas, tin chlorides involve both N and C moieties located at the interface of TMH 2, 11, 1 and 5. Further, screening of the in house TMH mutant library of Cdr1p displays the TMH12 interaction with tetrazolium chloride, trimethyltin chloride and a Ca(2+) ionophore, A23187. In silico localization reveals a binding site at the TMH 12, 9 and 10 interface, which is widely exposed to the lipid interface. Together, for the first time, our study shows the molecular localization of Cdr1p substrates-binding sites and demonstrates the participation of TMH12 in a peripheral drug binding site.
Glover, Lucy; Horn, David
DNA damage and repair in trypanosomatids impacts virulence, drug resistance and antigenic variation but, currently, little is known about DNA damage responses or cell cycle checkpoints in these divergent protozoa. One of the earliest markers of DNA damage in eukaryotes is γH2A(X), a serine phosphorylated histone H2A (variant). Here, we report the identification and initial characterization of γH2A in Trypanosoma brucei. We identified Thr(130) within the replication-dependent histone H2A as a candidate phosphorylation site and found that the abundance of this trypanosomal γH2A increased in vivo in response to DNA damage. Nuclear γH2A foci mark the sites of putative natural replication fork stalling, sites of meganuclease-induced DNA double strand breaks and sites of methyl methanesulphonate-induced DNA damage. Naturally occurring and meganuclease-induced γH2A and RAD51 double-positive repair foci are typically found in S-phase or G(2) nuclei. The results link trypanosomal γH2A, with an unusual histone modification motif, to DNA damage sensing and mitotic checkpoint signaling.
Bakker, Barbara M.; Krauth-Siegel, R. Luise; Clayton, Christine; Matthews, Keith; Girolami, Mark; Westerhoff, Hans V.; Michels, Paul A. M.; Breitling, Rainer; Barrett, Michael P.
African trypanosomes have emerged as promising unicellular model organisms for the next generation of systems biology. They offer unique advantages, due to their relative simplicity, the availability of all standard genomics techniques and a long history of quantitative research. Reproducible cultiv
Isolation rate and drug resistance patterns of Shigella species among ... use of water from unprotected sources and absence of latrine were the risk factors that ... to identify changes in the prevalence and antimicrobial resistance patterns of ...
Naiditch, Jessica A; Jie, Chunfa; Lautz, Timothy B; Yu, Songtao; Clark, Sandra; Voronov, Dimitry; Chu, Fei; Madonna, Mary Beth
Metastatic initiation has many phenotypic similarities to epithelial-to-mesenchymal transition, including loss of cell-cell adhesion, increased invasiveness, and increased cell mobility. We have previously demonstrated that drug resistance is associated with a metastatic phenotype in neuroblastoma (NB). The purpose of this project was to determine if the development of doxorubicin resistance is associated with characteristics of mesenchymal change in human NB cells. Total RNA was isolated from wild type (WT) and doxorubicin-resistant (DoxR) human NB cell lines (SK-N-SH and SK-N-BE(2)C) and analyzed using the Illumina Human HT-12 version 4 Expression BeadChip. Differentially expressed genes (DEGs) were identified. Volcano plots and heat maps were generated. Genes of interest with a fold change in expression >1.5 and an adjusted P change via multiple pathways in the transition to a drug-resistant state. Copyright © 2015 Elsevier Inc. All rights reserved.
Dr. Charlotte Kvasnovsky, a surgery resident and Ph.D. candidate in biostatistics, discusses various types of drug resistance in TB patients in South Africa. Created: 12/16/2016 by National Center for Emerging and Zoonotic Infectious Diseases (NCEZID). Date Released: 12/16/2016.
John I. Bruce
Full Text Available Drug resistance associated with the treatment of human schistosomiasis appears to be an emerging problem requiring more attention from the scientific community than the subject currently receives. Drug-resistant strains of Schistosoma mansoni have been isolated by various investigators as a result of laboratory experimentation or from a combination of field and laboratory studies. Review of this data appears to indicate that the lack of susceptibility observed for some of the isolated strains cannot be ascribed solely to previous administration of antischistosome drugs and thus further studies are required to elucidate this phenomena. Strains of S. mansoni have now been identified from Brazil which are resistant to oxamniquine, hycanthone and niridazole; from Puerto Rico which are resistant to hycanthone and oxamniquine; and from Kenya which are resistant to niridazole and probably oxamniquine. Strains derived by in vitro selection and resistant to oxamniquine and possibly to oltipraz are also available. All of these strains are currently maintained in the laboratory in snails and mice, thus providing for the first time an opportunity for indepth comparative studies. Preliminary data indicates that S. haematobium strains resistant to metrifonate may be occurring in Kenya. This problem could poise great difficulty in the eventual development of antischistosomal agents. Biomphalaria glabrata from Puerto Rico and Brazil were found to be susceptible to drug-resistant S. mansoni from each country.
AB. Reducing Sample Size and Improving Numbers of Identified Proteins: Phosphoproteomic Studies with SCX-IMAC and IMAC-RP Methods (American Society ...American Chemical Society 4176 dx.doi.org/10.1021/pr4005234 | J. Proteome Res. 2013, 12, 4176−4186 of large numbers of phosphopeptides.19−21 However...5% horse serum, 0.01 mg/mL pf insulin, 20 ng/mL of EGF, 100 ng/mL of cholera toxin, and 500 ng/mL of hydrocortisone. After growing to 80% confluence
Wang, Shanshan; Feng, Yi; Zhang, Zhe
Mycobacterium tuberculosis infection kills two million people every year, and the chemotherapy has led to significant amount of drug resistance. Signal transduction systems are used by bacteria to survive or adapt to their living environment, but the relationship to drug resistance is not well understood. In this article, we introduced the two-component signal transduction systems of M. tuberculosis and analyzed their relationship with drug resistance. We identified five two-component system pairs involved in the formation of drug resistance. Therefore, these two-component systems are good targeting sites for small biochemical drugs to target so as to reverse the drug resistance and virulence.
Fridkin, Scott K; Cleveland, Angela A; See, Isaac; Lynfield, Ruth
Across the United States, antimicrobial drug-resistant infections affect a diverse population, and effective interventions require concerted efforts across various public health and clinical programs. Since its onset in 1994, the Centers for Disease Control and Prevention Emerging Infections Program has provided robust and timely data on antimicrobial drug-resistant infections that have been used to inform public health action across a spectrum of partners with regard to many highly visible antimicrobial drug-resistance threats. These data span several activities within the Program, including respiratory bacterial infections, health care-associated infections, and some aspects of foodborne diseases. These data have contributed to estimates of national burden, identified populations at risk, and determined microbiological causes of infection and their outcomes, all of which have been used to inform national policy and guidelines to prevent antimicrobial drug-resistant infections.
Full Text Available Metabolic alterations, driven by genetic and epigenetic factors, have long been known to be associated with the etiology of cancer. Furthermore, accumulating evidence suggest that cancer metabolism is intimately linked to drug resistance, which is currently one of the most important challenges in cancer treatment. Altered metabolic pathways help cancer cells to proliferate at a rate higher than normal, adapt to nutrient limited conditions, and develop drug resistance phenotypes. Application of systems biology, boosted by recent advancement of novel high-throughput technologies to obtain cancer-associated, transcriptomic, proteomic and metabolomic data, is expected to make a significant contribution to our understanding of metabolic properties related to malignancy. Indeed, despite being at a very early stage, quantitative data obtained from the omics platforms and through applications of 13C metabolic flux analysis (MFA in in vitro studies, researchers have already began to gain insight into the complex metabolic mechanisms of cancer, paving the way for selection of molecular targets for therapeutic interventions. In this review, we discuss some of the major findings associated with the metabolic pathways in cancer cells and also discuss new evidences and achievements on specific metabolic enzyme targets and target-directed small molecules that can potentially be used as anti-cancer drugs.
Rahman, Mahbuba; Hasan, Mohammad Rubayet
Metabolic alterations, driven by genetic and epigenetic factors, have long been known to be associated with the etiology of cancer. Furthermore, accumulating evidence suggest that cancer metabolism is intimately linked to drug resistance, which is currently one of the most important challenges in cancer treatment. Altered metabolic pathways help cancer cells to proliferate at a rate higher than normal, adapt to nutrient limited conditions, and develop drug resistance phenotypes. Application of systems biology, boosted by recent advancement of novel high-throughput technologies to obtain cancer-associated, transcriptomic, proteomic and metabolomic data, is expected to make a significant contribution to our understanding of metabolic properties related to malignancy. Indeed, despite being at a very early stage, quantitative data obtained from the omics platforms and through applications of 13C metabolic flux analysis (MFA) in in vitro studies, researchers have already began to gain insight into the complex metabolic mechanisms of cancer, paving the way for selection of molecular targets for therapeutic interventions. In this review, we discuss some of the major findings associated with the metabolic pathways in cancer cells and also discuss new evidences and achievements on specific metabolic enzyme targets and target-directed small molecules that can potentially be used as anti-cancer drugs. PMID:26437434
Tseng, Hsiang-Kuang; Perfect, John R
Invasive fungal infections continue to cause significant morbidity and mortality in immunocompromised hosts. From more than half a million deaths from cryptococcosis in sub-Saharan Africa to an unchanging death rate from invasive candidiasis, despite three antifungal classes of drugs, insights into better strategies to reduce therapeutic failures or resistance are needed. This review examines the issues around antifungal drug resistance from both a basic description of the failures and how they are detected to the variety of issues that need to be addressed to help prevent failures for successful management. The reader will gain an understanding of the clinical complexities in this patient population for management of invasive fungal infections. Throughout the review, principles of management are given along with some specific clinical examples to illustrate the issues and frame the knowledge base. From this discussion it is hoped that the clinician can use the insights provided to manage individual patients and find links to the evidence-based material that support its conclusions. Also, this review specifically identifies the limitations of present management and directs clinicians to gather additional information and provide even better treatment strategies. Invasive fungal infections are life-threatening complications of serious underlying diseases. Their management can be complicated by both direct and clinical drug resistance and by understanding these possibilities and correcting them; most patients can be successfully managed with present antifungal drugs if the underlying diseases can be controlled.
Jamie R. Stevens
Full Text Available In the absence of a fossil record, the evolution of protozoa has until recently largely remained a matter for speculation. However, advances in molecular methods and phylogenetic analysis are now allowing interpretation of the "history written in the genes". This review focuses on recent progress in reconstruction of trypanosome phylogeny based on molecular data from ribosomal RNA, the miniexon and protein-coding genes. Sufficient data have now been gathered to demonstrate unequivocally that trypanosomes are monophyletic; the phylogenetic trees derived can serve as a framework to reinterpret the biology, taxonomy and present day distribution of trypanosome species, providing insights into the coevolution of trypanosomes with their vertebrate hosts and vectors. Different methods of dating the divergence of trypanosome lineages give rise to radically different evolutionary scenarios and these are reviewed. In particular, the use of one such biogeographically based approach provides new insights into the coevolution of the pathogens, Trypanosoma brucei and Trypanosoma cruzi, with their human hosts and the history of the diseases with which they are associated.
Full Text Available African trypanosomes are devastating human and animal pathogens that cause significant human mortality and limit economic development in sub-Saharan Africa. Studies of trypanosome biology generally consider these protozoan parasites as individual cells in suspension cultures or in animal models of infection. Here we report that the procyclic form of the African trypanosome Trypanosoma brucei engages in social behavior when cultivated on semisolid agarose surfaces. This behavior is characterized by trypanosomes assembling into multicellular communities that engage in polarized migrations across the agarose surface and cooperate to divert their movements in response to external signals. These cooperative movements are flagellum-mediated, since they do not occur in trypanin knockdown parasites that lack normal flagellum motility. We term this behavior social motility based on features shared with social motility and other types of surface-induced social behavior in bacteria. Social motility represents a novel and unexpected aspect of trypanosome biology and offers new paradigms for considering host-parasite interactions.
da Silva Martins, João Miguel
Drug resistance has been an increasing problem in patient treatment and drug development. Starting in the last century and becoming a major worry in the medical and scienti c communities in the early part of the current millennium, major research must be performed to address the issues of viral...... and bacterial resistance to common-use inhibitors, in such cases as multiple targeted proteins in the human immunode ciency virus infection and penicillinresistant Staphylococcus aureus. Thus, understanding the evolutionary pressures by which these arise and predicting future possible resistance mutations...... is of the utmost importance in developing better and less resistance-inducing drugs. A drug's in uence can be characterized in many diff erent ways, however, and the approaches I take in this work re ect those same different in uences. This is what I try to achieve in this work, through seemingly unrelated...
Grant, Robert M.; Porco, Travis C.; Getz, Wayne M.
Observed declines in drug resistance to nucleoside reverse transcriptase inhibitors among persons recently infected with HIV-1 in monitored subpopulations can be interpreted as a positive sign and lead public health officials to decrease efforts towards HIV prevention. By means of a mathematical model, we identified 3 processes that can account for the observed decline: increase in high-risk behavior, decrease in proportion of acutely infected persons whose conditions are treated, and change in treatment efficacy. These processes, singly or in combination, can lead to increases or decreases in disease and drug-resistance prevalence in the general population. We discuss the most appropriate public health response under each scenario and emphasize how further data collection and analyses are required to more reliably evaluate the observed time trends and the relative importance of forces shaping the epidemic. Our study highlights how drug resistance markers can be used as epidemiologic sentinels to devise public health solutions. PMID:16494741
Hutchinson, Rachel; Gibson, Wendy
The African tsetse-transmitted trypanosomes are considered to be a well-known group of parasitic protozoa, but in 2008 a novel and distinctive trypanosome related to Trypanosoma brucei was discovered among tsetse isolates from Msubugwe in Tanzania. The host range, distribution and potential pathogenicity of this new trypanosome remain to be elucidated; such studies would be facilitated by a sensitive and specific identification method. Here, we identified two highly repetitive elements in the genome of the new trypanosome: a 177 bp repeat, which was located predominantly on the highly abundant minichromosomes, and a 138 bp repeat, which was widely dispersed in the genome. A PCR test based on each repeat was specific for the new trypanosome and sensitive to Trypanosoma (Pycnomonas) suis. We also present data on the molecular karyotype and spliced leader (SL, miniexon) repeat of the new trypanosome, both of which distinguish T. suis from other, better-known African tsetse-transmitted trypanosomes. The rediscovery of T. suis opens new lines of research into the evolution and biology of the African trypanosomes.
This thesis focuses on various strategies to deal with cancer drug resistance and improve treatment efficacy. Technological advances have enabled researchers to gain more insight in the immense molecular complexity of cancer and mechanisms of drug resistance. The ability to measure cancer-related
El-Taweel, Hend Aly
Infections with intestinal protozoa continue to be a major health problem in many areas of the world. The widespread use of a limited number of therapeutic agents for their management and control raises concerns about development of drug resistance. Generally, the use of any antimicrobial agent should be accompanied by meticulous monitoring of its efficacy and measures to minimize resistance formation. Evidence for the occurrence of drug resistance in different intestinal protozoa comes from case studies and clinical trials, sometimes with a limited number of patients. Large-scale field-based assessment of drug resistance and drug sensitivity testing of clinical isolates are needed. Furthermore, the association of drug resistance with certain geographic isolates or genotypes deserves consideration. Drug resistance has been triggered in vitro and has been linked to modification of pyruvate:ferredoxin oxidoreductase, nitroreductases, antioxidant defense, or cytoskeletal system. Further mechanistic studies will have important implications in the development of second generation therapeutic agents.
Unciti-Broceta, Juan D.; Arias, José L.; Maceira, José; Soriano, Miguel; Ortiz-González, Matilde; Hernández-Quero, José; Muñóz-Torres, Manuel; de Koning, Harry P.; Magez, Stefan; Garcia-Salcedo, José A.
African trypanosomiasis is a deadly neglected disease caused by the extracellular parasite Trypanosoma brucei. Current therapies are characterized by high drug toxicity and increasing drug resistance mainly associated with loss-of-function mutations in the transporters involved in drug import. The introduction of new antiparasitic drugs into therapeutic use is a slow and expensive process. In contrast, specific targeting of existing drugs could represent a more rapid and cost-effective approach for neglected disease treatment, impacting through reduced systemic toxicity and circumventing resistance acquired through impaired compound uptake. We have generated nanoparticles of chitosan loaded with the trypanocidal drug pentamidine and coated by a single domain nanobody that specifically targets the surface of African trypanosomes. Once loaded into this nanocarrier, pentamidine enters trypanosomes through endocytosis instead of via classical cell surface transporters. The curative dose of pentamidine-loaded nanobody-chitosan nanoparticles was 100-fold lower than pentamidine alone in a murine model of acute African trypanosomiasis. Crucially, this new formulation displayed undiminished in vitro and in vivo activity against a trypanosome cell line resistant to pentamidine as a result of mutations in the surface transporter aquaglyceroporin 2. We conclude that this new drug delivery system increases drug efficacy and has the ability to overcome resistance to some anti-protozoal drugs. PMID:26110623
Unciti-Broceta, Juan D; Arias, José L; Maceira, José; Soriano, Miguel; Ortiz-González, Matilde; Hernández-Quero, José; Muñóz-Torres, Manuel; de Koning, Harry P; Magez, Stefan; Garcia-Salcedo, José A
African trypanosomiasis is a deadly neglected disease caused by the extracellular parasite Trypanosoma brucei. Current therapies are characterized by high drug toxicity and increasing drug resistance mainly associated with loss-of-function mutations in the transporters involved in drug import. The introduction of new antiparasitic drugs into therapeutic use is a slow and expensive process. In contrast, specific targeting of existing drugs could represent a more rapid and cost-effective approach for neglected disease treatment, impacting through reduced systemic toxicity and circumventing resistance acquired through impaired compound uptake. We have generated nanoparticles of chitosan loaded with the trypanocidal drug pentamidine and coated by a single domain nanobody that specifically targets the surface of African trypanosomes. Once loaded into this nanocarrier, pentamidine enters trypanosomes through endocytosis instead of via classical cell surface transporters. The curative dose of pentamidine-loaded nanobody-chitosan nanoparticles was 100-fold lower than pentamidine alone in a murine model of acute African trypanosomiasis. Crucially, this new formulation displayed undiminished in vitro and in vivo activity against a trypanosome cell line resistant to pentamidine as a result of mutations in the surface transporter aquaglyceroporin 2. We conclude that this new drug delivery system increases drug efficacy and has the ability to overcome resistance to some anti-protozoal drugs.
Juan D Unciti-Broceta
Full Text Available African trypanosomiasis is a deadly neglected disease caused by the extracellular parasite Trypanosoma brucei. Current therapies are characterized by high drug toxicity and increasing drug resistance mainly associated with loss-of-function mutations in the transporters involved in drug import. The introduction of new antiparasitic drugs into therapeutic use is a slow and expensive process. In contrast, specific targeting of existing drugs could represent a more rapid and cost-effective approach for neglected disease treatment, impacting through reduced systemic toxicity and circumventing resistance acquired through impaired compound uptake. We have generated nanoparticles of chitosan loaded with the trypanocidal drug pentamidine and coated by a single domain nanobody that specifically targets the surface of African trypanosomes. Once loaded into this nanocarrier, pentamidine enters trypanosomes through endocytosis instead of via classical cell surface transporters. The curative dose of pentamidine-loaded nanobody-chitosan nanoparticles was 100-fold lower than pentamidine alone in a murine model of acute African trypanosomiasis. Crucially, this new formulation displayed undiminished in vitro and in vivo activity against a trypanosome cell line resistant to pentamidine as a result of mutations in the surface transporter aquaglyceroporin 2. We conclude that this new drug delivery system increases drug efficacy and has the ability to overcome resistance to some anti-protozoal drugs.
Shor, Erika; Zhao, Yanan
Invasive fungal infections remain a major source of global morbidity and mortality, especially among patients with underlying immune suppression. Successful patient management requires antifungal therapy. Yet, treatment choices are restricted due to limited classes of antifungal agents and the emergence of antifungal drug resistance. In some settings, the evolution of multidrug-resistant strains insensitive to several classes of antifungal agents is a major concern. The resistance mechanisms responsible for acquired resistance are well characterized and include changes in drug target affinity and abundance, and reduction in the intracellular level of drug by biofilms and efflux pumps. The development of high-level and multidrug resistance occurs through a stepwise evolution of diverse mechanisms. The genetic factors that influence these mechanisms are emerging and they form a complex symphony of cellular interactions that enable the cell to adapt and/or overcome drug-induced stress. Drivers of resistance involve a complex blend of host and microbial factors. Understanding these mechanisms will facilitate development of better diagnostics and therapeutic strategies to overcome and prevent antifungal resistance. PMID:26120512
Baker, Nicola; Glover, Lucy; Munday, Jane C; Aguinaga Andrés, David; Barrett, Michael P; de Koning, Harry P; Horn, David
African trypanosomes cause sleeping sickness in humans, a disease that is typically fatal without chemotherapy. Unfortunately, drug resistance is common and melarsoprol-resistant trypanosomes often display cross-resistance to pentamidine. Although melarsoprol/pentamidine cross-resistance (MPXR) has been an area of intense interest for several decades, our understanding of the underlying mechanisms remains incomplete. Recently, a locus encoding two closely related aquaglyceroporins, AQP2 and AQP3, was linked to MPXR in a high-throughput loss-of-function screen. Here, we show that AQP2 has an unconventional "selectivity filter." AQP2-specific gene knockout generated MPXR trypanosomes but did not affect resistance to a lipophilic arsenical, whereas recombinant AQP2 reversed MPXR in cells lacking native AQP2 and AQP3. AQP2 was also shown to be disrupted in a laboratory-selected MPXR strain. Both AQP2 and AQP3 gained access to the surface plasma membrane in insect life-cycle-stage trypanosomes but, remarkably, AQP2 was specifically restricted to the flagellar pocket in the bloodstream stage. We conclude that the unconventional aquaglyceroporin, AQP2, renders cells sensitive to both melarsoprol and pentamidine and that loss of AQP2 function could explain cases of innate and acquired MPXR.
Manna, Paul T; Obado, Samson O; Boehm, Cordula; Gadelha, Catarina; Sali, Andrej; Chait, Brian T; Rout, Michael P; Field, Mark C
Clathrin-mediated endocytosis (CME) is the most evolutionarily ancient endocytic mechanism known, and in many lineages the sole mechanism for internalisation. Significantly, in mammalian cells CME is responsible for the vast bulk of endocytic flux and has likely undergone multiple adaptations to accommodate specific requirements by individual species. In African trypanosomes, we previously demonstrated that CME is independent of the AP-2 adaptor protein complex, that orthologues to many of the animal and fungal CME protein cohort are absent, and that a novel, trypanosome-restricted protein cohort interacts with clathrin and drives CME. Here, we used a novel cryomilling affinity isolation strategy to preserve transient low-affinity interactions, giving the most comprehensive trypanosome clathrin interactome to date. We identified the trypanosome AP-1 complex, Trypanosoma brucei (Tb)EpsinR, several endosomal SNAREs plus orthologues of SMAP and the AP-2 associated kinase AAK1 as interacting with clathrin. Novel lineage-specific proteins were identified, which we designate TbCAP80 and TbCAP141. Their depletion produced extensive defects in endocytosis and endomembrane system organisation, revealing a novel molecular pathway subtending an early-branching and highly divergent form of CME, which is conserved and likely functionally important across the kinetoplastid parasites. © 2017. Published by The Company of Biologists Ltd.
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.
Shafer, Robert W.; Jonathan M Schapiro
As more drugs for treating HIV have become available, drug resistance profiles within antiretroviral drug classes have become increasingly important for researchers developing new drugs and for clinicians integrating new drugs into their clinical practice. In vitro passage experiments and comprehensive phenotypic susceptibility testing are used for the pre-clinical evaluation of drug resistance. Clinical studies are required, however, to delineate the full spectrum of mutations responsible fo...
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 ...
Full Text Available Tuberculosis (TB is responsible for 1.4 million deaths annually. Wide-spread misuse of anti-tubercular drugs over three decades has resulted in emergence of drug resistant TB including multidrug-resistant TB and extensively drug-resistant TB globally. Accurate and rapid diagnosis of drug-resistant TB is one of the paramount importance for instituting appropriate clinical management and infection control measures. The present article provides an overview of the various diagnostic options available for drug resistant TB, by searching PubMed for recent articles. Rapid phenotypic tests still requires days to weeks to obtain final results, requiring biosafety and quality control measures. For newly developed molecular methods, infrastructure, training and quality assurance should be followed. Successful control of drug resistant TB globally will depend upon strengthening TB control programs, wider access to rapid diagnosis and provision of effective treatment. Therefore, political and fund provider commitment is essential to curb the spread of drug resistant TB.
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.
Masiá Canuto, Mar; Gutiérrez Rodero, Félix
There is an increased awareness of the morbidity and mortality associated with fungal infections caused by resistant fungi in various groups of patients. Epidemiological studies have identified risk factors associated with antifungal drug resistance. Selection pressure due to the continuous exposure to azoles seems to have an essential role in developing resistance to fluconazole in Candida species. Haematological malignancies, especially acute leukaemia with severe and prolonged neutropenia, seem to be the main risk factors for acquiring deep-seated mycosis caused by resistant filamentous fungi, such us Fusarium species, Scedosporium prolificans, and Aspergillus terreus. The still unacceptably high mortality rate associated with some resistant mycosis indicates that alternatives to existing therapeutic options are needed. Potential measures to overcome antifungal resistance ranges from the development of new drugs with better antifungal activity to improving current therapeutic strategies with the present antifungal agents. Among the new antifungal drugs, inhibitors of beta glucan synthesis and second-generation azole and triazole derivatives have characteristics that render them potentially suitable agents against some resistant fungi. Other strategies including the use of high doses of lipid formulations of amphotericin B, combination therapy, and adjunctive immune therapy with cytokines are under investigation. In addition, antifungal control programmes to prevent extensive and inappropriate use of antifungals may be needed.
Lin, Yan; Liu, Yan; Luo, Yan-Ping; Liu, Chang-Ting
To analyze the change in drug resistance of Staphylococcus aureus (SAU) in the PLA general hospital from January 2008 to December 2012, and to provide solid evidence to support the rational use of antibiotics for clinical applications. The SAU strains isolated from clinical samples in the hospital were collected and subjected to the Kirby-Bauer disk diffusion test. The results were assessed based on the 2002 American National Committee for Clinical Laboratory Standards (NCCLS) guidelines. SAU strains were mainly isolated from sputum, urine, blood and wound excreta and distributed in penology, neurology wards, orthopedics and surgery ICU wards. Except for glycopeptide drugs, methicillin-resistant Staphylococcus aureus (MRSA) had a higher drug resistance rate than those of the other drugs and had significantly more resistance than methicillin-sensitive Staphylococcus aureus (MSSA) (P resistance, we discovered a gradual increase in drug resistance to fourteen test drugs during the last five years. Drug resistance rate of SAU stayed at a higher level over the last five years; moreover, the detection ratio of MRSA keeps rising year by year. It is crucial for physicians to use antibiotics rationally and monitor the change in drug resistance in a dynamic way.
D.E. Bennett (Diane); R.J. Camacho (Ricardo Jorge); D. Otelea (Dan); D.R. Kuritzkes (Daniel); H. Fleury (Hervé); M. Kiuchi (Mark); W. Heneine (Walid); R. Kantor (Rami); M.R. Jordan (Michael); J.M. Schapiro (Jonathan); A.M. Vandamme (Anne Mieke); P. Sandstrom (Paul); C.A. Boucher (Charles); D.A.M.C. van de Vijver (David); S.Y. Rhee (Soo Yoon); T.F. Liu (Tommy); D. Pillay (Deenan); R.W. Shafer (Robert)
textabstractPrograms that monitor local, national, and regional levels of transmitted HIV-1 drug resistance inform treatment guidelines and provide feedback on the success of HIV-1 treatment and prevention programs. To accurately compare transmitted drug resistance rates across geographic regions an
Clutter, Dana S; Jordan, Michael R; Bertagnolio, Silvia; Shafer, Robert W
The global scale-up of antiretroviral (ARV) therapy (ART) has led to dramatic reductions in HIV-1 mortality and incidence. However, HIV drug resistance (HIVDR) poses a potential threat to the long-term success of ART and is emerging as a threat to the elimination of AIDS as a public health problem by 2030. In this review we describe the genetic mechanisms, epidemiology, and management of HIVDR at both individual and population levels across diverse economic and geographic settings. To describe the genetic mechanisms of HIVDR, we review the genetic barriers to resistance for the most commonly used ARVs and describe the extent of cross-resistance between them. To describe the epidemiology of HIVDR, we summarize the prevalence and patterns of transmitted drug resistance (TDR) and acquired drug resistance (ADR) in both high-income and low- and middle-income countries (LMICs). We also review to two categories of HIVDR with important public health relevance: (i) pre-treatment drug resistance (PDR), a World Health Organization-recommended HIVDR surveillance metric and (ii) and pre-exposure prophylaxis (PrEP)-related drug resistance, a type of ADR that can impact clinical outcomes if present at the time of treatment initiation. To summarize the implications of HIVDR for patient management, we review the role of genotypic resistance testing and treatment practices in both high-income and LMIC settings. In high-income countries where drug resistance testing is part of routine care, such an understanding can help clinicians prevent virological failure and accumulation of further HIVDR on an individual level by selecting the most efficacious regimens for their patients. Although there is reduced access to diagnostic testing and to many ARVs in LMIC, understanding the scientific basis and clinical implications of HIVDR is useful in all regions in order to shape appropriate surveillance, inform treatment algorithms, and manage difficult cases. Copyright Â© 2016 Elsevier B
Perelson, A.S.; Goldstein, B.; Korber, B.T. [and others
This is the final report of a one-year, Laboratory Directed Research and Development (LDRD) project at Los Alamos National Laboratory (LANL). The objectives of this project were to develop models of the spread of pathogens, such as HIV-1 and influenza, in humans, and then to use the models to address the possibility of designing appropriate drug therapies that may limit the ability of the pathogen to escape treatment by mutating into a drug resistant form. We have developed a model of drug-resistance to amantidine and rimantadine, the two major antiviral drugs used to treat influenza, and have used the model to suggest treatment strategies during an epidemic.
Rogier, Christophe; Pradines, Bruno; Bogreau, H.; Koeck, Jean-Louis; Kamil, Mohamed-Ali; Mercereau-Puijalon, Odile
Analysis of Plasmodium falciparum isolates collected before, during, and after a 1999 malaria epidemic in Djibouti shows that, despite a high prevalence of resistance to chloroquine, the epidemic cannot be attributed to a sudden increase in drug resistance of local parasite populations.
Chong Jie Hao
Full Text Available Background: Acute rhinosinusitis that usually caused by Streptococcus pneumoniae becomes the reason why patients seek for medical care. Drugs resistance in Streptococcus pneumoniae is increasing worldwide. This study was conducted to determine drugs resistance of Streptococcus pneumonia from acute rhinosinusitis in Dr. Hasan Sadikin General Hospital. Methods: A descriptive laboratory study was conducted in June–October 2014 at the Laboratory of Microbiology Faculty of Medicine Universitas Padjadjaran. The sample was taken using nasopharyngeal swabbing from 100 acute rhinosinusitis patients in Dr. Hasan Sadikin General Hospital and planted on tryptic soy agar containing 5% sheep blood and 5 μg/ml of gentamicin sulphate and then incubated in 5% CO2 incubator at 37°C for 24 hours. The identification of Streptococcus pneumonia was performed by optochin test. The susceptibility test against Streptococcus pneumoniae was done using disk diffusion method.The antibiotic disks were trimethoprim-sulfamethoxazole, oxacillin, levofloxacin, azithromycin, and doxycycline. Results: Out of 100 samples, 8 of them were tested positive for Streptococcus pneumoniae. Three of Streptococcus pneumoniae isolates died with unknown reason after it were stored at -80 .The drugs resistance test showed the resistance of Streptococcus pneumonia to oxacillin, azithromycin and trimethoprim were 6, whereas levofloxacin and doxycycline are 4. Conclusions: Streptococcus pneumonia drugs resistance in acute rhinosinusitis shows the resistance of Streptococcus pneumoniae to oxacillin, azithromycin and trimethoprim are 6, whereas the resistance to levofloxacin and doxycycline are 4.
Shiraishi, Yuji; Katsuragi, Naoya; Kita, Hidefumi; Toishi, Masayuki; Onda, Takahito
Extensively drug-resistant tuberculosis is becoming a global threat. It is a relatively new phenomenon, and its optimal management remains undetermined. We report our experience in using pulmonary resection for treating patients with this disease. Records were reviewed of 54 consecutive patients undergoing a pulmonary resection for multidrug-resistant tuberculosis at Fukujuji Hospital between 2000 and 2006. These patients were identified using the definition approved by the World Health Organization Global Task Force on extensively drug-resistant tuberculosis in October 2006. Five (9%) patients (3 men and 2 women) aged 31-60 years met the definition. None of the patients was HIV-positive. Although the best available multidrug regimens were initiated, no patient could achieve sputum conversion. Adjuvant resectional surgery was considered because the patients had localized disease. Procedures performed included pneumonectomy (2) and upper lobectomy (3). There was no operative mortality or morbidity. All patients attained sputum-negative status after the operation, and they were maintained on multidrug regimens for 12-25 months postoperatively. All patients remained free from disease at the time of follow-up. Pulmonary resection under cover of state-of-the-art chemotherapy is safe and effective for patients with localized extensively drug-resistant tuberculosis.
Lee, Alvin J X; Endesfelder, David; Rowan, Andrew J; Walther, Axel; Birkbak, Nicolai J; Futreal, P Andrew; Downward, Julian; Szallasi, Zoltan; Tomlinson, Ian P M; Kschischo, Maik; Swanton, Charles
Aneuploidy is associated with poor prognosis in solid tumours. Spontaneous chromosome mis-segregation events in aneuploid cells promote Chromosomal Instability (CIN) that may contribute to the acquisition of multi-drug resistance in vitro and heighten risk for tumour relapse in animal models. Identification of distinct therapeutic agents that target tumour karyotypic complexity has important clinical implications. In order to identify distinct therapeutic approaches to specifically limit the growth of CIN tumours we focussed on a panel of colorectal cancer (CRC) cell lines, previously classified as either chromosomally-unstable (CIN+) or diploid/near-diploid (CIN−), and treated them individually with a library of kinase inhibitors targeting components of signal transduction, cell cycle and trans-membrane receptor signalling pathways. CIN+ cell lines displayed significant intrinsic multi-drug resistance compared to CIN− cancer cell lines and this appeared to be independent of somatic mutation status and proliferation rate. Confirming the association of CIN rather than ploidy status with multi-drug resistance, tetraploid isogenic cells that had arisen from diploid cell lines displayed lower drug sensitivity than their diploid parental cells only with increasing chromosomal heterogeneity, and isogenic cell line models of CIN+ displayed multi-drug resistance relative to their CIN− parental cancer cell line derivatives. In a meta-analysis of CRC outcome following cytotoxic treatment, CIN+ predicted worse progression-free or disease-free survival relative to patients with CIN− disease. Our results suggest that stratifying tumour responses according to CIN status should be considered within the context of clinical trials to minimize the confounding effects of tumour CIN status on drug sensitivity. PMID:21363922
Full Text Available Background: In many African countries, access to antiretroviral treatment (ART has been significantly scaled up over the last five years. Nevertheless, data on drug resistance mutation are scarce. The objective of the current study was to determine the predominant subtypes of HIV-1 as well as to identify baseline mutations with potential drug resistance among ART-naïve patients from Ethiopia. Methods: Genotypic drug resistance on the entire protease and partial reverse transcriptase (codons 1–335 regions of the pol gene was determined by an in-house protocol in 160 ART-naïve patients. Genotypic drug resistance was defined as the presence of one or more resistance-related mutations, as specified by the consensus of the Stanford University HIV drug resistance database (HIVDB available at http://hivdb.stanford.edu/ and the 2011 International AIDS Society (IAS mutation list (http://www.iasusa.org/resistance-mutations/. Results: A predominance of HIV-1 subtype C (98.7% was observed. According to the IAS mutation list, antiretroviral drug resistance mutations were detected in 20 patients (13%. However, the level of drug resistance is 5.2% (8/155 when the most conservative method, HIVDB algorithms were applied. In both algorithms, none had major PI mutation and mutation-conferring resistance to NRTI and NNRTI were not overlapping. Conclusions: There is strong evidence for clade homogeneity in Ethiopia and low influx of other subtypes to the country. The level of transmitted drug resistance exceeds that of WHO estimates and indicates that many HIV-infected individuals on ART are practicing risk-related behaviours. The results also show that HIV drug resistance testing should be installed in resource limited settings.
Objectives: Drug resistance is a serious problem in the treatment of tuberculosis ... Design, setting, subjects, outcome measures: During a defined period, all adult ... Logistic regression analysis of the data indicated that drug resistance was not ...
The number of international travellers has increased. There is enormous diversity in medical backgrounds, purposes of travel, and travelling styles among travellers. Travellers are hospitalized abroad because of exotic and common diseases via medical tourism. This is one way of transporting and importing human bacteria between countries, including multi-drug resistant organisms. In developing countries, the antimicrobial resistance in Shigella sp. and Salmonella sp. have been a problem, because of this trend, the first choice of antibiotics has changed in some countries. Community acquired infections as well as hospital acquired infections with MRSA, multi-drug resistance (MDR) Pseudomonas aeruginosa, and ESBL have been a problem. This review will discuss the risk of MDR bacterial infectious diseases for travellers.
André, Maria do Rosário; Pedro, Ana; Lyden, David
In the last decades, several studies demonstrated that the tumor microenvironment is a critical determinant not only of tumor progression and metastasis, but also of resistance to therapy. Exosomes are small membrane vesicles of endocytic origin, which contain mRNAs, DNA fragments, and proteins, and are released by many different cell types, including cancer cells. Mounting evidence has shown that cancer-derived exosomes contribute to the recruitment and reprogramming of constituents associated with the tumor microenvironment. Understanding how exosomes and the tumor microenvironment impact drug resistance will allow novel and better strategies to overcome drug resistance and treat cancer. Here, we describe a technique for exosome purification from cell culture, and fresh and frozen plasma, and further analysis by electron microscopy, NanoSight microscope, and Western blot.
钟球; 钱明; 李建伟; 陈启亮; 卓文基; 江勇; 黄树智; 陈燕梅
Objective According to the guidelines of WHO/IUATLD proposed a global drug resistance surveillance of tuberculosis project,to set up a system for surveillance of drug resistance of pulmonary tuberculosis.to obtain the result on initianl and acquired drug resistance rate of pulmonary tuberculosis in Guangdong province of China.Methods 40 centres were radomly selected,39 cases of the smear positive of pulmonary tuberculosis were intook continuously in each centre.all samples were isolated and cultured.the identification and in each centre.all samples were isolated and cultured.the identification and susceptibility test were done for the strians of culture positive.Results The frequency of initial drug resistance was 18%,acquired drug resistance was 33.7%.Conclusion The result proved that drug resistance rate is higher(18%)in Guangdong province.National TB Control Program should be strengthen.%objective Based on the Guidelines for Surveillance of Drug Resistance in Tuberculosis of WHO/IUATLD set up a system for surveillance of drug resistance of pulmonary tuberculosis.To obtain the result on initial and acquired drug resistance rate of pulmonary tuberculosis in Guangdong province of China.Methods 40 counties were selected randomly in 113 counties of Guangdong province.39 cases of the new smear positive of pulmonary tuberculosis were intaken continuously in every county,including retreatment smear positive,Identify type of strains of culture positive and test drug resistance of the four kinds of antituberulosis drugs.Result Total drug resistance rate is 19.6%.Initial resistance rate was 18%.acquired drug resistance was 33.7%.Conclusion By strict training,all staff have grasped the drug resistance monitor system,based on the Guidelines for Surveillance of Drug Resistance in Tuberculosis of WHO/IUATLD.The result proved the drug resistance level in Guangdong is higher than that of developped countries.So national TB control program should be strengthen.
Asad U Khan
Drug resistance is becoming a great problem in developing countries due to excessive use and misuse of antibi-otics.The emergence of new pathogenic strains with resistance developed against most of the antibiotics which may cause,difficult to treat infection.To understand the current scenario in different mode of infection is most important for the clinicians and medical practitioners.This article summarized some common infections and an-tibiotic resistance pattern found among these pathogens.
Espinosa-Jovel, Camilo A; Sobrino-Mejía, Fidel E
Drug-resistant epilepsy, is a condition defined by the International League Against Epilepsy as persistent seizures despite having used at least two appropriate and adequate antiepileptic drug treatments. Approximately 20-30% of patients with epilepsy are going to be resistant to antiepileptic drugs, with different patterns of clinical presentation, which are related to the biological basis of this disease (de novo resistance, relapsing-remitting and progressive). Drug resistant epilepsy, impacts negatively the quality of life and significantly increases the risk of premature death. From the neurobiological point of view, this medical condition is the result of the interaction of multiple variables related to the underlying disease, drug interactions and proper genetic aspects of each patient. Thanks to advances in pharmacogenetics and molecular biology research, currently some hypotheses may explain the cause of this condition and promote the study of new therapeutic options. Currently, overexpression of membrane transporters such as P-glycoprotein, appears to be one of the most important mechanisms in the development of drug resistant epilepsy. The objective of this review is to deepen the general aspects of this clinical condition, addressing the definition, epidemiology, differential diagnosis and the pathophysiological bases.
de Jong, S; Timmer, T; Heijenbrok, FJ; de Vries, EGE
The efficacy of chemotherapeutic drugs is hampered by the occurrence of intrinsic and acquired drug resistance. A variety of mechanisms cause drug-resistance. A final common factor, however, is the reduced capacity of drug resistant cells to go into apoptosis following treatment with DNA damaging ag
Zhang, Jingru; Huang, Jiacheng; Zhu, Feng; Zhang, Jian
The transmission of drug-resistant parasites by the mosquito may be influenced by the altered biological fitness of drug-resistant parasites and different immune reactions or metabolic change in the mosquito. At this point, little is known about the variations in mosquito immunity and metabolism when mosquitoes are infected with drug-resistant parasites. To understand the differential gene expression in Anopheles following infection with drug-resistant Plasmodium, we conducted a genome-wide transcriptomic profiling analysis of Anopheles stephensi following feeding on mice with drug-resistant or drug-sensitive P. yoelii, observed changes in gene expression profiles and identified transcripts affected by the drug-resistant parasite. To study the impact of drug-resistant Plasmodium infections on An. stephensi gene transcription, we analyzed the three major transition stages of Plasmodium infections: at 24 h and 13 and 19 days after blood-feeding. Six cDNA libraries (R-As24h, R-As13d, R-As19d,S-As24h, S-As13dand S-As19d) were constructed, and RNA sequencing was subsequently performed. In total, approximately 50.1 million raw reads, 47.9 million clean reads and 7.18G clean bases were obtained. Following differentially expressed gene (DEG) analysis, GO enrichment analysis of DEGs, and functional classification by KEGG, we showed that the variations in gene expression in An. stephensi infected by the drug-resistant P. yoelii NSM occurred mainly at 13 days after blood meal during sporozoite migration through the hemolymph. The differentially expressed genes included those functioning in some important immune reaction and iron metabolism pathways, such as pattern recognition receptors, regulators of the JNK pathway, components of the phagosome pathway, regulators of the melanization response, activators of complement reactions, insulin signaling cascade members, oxidative stress and detoxification proteins. Our study shows that drug-resistant P. yoelii NSM has an
张丽; 张小兵; 杨维青; 黄娟; 张丽华; 张菊芬; 朱学海; 朱凯欣; 周静
目的：研究泛耐药肺炎克雷伯菌的相关耐药机制和治疗对策。方法细菌鉴定采用 VITEK2全自动细菌鉴定系统，药敏试验采用 K-B 法，通过产碳青霉烯酶确证试验（改良 Hodge 试验）及聚合酶链反应（PCR）检测 KPC-2基因，并进行序列测定。同时调查感染患者的诊疗情况。结果常规药敏试验显示，该菌株对阿米卡星敏感，对其他抗菌药物均耐药；Hodge试验阳性，PCR 检测到 KPC-2基因，序列测定与 GenBank 11844849序列一致。患者经拔除气管插管，入住隔离病房，加强支持治疗后，1个月内未检测到泛耐药肺炎克雷伯菌。结论加强泛耐药肺炎克雷伯菌监测，提高对泛耐药菌的认识有助于感染疾病的治疗和预防。%Objective To explore the extensively drug resistant mechanism and clinical treatment strategy of Klebsiella pneu-moniae .Methods The isolate was identified by Vitek2 Compact System.Antimicrobial susceptibility testing was conducted by Kirby-Bauer method.KPC-2 carbapenemase was detected by modified Hodge test.The gene encoding KPC-2 carbapenemase was amplified by polymerase chain reaction (PCR)and then sequenced.Results The strain was resistant to all antibiotics used in routine antimicrobial susceptibility testing except amikacin.Modified Hodge test showed positive result.KPC-2 gene was detected by PCR.The sequence was consistent with that of 11844849 in GenBank.After treatment for one month,no exten-sively drug resistant K.pneumoniae strain was detected from the patient.Conclusions It is necessary to strengthen the monito-ring and improve the awareness of extensively drug resistant K.pneumoniae for better control of such infections.
Cambiano, Valentina; Bertagnolio, Silvia; Jordan, Michael R
BACKGROUND: There is concern that the expansion of antiretroviral roll-out may impact future drug resistance levels and hence compromise the benefits of antiretroviral therapy (ART) at an individual and population level. We aimed to predict future drug resistance in South Africa and its long...... are maintained, in 20 years' time HIV incidence is projected to have declined by 22% (95% confidence interval, CI -23 to -21%), and the number of people carrying NNRTI resistance to be 2.9-fold higher. If enhancements in diagnosis and retention in care occur, and ART is initiated at CD4 cell count less than 500...... cells/μl, HIV incidence is projected to decline by 36% (95% CI: -37 to -36%) and the number of people with NNRTI resistance to be 4.1-fold higher than currently. Prevalence of people with viral load more than 500 copies/ml carrying NRMV is not projected to differ markedly according to future ART...
Chen, TianJun; Ren, Hui; Thakur, Asmitanand; Yang, Tian; Li, Yang; Zhang, Shuo; Wang, Ting; Chen, MingWei
Klotho is originally discovered as an anti-aging gene and recently identified as a tumor suppressor in various human cancers. Drug resistance is a major obstacle to affect the treatment of chemotherapy. In the present study, we explore the role of klotho on drug resistance in human lung cancers and investigate the mechanism of klotho on drug resistance in lung cancer cells. First, we detected a panel of six human lung cancer cell lines, including H460, SK-MES-1, cisplatin (DDP)-resistant A549/DDP, its parental subline A549, docetaxel (DTX)-resistant SPC-A-1/DTX, and SPC-A-1 by western blotting analysis. The results showed that klotho level was significantly decreased in chemotherapeutic drug-resistant lung cancer cells. Next, klotho was overexpressed in drug-resistant cancer cell lines and the results showed that overexpression of klotho significantly inhibited cell proliferation of A549/DDP and SPC-A-1/DTX. Conversely, knockdown of the expression of klotho significantly promoted cell growth of lung cancer cells. Furthermore, overexpression of klotho had synergistic effects with cisplatin to inhibit the proliferation of drug-resistant lung cancer cells in a dose- and time-dependent manner. The molecular mechanism was explored by western blotting analysis and the results revealed that the levels of beclin 1 and LC3-II were obviously increased, suggesting cell autophagy enhanced in drug-resistant cancer cells. Importantly, overexpression of klotho would inhibit cell autophagy in A549/DDP cells. All the results demonstrated that the levels of klotho were significantly decreased, which was accompanied by the increased cell autophagy in drug-resistant lung cancer cells. Overexpression of klotho would inhibit cell autophagy in drug-resistant lung cancers, which may probably contribute to reverse drug resistance in lung cancer cells.
Full Text Available Weisan Zhang,1 Ping Lei,1 Xifeng Dong,2 Cuiping Xu31Department of Geriatrics, 2Department of Hematology-Oncology, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 3Qianfoshan Hospital, Shandong University, Jinan, People’s Republic of ChinaAbstract: Lung cancer is one of the most deadly diseases worldwide. The current first-line therapies include chemotherapy using epidermal growth factor receptor tyrosine kinase inhibitors and radiotherapies. With the current progress in identifying new molecular targets, acquired drug resistance stands as an obstacle for good prognosis. About half the patients receiving epidermal growth factor receptor-tyrosine kinase inhibitor treatments develop resistance. Although extensive studies have been applied to elucidate the underlying mechanisms, evidence is far from enough to establish a well-defined picture to correct resistance. In the review, we will discuss four different currently developed strategies that have the potential to overcome drug resistance in lung cancer therapies and facilitate prolonged anticancer effects of the first-line therapies.Keywords: ALK receptors cancer stem cell, chemotherapy, EGFR-TKI, target therapy, pharmacology, molecular biology, biotherapy
Stäubert, Claudia; Bhuiyan, Hasanuzzaman; Lindahl, Anna; Broom, Oliver Jay; Zhu, Yafeng; Islam, Saiful; Linnarsson, Sten; Lehtiö, Janne; Nordström, Anders
Cancer cells that escape induction therapy are a major cause of relapse. Understanding metabolic alterations associated with drug resistance opens up unexplored opportunities for the development of new therapeutic strategies. Here, we applied a broad spectrum of technologies including RNA sequencing, global untargeted metabolomics, and stable isotope labeling mass spectrometry to identify metabolic changes in P-glycoprotein overexpressing T-cell acute lymphoblastic leukemia (ALL) cells, which escaped a therapeutically relevant daunorubicin treatment. We show that compared with sensitive ALL cells, resistant leukemia cells possess a fundamentally rewired central metabolism characterized by reduced dependence on glutamine despite a lack of expression of glutamate-ammonia ligase (GLUL), a higher demand for glucose and an altered rate of fatty acid β-oxidation, accompanied by a decreased pantothenic acid uptake capacity. We experimentally validate our findings by selectively targeting components of this metabolic switch, using approved drugs and starvation approaches followed by cell viability analyses in both the ALL cells and in an acute myeloid leukemia (AML) sensitive/resistant cell line pair. We demonstrate how comparative metabolomics and RNA expression profiling of drug-sensitive and -resistant cells expose targetable metabolic changes and potential resistance markers. Our results show that drug resistance is associated with significant metabolic costs in cancer cells, which could be exploited using new therapeutic strategies. PMID:25697355
Capewell, Paul; Cooper, Anneli; Clucas, Caroline; Weir, William; MacLeod, Annette
Trypanosoma brucei is the causative agent of African sleeping sickness in humans and one of several pathogens that cause the related veterinary disease Nagana. A complex co-evolution has occurred between these parasites and primates that led to the emergence of trypanosome-specific defences and counter-measures. The first line of defence in humans and several other catarrhine primates is the trypanolytic protein apolipoprotein-L1 (APOL1) found within two serum protein complexes, trypanosome l...
Siliciano, Janet D; Siliciano, Robert F
Once considered an inevitable consequence of HIV treatment, drug resistance is declining. This decline supports the hypothesis that antiretroviral therapy can arrest replication and prevent the evolution of resistance. Further support comes from excellent clinical outcomes, the failure of treatment intensification to reduce residual viremia, the lack of viral evolution in patients on optimal therapy, pharmacodynamics studies explaining the extraordinarily high antiviral activity of modern regimens, and recent reports of potential cures. Evidence supporting ongoing replication includes higher rates of certain complications in treated patients and an increase in circular forms of the viral genome after intensification with integrase inhibitors. Recent studies also provide an explanation for the observation that some patients fail protease-inhibitor based regimens without evidence for resistance. Copyright © 2013 Elsevier B.V. All rights reserved.
Full Text Available To classify the prevalence of multi-drug resistant tuberculosis (MDR-TB in two different geographic settings in western Kenya using the Lot Quality Assurance Sampling (LQAS methodology.The prevalence of drug resistance was classified among treatment-naïve smear positive TB patients in two settings, one rural and one urban. These regions were classified as having high or low prevalence of MDR-TB according to a static, two-way LQAS sampling plan selected to classify high resistance regions at greater than 5% resistance and low resistance regions at less than 1% resistance.This study classified both the urban and rural settings as having low levels of TB drug resistance. Out of the 105 patients screened in each setting, two patients were diagnosed with MDR-TB in the urban setting and one patient was diagnosed with MDR-TB in the rural setting. An additional 27 patients were diagnosed with a variety of mono- and poly- resistant strains.Further drug resistance surveillance using LQAS may help identify the levels and geographical distribution of drug resistance in Kenya and may have applications in other countries in the African Region facing similar resource constraints.
Bharat B. Bhanderi
Full Text Available In the 1990s, there were increased incidences of fungal infectious diseases in human population which might be due to increase in immunosuppressive diseases. But the major concern was increase in prevalence of resistance to antifungal drugs which were reported both in the fungal isolates of human beings and that of animal origin. In both animals and human beings, resistance to antimicrobial agents has important implications for morbidity, mortality and health care costs, because resistant strains are responsible for bulk of infection in animals and human beings, and large number of antimicrobial classes offers more diverse range of resistance mechanisms to study and resistance determinants move into standard well-characterized strains that facilitates the detailed study of molecular mechanisms of resistance in microorganisms. Studies on resistance to antifungal agents has been lagging behind that of antibacterial resistance for several reasons, the foremost reason might be fungal agents were not recognized as important animal and human pathogens, until relatively in recent past. But the initial studies of antifungal drug resistance in the early 1980s, have accumulated a wealth of knowledge concerning the clinical, biochemical, and genetic aspects of this phenomenon. Presently, exploration of the molecular aspects for antifungal drug resistance has been undertaken. Recently, the focus was on several points like developing a more detailed understanding of the mechanisms of antimicrobial resistance, improved methods to detect resistance when it occurs, methods to prevent the emergence and spread of resistance and new antimicrobial options for the treatment of infections caused by resistant organisms. [Vet. World 2009; 2(5.000: 204-207
Martin-Casabona, N; Alcaide, F; Coll, P; González, J; Manterola, J M; Salvadó, M; Caylà, J A
The aims of this multicenter study was to establish the level of primary and acquired drug resistance of M. Tuberculosis strains isolated in Barcelona and to identify possible risk groups using clinical data. All tuberculosis patients with isolation and identification of M. tuberculosis strains from October 1995 to September 1997 were included. Susceptibility tests isoniazid, rifampin, ethambutol, streptomycin and pyrazinamide were performed using the Bactec 460 system and the proportions method on solid medium. Logistic progression was used for statistical analysis. The total number of patients included was 1,749 (1,535 non-treated and 214 previously treated). Primary drug resistance was 5.7% (isoniazid 3.8%; rifampin 1.0%, streptomycin 2.1%, ethambutol 0.3% and pyrazinamide 1.0%). Acquired drug resistance was 20.5% (isoniazid 17.3%, rifampin 9.8%, ethambutol 1.9%, streptomycin 4.7% and pyrazinamide 6.5%). Primary drug resistance was associated with people over 60 years old and women. The low level of drug resistance enables antituberculosis treatment of non-treated patients to start with the standardised three-drug regimes except in the case of foreign people from countries with a high level of drug resistance. Susceptibility tests are recommended on all M. tuberculosis strains isolated, together with controlled studies of drug resistance surveillance.
Robert W. Shafer
Full Text Available Human immunodeficiency virus (HIV, hepatitis B virus (HBV, and hepatitis C virus (HCV are the most prevalent deadly chronic viral diseases. HIV is treated by small molecule inhibitors. HBV is treated by immunomodulation and small molecule inhibitors. HCV is currently treated primarily by immunomodulation but many small molecules are in clinical development. Although HIV is a retrovirus, HBV is a double-stranded DNA virus, and HCV is a single-stranded RNA virus, antiviral drug resistance complicates the development of drugs and the successful treatment of each of these viruses. Although their replication cycles, therapeutic targets, and evolutionary mechanisms are different, the fundamental approaches to identifying and characterizing HIV, HBV, and HCV drug resistance are similar. This review describes the evolution of HIV, HBV, and HCV within individuals and populations and the genetic mechanisms associated with drug resistance to each of the antiviral drug classes used for their treatment.
Holmes, Ann R; Cardno, Tony S; Strouse, J Jacob; Ivnitski-Steele, Irena; Keniya, Mikhail V; Lackovic, Kurt; Monk, Brian C; Sklar, Larry A; Cannon, Richard D
Resistance to antifungal drugs is an increasingly significant clinical problem. The most common antifungal resistance encountered is efflux pump-mediated resistance of Candida species to azole drugs. One approach to overcome this resistance is to inhibit the pumps and chemosensitize resistant strains to azole drugs. Drug discovery targeting fungal efflux pumps could thus result in the development of azole-enhancing combination therapy. Heterologous expression of fungal efflux pumps in Saccharomyces cerevisiae provides a versatile system for screening for pump inhibitors. Fungal efflux pumps transport a range of xenobiotics including fluorescent compounds. This enables the use of fluorescence-based detection, as well as growth inhibition assays, in screens to discover compounds targeting efflux-mediated antifungal drug resistance. A variety of medium- and high-throughput screens have been used to identify a number of chemical entities that inhibit fungal efflux pumps.
Coleman, David C
Candida dubliniensis was first described in 1995 and is the most closely related species to the predominant human fungal pathogen Candida albicans. C. dubliniensis is significantly less prevalent and less pathogenic than C. albicans and is primarily associated with infections in HIV-infected individuals and other immunocompromised cohorts. The population structure of C. dubliniensis consists of three well-defined major clades and is significantly less diverse than C. albicans. The majority of C. dubliniensis isolates are susceptible to antifungal drugs commonly used to treat Candida infections. To date only two major patterns of antifungal drug resistance have been identified and the molecular mechanisms of these are very similar to the resistance mechanisms that have been described previously in C. albicans. However, significant differences are evident in the predominant antifungal drug mechanisms employed by C. dubliniensis, differences that reflect its more clonal nature, its lower prevalence and characteristics of its genome, the complete sequence of which has only recently been determined.
Full Text Available BACKGROUND: The discovery of Nanobodies (Nbs with a direct toxic activity against African trypanosomes is a recent advancement towards a new strategy against these extracellular parasites. The anti-trypanosomal activity relies on perturbing the highly active recycling of the Variant-specific Surface Glycoprotein (VSG that occurs in the parasite's flagellar pocket. METHODOLOGY/PRINCIPAL FINDINGS: Here we expand the existing panel of Nbs with anti-Trypanosoma brucei potential and identify four categories based on their epitope specificity. We modified the binding properties of previously identified Nanobodies Nb_An05 and Nb_An33 by site-directed mutagenesis in the paratope and found this to strongly affect trypanotoxicity despite retention of antigen-targeting properties. Affinity measurements for all identified anti-trypanosomal Nbs reveal a strong correlation between trypanotoxicity and affinity (K(D, suggesting that it is a crucial determinant for this activity. Half maximal effective (50% affinity of 57 nM was calculated from the non-linear dose-response curves. In line with these observations, Nb humanizing mutations only preserved the trypanotoxic activity if the K(D remained unaffected. CONCLUSIONS/SIGNIFICANCE: This study reveals that the binding properties of Nanobodies need to be compatible with achieving an occupancy of >95% saturation of the parasite surface VSG in order to exert an anti-trypanosomal activity. As such, Nb-based approaches directed against the VSG target would require binding to an accessible, conserved epitope with high affinity.
Many studies have been conducted on drug resistance and the evolution of Mycobacterium tuberculosis. Notwithstanding, many molecular mechanisms facilitating the emergence, adaptation and spread of drug-resistant tuberculosis have yet to be discovered. This thesis reports studies of the adaptive mech
DEVRIES, EGE; HAMILTON, TC; LIND, M; DAUPLAT, J; NEIJT, JP; OZOLS, RF
Background: Both intrinsic and acquired drug resistance occur in ovarian cancer. Much work on in vivo or in vitro, obtained drug resistance has been done and this knowledge is presently being converted into clinical studies. Materials and methods: The review focuses on the detoxifying system, MDR (m
Many studies have been conducted on drug resistance and the evolution of Mycobacterium tuberculosis. Notwithstanding, many molecular mechanisms facilitating the emergence, adaptation and spread of drug-resistant tuberculosis have yet to be discovered. This thesis reports studies of the adaptive
Tong, Yaojun; Liu, Mei; Zhang, Yu
screening and whole-cell based mechanism study, identified a natural product, beauvericin (BEA) as a drug efflux pump modulator, which can reverse the multi-drug resistant phenotype of Candida albicans by specifically blocking the ATP-binding cassette (ABC) transporters; meantime, BEA alone has fungicidal...
Devaux, I.; Manissero, D.; Fernandez de la Hoz, K.; Kremer, K.; Soolingen, D. van
This paper describes the results of second-line drug (SLD) susceptibility tests among multidrug-resistant tuberculosis (MDR TB) cases reported in 20 European countries aiming to identify extensively drug-resistant tuberculosis (XDR TB) cases. A project on molecular surveillance of MDR TB cases was c
Padayatchi, Nesri; Loveday, Marian; Naidu, Naressa
We examine some aspects of the South African health system that have contributed to the current multi- and extensively drug-resistant tuberculosis (M(X)DR-TB) epidemic and identify opportunities for change and improvement. Implementation of several recent major scientific advances have the potential to accelerate the control of M(X)DR-TB, but health systems strengthening will be essential.
Hutchison, D C S; Drobniewski, F A; Milburn, H J
There has been a worldwide increase in multiple drug-resistant tuberculosis (MDR-TB) which has in the past been associated with a poor prognosis. In the U.K., about half of the cases live in the London area and we have set out to obtain further information on their treatment and outcome. We examined the risk factors, drug resistance, drug treatment, sputum conversion, and outcome in patients with MDR-TB at three hospitals in South London and diagnosed during the period June 1995-January 1999. Human Immunodeficiency Virus (HIV)-positive patients were excluded. There were 760 patients resident in Lambeth, Southwark and Lewisham Health Authority (LSLHA) who were notified as tuberculosis (TB) during the time period and who were of negative or unknown HIV status. (The population of LSLHA is approx.750,000.) There was a total of 13 patients with MDR-TB, known or presumed to be HlV negative. Their median age was 28 years (range 15-53); nine (69%) were born outside the U.K. and 11 had pulmonary disease; they had organisms resistant to a median of two first-line drugs (range 2-4) and to a median of four of all drugs tested (range 2-10). They received treatment with a median of six drugs (range 3-9). Eight were followed up for at least 3 years (range 3-6) after the completion of treatment; at their last assessment none had features of active TB and all were sputum negative (smear and culture). Two returned to their countries of origin during treatment; they were sputum negative at that time. Two patients are well and continue on treatment in the U.K. One patient (known HIV negative) died following treatment failure. In conclusion, we obtained disease-free survival in eight cases of MDR-TB, known or presumed to be HIV negative and followed up for 3 years or more. The prognosis for patients treated at specialised centres is good (and better than is generally believed). We describe a new protocol for the detection and management of MDR-TB.
Tetsu, Osamu; Hangauer, Matthew J.; Phuchareon, Janyaporn; Eisele, David W.; McCormick, Frank
Background The discovery of mutations in epidermal growth factor receptor (EGFR) has dramatically changed the treatment of patients with non-small cell lung cancer (NSCLC)—the leading cause of cancer death worldwide. EGFR-targeted therapies show considerable promise, but drug resistance has become a substantial issue. Methods We reviewed the literature to provide an overview of the drug resistance to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. Results The mechanisms causing primary, acquired, and persistent drug resistance to TKIs vary. Researchers and clinicians, who have used study findings to develop more effective therapeutic approaches, have found that the sequential use of single agents presents a formidable challenge, suggesting that multi-drug combinations must be considered. Conclusions In the era of precision medicine, oncologists should promptly obtain an accurate diagnosis of drug resistance in each patient to design the most relevant combination therapy to overcome patient-specific drug resistance. PMID:26910730
Ssemwanga, Deogratius; Lihana, Raphael W; Ugoji, Chinenye; Abimiku, Alash'le; Nkengasong, John; Dakum, Patrick; Ndembi, Nicaise
The last ten years have witnessed a significant scale-up and access to antiretroviral therapy in Africa, which has improved patient quality of life and survival. One major challenge associated with increased access to antiretroviral therapy is the development of antiretroviral resistance due to inconsistent drug supply and/or poor patient adherence. We review the current state of both acquired and transmitted drug resistance in Africa over the past ten years (2001-2011) to identify drug resistance associated with the different drug regimens used on the continent and to help guide affordable strategies for drug resistance surveillance. A total of 161 references (153 articles, six reports and two conference abstracts) were reviewed. Antiretroviral resistance data was available for 40 of 53 African countries. A total of 5,541 adult patients from 99 studies in Africa were included in this analysis. The pooled prevalence of drug resistance mutations in Africa was 10.6%, and Central Africa had the highest prevalence of 54.9%. The highest prevalence of nucleoside reverse transcriptase inhibitor mutations was in the west (55.3%) and central (54.8%) areas; nonnucleoside reverse transcriptase inhibitor mutations were highest in East Africa (57.0%) and protease inhibitors mutations highest in Southern Africa (16.3%). The major nucleoside reverse transcriptase inhibitor mutation in all four African regions was M184V. Major nonnucleoside reverse transcriptase inhibitor as well as protease inhibitor mutations varied by region. The prevalence of drug resistance has remained low in several African countries although the emergence of drug resistance mutations varied across countries. Continued surveillance of antiretroviral therapy resistance remains crucial in gauging the effectiveness of country antiretroviral therapy programs and strategizing on effective and affordable strategies for successful treatment.
Beltrán-Alzate, Camilo; López Díaz, Fernando; Romero-Montoya, Marcela; Sakamuri, Rama; Li, Wei; Kimura, Miyako; Brennan, Patrick
An active search for Mycobacterium leprae drug resistance was carried out, 243 multibacillary patients from endemic regions of Colombia were included from 2004 to 2013 in a surveillance program. This program was a World Health Organization initiative for drug resistance surveillance in leprosy, where Colombia is a sentinel country. M. leprae DNA from slit skin smear and/or skin biopsy samples was amplified and sequenced to identify mutations in the drug resistance determining region (DRDR) in rpoB, folP1, gyrA, and gyrB, the genes responsible for rifampicin, dapsone and ofloxacin drug-resistance, respectively. Three isolates exhibited mutations in the DRDR rpoB gene (Asp441Tyr, Ser456Leu, Ser458Met), two in the DRDR folP1 gene (Thr53Ala, Pro55Leu), and one isolate exhibited mutations in both DRDR rpoB (Ser456Met) and DRDR folP1 (Pro55Leu), suggesting multidrug resistance. One isolate had a double mutation in folP1 (Thr53Ala and Thr88Pro). Also, we detected mutations outside of DRDR that required in vivo evaluation of their association or not with drug resistance: rpoB Arg505Trp, folP1 Asp91His, Arg94Trp, and Thr88Pro, and gyrA Ala107Leu. Seventy percent of M. leprae mutations were related to drug resistance and were isolated from relapsed patients; the likelihood of relapse was significantly associated with the presence of confirmed resistance mutations (OR range 20.1–88.7, p < 0.05). Five of these relapsed patients received dapsone monotherapy as a primary treatment. In summary, the current study calls attention to M. leprae resistance in Colombia, especially the significant association between confirmed resistance mutations and relapse in leprosy patients. A high frequency of DRDR mutations for rifampicin was seen in a region where dapsone monotherapy was used extensively. PMID:27706165
M. R. Chorawala
Full Text Available The management of cancer involves surgery, radiotherapy and chemotherapy. Development of chemoresistance is a persistent problem during the chemotherapy treatment. Cytotoxic drugs that selectively, but not exclusively, target actively proliferating cells include such diverse groups as DNA-alkylating agents, anti-metabolites, intercalating agents and mitotic inhibitors. Resistance constitutes a lack of response to drug-induced tumour growth inhibition; it may be inherent in a subpopulation of heterogeneous cancer cells or be acquired as a cellular response to drug exposure. Principle mechanisms may include altered membrane transport involving the p-glycoprotein product of the multidrug resistance (MDR gene as well as other associated proteins, altered target enzyme, decreased drug activation, increased drug degradation due to altered expression of drug metabolising enzymes, drug inactivation due to conjugation with increased glutathione, subcellular redistribution, drug interaction, enhanced DNA repair and failure to apoptosis as a result of mutated cell cycle proteins such as p53. Attempts to overcome resistance involves the use of combination drug therapy using different classes of drugs with minimally overlapping toxicities to allow maximal dosages, necessary for bone marrow recovery. Adjuvant therapy with p-glycoprotein inhibitors and in speciﬁc instances, the use of growth factor and protein kinase C inhibitors are newer experimental approaches that may also prove effective in delaying onset of resistance. Gene knockout using antisense molecules may be effective way of blocking drug resistance.
Kuritzkes, Daniel R
Development of resistance to antiretroviral drugs (ARVs) is a major impediment to optimum treatment of HIV-1 infection. Although resistance testing can help to select subsequent regimens when virologic failure occurs, cross-resistance, which affects all classes of ARVs, may make it more difficult to achieve optimum control of HIV. We have known for some time that our first choice of antiretroviral therapy offers the best chance to control HIV replication and that initial therapy should be selected with an eye on future options. Potency is the first line of defense against the development of resistance. Other factors that affect resistance development include: tolerability, potential for optimum adherence, and genetic and pharmacologic barriers to development of resistance. If resistance emerges, only a single drug may be affected initially, and a rapid change in ARVs may preserve the efficacy of other components. One cautionary note is that we can no longer assume that a patient's HIV is fully susceptible to all ARVs even in the initial regimen. Transmission of drug-resistant HIV means that the genetic composition may be that of an "experienced" virus with reduced susceptibility to ARVs. Resistance testing at the time of transmission is most likely to reveal this resistance, but over time the dominant genetic pattern may revert to wild-type, and be missed by resistance testing. Because "archived" resistant HIV may emerge quickly once treatment is initiated, we need to keep this in mind when selecting initial therapy.
Taff, Heather T; Mitchell, Kaitlin F; Edward, Jessica A; Andes, David R
Candida commonly adheres to implanted medical devices, growing as a resilient biofilm capable of withstanding extraordinarily high antifungal concentrations. As currently available antifungals have minimal activity against biofilms, new drugs to treat these recalcitrant infections are urgently needed. Recent investigations have begun to shed light on the mechanisms behind the profound resistance associated with the biofilm mode of growth. This resistance appears to be multifactorial, involving both mechanisms similar to conventional, planktonic antifungal resistance, such as increased efflux pump activity, as well as mechanisms specific to the biofilm lifestyle. A unique biofilm property is the production of an extracellular matrix. Two components of this material, β-glucan and extracellular DNA, promote biofilm resistance to multiple antifungals. Biofilm formation also engages several stress response pathways that impair the activity of azole drugs. Resistance within a biofilm is often heterogeneous, with the development of a subpopulation of resistant persister cells. In this article we review the molecular mechanisms underlying Candida biofilm antifungal resistance and their relative contributions during various growth phases. PMID:24059922
Full Text Available Abstract A large investment is required to develop, license and deploy a new antimalarial drug. Too often, that investment has been rapidly devalued by the selection of parasite populations resistant to the drug action. To understand the mechanisms of selection, detailed information on the patterns of drug use in a variety of environments, and the geographic and temporal patterns of resistance is needed. Currently, there is no publically-accessible central database that contains information on the levels of resistance to antimalaria drugs. This paper outlines the resources that are available and the steps that might be taken to create a dynamic, open access database that would include current and historical data on clinical efficacy, in vitro responses and molecular markers related to drug resistance in Plasmodium falciparum and Plasmodium vivax. The goal is to include historical and current data on resistance to commonly used drugs, like chloroquine and sulfadoxine-pyrimethamine, and on the many combinations that are now being tested in different settings. The database will be accessible to all on the Web. The information in such a database will inform optimal utilization of current drugs and sustain the longest possible therapeutic life of newly introduced drugs and combinations. The database will protect the valuable investment represented by the development and deployment of novel therapies for malaria.
Celestine Michelle Atyame Nten
Full Text Available Trypanosoma secretome was shown to be involved in parasite virulence and is suspected of interfering in parasite life-cycle steps such as establishment in the Glossina midgut, metacyclogenesis. Therefore, we attempted to identify the proteins secreted by procyclic strains of T. brucei gambiense and T. brucei brucei, responsible for human and animal trypanosomiasis, respectively. Using mass spectrometry, 427 and 483 nonredundant proteins were characterized in T. brucei brucei and T. brucei gambiense secretomes, respectively; 35% and 42% of the corresponding secretome proteins were specifically secreted by T. brucei brucei and T. brucei gambiense, respectively, while 279 proteins were common to both subspecies. The proteins were assigned to 12 functional classes. Special attention was paid to the most abundant proteases (14 families because of their potential implication in the infection process and nutrient supply. The presence of proteins usually secreted via an exosome pathway suggests that this type of process is involved in trypanosome ESP secretion. The overall results provide leads for further research to develop novel tools for blocking trypanosome transmission.
Bhaskar Anand Jha
Full Text Available PUF proteins are a conserved family of RNA binding proteins found in all eukaryotes examined so far. This study focussed on PUF5, one of 11 PUF family members encoded in the Trypanosoma brucei genome. Native PUF5 is present at less than 50000 molecules per cell in both bloodstream and procyclic form trypanosomes. C-terminally myc-tagged PUF5 was mainly found in the cytoplasm and could be cross-linked to RNA. PUF5 knockdown by RNA interference had no effect on the growth of bloodstream forms. Procyclic forms lacking PUF5 grew normally, but expression of PUF5 bearing a 21 kDa tandem affinity purification tag inhibited growth. Knockdown of PUF5 did not have any effect on the ability of trypanosomes to differentiate from the mammalian to the insect form of the parasite.
Objective To explore whether docetaxel-resistant cells(MCF-7/Doc)and doxorubicin-resistant cells(MCF-7/ADM)can secrete Exosomes and their potential role in cell-cell drug-resistance transfer.Methods Exosomes were extracted from the cell culture supernatants of MCF-7/Doc and MCF-7/ADM cells by fractionation ultracentrifugation,and were identified by transmission
Sallum, Ulysses W.; Zheng, Xiang; Verma, Sarika; Hasan, Tayyaba
β-lactamase enzyme-activated photosensitizer (β-LEAP). We aim to exploit drug resistance mechanisms to selectively release photosensitizers (PSs) for a specific photodynamic antimicrobial effect and reduced host tissue damage. Consequently, the fluorescence emission intensity of the PSs increases and allows for the detection of enzyme activity. In this work we sought to evaluate β-LEAP for use as a sensitive molecular probe. We have reported the enzyme specific antibacterial action of β-LEAP. Here we report the use of β-LEAP for the rapid functional definition of a β-lactamase.
CRUZ*, ISA N.; COLEY*, HELEN M.; KRAMER, HOLGER B.; MADHURI, THUMULURU KAVITAH; SAFUWAN, NUR A.M.; ANGELINO, ANA RITA; YANG, MIN
Background: Carboplatin and paclitaxel form the cornerstone of chemotherapy for epithelial ovarian cancer, however, drug resistance to these agents continues to present challenges. Despite extensive research, the mechanisms underlying this resistance remain unclear. Materials and Methods: A 2D-gel proteomics method was used to analyze protein expression levels of three human ovarian cancer cell lines and five biopsy samples. Representative proteins identified were validated via western immunoblotting. Ingenuity pathway analysis revealed metabolomic pathway changes. Results: A total of 189 proteins were identified with restricted criteria. Combined treatment targeting the proteasome-ubiquitin pathway resulted in re-sensitisation of drug-resistant cells. In addition, examination of five surgical biopsies of ovarian tissues revealed α-enolase (ENOA), elongation factor Tu, mitochondrial (EFTU), glyceraldehyde-3-phosphate dehydrogenase (G3P), stress-70 protein, mitochondrial (GRP75), apolipoprotein A-1 (APOA1), peroxiredoxin (PRDX2) and annexin A (ANXA) as candidate biomarkers of drug-resistant disease. Conclusion: Proteomics combined with pathway analysis provided information for an effective combined treatment approach overcoming drug resistance. Analysis of cell lines and tissues revealed potential prognostic biomarkers for ovarian cancer. *These Authors contributed equally to this study. PMID:28031236
Islam, Md Mahmudul; Hameed, H M Adnan; Mugweru, Julius; Chhotaray, Chiranjibi; Wang, Changwei; Tan, Yaoju; Liu, Jianxiong; Li, Xinjie; Tan, Shouyong; Ojima, Iwao; Yew, Wing Wai; Nuermberger, Eric; Lamichhane, Gyanu; Zhang, Tianyu
Drug-resistant tuberculosis (TB) poses a significant challenge to the successful treatment and control of TB worldwide. Resistance to anti-TB drugs has existed since the beginning of the chemotherapy era. New insights into the resistant mechanisms of anti-TB drugs have been provided. Better understanding of drug resistance mechanisms helps in the development of new tools for the rapid diagnosis of drug-resistant TB. There is also a pressing need in the development of new drugs with novel targets to improve the current treatment of TB and to prevent the emergence of drug resistance in Mycobacterium tuberculosis. This review summarizes the anti-TB drug resistance mechanisms, furnishes some possible novel drug targets in the development of new agents for TB therapy and discusses the usefulness using known targets to develop new anti-TB drugs. Whole genome sequencing is currently an advanced technology to uncover drug resistance mechanisms in M. tuberculosis. However, further research is required to unravel the significance of some newly discovered gene mutations in their contribution to drug resistance.
Full Text Available Abstract Background Resistance to anti-malarial drugs is a widespread problem for control programmes for this devastating disease. Molecular tests are available for many anti-malarial drugs and are useful tools for the surveillance of drug resistance. However, the correlation of treatment outcome and molecular tests with particular parasite markers is not perfect, due in part to individuals who are able to clear genotypically drug-resistant parasites. This study aimed to identify molecular markers in the human genome that correlate with the clearance of malaria parasites after drug treatment, despite the drug resistance profile of the protozoan as predicted by molecular approaches. Methods 3721 samples from five African countries, which were known to contain genotypically drug resistant parasites, were analysed. These parasites were collected from patients who subsequently failed to clear their infection following drug treatment, as expected, but also from patients who successfully cleared their infections with drug-resistant parasites. 67 human polymorphisms (SNPs on 17 chromosomes were analysed using Sequenom's mass spectrometry iPLEX gold platform, to identify regions of the human genome, which contribute to enhanced clearance of drug resistant parasites. Results An analysis of all data from the five countries revealed significant associations between the phenotype of ability to clear drug-resistant Plasmodium falciparum infection and human immune response loci common to all populations. Overall, three SNPs showed a significant association with clearance of drug-resistant parasites with odds ratios of 0.76 for SNP rs2706384 (95% CI 0.71-0.92, P = 0.005, 0.66 for SNP rs1805015 (95% CI 0.45-0.97, P = 0.03, and 0.67 for SNP rs1128127 (95% CI 0.45-0.99, P = 0.05, after adjustment for possible confounding factors. The first two SNPs (rs2706384 and rs1805015 are within loci involved in pro-inflammatory (interferon-gamma and anti-inflammatory (IL-4
Marcili, Arlei; da Costa, Andrea P; Soares, Herbert S; Acosta, Igor da C L; de Lima, Julia T R; Minervino, Antonio H H; Melo, Andréia T L; Aguiar, Daniel M; Pacheco, Richard C; Gennari, Solange M
In the order Chiroptera, more than 30 trypanosome species belonging to the subgenera Herpetosoma, Schizotrypanum, Megatrypanum, and Trypanozoon have been described. The species Trypanosoma cruzi , Trypanosoma cruzi marinkellei, and Trypanosoma dionisii are the most common in bats and belong to the Schizotrypanum subgenus. Bats from 2 different biomes, Pantanal and Amazonia/Cerrado in the state of Mato Grosso, Brazil, were evaluated according to the presence of trypanosome parasites by means of hemoculture and PCR in primary samples (blood samples). A total of 211 bats from 20 different species were caught and the trypanosome prevalence, evaluated through hemoculture, was 9.0% (19), 15.5% (13), and 4.8% (6) in the municipalities of Confresa (Amazonia/Cerrado biome) and Poconé (Pantanal biome). Among the 123 primary samples obtained from the bats, only 3 (2.4%) were positive. Phylogenetic analysis using trypanosomatid barcoding (V7V8 region of SSU rDNA) identified all the isolates and primary samples as T. c. marinkellei. The sequences of the isolates were segregated according to the bat host genus or species and suggest that co-evolutionary patterns exist between hosts and parasites. Further studies in different Brazilian regions and biomes need to be conducted in order to gain real understanding of the diversity of trypanosomes in bats.
SHI Xiao-chun; LIU Xiao-qing; XIE Xiu-li; XU Ying-chun; ZHAO Zhi-xian
Background Gene chip array can differentiate isolated mycobacterial strains using vadous mycobacterium specific probes simultaneously.Gene chip array can evaluate drug resistance to isoniazid and rifampin of tuberculosis strains by detecting drug resistance related gene mutation.This technique has great potential for clinical application.We performed a retrospective study to investigate the capability of gene chip array in the rapid differentiation of species and detection of drug resistance in mycobacterium,and to evaluate its clinical efficacy.Methods We selected 39 patients (54 clinical mycobacterium isolates),used gene chip array to identify the species of these isolates and detect drug resistance to isoniazid and rifampin in Mycobacterium tuberculosis isolates.Meanwhile,these patients' clinical data were analyzed retrospectively.Results Among these 39 patients whose mycopacterium culture were positive,32 patients' isolates were identified as Mycobacterium tubercu/osis, all of them were clinical infection. Seven patients' isolates were identified as non-tuberculosis mycobacterium.Analyzed with their clinical data,only two patients were considered as clinical infection,both of them were diagnosed as hematogenous disseminated Mycobacterium introcellulare infection.The other five patients' isolates were of no clinical significance; their clinical samples were all respiratory specimens.Clinical manifestations of tuberculosis and non-tuberculous mycobacterial infections were similar.Isoniazid resistance was detected in two tuberculosis patients,while rifampin resistance was detected in one tuberculosis patient; there was another patient whose Mycobacterium tuberculosis isolate was resistant to both isoniazid and rifampin (belongs to multidrug resistance tuberculosis).The fact that this patient did not respond to routine anti-tuberculosis chemotherapy also confirmed this result.Conclusions Gene chip array may be a simple,rapid,and reliable method for the
Keira A. Cohen
Full Text Available Mycobacterium tuberculosis (M. tuberculosis is considered innately resistant to β-lactam antibiotics. However, there is evidence that susceptibility to β-lactam antibiotics in combination with β–lactamase inhibitors is variable among clinical isolates, and these may present therapeutic options for drug-resistant cases. Here we report our investigation of susceptibility to β-lactam/β–lactamase inhibitor combinations among clinical isolates of M. tuberculosis, and the use of comparative genomics to understand the observed heterogeneity in susceptibility. Eighty-nine South African clinical isolates of varying first and second-line drug susceptibility patterns and two reference strains of M. tuberculosis underwent minimum inhibitory concentration (MIC determination to two β-lactams: amoxicillin and meropenem, both alone and in combination with clavulanate, a β–lactamase inhibitor. 41/91 (45% of tested isolates were found to be hypersusceptible to amoxicillin/clavulanate relative to reference strains, including 14/24 (58% of multiple drug-resistant (MDR and 22/38 (58% of extensively drug-resistant (XDR isolates. Genome-wide polymorphisms identified using whole-genome sequencing were used in a phylogenetically-aware linear mixed model to identify polymorphisms associated with amoxicillin/clavulanate susceptibility. Susceptibility to amoxicillin/clavulanate was over-represented among isolates within a specific clade (LAM4, in particular among XDR strains. Twelve sets of polymorphisms were identified as putative markers of amoxicillin/clavulanate susceptibility, five of which were confined solely to LAM4. Within the LAM4 clade, ‘paradoxical hypersusceptibility’ to amoxicillin/clavulanate has evolved in parallel to first and second-line drug resistance. Given the high prevalence of LAM4 among XDR TB in South Africa, our data support an expanded role for β-lactam/β-lactamase inhibitor combinations for treatment of drug-resistant M
Yadav, Vinod Kumar; Kumar, Akinchan; Mann, Anita; Aggarwal, Suruchi; Kumar, Maneesh; Roy, Sumitabho Deb; Pore, Subrata Kumar; Banerjee, Rajkumar; Mahesh Kumar, Jerald; Thakur, Ram Krishna; Chowdhury, Shantanu
Building molecular correlates of drug resistance in cancer and exploiting them for therapeutic intervention remains a pressing clinical need. To identify factors that impact drug resistance herein we built a model that couples inherent cell-based response toward drugs with transcriptomes of resistant/sensitive cells. To test this model, we focused on a group of genes called metastasis suppressor genes (MSGs) that influence aggressiveness and metastatic potential of cancers. Interestingly, modeling of 84 000 drug response transcriptome combinations predicted multiple MSGs to be associated with resistance of different cell types and drugs. As a case study, on inducing MSG levels in a drug resistant breast cancer line resistance to anticancer drugs caerulomycin, camptothecin and topotecan decreased by more than 50-60%, in both culture conditions and also in tumors generated in mice, in contrast to control un-induced cells. To our knowledge, this is the first demonstration of engineered reversal of drug resistance in cancer cells based on a model that exploits inherent cellular response profiles.
da Silva Garrido, M; Ramasawmy, R; Perez-Porcuna, T M; Zaranza, E; Chrusciak Talhari, A; Martinez-Espinosa, F E; Bührer-Sékula, S
Multidrug-resistant tuberculosis (MDR-TB) is the main indicator of previous treatment in tuberculosis (TB) patients. MDR-TB among treatment-naïve patients indicates infection with drug-resistant Mycobacterium tuberculosis strains, and such cases are considered primary drug-resistant cases. To estimate the prevalence of drug resistance in pulmonary TB (PTB) treatment-naïve patients and to identify the socio-demographic and clinical characteristics of the resistant population. A total of 205 treatment-naïve PTB patients from Manaus, Amazonas State, Brazil, were enrolled. Drug susceptibility testing (DST) was performed on all positive mycobacterial cultures using the 1% proportion method. Positive M. tuberculosis cultures were obtained from only 175 patients for DST. The prevalence of primary MDR-TB was 1.7% (3/175); 14.3% (25/175) of the cultures presented resistance to at least one of the drugs. Resistance to streptomycin, isoniazid, rifampicin and ethambutol was respectively 8.6%, 6.9%, 3.4% and 2.3%. An association between TB patients with resistance to more than one drug and known previous household contact with a TB patient was observed (P= 0.008, OR 6.7, 95%CI 1.2-67.3). Although the prevalence of primary MDR-TB currently is relatively low, it may become a major public health problem if tailored treatment is not provided, as resistance to more than one drug is significantly associated with household contact.
Hasanin, Ahmed; Eladawy, Akram; Mohamed, Hossam; Salah, Yasmin; Lotfy, Ahmed; Mostafa, Hanan; Ghaith, Doaa; Mukhtar, Ahmed
The prevalence of extensively drug resistant gram negative bacilli (XDR-GNB) is rapidly progressing; however in Egypt data are sparse. We conducted the present study to quantify the incidence, risk factors and outcome of patients harboring XDR-GNB. A one year prospective study was done by collecting all the bacteriological reports for cultures sent from the surgical intensive care unit, Cairo university teaching hospital. XDR-GNB were defined as any gram negative bacilli resistant to three or more classes of antimicrobial agents. Patients with XDR-GNB compared with those sustaining non extensively drug-resistant infection. A multivariate logistic regression model was created to identify independent predictors of multi-resistance. During one-year study period, a total of 152 samples (65%) out of 234 gram negative bacilli samples developed extensively drug resistant infection. XDR strains were significantly higher in Acinetobacterspp (86%), followed by Pseudomonas (63%), then Proteus (61%), Klebsiella (52%), and E coli (47%). Fourth generation cephalosporine (Cefipime) had the lowest susceptibility (10%) followed by third generation cephalosporines (11%), Quinolones (31%), Amikacin (42%), Tazobactam (52%), Carbapinems (52%), and colistin (90%). Relaparotomy was the only significant risk factor for acquisition of XDR infection. Extensively drug-resistant gram negative infections are frequent in our ICU. This is an alarming health care issue in Egypt which emphasizes the need to rigorously implement infection control practices.
Full Text Available We present a novel study on label-free recognition and distinction of drug resistant breast cancer cells (MCF-7 DOX from their parental cells (MCF-7 WT via impedimetric measurements. Drug resistant cells exhibited significant differences in their dielectric properties compared to wild-type cells, exerting much higher extracellular resistance (Rextra . Immunostaining revealed that MCF-7 DOX cells gained a much denser F-actin network upon acquiring drug resistance indicating that remodeling of actin cytoskeleton is probably the reason behind higher Rextra , providing stronger cell architecture. Moreover, having exposed both cell types to doxorubicin, we were able to distinguish these two phenotypes based on their substantially different drug response. Interestingly, impedimetric measurements identified a concentration-dependent and reversible increase in cell stiffness in the presence of low non-lethal drug doses. Combined with a profound frequency analysis, these findings enabled distinguishing distinct cellular responses during drug exposure within four concentration ranges without using any labeling. Overall, this study highlights the possibility to differentiate drug resistant phenotypes from their parental cells and to assess their drug response by using microelectrodes, offering direct, real-time and noninvasive measurements of cell dependent parameters under drug exposure, hence providing a promising step for personalized medicine applications such as evaluation of the disease progress and optimization of the drug treatment of a patient during chemotherapy.
Daniel R Ripoll
Full Text Available Quantitatively predicting changes in drug sensitivity associated with residue mutations is a major challenge in structural biology. By expanding the limits of free energy calculations, we successfully identified mutations in influenza neuraminidase (NA that confer drug resistance to two antiviral drugs, zanamivir and oseltamivir. We augmented molecular dynamics (MD with Hamiltonian Replica Exchange and calculated binding free energy changes for H274Y, N294S, and Y252H mutants. Based on experimental data, our calculations achieved high accuracy and precision compared with results from established computational methods. Analysis of 15 micros of aggregated MD trajectories provided insights into the molecular mechanisms underlying drug resistance that are at odds with current interpretations of the crystallographic data. Contrary to the notion that resistance is caused by mutant-induced changes in hydrophobicity of the binding pocket, our simulations showed that drug resistance mutations in NA led to subtle rearrangements in the protein structure and its dynamics that together alter the active-site electrostatic environment and modulate inhibitor binding. Importantly, different mutations confer resistance through different conformational changes, suggesting that a generalized mechanism for NA drug resistance is unlikely.
Hu, Yongfei; Zhu, Yuying; Ma, Yanan; Liu, Fei; Lu, Na; Yang, Xi; Luan, Chunguang; Yi, Yong; Zhu, Baoli
Achromobacter xylosoxidans is an opportunistic pathogen known to be resistant to a wide range of antibiotics; however, the knowledge about the drug resistance mechanisms is limited. We used a high-throughput sequencing approach to sequence the genomes of the A. xylosoxidans type strain ATCC 27061 and a clinical isolate, A. xylosoxidans X02736, and then we used different bioinformatics tools to analyze the drug resistance genes in these bacteria. We obtained the complete genome sequence for A. xylosoxidans ATCC 27061 and the draft sequence for X02736. We predicted a total of 50 drug resistance-associated genes in the type strain, including 5 genes for β-lactamases and 17 genes for efflux pump systems; these genes are also conserved among other A. xylosoxidans genomes. In the clinical isolate, except for the conserved resistance genes, we also identified several acquired resistance genes carried by a new transposon embedded in a novel integrative and conjugative element. Our study provides new insights into the intrinsic and acquired drug resistance mechanisms in A. xylosoxidans, which will be helpful for better understanding the physiology of A. xylosoxidans and the evolution of antibiotic resistance in this bacterium.
Pan, Jing-Jing; Xie, Xiao-Juan; Li, Xu; Chen, Wei
Long non-coding RNAs (lncRNAs) are emerging as key players in gene expression that govern cell developmental processes, and thus contributing to diseases, especially cancers. Many studies have suggested that aberrant expression of lncRNAs is responsible for drug resistance, a substantial obstacle for cancer therapy. Drug resistance not only results from individual variations in patients, but also from genetic and epigenetic differences in tumors. It is reported that drug resistance is tightly modulated by lncRNAs which change the stability and translation of mRNAs encoding factors involved in cell survival, proliferation, and drug metabolism. In this review, we summarize recent advances in research on lncRNAs associated with drug resistance and underlying molecular or cellular mechanisms, which may contribute helpful approaches for the development of new therapeutic strategies to overcome treatment failure.
Baird, R D; Kaye, S B
Clinical drug resistance is a major barrier to overcome before chemotherapy can become curative for most patients presenting with metastatic cancer. Rational attempts to tackle clinical drug resistance need to be based on an understanding of the mechanisms involved; these are likely to be complex and multifactorial, and may be due to inadequate drug exposure or alterations in the cancer cell itself. This article reviews a number of strategies used to tackle drug resistance, focussing on work in our institution related to the treatment of ovarian cancer and resistance to platinum and taxane-based chemotherapy. Further progress towards drug resistance reversal will require a three-pronged approach, namely: the development of novel cytotoxics which exploit selectively expressed targets; modulation of resistance to conventional agents and, most importantly, a serious attempt to understand resistance mechanisms in tumour samples taken both pre- and post-chemotherapy.
Gautam, Ankur; Chaudhary, Kumardeep; Kumar, Rahul; Gupta, Sudheer; Singh, Harinder; Raghava, Gajendra P S
Understanding and managing cancer drug resistance is the main goal of the modern oncology programs worldwide. One of the major factors contributing to drug resistance in cancer cells is the acquired mutations in drug targets. Advances in sequencing technologies and high-throughput screening assays have generated huge information related to pharmaco-profiling of anticancer drugs and revealed the mutational spectrum of different cancers. Systematic meta-analysis of this complex data is very essential to make useful conclusions in order to manage cancer drug resistance. Bioinformatics can play a significant role to interpret this complex data into useful conclusions. In this chapter, the use of bioinformatics platforms, particularly CancerDR, in understanding the cancer drug resistance is described.
Full Text Available Trypanosomes are protozoan parasites that cause diseases in humans and livestock for which no vaccines are available. Disease eradication requires sensitive diagnostic tools and efficient treatment strategies. Immunodiagnostics based on antigen detection are preferable to antibody detection because the latter cannot differentiate between active infection and cure. Classical monoclonal antibodies are inaccessible to cryptic epitopes (based on their size-150 kDa, costly to produce and require cold chain maintenance, a condition that is difficult to achieve in trypanosomiasis endemic regions, which are mostly rural. Nanobodies are recombinant, heat-stable, small-sized (15 kDa, antigen-specific, single-domain, variable fragments derived from heavy chain-only antibodies in camelids. Because of numerous advantages over classical antibodies, we investigated the use of nanobodies for the targeting of trypanosome-specific antigens and diagnostic potential. An alpaca was immunized using lysates of Trypanosoma evansi. Using phage display and bio-panning techniques, a cross-reactive nanobody (Nb392 targeting all trypanosome species and isolates tested was selected. Imunoblotting, immunofluorescence microscopy, immunoprecipitation and mass spectrometry assays were combined to identify the target recognized. Nb392 targets paraflagellar rod protein (PFR1 of T. evansi, T. brucei, T. congolense and T. vivax. Two different RNAi mutants with defective PFR assembly (PFR2RNAi and KIF9BRNAi were used to confirm its specificity. In conclusion, using a complex protein mixture for alpaca immunization, we generated a highly specific nanobody (Nb392 that targets a conserved trypanosome protein, i.e., PFR1 in the flagella of trypanosomes. Nb392 is an excellent marker for the PFR and can be useful in the diagnosis of trypanosomiasis. In addition, as demonstrated, Nb392 can be a useful research or PFR protein isolation tool.
Mitnick, Carole D; Shin, Sonya S; Seung, Kwonjune J; Rich, Michael L; Atwood, Sidney S; Furin, Jennifer J; Fitzmaurice, Garrett M; Alcantara Viru, Felix A; Appleton, Sasha C; Bayona, Jaime N; Bonilla, Cesar A; Chalco, Katiuska; Choi, Sharon; Franke, Molly F; Fraser, Hamish S F; Guerra, Dalia; Hurtado, Rocio M; Jazayeri, Darius; Joseph, Keith; Llaro, Karim; Mestanza, Lorena; Mukherjee, Joia S; Muñoz, Maribel; Palacios, Eda; Sanchez, Epifanio; Sloutsky, Alexander; Becerra, Mercedes C
Extensively drug-resistant tuberculosis has been reported in 45 countries, including countries with limited resources and a high burden of tuberculosis. We describe the management of extensively drug-resistant tuberculosis and treatment outcomes among patients who were referred for individualized outpatient therapy in Peru. A total of 810 patients were referred for free individualized therapy, including drug treatment, resective surgery, adverse-event management, and nutritional and psychosocial support. We tested isolates from 651 patients for extensively drug-resistant tuberculosis and developed regimens that included five or more drugs to which the infecting isolate was not resistant. Of the 651 patients tested, 48 (7.4%) had extensively drug-resistant tuberculosis; the remaining 603 patients had multidrug-resistant tuberculosis. The patients with extensively drug-resistant tuberculosis had undergone more treatment than the other patients (mean [+/-SD] number of regimens, 4.2+/-1.9 vs. 3.2+/-1.6; P<0.001) and had isolates that were resistant to more drugs (number of drugs, 8.4+/-1.1 vs. 5.3+/-1.5; P<0.001). None of the patients with extensively drug-resistant tuberculosis were coinfected with the human immunodeficiency virus (HIV). Patients with extensively drug-resistant tuberculosis received daily, supervised therapy with an average of 5.3+/-1.3 drugs, including cycloserine, an injectable drug, and a fluoroquinolone. Twenty-nine of these patients (60.4%) completed treatment or were cured, as compared with 400 patients (66.3%) with multidrug-resistant tuberculosis (P=0.36). Extensively drug-resistant tuberculosis can be cured in HIV-negative patients through outpatient treatment, even in those who have received multiple prior courses of therapy for tuberculosis. 2008 Massachusetts Medical Society
Long, Quanxin; Huang, Changwu; Liao, Pu; Xie, Jianping
Acinetobacter baumannii is an important opportunist pathogen, due to severe antibiotic resistance and nosocomial infection. The epidemiology and antibiotic resistance of A.baumannii have been extensively reviewed, but the pathogenesis and virulence remain unclear. Proteomics analysis has been applied to study the mechanism of drug resistance, biofilm, micronutrient acquisition, and the extracellular compartment. This review summarizes applications of proteomics in A. baumannii, aiming to summarize novel insights into the mechanism of A. baumannii pathogenesis and drug resistance.
Barrett, Michael P.; Bakker, Barbara M.; Breitling, Rainer
Metabolomics analysis, which aims at the systematic identification and quantification of all metabolites in biological systems, is emerging as a powerful new tool to identify biomarkers of disease, report on cellular responses to environmental perturbation, and to identify the targets of drugs. Here
Avner, Benjamin S; Fialho, Arsenio M; Chakrabarty, Ananda M
Resistance development against multiple drugs is a common feature among many pathogens--including bacteria such as Pseudomonas aeruginosa, viruses, and parasites--and also among cancers. The reasons are two-fold. Most commonly-used rationally-designed small molecule drugs or monoclonal antibodies, as well as antibiotics, strongly inhibit a key single step in the growth and proliferation of the pathogen or cancer cells. The disease agents quickly change or switch off this single target, or activate the efflux mechanisms to pump out the drug, thereby becoming resistant to the drug. A second problem is the way drugs are designed. The pharmaceutical industry chooses to use, by high-throughput screening, compounds that are maximally inhibitory to the key single step in the growth of the pathogen or cancer, thereby promoting selective pressure. An ideal drug would be one that inhibits multiple steps in the disease progression pathways with less stringency in these steps. Low levels of inhibition at multiple steps provide cumulative strong inhibitory effect, but little incentives or ability on the part of the pathogen/cancer to develop resistance. Such intelligent drug design involving multiple less stringent inhibitory steps is beyond the scope of the drug industry and requires evolutionary wisdom commonly possessed by bacteria. This review surveys assessments of the current clinical situation with regard to drug resistance in P. aeruginosa, and examines tools currently employed to limit this trend. We then provide a conceptual framework in which we explore the similarities between multi-drug resistance in pathogens and in cancers. We summarize promising work on anti-cancer drugs derived from the evolutionary wisdom of bacteria such as P. aeruginosa, and how such strategies can be the basis for how to look for candidate protein/peptide antibiotic drugs from bioengineered bugs. Such multi-domain proteins, unlike diffusible antibiotics, are not diffusible because of their
Bastin, Philippe; Rotureau, Brice
African trypanosomes grown on agarose plates exhibit behaviours akin to social motility. This phenomenon has not been observed in vivo so far but recently turned out to be instrumental in the definition of two specific stages of the parasite cycle and as a tool to probe for trypanosome sensing functions. Copyright © 2015 Elsevier Ltd. All rights reserved.
Dondorp Arjen M
Full Text Available Abstract Background Most malaria-endemic countries are implementing a change in anti-malarial drug policy to artemisinin-based combination therapy (ACT. The impact of different drug choices and implementation strategies is uncertain. Data from many epidemiological studies in different levels of malaria endemicity and in areas with the highest prevalence of drug resistance like borders of Thailand are certainly valuable. Formulating an appropriate dynamic data-driven model is a powerful predictive tool for exploring the impact of these strategies quantitatively. Methods A comprehensive model was constructed incorporating important epidemiological and biological factors of human, mosquito, parasite and treatment. The iterative process of developing the model, identifying data needed, and parameterization has been taken to strongly link the model to the empirical evidence. The model provides quantitative measures of outcomes, such as malaria prevalence/incidence and treatment failure, and illustrates the spread of resistance in low and high transmission settings. The model was used to evaluate different anti-malarial policy options focusing on ACT deployment. Results The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and treatment failure is the main force driving the spread of drug resistance. In low transmission settings, ACT slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. In the high transmission settings, however, drug resistance is driven by the proportion of the human population with a residual drug level, which gives resistant parasites some survival advantage. The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with
Pongtavornpinyo, Wirichada; Yeung, Shunmay; Hastings, Ian M; Dondorp, Arjen M; Day, Nicholas P J; White, Nicholas J
Most malaria-endemic countries are implementing a change in anti-malarial drug policy to artemisinin-based combination therapy (ACT). The impact of different drug choices and implementation strategies is uncertain. Data from many epidemiological studies in different levels of malaria endemicity and in areas with the highest prevalence of drug resistance like borders of Thailand are certainly valuable. Formulating an appropriate dynamic data-driven model is a powerful predictive tool for exploring the impact of these strategies quantitatively. A comprehensive model was constructed incorporating important epidemiological and biological factors of human, mosquito, parasite and treatment. The iterative process of developing the model, identifying data needed, and parameterization has been taken to strongly link the model to the empirical evidence. The model provides quantitative measures of outcomes, such as malaria prevalence/incidence and treatment failure, and illustrates the spread of resistance in low and high transmission settings. The model was used to evaluate different anti-malarial policy options focusing on ACT deployment. The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and treatment failure is the main force driving the spread of drug resistance. In low transmission settings, ACT slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. In the high transmission settings, however, drug resistance is driven by the proportion of the human population with a residual drug level, which gives resistant parasites some survival advantage. The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with mismatched half-lives, together with reducing malaria
Truong, Hong-Ha M.; Kellogg, Timothy A.; McFarland, Willi; Louie, Brian; Klausner, Jeffrey D.; Philip, Susan S.; Grant, Robert M.
Background HIV-1 acute infection, recent infection and transmitted drug resistance screening was integrated into voluntary HIV counseling and testing (VCT) services to enhance the existing surveillance program in San Francisco. This study describes newly-diagnosed HIV cases and characterizes correlates associated with infection. Methodology/Principal Findings A consecutive sample of persons presenting for HIV VCT at the municipal sexually transmitted infections (STI) clinic from 2004 to 2006 (N = 9,868) were evaluated by standard enzyme-linked immunoassays (EIA). HIV antibody-positive specimens were characterized as recent infections using a less-sensitive EIA. HIV-RNA pooled testing was performed on HIV antibody-negative specimens to identify acute infections. HIV antibody-positive and acute infection specimens were evaluated for drug resistance by sequence analysis. Multivariable logistic regression was performed to evaluate associations. The 380 newly-diagnosed HIV cases included 29 acute infections, 128 recent infections, and 47 drug-resistant cases, with no significant increases or decreases in prevalence over the three years studied. HIV-1 transmitted drug resistance prevalence was 11.0% in 2004, 13.4% in 2005 and 14.9% in 2006 (p = 0.36). Resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) was the most common pattern detected, present in 28 cases of resistance (59.6%). Among MSM, recent infection was associated with amphetamine use (AOR = 2.67; p<0.001), unprotected anal intercourse (AOR = 2.27; p<0.001), sex with a known HIV-infected partner (AOR = 1.64; p = 0.02), and history of gonorrhea (AOR = 1.62; p = 0.03). Conclusions New HIV diagnoses, recent infections, acute infections and transmitted drug resistance prevalence remained stable between 2004 and 2006. Resistance to NNRTI comprised more than half of the drug-resistant cases, a worrisome finding given its role as the backbone of first
Hong-Ha M Truong
Full Text Available HIV-1 acute infection, recent infection and transmitted drug resistance screening was integrated into voluntary HIV counseling and testing (VCT services to enhance the existing surveillance program in San Francisco. This study describes newly-diagnosed HIV cases and characterizes correlates associated with infection.A consecutive sample of persons presenting for HIV VCT at the municipal sexually transmitted infections (STI clinic from 2004 to 2006 (N = 9,868 were evaluated by standard enzyme-linked immunoassays (EIA. HIV antibody-positive specimens were characterized as recent infections using a less-sensitive EIA. HIV-RNA pooled testing was performed on HIV antibody-negative specimens to identify acute infections. HIV antibody-positive and acute infection specimens were evaluated for drug resistance by sequence analysis. Multivariable logistic regression was performed to evaluate associations. The 380 newly-diagnosed HIV cases included 29 acute infections, 128 recent infections, and 47 drug-resistant cases, with no significant increases or decreases in prevalence over the three years studied. HIV-1 transmitted drug resistance prevalence was 11.0% in 2004, 13.4% in 2005 and 14.9% in 2006 (p = 0.36. Resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI was the most common pattern detected, present in 28 cases of resistance (59.6%. Among MSM, recent infection was associated with amphetamine use (AOR = 2.67; p<0.001, unprotected anal intercourse (AOR = 2.27; p<0.001, sex with a known HIV-infected partner (AOR = 1.64; p = 0.02, and history of gonorrhea (AOR = 1.62; p = 0.03.New HIV diagnoses, recent infections, acute infections and transmitted drug resistance prevalence remained stable between 2004 and 2006. Resistance to NNRTI comprised more than half of the drug-resistant cases, a worrisome finding given its role as the backbone of first-line antiretroviral therapy in San Francisco as well as worldwide. The integration of HIV-1 drug
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.
Full Text Available Multi drug resistant tuberculosis (MDR-TB is defined as tuberculosis that is resistant to at least isoniazid and rifampicin, the two most powerful first-line anti-TB drugs. Extensively drug resistant tuberculosis (XDR-TB is defined as tuberculosis that is resistant to resistant to isoniazid and rifampin and to any fluoroquinolone and at least one of three injectable second-line drugs (namely, amikacin, kanamicin, or capreomycin. MDR-TB and XDR- TB are great dangers that threaten the public health. XDR-TB has been reported from many countries including the United States. In Turkey, among newly diagnosed cases, it was reported that the number of MDR-TB patients was 101 (3.1%, MDR-TB rate in the retreatment cases was 17.7% (90 patients, and MDR-TB rate in all cases was 5.1 (191 patients in 2005. The percentages were calculated through the number of patients who were tested in terms of susceptibility for both isoniazide and rifampin. In 2009, it was reported that the number of MDR-TB patients was 99 (2.7% among newly diagnosed cases, it was 123 (20.5 % in the retreatment cases and the total number of MDR-TB cases was 222 (5.1%. The first patient with XDR-TB was identified in 2010 in Turkey. Diagnosis of XDR TB takes several weeks by using conventional culture-based methods, although (however some molecular test can detect it rapidly. Treatment of XDR-TB patients is difficult and usually requiring at least 18-24 months of four to six second-line anti-TB drugs. The success rate with the treatment is about 30-50%, and mortality rate is higher in HIV-infected patients. Prevention of contact to XDR-TB patients is more complicated by the lack of a proven effective preventive treatment for XDR latent tuberculosis infection. Rapid diagnostic tests and new anti-TB drugs are needed to control the spread of this worldwide public health problem. [Dis Mol Med 2013; 1(4.000: 72-76
Full Text Available Abstract Background The emergence of drug-resistant tuberculosis (TB hampers TB control. Ten provinces in China performed drug resistance surveys among tuberculosis (TB patients in 1996–2004 to assess levels of drug resistance. Methods Provincial drug resistance surveys included all isolates from newly diagnosed, smear-positive TB patients. Drug susceptibility testing (DST against isoniazid, rifampicin, streptomycin and ethambutol was carried out in the provincial laboratories. For purposes of quality assurance, a random sample (11.6% was re-tested by the national reference laboratory (NRL. Results Of 14,059 patients tested 11,052 (79% were new TB cases. The weighted mean prevalence of multi-drug resistant tuberculosis (MDR-TB among all cases was 9.3% (range 2.2%–10.4%; 5.4% (range 2.1% – 10.4% among new cases and 25.6% (range 11.7%–36.9% among previously treated cases. Adjusting the drug resistance proportions using the re-testing results did not change the estimated national mean prevalence significantly. However, in some individual provinces the estimated resistance proportions were greatly influenced, especially among re-treatment patients. Conclusion MDR-TB levels varied greatly between provinces in China, but on average were high compared to the global estimated average of 4.8%. This study shows the importance of quality-assured laboratory performance. Programmatic management of drug-resistant TB, including high quality DST for patients at high risk of resistance and treatment with second-line drugs, should become the standard, especially in high MDR-TB settings.
Full Text Available Intracranial EEG (icEEG monitoring is critical in epilepsy surgical planning, but it has limitations. The advances of neuroimaging have made it possible to reveal epileptic abnormalities that could not be identified previously and improve the localization of the seizure focus and the vital cortex. A frequently asked question in the field is whether non-invasive neuroimaging could replace invasive icEEG or reduce the need for icEEG in presurgical evaluation. This review considers promising neuroimaging techniques in epilepsy presurgical assessment in order to address this question. In addition, due to large variations in the accuracies of neuroimaging across epilepsy centers, multicenter neuroimaging studies are reviewed, and there is much need for randomized controlled trials (RCTs to better reveal the utility of presurgical neuroimaging. The results of multiple studies indicate that non-invasive neuroimaging could not replace invasive icEEG in surgical planning especially in non-lesional or extratemporal lobe epilepsies, but it could reduce the need for icEEG in certain cases. With technical advances, multimodal neuroimaging may play a greater role in presurgical evaluation to reduce the costs and risks of epilepsy surgery, and provide surgical options for more patients with drug-resistant epilepsy.
Zhang, Jing; Liu, Weifang; Chen, Hui; Xia, Hong; Zhou, Zhen; Mei, Shanshan; Liu, Qingzhu; Li, Yunlin
Intracranial EEG (icEEG) monitoring is critical in epilepsy surgical planning, but it has limitations. The advances of neuroimaging have made it possible to reveal epileptic abnormalities that could not be identified previously and improve the localization of the seizure focus and the vital cortex. A frequently asked question in the field is whether non-invasive neuroimaging could replace invasive icEEG or reduce the need for icEEG in presurgical evaluation. This review considers promising neuroimaging techniques in epilepsy presurgical assessment in order to address this question. In addition, due to large variations in the accuracies of neuroimaging across epilepsy centers, multicenter neuroimaging studies are reviewed, and there is much need for randomized controlled trials (RCTs) to better reveal the utility of presurgical neuroimaging. The results of multiple studies indicate that non-invasive neuroimaging could not replace invasive icEEG in surgical planning especially in non-lesional or extratemporal lobe epilepsies, but it could reduce the need for icEEG in certain cases. With technical advances, multimodal neuroimaging may play a greater role in presurgical evaluation to reduce the costs and risks of epilepsy surgery, and provide surgical options for more patients with drug-resistant epilepsy.
Gould, Matthew K; Bachmaier, Sabine; Ali, Juma A M; Alsford, Sam; Tagoe, Daniel N A; Munday, Jane C; Schnaufer, Achim C; Horn, David; Boshart, Michael; de Koning, Harry P
One of the most promising new targets for trypanocidal drugs to emerge in recent years is the cyclic AMP (cAMP) phosphodiesterase (PDE) activity encoded by TbrPDEB1 and TbrPDEB2. These genes were genetically confirmed as essential, and a high-affinity inhibitor, CpdA, displays potent antitrypanosomal activity. To identify effectors of the elevated cAMP levels resulting from CpdA action and, consequently, potential sites for adaptations giving resistance to PDE inhibitors, resistance to the drug was induced. Selection of mutagenized trypanosomes resulted in resistance to CpdA as well as cross-resistance to membrane-permeable cAMP analogues but not to currently used trypanocidal drugs. Resistance was not due to changes in cAMP levels or in PDEB genes. A second approach, a genome-wide RNA interference (RNAi) library screen, returned four genes giving resistance to CpdA upon knockdown. Validation by independent RNAi strategies confirmed resistance to CpdA and suggested a role for the identified cAMP Response Proteins (CARPs) in cAMP action. CARP1 is unique to kinetoplastid parasites and has predicted cyclic nucleotide binding-like domains, and RNAi repression resulted in >100-fold resistance. CARP2 and CARP4 are hypothetical conserved proteins associated with the eukaryotic flagellar proteome or with flagellar function, with an orthologue of CARP4 implicated in human disease. CARP3 is a hypothetical protein, unique to Trypanosoma. CARP1 to CARP4 likely represent components of a novel cAMP signaling pathway in the parasite. As cAMP metabolism is validated as a drug target in Trypanosoma brucei, cAMP effectors highly divergent from the mammalian host, such as CARP1, lend themselves to further pharmacological development.
Full Text Available The growing problem of drug resistance has greatly complicated the treatment for falciparum malaria. Whereaschloroquine and sulfadoxine/pyrimethamine could once cure most infections, this is no longer true and requiresexamination of alternative regimens. Not all treatment failures are drug resistant and other issues such asexpired antimalarials and patient compliance need to be considered. Continuation of a failing treatment policyafter drug resistance is established suppresses infections rather than curing them, leading to increasedtransmission of malaria, promotion of epidemics and loss of public confidence in malaria control programs.Antifolate drug resistance (i.e. pyrimethamine means that new combinations are urgently needed particularlybecause addition of a single drug to an already failing regimen is rarely effective for very long. Atovaquone/proguanil and mefloquine have been used against multiple drug resistant falciparum malaria with resistance toeach having been documented soon after drug introduction. Drug combinations delay further transmission ofresistant parasites by increasing cure rates and inhibiting formation of gametocytes. Most currentlyrecommended drug combinations for falciparum malaria are variants of artemisinin combination therapy wherea rapidly acting artemisinin compound is combined with a longer half-life drug of a different class. Artemisininsused include dihydroartemisinin, artesunate, artemether and companion drugs include mefloquine, amodiaquine,sulfadoxine/pyrimethamine, lumefantrine, piperaquine, pyronaridine, chlorproguanil/dapsone. The standard ofcare must be to cure malaria by killing the last parasite. Combination antimalarial treatment is vital not only tothe successful treatment of individual patients but also for public health control of malaria.
Bharti, Pratibha; Anand, Vivek; Chander, Jagdish; Singh, Inder Pal; Singh, Tej Vir; Tewari, Rupinder
Background & objectives: Drug resistant microbes are a serious challenge to human health. During the search for novel antibiotics/inhibitors from the agricultural soil, a bacterial colony was found to inhibit the growth of clinical isolates including Staphylococcus (resistant to amikacin, ciprofloxacin, clindamycin, clinafloxacin, erythromycin, gentamicin and methicillin) and Candida (resistant to fluconazole and itraconazole). The culture was identified as Burkholderia gladioli and produced at least five different antimicrobial compounds which were highly stable at high temperature (121°C) and in the broad pH range (3.0-11.0). We report here the antimicrobial activity of B. gladioli against drug resistant bacterial pathogens. Methods: The bacterial culture was identified using morphological, biochemical and 16S rRNA gene sequencing techniques. The antimicrobial activity of the identified organism against a range of microbial pathogens was checked by Kirby-Bauer's disc diffusion method. The antimicrobial compounds in the cell free supernatant were chloroform-extracted and separated by thin layer chromatography (TLC). Results: B. gladioli OR1 exhibited broad spectrum antimicrobial activity against drug resistant clinical isolates belonging to various genera of bacteria (Staphylococcus, Enterobacter, Enterococcus, Acinetobacter and Citrobacter) and a fungus (Candida). Based on TLC profile and bioautography studies, the chloroform extract of B. gladioli OR1 consisted of at least three anti-staphylococcal and two anti-Candida metabolites. The antimicrobial activity was heat stable (121°C/20 min) as well as pH stable (3.0-11.0). Interpretation & conclusions: The bacterial soil isolate, B. gladioli OR1 possessed the ability to kill various drug resistant bacteria and a fungus. This organism produced many antimicrobial metabolites which might have the potential to be used as antibiotics in future. PMID:22771597
Jiang, Yu-Chen; Feng, Hui; Lin, Yu-Chun; Guo, Xiu-Rong
Herpes simplex virus (HSV), a member of the Herpesviridae family, is a significant human pathogen that results in mucocutaneous lesions in the oral cavity or genital infections. Acyclovir (ACV) and related nucleoside analogues can successfully treat HSV infections, but the emergence of drug resistance to ACV has created a barrier for the treatment of HSV infections, especially in immunocompromised patients. There is an urgent need to explore new and effective tactics to circumvent drug resistance to HSV. This review summarises the current strategies in the development of new targets (the DNA helicase/primase (H/P) complex), new types of molecules (nature products) and new antiviral mechanisms (lethal mutagenesis of Janus-type nucleosides) to fight the drug resistance of HSV. PMID:27025259
Pepper, John W
Many of the greatest challenges in medicine and public health involve the evolution of drug resistance by pathogens. Recent advances in the theory of natural selection suggest that there are two broad classes of pathogen traits that can be targeted by drugs or vaccines. The first class, consisting of traits that benefit the individual organisms bearing them, causes a strong evolutionary response and the rapid emergence of drug resistance. The second class, consisting of traits that benefit groups of pathogen organisms including the individual provider, causes a weaker evolutionary response and less drug resistance. Although most previous drug development has targeted the first class, it would be advantageous to focus on the second class as targets for drug and vaccine development. Specific examples and test cases are discussed.
Sander, Peter; Springer, Burkhard; Prammananan, Therdsak; Sturmfels, Antje; Kappler, Martin; Pletschette, Michel; Böttger, Erik C
To study the cost of chromosomal drug resistance mutations to bacteria, we investigated the fitness cost of mutations that confer resistance to different classes of antibiotics affecting bacterial protein synthesis (aminocyclitols, 2-deoxystreptamines, macrolides). We used a model system based on an in vitro competition assay with defined Mycobacterium smegmatis laboratory mutants; selected mutations were introduced by genetic techniques to address the possibility that compensatory mutations ameliorate the resistance cost. We found that the chromosomal drug resistance mutations studied often had only a small fitness cost; compensatory mutations were not involved in low-cost or no-cost resistance mutations. When drug resistance mutations found in clinical isolates were considered, selection of those mutations that have little or no fitness cost in the in vitro competition assay seems to occur. These results argue against expectations that link decreased levels of antibiotic consumption with the decline in the level of resistance.
Guifa Xi; Barbara Mania-Farnell; Ting Lei; Tadanori Tomita
Patients with brain tumors, specificaly, malignant forms such as glioblastoma, meduloblas-toma and ependymoma, exhibit dismal survival rates despite advances in treatment strategies. Chemotherapeutics, the primary adjuvant treatment for human brain tumors folowing surgery, commonly lack eficacy due to either intrinsic or acquired drug resistance. New treatments tar-geting epigenetic factors are being explored. Post-translational histone modification provides a critical regulatory platform for processes such as chromosome condensation and segregation, apoptosis, gene transcription, and DNA replication and repair. This work reviews how aberrant histone modifications and alterations in histone-modifying enzymes can drive the acquisition of drug resistance in brain tumors. Elucidating these mechanisms should lead to new treatments for overcoming drug resistance.
Targeted therapies have revolutionized cancer treatment. Unfortunately, their success is limited due to the development of drug resistance within the tumor, which is an evolutionary process. Understanding how drug resistance evolves is a prerequisite to a better success of targeted therapies. Resistance is usually explained as a response to evolutionary pressure imposed by treatment. Thus, evolutionary understanding can and should be used in the design and treatment of cancer. In this article, drug-resistance to targeted therapies is reviewed from an evolutionary standpoint. The concept of apoptosis-induced compensatory proliferation (AICP) is developed. It is shown that AICP helps to explain some of the phenomena that are observed experimentally in cancers. Finally, potential drug targets are suggested in light of AICP.
Papadopoulou, B; Kündig, C; Singh, A; Ouellette, M
The main line of defense available against parasitic protozoa is chemotherapy. Drug resistance has emerged however, as a primary obstacle to the successful treatment and control of parasitic diseases. Leishmania spp., the causative agents of leishmaniasis, have served as a useful model for studying mechanisms of drug resistance in vitro. Antimonials and amphotericin B are the first line drugs to treat Leishmania followed by pentamidine and a number of other drugs. Parasites resistant against all these classes of drugs have been selected under laboratory conditions. A multiplicity of resistance mechanisms has been detected, the most prevalent being gene amplification and transport mutations. With the tools now available, it should be possible to elucidate the mechanisms that govern drug resistance in field isolates and develop more effective chemotherapeutic agents.
Yu-Chen Jiang; Hui Feng; Yu-Chun Lin; Xiu-Rong Guo
Herpes simplex virus (HSV), a member of the Herpesviridae family, is a significant human pathogen that results in mucocutaneous lesions in the oral cavity or genital infections. Acyclovir (ACV) and related nucleoside analogues can successfully treat HSV infections, but the emergence of drug resistance to ACV has created a barrier for the treatment of HSV infections, especially in immunocompromised patients. There is an urgent need to explore new and effective tactics to circumvent drug resistance to HSV. This review summarises the current strategies in the development of new targets (the DNA helicase/primase (H/P) complex), new types of molecules (nature products) and new antiviral mechanisms (lethal mutagenesis of Janus-type nucleosides) to fight the drug resistance of HSV.
Full Text Available Abstract Background The role of HIV-1 RNA in the emergence of resistance to antiretroviral therapies (ARTs is well documented while less is known about the role of historical viruses stored in the proviral DNA. The primary focus of this work was to characterize the genetic diversity and evolution of HIV drug resistant variants in an individual’s provirus during antiretroviral therapy using next generation sequencing. Methods Blood samples were collected prior to antiretroviral therapy exposure and during the course of treatment from five patients in whom drug resistance mutations had previously been identified using consensus sequencing. The spectrum of viral variants present in the provirus at each sampling time-point were characterized using 454 pyrosequencing from multiple combined PCR products. The prevalence of viral variants containing drug resistant mutations (DRMs was characterized at each time-point. Results Low abundance drug resistant viruses were identified in 14 of 15 sampling time-points from the five patients. In all individuals DRMs against current therapy were identified at one or more of the sampling time-points. In two of the five individuals studied these DRMs were present prior to treatment exposure and were present at high prevalence within the amplified and sequenced viral population. DRMs to drugs other than those being currently used were identified in four of the five individuals. Conclusion The presence of DRMs in the provirus, regardless of their observed prevalence did not appear to have an effect on clinical outcomes in the short term suggesting that the drug resistant viral variants present in the proviral DNA do not appear to play a role in the short term in facilitating the emergence of drug resistance.
Full Text Available Smita Sarma, Shalini Upadhyay Department of Microbiology, Medanta – The Medicity, Gurgaon, Haryana, India Abstract: Candida auris is an emerging fungus that presents a serious threat to global health. The organism is difficult to identify using conventional biochemical methods. C. auris has also attracted attention because of its reduced susceptibility to azoles, polyenes, and echinocandins, with a few strains even resistant to all three classes of antifungals. In this review paper we discuss the trends in emergence of C. auris in different parts of the world, associated risk factors, drug resistance, and diagnostic challenges. Strategies for prevention and therapeutic options for such infections is also addressed. Keywords: Candidemia, Candida haemulonii, outbreak, drug resistance
Obermeier, Martin; Pironti, Alejandro; Berg, Thomas; Braun, Patrick; Däumer, Martin; Eberle, Josef; Ehret, Robert; Kaiser, Rolf; Kleinkauf, Niels; Korn, Klaus; Kücherer, Claudia; Müller, Harm; Noah, Christian; Stürmer, Martin; Thielen, Alexander; Wolf, Eva; Walter, Hauke
Genotypic drug resistance testing provides essential information for guiding treatment in HIV-infected patients. It may either be used for identifying patients with transmitted drug resistance or to clarify reasons for treatment failure and to check for remaining treatment options. While different approaches for the interpretation of HIV sequence information are already available, no other available rules-based systems specifically have looked into the effects of combinations of drugs. HIV-GRADE (Genotypischer Resistenz Algorithmus Deutschland) was planned as a countrywide approach to establish standardized drug resistance interpretation in Germany and also to introduce rules for estimating the influence of mutations on drug combinations. The rules for HIV-GRADE are taken from the literature, clinical follow-up data and from a bioinformatics-driven interpretation system (geno2pheno([resistance])). HIV-GRADE presents the option of seeing the rules and results of other drug resistance algorithms for a given sequence simultaneously. The HIV-GRADE rules-based interpretation system was developed by the members of the HIV-GRADE registered society. For continuous updates, this expert committee meets twice a year to analyze data from various sources. Besides data from clinical studies and the centers involved, published correlations for mutations with drug resistance and genotype-phenotype correlation data information from the bioinformatic models of geno2pheno are used to generate the rules for the HIV-GRADE interpretation system. A freely available online tool was developed on the basis of the Stanford HIVdb rules interpretation tool using the algorithm specification interface. Clinical validation of the interpretation system was performed on the data of treatment episodes consisting of sequence information, antiretroviral treatment and viral load, before and 3 months after treatment change. Data were analyzed using multiple linear regression. As the developed online
Benita Mercy R
Full Text Available Drug resistance by bacterial pathogens becomes a major health problem worldwide. Hence, it is important to search for broad spectrum of antibiotic from natural sources. Marine actinomycetes isolated from marine sediments collected at different sampling sites along the southeast coast of Bay of Bengal, India were investigated for antagonistic activity against selected drug resistant Gram positivebacterial pathogens. All actinomycetes isolates were screened for antibacterial activity against standard drug resistant ATCC strains. The potential isolate which showed higher inhibitory activity against drug resistant pathogens was mass cultured and the ethyl acetate (EA extract of the cell free culture broth was tested for antibacterial activity. The biochemical, morphological and physiological characterisation of the isolate revealed that it was Gram-positive rod, sporulating and produced grey aerial mycelium. The spore chain morphology, and smooth surface morphology showed that it belongs to the genus Streptomyces.Based on Nonomura’s key for classification of Streptomycesand Bergey’s Manual of Determinative Bacteriology, the isolatewas identified as Streptomyces species and designated as Streptomyces sp. VITBRK4.Purification and characterization of EA extract of the isolate by thin layer chromatography (TLC and HPLC-DAD analysis showed the presence of indolo compound along with few other unidentified metabolites. The result of this study showed that the antibacterial activity of the EA extract against drug resistant strains may be due to indolo compound present in the extract.
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.
Rao, Pavitra N; Uplekar, Swapna; Kayal, Sriti; Mallick, Prashant K; Bandyopadhyay, Nabamita; Kale, Sonal; Singh, Om P; Mohanty, Akshaya; Mohanty, Sanjib; Wassmer, Samuel C; Carlton, Jane M
A major challenge to global malaria control and elimination is early detection and containment of emerging drug resistance. Next-generation sequencing (NGS) methods provide the resolution, scalability, and sensitivity required for high-throughput surveillance of molecular markers of drug resistance. We have developed an amplicon sequencing method on the Ion Torrent PGM platform for targeted resequencing of a panel of six Plasmodium falciparum genes implicated in resistance to first-line antimalarial therapy, including artemisinin combination therapy, chloroquine, and sulfadoxine-pyrimethamine. The protocol was optimized using 12 geographically diverse P. falciparum reference strains and successfully applied to multiplexed sequencing of 16 clinical isolates from India. The sequencing results from the reference strains showed 100% concordance with previously reported drug resistance-associated mutations. Single-nucleotide polymorphisms (SNPs) in clinical isolates revealed a number of known resistance-associated mutations and other nonsynonymous mutations that have not been implicated in drug resistance. SNP positions containing multiple allelic variants were used to identify three clinical samples containing mixed genotypes indicative of multiclonal infections. The amplicon sequencing protocol has been designed for the benchtop Ion Torrent PGM platform and can be operated with minimal bioinformatics infrastructure, making it ideal for use in countries that are endemic for the disease to facilitate routine large-scale surveillance of the emergence of drug resistance and to ensure continued success of the malaria treatment policy.
Africa, Charlene Wilma Joyce; Abrantes, Pedro Miguel dos Santos
Background: Candida infections are responsible for increased morbidity and mortality rates in at-risk patients, especially in developing countries where there is limited access to antifungal drugs and a high burden of HIV co-infection. Objectives: This study aimed to identify antifungal drug resistance patterns within the subcontinent of Africa. Methods: A literature search was conducted on published studies that employed antifungal susceptibility testing on clinical Candida isolates from sub-Saharan African countries using Pubmed and Google Scholar. Results: A total of 21 studies from 8 countries constituted this review. Only studies conducted in sub-Saharan Africa and employing antifungal drug susceptibility testing were included. Regional differences in Candida species prevalence and resistance patterns were identified. Discussion: The outcomes of this review highlight the need for a revision of antifungal therapy guidelines in regions most affected by Candida drug resistance. Better controls in antimicrobial drug distribution and the implementation of regional antimicrobial susceptibility surveillance programmes are required in order to reduce the high Candida drug resistance levels seen to be emerging in sub-Saharan Africa. PMID:28154753
Asadollahi, Marjan; Sperling, Michael R; Rabiei, Amin H; Asadi-Pooya, Ali A
We reviewed a large surgical cohort to investigate the clinical manifestations, EEG and neuroimaging findings, and postoperative seizure outcome in patients with drug-resistant parietal lobe epilepsy (PLE). All drug-resistant PLE patients, who were investigated for epilepsy surgery at Jefferson Comprehensive Epilepsy Center between 1986 and 2015, were identified. Demographic data, seizure data, EEG recordings, brain MRI, pathological findings, and postsurgical seizure outcome were reviewed. In total, 18 patients (11 males and seven females) were identified. Sixteen patients (88%) had tonic-clonic seizures, 12 (66%) had focal seizures with impaired awareness, and 13 (72%) described auras. Among 15 patients who had brain MRI, 14 patients (93%) had parietal lobe lesions. Only three of 15 patients (20%) who had interictal scalp EEG recordings showed parietal interictal spikes. Of 12 patients with available ictal surface EEG recordings, only three patients (25%) had parietal ictal EEG onset. After a mean follow-up duration of 8.6 years, 14 patients (77.7%) showed a favourable postoperative seizure outcome. In patients with PLE, semiology and EEG may be misleading and brain MRI is the most valuable tool to localize the epileptogenic zone. Postsurgical seizure outcome was favourable in our patients with drug-resistant parietal lobe epilepsy.
Courtney, Colleen; Chatterjee, Anushree
``Super-bugs'' or ``multi-drug resistant organisms'' are a serious international health problem, with devastating consequences to patient health care. The Center for Disease Control has identified antibiotic resistance as one of the world's most pressing public health problems as a significant fraction of bacterial infections contracted are drug resistant. Typically, antibiotic resistance is encoded by ``resistance-genes'' which express proteins that carryout the resistance causing functions inside the bacterium. We present a RNA based therapeutic strategy for designing antimicrobials capable of re-sensitizing resistant bacteria to antibiotics by targeting labile regions of messenger RNAs encoding for resistance-causing proteins. We perform in silico RNA secondary structure modeling to identify labile target regions in an mRNA of interest. A synthetic biology approach is then used to administer antisense nucleic acids to our model system of ampicillin resistant Escherichia coli. Our results show a prolonged lag phase and decrease in viability of drug-resistant E. colitreated with antisense molecules. The antisense strategy can be applied to alter expression of other genes in antibiotic resistance pathways or other pathways of interest.
Bruno R. Fermino
Full Text Available Trypanosoma terena and Trypanosoma ralphi are known species of the South American crocodilians Caiman crocodilus, Caiman yacare and Melanosuchus niger and are phylogenetically related to the tsetse-transmitted Trypanosoma grayi of the African Crocodylus niloticus. These trypanosomes form the Crocodilian clade of the terrestrial clade of the genus Trypanosoma. A PCR-survey for trypanosomes in caiman blood samples and in leeches taken from caimans revealed unknown trypanosome diversity and frequent mixed infections. Phylogenies based on SSU (small subunit of rRNA and gGAPDH (glycosomal Glyceraldehyde Phosphate Dehydrogenase gene sequences revealed a new trypanosome species clustering with T. terena and T. ralphi in the crocodilian clade and an additional new species nesting in the distant Aquatic clade of trypanosomes, which is herein named Trypanosoma clandestinus n. sp. This new species was found in Caiman yacare, Caiman crocodilus and M. niger from the Pantanal and Amazonian biomes in Brazil. Large numbers of dividing epimastigotes and unique thin and long trypomastigotes were found in the guts of leeches (Haementeria sp. removed from the mouths of caimans. The trypanosomes recovered from the leeches had sequences identical to those of T. clandestinus of caiman blood samples. Experimental infestation of young caimans (Caiman yacare with infected leeches resulted in long-lasting T. clandestinus infections that permitted us to delineate its life cycle. In contrast to T. terena, T. ralphi and T. grayi, which are detectable by hemoculturing, microscopy and standard PCR of caiman blood, T. clandestinus passes undetected by these methods due to very low parasitemia and could be detected solely by the more sensitive nested PCR method. T. clandestinus n. sp. is the first crocodilian trypanosome known to be transmitted by leeches and positioned in the aquatic clade closest to fish trypanosomes. Our data show that caimans can host trypanosomes
Fermino, Bruno R.; Paiva, Fernando; Soares, Priscilla; Tavares, Luiz Eduardo R.; Viola, Laerte B.; Ferreira, Robson C.; Botero-Arias, Robinson; de-Paula, Cátia D.; Campaner, Marta; Takata, Carmen S.A.; Teixeira, Marta M.G.; Camargo, Erney P.
Trypanosoma terena and Trypanosoma ralphi are known species of the South American crocodilians Caiman crocodilus, Caiman yacare and Melanosuchus niger and are phylogenetically related to the tsetse-transmitted Trypanosoma grayi of the African Crocodylus niloticus. These trypanosomes form the Crocodilian clade of the terrestrial clade of the genus Trypanosoma. A PCR-survey for trypanosomes in caiman blood samples and in leeches taken from caimans revealed unknown trypanosome diversity and frequent mixed infections. Phylogenies based on SSU (small subunit) of rRNA and gGAPDH (glycosomal Glyceraldehyde Phosphate Dehydrogenase) gene sequences revealed a new trypanosome species clustering with T. terena and T. ralphi in the crocodilian clade and an additional new species nesting in the distant Aquatic clade of trypanosomes, which is herein named Trypanosoma clandestinus n. sp. This new species was found in Caiman yacare, Caiman crocodilus and M. niger from the Pantanal and Amazonian biomes in Brazil. Large numbers of dividing epimastigotes and unique thin and long trypomastigotes were found in the guts of leeches (Haementeria sp.) removed from the mouths of caimans. The trypanosomes recovered from the leeches had sequences identical to those of T. clandestinus of caiman blood samples. Experimental infestation of young caimans (Caiman yacare) with infected leeches resulted in long-lasting T. clandestinus infections that permitted us to delineate its life cycle. In contrast to T. terena, T. ralphi and T. grayi, which are detectable by hemoculturing, microscopy and standard PCR of caiman blood, T. clandestinus passes undetected by these methods due to very low parasitemia and could be detected solely by the more sensitive nested PCR method. T. clandestinus n. sp. is the first crocodilian trypanosome known to be transmitted by leeches and positioned in the aquatic clade closest to fish trypanosomes. Our data show that caimans can host trypanosomes of the aquatic or
Kuan, Chee Sian; Chan, Chai Ling; Yew, Su Mei; Toh, Yue Fen; Khoo, Jia-Shiun; Chong, Jennifer; Lee, Kok Wei; Tan, Yung-Chie; Yee, Wai-Yan; Ngeow, Yun Fong; Ng, Kee Peng
The outbreak of extensively drug-resistant tuberculosis (XDR-TB) has become an increasing problem in many TB-burdened countries. The underlying drug resistance mechanisms, including the genetic variation favored by selective pressure in the resistant population, are partially understood. Recently, the first case of XDR-TB was reported in Malaysia. However, the detailed genotype family and mechanisms of the formation of multiple drugs resistance are unknown. We sequenced the whole genome of the UM 1072388579 strain with a 2-kb insert-size library and combined with that from previously sequenced 500-bp-insert paired-end reads to produce an improved sequence with maximal sequencing coverage across the genome. In silico spoligotyping and phylogenetic analyses demonstrated that UM 1072388579 strain belongs to an ancestral-like, non-Beijing clade of East Asia lineage. This is supported by the presence of a number of lineage-specific markers, including fadD28, embA, nuoD and pks7. Polymorphism analysis showed that the drug-susceptibility profile is correlated with the pattern of resistance mutations. Mutations in drug-efflux pumps and the cell wall biogenesis pathway such as mmpL, pks and fadD genes may play an important role in survival and adaptation of this strain to its surrounding environment. In this work, fifty-seven putative promoter SNPs were identified. Among them, we identified a novel SNP located at -4 T allele of TetR/acrR promoter as an informative marker to recognize strains of East Asian lineage. Our work indicates that the UM 1072388579 harbors both classical and uncommon SNPs that allow it to escape from inhibition by many antibiotics. This study provides a strong foundation to dissect the biology and underlying resistance mechanisms of the first reported XDR M. tuberculosis in Malaysia.
Chee Sian Kuan
Full Text Available The outbreak of extensively drug-resistant tuberculosis (XDR-TB has become an increasing problem in many TB-burdened countries. The underlying drug resistance mechanisms, including the genetic variation favored by selective pressure in the resistant population, are partially understood. Recently, the first case of XDR-TB was reported in Malaysia. However, the detailed genotype family and mechanisms of the formation of multiple drugs resistance are unknown. We sequenced the whole genome of the UM 1072388579 strain with a 2-kb insert-size library and combined with that from previously sequenced 500-bp-insert paired-end reads to produce an improved sequence with maximal sequencing coverage across the genome. In silico spoligotyping and phylogenetic analyses demonstrated that UM 1072388579 strain belongs to an ancestral-like, non-Beijing clade of East Asia lineage. This is supported by the presence of a number of lineage-specific markers, including fadD28, embA, nuoD and pks7. Polymorphism analysis showed that the drug-susceptibility profile is correlated with the pattern of resistance mutations. Mutations in drug-efflux pumps and the cell wall biogenesis pathway such as mmpL, pks and fadD genes may play an important role in survival and adaptation of this strain to its surrounding environment. In this work, fifty-seven putative promoter SNPs were identified. Among them, we identified a novel SNP located at -4 T allele of TetR/acrR promoter as an informative marker to recognize strains of East Asian lineage. Our work indicates that the UM 1072388579 harbors both classical and uncommon SNPs that allow it to escape from inhibition by many antibiotics. This study provides a strong foundation to dissect the biology and underlying resistance mechanisms of the first reported XDR M. tuberculosis in Malaysia.
Thompson, Craig K; Thompson, R C Andrew
Trypanosomes infect humans, domestic animals, and wildlife, and are transmitted by haematophagous invertebrate vectors. Eight native trypanosome species have been described from Australian indigenous mammals, along with other unnamed isolates and genotypes. Associated difficulties relating to the confirmation of cyclical and mechanical vector candidates has hindered vector identification in Australia, with no successful experimental transmission documented for any of these native trypanosomes to indigenous mammals. We discuss pending biosecurity issues, with significant importance placed on the close phylogenetic and phenotypic relationship shared between Trypanosoma cruzi and some Australian trypanosomes. With such a dearth of information, we highlight the importance of keeping an open mind, which considers all possibilities during future investigations of vectors and their associated biosecurity issues in Australia.
Frevert, Ute; Movila, Alexandru; Nikolskaia, Olga V; Raper, Jayne; Mackey, Zachary B; Abdulla, Maha; McKerrow, James; Grab, Dennis J
.... Based mostly on data from animal models, it is currently thought that trypanosome entry into the brain occurs by initial infection of the choroid plexus and the circumventricular organs followed days...
Kang, Cheol-In; Baek, Jin Yang; Jeon, Kyeongman; Kim, So Hyun; Chung, Doo Ryeon; Peck, Kyong Ran; Lee, Nam Yong; Song, Jae-Hoon
The emergence of antimicrobial resistance threatens the successful treatment of pneumococcal infections. Here we report a case of bacteremic pneumonia caused by an extremely drug-resistant strain of Streptococcus pneumoniae, nonsusceptible to at least one agent in all classes but vancomycin and linezolid, posing an important new public health threat in our region.
DENG Chao-hua; ZHANG Qiu-ping
Objective To review the central role of leukemia stem cells (LSCs) in drug resistance and metastasis, aiming to provide key insights into leukemogenic pathology and developing novel therapeutic strategies against the relapse of leukemia.Data sources The data used in this review were obtained mainly from the studies reported in PubMed using the key terms "tumor-initiating cells", "leukemia stem cells", "drug resistance" and "metastasis".Study selection Relevant articles on studies of leukemia stem cells were selected.Results Increasing numbers of studies have suggested the importance of cancer stem cells (CSCs) in the initiation and maintenance of cancer, especially in leukemia. This review has summarized the origin, characteristics, isolation and identification of LSCs. It highlights the crucial role of LSCs in drug resistance and metastasis of leukemia by illustrating possible mechanisms and aims to provide novel therapeutic strategies for LSCs-targeted treatment.Conclusion LSCs play a crucial role in drug resistance and metastasis of leukemia and new promising LSCs-targeted therapies warrant investigation in both experimental models and clinical practice.
Bertognolio, Silvio; Derdelinckx, Inge; Parker, Monica; Fitzgibbon, Joseph; Fleury, Herve; Peeters, Martin; Schuurman, Rob; Pillay, Deenan; Morris, Lynn; Tanuri, Amilcar; Gershy-Damet, Guy-Michel; Nkengasong, John; Gilks, Charles F.; Sutherland, Donald; Sandstrom, Paul
With rapidly increasing access to antiretroviral drugs globally, HIV drug resistance (HIVDR) has become a significant public health issue, This requires a coordinated and collaborative response from country level to international level to assess the extent of HIVDR and the establishment of efficient
Sietsma, H; Dijkhuis, AJ; Kamps, W; Kok, JW
Disseminated neuroblastoma usually calls for chemotherapy as the primary approach for treatment. Treatment failure is often attributable to drug resistance. This involves a variety of cellular mechanisms, including increased drug efflux through expression of ATP-binding cassette transporters (e.g.,
Issa, Mark E; Takhsha, Farnaz Sedigheh; Chirumamilla, Chandra Sekhar; Perez-Novo, Claudina; Vanden Berghe, Wim; Cuendet, Muriel
Multiple myeloma (MM) is a hematological malignancy, which remains incurable because most patients eventually relapse or become refractory to current treatments. Due to heterogeneity within the cancer cell microenvironment, cancer cell populations employ a dynamic survival strategy to chemotherapeutic treatments, which frequently results in a rapid acquisition of therapy resistance. Besides resistance-conferring genetic alterations within a tumor cell population selected during drug treatment, recent findings also reveal non-mutational mechanisms of drug resistance, involving a small population of "cancer stem cells" (CSCs) which are intrinsically more refractory to the effects of a variety of anticancer drugs. Other studies have implicated epigenetic mechanisms in reversible drug tolerance to protect the population from eradication by potentially lethal exposures, suggesting that acquired drug resistance does not necessarily require a stable heritable genetic alteration. Clonal evolution of MM cells and the bone marrow microenvironment changes contribute to drug resistance. MM-CSCs may not be a static population and survive as phenotypically and functionally different cell types via the transition between stem-like and non-stem-like states in local microenvironments, as observed in other types of cancers. Targeting MM-CSCs is clinically relevant, and different approaches have been suggested to target molecular, metabolic and epigenetic signatures, and the self-renewal signaling characteristic of MM CSC-like cells. Here, we summarize epigenetic strategies to reverse drug resistance in heterogeneous multiple myeloma.
Full Text Available Abstract Background The incidence of tuberculosis in Pakistan is 181/100,000 population. However, information about transmission and geographical prevalence of Mycobacterium tuberculosis strains and their evolutionary genetics as well as drug resistance remains limited. Our objective was to determine the clonal composition, evolutionary genetics and drug resistance of M. tuberculosis isolates from different regions of the country. Methods M. tuberculosis strains isolated (2003–2005 from specimens submitted to the laboratory through collection units nationwide were included. Drug susceptibility was performed and strains were spoligotyped. Results Of 926 M. tuberculosis strains studied, 721(78% were grouped into 59 "shared types", while 205 (22% were identified as "Orphan" spoligotypes. Amongst the predominant genotypes 61% were Central Asian strains (CAS ; including CAS1, CAS sub-families and Orphan Pak clusters, 4% East African-Indian (EAI, 3% Beijing, 2% poorly defined TB strains (T, 2% Haarlem and LAM (0.2. Also TbD1 analysis (M. tuberculosis specific deletion 1 confirmed that CAS1 was of "modern" origin while EAI isolates belonged to "ancestral" strain types. Prevalence of CAS1 clade was significantly higher in Punjab (P Conclusion Our results show variation of prevalent M. tuberculosis strain with greater association of CAS1 with the Punjab province. The fact that the prevalent CAS genotype was not associated with drug resistance is encouraging. It further suggests a more effective treatment and control programme should be successful in reducing the tuberculosis burden in Pakistan.
Full Text Available Abstract Background Correlations of disease phenotypes with glycosylation changes have been analysed intensively in the tumor biology field. Glycoforms potentially associated with carcinogenesis, tumor progression and cancer metastasis have been identified. In cancer therapy, drug resistance is a severe problem, reducing therapeutic effect of drugs and adding to patient suffering. Although multiple mechanisms likely underlie resistance of cancer cells to anticancer drugs, including overexpression of transporters, the relationship of glycans to drug resistance is not well understood. Results We established epirubicin (EPI – and mitoxantrone (MIT – resistant cell lines (HLE-EPI and HLE-MIT from the human hepatocellular carcinoma cell line (HLE. HLE-EPI and HLE-MIT overexpressed transporters MDR1/ABCB1 and BCRP/ABCG2, respectively. Here we compared the glycomics of HLE-EPI and HLE-MIT cells with the parental HLE line. Core fucosylated triantennary oligosaccharides were increased in the two resistant lines. We investigated mRNA levels of glycosyltransferases synthesizing this oligosaccharide, namely, N-acetylglucosaminyltransferase (GnT-IVa, GnT-IVb and α1,6-fucosyltransferase (α1,6-FucT, and found that α1,6-FucT was particularly overexpressed in HLE-MIT cells. In HLE-EPI cells, GnT-IVa expression was decreased, while GnT-IVb was increased. Both GnT-IVs were downregulated in HLE-MIT cells. HLE-MIT cells also showed decreases in fucosylated tetraantennary oligosaccharide, the product of GnT-V. GnT-V expression was decreased in both lines, but particularly so in HLE-MIT cells. Thus both N-glycan and glycosyltransferase expression was altered as cells acquired tolerance, suggesting novel mechanisms of drug resistance. Conclusion N-glycan and glycosyltransferase expression in HLE-EPI and HLE-MIT were analysed and presented that glycans altered according with acquired tolerance. These results suggested novel mechanisms of drug resistance.
Murillo, Wendy; Lorenzana de Rivera, Ivette; Albert, Jan; Guardado, María Elena; Nieto, Ana Isabel; Paz-Bailey, Gabriela
Transmitted drug resistance has important implications for the successful use and management of therapy among persons infected with HIV. We estimated the prevalence of transmitted drug resistance in 145 samples from female sex workers (n = 47) and men who have sex with men (n = 98) in El Salvador. Samples were collected during March to September 2008, using a respondent driven sampling. The HIV-1 pol gene was sequenced to identify drug resistance mutations and transmitted drug resistance was scored as recommended by World Health Organization. Specimens were classified as recent or established infections using the Immunoglobulin G-Capture BED-Enzyme Immunoassay. The overall prevalence of transmitted drug resistance was 9.4% (95% CI: 4.7-16.1%), and was 5.9% for non-nucleoside reverse transcriptase inhibitors, 4.2% for nucleoside reverse transcriptase inhibitors, and 0.8% for protease inhibitors. Transmitted drug resistance prevalence was 10.3% (95% CI: 2.8-24.2%) among female sex workers, and 9.0% (95% CI: 3.6-17.6%) among men who have sex with men. Nineteen patients were classified as having recent infection (16.2%, 95% CI: 10.1-24.2%), while 98 patients (83.8%, 95% CI: 75.8-89.9%) were classified as having established infections. Transmitted drug resistance among recent and established infections was similar at 10.5% and 9.2%, respectively. This study shows that the prevalence of transmitted drug resistance is moderate among female sex workers and men who have sex with men in El Salvador. These results highlight the importance of transmitted drug resistance surveillance in a representative sample of recently infected patients following the World Health Organization guidelines. Copyright © 2012 Wiley Periodicals, Inc.
Van Helden Paul D
Full Text Available Abstract Background The Beijing genotype of M. tuberculosis is a virulent strain that is disseminating worldwide and has a strong association with drug resistance. In the Western Cape of South Africa, epidemiological studies have identified the R220 cluster of the Beijing genotype as a major contributor to a recent outbreak of drug-resistant tuberculosis. Although the outbreak is considered to be due to clonal transmission, the relationship among drug resistant isolates has not yet been established. Results To better understand the evolution of drug resistance among these strains, 14 drug-resistant clinical isolates of the Beijing genotype were sequenced by whole-genome sequencing, including eight from R220 and six from a more ancestral Beijing cluster, R86, for comparison. While each cluster shares a distinct resistance mutation for isoniazid, mapping of other drug-resistance mutations onto a phylogenetic tree constructed from single nucleotide polymorphisms shows that resistance mutations to many drugs have arisen multiple times independently within each cluster of isolates. Thus, drug resistance among these isolates appears to be acquired, not clonally derived. This observation suggests that, although the Beijing genotype as a whole might have selective advantages enabling its rapid dissemination, the XDR isolates are relatively less fit and do not propagate well. Although it has been hypothesized that the increased frequency of drug resistance in some Beijing lineages might be caused by a mutator phenotype, no significant shift in synonymous substitution patterns is observed in the genomes. Conclusion While MDR-TB is spreading by transmission in the Western Cape, our data suggests that further drug resistance (i.e. XDR-TB at this stage is acquired.
Menon, A K; Eppinger, M; Mayor, S; Schwarz, R T
A variety of eukaryotic cell surface proteins, including the variant surface glycoproteins of African trypanosomes, rely on a covalently attached lipid, glycosylphosphatidylinositol (GPI), for membrane attachment. GPI anchors are synthesized in the endoplasmic reticulum by stepwise glycosylation of phosphatidylinositol (via UDP-GlcNAc and dolichol-P-mannose) followed by the addition of phosphoethanolamine. The experiments described in this paper are aimed at identifying the biosynthetic origin of the terminal phosphoethanolamine group. We show that trypanosome GPIs can be labelled via CDP-[3H]ethanolamine or [beta-32P]CDP-ethanolamine in a cell-free system, indicating that phosphoethanolamine is acquired en bloc. In pulse-chase experiments with CDP-[3H]ethanolamine we show that the GPI phosphoethanolamine is not derived directly from CDP-ethanolamine, but instead from a relatively stable metabolite, such as phosphatidylethanolamine (PE), generated from CDP-ethanolamine in the cell-free system. To test the possibility that PE is the immediate donor of the GPI phosphoethanolamine moiety, we describe metabolic labelling experiments with [3H]serine and show that GPIs can be labelled in the absence of detectable radiolabelled CDP-ethanolamine, presumably via [3H]PE generated from [3H]phosphatidylserine (PS). The data support the proposal that the terminal phosphoethanolamine group in trypanosome GPIs is derived from PE. PMID:8491183
Full Text Available Fungal biofilms are a major cause of human mortality and are recalcitrant to most treatments due to intrinsic drug resistance. These complex communities of multiple cell types form on indwelling medical devices and their eradication often requires surgical removal of infected devices. Here we implicate the molecular chaperone Hsp90 as a key regulator of biofilm dispersion and drug resistance. We previously established that in the leading human fungal pathogen, Candida albicans, Hsp90 enables the emergence and maintenance of drug resistance in planktonic conditions by stabilizing the protein phosphatase calcineurin and MAPK Mkc1. Hsp90 also regulates temperature-dependent C. albicans morphogenesis through repression of cAMP-PKA signalling. Here we demonstrate that genetic depletion of Hsp90 reduced C. albicans biofilm growth and maturation in vitro and impaired dispersal of biofilm cells. Further, compromising Hsp90 function in vitro abrogated resistance of C. albicans biofilms to the most widely deployed class of antifungal drugs, the azoles. Depletion of Hsp90 led to reduction of calcineurin and Mkc1 in planktonic but not biofilm conditions, suggesting that Hsp90 regulates drug resistance through different mechanisms in these distinct cellular states. Reduction of Hsp90 levels led to a marked decrease in matrix glucan levels, providing a compelling mechanism through which Hsp90 might regulate biofilm azole resistance. Impairment of Hsp90 function genetically or pharmacologically transformed fluconazole from ineffectual to highly effective in eradicating biofilms in a rat venous catheter infection model. Finally, inhibition of Hsp90 reduced resistance of biofilms of the most lethal mould, Aspergillus fumigatus, to the newest class of antifungals to reach the clinic, the echinocandins. Thus, we establish a novel mechanism regulating biofilm drug resistance and dispersion and that targeting Hsp90 provides a much-needed strategy for improving
Amita Jain; Pratima Dixit
Drug resistant tuberculosis is a man made problem. While tuberculosis is hundred percent curable, multidrug resistant tuberculosis (MDR-TB) is difficult to treat. Inadequate and incomplete treatment and poor treatment adherence has led to a newer form of drug resistance known as extensively drug resistant tuberculosis (XDR-TB). XDR-TB is defined as tuberculosis caused by Mycobacterium tuberculosis strain, which is resistant to at least rifampicin and isoniazid among the first line anti tubercular drugs (MDR-TB) in addition to resistance to any fluroquinolones and at least one of three injectable second line anti tubercular drugs i.e. amikacin, kanamycin and/or capreomycin. Mismanagement of tuberculosis paves the way to drug resistant tuberculosis. Emergence of XDR-TB is reported world wide. Reported prevalence rates of XDR-TB of total MDR cases are; 6.6% overall worldwide, 6.5% in industrialized countries, 13.6% in Russia and Eastern Europe, 1.5% in Asia, 0.6% in Africa and Middle East and 15.4% in Republic of Korea. Better management and control of tuberculosis specially drug resistant TB by experienced and qualified doctors, access to standard microbiology laboratory, co-morbitidy of HIV and tuberculosis, new anti-TB drug regimens, better diagnostic tests, international standards for second line drugs (SLD)-susceptibility testing, invention of newer anti-tubercular molecules and vaccines and knowing the real magnitude of XDR-TB are some of the important issues to be addressed for effective prevention and management of XDR-TB.
Gerald F Davies
Full Text Available Gerald F Davies1, Bernhard HJ Juurlink2, Troy AA Harkness11Department of Anatomy and Cell Biology, College of Medicine, University of Saskatchewan, Saskatoon, Canada; 2College of Medicine, Alfaisal University, Riyadh, Kingdom of Saudi ArabiaAbstract: A major problem in treating cancer is the development of drug resistance. We previously demonstrated doxorubicin (DOX resistance in K562 human leukemia cells that was associated with upregulation of glyoxalase 1 (GLO-1 and histone H3 expression. The thiazolidinedione troglitazone (TRG downregulated GLO-1 expression and further upregulated histone H3 expression and post-translational modifications in these cells, leading to a regained sensitivity to DOX. Given the pleiotropic effects of epigenetic changes in cancer development, we hypothesized that TRG may downregulate the multiple drug resistance (MDR phenotype in a variety of cancer cells. To test this, MCF7 human breast cancer cells and K562 cells were cultured in the presence of low-dose DOX to establish DOX-resistant cell lines (K562/DOX and MCF7/DOX. The MDR phenotype was confirmed by Western blot analysis of the 170 kDa P-glycoprotein (Pgp drug efflux pump multiple drug resistance protein 1 (MDR-1, and the breast cancer resistance protein (BCRP. TRG markedly decreased expression of both MDR-1 and BCRP in these cells, resulting in sensitivity to DOX. Silencing of MDR-1 expression also sensitized MCF7/DOX cells to DOX. Use of the specific and irreversible peroxisome proliferator-activated receptor gamma (PPARγ inhibitor GW9662 in the nanomolar range not only demonstrated that the action of TRG on MCF/DOX was PPARγ-independent, but indicated that PPARγ may play a role in the MDR phenotype, which is antagonized by TRG. We conclude that TRG is potentially a useful adjunct therapy in chemoresistant cancers. Keywords: chemotherapy, doxorubicin, breast cancer resistance protein-1, multiple drug resistance, multiple drug resistance protein 1
A K Singh
Full Text Available Background: The emergence of extensively drug-resistant tuberculosis (XDR-TB is a major concern in the India. The burden of XDR-TB is increasing due to inadequate monitoring, lack of proper diagnosis, and treatment. The GenoType ® Mycobacterium tuberculosis drug resistance second line (MTBDRsl assay is a novel line probe assay used for the rapid detection of mutational patterns conferring resistance to XDR-TB. Aim: The aim of this study was to study the rapid detection of drug resistance and mutational patterns of the XDR-TB by a novel GenoType ® MTBDRsl assay. Materials and Methods: We evaluated 98 multidrug-resistant (MDR M. tuberculosis isolates for second line drugs susceptibility testing by 1% proportion method (BacT/ALERT 3D system and GenoType ® MTBDRsl assay for rapid detection of conferring drug resistance to XDR-TB. Results: A total of seven (17.4% were identified as XDR-TB by using standard phenotypic method. The concordance between phenotypic and GenoType ® MTBDRsl assay was 91.7-100% for different antibiotics. The sensitivity and specificity of the MTBDRsl assay were 100% and 100% for aminoglycosides; 100% and 100% for fluoroquinolones; 91.7% and 100% for ethambutol. The most frequent mutations and patterns were gyrA MUT1 (A90V in seven (41.2% and gyrA + WT1-3 + MUT1 in four (23.5%; rrs MUT1 (A1401G in 11 (64.7%, and rrs WT1-2 + MUT1 in eight (47.1%; and embB MUT1B (M306V in 11 (64.7% strains. Conclusions: These data suggest that the GenoType ® MTBDRsl assay is rapid, novel test for detection of resistance to second line anti-tubercular drugs. This assay provides additional information about the frequency and mutational patterns responsible for XDR-TB resistance.
Umaer, Khan; Ciganda, Martin
Large ribosomal subunit protein L5 is responsible for the stability and trafficking of 5S rRNA to the site of eukaryotic ribosomal assembly. In Trypanosoma brucei, in addition to L5, trypanosome-specific proteins P34 and P37 also participate in this process. These two essential proteins form a novel preribosomal particle through interactions with both the ribosomal protein L5 and 5S rRNA. We have generated a procyclic L5 RNA interference cell line and found that L5 itself is a protein essential for trypanosome growth, despite the presence of other 5S rRNA binding proteins. Loss of L5 decreases the levels of all large-subunit rRNAs, 25/28S, 5.8S, and 5S rRNAs, but does not alter small-subunit 18S rRNA. Depletion of L5 specifically reduced the levels of the other large ribosomal proteins, L3 and L11, whereas the steady-state levels of the mRNA for these proteins were increased. L5-knockdown cells showed an increase in the 40S ribosomal subunit and a loss of the 60S ribosomal subunits, 80S monosomes, and polysomes. In addition, L5 was involved in the processing and maturation of precursor rRNAs. Analysis of polysomal fractions revealed that unprocessed rRNA intermediates accumulate in the ribosome when L5 is depleted. Although we previously found that the loss of P34 and P37 does not result in a change in the levels of L5, the loss of L5 resulted in an increase of P34 and P37 proteins, suggesting the presence of a compensatory feedback loop. This study demonstrates that ribosomal protein L5 has conserved functions, in addition to nonconserved trypanosome-specific features, which could be targeted for drug intervention. PMID:24706018
Full Text Available OBJECTIVE: Transmission patterns of drug-resistant Mycobacterium tuberculosis (MTB may be influenced by differences in socio-demographics, local tuberculosis (TB endemicity and efficaciousness of TB control programs. This study aimed to investigate the impact of DOTS on the transmission of drug-resistant TB in eastern rural China. METHODS: We conducted a cross-sectional study of all patients diagnosed with drug-resistant TB over a one-year period in two rural Chinese counties with varying lengths of DOTS implementation. Counties included Deqing, with over 11 years' DOTS implementation and Guanyun, where DOTS was introduced 1 year prior to start of this study. We combined demographic, clinical and epidemiologic information with IS6110-based restricted fragment length polymorphism (RFLP and Spoligotyping analysis of MTB isolates. In addition, we conducted DNA sequencing of resistance determining regions to first-line anti-tuberculosis agents. RESULTS: Of the 223 drug-resistant isolates, 73(32.7% isolates were identified with clustered IS6110RFLP patterns. The clustering proportion among total drug-resistant TB was higher in Guanyun than Deqing (26/101.vs.47/122; p,0.04, but not significantly different among the 53 multidrug-resistant isolates (10/18.vs.24/35; p,0.35. Patients with cavitary had increased risk of clustering in both counties. In Guanyun, patients with positive smear test or previous treatment history had a higher clustering proportion. Beijing genotype and isolates resistant to isoniazid and/or rifampicin were more likely to be clustered. Of the 73 patients with clustered drug-resistant isolates, 71.2% lived in the same or neighboring villages. Epidemiological link (household and social contact was confirmed in 12.3% of the clustered isolates. CONCLUSION: Transmission of drug-resistant TB in eastern rural China is characterized by small clusters and limited geographic spread. Our observations highlight the need for supplementing DOTS
Simen, Birgitte B; Braverman, Michael S; Abbate, Isabella; Aerssens, Jeroen; Bidet, Yannick; Bouchez, Olivier; Gabriel, Christian; Izopet, Jacques; Kessler, Harald H; Stelzl, Evelyn; Di Giallonardo, Francesca; Schlapbach, Ralph; Radonic, Aleksander; Paredes, Roger; Recordon-Pinson, Patricia; Sakwa, James; St John, Elizabeth P; Schmitz-Agheguian, Gudrun G; Metzner, Karin J; Däumer, Martin P
The detection of mutant spectra within the viral quasispecies is critical for therapeutic management of HIV-1 infections. Routine clinical application of ultrasensitive genotyping requires reproducibility and concordance within and between laboratories. The goal of the study was to evaluate a new protocol on HIV-1 drug resistance testing by 454 ultra-deep pyrosequencing (454-UDS) in an international multicenter study. Sixteen blinded HIV-1 subtype B samples were provided for 454-UDS as both RNA and cDNA with viral titers of 88,600-573,000 HIV-1 RNA copies/ml. Eight overlapping amplicons spanning protease (PR) codons 10-99 and reverse transcriptase (RT) codons 1-251 were generated using molecular barcoded primers. 454-UDS was performed using the 454 Life Sciences/Roche GS FLX platform. PR and RT sequences were analyzed using 454 Life Sciences Amplicon Variant Analyzer (AVA) software. Quantified variation data were analyzed for intra-laboratory reproducibility and inter-laboratory concordance. Routine population sequencing was performed using the ViroSeq HIV-1 genotyping system. Eleven laboratories and the reference laboratory 454 Life Sciences sequenced the HIV-1 sample set. Data presented are derived from seven laboratories and the reference laboratory since severe study protocol execution errors occurred in four laboratories leading to exclusion. The median sequencing depth across all sites was 1364 reads per position (IQR=809-2065). 100% of the ViroSeq-reported mutations were also detected by 454-UDS. Minority HIV-1 drug resistance mutations, defined as HIV-1 drug resistance mutations identified at frequencies of 1-25%, were only detected by 454-UDS. Analysis of 10 preselected majority and minority mutations were consistently found across sites. The analysis of drug-resistance mutations detected between 1 and 10% demonstrated high intra- and inter-laboratory consistency in frequency estimates for both RNA and prepared cDNA samples, indicating robustness of the
Gandolfi-Decristophoris, Paola; 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.
Lobo, Lis; de Sousa, Bruno; Cabral, Lília; Cristiano, Maria LS; Nogueira, Fátima
Ever increasing multi-drug resistance by Plasmodium falciparum is creating new challenges in malaria chemotherapy. In the absence of licensed vaccines, treatment and prevention of malaria is heavily dependent on drugs. Potency, range of activity, safety, low cost and ease of administration are crucial issues in the design and formulation of antimalarials. We have tested three synthetic ozonides NAC89, LC50 and LCD67 in vitro and in vivo against multidrug resistant Plasmodium. In vitro, LC50 was at least 10 times more efficient inhibiting P. falciparum multidrug resistant Dd2 strain than chloroquine and mefloquine and as efficient as artemisinin (ART), artesunate and dihydroartemisinin. All three ozonides showed high efficacy in clearing parasitaemia in mice, caused by multi-drug resistant Plasmodium chabaudi strains, by subcutaneous administration, demonstrating high efficacy in vivo against ART and artesunate resistant parasites. PMID:27276364
Yang, Wen-Chi; Lin, Sheng-Fung
Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients eventually relapse or become refractory to current treatments. Although the treatments have improved, the major problem in MM is resistance to therapy. Clonal evolution of MM cells and bone marrow microenvironment changes contribute to drug resistance. Some mechanisms affect both MM cells and microenvironment, including the up- and downregulation of microRNAs and programmed death factor 1 (PD-1)/PD-L1 interaction. Here, we review the pathogenesis of MM cells and bone marrow microenvironment and highlight possible drug resistance mechanisms. We also review a potential molecular targeting treatment and immunotherapy for patients with refractory or relapse MM. PMID:26649299
Full Text Available Ever increasing multi-drug resistance by Plasmodium falciparum is creating new challenges in malaria chemotherapy. In the absence of licensed vaccines, treatment and prevention of malaria is heavily dependent on drugs. Potency, range of activity, safety, low cost and ease of administration are crucial issues in the design and formulation of antimalarials. We have tested three synthetic ozonides NAC89, LC50 and LCD67 in vitro and in vivo against multidrug resistant Plasmodium. In vitro, LC50 was at least 10 times more efficient inhibiting P. falciparum multidrug resistant Dd2 strain than chloroquine and mefloquine and as efficient as artemisinin (ART, artesunate and dihydroartemisinin. All three ozonides showed high efficacy in clearing parasitaemia in mice, caused by multi-drug resistant Plasmodium chabaudi strains, by subcutaneous administration, demonstrating high efficacy in vivo against ART and artesunate resistant parasites.
Senbayrak, Seniha; Ozkutuk, Nuri; Erdem, Hakan
BACKGROUND: Tuberculous meningitis (TBM) caused by Mycobacterium tuberculosis resistant to antituberculosis drugs is an increasingly common clinical problem. This study aimed to evaluate drug resistance profiles of TBM isolates in adult patients in nine European countries involving 32 centers...... to provide insight into the empiric treatment of TBM. METHODS: Mycobacterium tuberculosis was cultured from the cerebrospinal fluid (CSF) of 142 patients and was tested for susceptibility to first-line antituberculosis drugs, streptomycin (SM), isoniazid (INH), rifampicin (RIF) and ethambutol (EMB). RESULTS...
Abstract: Chlamydia Trachomatis (C.T.) is one of the most common pathogens of human sexually transmitted diseases. Treatment of C.T. infection primarily depends on Tetracyclines, Macrolides and Quinolones, but with the wide use of antibiotics an increasing number of drug-resistant Chlamydia trachomatis cases have been reported. This review summarizes the resistant conditions and the possible resistance mechanisms of C.T..
Background and Purpose: Clinical prediction rules (CPR) are clinical decision-making tools containing variables such as history, physical examination, diagnostic tests by developing scoring model from potential risk factors. This study is to establish clinical prediction scoring of drug-resistant epilepsy (DRE) in children using clinical manifestationa and only basic electroencephalography (EEG). Methods: Retrospective cohort study was conducted. A total of 308 children with diagnosed epileps...
A Sobhani; H. Shodjai S. Javanbakht
Bacteremia is an important infectious disease which may lead to death. Common bacteria and pattern of antibiotic resistance in different communities are different and understanding these differences is important. In the present study, relative frequency and pattern of drug resistance have been examined in bacteria isolated from blood cultures in Razi Hospital laboratory. The method of the study was descriptive. Data collection was carried out retrospectively. Total sample consisted of 311 pos...
heterologous expressions system in yeast for potential drug target enzymes. The yeast expression system should allow rapid screening of new drugs , greatly...medication yet the world faces a crisis-drug resistance is emerging and spreading faster than drugs are being developed and the flow in the pipeline of new ... drugs has all but stopped. This represents a particular threat to the US Military. In a short time there may be parts of the world where no effective
Full Text Available A total of 610 strains of Shigellae isolated from cases of diarrhea in Iran during 1962-73 were studied with respect to their phage type, as well as antibiotic resistance and transferable drug resistance along with serotyping. It was shown that there was some relation between serotypes and phage types but no association could be found between phage types and resistance pattern.
Smita U Shevade, Gopal N Agrawal
Background: Urinary tract infections (UTI) are amongst the most common infectionsencountered in clinical practice. Drug resistant uropatho-genshas been increasingly observed, not only in nosocomial UTI but also in community-acquired (CA) UTI leaving very few options for the treatment. CA and nosocomial UTI differ aetiologically, epidemiologically; they also have different antibiotic resistance pattern. Therefore, we planned to study the bacterial aetiology and antibiotic susceptibility of uro...
Abubakar, I; Zignol, M; Falzon, D; Raviglione, M.; Ditiu, L; Masham, S; Adetifa, I; Ford, N.; Cox, H.; Lawn, SD; Marais, BJ; McHugh, TD; Mwaba, P.; Bates, M; M. Lipman
Two decades ago, WHO declared tuberculosis a global emergency, and invested in the highly cost-effective directly observed treatment short-course programme to control the epidemic. At that time, most strains of Mycobacterium tuberculosis were susceptible to first-line tuberculosis drugs, and drug resistance was not a major issue. However, in 2013, tuberculosis remains a major public health concern worldwide, with prevalence of multidrug-resistant (MDR) tuberculosis rising. WHO estimates rough...
Theodor H. Lippert, Hans-Jörg Ruoff, Manfred Volm
Full Text Available Drug resistance is the main cause of the failure of chemotherapy of malignant tumors, resistance being either preexisting (intrinsic resistance or induced by the drugs (acquired resistance. At present, resistance is usually diagnosed during treatment after a long period of drug administration.In the present paper, methods for a rapid assessment of drug resistance are described. Three main classes of test procedures can be found in the literature, i.e. fresh tumor cell culture tests, cancer biomarker tests and positron emission tomography (PET tests. The methods are based on the evaluation of molecular processes, i.e. metabolic activities of cancer cells. Drug resistance can be diagnosed before treatment in-vitro with fresh tumor cell culture tests, and after a short time of treatment in-vivo with PET tests. Cancer biomarker tests, for which great potential has been predicted, are largely still in the development stage. Individual resistance surveillance with tests delivering rapid results signifies progress in cancer therapy management, by providing the possibility to avoid drug therapies that are ineffective and only harmful.
Haque, Ubydul; Glass, Gregory E; Haque, Waziul; Islam, Nazrul; Roy, Shyamal; Karim, Jahirul; Noedl, Harald
Malaria remains an important health problem in Bangladesh, with approximately 14 million people at risk. Antimalarial drug resistance is a major obstacle to the control of malaria in endemic countries. In 2012, Bangladesh reported an estimated 29 522 malaria episodes, of which 94% were reported as being caused by Plasmodium falciparum. In this study, we reviewed and summarized antimalarial drug resistance data from Bangladesh published until June 2013. We searched published sources for data referring to any type of P. falciparum drug resistance (in vivo, in vitro, or molecular) and found 169 articles published in peer-reviewed journals. Of these, 143 articles were excluded because they did not meet our inclusion criteria. After detailed review of the remaining 26 articles, 14 were selected for evaluation. Published studies indicate that P. falciparum shows varying levels of resistance to chloroquine, mefloquine and sulfadoxine-pyrimethamine. Combination therapy of chloroquine and primaquine has proven ineffective and combinations of sulfadoxine-pyrimethamine with either quinine or chloroquine have also shown poor efficacy. Recent studies indicate that artemisinin derivatives, such as artesunate, remain highly efficacious in treating P. falciparum malaria. Available data suggest that artemisinins, quinine, doxycyline, mefloquine-artesunate and azithromycin-artesunate combination therapy remain efficacious in the treatment of P. falciparum malaria in Bangladesh.
Full Text Available Autoimmune diseases such as systemic lupus erythematosus (SLE, rheumatoid arthritis (RA and psoriatic arthritis (PsA are chronic inflammatory disorders of unknown etiology characterized by a wide range of abnormalities of the immune system that may compromise the function of several organs, such as kidney, heart, joints, brain and skin. Corticosteroids (CCS, synthetic and biologic immunosuppressive agents have demonstrated the capacity to improve the course of autoimmune diseases. However, a significant number of patients do not respond or develop resistance to these therapies over time. P-glycoprotein (P-gp is a transmembrane protein that pumps several drugs out of the cell, including CCS and immunosuppressants; thus, its over-expression or hyper-function has been proposed as a possible mechanism of drug resistance in patients with autoimmune disorders. Recently, different authors have demonstrated that P-gp inhibitors, such as cyclosporine A (CsA and its analogue Tacrolimus, are able to reduce P-gp expression and or function in SLE, RA and PsA patients. These observations suggest that P-gp antagonists could be adopted to revert drug resistance and improve disease outcome. The complex inter-relationship among drug resistance, P-gp expression and autoimmunity still remains elusive.
Full Text Available Roxana Rustomjee,1 Alimuddin Zumla2,31South African Medical Research Council, Cape Town, South Africa; 2Division of Infection and Immunity, University College London, London, UK; 3NIHR Biomedical Research Centre, University College Hospitals NHS Foundation Trust, London, UKAbstract: Tuberculosis (TB remains a global emergency and is one of the most common infectious disease causes of death in developing countries. Current treatment regimens for multi-drug resistant TB are associated with low treatment success rates, are toxic, and require long duration of treatment. The need for shorter and more effective treatment regimens is urgent. Delamanid (Deltyba, or formerly known as OPC-67683 is a new dihydro-imidazooxazole anti-TB drug active against resistant forms of pulmonary TB. Delamanid kills Mycobacterium tuberculosis by inhibiting the synthesis of mycolic acids required for cell wall synthesis. Whilst delamanid has been included in the WHO Model List of Essential Medicine by the World Health Organization Expert Committee on Selection and Use of Essential Medicines and in international guidance for the treatment of multi-drug resistant TB since April 2014, its access in countries with the greatest need, has proven challenging. This review provides an update on currently available clinical safety and efficacy data on delamanid and offers a discussion on research priorities and recommendations for expedited, expanded access.Keywords: delamanid, tuberculosis, drug resistance, MDR-TB, expanded access
Gudepalya Renukaiah Rudramurthy
Full Text Available Antimicrobial substances may be synthetic, semisynthetic, or of natural origin (i.e., from plants and animals. Antimicrobials are considered “miracle drugs” and can determine if an infected patient/animal recovers or dies. However, the misuse of antimicrobials has led to the development of multi-drug-resistant bacteria, which is one of the greatest challenges for healthcare practitioners and is a significant global threat. The major concern with the development of antimicrobial resistance is the spread of resistant organisms. The replacement of conventional antimicrobials by new technology to counteract antimicrobial resistance is ongoing. Nanotechnology-driven innovations provide hope for patients and practitioners in overcoming the problem of drug resistance. Nanomaterials have tremendous potential in both the medical and veterinary fields. Several nanostructures comprising metallic particles have been developed to counteract microbial pathogens. The effectiveness of nanoparticles (NPs depends on the interaction between the microorganism and the NPs. The development of effective nanomaterials requires in-depth knowledge of the physicochemical properties of NPs and the biological aspects of microorganisms. However, the risks associated with using NPs in healthcare need to be addressed. The present review highlights the antimicrobial effects of various nanomaterials and their potential advantages, drawbacks, or side effects. In addition, this comprehensive information may be useful in the discovery of broad-spectrum antimicrobial drugs for use against multi-drug-resistant microbial pathogens in the near future.
Full Text Available The evolution of substitutions conferring drug resistance to HIV-1 is both episodic, occurring when patients are on antiretroviral therapy, and strongly directional, with site-specific resistant residues increasing in frequency over time. While methods exist to detect episodic diversifying selection and continuous directional selection, no evolutionary model combining these two properties has been proposed. We present two models of episodic directional selection (MEDS and EDEPS which allow the a priori specification of lineages expected to have undergone directional selection. The models infer the sites and target residues that were likely subject to directional selection, using either codon or protein sequences. Compared to its null model of episodic diversifying selection, MEDS provides a superior fit to most sites known to be involved in drug resistance, and neither one test for episodic diversifying selection nor another for constant directional selection are able to detect as many true positives as MEDS and EDEPS while maintaining acceptable levels of false positives. This suggests that episodic directional selection is a better description of the process driving the evolution of drug resistance.
Abubakar, Ibrahim; Zignol, Matteo; Falzon, Dennis; Raviglione, Mario; Ditiu, Lucica; Masham, Susan; Adetifa, Ifedayo; Ford, Nathan; Cox, Helen; Lawn, Stephen D; Marais, Ben J; McHugh, Timothy D; Mwaba, Peter; Bates, Matthew; Lipman, Marc; Zijenah, Lynn; Logan, Simon; McNerney, Ruth; Zumla, Adam; Sarda, Krishna; Nahid, Payam; Hoelscher, Michael; Pletschette, Michel; Memish, Ziad A; Kim, Peter; Hafner, Richard; Cole, Stewart; Migliori, Giovanni Battista; Maeurer, Markus; Schito, Marco; Zumla, Alimuddin
Two decades ago, WHO declared tuberculosis a global emergency, and invested in the highly cost-effective directly observed treatment short-course programme to control the epidemic. At that time, most strains of Mycobacterium tuberculosis were susceptible to first-line tuberculosis drugs, and drug resistance was not a major issue. However, in 2013, tuberculosis remains a major public health concern worldwide, with prevalence of multidrug-resistant (MDR) tuberculosis rising. WHO estimates roughly 630 000 cases of MDR tuberculosis worldwide, with great variation in the frequency of MDR tuberculosis between countries. In the past 8 years, extensively drug-resistant (XDR) tuberculosis has emerged, and has been reported in 84 countries, heralding the possibility of virtually untreatable tuberculosis. Increased population movement, the continuing HIV pandemic, and the rise in MDR tuberculosis pose formidable challenges to the global control of tuberculosis. We provide an overview of the global burden of drug-resistant disease; discuss the social, health service, management, and control issues that fuel and sustain the epidemic; and suggest specific recommendations for important next steps. Visionary political leadership is needed to curb the rise of MDR and XDR tuberculosis worldwide, through sustained funding and the implementation of global and regional action plans.
Glover, Lucy; Jun, Junho; Horn, David
Antigenic variation in African trypanosomes is induced by DNA double-strand breaks (DSBs). In these protozoan parasites, DSB repair (DSBR) is dominated by homologous recombination (HR) and microhomology-mediated end joining (MMEJ), while non-homologous end joining (NHEJ) has not been reported. To facilitate the analysis of chromosomal end-joining, we established a system whereby inter-allelic repair by HR is lethal due to loss of an essential gene. Analysis of intrachromosomal end joining in individual DSBR survivors exclusively revealed MMEJ-based deletions but no NHEJ. A survey of microhomologies typically revealed sequences of between 5 and 20 bp in length with several mismatches tolerated in longer stretches. Mean deletions were of 54 bp on the side closest to the break and 284 bp in total. Break proximity, microhomology length and GC-content all favored repair and the pattern of MMEJ described above was similar at several different loci across the genome. We also identified interchromosomal gene conversion involving HR and MMEJ at different ends of a duplicated sequence. While MMEJ-based deletions were RAD51-independent, one-sided MMEJ was RAD51 dependent. Thus, we describe the features of MMEJ in Trypanosoma brucei, which is analogous to micro single-strand annealing; and RAD51 dependent, one-sided MMEJ. We discuss the contribution of MMEJ pathways to genome evolution, subtelomere recombination and antigenic variation.
Fred, D; Desai, M; Song, R; Bamrah, S; Pavlin, B I; Heetderks, A; Ekiek, M J
Multi-drug resistant tuberculosis (MDR TB) is a growing public health concern, particularly for the Pacific, where rates of tuberculosis infection are extremely high. In May 2008, a cluster of patients with MDR TB were identified in Chuuk State, Federated States of Micronesia. A multi-agency investigation led to the eventual discovery of 21 cases, and over 100 latent TB infections. Incomplete implementation of Directly Observed Therapy (DOT) and contact investigation were major contributors to the outbreak. The problem of MDR TB in Chuuk was controlled only after a concerted effort on the part of multiple agencies coupled with the highest level of political commitment.
Dzangare, J; Gonese, E; Mugurungi, O; Shamu, T; Apollo, T; Bennett, D E; Kelley, K F; Jordan, M R; Chakanyuka, C; Cham, F; Banda, R M
Monitoring human immunodeficiency virus drug resistance (HIVDR) early warning indicators (EWIs) can help national antiretroviral treatment (ART) programs to identify clinic factors associated with HIVDR emergence and provide evidence to support national program and clinic-level adjustments, if necessary. World Health Organization-recommended HIVDR EWIs were monitored in Zimbabwe using routinely available data at selected ART clinics between 2007 and 2009. As Zimbabwe's national ART coverage increases, improved ART information systems are required to strengthen routine national ART monitoring and evaluation and facilitate scale-up of HIVDR EWI monitoring. Attention should be paid to minimizing loss to follow-up, supporting adherence, and ensuring clinic-level drug supply continuity.
Liu, Zhigang [Wayne State Univ., Detroit, MI (United States); Harbor Hospital Baltimore, MD (United States); Yedidi, Ravikiran S. [Wayne State Univ., Detroit, MI (United States); National Inst. of Health (NIH), Bethesda, MD (United States); Wang, Yong [Wayne State Univ., Detroit, MI (United States); Dewdney, Tamaria G. [Wayne State Univ., Detroit, MI (United States); Reiter, Samuel J. [Wayne State Univ., Detroit, MI (United States); Brunzelle, Joseph S. [Northwestern Univ., Chicago, IL (United States); Kovari, Iulia A. [Wayne State Univ., Detroit, MI (United States); Kovari, Ladislau C. [Wayne State Univ., Detroit, MI (United States)
Ritonavir (RTV) is a first generation HIV-1 protease inhibitor with rapidly emerging drug resistance. Mutations at residues 46, 54, 82 and 84 render the HIV-1 protease drug resistant against RTV. We report the crystal structure of multi-drug resistant (MDR) 769 HIV-1 protease (carrying resistant mutations at residues 10, 36, 46, 54, 62, 63, 71, 82, 84 and 90) complexed with RTV and the in vitro enzymatic IC50 of RTV against MDR HIV-1 protease. The structural and functional studies demonstrate significant drug resistance of MDR HIV-1 protease against RTV, arising from reduced hydrogen bonds and Van der Waals interactions between RTV and MDR HIV-1 protease.
Goncharov, I; Palfi, Z; Bindereif, A; Michaeli, S
Trans-splicing in trypanosomes involves the addition of a common spliced leader (SL) sequence, which is derived from a small RNA, the SL RNA, to all mRNA precursors. The SL RNA is present in the cell in the form of a ribonucleoprotein, the SL RNP. Using conventional chromatography and affinity selection with 2'-O-methylated RNA oligonucleotides at high ionic strength, five proteins of 70, 16, 13, 12, and 8 kDa were co-selected with the SL RNA from Leptomonas collosoma, representing the SL RNP core particle. Under conditions of lower ionic strength, additional proteins of 28 and 20 kDa were revealed. On the basis of peptide sequences, the gene coding for a protein with a predicted molecular weight of 11.9 kDa was cloned and identified as homologue of the cis-spliceosomal SmE. The protein carries the Sm motifs 1 and 2 characteristic of Sm antigens that bind to all known cis-spliceosomal uridylic acid-rich small nuclear RNAs (U snRNAs), suggesting the existence of Sm proteins in trypanosomes. This finding is of special interest because trypanosome snRNPs are the only snRNPs examined to date that are not recognized by anti-Sm antibodies. Because of the early divergence of trypanosomes from the eukaryotic lineage, the trypanosome SmE protein represents one of the primordial Sm proteins in nature.
Conclusion: Our data show an nsSNP in the drrA efflux pump gene that may result in upregulation of drug efflux mechanisms in MTB strains. It is therefore imperative to understand the mechanism of efflux and its role in drug resistance, which will enable the identification of new drug targets and development of new drug regimens to counteract the drug efflux mechanism of MTB.
Tian, Nan; Han, Ziwu; Li, Zhaohui; Zhou, Mingjie; Fan, Chunlei
Hepatocellular carcinoma (HCC) is highly resistant to chemotherapeutic drugs, which markedly reduces the effect of chemotherapy. Lin28 has been shown to contribute to tumor relapse after chemotherapy; however, the relationship between Lin28 and chemotherapy drug resistance is unknown. In the present study, we established a drug-resistant Hep3B cell line to investigate the association between Lin28 and drug resistance in HCC, and we identified the underlying mechanisms. We found that the expression of Lin28 was closely associated with resistance to paclitaxel. The drug‑resistant Hep3B cell line, which expresses high levels of Lin28, is more resistant to paclitaxel and other anticancer drugs than the parental cell line. Moreover, further studies showed that dysregulation of Lin28 inhibited let-7 family microRNA levels and upregulated the anti-apoptotic protein Bcl-xL, which is a target of let-7. Our results indicate that the Lin28/let-7/Bcl-xL pathway underlies the drug resistance of Hep3B cells.
DeGoey, David A.; Grampovnik, David J.; Chen, Hui-Ju; Flosi, William J.; Klein, Larry L.; Dekhtyar, Tatyana; Stoll, Vincent; Mamo, Mulugeta; Molla, Akhteruzzaman; Kempf, Dale J. (Abbott)
Because there is currently no cure for HIV infection, patients must remain on long-term drug therapy, leading to concerns over potential drug side effects and the emergence of drug resistance. For this reason, new and safe antiretroviral agents with improved potency against drug-resistant strains of HIV are needed. A series of HIV protease inhibitors (PIs) with potent activity against both wild-type (WT) virus and drug-resistant strains of HIV was designed and synthesized. The incorporation of substituents with hydrogen bond donor and acceptor groups at the P1 position of our symmetry-based inhibitor series resulted in significant potency improvements against the resistant mutants. By this approach, several compounds, such as 13, 24, and 29, were identified that demonstrated similar or improved potencies compared to 1 against highly mutated strains of HIV derived from patients who previously failed HIV PI therapy. Overall, compound 13 demonstrated the best balance of potency against drug resistant strains of HIV and oral bioavailability in pharmacokinetic studies. X-ray analysis of an HIV PI with an improved resistance profile bound to WT HIV protease is also reported.
McCrackin, M A; Helke, Kristi L; Galloway, Ashley M; Poole, Ann Z; Salgado, Cassandra D; Marriott, Bernadette P
Controversy continues concerning antimicrobial use in food animals and its relationship to drug-resistant infections in humans. We systematically reviewed published literature for evidence of a relationship between antimicrobial use in agricultural animals and drug-resistant foodborne campylobacteriosis in humans. Based on publications from the United States (U.S.), Canada and Denmark from 2010 to July 2014, 195 articles were retained for abstract review, 50 met study criteria for full article review with 36 retained for which data are presented. Two publications reported increase in macrolide resistance of Campylobacter coli isolated from feces of swine receiving macrolides in feed, and one of these described similar findings for tetracyclines and fluoroquinolones. A study in growing turkeys demonstrated increased macrolide resistance associated with therapeutic dosing with Tylan® in drinking water. One publication linked tetracycline-resistant C. jejuni clone SA in raw cow's milk to a foodborne outbreak in humans. No studies that identified farm antimicrobial use also traced antimicrobial-resistant Campylobacter from farm to fork. Recent literature confirms that on farm antibiotic selection pressure can increase colonization of animals with drug-resistant Campylobacter spp. but is inadequately detailed to establish a causal relationship between use of antimicrobials in agricultural animals and prevalence of drug-resistant foodborne campylobacteriosis in humans.
Grandjean, Louis; Moore, David A J
Globally tuberculosis is mainly diagnosed by sputum smear microscopy, which fails to detect half of all cases and fails to identify drug resistance. Inadequate global tuberculosis control through the directly observed therapy short course strategy alone and the growing threat of multidrug-resistant and extensively drug-resistant tuberculosis has driven recent development of new commercial and noncommercial tests, which are most desperately needed in resource-limited, high-burden settings. This review outlines the range of options currently available, highlighting particularly those recent developments with greatest potential for addressing the growing multidrug-resistant and extensively drug-resistant disaster as it affects those communities least technically and financially capable of controlling it. Simplification of molecular-diagnostic techniques, rapid-liquid culture and the use of colorimetric indicators have improved the sensitivity, speed and reliability of tuberculosis and multidrug-resistant tuberculosis detection, while decreasing cost and bringing diagnosis closer towards (though still some way from) the point-of-care. Global tuberculosis control in 2008 demands the use of new tools for more sensitive and rapid detection of active disease and of drug resistance. Improved technologies are available for reference laboratories but for settings where resources and technical capacity are limited there is little ready for field implementation. The pipeline is promising, but in the interim wider use of liquid culture and manual or colorimetric drug susceptibility testing should be promoted.
Song, Chengli; Wang, Lina; Xu, Qiang; Wang, Kai; Xie, Dan; Yu, Zhe; Jiang, Kui; Liao, Lujian; Yates, John R.; Lee, Jiing-Dwan; Yang, Qingkai
Combined inhibition of BRAF and MEK1/2 (CIBM) improves therapeutic efficacy of BRAF-mutant melanoma. However, drug resistance to CIBM is inevitable and the drug resistance mechanisms still remain to be elucidated. Here, we show that BMK1 pathway contributes to the drug resistance to CIBM. Considering that ERK1/2 pathway regulates cellular processes by phosphorylating, we first performed a SILAC phosphoproteomic profiling of CIBM. Phosphorylation of 239 proteins was identified to be downregulated, while phosphorylation of 47 proteins was upregulated. Following siRNA screening of 47 upregulated proteins indicated that the knockdown of BMK1 showed the most significant ability to inhibit the proliferation of CIBM resistant cells. It was found that phosphorylation of BMK1 was enhanced in resistant cells, which suggested an association of BMK1 with drug resistance. Further study indicated that phospho-activation of BMK1 by MEK5D enhanced the resistance to CIBM. Conversely, inhibition of BMK1 by shRNAi or BMK1 inhibitor (XMD8-92) impaired not only the acquirement of resistance to CIBM, but also the proliferation of CIBM resistant cells. Further kinome-scale siRNA screening demonstrated that SRC\\MEK5 cascade promotes the phospho-activation of BMK1 in response to CIBM. Our study not only provides a global phosphoproteomic view of CIBM in melanoma, but also demonstrates that inhibition of BMK1 has therapeutic potential for the treatment of melanoma. PMID:28387310
Seneviratne, Chaminda J; Suriyanarayanan, Tanujaa; Swarup, Sanjay; Chia, Kuan Hui Burton; Nagarajan, Niranjan; Zhang, Chengfei
Enterococcus faecalis is a gram-positive bacterium associated with endodontic infections and is capable of forming biofilms that can confer drug resistance to the bacterium, resulting in treatment failure. Current knowledge on E. faecalis drug resistance is of a limited and conflicting nature. The present study examined the genetic basis of E. faecalis biofilm formation and drug resistance using a RNA sequencing (RNA-Seq)-based transcriptome approach. Eighteen clinical isolates of E. faecalis were screened for their biofilm formation abilities using the crystal violet assay, colony counting, and confocal imaging. Selected isolates were then evaluated for antibiotic susceptibility in planktonic and biofilm growth modes followed by RNA-Seq analysis of E. faecalis planktonic, biofilm, and vancomycin-treated biofilm samples and Kyoto Encyclopedia of Genes and Genomes mapping in order to identify genes associated with biofilm formation and drug resistance of E. faecalis. All 18 clinical isolates retained biofilm formation ability and were classified as strong, weak, or laboratory American Type Culture Collection strainlike biofilm formers. Interestingly, both the strong and weak biofilm-forming isolates were uniformly resistant to ampicillin and vancomycin at the treated concentrations (256-4096 μg/mL). RNA-Seq analysis of these isolates identified a total of 163 and 101 differentially regulated genes in planktonic versus biofilm and vancomycin-treated biofilm versus biofilm comparisons, respectively, with significant differences in arsenic resistance operon genes arsR and arsD, sporulation regulatory gene paiA, ABC drug transporter classes, and penicillin-binding proteins. The present transcriptomic study revealed putative genes associated with E. faecalis biofilm formation and drug resistance, which will provide a foundation for improved therapeutic strategies against E. faecalis infections in the future. Copyright © 2017 American Association of Endodontists
Full Text Available Objective: To determine resistance patterns of Staphylococcus aureus (S. aureus isolated from different areas of Pakistan and to identify antimicrobial agents against multi-drug resistant S. aureus strains. Methods: A total of 67 samples (sewerage, nasal and milk were collected from different farm areas of Pakistan to identify local strains of S. aureus. Sixteen out of 67 samples were positive for S. aureus. Only 6 out of 16 S. aureus strains showed resistance to antibiotics. Then the antibacterial effect of 29 medicinal plants was evaluated on these S. aureus isolates and a standard S. aureus strain ATCC 25923. The solvents used for the extraction of plants were acetone, dimethyl sulfoxide and methanol. The in vitro antibacterial activity was performed using agar disc diffusion method. Moreover, minimum inhibitory concentration of effective medicinal plant extracts was identified through micro-dilution method to find out their 50% inhibitory concentration. Results: Plant extracts of 5 medicinal plants (Psidium guajava, Nigella sativa, Piper nigrum, Valeriana jatamansi, and Cucurbita pepo exhibited antibacterial activity against locally isolated multidrug resistant strains of S. aureus. The minimum inhibitory concentration of these extracts was ranged from 0.328 to 5.000 mg/mL. Conclusions: Plant extracts of Psidium guajava, Piper nigrum seed, Valeriana jatamansi, Cucurbita pepo and Nigella sativa showed significant in vitro antibacterial activity and thus, such findings may serve as valuable contribution in the treatment of infection and may contribute to the development of potential antimicrobial agents against multi drug resistant strains of S. aureus
Rahat Ejaz; Usman A Ashfaq; Sobia Idrees
Objective: To determine resistance patterns of Staphylococcus aureus (S. aureus) isolated from different areas of Pakistan and to identify antimicrobial agents against multi-drug resistant S.aureus strains. Methods: A total of 67 samples (sewerage, nasal and milk) were collected from different farm areas of Pakistan to identify local strains of S. aureus. Sixteen out of 67 samples were positive for S.aureus. Only 6 out of 16 S. aureus strains showed resistance to antibiotics. Then the antibacterial effect of 29 medicinal plants was evaluated on these S. aureus isolates and a standard S. aureus strain ATCC 25923. The solvents used for the extraction of plants were acetone, dimethyl sulfoxide and methanol. The in vitro antibacterial activity was performed using agar disc diffusion method. Moreover, minimum inhibitory concentration of effective medicinal plant extracts was identified through micro-dilution method to find out their 50% inhibitory concentration.Results:Plant extracts of 5 medicinal plants (Psidium guajava, Nigella sativa, Piper nigrum, Valeriana jatamansi, and Cucurbita pepo) exhibited antibacterial activity against locally isolated multidrug resistant strains of S. aureus. The minimum inhibitory concentration of these extracts was ranged from 0.328 to 5.000 mg/mL. Conclusions: Plant extracts of Psidium guajava, Piper nigrum seed, Valeriana jatamansi, Cucurbita pepo and Nigella sativa showed significant in vitro antibacterial activity and thus, such findings may serve as valuable contribution in the treatment of infection and may contribute to the development of potential antimicrobial agents against multi drug resistant strains of S. aureus.
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.
Ramaratnam, Sridharan; Panebianco, Mariangela; Marson, Anthony G
This is an updated version of the Cochrane review published in The Cochrane Library 2010, Issue 1.Epilepsy is a common neurological disorder, affecting almost 0.5% to 1% of the population. For nearly 30% of these people, their epilepsy is refractory to currently available drugs. Pharmacological treatment remains the first choice to control epilepsy. Lamotrigine is one of the newer antiepileptic drugs and is the topic of this review. Lamotrigine in combination with other antiepileptic drugs (add-on) can reduce seizures, but with some adverse effects. The aim of this systematic review was to overview the current evidence for the efficacy and tolerability of lamotrigine when used as an adjunctive treatment for people with refractory partial epilepsy. To determine the effects of lamotrigine on (1) seizures, (2) adverse effect profile, and (3) cognition and quality of life, compared to placebo controls, when used as an add-on treatment for people with refractory partial epilepsy. For the previous version of the review, the authors searched the Cochrane Epilepsy Group Specialized Register (January 2010), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2010, Issue 1), MEDLINE (1950 to January 2010), and reference lists of articles.For this update, we searched the Cochrane Epilepsy Group Specialized Register (28 May 2015), CENTRAL (The Cochrane Library 2015, Issue 4), MEDLINE (Ovid, 1946 to May 2015), and reference lists of articles. We also contacted the manufacturers of lamotrigine (GlaxoSmithKline). No language restrictions were imposed. Randomised placebo-controlled trials of people with drug-resistant partial epilepsy of any age, in which an adequate method of concealment of randomisation was used. The studies were double-, single- or unblinded. For cross-over studies, the first treatment period was treated as a parallel trial. Eligible participants were adults or children with drug-resistant partial epilepsy. For this update, two
Baker, Nicola; de Koning, Harry P; Mäser, Pascal; Horn, David
Melarsoprol and pentamidine represent the two main classes of drugs, the arsenicals and diamidines, historically used to treat the diseases caused by African trypanosomes: sleeping sickness in humans and Nagana in livestock. Cross-resistance to these drugs was first observed over 60 years ago and remains the only example of cross-resistance among sleeping sickness therapies. A Trypanosoma brucei adenosine transporter is well known for its role in the uptake of both drugs. More recently, aquaglyceroporin 2 (AQP2) loss of function was linked to melarsoprol-pentamidine cross-resistance. AQP2, a channel that appears to facilitate drug accumulation, may also be linked to clinical cases of resistance. Here, we review these findings and consider some new questions as well as future prospects for tackling the devastating diseases caused by these parasites.
Full Text Available Abstract Background Emergence of multi-drug resistant (MDR serotype 19A Streptococcus pneumoniae (SPN is well-documented but causal factors remain unclear. Canadian SPN isolates (1993-2008, n = 11,083 were serotyped and in vitro susceptibility tested. A subset of MDR 19A were multi-locus sequence typed (MLST and representative isolates' whole genomes sequenced. Results MDR 19A increased in the post-PCV7 era while 19F, 6B, and 23F concurrently declined. MLST of MDR 19A (n = 97 revealed that sequence type (ST 320 predominated. ST320 was unique amongst MDR 19A in that its minimum inhibitory concentration (MIC values for penicillin, amoxicillin, ceftriaxone, and erythromycin were higher than for other ST present amongst post-PCV7 MDR 19A. DNA sequencing revealed that alleles at key drug resistance loci pbp2a, pbp2x, pbp2b, ermB, mefA/E, and tetM were conserved between pre-PCV7 ST 320 19F and post-PCV7 ST 320 19A most likely due to a capsule switch recombination event. A genome wide comparison of MDR 19A ST320 with MDR 19F ST320 identified 822 unique SNPs in 19A, 61 of which were present in antimicrobial resistance genes and 100 in virulence factors. Conclusions Our results suggest a complex genetic picture where high-level drug resistance, vaccine selection pressure, and SPN mutational events have created a "perfect storm" for the emergence of MDR 19A.
Turkington, R C; Longley, D B; Allen, W L; Stevenson, L; McLaughlin, K; Dunne, P D; Blayney, J K; Salto-Tellez, M; Van Schaeybroeck, S; Johnston, P G
The discovery of underlying mechanisms of drug resistance, and the development of novel agents to target these pathways, is a priority for patients with advanced colorectal cancer (CRC). We previously undertook a systems biology approach to design a functional genomic screen and identified fibroblast growth factor receptor 4 (FGFR4) as a potential mediator of drug resistance. The aim of this study was to examine the role of FGFR4 in drug resistance using RNAi and the small-molecule inhibitor BGJ398 (Novartis). We found that FGFR4 is highly expressed at the RNA and protein levels in colon cancer tumour tissue compared with normal colonic mucosa and other tumours. Silencing of FGFR4 reduced cell viability in a panel of colon cancer cell lines and increased caspase-dependent apoptosis. A synergistic interaction was also observed between FGFR4 silencing and 5-fluorouracil (5-FU) and oxaliplatin chemotherapy in colon cancer cell lines. Mechanistically, FGFR4 silencing decreased activity of the pro-survival STAT3 transcription factor and expression of the anti-apoptotic protein c-FLIP. Furthermore, silencing of STAT3 resulted in downregulation of c-FLIP protein expression, suggesting that FGFR4 may regulate c-FLIP expression via STAT3. A similar phenotype and downstream pathway changes were observed following FGFR4 silencing in cell lines resistant to 5-FU, oxaliplatin and SN38 and upon exposure of parental cells to the FGFR small-molecule inhibitor BGJ398. Our results indicate that FGFR4 is a targetable regulator of chemo-resistance in CRC, and hence inhibiting FGFR4 in combination with 5-FU and oxaliplatin is a potential therapeutic strategy for this disease.
Louis, John M; Tözsér, József; Roche, Julien; Matúz, Krisztina; Aniana, Annie; Sayer, Jane M
During treatment, mutations in HIV-1 protease (PR) are selected rapidly that confer resistance by decreasing affinity to clinical protease inhibitors (PIs). As these unique drug resistance mutations can compromise the fitness of the virus to replicate, mutations that restore conformational stability and activity while retaining drug resistance are selected on further evolution. Here we identify several compensating mechanisms by which an extreme drug-resistant mutant bearing 20 mutations (PR20) with >5-fold increased Kd and >4000-fold decreased affinity to the PI darunavir functions. (1) PR20 cleaves, albeit poorly, Gag polyprotein substrates essential for viral maturation. (2) PR20 dimer, which exhibits distinctly enhanced thermal stability, has highly attenuated autoproteolysis, thus likely prolonging its lifetime in vivo. (3) The enhanced stability of PR20 results from stabilization of the monomer fold. Both monomeric PR20(T26A) and dimeric PR20 exhibit Tm values 6-7.5 °C higher than those for their PR counterparts. Two specific mutations in PR20, L33F and L63P at sites of autoproteolysis, increase the Tm of monomeric PR(T26A) by ~8 °C, similar to PR20(T26A). However, without other compensatory mutations as seen in PR20, L33F and L63P substitutions, together, neither restrict autoproteolysis nor significantly reduce binding affinity to darunavir. To determine whether dimer stability contributes to binding affinity for inhibitors, we examined single-chain dimers of PR and PR(D25N) in which the corresponding identical monomer units were covalently linked by GGSSG sequence. Linking of the subunits did not appreciably change the ΔTm on inhibitor binding; thus stabilization by tethering appears to have little direct effect on enhancing inhibitor affinity.
XIE Yi; JIA Wen-xiang; ZENG Wei; YANG Wei-qing; CHENG Xi; LI Xue-ru; WANG Lan-lan; KANG Mei; ZHANG Zai-rong
Background There is a growing interest in studying the relationship between intrinsic resistance and biofilms resistance to drugs. However, the relationship still remains unclear in the macroscopic bacterial growth. Our study is to illuminate the change of bacterial drug resistance of gyrA mutant and active efflux pump during the development of Pseudomonas aeruginosa (P. aeruginosa) biofilms. Methods The strains of type Ⅱ topoisomerase gene mutant (gyrA mutant) and multidrug resistance (MDR) efflux pump were clinical isolates and detected by polymerase chain reaction (PCR). The process of bacterial biofilms development was observed by scanning electron microscope. Triparental mating experiments were performed to transfer report gene of green fluorescent protein (GFP) into P. aeruginosa biofilms strains and followed by analysis of bacterial survival rate between intrinsic resistance and biofilms resistance.Results The fluorescent strains with pGFPuv could develop mature biofilms on Teflon surface. Before a period of 72 hours, the survival rate of biofilms bacteria and intrinsic resistance strains in ciprofloxacin solution was significantly different (P0.05). The carbonyl cyanide m-chlorophenylhydrazone and azithromycin could significantly reduce the drug resistance of biofilm strains and efflux pump strains.Conclusions In the development of P. aeruginosa biofilms, the strains of gyrA mutation and MDR efflux could be conferred with new level of drug resistance. When co-cultured mutated strains with biofilm strains, biofilms may play a major role in bacterial resistance. But after 72 hours incubation (a mature biofilms had been developed), there was no clearly difference between the number of mutant strains and biofilm strains.
Oelschlegel, Anja M; Weissmann, Charles
We have reported that properties of prion strains may change when propagated in different environments. For example, when swainsonine-sensitive 22L prions were propagated in PK1 cells in the presence of swainsonine, drug-resistant variants emerged. We proposed that prions constitute quasi- populations comprising a range of variants with different properties, from which the fittest are selected in a particular environment. Prion populations developed heterogeneity even after biological cloning, indicating that during propagation mutation-like processes occur at the conformational level. Because brain-derived 22L prions are naturally swainsonine resistant, it was not too surprising that prions which had become swa sensitive after propagation in cells could revert to drug resistance. Because RML prions, both after propagation in brain or in PK1 cells, are swainsonine sensitive, we investigated whether it was nonetheless possible to select swainsonine-resistant variants by propagation in the presence of the drug. Interestingly, this was not possible with the standard line of PK1 cells, but in certain PK1 sublines not only swainsonine-resistant, but even swainsonine-dependent populations (i.e. that propagated more rapidly in the presence of the drug) could be isolated. Once established, they could be passaged indefinitely in PK1 cells, even in the absence of the drug, without losing swainsonine dependence. The misfolded prion protein (PrP(Sc)) associated with a swainsonine-dependent variant was less rapidly cleared in PK1 cells than that associated with its drug-sensitive counterpart, indicating that likely structural differences of the misfolded PrP underlie the properties of the prions. In summary, propagation of prions in the presence of an inhibitory drug may not only cause the selection of drug-resistant prions but even of stable variants that propagate more efficiently in the presence of the drug. These adaptations are most likely due to conformational changes of
Full Text Available There is an urgent need to develop a safe, effective, orally active, and inexpensive therapy for African trypanosomiasis due to the drawbacks of current drugs. Selective tubulin inhibitors have the potential to be promising drug candidates for the treatment of this disease, which is based on the tubulin protein structural difference between mammalian and trypanosome cells. We propose to identify novel tubulin inhibitors from a compound library developed based on the lead compounds that selectively target trypanosomiasis.We used Trypanosoma brucei brucei as the parasite model, and human normal kidney cells and mouse microphage cells as the host model. Growth rates of both trypanosomes and mammalian cells were determined as a means to screen compounds that selectively inhibit the proliferation of parasites. Furthermore, we examined the cell cycle profile of the parasite and compared tubulin polymerization dynamics before and after the treatment using identified compounds. Last, in vivo anti-parasite activities of these compounds were determined in T. brucei-infected mice.Three compounds were selected that are 100 fold more effective against the growth of T. brucei cells than mammalian cells. These compounds caused cell cycle progression defects in T. brucei cells. Western analyses indicated that these compounds decreased tubulin polymerization in T. brucei cells. The in vivo investigation revealed that these compounds, when admitted orally, inhibited T. brucei cell proliferation in mouse blood. However, they were not potent enough to clear up the infection completely.These compounds are promising lead compounds as orally active agents for drug development of anti-trypanosome agents. A more detail structure activity relationship (SAR was summarized that will be used to guide future lead optimization to improve the selectivity and potency of the current compounds.
Full Text Available A study was carried out to evaluate the drug resistance pattern and penicillinase production in skin isolated Staphylococcus aurpus. The disk diffusion method showed prevalence of: multidrug resistance among S. aureus, strains, isolated from locafised skin abscesses. method for detection of penicilfinase could detect this enzyme m 98.60/o of the isolates all fo which were resistant to penicillin and ampicillin. C16xacillin resistance as detected by the agar dilution method was found in 1.4% of the isolates. On the whole cloxacillin and gentamy′cin were found to be the most effective ′antistaphylococcal antibotics.
Alphienes Stanley Xavier
Full Text Available Intense search has been made in the discovery of newer anti-TB drugs to tackle the issues such as drug resistance, HIV co-infection and risk of drug-drug interactions in the management of TB. Delamanid, a newer mycobacterial cell wall synthesis inhibitor, received a conditional approval from European medicines agency (EMA for the treatment of MDR-TB. Preclinical and clinical studies have shown that delamanid has high potency, least risk for drug-drug interactions and better tolerability.
Rupérez, María; Pou, Christian; Maculuve, Sonia; Cedeño, Samandhy; Luis, Leopoldina; Rodríguez, Judith; Letang, Emilio; Moltó, José; Macete, Eusébio; Clotet, Bonaventura; Alonso, Pedro; Menéndez, Clara; Naniche, Denise; Paredes, Roger
The objective of this study was to inform public health actions to limit first-line ART failure and HIV drug resistance in Mozambique. This was a cross-sectional study. HIV-1-infected adults on first-line ART for at least 1 year attending routine visits in the Manhiça District Hospital, in a semi-rural area in southern Mozambique with no HIV-1 RNA monitoring available, were evaluated for clinical, socio-demographic, therapeutic, immunological and virological characteristics. Factors associated with HIV-1 RNA ≥1000 copies/mL and HIV drug resistance were determined using multivariate logistic regression. The study included 334 adults on first-line ART for a median of 3 years, of which 65% (214/332) had suppressed viraemia, 11% (37/332) had low-level viraemia (HIV-1 RNA 150-999 copies/mL) and 24% (81/332) had overt virological failure (HIV-1 RNA ≥1000 copies/mL). HIV drug resistance was detected in 89% of subjects with virological failure, but in none with low-level viraemia. Younger age [OR = 0.97 per additional year (95% CI = 0.94-1.00), P = 0.039], ART initiation at WHO stage III/IV [OR = 2.10 (95% CI = 1.23-3.57), P = 0.003] and low ART adherence [OR = 2.69 (95% CI = 1.39-5.19), P = 0.003] were associated with virological failure. Longer time on ART [OR = 1.55 per additional year (95% CI = 1.00-2.43), P = 0.052] and illiteracy [OR = 0.24 (95% CI = 0.07-0.89), P = 0.033] were associated with HIV drug resistance. Compared with HIV-1 RNA, clinician's judgement of ART failure, based on clinical and immunological outcomes, only achieved 29% sensitivity and misdiagnosed 1 out of every 4.5 subjects. Public health programmes in Mozambique should focus on early HIV diagnosis, early ART initiation and adherence support. Virological monitoring drastically improves the diagnosis of ART failure, enabling a better use of resources. © The Author 2015. Published by Oxford University Press on behalf of the British
Al-Tawfiq, J A; Memish, Z A
Antibiotics were once considered the miracle cure for infectious diseases. The tragedy would be the loss of these miracles as we witness increased antibiotic resistance throughout the world. One of the concerns during mass gatherings is the transmission of antibiotic resistance. Hajj is one of the most common recurring mass gatherings, attracting millions of people from around the world. The transmission of drug-resistant organisms during the Hajj is not well described. In the current review, we summarize the available literature on the transmission and acquisition of antibiotic resistance during the Hajj and present possible solutions.
Full Text Available Enlargement of the mediastinal lymphatic glands is a common presentation of intrathoracic tuberculosis (TB in children. However, usually, the mediastinal TB nodes enlarge to 2.8 ± 1.0 cm. In this report, we describe a case of anterior mediastinal lymphnode TB seen as huge mass (7 cm on computed tomography (CT thorax without respiratory or food pipe compromise despite anterior mediastinum being an enclosed space. CT guided biopsy of the mass cultured Mycobacterium TB complex which was resistant to isoniazide, rifampicin, streptomycin ofloxacin, moxifloxacin, and pyrazinamide. Hence, we report primary multi drug resistant TB presenting as anterior mediastinal mass as a rare case report.
Liu, S; Wang, C; Fu, Y X
Objective: To know the drug resistance of Acinetobacter baumannii (AB) in wound of children with traffic injury and its relationship with antibiotic use. Methods: Wound exudate of 226 children with traffic injury admitted to our unit from January 2010 to December 2015 were collected. API bacteria identification panels and fully automatic microbiological identification system were used to identify pathogens. Kirby-Bauer paper disk diffusion method was used to detect the drug resistance of pathogens to 18 antibiotics including amoxycillin/clavulanic acid, piperacillin/tazobactam, and imipenem. The detection situation of pathogen of children's wounds and drug resistance of detected AB to 18 antibiotics in each year were collected. Forty-six AB positive children (2 children excluded) were divided into imipenem-resistant group (IR, n=19) and non imipenem-resistant group (NIR, n=25) according to whether AB was 100% resistant to imipenem. Drug resistance of AB in wounds of children to 18 antibiotics in two groups was compared. The antibiotic use of AB positive children was collected, and the antibiotic use intensity of children in two groups was compared. Data were processed with Fisher's exact test, independent sample t test, and corrected t test. Results: (1) The detection rates of pathogen in wounds of children in 2010-2015 were 95.6% (43/45), 89.8% (53/59), 81.3% (148/182), 81.1% (107/132), 81.6% (120/147), and 77.5% (62/80), respectively, showing a trend of decreasing year by year. A total of 665 strains and 75 pathogens were detected, and the top 5 pathogens with detection rate from high to low were AB, Pseudomonas aeruginosa, Enterobacter cloacae, Staphylococcus epidermidis, and Escherichia coli, respectively. (2) Drug resistance rates of AB to amoxycillin/clavulanic acid, cefazolin, aztreonam, and piperacillin were all 100%, while AB was 100% sensitive to polymyxin, and the total drug resistance rates of AB to the other 13 antibiotics were all above 50%. The drug
Aye, Khin Saw; Nakajima, Chie; Yamaguchi, Tomoyuki; Win, Min Min; Shwe, Mu Mu; Win, Aye Aye; Lwin, Thandar; Nyunt, Wint Wint; Ti, Ti; Suzuki, Yasuhiko
The number of multi-drug-resistant tuberculosis (MDR-TB) cases is rising worldwide. As a countermeasure against this situation, the implementation of rapid molecular tests to identify MDR-TB would be effective. To develop such tests, information on the frequency and distribution of mutations associating with phenotypic drug resistance in Mycobacterium tuberculosis is required in each country. During 2010, the common mutations in the rpoB, katG and inhA of 178 phenotypically MDR M. tuberculosis isolates collected by the National Tuberculosis Control Program (NTP) in Myanmar were investigated by DNA sequencing. Mutations affecting the 81-bp rifampicin (RIF) resistance-determining region (RRDR) of the rpoB were identified in 127 of 178 isolates (71.3%). Two of the most frequently affected codons were 531 and 526, with percentages of 48.3% and 14.0% respectively. For isoniazid (INH) resistance, 114 of 178 MDR-TB isolates (64.0%) had mutations in the katG in which a mutation-conferring amino acid substitution at codon 315 from Ser to Thr was the most common. Mutations in the inhA regulatory region were also detected in 20 (11.2%) isolates, with the majority at position -15. Distinct mutation rate and pattern from surrounding countries might suggest that MDR-TB has developed and spread domestically in Myanmar.
Keira A Cohen
Full Text Available The largest global outbreak of extensively drug-resistant (XDR tuberculosis (TB was identified in Tugela Ferry, KwaZulu-Natal (KZN, South Africa in 2005. The antecedents and timing of the emergence of drug resistance in this fatal epidemic XDR outbreak are unknown, and it is unclear whether drug resistance in this region continues to be driven by clonal spread or by the development of de novo resistance. A whole genome sequencing and drug susceptibility testing (DST was performed on 337 clinical isolates of Mycobacterium tuberculosis (M.tb collected in KZN from 2008 to 2013, in addition to three historical isolates, one of which was isolated during the Tugela Ferry outbreak. Using a variety of whole genome comparative approaches, 11 drug-resistant clones of M.tb circulating from 2008 to 2013 were identified, including a 50-member clone of XDR M.tb that was highly related to the Tugela Ferry XDR outbreak strain. It was calculated that the evolutionary trajectory from first-line drug resistance to XDR in this clone spanned more than four decades and began at the start of the antibiotic era. It was also observed that frequent de novo evolution of MDR and XDR was present, with 56 and 9 independent evolutions, respectively. Thus, ongoing amplification of drug-resistance in KwaZulu-Natal is driven by both clonal spread and de novo acquisition of resistance. In drug-resistant TB, isoniazid resistance was overwhelmingly the initial resistance mutation to be acquired, which would not be detected by current rapid molecular diagnostics that assess only rifampicin resistance.
Full Text Available Based on phylogenetic analysis of 18S rRNA sequences and clade taxon composition, this paper adopts a biogeographical approach to understanding the evolutionary relationships of the human and primate infective trypanosomes, Trypanosoma cruzi, T. brucei, T. rangeli and T. cyclops. Results indicate that these parasites have divergent origins and fundamentally different patterns of evolution. T. cruzi is placed in a clade with T. rangeli and trypanosomes specific to bats and a kangaroo. The predominantly South American and Australian origins of parasites within this clade suggest an ancient southern super-continent origin for ancestral T. cruzi, possibly in marsupials. T. brucei clusters exclusively with mammalian, salivarian trypanosomes of African origin, suggesting an evolutionary history confined to Africa, while T. cyclops, from an Asian primate appears to have evolved separately and is placed in a clade with T. (Megatrypanum species. Relating clade taxon composition to palaeogeographic evidence, the divergence of T. brucei and T. cruzi can be dated to the mid-Cretaceous, around 100 million years before present, following the separation of Africa, South America and Euramerica. Such an estimate of divergence time is considerably more recent than those of most previous studies based on molecular clock methods. Perhaps significantly, Salivarian trypanosomes appear, from these data, to be evolving several times faster than Schizotrypanum species, a factor which may have contributed to previous anomalous estimates of divergence times.
Mario Arturo Alonso-Vanegas
Full Text Available Cerebral cavernous malformations (CM are dynamic lesions characterized by continuous size changes and repeated bleeding. When involving cortical tissue, CM pose a significant risk for the development of drug-resistant epilepsy, which is thought to be result of an altered neuronal network caused by the lesion itself and its blood degradation products. Preoperative evaluation should comprise a complete seizure history, neurological examination, epilepsy-oriented MRI, EEG, video-EEG, completed with SPECT, PET, functional MRI and/or invasive monitoring as needed. Radiosurgery shows variable rates of seizure freedom and a high incidence of complications, thus microsurgical resection remains the optimal treatment for CM coursing with drug-resistant epilepsy.Two thirds of patients reach Engel I class at three-year follow-up, regardless of lobar location. Those with secondarily generalized seizures, a higher seizure frequency, and generalized abnormalities on preoperative or postoperative EEG, show poorer outcomes, while factors such as gender, duration of epilepsy, lesion size, age, bleeding at the time of surgery, do not correlate consistently with seizure outcome. Electrocorticography and a meticulous removal of all cortical hemosiderin –beyond pure lesionectomy– reduce the risk of symptomatic recurrences.
Couce, Alejandro; Rodríguez-Rojas, Alexandro; Blázquez, Jesús
Any pathogen population sufficiently large is expected to harbor spontaneous drug-resistant mutants, often responsible for disease relapse after antibiotic therapy. It is seldom appreciated, however, that while larger populations harbor more mutants, the abundance distribution of these mutants is expected to be markedly uneven. This is because a larger population size allows early mutants to expand for longer, exacerbating their predominance in the final mutant subpopulation. Here, we investigate the extent to which this reduction in evenness can constrain the genetic diversity of spontaneous drug resistance in bacteria. Combining theory and experiments, we show that even small variations in growth rate between resistant mutants and the wild type result in orders-of-magnitude differences in genetic diversity. Indeed, only a slight fitness advantage for the mutant is enough to keep diversity low and independent of population size. These results have important clinical implications. Genetic diversity at antibiotic resistance loci can determine a population's capacity to cope with future challenges (i.e., second-line therapy). We thus revealed an unanticipated way in which the fitness effects of antibiotic resistance can affect the evolvability of pathogens surviving a drug-induced bottleneck. This insight will assist in the fight against multidrug-resistant microbes, as well as contribute to theories aimed at predicting cancer evolution.
Clinical case definitions are the cornerstone of clinical communication and of clinical and epidemiologic research. The ramifications of establishing a case definition are extensive, including potentially large changes in epidemiologic estimates of frequency, and decisions for clinical management. Yet, defining a condition entails numerous challenges such as defining the scope and purpose, incorporating the strongest evidence base with clinical expertise, accounting for patients' values, and considering impact on care. The clinical case definition of drug-resistant epilepsy, in addition, must address what constitutes an adequate intervention for an individual drug, what are the outcomes of relevance, what period of observation is sufficient to determine success or failure, how many medications should be tried, whether seizure frequency should play a role, and what is the role of side effects and tolerability. On the other hand, the principles of evidence-based medicine (EBM) aim at providing a systematic approach to incorporating the best available evidence into the process of clinical decision for individual patients. The case definition of drug-resistant epilepsy proposed by the the International League Against Epilepsy (ILAE) in 2009 is evaluated in terms of the principles of EBM as well as the stated goals of the authors of the definition.
Spring, Bryan Q.; Rizvi, Imran; Xu, Nan; Hasan, Tayyaba
Many modalities of cancer therapy induce mechanisms of treatment resistance and escape pathways during chronic treatments, including photodynamic therapy (PDT). It is conceivable that resistance induced by one treatment might be overcome by another treatment. Emerging evidence suggests that the unique mechanisms of tumor cell and microenvironment damage produced by PDT could be utilized to overcome cancer drug resistance, to mitigate the compensatory induction of survival pathways and even to re-sensitize resistant cells to standard therapies. Approaches that capture the unique features of PDT, therefore, offer promising factors for increasing the efficacy of a broad range of therapeutic modalities. Here, we highlight key preclinical findings utilizing PDT to overcome classical drug resistance or escape pathways and thus enhance the efficacy of many pharmaceuticals, possibly explaining the clinical observations of the PDT response to otherwise treatment-resistant diseases. With the development of nanotechnology, it is possible that light activation may be used not only to damage and sensitize tumors but also to enable controlled drug release to inhibit escape pathways that may lead to resistance or cell proliferation. PMID:25856800
Dennis J Grab
Full Text Available BACKGROUND: Using human brain microvascular endothelial cells (HBMECs as an in vitro model for how African trypanosomes cross the human blood-brain barrier (BBB we recently reported that the parasites cross the BBB by generating calcium activation signals in HBMECs through the activity of parasite cysteine proteases, particularly cathepsin L (brucipain. In the current study, we examined the possible role of a class of protease stimulated HBMEC G protein coupled receptors (GPCRs known as protease activated receptors (PARs that might be implicated in calcium signaling by African trypanosomes. METHODOLOGY/PRINCIPAL FINDINGS: Using RNA interference (RNAi we found that in vitro PAR-2 gene (F2RL1 expression in HBMEC monolayers could be reduced by over 95%. We also found that the ability of Trypanosoma brucei rhodesiense to cross F2RL1-silenced HBMEC monolayers was reduced (39%-49% and that HBMECs silenced for F2RL1 maintained control levels of barrier function in the presence of the parasite. Consistent with the role of PAR-2, we found that HBMEC barrier function was also maintained after blockade of Galpha(q with Pasteurella multocida toxin (PMT. PAR-2 signaling has been shown in other systems to have neuroinflammatory and neuroprotective roles and our data implicate a role for proteases (i.e. brucipain and PAR-2 in African trypanosome/HBMEC interactions. Using gene-profiling methods to interrogate candidate HBMEC pathways specifically triggered by brucipain, several pathways that potentially link some pathophysiologic processes associated with CNS HAT were identified. CONCLUSIONS/SIGNIFICANCE: Together, the data support a role, in part, for GPCRs as molecular targets for parasite proteases that lead to the activation of Galpha(q-mediated calcium signaling. The consequence of these events is predicted to be increased permeability of the BBB to parasite transmigration and the initiation of neuroinflammation, events precursory to CNS disease.
Maganga Gaël Darren
Full Text Available The aim of this study was to provide information on trypanosome species infecting trypanotolerant cattle from southern Gabon. The study was conducted on 224 trypanotolerant cattle from three regions located in southern Gabon, using ITS1 primer-based PCR. Seventy-two (32% N’dama cattle were found polymerase chain reaction (PCR positive with trypanosomes. The overall prevalence of trypanosomosis was 57% (63/110, 4% (4/100, and 36% (5/14 in the Gala section of the Nyanga ranch, the Miyama ranch, and Ossiele, respectively. Trypanosoma congolense and Trypanosoma vivax were identified. In Gala section and Ossiele, T. congolense and T. vivax were found. In the Miyama ranch, only T. vivax was identified. Mixed infections were also found. The forest (9% and savannah (63% subgroups of T. congolense were identified. The presence of the two subgroups was detected in 16 out of 56 cattle (29%. T. congolense and T. vivax would appear to be the main agents responsible for bovine trypanosomosis in southern Gabon. Although trypanotolerant, N’dama cattle may serve as a reservoir, and this should be further studied. On the other hand, these trypanotolerant cattle can be reared in such tsetse infested areas, which gives them an advantage compared to other trypanosensitive breeds, and this shows that they represent a key factor in biodiversity which has to be promoted.
Fenner, Lukas; Egger, Matthias; Bodmer, Thomas; Altpeter, Ekkehardt; Zwahlen, Marcel; Jaton, Katia; Pfyffer, Gaby E; Borrell, Sonia; Dubuis, Olivier; Bruderer, Thomas; Siegrist, Hans H; Furrer, Hansjakob; Calmy, Alexandra; Fehr, Jan; Stalder, Jesica Mazza; Ninet, Béatrice; Böttger, Erik C; Gagneux, Sebastien
Bacterial factors may contribute to the global emergence and spread of drug-resistant tuberculosis (TB). Only a few studies have reported on the interactions between different bacterial factors. We studied drug-resistant Mycobacterium tuberculosis isolates from a nationwide study conducted from 2000 to 2008 in Switzerland. We determined quantitative drug resistance levels of first-line drugs by using Bactec MGIT-960 and drug resistance genotypes by sequencing the hot-spot regions of the relevant genes. We determined recent transmission by molecular methods and collected clinical data. Overall, we analyzed 158 isolates that were resistant to isoniazid, rifampin, or ethambutol, 48 (30.4%) of which were multidrug resistant. Among 154 isoniazid-resistant strains, katG mutations were associated with high-level and inhA promoter mutations with low-level drug resistance. Only katG(S315T) (65.6% of all isoniazid-resistant strains) and inhA promoter -15C/T (22.7%) were found in molecular clusters. M. tuberculosis lineage 2 (includes Beijing genotype) was associated with any drug resistance (adjusted odds ratio [OR], 3.0; 95% confidence interval [CI], 1.7 to 5.6; P mutations (OR, 6.4; 95% CI, 2.0 to 20.7; P = 0.002). We found that the genetic strain background influences the level of isoniazid resistance conveyed by particular mutations (interaction tests of drug resistance mutations across all lineages; P tuberculosis drug resistance mutations were associated with various levels of drug resistance and transmission, and M. tuberculosis lineages were associated with particular drug resistance-conferring mutations and phenotypic drug resistance. Our study also supports a role for epistatic interactions between different drug resistance mutations and strain genetic backgrounds in M. tuberculosis drug resistance.
Full Text Available The population of the French Departments of the Americas (FDA is highly influenced by the intense migratory flows with mainland France and surrounding countries of the Caribbean and Latin America, some of which have high incidence rates of tuberculosis (Haiti: 230/100,000; Guyana: 111/100,000; and Suriname: 145/100,000 and drug resistance. Since the development of drug resistance to conventional antituberculous drugs has a major impact on the treatment success of tuberculosis, we therefore decided to review carefully Mycobacterium tuberculosis drug resistance and associated genotypic lineages in the FDA over a seventeen-year period (January 1995–December 2011. A total of 1239 cases were studied, including 153 drug-resistant and 26 multidrug-resistant- (MDR- TB cases, representing 12.3% and 2.1% of the TB cases in our study setting. A significantly higher proportion of M. tuberculosis isolates among relapse cases showed drug resistance to isoniazid (22.5%, P=0.002, rifampicin (20.0%, P<0.001, or both (MDR-TB, 17.5%; P<0.001. Determination of spoligotyping based phylogenetic clades showed that among the five major lineages observed—T family (30.1%; Latin-American and Mediterranean (LAM, 23.7%; Haarlem (H, 22.2%; East-African Indian (EAI, 7.2%; and X family (6.5%—two lineages, X and LAM, were overrepresented in drug-resistant and MDR-TB cases, respectively. Finally, 19 predominant spoligotypes were identified for the 1239 isolates of M. tuberculosis in our study among which 4 were significantly associated with drug resistance corresponding to SIT20/LAM1, SIT64/LAM6, SIT45/H1, and SIT46/undefined lineage.
Objective: To investigate the co-expression of drug resistance- and apoptosis-related genes of cisplatin (CDDP)-selected lung adenocarcinoma cell line A549DDP for compared to the parental cell line A549, and reverse of drug resistance by antisense s-oligodeoxynucleotides (S-ODNs) of differentially expressed genes. Methods: Sense and antisense S-ODN were transferred into A549DDP cells by lipofectin. The expression of drug resistance and apoptosis related genes was examined by RT-PCR, immunocytochemistry and flow cytometry, respectively. Apoptostic cells were identified by DNA electrophoresis and terminal deoxynucleotidyl transferase (TdT)-mediated biotin dUTP nick end-labeling(TUNEL). Drug resistance of tumor cells was detected by a cell viability (MTT) assay. Results: The expression of bc1-2 was positive and that of multidrug resistance-associated protein (MRP) at mRNA and protein level was increased in A549DDP compared to A549 cells. MDR1, c-myc and topoisomeras II (TOPO II) were similarly co-expressed in two cell lines. Both cell lines were negative for c-erbB-2 expression. In A549DDP cells, the expression of bc1-2 and MRP was significantly inhibited by their respective antisense S-ODNs. Antisense S-ODNs could also decrease significantly drug resistance of A549DDP cells to CDDP by promoting cell apoptosis. Conclusion: Both intrinsic and acquired drug resistance were involved in co-expression of multiple MDR-related genes in lung adenocarcinoma. Co- operation of bc1-2 and MRP genes appeared to play an important action to confer the resistance of A549DDP cells to CDDP. Their antisense S-ODNs are responsible for the decrease of drug resistance of this cell line by promoting apoptosis.
Paul M Grandgenett
Full Text Available The Trypanosoma brucei genome encodes three groups of zinc metalloproteases, each of which contains approximately 30% amino acid identity with the major surface protease (MSP, also called GP63 of Leishmania. One of these proteases, TbMSP-B, is encoded by four nearly identical, tandem genes transcribed in both bloodstream and procyclic trypanosomes. Earlier work showed that RNA interference against TbMSP-B prevents release of a recombinant variant surface glycoprotein (VSG from procyclic trypanosomes. Here, we used gene deletions to show that TbMSP-B and a phospholipase C (GPI-PLC act in concert to remove native VSG during differentiation of bloodstream trypanosomes to procyclic form. When the four tandem TbMSP-B genes were deleted from both chromosomal alleles, bloodstream B (-/- trypanosomes could still differentiate to procyclic form, but VSG was removed more slowly and in a non-truncated form compared to differentiation of wild-type organisms. Similarly, when both alleles of the single-copy GPI-PLC gene were deleted, bloodstream PLC (-/- cells could still differentiate. However, when all the genes for both TbMSP-B and GPI-PLC were deleted from the diploid genome, the bloodstream B (-/- PLC (-/- trypanosomes did not proliferate in the differentiation medium, and 60% of the VSG remained on the cell surface. Inhibitors of cysteine proteases did not affect this result. These findings demonstrate that removal of 60% of the VSG during differentiation from bloodstream to procyclic form is due to the synergistic activities of GPI-PLC and TbMSP-B.
Ejo, Mebrat; Gehre, Florian; Barry, Mamadou Dian; Sow, Oumou; Bah, Nene Mamata; Camara, Mory; Bah, Boubacar; Uwizeye, Cecile; Nduwamahoro, Elie; Fissette, Kristina; De Rijk, Pim; Merle, Corinne; Olliaro, Piero; Burgos, Marcos; Lienhardt, Christian; Rigouts, Leen; de Jong, Bouke C
In this study we assessed first-line anti-tuberculosis drug resistance and the genotypic distribution of Mycobacterium tuberculosis complex (MTBC) isolates that had been collected from consecutive new tuberculosis patients enrolled in two clinical trials conducted in Guinea between 2005 and 2010. Among the total 359 MTBC strains that were analyzed in this study, 22.8% were resistant to at least one of the first line anti-tuberculosis drugs, including 2.5% multidrug resistance and 17.5% isoniazid resistance, with or without other drugs. In addition, further characterization of isolates from a subset of the two trials (n = 184) revealed a total of 80 different spoligotype patterns, 29 "orphan" and 51 shared patterns. We identified the six major MTBC lineages of human relevance, with predominance of the Euro-American lineage. In total, 132 (71.7%) of the strains were genotypically clustered, and further analysis (using the DESTUS model) suggesting significantly faster spread of LAM10_CAM family (p = 0.00016). In conclusion, our findings provide a first insight into drug resistance and the population structure of the MTBC in Guinea, with relevance for public health scientists in tuberculosis control programs.
Full Text Available Background: Urinary tract infections are the most prevalent bacterial infections in the world and using empiric antibiotic therapy may increase the drug resistance. This cross- sectional study accomplished to determine the prevalence of UTI and related antibiotic resistance pattern. Methods: UTI suspected patients referred to Yazd central laboratory studied. The urine samples cultured colonies with colony count of > 105 cfu/ml identified, and antibiotic resistance patterns determined by the standard disk diffusion method (Kirby-Bauer. Results: Out of 17353 samples 1623 (9.35% were positive culture. The most prevalent microorganisms were as follows: E.coli (47.07%. Enterobacter (12.07%. S. aureus (10.96%, Klebsiella pneumoniae (9.85%, CNS (8.37%, group B streptococci (4.86%. Enterococci (2.09%. Pseudomonas aeruginosa (1.54%. Proteus (1.17%. Nonhemolytic streptococci (0.86%, Citrobacter and α hemolytic Streptococci (0.55%. The antibiogram results showed that isolated strains had the most drug resistance as follows: to ampicillin (80%, SXT (53.66%, tetracycline (50.33%, cephalexin (22.92%, nalidixic acid (19.4%, nitrofruntain (17.12%, ceftizoxime (8.5% and ciprofloxacin (8%. Gram (+ cocci strains were 100% sensitive to vancomycin. Conclusion: selection of proper antibiotic against isolated species though susceptibility testing decreases the dissemination of resistant strains.
Full Text Available Grania Brigden,1 Cathy Hewison,2 Francis Varaine21Access Campaign, Médecins Sans Frontières, Geneva, Switzerland; 2Medical Department, Médecins Sans Frontières, Paris, France Abstract: The current treatment for drug-resistant tuberculosis (TB is long, complex, and associated with severe and life-threatening side effects and poor outcomes. For the first time in nearly 50 years, there have been two new drugs registered for use in multidrug-resistant TB (MDR-TB. Bedaquiline, a diarylquinoline, and delamanid, a nitromidoxazole, have received conditional stringent regulatory approval and have World Health Organization interim policy guidance for their use. As countries improve and scale up their diagnostic services, increasing number of patients with MDR-TB and extensively drug-resistant TB are identified. These two new drugs offer a real opportunity to improve the outcomes of these patients. This article reviews the evidence for these two new drugs and discusses the clinical questions raised as they are used outside clinical trial settings. It also reviews the importance of the accompanying drugs used with these new drugs. It is important that barriers hindering the use of these two new drugs are addressed and that the existing clinical experience in using these drugs is shared, such that their routine-use programmatic conditions is scaled up, ensuring maximum benefit for patients and countries battling the MDR-TB crisis. Keywords: MDR-TB, XDR-TB, tuberculosis drugs, group 5 drugs
Full Text Available OBJECTIVES: Human immunodeficiency virus type 1 (HIV-1 infection has been detected in all provinces of China. Although epidemiological and phylogenetic studies have been conducted in many regions, such analyses are lacking from Jilin province in northeastern China. METHOD: Epidemiological and phylogenetic analyses, as well as detection of drug-resistant mutations, were conducted on 57 HIV-1 infected patients from Changchun city identified and confirmed through annual surveillance by local Centers for Disease Control in Jilin province of northeastern China in 2012. RESULTS: Sexual contact was determined to be the major pathway for HIV-1 transmission in Jilin, where hetero- and homosexual activities contributed almost equally. Phylogenetic analyses detected multiple subtypes of HIV-1 including subtype G circulating in Jilin, with multiple origins for each of them. Both subtype B and CRF01_AE were dominant, and evidence of subtype B transmitting between different high-risk groups was observed. Mutations in the viral protease at position 71 indicated the presence of a selective pressure. Several drug-resistant mutations were detected, although they were predicted with low-level resistance to antiviral treatments. CONCLUSIONS: Information from this study fills the gap in knowledge of HIV-1 transmission in Changchun city, Jilin province, China. By revealing the origin and evolutionary status of local HIV-1 strains, this work contributes to ongoing efforts in the control and prevention of AIDS.
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.
He, Yan; Tian, Jun; Chen, Xintao; Sun, Weiguang; Zhu, Hucheng; Li, Qin; Lei, Liang; Yao, Guangmin; Xue, Yongbo; Wang, Jianping; Li, Hua; Zhang, Yonghui
Four naphtho-γ-pyrones (fonsecinones A and C and aurasperones A and E) were identified as potential antibacterial agents against Escherichia coli, extended-spectrum β-lactamase (ESBL)-producing E. coli, Pseudomonas aeruginosa, Enterococcus faecalis, and methicillin-resistant Staphylococcus aureus (MRSA) in an in vitro antibacterial screen of 218 fungal metabolites. Fonsecinone A (2) exhibited the most potent antibacterial activity, with minimum inhibitory concentrations (MICs) of 4.26, 17.04, and 4.26 μg/mL against ESBL-producing E. coli, P. aeruginosa, and E. faecalis, respectively. The inhibitory effects of fonsecinones A (2) and C (3) against E. coli and ESBL-producing E. coli were comparable to those of amikacin. Molecular docking-based target identification of naphtho-γ-pyrones 1-8 revealed bacterial enoyl-acyl carrier protein reductase (FabI) as an antibacterial target, which was further validated by FabI affinity and inhibition assays. Fonsecinones A (2) and C (3) and aurasperones A (6) and E (7) bound FabI specifically and produced concentration-dependent inhibition effects. This work is the first report of anti-drug-resistant bacterial activities of naphtho-γ-pyrones 1-8 and their possible antibacterial mechanism of action and provides an example of the successful application of in silico methods for drug target identification and validation and the identification of new lead antibiotic compounds against drug-resistant pathogens.
Li, Yong-Tao; Yu, Cheng-Bo; Huang, Jian-Rong; Qin, Zheng-Ji; Li, Lan-Juan
To investigate the microbiological characteristics and drug resistance in liver cirrhosis patients with spontaneous peritonitis. We analyzed the data of patients with liver cirrhosis and abdominal infection at the First Affiliated Hospital of Zhejiang University between January 2011 and December 2013. Pathogens present in the ascites were identified, and their sensitivity to various antibiotics was determined. We isolated 306 pathogenic bacteria from 288 cases: In 178 cases, the infection was caused by gram-negative strains (58.2%); in 85 cases, gram-positive strains (27.8%); in 9 cases, fungi (2.9%); and in 16 cases, more than one pathogen. The main pathogens were Escherichia coli (E. coli) (24.2%), Klebsiella pneumoniae (18.9%), Enterococcus spp. (11.1%), and Staphylococcus aureus (7.5%). Of the 306 isolated pathogens, 99 caused nosocomial infections and 207 caused community-acquired and other infections. The E. coli and K. pneumoniae strains produced more extended-spectrum β-lactamases in cases of nosocomial infections than non-nosocomial infections (62.5% vs 38%, P antibiotics differed between nosocomial and non-nosocomial infections: Piperacillin/tazobactam was significantly more effective against non-nosocomial E. coli infections (4% vs 20.8%, P nosocomial infections (36.4% vs 86.3%, P infection in patients with liver cirrhosis are gram-negative, and drug resistance is significantly higher in nosocomial infections than in non-nosocomial infections.
Full Text Available One possible explanation of the maintenance of many historical foci of sleeping sickness in Central Africa could be the existence of a wild animal reservoir. In this study, PCR was used to detect the different trypanosome species present in wild animal captured by hunters in the southern forest belt of Cameroon (Bipindi. Trypanosomes were also detected by a parasitological method (Quantitative buffy coat : QBC. Parasite could not be isolated in culture medium (Kit for in vitro isolation : KIVI. Specific primers of T. brucei s.l., T. congolense forest type, T. congolense savannah type, T. vivax, T. simiae and T. b. gambiense group 1 were used to identify parasites in the blood of 164 animals belonging to 24 different species including ungulates, rodents, pangolins, carnivores, reptiles and primates. Of the 24 studied species, eight were carrying T. b. gambiense group 1. Those parasites pathogenic to man were found in monkeys (Cercocebus torquatus and Cercopithecus nictitans, in ungulates (Cephalophus dorsalis and C. monticola, in carnivores (Nandinia binotata and Genetta servalina and in rodents (Cricetomys gambianus and Atherurus africanus. 13 species (54 % were carrying T. brucei s.l. identified as non-gambiense group 1.
Du, Bowen; Shim, Joong Sup
Epithelial-mesenchymal transition (EMT) is known to play an important role in cancer progression, metastasis and drug resistance. Although there are controversies surrounding the causal relationship between EMT and cancer metastasis, the role of EMT in cancer drug resistance has been increasingly recognized. Numerous EMT-related signaling pathways are involved in drug resistance in cancer cells. Cells undergoing EMT show a feature similar to cancer stem cells (CSCs), such as an increase in drug efflux pumps and anti-apoptotic effects. Therefore, targeting EMT has been considered a novel opportunity to overcome cancer drug resistance. This review describes the mechanism by which EMT contributes to drug resistance in cancer cells and summarizes new advances in research in EMT-associated drug resistance.
Lavu, Evelyn; Kave, Ellan; Mosoro, Euodia; Markby, Jessica; Aleksic, Eman; Gare, Janet; Elsum, Imogen A; Nano, Gideon; Kaima, Petronia; Dala, Nick; Gurung, Anup; Bertagnolio, Silvia; Crowe, Suzanne M; Myatt, Mark; Hearps, Anna C; Jordan, Michael R
Papua New Guinea is a Pacific Island nation of 7.3 million people with an estimated HIV prevalence of 0.8%. ART initiation and monitoring are guided by clinical staging and CD4 cell counts, when available. Little is known about levels of transmitted HIV drug resistance in recently infected individuals in Papua New Guinea. Surveillance of transmitted HIV drug resistance in a total of 123 individuals recently infected with HIV and aged less than 30 years was implemented in Port Moresby (n = 62) and Mount Hagen (n = 61) during the period May 2013-April 2014. HIV drug resistance testing was performed using dried blood spots. Transmitted HIV drug resistance was defined by the presence of one or more drug resistance mutations as defined by the World Health Organization surveillance drug resistance mutations list. The prevalence of non-nucleoside reverse transcriptase inhibitor transmitted HIV drug resistance was 16.1% (95% CI 8.8%-27.4%) and 8.2% (95% CI 3.2%-18.2%) in Port Moresby and Mount Hagen, respectively. The prevalence of nucleoside reverse transcriptase inhibitor transmitted HIV drug resistance was 3.2% (95% CI 0.2%-11.7%) and 3.3% (95% CI 0.2%-11.8%) in Port Moresby and Mount Hagen, respectively. No protease inhibitor transmitted HIV drug resistance was observed. The level of non-nucleoside reverse transcriptase inhibitor drug resistance in antiretroviral drug naïve individuals recently infected with HIV in Port Moresby is amongst the highest reported globally. This alarming level of transmitted HIV drug resistance in a young sexually active population threatens to limit the on-going effective use of NNRTIs as a component of first-line ART in Papua New Guinea. To support the choice of nationally recommended first-line antiretroviral therapy, representative surveillance of HIV drug resistance among antiretroviral therapy initiators in Papua New Guinea should be urgently implemented.
Lavu, Evelyn; Kave, Ellan; Mosoro, Euodia; Markby, Jessica; Aleksic, Eman; Gare, Janet; Elsum, Imogen A.; Nano, Gideon; Kaima, Petronia; Dala, Nick; Gurung, Anup; Bertagnolio, Silvia; Crowe, Suzanne M.; Myatt, Mark
Introduction Papua New Guinea is a Pacific Island nation of 7.3 million people with an estimated HIV prevalence of 0.8%. ART initiation and monitoring are guided by clinical staging and CD4 cell counts, when available. Little is known about levels of transmitted HIV drug resistance in recently infected individuals in Papua New Guinea. Methods Surveillance of transmitted HIV drug resistance in a total of 123 individuals recently infected with HIV and aged less than 30 years was implemented in Port Moresby (n = 62) and Mount Hagen (n = 61) during the period May 2013-April 2014. HIV drug resistance testing was performed using dried blood spots. Transmitted HIV drug resistance was defined by the presence of one or more drug resistance mutations as defined by the World Health Organization surveillance drug resistance mutations list. Results The prevalence of non-nucleoside reverse transcriptase inhibitor transmitted HIV drug resistance was 16.1% (95% CI 8.8%-27.4%) and 8.2% (95% CI 3.2%-18.2%) in Port Moresby and Mount Hagen, respectively. The prevalence of nucleoside reverse transcriptase inhibitor transmitted HIV drug resistance was 3.2% (95% CI 0.2%-11.7%) and 3.3% (95% CI 0.2%-11.8%) in Port Moresby and Mount Hagen, respectively. No protease inhibitor transmitted HIV drug resistance was observed. Conclusions The level of non-nucleoside reverse transcriptase inhibitor drug resistance in antiretroviral drug naïve individuals recently infected with HIV in Port Moresby is amongst the highest reported globally. This alarming level of transmitted HIV drug resistance in a young sexually active population threatens to limit the on-going effective use of NNRTIs as a component of first-line ART in Papua New Guinea. To support the choice of nationally recommended first-line antiretroviral therapy, representative surveillance of HIV drug resistance among antiretroviral therapy initiators in Papua New Guinea should be urgently implemented. PMID:28146591
Devinsky, O.; Cross, J. H.; Laux, L.; E Marsh; Miller, I.; Nabbout, R.; Scheffer, I. E.; Thiele, E.A.; Wright, S.
BACKGROUND: The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome. METHODS: In this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram...
Phillips, Andrew; Cambiano, Valentina; Nakagawa, Fumiyo
BACKGROUND: To guide future need for cheap resistance tests for use in low income settings, we assessed cost-effectiveness of drug resistance testing as part of monitoring of people on first line ART - with switching from first to second line ART being conditional on NNRTI drug resistance mutations...... being identified. METHODS: An individual level simulation model of HIV transmission, progression and the effect of ART which accounts for adherence and resistance development was used to compare outcomes of various potential monitoring strategies in a typical low income setting in sub-Saharan Africa....... Underlying monitoring strategies considered were based on clinical disease, CD4 count or viral load. Within each we considered a strategy in which no further measures are performed, one with a viral load measure to confirm failure, and one with both a viral load measure and a resistance test. Predicted...
Mbehang Nguema, Pierre Philippe; Okubo, Torahiko; Tsuchida, Sayaka; Fujita, Shiho; Yamagiwa, Juichi; Tamura, Yutaka; Ushida, Kazunari
Prevalence of drug-resistant bacteria in wildlife can reveal the actual level of anthropological burden on the wildlife. In this study, we isolated two multiple drug-resistant strains, GG6-2 and GG6-1-1, from 27 fresh feces of wild western lowland gorillas in Moukalaba-Doudou National Park, Gabon. Isolates were identified as Achromobacter xylosoxidans and Providencia sp., respectively. Minimum inhibitory concentrations of the following 12 drugs-ampicillin (ABPC), cefazolin (CEZ), cefotaxime (CTX), streptomycin (SM), gentamicin (GM), kanamycin (KM), tetracycline (TC), nalidixic acid (NA), ciprofloxacin (CPFX), colistin (CL), chloramphenicol (CP) and trimethoprim (TMP)-were determined. Isolate GG6-2 was resistant to all antimicrobials tested and highly resistant to CTX, SM, TC, NA and TMP. Isolate GG6-1-1 was resistant to ABPC, CEZ, TC, CL, CP and TMP.
Yonatan Moges Mesfin
Full Text Available BACKGROUND: Human immunodeficiency virus (HIV, multi-drug resistant tuberculosis (MDR is emerging as major challenge facing tuberculosis control programs worldwide particularly in Asia and Africa. Findings from different studies on associations of HIV co-infection and drug resistance among patients with TB have been contradictory (discordant. Some institution based studies found strongly increased risks for multi-drug resistant TB (MDR TB among patients co-infected with TB and HIV, whereas other studies found no increased risk (it remains less clear in community based studies. The aim was to conduct a systematic review and meta-analysis of the association between multi-drug resistant tuberculosis and HIV infection. METHODS AND FINDINGS: Systematic review of the published literature of observational studies was conducted. Original studies were identified using databases of Medline/Pubmed, Google Scholar and HINARI. The descriptions of original studies were made using frequency and forest plot. Publication bias was assessed using Funnel plot graphically and Egger weighted and Begg rank regression tests statistically. Heterogeneity across studies was checked using Cochrane Q test statistic and I(2. Pool risk estimates of MDR-TB and sub-grouping analysis were computed to analyze associations with HIV. Random effects of the meta-analysis of all 24 observational studies showed that HIV is associated with a marginal increased risk of multi-drug resistant tuberculosis (estimated Pooled OR 1.24; 95%, 1.04-1.43. Subgroup analyses showed that effect estimates were higher (Pooled OR 2.28; 95%, 1.52-3.04 for primary multi-drug resistance tuberculosis and moderate association between HIV/AIDS and MDR-TB among population based studies and no significant association in institution settings. CONCLUSIONS: This study demonstrated that there is association between MDR-TB and HIV. Capacity for diagnosis of MDR-TB and initiating and scale up of antiretroviral
王欣; 李秋; 邹声泉; 孙自庸; 朱峰
The bile was collected from fro patients with biliary infections, with the bacterium isolated to study the sensitivity of each kind of the bacterium to several antibiotics in common use. Except G- bacterium, we also found some kinds of G+ bacterium in infection bile. G- bacterium were not sensitive to Clindamycin, G+ bacterium were sensitive to Ciprofloxacin. Escherichia coli,Xanthomonas maltophilia, Enterobacter cloacae, Pseudomonas aeruginosa were sensitive to Ampicillin. G+ bacterium were not sensitive to Azactam. Enterococcus faecalis, Enterococcus faecium,Enterobacter cloacae were not sensitive to Ceftazidime. Enterococcus faecalis, Staphylococcus coagulase negative, Staphylococcus epidermidis, Pseudomonas aeruginosa were not sensitive to Ceftriaxone Sodium. We didn't found any bacterium resistance Imipenem. The possibility of the existence of G+ bacterium as well as drug resistance should be considered n patients with biliary infections.The value of susceptibility test should be respected to avoid drug abuse of antibiotics.
Møller, JK; Bak, AL; Bülow, P
Drug resistance to 8 different antibiotics in Enterobacteriaceae isolated from different hospitals and two groups of general practitioners was studied. Escherichia coli dominated among the 632 strains investigated. Drug resistance was found in 62% of the 512 hospital strains and in 38% of the 120...... strains from general practice. Multiple resistance was common especially in strains from hospital. R factors was found in 23% of the 317 drug-resistant strains from hospital and in 11% of the 46 drug-resistant strains from general practice. Resistance to streptomycin, sulphonamide and tetracycline either...
Domínguez, J; Boettger, E C; Cirillo, D; Cobelens, F; Eisenach, K D; Gagneux, S; Hillemann, D; Horsburgh, R; Molina-Moya, B; Niemann, S; Tortoli, E; Whitelaw, A; Lange, C
The emergence of drug-resistant strains of Mycobacterium tuberculosis is a challenge to global tuberculosis (TB) control. Although culture-based methods have been regarded as the gold standard for drug susceptibility testing (DST), molecular methods provide rapid information on mutations in the M. tuberculosis genome associated with resistance to anti-tuberculosis drugs. We ascertained consensus on the use of the results of molecular DST for clinical treatment decisions in TB patients. This document has been developed by TBNET and RESIST-TB groups to reach a consensus about reporting standards in the clinical use of molecular DST results. Review of the available literature and the search for evidence included hand-searching journals and searching electronic databases. The panel identified single nucleotide mutations in genomic regions of M. tuberculosis coding for katG, inhA, rpoB, embB, rrs, rpsL and gyrA that are likely related to drug resistance in vivo. Identification of any of these mutations in clinical isolates of M. tuberculosis has implications for the management of TB patients, pending the results of in vitro DST. However, false-positive and false-negative results in detecting resistance-associated mutations in drugs for which there is poor or unproven correlation between phenotypic and clinical drug resistance complicate the interpretation. Reports of molecular DST results should therefore include specific information on the mutations identified and provide guidance for clinicians on interpretation and on the choice of the appropriate initial drug regimen.
Khawcharoenporn, T; Apisarnthanarak, A; Mundy, L M
Treatment limitations exist for drug-resistant Acinetobacter baumannii central nervous system (CNS) infection. We conducted a retrospective study and systematic literature review to identify patients with drug-resistant A. baumannii CNS infection who received primary or adjunct intrathecal or intraventricular (IT/IVT) colistin. In a case series of seven Thai patients and 17 patients identified in the literature, clinical and microbiological cure rates with IT/IVT colistin therapy were 83% and 92%, respectively. Three patients (13%) developed chemical ventriculitis and one (4%) experienced treatment-associated seizures. Death was associated with delayed IT/IVT colistin therapy compared to survival (mean time from diagnosis to IT/IVT colistin, 7 vs. 2 days; p 0.01). The only independent predictor of mortality was the severity of illness (APACHE II score > 19, adjusted odds ratio 49.5; 95% CI 1.7-1428.6; p 0.02). This case series suggests that administration of primary or adjunctive IT/IVT colistin therapy was effective for drug-resistant A. baumannii CNS infection.
Abdelbary, B E; Garcia-Viveros, M; Ramirez-Oropesa, H; Rahbar, M H; Restrepo, B I
The purpose of this study was to develop a method for identifying newly diagnosed tuberculosis (TB) patients at risk for TB adverse events in Tamaulipas, Mexico. Surveillance data between 2006 and 2013 (8431 subjects) was used to develop risk scores based on predictive modelling. The final models revealed that TB patients failing their treatment regimen were more likely to have at most a primary school education, multi-drug resistance (MDR)-TB, and few to moderate bacilli on acid-fast bacilli smear. TB patients who died were more likely to be older males with MDR-TB, HIV, malnutrition, and reporting excessive alcohol use. Modified risk scores were developed with strong predictability for treatment failure and death (c-statistic 0·65 and 0·70, respectively), and moderate predictability for drug resistance (c-statistic 0·57). Among TB patients with diabetes, risk scores showed moderate predictability for death (c-statistic 0·68). Our findings suggest that in the clinical setting, the use of our risk scores for TB treatment failure or death will help identify these individuals for tailored management to prevent these adverse events. In contrast, the available variables in the TB surveillance dataset are not robust predictors of drug resistance, indicating the need for prompt testing at time of diagnosis.
Fernández, Javier; Bert, Frédéric; Nicolas-Chanoine, Marie-Hélène
Antimicrobial resistance has become a major global public health security problem that needs coordinated approaches at regional, national and international levels. Antibiotic overuse and the failure of control measures to prevent the spread of resistant bacteria in the healthcare environment have led to an alarming increase in the number of infections caused by resistant bacteria, organisms that resist many (multi-drug and extensively drug-resistant strains), if not all (pan-drug-resistant bacteria) currently available antibiotics. While Gram-positive cocci resistance (methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci) shows a heterogeneous geographical distribution, extended-spectrum β-lactamase-producing Enterobacteriaceae and carbapenem-resistant Enterobacteriaceae have become pandemic worldwide and endemic in some parts of the world, respectively. Moreover, currently available therapeutic options for resistant bacteria are very limited, with very few new agents in development. Antimicrobial resistance is especially relevant in decompensated cirrhosis. Firstly, cirrhotic patients are highly susceptible to develop infections caused by resistant bacteria as risk factors of multiresistance concentrate in this population (mainly repeated hospitalizations and antibiotic exposure). Secondly, inappropriate empirical antibiotic schedules easily translate into increased morbidity (acute kidney injury, acute-on-chronic liver failure, septic shock) and hospital mortality in advanced cirrhosis. Therefore, hepatologists must face nowadays a complex clinical scenario that requires new empirical antibiotic strategies that may further spread resistance. Global, regional and local preventive measures should therefore be implemented to combat antimicrobial resistance in cirrhosis including the restriction of antibiotic prophylaxis to high-risk populations, investigation on non-antibiotic prophylaxis, stewardship programs on adequate antibiotic
Full Text Available Abstract Background The increasing levels of Plasmodium falciparum resistance to chloroquine (CQ in Thailand have led to the use of alternative antimalarials, which are at present also becoming ineffective. In this context, any strategies that help improve the surveillance of drug resistance, become crucial in overcoming the problem. Methods In the present study, we have established the in vitro sensitivity to CQ, mefloquine (MF, quinine (QUIN and amodiaquine (AMQ of 52 P. falciparum isolates collected in Thailand, and assessed the prevalence of four putative genetic polymorphisms of drug resistance, pfcrt K76T, pfmdr1 N86Y, pfmdr1 D1042N and pfmdr1 Y1246D, by PCR-RFLP. Results The percentage of isolates resistant to CQ, MF, and AMQ was 96% (50/52, 62% (32/52, and 58% (18/31, respectively, while all parasites were found to be sensitive to QUIN. In addition, 41 (79% of the isolates assayed were resistant simultaneously to more than one drug; 25 to CQ and MF, 9 to CQ and AMQ, and 7 to all three drugs, CQ, MF and AMQ. There were two significant associations between drug sensitivity and presence of particular molecular markers, i CQ resistance / pfcrt 76T (P = 0.001, and ii MF resistance / pfmdr1 86N (P Conclusions i In Thailand, the high levels of CQ pressure have led to strong selection of the pfcrt 76T polymorphism and ii pfmdr1 86N appears to be a good predictor of in vitro MF resistance.
Full Text Available Nearly one-third of newly diagnosed patients with epilepsy remain unresponsive to antiepileptic drugs (AEDs, etiopathogenesis of which is poorly understood. The genes encoding the proteins that regulate the pharmacokinetics such as P-glycoprotein [ABCBI], major vault protein [MVP gene] and drug metabolizing enzymes [ABCB1, ABCG2, MVP, CYP2C9, CYP2C19, CYP3A4, CYP3A5, EPHX1, UGT1A1, UGT2B7], and pharmacodynamics such as sodium channels [SCN1A, SCN2A] and GABA receptors [GABRA1, GABRA6, GABRB2, GABRG2] of AEDs are under intense investigation to unravel the mysteries of AED-resistance. However, till today, a consistent and reliable result that could help the clinician either to predict drug resistance or to overcome it has not been forthcoming. The discrepant results may be related to variations in the definition of drug-resistance, heterogeneous patient populations, ethnic variations in the frequency distribution of single nucleotide polymorphisms (SNPs and the selection of SNPs. Understanding of these limitations of existing studies, hopefully, will help in designing better studies. Nearly one-third of newly diagnosed patients with epilepsy remain unresponsive toantiepileptic drugs (AEDs, etiopathogenesis of which is poorly understood. The genesencoding the proteins that regulate the pharmacokinetics such as P-glycoprotein[ABCBI], major vault protein [MVP gene] and drug metabolizing enzymes [ABCB1,ABCG2, MVP, CYP2C9, CYP2C19, CYP3A4, CYP3A5, EPHX1, UGT1A1, UGT2B7],and pharmacodynamics such as sodium channels [SCN1A, SCN2A] and GABAreceptors [GABRA1, GABRA6, GABRB2, GABRG2] of AEDs are under intenseinvestigation to unravel the mysteries of AED-resistance. However, till today, aconsistent and reliable result that could help the clinician either to predict drugresistanceor to overcome it has not been forthcoming. The discrepant results may berelated to variations in the definition of drug-resistance, heterogeneous patientpopulations, ethnic
Ramos, Sónia; Silva, Nuno; Hébraud, Michel; Santos, Hugo M; Nunes-Miranda, Júlio Dinis; Pinto, Luís; Pereira, José E; Capelo, José-Luis; Poeta, Patrícia; Igrejas, Gilberto
Understanding global drug resistance demands an integrated vision, focusing on both human and veterinary medicine. Omics technologies offer new vistas to decipher mechanisms of drug resistance in the food chain. For example, Escherichia coli resistance to major antibiotics is increasing whereas multidrug resistance (MDR) strains are now commonly found in humans and animals. Little is known about the structural and metabolic changes in the cell that trigger resistance to antimicrobial agents. Proteomics is an emerging field that is used to advance our knowledge in global health and drug resistance in the food chain. In the present proteomic analysis, we offer an overview of the global protein expression of different MDR E. coli strains from fecal samples of pigs slaughtered for human consumption. A full proteomic survey of the drug-resistant strains SU60, SU62, SU76, and SU23, under normal growth conditions, was made by two-dimensional electrophoresis, identifying proteins by MALDI-TOF/MS. The proteomes of these four E. coli strains with different genetic profiles were compared in detail. Identical transport, stress response, or metabolic proteins were discovered in the four strains. Several of the identified proteins are essential in bacterial pathogenesis (GAPDH, LuxS, FKBPs), development of bacterial resistance (Omp's, TolC, GroEL, ClpB, or SOD), and potential antibacterial targets (FBPA, FabB, ACC's, or Fab1). Effective therapies against resistant bacteria are crucial and, to accomplish this, a comprehensive understanding of putative resistance mechanisms is essential. Moving forward, we suggest that multi-omics research will further improve our knowledge about bacterial growth and virulence on the food chain, especially under antibiotic stress.
Full Text Available The aim of this study was to establish the phylogenetic relationships of trypanosomes present in blood samples of Bolivian Carollia bats. Eighteen cloned stocks were isolated from 115 bats belonging to Carollia perspicillata (Phyllostomidae from three Amazonian areas of the Chapare Province of Bolivia and studied by xenodiagnosis using the vectors Rhodnius robustus and Triatoma infestans (Trypanosoma cruzi marenkellei or haemoculture (Trypanosoma dionisii. The PCR DNA amplified was analyzed by nucleotide sequences of maxicircles encoding cytochrome b and by means of the molecular size of hyper variable regions of minicircles. Ten samples were classified as Trypanosoma cruzi marinkellei and 8 samples as Trypanosoma dionisii. The two species have a different molecular size profile with respect to the amplified regions of minicircles and also with respect to Trypanosoma cruzi and Trypanosoma rangeli used for comparative purpose. We conclude the presence of two species of bat trypanosomes in these samples, which can clearly be identified by the methods used in this study. The presence of these trypanosomes in Amazonian bats is discussed.
Terefe, Endashaw; Haile, Aynalem; Mulatu, Wudyalew; Dessie, Tadelle; Mwai, Okeyo
The study was conducted to characterize the morphological features of Mursi cattle breed and to identify the species of trypanosome infecting the cattle and its prevalence in these traditionally managed cattle in the Bodi and Mursi pastoral communities. Cattle body description and measurements were made on 201 matured animals. Blood samples were collected from 409 animals into heparin-treated capillary tubes and were centrifuged to 12,000 rpm for 5 min to identify trypanosome species from the wet smeared buffy coat and to estimate the degree of anemia (PCV). Tsetse flies were collected using phenol-treated biconical trap and the caught flies identified to species level. The breed possesses variable coat color pattern, coat color type, and have small to medium hump size on the thoracic vertebrae. Body measurement of Mursi cattle in the two locations did not show significant differences except chest girth, rump width, and horn length. Trypanosome prevalence in the Mursi cattle breed was 6.1%. The highest trypanosome infection was caused by Trypanosoma congolense (56%) followed by Trypanosoma vivax (40%) and Trypanosoma brucei (4%). Trypanosome prevalence significantly varies between dry (2.0%) and late rainy (10.1%) seasons (P < 0.001) and between lean (11.9%) and medium (2.4%) body condition score (P < 0.01). The PCV value was 22.1 ± 0.5%, which is significantly varied with season (P < 0.01) and parasitism (P < 0.001). Parasitaemic cattle show the lowest PCV value (20.4 ± 1%) than aparasitaemic (23.7 ± 0.3%) cattle and cattle with lean BCS showed the lowest (P < 0.0001) PCV value (20.4 ± 0.6%). Tsetse fly species identified in the study area were Glossina pallidipes, Glossina morsitans submorsitans, and Glossina fuscipes. The number of flies captured in late rainy season was higher than in dry season (P < 0.01). Despite the existence of trypanosome and high tsetse fly infestation in the areas, large proportion of the Mursi
Mony, Binny M; Matthews, Keith R
African trypanosomes, parasites that cause human sleeping sickness, undergo a density-dependent differentiation in the bloodstream of their mammalian hosts. This process is driven by a released parasite-derived factor that causes parasites to accumulate in G1 and become quiescent. This is accompanied by morphological transformation to 'stumpy' forms that are adapted to survival and further development when taken up in the blood meal of tsetse flies, the vector for trypanosomiasis. Although the soluble signal driving differentiation to stumpy forms is unidentified, a recent genome-wide RNAi screen identified many of the intracellular signalling and effector molecules required for the response to this signal. These resemble components of nutritional starvation and quiescence pathways in other eukaryotes, suggesting that parasite development shares similarities with the adaptive quiescence of organisms such as yeasts and Dictyostelium in response to nutritional starvation and stress. Here, the trypanosome signalling pathway is discussed in the context of these conserved pathways and the possible contributions of opposing 'slender retainer' and 'stumpy inducer' arms described. As evolutionarily highly divergent eukaryotes, the organisation and conservation of this developmental pathway can provide insight into the developmental cycle of other protozoan parasites, as well as the adaptive and programmed developmental responses of all eukaryotic cells.
Full Text Available Understanding African Trypanosomiasis (AT host-pathogen interaction is the key to an "anti-disease vaccine", a novel strategy to control AT. Here we provide a better insight into this poorly described interaction by characterizing the activation of a panel of endothelial cells by bloodstream forms of four African trypanosome species, known to interact with host endothelium. T. congolense, T. vivax, and T. b. gambiense activated the endothelial NF-κB pathway, but interestingly, not T. b. brucei. The parasitic TS (trans-sialidases mediated this NF-κB activation, remarkably via their lectin-like domain and induced production of pro-inflammatory molecules not only in vitro but also in vivo, suggesting a considerable impact on pathogenesis. For the first time, TS activity was identified in T. b. gambiense BSF which distinguishes it from the subspecies T. b. brucei. The corresponding TS were characterized and shown to activate endothelial cells, suggesting that TS represent a common mediator of endothelium activation among trypanosome species with divergent physiopathologies.
Roesch, Alexander; Vultur, Adina; Bogeski, Ivan; Wang, Huan; Zimmermann, Katharina M.; Speicher, David; Körbel, Christina; Laschke, Matthias W.; Gimotty, Phyllis A.; Philipp, Stephan E.; Krause, Elmar; Pätzold, Sylvie; Villanueva, Jessie; Krepler, Clemens; Fukunaga-Kalabis, Mizuho; Hoth, Markus; Bastian, Boris; Vogt, Thomas; Herlyn, Meenhard
Summary Despite success with BRAFV600E–inhibitors, therapeutic responses in patients with metastatic melanoma are short-lived because of the acquisition of drug resistance. We identified a mechanism of intrinsic multi-drug resistance based on the survival of a tumor cell subpopulation. Treatment with various drugs, including cisplatin and vemurafenib, uniformly leads to enrichment of slow-cycling, long-term tumor-maintaining melanoma cells expressing the H3K4-demethylase JARID1B/KDM5B/PLU-1. Proteome-profiling revealed an upregulation in enzymes of mitochondrial oxidative-ATP-synthesis (OXPHOS) in this subpopulation. Inhibition of mitochondrial respiration blocked the emergence of the JARID1Bhigh subpopulation and sensitized melanoma cells to therapy, independent of their genotype. Our findings support a two-tiered approach combining anti-cancer agents that eliminate rapidly proliferating melanoma cells with inhibitors of the drug-resistant slow-cycling subpopulation. PMID:23764003
Elizabeth J Polvi
Full Text Available Fungal pathogens have evolved diverse strategies to sense host-relevant cues and coordinate cellular responses, which enable virulence and drug resistance. Defining circuitry controlling these traits opens new opportunities for chemical diversity in therapeutics, as the cognate inhibitors are rarely explored by conventional screening approaches. This has great potential to address the pressing need for new therapeutic strategies for invasive fungal infections, which have a staggering impact on human health. To explore this approach, we focused on a leading human fungal pathogen, Candida albicans, and screened 1,280 pharmacologically active compounds to identify those that potentiate the activity of echinocandins, which are front-line therapeutics that target fungal cell wall synthesis. We identified 19 compounds that enhance activity of the echinocandin caspofungin against an echinocandin-resistant clinical isolate, with the broad-spectrum chelator DTPA demonstrating the greatest synergistic activity. We found that DTPA increases susceptibility to echinocandins via chelation of magnesium. Whole genome sequencing of mutants resistant to the combination of DTPA and caspofungin identified mutations in the histidine kinase gene NIK1 that confer resistance to the combination. Functional analyses demonstrated that DTPA activates the mitogen-activated protein kinase Hog1, and that NIK1 mutations block Hog1 activation in response to both caspofungin and DTPA. The combination has therapeutic relevance as DTPA enhanced the efficacy of caspofungin in a mouse model of echinocandin-resistant candidiasis. We found that DTPA not only reduces drug resistance but also modulates morphogenesis, a key virulence trait that is normally regulated by environmental cues. DTPA induced filamentation via depletion of zinc, in a manner that is contingent upon Ras1-PKA signaling, as well as the transcription factors Brg1 and Rob1. Thus, we establish a new mechanism by which
Full Text Available INTRODUCTION: Rapid tests for rifampicin resistance may be useful for identifying isolates at high risk of drug resistance, including multidrug-resistant TB (MDR-TB. However, choice of diagnostic test and prevalence of rifampicin resistance may both impact a diagnostic strategy for identifying drug resistant-TB. We performed a systematic review to evaluate the performance of WHO-endorsed rapid tests for rifampicin resistance detection. METHODS: We searched MEDLINE, Embase and the Cochrane Library through January 1, 2012. For each rapid test, we determined pooled sensitivity and specificity estimates using a hierarchical random effects model. Predictive values of the tests were determined at different prevalence rates of rifampicin resistance and MDR-TB. RESULTS: We identified 60 publications involving six different tests (INNO-LiPA Rif. TB assay, Genotype MTBDR assay, Genotype MTBDRplus assay, Colorimetric Redox Indicator (CRI assay, Nitrate Reductase Assay (NRA and MODS tests: for all tests, negative predictive values were high when rifampicin resistance prevalence was ≤ 30%. However, positive predictive values were considerably reduced for the INNO-LiPA Rif. TB assay, the MTBDRplus assay and MODS when rifampicin resistance prevalence was < 5%. LIMITATIONS: In many studies, it was unclear whether patient selection or index test performance could have introduced bias. In addition, we were unable to evaluate critical concentration thresholds for the colorimetric tests. DISCUSSION: Rapid tests for rifampicin resistance alone cannot accurately predict rifampicin resistance or MDR-TB in areas with a low prevalence of rifampicin resistance. However, in areas with a high prevalence of rifampicin resistance and MDR-TB, these tests may be a valuable component of an MDR-TB management strategy.
Averette, Anna F.; Lee, Soo Chan; Kim, Taeyup; Bahn, Yong-Sun; Robbins, Nicole; Heitman, Joseph; Cowen, Leah E.
Fungal pathogens have evolved diverse strategies to sense host-relevant cues and coordinate cellular responses, which enable virulence and drug resistance. Defining circuitry controlling these traits opens new opportunities for chemical diversity in therapeutics, as the cognate inhibitors are rarely explored by conventional screening approaches. This has great potential to address the pressing need for new therapeutic strategies for invasive fungal infections, which have a staggering impact on human health. To explore this approach, we focused on a leading human fungal pathogen, Candida albicans, and screened 1,280 pharmacologically active compounds to identify those that potentiate the activity of echinocandins, which are front-line therapeutics that target fungal cell wall synthesis. We identified 19 compounds that enhance activity of the echinocandin caspofungin against an echinocandin-resistant clinical isolate, with the broad-spectrum chelator DTPA demonstrating the greatest synergistic activity. We found that DTPA increases susceptibility to echinocandins via chelation of magnesium. Whole genome sequencing of mutants resistant to the combination of DTPA and caspofungin identified mutations in the histidine kinase gene NIK1 that confer resistance to the combination. Functional analyses demonstrated that DTPA activates the mitogen-activated protein kinase Hog1, and that NIK1 mutations block Hog1 activation in response to both caspofungin and DTPA. The combination has therapeutic relevance as DTPA enhanced the efficacy of caspofungin in a mouse model of echinocandin-resistant candidiasis. We found that DTPA not only reduces drug resistance but also modulates morphogenesis, a key virulence trait that is normally regulated by environmental cues. DTPA induced filamentation via depletion of zinc, in a manner that is contingent upon Ras1-PKA signaling, as well as the transcription factors Brg1 and Rob1. Thus, we establish a new mechanism by which metal chelation
Full Text Available [ Credits ] BLAST Search Image Search Home About Archive Update History Contact us Trypanosomes Database... Database Description General information of database Database name Trypanosomes Database...rmation and Systems Yata 1111, Mishima, Shizuoka 411-8540, JAPAN E mail: Database... classification Protein sequence databases Organism Taxonomy Name: Trypanosoma Taxonomy ID: 5690 Taxonomy Na...me: Homo sapiens Taxonomy ID: 9606 Database description The Trypanosomes database is a database providing th
Menachery, Anoop; Kremer, Clemens; Wong, Pui E.; Carlsson, Allan; Neale, Steven L.; Barrett, Michael P.; Cooper, Jonathan M.
Human African trypanosomiasis or sleeping sickness is a deadly disease endemic in sub-Saharan Africa, caused by single-celled protozoan parasites. Although it has been targeted for elimination by 2020, this will only be realized if diagnosis can be improved to enable identification and treatment of afflicted patients. Existing techniques of detection are restricted by their limited field-applicability, sensitivity and capacity for automation. Microfluidic-based technologies offer the potential for highly sensitive automated devices that could achieve detection at the lowest levels of parasitemia and consequently help in the elimination programme. In this work we implement an electrokinetic technique for the separation of trypanosomes from both mouse and human blood. This technique utilises differences in polarisability between the blood cells and trypanosomes to achieve separation through opposed bi-directional movement (cell counterflow). We combine this enrichment technique with an automated image analysis detection algorithm, negating the need for a human operator.
Chimukangara, Benjamin; Varyani, Bhavini; Shamu, Tinei; Mutsvangwa, Junior; Manasa, Justen; White, Elizabeth; Chimbetete, Cleophas; Luethy, Ruedi; Katzenstein, David
HIV genotyping is often unavailable in low and middle-income countries due to infrastructure requirements and cost. We compared genotype resistance testing in patients with virologic failure, by amplification of HIV pol gene, followed by "in-house" sequencing and commercial sequencing. Remnant plasma samples from adults and children failing second-line ART were amplified and sequenced using in-house and commercial di-deoxysequencing, and analyzed in Harare, Zimbabwe and at Stanford, U.S.A, respectively. HIV drug resistance mutations were determined using the Stanford HIV drug resistance database. Twenty-six of 28 samples were amplified and 25 were successfully genotyped. Comparison of average percent nucleotide and amino acid identities between 23 pairs sequenced in both laboratories were 99.51 (±0.56) and 99.11 (±0.95), respectively. All pairs clustered together in phylogenetic analysis. Sequencing analysis identified 6/23 pairs with mutation discordances resulting in differences in phenotype, but these did not impact future regimens. The results demonstrate our ability to produce good quality drug resistance data in-house. Despite discordant mutations in some sequence pairs, the phenotypic predictions were not clinically significant. Copyright © 2016 Elsevier B.V. All rights reserved.
Hao, Ge-Fei; Zhu, Xiao-Lei; Ji, Feng-Qin; Zhang, Li; Yang, Guang-Fu; Zhan, Chang-Guo
Protoporphyrinogen oxidase (PPO; EC 188.8.131.52) is the last common enzyme for the enzymatic transformation of protoporphyrinogen-IX to protoporphyrin-IX, which is the key common intermediate leading to heme and chlorophyll. Hence, PPO has been identified as one of the most importance action targets for the treatment of some important diseases including cancer and variegated porphyria (VP). In the agricultural field, PPO inhibitors have been used as herbicides for many years. Recently, a unique drug resistance was found to be associated with a nonactive site residue (Gly210) deletion rather than substitution in A. tuberculatus PPO. In the present study, extensive computational simulations, including homology modeling, molecular dynamics (MD) simulations, and molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) calculations, have been carried out to uncover the detailed molecular mechanism of drug resistance associated with Gly210 deletion. Although Gly210 in the wild-type A. tuberculatus PPO has no direct interaction with the inhibitors, all the computational models and energetic results indicated that Gly210 deletion has great effects on the hydrogen-bonding network and the conformational change of the binding pocket. An interchain hydrogen bond between Gly210 with Ser424, playing an important role in stabilizing the local conformation of the wild-type enzyme, disappeared after Gly210 deletion. As a result, the mutant-type PPO has a lower affinity than the wild-type enzyme, which accounts for the molecular mechanism of drug resistance. The structural and mechanistic insights obtained from the present study provide a new starting point for future rational design of novel PPO inhibitors to overcome drug resistance associated with Gly210 deletion.
Full Text Available Combinatorial libraries of artificial zinc-finger transcription factors (ZF-TFs provide a robust tool for inducing and understanding various functional components of the cancer phenotype. Herein, we utilized combinatorial ZF-TF library technology to better understand how breast cancer cells acquire resistance to fulvestrant, a clinically important anti-endocrine therapeutic agent. From a diverse collection of nearly 400,000 different ZF-TFs, we isolated six ZF-TF library members capable of inducing stable, long-term anti-endocrine drug-resistance in two independent estrogen receptor-positive breast cancer cell lines. Comparative gene expression profile analysis of the six different ZF-TF-transduced breast cancer cell lines revealed five distinct clusters of differentially expressed genes. One cluster was shared among all 6 ZF-TF-transduced cell lines and therefore constituted a common fulvestrant-resistant gene expression signature. Pathway enrichment-analysis of this common fulvestrant resistant signature also revealed significant overlap with gene sets associated with an estrogen receptor-negative-like state and with gene sets associated with drug resistance to different classes of breast cancer anti-endocrine therapeutic agents. Enrichment-analysis of the four remaining unique gene clusters revealed overlap with myb-regulated genes. Finally, we also demonstrated that the common fulvestrant-resistant signature is associated with poor prognosis by interrogating five independent, publicly available human breast cancer gene expression datasets. Our results demonstrate that artificial ZF-TF libraries can be used successfully to induce stable drug-resistance in human cancer cell lines and to identify a gene expression signature that is associated with a clinically relevant drug-resistance phenotype.
Full Text Available Human African trypanosomiasis or sleeping sickness is a vector-borne parasitic disease that has a major impact on human health and welfare in sub-Saharan countries. Based mostly on data from animal models, it is currently thought that trypanosome entry into the brain occurs by initial infection of the choroid plexus and the circumventricular organs followed days to weeks later by entry into the brain parenchyma. However, Trypanosoma brucei bloodstream forms rapidly cross human brain microvascular endothelial cells in vitro and appear to be able to enter the murine brain without inflicting cerebral injury. Using a murine model and intravital brain imaging, we show that bloodstream forms of T. b. brucei and T. b. rhodesiense enter the brain parenchyma within hours, before a significant level of microvascular inflammation is detectable. Extravascular bloodstream forms were viable as indicated by motility and cell division, and remained detectable for at least 3 days post infection suggesting the potential for parasite survival in the brain parenchyma. Vascular inflammation, as reflected by leukocyte recruitment and emigration from cortical microvessels, became apparent only with increasing parasitemia at later stages of the infection, but was not associated with neurological signs. Extravascular trypanosomes were predominantly associated with postcapillary venules suggesting that early brain infection occurs by parasite passage across the neuroimmunological blood brain barrier. Thus, trypanosomes can invade the murine brain parenchyma during the early stages of the disease before meningoencephalitis is fully established. Whether individual trypanosomes can act alone or require the interaction from a quorum of parasites remains to be shown. The significance of these findings for disease development is now testable.
Full Text Available Overexpression of human epidermal growth factor receptor (HER-2 occurs in 20–30% of breast cancers and confers survival and proliferative advantages on the tumour cells making HER-2 an ideal therapeutic target for drugs like Herceptin. Continued delineation of tumour biology has identified splice variants of HER-2, with contrasting roles in tumour cell biology. For example, the splice variant 16HER-2 (results from exon 16 skipping increases transformation of cancer cells and is associated with treatment resistance; conversely, Herstatin (results from intron 8 retention and p100 (results from intron 15 retention inhibit tumour cell proliferation. This review focuses on the potential clinical implications of the expression and coexistence of HER-2 splice variants in cancer cells in relation to breast cancer progression and drug resistance. “Individualised” strategies currently guide breast cancer management; in accordance, HER-2 splice variants may prove valuable as future prognostic and predictive factors, as well as potential therapeutic targets.
Wang, Xu; Wang, He; Liu, Man-Qing; Li, Jie-Liang; Zhou, Run-Hong; Zhou, Yu; Wang, Yi-Zhong; Zhou, Wang; Ho, Wen-Zhe
Type III interferons (IFN-λs) have been demonstrated to inhibit a number of viruses, including HIV. Here, we further examined the anti-HIV effect of IFN-λs in macrophages. We found that IFN-λs synergistically enhanced anti-HIV activity of antiretrovirals [azidothymidine (AZT), efavirenz, indinavir, and enfuvirtide] in infected macrophages. Importantly, IFN-λs could suppress HIV infection of macrophages with the drug-resistant strains, including AZT-resistant virus (A012) and reverse transcriptase inhibitor-resistant virus (TC49). Mechanistically, IFN-λs were able to induce the expression of several important anti-HIV cellular factors, including myxovirus resistance 2 (Mx2), a newly identified HIV post-entry inhibitor and tetherin, a restriction factor that blocks HIV release from infected cells. These observations provide additional evidence to support the potential use of IFN-λs as therapeutics agents for the treatment of HIV infection. PMID:28321215
Full Text Available A total of 1021 randomly selected serum samples of adult male goats that had been screened for trypanosome infection were assayed for sperm antibodies using the immunoperoxidase staining technique. The result of the trypanosome screening revealed that 586(57.39% goats were positive for trypanosome infection, while 435(42.61% were negative. The assay for sperm antibodies showed that 482(47.21% animals were positive, while 539(52.79% were negative. In the group that was positive for trypanosome infection, 364(62.12% animals were positive, whereas 222(37.88% were negative for sperm antibodies (P<0.001. The group that was negative for trypanosome infection, had a significantly lower number and proportion 118(27.13% of positive compared to 317(72.87% negative for sperm antibodies. Out of a total 482 goats that were positive for sperm antibodies, a significantly higher number, 364(75.52%, were positive than 118(24.48% that were negative for trypanosome infection (P<0.001. In the group that was found negative for sperm antibodies, a significantly lower proportion, 222(41.19%, was positive compared to 317(58.81% that were negative for trypanosome infection (P<0.001. Seropositivity to sperm antibodies was positively correlated to trypanosome infection (P<0.001. Further work on the pathogenesis of sperm antibody production in trypanosome infection is advocated.
Full Text Available List Contact us Trypanosomes Database Update History of This Database Date Update contents 2014/05/07 The co...ntact information is corrected. The features and manner of utilization of the database are corrected. 2014/02/04 Trypanosomes Databas...e English archive site is opened. 2011/04/04 Trypanosomes Database ( http://www.tan...paku.org/tdb/ ) is opened. About This Database Database Description Download Lice...nse Update History of This Database Site Policy | Contact Us Update History of This Database - Trypanosomes Database | LSDB Archive ...
Full Text Available Acinetobacter baumannii is one of the most important opportunistic pathogens that causes serious health care associated complications in critically ill patients. In the current study we report on the diversity of the clinical multi-drug resistant A. baumannii in Kuwait by molecular characterization. One hundred A. baumannii were isolated from one of the largest governmental hospitals in Kuwait. Following the identification of the isolates by molecular methods, the amplified blaOXA-51-like gene product of one isolate (KO-12 recovered from blood showed the insertion of the ISAba19 at position 379 in blaOXA-78. Of the 33 multi-drug resistant isolates, 28 (85% contained blaOXA-23, 2 (6% blaOXA-24 and 6 (18% blaPER-1 gene. We did not detect blaOXA-58, blaVIM, blaIMP, blaGES, blaVEB and blaNDM genes in any of the tested isolates. In 3 blaPER-1 positive isolates the genetic environment of blaPER-1 consisted of two copies of ISPa12 (tnpiA1 surrounding the blaPER-1 gene on a highly stable plasmid of ca. 140-kb. MLST analysis of the 33 A. baumannii isolates identified 20 different STs, of which 6 (ST-607, ST-608, ST-609, ST-610, ST-611 and ST-612 were novel. Emerging STs such as ST15 (identified for the first time in the Middle East, ST78 and ST25 were also detected. The predominant clonal complex was CC2. PFGE and MLST defined the MDR isolates as multi-clonal with diverse lineages. Our results lead us to believe that A. baumannii is diverse in clonal origins and / or is undergoing clonal expansion continuously while multiple lineages of MDR A. baumannii circulate in hospital wards simultaneously.
Artzy-Randrup, Yael; Alonso, David; Pascual, Mercedes
Although the spread of drug resistance and the influence of climate change on malaria are most often considered separately, these factors have the potential to interact through altered levels of transmission intensity. The influence of transmission intensity on the evolution of drug resistance has b
Cho, Sun Young; Baek, Jin Yang; Kang, Cheol-In; Kim, So Hyun; Ha, Young Eun; Chung, Doo Ryeon; Lee, Nam Yong; Peck, Kyong Ran; Song, Jae-Hoon
To better understand extensively drug resistant Streptococcus pneumoniae, we assessed clinical and microbiological characteristics of 5 extensively drug-resistant pneumococcal isolates. We concluded that long-term care facility residents who had undergone tracheostomy might be reservoirs of these pneumococci; 13- and 23-valent pneumococcal vaccines should be considered for high-risk persons; and antimicrobial drugs should be used judiciously.
Full Text Available Abstract Background Multi-drug-resistant Mycobacterium tuberculosis has been an important problem in public health around the world. However, limited information about disinfectant-susceptibility of multi-drug-resistant strain of M. tuberculosis was available. Findings We studied susceptibility of several Japanese isolates of multi-drug-resistant M. tuberculosis against disinfectants, which are commonly used in clinical and research laboratories. We selected a laboratory reference strain (H37Rv and eight Japanese isolates, containing five drug-susceptible strains and three multi-drug-resistant strains, and determined profiles of susceptibility against eight disinfectants. The M. tuberculosis strains were distinguished into two groups by the susceptibility profile. There was no relationship between multi-drug-resistance and disinfectant-susceptibility in the M. tuberculosis strains. Cresol soap and oxydol were effective against all strains we tested, regardless of drug resistance. Conclusions Disinfectant-resistance is independent from multi-drug-resistance in M. tuberculosis. Cresol soap and oxydol were effective against all strains we tested, regardless of drug resistance.
Conclusion: As Belarus is a high-burden MDR-TB country and treatment of drug-resistant TB is long and complicated, the findings of this study provided useful information to deliver effective community-based disease control measures and a proposed plane for the effective management of drug-resistant TB at the national level.
Nicita, Francesco; Spalice, Alberto; Papetti, Laura;
Verapamil, a voltage-gated calcium channel blocker, has been occasionally reported to have some effect on reducing seizure frequency in drug-resistant epilepsy or status epilepticus. We aimed to investigate the efficacy of verapamil as add-on treatment in children with drug-resistant epilepsy....
D. Frentz (Dineke); D.A.M.C. van de Vijver (David); A.B. Abecasis (Ana ); J. Albert (Jan); O. Hamouda (Osamah); L.B. Jørgensen (Louise); C. Kücherer (Claudia); D. Struck (Daniel); J.-C. Schmit (Jean-Claude); J. Vercauteren (Jurgen); B. Åsjö (Birgitta); C. Balotta (Claudia); P. Bergin; D. Beshkov (Danail); R.J. Camacho (Ricardo Jorge); B. Clotet (Bonaventura); A. Griskevicius (Algis); Z. Grossman (Zehava); A. Horban (Andrzej); T. Kolupajeva (Tatjana); K. Korn (Klaus); L.G. Kostrikis (Leondios); K.L.M. Linka (Kirsi Liitsola Marek); C. Nielsen (Claus); D. Otelea (Dan); D. Paraskevis (Dimitrios); R. Paredes (Roger); M. Poljak (Mario); E. Puchhammer-Stöckl (Elisabeth); A. Sonnerborg (Anders); D. Stanekova (Danica); M. Stanojevic (Maja); A.M. Vandamme (Anne Mieke); C.A. Boucher (Charles); A.M.J. Wensing (Annemarie)
textabstractBackground: In Europe, a continuous programme (SPREAD) has been in place for ten years to study transmission of drug resistant HIV. We analysed time trends of transmitted drug resistance mutations (TDRM) in relation to the risk behaviour reported. Methods: HIV-1 patients newly diagnosed
Zhang, Mei-hua; Lu, Feng; Cao, Jun; Gao, Qi
Effective chemotherapy is the mainstay of malaria control. However, it is undergoing the serious threat by resis- tance of falciparum malaria to antimalarial drugs. In recent years, with the development of molecular biology technology, molec- ular markers have been widely used to monitor antimalarial drug resistance. This paper reviews the researches on the common molecular markers related to Plasmodiumfalciparum drug resistance.
Surajit Lahiri; Abhijit Mukherjee; Supabitra Hazra; Pulak Jana; Sandip Roy; Brojo Kishore Saha
Background: Programmatic management of drug-resistant TB (PMDT) under the RNTCP is being implemented in West Bengal in a phased manner since 2011. During the initial years MDR-TB cases were identified based on criteria A. This study examines the first line anti-tubercular drug resistance pattern of mycobacteria cultured from sputum samples of MDR suspects who were retreatment cases smear positive from 4 th month onwards. Materials and Methods: In the following retrospective record based study...
Full Text Available Linda Dalic,1 Mark J Cook2,3 1Department of Neurology, Austin Health, 2St Vincent’s Hospital, Centre for Clinical Neurosciences and Neurological Research, 3Department of Medicine, The University of Melbourne, Melbourne, Australia Abstract: Despite the development of new antiepileptic drugs (AEDs, ~20%–30% of people with epilepsy remain refractory to treatment and are said to have drug-resistant epilepsy (DRE. This multifaceted condition comprises intractable seizures, neurobiochemical changes, cognitive decline, and psychosocial dysfunction. An ongoing challenge to both researchers and clinicians alike, DRE management is complicated by the heterogeneity among this patient group. The underlying mechanism of DRE is not completely understood. Many hypotheses exist, and relate to both the intrinsic characteristics of the particular epilepsy (associated syndrome/lesion, initial response to AED, and the number and type of seizures prior to diagnosis and other pharmacological mechanisms of resistance. The four current hypotheses behind pharmacological resistance are the “transporter”, “target”, “network”, and “intrinsic severity” hypotheses, and these are reviewed in this paper. Of equal challenge is managing patients with DRE, and this requires a multidisciplinary approach, involving physicians, surgeons, psychiatrists, neuropsychologists, pharmacists, dietitians, and specialist nurses. Attention to comorbid psychiatric and other diseases is paramount, given the higher prevalence in this cohort and associated poorer health outcomes. Treatment options need to consider the economic burden to the patient and the likelihood of AED compliance and tolerability. Most importantly, higher mortality rates, due to comorbidities, suicide, and sudden death, emphasize the importance of seizure control in reducing this risk. Overall, resective surgery offers the best rates of seizure control. It is not an option for all patients, and there is
Laxminarayan, Ramanan; Klugman, Keith P
Background Antibiotic resistance is a growing problem worldwide, but communicating this challenge to policymakers and non-experts is complicated by the multiplicity of bacterial pathogens and the distinct classes of antibiotics used to treat them. It is difficult, even for experts aware of the pharmacodynamics of antibiotics, to infer the seriousness of resistance without information on how commonly the antibiotic is being used and whether alternative antibiotics are available. Difficulty in aggregating resistance to multiple drugs to assess trends poses a further challenge to quantifying and communicating changes in resistance over time and across locations. Methods We developed a method for aggregating bacterial resistance to multiple antibiotics, creating an index comparable to the composite economic indices that measure consumer prices and stock market values. The resulting drug resistance index (DRI) and various subindices show antibiotic resistance and consumption trends in the USA but can be applied at any geographical level. Findings The DRI based on use patterns in 1999 for Escherichia coli rose from 0.25 (95% CI 0.23 to 0.26) to 0.30 (95% CI 0.29 to 0.32) between 1999 and 2006. However, the adaptive DRI, which includes treatment of baseline resistant strains with alternative agents, climbed from 0.25 to 0.27 (95% CI 0.25 to 0.28) during that period. In contrast, both the static-use and the adaptive DRIs for Acinetobacter spp. rose from 0.41 (95% CI 0.4 to 0.42) to 0.48 (95% CI 0.46 to 0.49) between 1999 and 2006. Interpretation Divergence between the static-use and the adaptive-use DRIs for E coli reflects the ability of physicians to adapt to increasing resistance. However, antibiotic use patterns did not change much in response to growing resistance to Acinetobacter spp. because physicians were unable to adapt; new drugs for Acinetobacter spp. are therefore needed. Composite indices that aggregate resistance to various drugs can be useful for assessing
DAI Ning; ZHANG Wei; LI Jia-shu; YU Qin; WAN Huan-ying; MU Lan; ZHONG Xiao-ning; WEI Li-ping; MA Jian-jun; WANG Qiu-yue; HU Ke; LI De-zhi; TIAN Gui-zhen; CAI Shao-xi; WANG Rui-qin; HE Bei; WANG Si-qin; WANG Zhan-wei; ZHAO Su-rui; GAO Zhan-cheng; CHEN Ji-chao; CHEN Yu-sheng; GENG Rong; HU Ying-hui; YANG Jing-ping; DU Juan; HU Cheng-ping
Background Acinetobacter baumanii (A. baumanii) remains an important microbial pathogen resulting in nosocomial acquired infections with significant morbidity and mortality. The mechanism by which nosocomial bacteria, like A.baumanii, attain multidrug resistance to antibiotics is of considerable interest. The aim in this study was to investigate the spread status of antibiotic resistance genes, such as multiple β-lactamase genes and aminoglycoside-modifying enzyme genes, from A. baumanii strains isolated from patients with lower respiratory tract infections (LRTIs).Methods Two thousand six hundred and ninety-eight sputum or the bronchoalveolar lavage samples from inpatients with LRTIs were collected in 21 hospitals in the mainland of China from November 2007 to February 2009. All samples were routinely inoculated. The isolated bacterial strains and their susceptibility were analyzed via VITEK-2 expert system.Several kinds of antibiotic resistant genes were further differentiated via polymerase chain reaction and sequencing methods.Results Totally, 39 A. baumanii strains were isolated from 2698 sputum or bronchoalveolar lavage samples. There was not only a high resistant rate of the isolated A. baumanii strains to ampicillin and first- and second-generation cephalosporins (94.87%, 100% and 97.44%, respectively), but also to the third-generation cephalosporins (ceftriaxone at 92.31%, ceftazidine at 51.28%) and imipenem (43.59%) as well. The lowest antibiotic resistance rate of 20.51% was found to amikacin. The OXA-23 gene was identified in 17 strains of A. baumanii, and the AmpC gene in 23 strains. The TEM-1 gene was carried in 15 strains. PER-1 and SHV-2 genes were detected in two different strains.Aminoglycoside-modifying enzyme gene aac-3-la was found in 23 strains, and the aac-6'-lb gene in 19 strains, aac-3-la and aac-6'-lb genes hibernated in three A. baumanii strains that showed no drug-resistant phenotype.Conclusions A. baumaniican carry multiple drug-resistant
Kazem Baesi; Majedeh Moradbeigi; Mehrdad Ravanshad; Ashrafolnesa Baghban
Objective: To survey the level and patterns of reverse transcriptase-based drug resistance and subtype distribution among antiretroviral-treated HIV-infected patients receiving only reverse transcriptase inhibitors in Iran. Methods: A total of 25 samples of antiretroviral therapy experienced patients with no history of using protease inhibitors were collected. After RNA extraction, reverse transcriptase-nested PCR was performed. The final products were sequenced and then analysed for drug-resistant mutations and subtypes. Results: No drug resistant mutations were observed among the 25 subjects. The results showed the following subtypes among patients:CRF 35_AD (88%), CRF 28_BF (8%), and CRF 29_BF (4%). Conclusions: A significant increase in drug resistance has been noted in recently-infected patients worldwide. Subtype distributions are needed to perform properly-designed surveillance studies to continuously monitor rates and patterns of transmitted drug resistance and subtypes to help guide therapeutic approaches and limit transmission of these variants.
Wu, Hao; Xia, Shibo; Bu, Fanyun; Qi, Jing; Liu, Yuqing; Xu, Hai
The dissemination of drug-resistant Escherichia coli in poultry products is becoming a public concern, as it endangers food security and human health. It is very common for E. coli to exhibit drug resistance in the poultry industry in China due to the excessive use of antibiotics. However, few studies have examined the drug resistance endowed by integrons and integron-associated gene cassettes in different phylogenetic groups of E. coli isolated from broiler carcasses. In this study, 373 antibiotic-resistant E. coli strains were isolated from the surfaces or insides of broiler carcasses from a slaughterhouse in Shandong Province, China. According to phylogenetic assays of chuA, yjaA, and an anonymous DNA fragment, TSPE4-C2, these isolates belong to four phylogenetic groups (A, B1, B2, and D) and seven subgroups (A0, A1, B1, B21, B22, D1, and D2). Of the tested isolates, 95.71% (n=357) are multi-drug resistant, among which group B1 was predominant, accounting for 33.51% (n=125) of the tested isolates. A high percentage of the E. coli isolates were resistant to amoxicillin-clavulanic acid (99.20%, n=370), doxycycline (92.23%, n=344), sulfamethoxazole-trimethoprim (90.88%, n=339), ciprofloxacin, (64.61%, n=241), sulbactam-cefoperazone (51.21%, n=191), and amikacin (33.78%, n=126). Furthermore, among the 373 isolates, class 1 and 2 integrons were identified in 292 (78.28%) and 49 (13.14%) of the isolates, respectively, while no class 3 integrons were detected. The most prevalent gene cassette arrays were dfrA17-aadA5 and dfrA12-orfF-aadA2 in the variable region of class 1 integrons, while only one gene cassette array (dfrA1-sat2-aadA1) was detected in the variable region of class 2 integrons. Class 1 integrons were distributed in various physiological subtypes, whereas no predominant phylogenetic groups could be identified. The presence of class 2 integrons in the B21 subtype was significantly higher than in the other subtypes, and it coexisted with the class 1
Full Text Available Abstract Background Anti-malarial drug resistance poses a threat to current global efforts towards control and elimination of malaria. Several methods are used in monitoring anti-malarial drug resistance. Molecular markers such as single nucleotide polymorphism (SNP for example are increasingly being used to identify genetic mutations related to anti-malarial drug resistance. Several methods are currently being used in analysis of SNP associated with anti-malarial drug resistance and although each one of these methods has unique strengths and shortcoming, there is still need to improve and/or develop new methods that will close the gap found in the current methods. Methods TaqMan Allelic Discrimination assays for detection of SNPs associated with anti-malarial drug resistance were designed for analysis on Applied Biosystems PCR platform. These assays were designed by submitting SNP sequences associated with anti-malarial drug resistance to Applied Biosystems website. Eleven SNPs associated with resistance to anti-malarial drugs were selected and tested. The performance of each SNP assay was tested by creating plasmid DNAs carrying codons of interests and analysing them for analysis. To test the sensitivity and specificity of each SNP assay, 12 clinical samples were sequenced at codons of interest and used in the analysis. Plasmid DNAs were used to establish the Limit of Detection (LoD for each assay. Results Data from genetic profiles of the Plasmodium falciparum laboratory strains and sequence data from 12 clinical samples was used as the reference method with which the performance of the SNP assays were compared to. The sensitivity and specificity of each SNP assay was establish at 100%. LoD for each assay was established at 2 GE, equivalent to less than 1 parasite/μL. SNP assays performed well in detecting mixed infection and analysis of clinical samples. Conclusion TaqMan Allelic Discrimination assay provides a good alternative tool in
Wragg, Joseph W; Heath, Victoria L; Bicknell, Roy
Anti-angiogenic therapies have failed to confer survival benefits in patients with metastatic breast cancer (mBC). However, to date there has not been an inquiry into roles for acquired versus innate drug resistance in this setting. In this study, we report roles for these distinct phenotypes in determining therapeutic response in a murine model of mBC resistance to the anti-angiogenic tyrosine kinase inhibitor sunitinib. Using tumor measurement and vascular patterning approaches, we differentiated tumors displaying innate versus acquired resistance. Bioluminescent imaging of tumor metastases to the liver, lungs and spleen revealed that sunitinib administration enhances metastasis, but only in tumors displaying innate resistance to therapy. Transcriptomic analysis of tumors displaying acquired versus innate resistance allowed the identification of specific biomarkers, many of which have a role in angiogenesis. In particular, aquaporin-1 upregulation occurred in acquired resistance, mTOR in innate resistance, and pleiotrophin in both settings, suggesting their utility as candidate diagnostics to predict drug response or to design tactics to circumvent resistance. Our results unravel specific features of antiangiogenic resistance, with potential therapeutic implications. PMID:28011623
Full Text Available Abstract Background Malaria parasites that concurrently infect a host compete on the basis of their intrinsic growth rates and by stimulating cross-reactive immune responses that inhibit each others' growth. If the phenotypes also show different drug sensitivities ('sensitive' vs. 'resistant' strains, drug treatment can change their joint dynamics and the long-term outcome of the infection: most obviously, persistent drug pressure can permit the more resistant, but otherwise competitively-inferior, strains to dominate. Methods Here a mathematical model is developed to analyse how these and more subtle effects of antimalarial drug use are modulated by immune response, repeated re-inoculation of parasites, drug pharmacokinetic parameters, dose and treatment frequency. Results The model quantifies possible effects of single and multiple (periodic treatment on the outcome of parasite competition. In the absence of further inoculation, the dosage and/or treatment frequency required for complete clearance can be estimated. With persistent superinfection, time-average parasite densities can be derived in terms of the basic immune-regulating parameters, the drug efficacy and treatment regimen. Conclusion The functional relations in the model are applicable to a wide range of conditions and transmission environments, allowing predictions to be made on both the individual and the community levels, and, in particular, transitions from drug-sensitive to drug-resistant parasite dominance to be projected on both levels.
Full Text Available Tumor heterogeneity has been compared with Darwinian evolution and survival of the fittest. The evolutionary ecosystem of tumors consisting of heterogeneous tumor cell populations represents a considerable challenge to tumor therapy, since all genetically and phenotypically different subpopulations have to be efficiently killed by therapy. Otherwise, even small surviving subpopulations may cause repopulation and refractory tumors. Single-cell sequencing allows for a better understanding of the genomic principles of tumor heterogeneity and represents the basis for more successful tumor treatments. The isolation and sequencing of single tumor cells still represents a considerable technical challenge and consists of three major steps: (1 single cell isolation (e.g., by laser-capture microdissection, fluorescence-activated cell sorting, micromanipulation, whole genome amplification (e.g., with the help of Phi29 DNA polymerase, and transcriptome-wide next generation sequencing technologies (e.g., 454 pyrosequencing, Illumina sequencing, and other systems. Data demonstrating the feasibility of single-cell sequencing for monitoring the emergence of drug-resistant cell clones in patient samples are discussed herein. It is envisioned that single-cell sequencing will be a valuable asset to assist the design of regimens for personalized tumor therapies based on tumor subpopulation-specific genetic alterations in individual patients.
Pielak, Rafal M; Chou, James J
The M2 proteins of influenza A and B virus, AM2 and BM2, respectively, are transmembrane proteins that oligomerize in the viral membrane to form proton-selective channels. Proton conductance of the M2 proteins is required for viral replication; it is believed to equilibrate pH across the viral membrane during cell entry and across the trans-Golgi membrane of infected cells during viral maturation. In addition to the role of M2 in proton conductance, recent mutagenesis and structural studies suggest that the cytoplasmic domains of the M2 proteins also play a role in recruiting the matrix proteins to the cell surface during virus budding. As viral ion channels of minimalist architecture, the membrane-embedded channel domain of M2 has been a model system for investigating the mechanism of proton conduction. Moreover, as a proven drug target for the treatment of influenza A infection, M2 has been the subject of intense research for developing new anti-flu therapeutics. AM2 is the target of two anti-influenza A drugs, amantadine and rimantadine, both belonging to the adamantane class of compounds. However, resistance of influenza A to adamantane is now widespread due to mutations in the channel domain of AM2. This review summarizes the structure and function of both AM2 and BM2 channels, the mechanism of drug inhibition and drug resistance of AM2, as well as the development of new M2 inhibitors as potential anti-flu drugs.
Rodrigues, João V; Bershtein, Shimon; Li, Anna; Lozovsky, Elena R; Hartl, Daniel L; Shakhnovich, Eugene I
Fitness landscapes of drug resistance constitute powerful tools to elucidate mutational pathways of antibiotic escape. Here, we developed a predictive biophysics-based fitness landscape of trimethoprim (TMP) resistance for Escherichia coli dihydrofolate reductase (DHFR). We investigated the activity, binding, folding stability, and intracellular abundance for a complete set of combinatorial DHFR mutants made out of three key resistance mutations and extended this analysis to DHFR originated from Chlamydia muridarum and Listeria grayi We found that the acquisition of TMP resistance via decreased drug affinity is limited by a trade-off in catalytic efficiency. Protein stability is concurrently affected by the resistant mutants, which precludes a precise description of fitness from a single molecular trait. Application of the kinetic flux theory provided an accurate model to predict resistance phenotypes (IC50) quantitatively from a unique combination of the in vitro protein molecular properties. Further, we found that a controlled modulation of the GroEL/ES chaperonins and Lon protease levels affects the intracellular steady-state concentration of DHFR in a mutation-specific manner, whereas IC50 is changed proportionally, as indeed predicted by the model. This unveils a molecular rationale for the pleiotropic role of the protein quality control machinery on the evolution of antibiotic resistance, which, as we illustrate here, may drastically confound the evolutionary outcome. These results provide a comprehensive quantitative genotype-phenotype map for the essential enzyme that serves as an important target of antibiotic and anticancer therapies.
Daniela M Cirillo
A user-friendly interface designed for nonexpert or expert operability.A standardized and validated analysis pipeline for variant analyses of M. tuberculosis next-generation sequencing (NGS data.Access to data beyond the published literature with dynamic and iterative updates of new data generated by global surveillance and clinical trials.A well-developed legal structure to ensure intellectual property rights and data ownership remain with contributors.A structured data-sharing architecture to restrict access to sensitive or unpublished data sets.Metadata standardization using CDISC: supports global, platform-independent data standards that enable information system interoperability.An emphasis on data quality and rigorous, expert curation with multiple quality control checks for whole-genome sequencing and other metadata.Validation of NGS analysis output by an expert committee with grading of resistance conferring mutations based on rigorous statistical standards.Regulatory-compliant analysis pipeline and database architecture. Successful execution of such an extensive database platform requires substantial collaboration from scientists investigating the genetic basis for drug resistance worldwide, and from developers with expertise in database design and implementation.
Full Text Available Bacteremia is an important infectious disease which may lead to death. Common bacteria and pattern of antibiotic resistance in different communities are different and understanding these differences is important. In the present study, relative frequency and pattern of drug resistance have been examined in bacteria isolated from blood cultures in Razi Hospital laboratory. The method of the study was descriptive. Data collection was carried out retrospectively. Total sample consisted of 311 positive blood cultures from 1999 to 2001. Variables under study were bacterial strains, antibiotics examined in antibiogram, microbial resistance, and patients' age and sex. The most common isolated bacteria were Salmonella typhi (22.2% and the least common ones were Citrobacter (1.6%. The highest antibiotic resistance was seen against amoxicillin (88.4%. The proportion of males to females was1: 1/1 and the most common age group was 15-44 (47.3%. Common bacteria and pattern of antibiotic resistance were different in some areas and this subject requires further studies in the future.
Yu, Dan-dan; Wu, Ying; Shen, Hong-yu; Lv, Meng-meng; Chen, Wei-xian; Zhang, Xiao-hui; Zhong, Shan-liang; Tang, Jin-hai; Zhao, Jian-hua
Transport through the cell membrane can be divided into active, passive and vesicular types (exosomes). Exosomes are nano-sized vesicles released by a variety of cells. Emerging evidence shows that exosomes play a critical role in cancers. Exosomes mediate communication between stroma and cancer cells through the transfer of nucleic acid and proteins. It is demonstrated that the contents and the quantity of exosomes will change after occurrence of cancers. Over the last decade, growing attention has been paid to the role of exosomes in the development of breast cancer, the most life-threatening cancer in women. Breast cancer could induce salivary glands to secret specific exosomes, which could be used as biomarkers in the diagnosis of early breast cancer. Exosome-delivered nucleic acid and proteins partly facilitate the tumorigenesis, metastasis and resistance of breast cancer. Exosomes could also transmit anti-cancer drugs outside breast cancer cells, therefore leading to drug resistance. However, exosomes are effective tools for transportation of anti-cancer drugs with lower immunogenicity and toxicity. This is a promising way to establish a drug delivery system.
Full Text Available "nThe combinations of antiretroviral (ARV drugs have proven effective in controlling the progression of AIDS, but these benefits can be compromised by drug resistance. Thus, drug-resistance testing has become an important tool in the management of HIV-infected individuals.1 Drug resistance develops when mutations in the HIV virus proteins occur due to amino acid substitutions.2 Drug resistance testing is done in two ways: phenotypic test and genotypic test.3 In the first method, virus proliferation is measured in the presence of different concentrations of the drugs. In the second, the genetic structure of viral genome sequences are investigated.4 Although, the first case of HIV infection in Iran was identified 23 years ago (1988, there is still no study published on its drug resistance. The main purpose of this study was to determine the prevalence of drug resistance mutations in patients with HIV/AIDS attending Imam Khomeini Hospital in Tehran. The secondary objectives of the study were to determine the frequency of drug resistance to specific drugs such as nucleoside reverse transcriptase inhibitors (NRTIs, non-nucleoside reverse transcriptase inhibitors (NNRTIs and protease inhibitors (PI. We collected plasma samples from 25 patients with HIV/AIDS and immunological failure. After the extraction of the viral RNA from plasma, genomic sequencing was performed. Finally, the data for determining drug resistance were analyzed by the Stanford HIV Drug Resistance Database (http://hivdb.stanford.edu software. Out of the 25 patients under study, 20 were male (80% and five were female (20%. Routes of HIV transmission were: 56% by needle sharing among injecting drug users (IDUs, 20% through sexual contact, 12% through blood transfusions and 12% by unknown routes. High-level drug resistance for ARV drugs included: 24% to NRTIs, 28% to NNRTIs and zero percent to PI drugs. In addition, 15 patients had been infected with genotype A and 10 patients with
Ximena E. Bernal
Full Text Available Trypanosomes are a diverse group of protozoan parasites of vertebrates transmitted by a variety of hematophagous invertebrate vectors. Anuran trypanosomes and their vectors have received relatively little attention even though these parasites have been reported from frog and toad species worldwide. Blood samples collected from túngara frogs (Engystomops pustulosus, a Neotropical anuran species heavily preyed upon by eavesdropping frog-biting midges (Corethrella spp., were examined for trypanosomes. Our results revealed sexual differences in trypanosome prevalence with female frogs being rarely infected (<1%. This finding suggests this protozoan parasite may be transmitted by frog-biting midges that find their host using the mating calls produced by male frogs. Following previous anuran trypanosome studies, we examined 18S ribosomal RNA gene to characterize and establish the phylogenetic relationship of the trypanosome species found in túngara frogs. A new species of giant trypanosome, Trypanosoma tungarae n. sp., is described in this study. Overall the morphometric data revealed that the trypomastigotes of T. tungarae n. sp. are similar to other giant trypanosomes such as Trypanosoma rotatorium and Trypanosoma ranarum. Despite its slender and long cell shape, however, 18S rRNA gene sequences revealed that T. tungarae n. sp. is sister to the rounded-bodied giant trypanosome, Trypanosoma chattoni. Therefore, morphological convergence explains similar morphology among members of two non-closely related groups of trypanosomes infecting frogs. The results from this study underscore the value of coupling morphological identification with molecular characterization of anuran trypanosomes.
Andrade, Solange Dourado de; Sabidó, Meritxell; Monteiro, Wuelton Marcelo; Benzaken, Adele Schwartz; Tanuri, Amilcar
To determine the prevalence of drug resistance mutations (DRM), the prevalence of drug susceptibility [transmitted drug resistance (TDR)] and the prevalence of HIV-1 variants among treatment-naive HIV-infected children in Manaus, Amazonas state, Brazil. Children born to HIV-infected mothers and diagnosed with HIV in an HIV reference service centre and with available pol sequence between 2010 and 2015 prior to antiretroviral initiation were included. TDR was identified using the Calibrated Population Resistance Tool. HIV-1 subtypes were defined by Rega and phylogenetic analyses. One hundred and seventeen HIV-infected children with a median age of 3.7 years were included. Among them, 28.2% had been exposed to some form of prevention of mother-to-child transmission (PMTCT). HIV DRM were present in 21.4% of all children. Among PMTCT-exposed children, 3% had NRTI mutations, 15.2% had NNRTI mutations and 3% had PI mutations. Among PMTCT-unexposed children, 1.2% had NRTI mutations, 21.4% had non-NNRTI mutations and 1.2% had PI mutations. The most common DRM was E138A (8.5%). The prevalence of TDR was 16.2%; 21.1% among PMTCT-exposed children and 14.3% among PMTC-unexposed children. The analysis of HIV-1 subtypes revealed that 80.2% were subtype B, 6.0% were subtype C, 3.4% were subtype F1 and 10.3% were possible unique recombinant forms (BF1, 4.3%; DB, 4.3%; BC, 0.9%; KC, 0.9%). We report a high prevalence of DRM in this population, including in almost a quarter of children with no reported PMTCT. The high prevalence of TDR observed might compromise ART effectiveness. Results show extensive HIV-1 diversity and expansion of subtype C, which highlights the need for surveillance of HIV-1 subtypes in Amazonas state.
Alvarez, Patricia; Fernández McPhee, Carolina; Prieto, Luis; Martín, Leticia; Obiang, Jacinta; Avedillo, Pedro; Vargas, Antonio; Rojo, Pablo; Benito, Agustín; Ramos, José Tomás; Holguín, África
Objectives This is the first study describing drug resistance mutations (DRM) and HIV-1 variants among infected pregnant women in Equatorial Guinea (GQ), a country with high (6.2%) and increasing HIV prevalence. Methods Dried blood spots (DBS) were collected from November 2012 to December 2013 from 69 HIV-1 infected women participating in a prevention of mother-to-child transmission program in the Hospital Regional of Bata and Primary Health Care Centre María Rafols, Bata, GQ. The transmitted (TDR) or acquired (ADR) antiretroviral drug resistance mutations at partial pol sequence among naive or antiretroviral therapy (ART)-exposed women were defined following WHO or IAS USA 2015 lists, respectively. HIV-1 variants were identified by phylogenetic analyses. Results A total of 38 of 69 HIV-1 specimens were successfully amplified and sequenced. Thirty (79%) belonged to ART-experienced women: 15 exposed to nucleoside reverse transcriptase inhibitors (NRTI) monotherapy, and 15 to combined ART (cART) as first regimen including two NRTI and one non-NRTI (NNRTI) or one protease inhibitor (PI). The TDR rate was only found for PI (3.4%). The ADR rate was 37.5% for NNRTI, 8.7% for NRTI and absent for PI or NRTI+NNRTI. HIV-1 group M non-B variants caused most (97.4%) infections, mainly (78.9%) recombinants: CRF02_AG (55.2%), CRF22_A101 (10.5%), subtype C (10.5%), unique recombinants (5.3%), and A3, D, F2, G, CRF06_cpx and CRF11_cpx (2.6% each). Conclusions The high rate of ADR to retrotranscriptase inhibitors (mainly to NNRTIs) observed among pretreated pregnant women reinforces the importance of systematic DRM monitoring in GQ to reduce HIV-1 resistance transmission and to optimize first and second-line ART regimens when DRM are present. PMID:27798676
Dulce Celina Adolfo Bila
Full Text Available An observational study was conducted in Maputo, Mozambique, to investigate trends in prevalence of HIV drug resistance (HIVDR in antiretroviral (ART naïve subjects initiating highly active antiretroviral treatment (HAART.To evaluate the pattern of drug resistance mutations (DRMs found in adults on ART failing first-line HAART [patients with detectable viral load (VL]. Untreated subjects [Group 1 (G1; n=99] and 274 treated subjects with variable length of exposure to ARV´s [6-12 months, Group 2 (G2;n=93; 12-24 months, Group 3 (G3;n=81; >24 months (G4;n=100] were enrolled. Virological and immunological failure (VF and IF were measured based on viral load (VL and T lymphocyte CD4+ cells (TCD4+ count and genotypic resistance was also performed. Major subtype found was C (untreated: n=66, 97,06%; treated: n=36, 91.7%. Maximum virological suppression was observed in G3, and significant differences intragroup were observed between VF and IF in G4 (p=0.022. Intergroup differences were observed between G3 and G4 for VF (p=0.023 and IF between G2 and G4 (p=0.0018. Viral suppression (5000 copies/ml identified 50% of subjects carrying DRM compared to 100% when lower VL cut-off was used (<50 copies/ml. Length of exposure to ARVs was directly proportional to the complexity of DRM patterns. In Mozambique, VL suppression was achieved in 76% of individuals after 24 months on HAART. This is in agreement with WHO target for HIVDR prevention target (70%.We demonstrated that the best way to determine therapeutic failure is VL compared to CD4 counts. The rationalized use of VL testing is needed to ensure timely detection of treatment failures preventing the occurrence of TDR and new infections.
Ihsan Ali; Zara Rafaque; Safia Ahmed; Sajid Malik; Javid Iqbal Dasti
Objective: To scrutinize patterns of multi-drug-resistant uropathogenic Escherichia coli (UPEC) strains and particularly of fluoroquinolone-resistance this is an alternative choice for the treatment of urinary tract infections. Methods: Bacterial samples (n = 250) were collected from out-patients from August 2012 to August 2014 Islamabad. Antibiotic susceptibility profiling and determination of mini-mum inhibitory concentrations (MICs) and minimum bactericidal concentrations were performed according to the guidelines of Clinical and Laboratory Standards Institute (CLSI, 2012). Genes, qnrA, qnrB and qnrS were identified by DNA amplification and sequencing. Results: The highest percentage of UPEC isolates were resistant to co-trimoxazole (82%) followed by cephalothin (80%), 2nd Gen, 3rd Gen and 4th Gen cephalosporins, respectively. Resistance against gentamicin, amikacin remained 29% and 4%. For other drugs including nitrofurantoin, tetracycline, carbapenem and beta-lactam inhibitors remained below 10%. Altogether, 59% of the isolates were resistant to at least three antibiotics including one fluoroquinolone. Overall, MICs for ciprofloxacin remained (MIC≥256 mg/mL) and for levofloxacin (MIC≥16 mg/mL and 32 mg/mL). No significant differences were observed regarding MIC values of extended spectrum b-lactamase (ESBL) and non-ESBL producers. For qnrS and qnrB positive isolates MICs remained above 32 mg/mL. Prevalence of UPEC was significantly higher among females and 40% of the isolates were ESBL producers. Conclusions: Higher percentages of ESBL producing UPEC were associated with uri-nary tract infections. Moreover, the majority of these isolates were multi-drug resistant and fluoroquinolone-resistant.
Ihsan Ali; Zara Rafaque; Safia Ahmed; Sajid Malik; Javid Iqbal Dasti
Objective:To scrutinize patterns of multi-drug-resistant uropathogenic Escherichia coli(UPEC) strains and particularly of fluoroquinolone-resistance this is an alternative choice for the treatment of urinary tract infections.Methods:Bacterial samples(n = 250) were collected from out-patients from August 2012 to August 2014 Islamabad.Antibiotic susceptibility profiling and determination of minimum inhibitory concentrations(MICs) and minimum bactericidal concentrations were performed according to the guidelines of Clinical and Laboratory Standards Institute(CLSI,2012).Genes,qnrA,qnrB and qnrS were identified by DNA amplification and sequencing.Results:The highest percentage of UPEC isolates were resistant to co-trimoxazole(82%) followed by cephalothin(80%),2nd Gen,3rd Gen and 4th Gen cephalosporins,respectively.Resistance against gentamicin,amikacin remained 29% and 4%.For other drugs including nitrofurantoin,tetracycline,carbapenem and beta-lactam inhibitors remained below 10%.Altogether,59% of the isolates were resistant to at least three antibiotics including one fluoroquinolone.Overall,MICs for ciprofloxacin remained(MIC≥256 μg/mL) and for levofloxacin(MIC≥16 μg/mL and 32 μg/mL).No significant differences were observed regarding MIC values of extended spectrumβ-lactamase(ESBL) and non-ESBL producers.For qnrS and qnrB positive isolates MICs remained above 32 μg/mL.Prevalence of UPEC was significantly higher among females and 40% of the isolates were ESBL producers.Conclusions:Higher percentages of ESBL producing UPEC were associated with urinary tract infections.Moreover,the majority of these isolates were multi-drug resistant and fluoroquinolone-resistant.
Guimarães, Paula Morena de Souza; Ferreira, João Leandro de Paula; Coelho, Luana Portes Ozório; Cavalcanti, Jaqueline de Souza; Lopes, Giselle Ibette Silva Lopez; Matsuda, Elaine Monteiro; Almeida, Flávia Jacqueline; Almeida, Valéria Correia; Campeas, Alexandre Ely; Junior, Luiz Carlos Pereira; Brígido, Luís Fernando de Macedo
Transmitted drug resistance mutations (TDRM) have been a constant threat to treatment efficacy. We evaluated TDRM in plasma RNA of 217 antiretroviral therapy-naive patients from sites in the São Paulo metropolitan area, collected from 2012 to 2014. The partial HIV-1 polymerase region was sequenced using Big Dye terminators at an ABI 3130 Genetic Analyzer. TDRM was defined according to the Stanford database calibrated population resistance (CPR v.6.0), but other drug resistance mutations (DRM) considered at the IAS list (IAS, 2014) and at the Stanford HIV Database Genotyping Resistance Interpretation (GRI-HIVdb) were also described. Out of 78% (170/217) of patients with information on the time of diagnosis, most (83%, 141/170) had been recently diagnosed, with the first positive HIV serology at a median of 58 days (IQR 18-184). Subtype B predominated (70%), followed by subtype F (10%), BF (7.5%), C (7.5%), and BC (5%). TDRMs were observed in 9.2% (20/217, CI 95% 5.9% to 13.6%), mostly (5.2%) to nonnucleoside reverse transcriptase inhibitor (NNRTI) antiretroviral class. Among children and adolescents, only a single patient showed TDRMs. Additional non-CPR mutations were observed: 11.5% (25/217) according to IAS or 4.6% (10/217) according to GRI-HIVdb. Overall, 23.5% (51/217) of the cases had one or more DRM identified. TDRM prevalence differed significantly among some sites. These trends deserve continuous and systematic surveillance, especially with the new policies of treatment as prevention being implemented in the country.
Objectives: The global increase in drug resistance in Mycobacterium tuberculosis (MTB) strains increases the focus on improved molecular diagnostics for MTB. Extensively drug-resistant (XDR) - TB is caused by MTB strains resistant to rifampicin, isoniazid, fluoroquinolone and aminoglycoside antibiotics. Resistance to anti-tuberculous drugs has been associated with single nucleotide polymorphisms (SNPs), in particular MTB genes. However, there is regional variation between MTB lineages and the SNPs associated with resistance. Therefore, there is a need to identify common resistance conferring SNPs so that effective molecular-based diagnostic tests for MTB can be developed. This study investigated used whole genome sequencing (WGS) to characterize 37 XDR MTB isolates from Pakistan and investigated SNPs related to drug resistance. Methods: XDR-TB strains were selected. DNA was extracted from MTB strains, and samples underwent WGS with 76-base-paired end fragment sizes using Illumina paired end HiSeq2000 technology. Raw sequence data were mapped uniquely to H37Rv reference genome. The mappings allowed SNPs and small indels to be called using SAMtools/BCFtools. Results: This study found that in all XDR strains, rifampicin resistance was attributable to SNPs in the rpoB RDR region. Isoniazid resistance-associated mutations were primarily related to katG codon 315 followed by inhA S94A. Fluoroquinolone resistance was attributable to gyrA 91-94 codons in most strains, while one did not have SNPs in either gyrA or gyrB. Aminoglycoside resistance was mostly associated with SNPs in rrs, except in 6 strains. Ethambutol resistant strains had embB codon 306 mutations, but many strains did not have this present. The SNPs were compared with those present in commercial assays such as LiPA Hain MDRTBsl, and the sensitivity of the assays for these strains was evaluated. Conclusions: If common drug resistance associated with SNPs evaluated the concordance between phenotypic and
L.M. Hofstra (L. Marije); N. Sauvageot (Nicolas); J. Albert (Jan); I. Alexiev (Ivailo); F. Garcia (Federico); D. Struck (Daniel); D.A.M.C. van de Vijver (David); B. Asjö (Birgitta); D. Beshkov (Danail); S. Coughlan (Suzie); D. Descamps (Diane); A. Griskevicius (Algis); O. Hamouda (Osamah); A. Horban (Andrzej); M.E.E. van Kasteren (Marjo); T. Kolupajeva (Tatjana); L.G. Kostrikis (Leondios); K. Liitsola (Kirsi); M. Linka (Marek); O. Mor (Orna); C. Nielsen (Claus); D. Otelea (Dan); D. Paraskevis (Dimitrios); R. Paredes (Roger); M. Poljak (Mario); E. Puchhammer-Stockl E. (E.); A. Sonnerborg (Anders); D. Stanekova (Danica); M. Stanojevic (Maja); K. Van Laethem (Kristel); M. Zazzi (Maurizio); S. Zidovec Lepej (Snjezana); C.A.B. Boucher (Charles A. B.); J.-C. Schmit (Jean-Claude); A.M.J. Wensing (Annemarie); E. Puchhammer-Stöckl (Elisabeth); M. Sarcletti (M.); B. Schmied (B.); M. Geit (M.); G. Balluch (G.); A.-M. Vandamme; J. Vercauteren (Jurgen); I. Derdelinckx; A. Sasse; M. Bogaert; H. Ceunen (H.); A. de Roo (Annie); S. De Wit; F. Echahidi (F.); K. Fransen; J.-C. Goffard (J.); P. Goubau; E. Goudeseune (E.); J.-C. Yombi (J.); P. Lacor; C. Liesnard (C.); M. Moutschen; L.A. Pierard; R. Rens (R.); J. Schrooten; D. Vaira; L.P.R. Vandekerckhove; A. van den Heuvel (A.); B. van der Gucht (B.); M. Van Ranst; E. Van Wijngaerden; B. Vandercam; M. Vekemans; C. Verhofstede; N. Clumeck (N.); K. van Laethem (Kristel); D. Beshkov; I. Alexiev; S.Z. Lepej (Snjezana); J. Begovac; L.G. Kostrikis (Leondios); I. Demetriades (I.); I. Kousiappa (Ioanna); V.L. Demetriou (Victoria); J. Hezka (Johana); M. Linka; M. Maly; L. MacHala; C. Nielsen; L.B. Jørgensen; J. Gerstoft (J.); L. Mathiesen (L.); C. Pedersen (Court); H. Nielsen; A. Laursen (A.); B. Kvinesdal (B.); K. Liitsola (Kirsi); M. Ristola (M.); J. Suni; J. Sutinen (J.); D. Descamps; L. Assoumou; G. Castor; M. Grude; P. Flandre; A. Storto; O. Hamouda (Osamah); C. K̈ucherer (C.); T. Berg; P. Braun; G. Poggensee; M. Daumer (Martin); J. Eberle; H. Heiken; R. Kaiser; H. Knechten (H.); K. Korn; H. Müller; S. Neifer; B. Schmidt; H. Walter; B. Gunsenheimer-Bartmeyer (B.); T. Harrer (T.); D. Paraskevis (Dimitrios); A. Hatzakis (Angelos); A. Zavitsanou (A.); A. Vassilakis; M. Lazanas; L. Chini; A. Lioni; V. Sakka (V.); S. Kourkounti (S.); V. Paparizos (V.); A. Antoniadou (A.); A. Papadopoulos; G. Poulakou; I. Katsarolis; K. Protopapas; G. Chryssos (G.); S. Drimis (S.); P. Gargalianos; G. Xylomenos; G. Lourida; M. Psichogiou (M.); G.L. Daikos (G.); N.V. Sipsas; A. Kontos (Angelos); M.N. Gamaletsou; G. Koratzanis (G.); H. Sambatakou; H. Mariolis; A. Skoutelis; V. Papastamopoulos; O. Georgiou; P. Panagopoulos (P.); E. Maltezos; S. Coughlan (Suzie); C. de Gascun (Cillian); C. Byrne; M. Duffy; P. Bergin; D. Reidy; G. Farrell; J. Lambert; E. O'Connor; A. Rochford; J. Low; P. Coakely (P.); S. O'Dea; W. Hall; O. Mor; I. Levi (I.); D. Chemtob (D.); Z. Grossman (Zehava); M. Zazzi; A. de Luca (Andrea); C. Balotta (Claudia); C. Riva (Chiara); C. Mussini (C.); I. Caramma (I.); A. Capetti (A.); M. Colombo (Massimo); C. Rossi; F. Prati (Francesco); F. Tramuto; F. Vitale (F.); M. Ciccozzi; G. Angarano (Guiseppe); G. Rezza (G.); T. Kolupajeva; O. Vasins; A. Griskevicius (Algis); V. Lipnickiene; J.C. Schmit; D. Struck (Daniel); N. Sauvageot; R. Hemmer (R.); V. Arendt (V.); C. Michaux; T. Staub (T.); C. Sequin-Devaux; A.M.J. Wensing (Annemarie); C.A. Boucher (Charles); D.A.M.C. van de Vijver (David); A. Van Kessel; P.H.M. Van Bentum; K. Brinkman; B.J. Connell; M.E. van der Ende (Marchina); I.M. Hoepelman (Ilja Mohandas); M.E.E. van Kasteren (Marjo); M. Kuipers; N. Langebeek (Nienke); C. Richter; R.M.W.J. Santegoets (R. M W J); L. Schrijnders-Gudde (L.); R. Schuurman (Rob); B.J.M. van de Ven (B. J M); B. Åsjö (Birgitta); A.-M.B. Kran (A.-M. Bakken); V. Ormaasen (Vidar); P. Aavitsland (P.); A. Horban (Andrzej); J. Stanczak (J.); G.P. Stanczak (G.); E. Firlag-Burkacka (E.); A. Wiercinska-Drapalo; E. Jablonowska (E.); E. Maolepsza; M. Leszczyszyn-Pynka (M.); W. Szata (W.); R.J. Camacho (Ricardo Jorge); A. de Palma (Andre); F. Borges (F.); T. Paixão; V. Duque (V.); F. Araújo; D. Otelea; C. Paraschiv (Corina); A.M. Tudor; R. Cernat; C. Chiriac; F. Dumitrescu; L.J. Prisecariu; M. Stanojevic (Maja); D.J. Jevtovic (D.); D. Salemovic (D.); D. Stanekova; M. Habekova (M.); Z. Chabadová; T. Drobkova; P. Bukovinova; A. Shunnar; P. Truska; M. Poljak (Mario); M.M. Lunar (Maja M.); D. Babic; J. Tomazic (J.); S. Vidmar (Suzanna); T. Vovko; P. Karner (P.); F. Garcia; R. Paredes (Roger); S. Monge; S. Moreno; J. Del Amo; V. Asensi; J.L. Sirvent; C. de Mendoza (Carmen); R. Delgado; F. Gutiérrez; J. Berenguer; S. Garcia-Bujalance; N. Stella; I. De Los Santos; J.R. Blanco; D. Dalmau; M. Rivero; F. Segura; M.J.P. Elías (M. J. Pcrossed); M. Alvarez; N. Chueca; C. Rodríguez-Martín; C. Vidal; J.C. Palomares; I. Viciana; P. Viciana; J. Cordoba; A. Aguilera; P. Domingo; M.J. Galindo; C. Miralles; M.A. Del Pozo; E. Ribera; C. Iribarren (Carlos); L. Ruiz; J. De La Torre; F. Vidal; B. Clotet (Bonaventura); J. Albert; A. Heidarian; K. Aperia-Peipke (K.); M. Axelsson; M. Mild; A. Karlsson; A. Sonnerborg (Anders); A. Thalme; L. Navénr; G. Bratt (G.); A. Karlsson; A. Blaxhult; M. Gisslénn; B. Svennerholm; I.-M. Bergbrant (I.); P. Bj̈orkman (P.); C. Säll; A. Mellgren; A. Lindholm; N. Kuylenstierna; R. Montelius; F. Azimi; B. Johansson; M. Carlsson; E. Johansson; B. Ljungberg; H. Ekvall; A. Strand; S. Mäkitalo; S. Öberg; P. Holmblad; M. Höfer; H. Holmberg; P. Josefson; U. Ryding
textabstractBackground. Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, the
Hofstra, L. Marije; Sauvageot, Nicolas; Albert, Jan; Alexiev, Ivailo; Garcia, Federico; Struck, Daniel; Van De Vijver, David A M C; Åsjö, Birgitta; Beshkov, Danail; Coughlan, Suzie; Descamps, Diane; Griskevicius, Algirdas; Hamouda, Osamah; Horban, Andrzej; Van Kasteren, Marjo; Kolupajeva, Tatjana; Kostrikis, Leontios G.; Liitsola, Kirsi; Linka, Marek; Mor, Orna; Nielsen, Claus; Otelea, Dan; Paraskevis, Dimitrios; Paredes, Roger; Poljak, Mario; Puchhammer-Stöckl, Elisabeth; Sönnerborg, Anders; Staneková, Danica; Stanojevic, Maja; Van Laethem, Kristel; Zazzi, Maurizio; Lepej, Snjezana Zidovec; Boucher, Charles A B; Schmit, Jean Claude; Wensing, Annemarie M J; Puchhammer-Stockl, E.; Sarcletti, M.; Schmied, B.; Geit, M.; Balluch, G.; Vandamme, A. M.; Vercauteren, J.; Derdelinckx, I.; Sasse, A.; Bogaert, M.; Ceunen, H.; De Roo, A.; De Wit, S.; Echahidi, F.; Fransen, K.; Goffard, J. C.; Goubau, P.; Goudeseune, E.; Yombi, J. C.; Lacor, P.; Liesnard, C.; Moutschen, M.; Pierard, D.; Rens, R.; Schrooten, Y.; Vaira, D.; Vandekerckhove, L. P R; Van Den Heuvel, A.; Van Der Gucht, B.; Van Ranst, M.; Van Wijngaerden, E.; Vandercam, B.; Vekemans, M.; Verhofstede, C.; Clumeck, N.; Van Laethem, K.; Beshkov, D.; Alexiev, I.; Lepej, S. Zidovec; Begovac, J.; Kostrikis, Leontios G.; Demetriades, I.; Kousiappa, I.; Demetriou, V.; Hezka, J.; Linka, M.; Maly, M.; Machala, L.; Nielsen, C.; Jørgensen, L. B.; Gerstoft, J.; Mathiesen, L.; Pedersen, C.; Nielsen, H.; Laursen, A.; Kvinesdal, B.; Liitsola, K.; Ristola, M.; Suni, J.; Sutinen, J.; Descamps, D.; Assoumou, L.; Castor, G.; Grude, M.; Flandre, P.; Storto, A.; Hamouda, O.; Kücherer, C.; Berg, T.; Braun, P.; Poggensee, G.; Däumer, M.; Eberle, J.; Heiken, H.; Kaiser, R.; Knechten, H.; Korn, K.; Müller, H.; Neifer, S.; Schmidt, B.; Walter, H.; Gunsenheimer-Bartmeyer, B.; Harrer, T.; Paraskevis, D.; Hatzakis, A.; Zavitsanou, A.; Vassilakis, A.; Lazanas, M.; Chini, M.; Lioni, A.; Sakka, V.; Kourkounti, S.; Paparizos, V.; Antoniadou, A.; Papadopoulos, A.; Poulakou, G.; Katsarolis, I.; Protopapas, K.; Chryssos, G.; Drimis, S.; Gargalianos, P.; Xylomenos, G.; Lourida, G.; Psichogiou, M.; Daikos, G. L.; Sipsas, N. V.; Kontos, A.; Gamaletsou, M. N.; Koratzanis, G.; Sambatakou, E.; Mariolis, H.; Skoutelis, A.; Papastamopoulos, V.; Georgiou, O.; Panagopoulos, P.; Maltezos, E.; Coughlan, S.; De Gascun, C.; Byrne, C.; Duffy, M.; Bergin, C.; Reidy, D.; Farrell, G.; Lambert, J.; O'Connor, E.; Rochford, A.; Low, J.; Coakely, P.; O'Dea, S.; Hall, W.; Mor, O.; Levi, I.; Chemtob, D.; Grossman, Z.; Zazzi, M.; De Luca, A.; Balotta, C.; Riva, C.; Mussini, C.; Caramma, I.; Capetti, A.; Colombo, M. C.; Rossi, C.; Prati, F.; Tramuto, F.; Vitale, F.; Ciccozzi, M.; Angarano, G.; Rezza, G.; Kolupajeva, T.; Kolupajeva, T.; Vasins, O.; Griskevicius, A.; Lipnickiene, V.; Schmit, J. C.; Struck, D.; Sauvageot, N.; Hemmer, R.; Arendt, V.; Michaux, C.; Staub, T.; Sequin-Devaux, C.; Wensing, A. M J; Boucher, C. A B; Van Kessel, A.; Van Bentum, P. H M; Brinkman, K.; Connell, B. J.; Van Der Ende, M. E.; Hoepelman, I. M.; Van Kasteren, M.; Kuipers, M.; Langebeek, N.; Richter, C.; Santegoets, R. M W J; Schrijnders-Gudde, L.; Schuurman, R.; Van De Ven, B. J M; Åsjö, B.; Kran, A. M Bakken; Ormaasen, V.; Aavitsland, P.; Horban, A.; Stanczak, J. J.; Stanczak, G. P.; Firlag-Burkacka, E.; Wiercinska-Drapalo, A.; Jablonowska, E.; Maolepsza, E.; Leszczyszyn-Pynka, M.; Szata, W.; Camacho, R.; Palma, C.; Borges, F.; Paixão, T.; Duque, V.; Araújo, F.; Otelea, D.; Paraschiv, S.; Tudor, A. M.; Cernat, R.; Chiriac, C.; Dumitrescu, F.; Prisecariu, L. J.; Stanojevic, M.; Jevtovic, Dj; Salemovic, D.; Stanekova, D.; Habekova, M.; Chabadová, Z.; Drobkova, T.; Bukovinova, P.; Shunnar, A.; Truska, P.; Poljak, M.; Lunar, M.; Babic, D.; Tomazic, J.; Vidmar, L.; Vovko, T.; Karner, P.; Garcia, F.; Paredes, R.; Monge, S.; Moreno, S.; Del Amo, J.; Asensi, V.; Sirvent, J. L.; De Mendoza, C.; Delgado, R.; Gutiérrez, F.; Berenguer, J.; Garcia-Bujalance, S.; Stella, N.; De Los Santos, I.; Blanco, J. R.; Dalmau, D.; Rivero, M.; Segura, F.; Elías, M. J Pérez; Alvarez, M.; Chueca, N.; Rodríguez-Martín, C.; Vidal, C.; Palomares, J. C.; Viciana, I.; Viciana, P.; Cordoba, J.; Aguilera, A.; Domingo, P.; Galindo, M. J.; Miralles, C.; Del Pozo, M. A.; Ribera, E.; Iribarren, J. A.; Ruiz, L.; De La Torre, J.; Vidal, F.; Clotet, B.; Albert, J.; Heidarian, A.; Aperia-Peipke, K.; Axelsson, M.; Mild, M.; Karlsson, A.; Sönnerborg, A.; Thalme, A.; Navér, L.; Bratt, G.; Karlsson, A.; Blaxhult, A.; Gisslén, M.; Svennerholm, B.; Bergbrant, I.; Björkman, P.; Säll, C.; Lindholm, A.; Kuylenstierna, N.; Montelius, R.; Azimi, F.; Johansson, B.; Carlsson, M.; Johansson, E.; Ljungberg, B.; Ekvall, H.; Strand, A.; Mäkitalo, S.; Öberg, S.; Holmblad, P.; Höfer, M.; Holmberg, H.; Josefson, P.; Ryding, U.
Background. Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline
Dam, van J.T.P.
In a series of experiments the interaction between nutrition and energy- and nitrogen metabolism of West African Dwarf goats, infected with trypanosomes was studied. Animals were injected with trypanosomes, and feed intake, energy and nitrogen balance and blood metabolites and hormones were measured
Dam, van J.T.P.
In a series of experiments the interaction between nutrition and energy- and nitrogen metabolism of West African Dwarf goats, infected with trypanosomes was studied. Animals were injected with trypanosomes, and feed intake, energy and nitrogen balance and blood metabolites and hormones were measured
Kartaloglu, Zafer; Bozkanat, Erkan; Ozturkeri, Hakan; Okutan, Oguzhan; Ilvan, Ahmet
The aim of this study was to investigate the prevalence of primary drug resistance to tuberculosis. We evaluated the clinical data, radiological features and sputum samples from 365 newly diagnosed patients with a positive culture of pulmonary tuberculosis at the Turkish Military Chest Diseases Hospital, Istanbul, Turkey. No patients had taken antituberculosis drugs previously. The Bactec method was used to perform drug susceptibility testing for isoniazid, rifampicin, ethambutol, and streptomycin. Primary resistance to one or more drugs was detected in 87 (23.8%) patients; resistance to isoniazid was most common (54 patients) followed by resistance to ethambutol (n = 39), rifampicin (n = 11), and streptomycin (n = 9). One-drug resistance was detected in 69 patients; two-drug resistance in 11, three-drug resistance in 6, and four-drug resistance in 1. Multidrug resistance (resistance to at least isoniazid and rifampicin) was detected in 10 patients. In logistic-regression analysis, primary drug resistance was associated with radiological advanced tuberculosis (p < 0.001). Primary resistance to one or more drugs used in treating tuberculosis is relatively high. It is necessary to regularly screen for and treat drug resistance among those who live in close quarters, such as army barracks, school dormitories and prisons. Regular surveillance of drug sensitivity patterns should be maintained to determine appropriate alternate drug regimens and detect the spread of resistant stains in the population. Copyright 2002 S. Karger AG, Basel
Full Text Available 1 Fifty coagulase posittve strains of staphylococc~~ ~folated fr.o~ .the nose"nand wrist of Hospital nurses have been examined for sensltfvlty to pemcilhn, tetracyclines,"nchloramphenicol, dihydrostreptomycin, erythrorriycm, neomycin, kana.n:ycin,"nbacitracin, polymyxin-B and the triple sulfa. The percentages of fully sensittve strains at the present are as followe: Erythromycin 100%"nNeomycin 78%"nKanamycin 78%"nChloramphenicol 68%"nDihydrostreptomycin 52%"nPenicillin 18%"nTetracyclines 16%"nPolymyxin-B 1%"nTriple sulfa 0%"n2 The following topics have been discussed:"na The origin anr" mechanism of drug resistance"nb Cross-resistr.nee"nc The hospital epidemiology of Staphylococcus"nd The clinical implications of Staphylococcus drug-resistance
Long, Qian; Qu, Yan; Lucas, Henry
China has the second highest caseload of multidrug-resistant tuberculosis (MDR-TB) in the world. In 2009, the Chinese government agreed to draw up a plan for MDR-TB prevention and control in the context of a comprehensive health system reform launched in the same year. China is facing high prevalence rates of drug-resistant TB and MDR-TB. MDR-TB disproportionally affects the poor rural population and the highest rates are in less developed regions largely due to interrupted and/or inappropriate TB treatment. Most households with an affected member suffer a heavy financial burden because of a combination of treatment and other related costs. The influential Global Fund programme for MDR-TB control in China provides technical and financial support for MDR-TB diagnosis and treatment. However, this programme has a fixed timeline and cannot provide a long term solution. In 2009, the Bill and Melinda Gates Foundation, in cooperation with the National Health and Family Planning Commission of China, started to develop innovative approaches to TB/MDR-TB management and case-based payment mechanisms for treatment, alongside increased health insurance benefits for patients, in order to contain medical costs and reduce financial barriers to treatment. Although these efforts appear to be in the right direction, they may not be sufficient unless (a) domestic sources are mobilized to raise funding for TB/MDR-TB prevention and control and (b) appropriate incentives are given to both health facilities and their care providers. Along with the on-going Chinese health system reform, sustained government financing and social health protection schemes will be critical to ensure universal access to appropriate TB treatment in order to reduce risk of developing MDR-TB and systematic MDR-TB treatment and management.
Qian Long; Yan Qu; Henry Lucas
Background:China has the second highest caseload of multidrug-resistant tuberculosis (MDR-TB) in the world.In 2009,the Chinese government agreed to draw up a plan for MDR-TB prevention and control in the context of a comprehensive health system reform launched in the same year.Discussion:China is facing high prevalence rates of drug-resistant TB and MDR-TB.MDR-TB disproportionally affects the poor rural population and the highest rates are in less developed regions largely due to interrupted and/or inappropriate TB treatment.Most households with an affected member suffer a heavy financial burden because of a combination of treatment and other related costs.The influential Global Fund programme for MDR-TB control in China provides technical and financial support for MDR-TB diagnosis and treatment.However,this programme has a fixed timeline and cannot provide a long term solution.In 2009,the Bill and Melinda Gates Foundation,in cooperation with the National Health and Family Planning Commission of China,started to develop innovative approaches to TB/MDR-TB management and case-based payment mechanisms for treatment,alongside increased health insurance benefits for patients,in order to contain medical costs and reduce financial barriers to treatment.Although these efforts appear to be in the right direction,they may not be sufficient unless (a) domestic sources are mobilized to raise funding for TB/MDR-TB prevention and control and (b) appropriate incentives are given to both health facilities and their care providers.Summary:Along with the on-going Chinese health system reform,sustained government financing and social health protection schemes will be critical to ensure universal access to appropriate TB treatment in order to reduce risk of developing MDR-TB and systematic MDR-TB treatment and management.
Dalic, Linda; Cook, Mark J
Despite the development of new antiepileptic drugs (AEDs), ~20%–30% of people with epilepsy remain refractory to treatment and are said to have drug-resistant epilepsy (DRE). This multifaceted condition comprises intractable seizures, neurobiochemical changes, cognitive decline, and psychosocial dysfunction. An ongoing challenge to both researchers and clinicians alike, DRE management is complicated by the heterogeneity among this patient group. The underlying mechanism of DRE is not completely understood. Many hypotheses exist, and relate to both the intrinsic characteristics of the particular epilepsy (associated syndrome/lesion, initial response to AED, and the number and type of seizures prior to diagnosis) and other pharmacological mechanisms of resistance. The four current hypotheses behind pharmacological resistance are the “transporter”, “target”, “network”, and “intrinsic severity” hypotheses, and these are reviewed in this paper. Of equal challenge is managing patients with DRE, and this requires a multidisciplinary approach, involving physicians, surgeons, psychiatrists, neuropsychologists, pharmacists, dietitians, and specialist nurses. Attention to comorbid psychiatric and other diseases is paramount, given the higher prevalence in this cohort and associated poorer health outcomes. Treatment options need to consider the economic burden to the patient and the likelihood of AED compliance and tolerability. Most importantly, higher mortality rates, due to comorbidities, suicide, and sudden death, emphasize the importance of seizure control in reducing this risk. Overall, resective surgery offers the best rates of seizure control. It is not an option for all patients, and there is often a significant delay in referring to epilepsy surgery centers. Optimization of AEDs, identification and treatment of comorbidities, patient education to promote adherence to treatment, and avoidance of triggers should be periodically performed until further
Jain, Vivek; Sucupira, Maria C.; Bacchetti, Peter; Hartogensis, Wendy; Diaz, Ricardo S.; Kallas, Esper G.; Janini, Luiz M.; Liegler, Teri; Pilcher, Christopher D.; Grant, Robert M.; Cortes, Rodrigo; Deeks, Steven G.
Background. Transmitted human immunodeficiency virus type 1 (HIV-1) drug resistance (TDR) mutations can become replaced over time by emerging wild-type viral variants with improved fitness. The impact of class-specific mutations on this rate of mutation replacement is uncertain. Methods. We studied participants with acute and/or early HIV infection and TDR in 2 cohorts (San Francisco, California, and São Paulo, Brazil). We followed baseline mutations longitudinally and compared replacement rates between mutation classes with use of a parametric proportional hazards model. Results. Among 75 individuals with 195 TDR mutations, M184V/I became undetectable markedly faster than did nonnucleoside reverse-transcriptase inhibitor (NNRTI) mutations (hazard ratio, 77.5; 95% confidence interval [CI], 14.7–408.2; P < .0001), while protease inhibitor and NNRTI replacement rates were similar. Higher plasma HIV-1 RNA level predicted faster mutation replacement, but this was not statistically significant (hazard ratio, 1.71 log10 copies/mL; 95% CI, .90–3.25 log10 copies/mL; P = .11). We found substantial person-to-person variability in mutation replacement rates not accounted for by viral load or mutation class (P < .0001). Conclusions. The rapid replacement of M184V/I mutations is consistent with known fitness costs. The long-term persistence of NNRTI and protease inhibitor mutations suggests a risk for person-to-person propagation. Host and/or viral factors not accounted for by viral load or mutation class are likely influencing mutation replacement and warrant further study. PMID:21451005
REBECCA L DUNNE; LINDA A DUNN; PETER UPCROFT; PETER J O'DONOGHUE; JACQUELINE A UPCROFT
Trichomoniasis is the most common, sexually transmitted infection. It is caused by the flagellated protozoan parasite Trichomonas vaginalis. Symptoms include vaginitis and infections have been associated with preterm delivery, low birth weight and increased infant mortality, as well as predisposing to HIV/AIDS and cervical cancer. Trichomoniasis has the highest prevalence and incidence of any sexually transmitted infection. The 5-nitroimidazole drugs, of which metronidazole is the most prescribed, are the only approved,effective drugs to treat trichomoniasis. Resistance against metronidazole is frequently reported and crossresistance among the family of 5-nitroimidazole drugs is common, leaving no alternative for treatment, with some cases remaining unresolved. The mechanism of metronidazole resistance in T. vaginalis from treatment failures is not well understood, unlike resistance which is developed in the laboratory under increasing metronidazole pressure. In the latter situation, hydrogenosomal function which is involved in activation of the prodrug, metronidazole, is down-regulated. Reversion to sensitivity is incomplete after removal of drug pressure in the highly resistant parasites while clinically resistant strains, so far analysed, maintain their resistance levels in the absence of drug pressure. Although anaerobic resistance has been regarded as a laboratory induced phenomenon, it clearly has been demonstrated in clinical isolates. Pursuit of both approaches will allow dissection of the underlying mechanisms. Many alternative drugs and treatments have been tested in vivo in cases of refractory trichomoniasis, as well as in vitro with some successes including the broad spectrum anti-parasitic drug nitazoxanide. Drug resistance incidence in T. vaginalis appears to be on the increase and improved surveillance of treatment failures is urged.
Full Text Available The rapid spreading of HIV drug resistance is threatening the overall success of free HAART in China. Much work has been done on drug-resistant mutations, however, most of which were based on subtype B. Due to different genetic background, subtypes difference would have an effect on the development of drug-resistant mutations, which has already been proved by more and more studies. In China, the main epidemic subtypes are CRF07_BC, CRF08_BC, Thai B and CRF01_AE. The depiction of drug resistance mutations in those subtypes will be helpful for the selection of regimens for Chinese. In this study, the distributions difference of amino acids at sites related to HIV drug resistance were compared among subtype B, CRF01_AE, CRF07_BC and CRF08_BC strains prevalent in China. The amino acid composition of sequences belonging to different subtypes, which were obtained from untreated and treated individuals separately, were also compared. The amino acids proportions of 19 sites in RT among subtype B, CRF01_AE and CRF08_BC have significant difference in drug resistance groups (chi-square test, p<0.05. Genetic barriers analysis revealed that sites 69, 138, 181, 215 and 238 were significantly different among subtypes (Kruskal Wallis test, p<0.05. All subtypes shared three highest prevalent drug resistance sites 103, 181 and 184 in common. Many drug resistant sites in protease show surprising high proportions in almost all subtypes in drug-naïve patients. This is the first comprehensive study in China on different development of drug resistance among different subtypes. The detailed data will lay a foundation for HIV treatment regimens design and improve HIV therapy in China.
Horvath, Anton; Berry, Edward A.; Maslov, Dmitri A.
The type of RNA editing found in the kinetoplast-mitochondria of trypanosomes and related protozoa, involving uridylate insertions and deletions, creates translatable messenger RNAs (mRNAs) out of nonsense pre-edited RNAs by correcting encoded defects that vary from simple frameshifts to large ''cryptic'' regions. However, any evidence for translation of these mRNAs in the kinetoplast has been missing for decades. We identified a kinetoplast-encoded protein, apocytochrome b, whose mRNA is edited in the 5' region. The determined amino-terminal sequence of the protein coincides with the predicted sequence derived from the edited region, demonstrating that the cognate apocytochrome b mRNA is translated into a functional protein. This finding represents the first direct evidence for a functional translation system in the kinetoplasts.
Dolgusev, O; Obevzenco, N; Padalco, O; Pankrushev, S; Ramsay, A; Van den Bergh, R; Manzi, M; Denisiuk, O; Zachariah, R
This cohort study assessed drug susceptibility testing (DST) patterns and associated treatment outcomes from Transnistria, Moldova, from 2009 to 2012. Of 1089 newly registered tuberculosis (TB) patients with available DST results, 556 (51%) had some form of drug resistance, while 369 (34%) had multidrug-resistant TB (MDR-TB). There were four cases of extensively drug-resistant TB. MDR-TB patients had poor treatment success (45%); human immunodeficiency virus positivity and a history of incarceration were associated with an unfavourable treatment outcome. This first study from Trans-nistria shows a high level of drug-resistant TB, which constitutes a major public health problem requiring urgent attention.
张杰; 顾怡明; 俞云松; 周志慧; 杜小玲
@@The main drug-resistance mechanism of gram-negative bacteria is producing β-lactamases. Two kinds of enzymes cause drug resistance by hydrolyzing oxyimino-cephalosporins and aztreonam: one is chromosomally encoded AmpC β-lactamases, the other is plasmid-mediated extended-spectrum β-lactamases (ESBLs). Enterobacter cloacae can produce both of them, so that these strains are seriously resistance to many antibiotics. In order to study the main drug-resistant mechanism in Enterobacter cloacae, PCR and nucleotide sequencing were performed on 58 multidrug resistant strains.
Ren, Lu; Deng, Lin-Hua; Zhang, Ri-Peng; Wang, Cheng-Dong; Li, De-Sheng; Xi, Li-Xin; Chen, Zhen-rong; Yang, Rui; Huang, Jie; Zeng, Yang-ru; Wu, Hong-Lin; Cao, San-Jie; Wu, Rui; Huang, Yong; Yan, Qi-Gui
Abstract Background: To detect drug resistance in Shigella obtained from the dung of the giant panda, explore the factors leading to drug resistance in Shigella, understand the characteristics of clustered, regularly interspaced, short, palindromic repeats (CRISPR), and assess the relationship between CRISPR and drug resistance. Methods: We collected fresh feces from 27 healthy giant pandas in the Giant Panda Conservation base (Wolong, China). We identified the strains of Shigella in the samples by using nucleotide sequence analysis. Further, the Kirby-Bauer paper method was used to determine drug sensitivity of the Shigella strains. CRISPR-associated protein genes cas1 and cas2 in Shigella were detected by polymerase chain reaction (PCR), and the PCR products were sequenced and compared. Results: We isolated and identified 17 strains of Shigella from 27 samples, including 14 strains of Shigella flexneri, 2 strains of Shigella sonnei, and 1 strain of Shigella dysenteriae. Further, drug resistance to cefazolin, imipenem, and amoxicillin–clavulanic acid was identified as a serious problem, as multidrug-resistant strains were detected. Further, cas1 and cas2 showed different degrees of point mutations. Conclusion: The CRISPR system widely exists in Shigella and shares homology with that in Escherichia coli. The cas1 and cas 2 mutations contribute to the different levels of resistance. Point mutations at sites 3176455, 3176590, and 3176465 in cas1 (a); sites 3176989, 3176992, and 3176995 in cas1 (b); sites 3176156 and 3176236 in cas2 may affect the resistance of bacteria, cause emergence of multidrug resistance, and increase the types of drug resistance. PMID:28207509
Ren, Lu; Deng, Lin-Hua; Zhang, Ri-Peng; Wang, Cheng-Dong; Li, De-Sheng; Xi, Li-Xin; Chen, Zhen-Rong; Yang, Rui; Huang, Jie; Zeng, Yang-Ru; Wu, Hong-Lin; Cao, San-Jie; Wu, Rui; Huang, Yong; Yan, Qi-Gui
To detect drug resistance in Shigella obtained from the dung of the giant panda, explore the factors leading to drug resistance in Shigella, understand the characteristics of clustered, regularly interspaced, short, palindromic repeats (CRISPR), and assess the relationship between CRISPR and drug resistance. We collected fresh feces from 27 healthy giant pandas in the Giant Panda Conservation base (Wolong, China). We identified the strains of Shigella in the samples by using nucleotide sequence analysis. Further, the Kirby-Bauer paper method was used to determine drug sensitivity of the Shigella strains. CRISPR-associated protein genes cas1 and cas2 in Shigella were detected by polymerase chain reaction (PCR), and the PCR products were sequenced and compared. We isolated and identified 17 strains of Shigella from 27 samples, including 14 strains of Shigella flexneri, 2 strains of Shigella sonnei, and 1 strain of Shigella dysenteriae. Further, drug resistance to cefazolin, imipenem, and amoxicillin-clavulanic acid was identified as a serious problem, as multidrug-resistant strains were detected. Further, cas1 and cas2 showed different degrees of point mutations. The CRISPR system widely exists in Shigella and shares homology with that in Escherichia coli. The cas1 and cas 2 mutations contribute to the different levels of resistance. Point mutations at sites 3176455, 3176590, and 3176465 in cas1 (a); sites 3176989, 3176992, and 3176995 in cas1 (b); sites 3176156 and 3176236 in cas2 may affect the resistance of bacteria, cause emergence of multidrug resistance, and increase the types of drug resistance.
Full Text Available List Contact us Trypanosomes Database License License to Use This Database Last updated : 2014/02/04 You may use this database...pecifies the license terms regarding the use of this database and the requirements you must follow in using this database.... The license for this database is specified in the Creative Commons... Attribution-Share Alike 2.1 Japan . If you use data from this database, please be sure attribute this database...pan is found here . With regard to this database, you are licensed to: freely access part or whole of this database
Bellisola, Giuseppe; Cinque, Gianfelice; Vezzalini, Marzia; Moratti, Elisabetta; Silvestri, Giovannino; Redaelli, Sara; Gambacorti Passerini, Carlo; Wehbe, Katia; Sorio, Claudio
We tested the ability of Fourier Transform (FT) InfraRed (IR) microspectroscopy (microFTIR) in combination with unsupervised Hierarchical Cluster Analysis (HCA) in identifying drug-resistance/sensitivity in leukemic cells exposed to tyrosine kinase inhibitors (TKIs). Experiments were carried out in a well-established mouse model of human Chronic Myelogenous Leukemia (CML). Mouse-derived pro-B Ba/F3 cells transfected with and stably expressing the human p210(BCR-ABL) drug-sensitive wild-type BCR-ABL or the V299L or T315I p210(BCR-ABL) drug-resistant BCR-ABL mutants were exposed to imatinib-mesylate (IMA) or dasatinib (DAS). MicroFTIR was carried out at the Diamond IR beamline MIRIAM where the mid-IR absorbance spectra of individual Ba/F3 cells were acquired using the high brilliance IR synchrotron radiation (SR) via aperture of 15 × 15 μm(2) in sizes. A conventional IR source (globar) was used to compare average spectra over 15 cells or more. IR signatures of drug actions were identified by supervised analyses in the spectra of TKI-sensitive cells. Unsupervised HCA applied to selected intervals of wavenumber allowed us to classify the IR patterns of viable (drug-resistant) and apoptotic (drug-sensitive) cells with an accuracy of >95%. The results from microFTIR + HCA analysis were cross-validated with those obtained via immunochemical methods, i.e. immunoblotting and flow cytometry (FC) that resulted directly and significantly correlated. We conclude that this combined microFTIR + HCA method potentially represents a rapid, convenient and robust screening approach to study the impact of drugs in leukemic cells as well as in peripheral blasts from patients in clinical trials with new anti-leukemic drugs.
Full Text Available Alberto Matteelli,1 Alberto Roggi,1 Anna CC Carvalho21Institute of Infectious and Tropical Diseases, WHO Collaborating Centre for TB/HIV Co-Infection, University of Brescia, Brescia, Italy; 2Laboratory of Innovations in Therapies, Education and Bioproducts (LITEB, Oswaldo Cruz Institute (IOC, Oswaldo Cruz Foundation (Fiocruz, Rio de Janeiro, BrazilAbstract: The advent of antibiotics for the treatment of tuberculosis (TB represented a major breakthrough in the fight against the disease. However, since its first use, antibiotic therapy has been associated with the emergence of resistance to drugs. The incorrect use of anti-TB drugs, either due to prescription errors, low patient compliance, or poor quality of drugs, led to the widespread emergence of Mycobacterium tuberculosis strains with an expanding spectrum of resistance. The spread of multidrug-resistant (MDR strains (ie, strains resistant to both isoniazid and rifampicin has represented a major threat to TB control since the 1990s. In 2006, the first cases of MDR strains with further resistance to fluoroquinolone and injectable drugs were described and named extensively drug-resistant TB (XDR-TB. The emergence of XDR-TB strains is a result of mismanagement of MDR cases, and treatment relies on drugs that are less potent and more toxic than those used to treat drug-susceptible or MDR strains. Furthermore, treatment success is lower and mortality higher than achieved in MDR-TB cases, and the number of drugs necessary in the intensive phase of treatment may be higher than the four drugs recommended for MDR-TB. Linezolid may represent a valuable drug to treat cases of XDR-TB. Delamanid, bedaquiline, and PA-824 are new anti-TB agents in the development pipeline that have the potential to enhance the cure rate of XDR-TB. The best measures to prevent new cases of XDR-TB are the correct management of MDR-TB patients, early detection, and proper treatment of existing patients with XDR
Full Text Available is limited in low-resource settings. In this paper we investigate machine learning techniques for drug resistance prediction from routine treatment and laboratory data to help clinicians select patients for confirmatory genotype testing. The techniques...
Pranger, A. D.; Alffenaar, J. W. C.; Aarnoutse, R. E.
Fluoroquinolones (FQs) are important drugs to treat drug-resistant tuberculosis. In this review we integrated pharmacokinetic properties (PK) and microbiological susceptibility against M. tuberculosis and eventually evaluated the pharmcodynamic (PD) properties, as well as the influence of
Koosha Paydary; Parisa Khaghani; Sahra Emamzadeh-Fard; SeyedAhmad SeyedAlinaghi; Kazem Baesi
After its identification in 1980s, HIV has infected more than 30 million people worldwide. In the era of highly active anti-retroviral therapy, anti-retroviral drug resistance results from insufficient anti-retroviral pressure, which may lead to treatment failure. Preliminary studies support the idea that anti-retroviral drug resistance has evolved largely as a result of low-adherence of patients to therapy and extensive use of anti-retroviral drugs in the developed world;however, a highly heterogeneous horde of viral quasi-species are currently circulating in developing nations. Thus, the prioritizing of strategies adopted in such two worlds should be quite different considering the varying anti-retroviral drug resistance prevalence. In this article, we explore differences in anti-retroviral drug resistance patterns between developed and developing countries, as they represent two distinct ecological niches of HIV from an evolutionary standpoint.
C Brandon Ogbunugafor; C Scott Wylie; Ibrahim Diakite; Daniel M Weinreich; Daniel L Hartl
The adaptive landscape analogy has found practical use in recent years, as many have explored how their understanding can inform therapeutic strategies that subvert the evolution of drug resistance...
Kim, Jeong Han; Park, Yong Kwang; Park, Eun-Sook; Kim, Kyun-Hwan
Oral antiviral agents have been developed in the last two decades for the treatment of chronic hepatitis B (CHB). However, antiviral resistance remains an important challenge for long-term CHB therapy. All of the clinically available oral antiviral agents are nucleoside or nucleotide analogues that target the activity of viral reverse transcriptase (RT), and all are reported to have resistant mutations. Since the hepatitis B virus (HBV) RT, like other viral polymerases, lacks proofreading activity, the emergence of drug-resistance occurs readily under selective pressure from the administration of antiviral agents. The molecular diagnosis of drug-resistant HBV is based on sequence variations, and current diagnostic methods include sequencing, restriction fragment polymorphism analysis, and hybridization. Here, we will discuss the currently available molecular diagnosis tools, in vitro phenotypic assays for validation of drug-resistant HBV, and treatment options for drug-resistant HBV.
on various aspects of the epidemiological cycles of the infection is essential and can ... mental studies have shown that multiple trypanocidal drug resistant to both .... According to the questionnaire 30% of livestock owners are treating their cat-.
Zee, Ate Gerard Jan van der
In this thesis diverse cell biological features that in cultured (ovarian) tumor cells have been linked to drug resistance and/or tumor aggressiveness are studied in tumor specimens of epithelial ovarian carcinomas.
Asih, P.B.; Rogers, W.O.; Susanti, A.I.; Rahmat, A.; Rozi, I.E.; Kusumaningtyas, M.A.; Dewi, R.M.; Coutrier, F.N.; Sutamihardja, A.; Ven, A.J.A.M. van der; Sauerwein, R.W.; Syafruddin, D.
BACKGROUND: Drug resistant malaria poses an increasing public health problem in Indonesia, especially eastern Indonesia, where malaria is highly endemic. Widespread chloroquine (CQ) resistance and increasing sulphadoxine-pyrimethamine (SP) resistance prompted Indonesia to adopt artemisinin-based com
Leonard, Guy; Soanes, Darren M; Stevens, Jamie R
Since the first attempts to classify the evolutionary history of trypanosomes, there have been conflicting reports regarding their true phylogenetic relationships and, in particular, their relationships with other vertebrate trypanosomatids, e.g. Leishmania sp., as well as with the many insect parasitising trypanosomatids. Perhaps the issue that has provided most debate is that concerning the monophyly (or otherwise) of genus Trypanosoma and, even with the advent of molecular methods, the findings of numerous studies have varied significantly depending on the gene sequences analysed, number of taxa included, choice of outgroup and phylogenetic methodology. While of arguably limited applied importance, resolution of the question as to whether or not trypanosomes are monophyletic is critical to accurate evaluation of competing, mutually exclusive evolutionary scenarios for these parasites, namely the 'vertebrate-first' or 'insect-first' hypotheses. Therefore, a new approach, which could overcome previous limitations was needed. At its most simple, the problem can be defined within the framework of a trifurcated tree with three hypothetical positions at which the root can be placed. Using BLASTp and whole-genome gene-by-gene phylogenetic analyses of Trypanosoma brucei, Trypanosoma cruzi, Leishmania major and Naegleria gruberi, we have identified 599 gene markers--putative homologues--that were shared between the genomes of these four taxa. Of these, 75 homologous gene families that demonstrate monophyly of the kinetoplastids were identified. We then used these data sets in combination with an additional outgroup, Euglena gracilis, coupled with large-scale gene concatenation and diverse phylogenetic techniques to investigate the relative branching order of T. brucei, T. cruzi and L. major. Our findings confirm the monophyly of genus Trypanosoma and demonstrate that <1% of the analysed gene markers shared between the genomes of T. brucei, T. cruzi and L. major reject
Van Tyne, Daria Natalie
Malaria has plagued mankind for millennia. Antimalarial drug use over the last century has generated highly drug-resistant parasites, which amplify the burden of this disease and pose a serious obstacle to control efforts. This dissertation is motivated by the simple fact that malaria parasites have become resistant to nearly every antimalarial drug that has ever been used, yet the precise genetic mechanisms of parasite drug resistance remain largely unknown. Our work pairs genomics-age techn...
Charlebois, Daniel A; Kaern, Mads
We show that the effect of stress on the reproductive fitness of noisy cell populations can be modelled as first-passage time problem, and demonstrate that even relatively short-lived fluctuations in gene expression can ensure long-term survival of a drug-resistant population. We examine how this effect contributes to the development of drug-resistant cancer cells, and demonstrate that permanent immunity can arise independently of mutations.
Wu, N N; Yin, Y Q; Yuan, R; Wang, B
Objective: To assess the relationship between HIV genetic subtypes and HIV resistance in China. Methods: The literature retrieval was conducted by using Chinese Science-Technology Journal Database (VIP), Wanfang Data, Chinese Journal Full-text Database (CNKI), PubMed and Web of Science to select the papers on the relationship between HIV subtypes and HIV drug resistance in China during 2005-2015. Eligible papers were included according to the inclusion. Meta-analysis was performed by using software Stata 12.0. Results: A total of 43 papers were selected and the pooled rate of drug resistance was 15.1% and the rate of primary drug resistance was 9.5%, the subtypes associated drug resistance were CRF01_AE, CRF07_BC, CRF08_ BC, B/B'and C. The pooled rates of drug resistance of each subtype were 12.8%, 7.4%, 14.3%, 25.7% and 34.9% and the rates of primary drug resistance of each subtype were 7.3%, 5.7%, 11.5%,15.5% and 23.9%, respectively. Subgroup analysis showed that both treated and area subgroup showed a significant difference among groups (PChina and southwestern China were higher than that in southern China. Conclusion: The distribution of HIV genotypes in China was complex and the prevalence of primary drug resistance of each subtype was high, together with a significant difference among subtypes. It is necessary to strengthen the monitoring of different subtypes of drug resistant strains in China to prevent the recombination and spreading of resistant strains.
Wang, Debby D.; Weiqiang Zhou; Hong Yan; Maria Wong; Victor Lee
EGFR mutation-induced drug resistance has significantly impaired the potency of small molecule tyrosine kinase inhibitors in lung cancer treatment. Computational approaches can provide powerful and efficient techniques in the investigation of drug resistance. In our work, the EGFR mutation feature is characterized by the energy components of binding free energy (concerning the mutant-inhibitor complex), and we combine it with specific personal features for 168 clinical subjects to construct a...
Zajícek, P; Pecková, H
The interactions of fish trypanosome culture forms with 11 purified lectins were compared using the agglutination test in microwell plates. Altogether, ten stocks of ten different freshwater fish species were examined. Three basic types of cell-lectin interactions were observed on the microscopical level. The strong agglutination of all stocks regardless their original host was found in the presence of Con A, PSA, RCA60, and RCA120, which implies the presence of relatively high amounts of sugar residues of D-mannose and D-galactose in the surface of culture forms of these parasites. Weak agglutinations of some stocks were observed in the presence of LCA, PNA, SBA, and WGA lectins, but their low intensity makes them not sufficiently reliable for stock characterization. The lectins UEA I, HPA, and PHA caused no agglutination. In conclusion, in case of unequivocal results no remarkable differences in the interactions of various stocks of trypanosomes culture forms with used lectins were observed. These results imply the high degree of similarity of their main cell surface saccharide structures.
Young Geol Yoon; Michael Duane Koob
Due to technical difficulties, the genetic transformation of mitochondria in mammalian cells is still a challenge. In this report, we described our attempts to transform mammalian mitochondria with an engineered mitochondrial genome based on selection using a drug resistance gene. Because the standard drug-resistant neomycin phosphotransferase confers resistance to high concentrations of G418 when targeted to the mitochondria, we generated a recoded neomycin resistance gene that uses the mammalian mitochondrial genetic code to direct the synthesis of this protein in the mitochondria, but not in the nucleus (mitochondrial version). We also generated a universal version of the recoded neomycin resistance gene that allows synthesis of the drug-resistant proteins both in the mitochondria and nucleus. When we transfected these recoded neomycin resistance genes that were incorporated into the mouse mitochondrial genome clones into mouse tissue culture cells by electroporation, no DNA constructs were delivered into the mitochondria. We found that the universal version of the recoded neomycin resistance gene was expressed in the nucleus and thus conferred drug resistance to G418 selection, while the synthetic mitochondrial version of the gene produced no background drug-resistant cells from nuclear transformation. These recoded synthetic drug-resistant genes could be a useful tool for selecting mitochondrial genetic transformants as a precise technology for mitochondrial transformation is developed.
Wang, Linlin; Wang, Yingfang; Duan, Guangcai; Xue, Zerun; Guo, Xiangjiao; Wang, Pengfei; Xi, Yuanlin; Yang, Haiyan
To detect clustered regularly interspaced short palindromic repeats (CRISPR) in Shigella, and to analyze its relationship to drug resistance. Four pairs of primers were used for the detection of convincing CRISPR structures CRISPR-S2 and CRISPR-S4, questionable CRISPR structures CRISPR-S1 and CRISPR-S3 in 60 Shigella strains. All primers were designed using sequences in CRISPR database. CRISPR Finder was used to analyze CRISPR and susceptibilities of Shigella strains were tested by agar diffusion method. Furthermore, we analyzed the relationship between drug resistance and CRISPR-S4. The positive rate of convincing CRISPR structures was 95%. The four CRISPR loci formed 12 spectral patterns (A-L), all of which contained convincing CRISPR structures except type K. We found one new repeat and 12 new spacers. The multi-drug resistance rate was 53. 33% . We found no significant difference between CRISPR-S4 and drug resistant. However, the repeat sequence of CRISPR-S4 in multi- or TE-resistance strains was mainly R4.1 with AC deletions in the 3' end, and the spacer sequences of CRISPR-S4 in multi-drug resistance strains were mainly Sp5.1, Sp6.1 and Sp7. CRISPR was common in Shigella. Variations df repeat sequences and diversities of spacer sequences might be related to drug resistance in Shigella.
Gómez, Ingrid T; Llerena, Claudia R; Zabaleta, Angie P
To characterize tuberculosis drug-resistance using anti-tuberculosis drug-sensitivity tests in Colombian prisoners. Descriptive-retrospective analyses were performed on cases of tuberculosis in prisoners. Samples were evaluated by the National Reference Laboratory. Conditions like gender, TB/VIH co-infection and drug-resistance were evaluated. Anti-tuberculosis drug-sensitivity tests were carried out on 72 prisoners. Results showed a distribution of 90.7 % of cases in males and 9.3 % of cases in females. 12 % of cases were TB/VIH co-infections, 94 % of the cases had not received any anti-tuberculosis treatment before, six isolates were drug-resistant corresponding to 8.8 % of total cases, and two cases were multi drug-resistant representing 1.3 % of the cases. Of the drug-resistant cases, 83.3 % were TB/VIH co-infected. Previously treated cases corresponded to 5.6 % of the total cases analyzed. One case with TB/VIH co-infection and rifampicin resistance was observed, representing 1.3 % of the total cases. The government must create a clear policy for prisoners in Colombia, because a high rate of disease in prisoners was observed. In addition, the results showed an association between drug-resistance and TB/VIH co-infection. Overcrowding and low quality of life in penitentiaries could become an important public health problem.
高振强; 高志萍; 刘喜富; 张涛
According to the fact that CEA gene expressed only in lung adenocarcinoma and not in normal lung cells, a retroviral vector (pCEAMR) was constructed which carried the CEA promoter coupled to MDR1 ribozyme gene. pCEAMR was introduced into drug-resistant lung adenocarcinoma cells GAOK with CEA expression and HeLaK without CEA expression; the expression of pCEAMR and drug resistance in the infected cells were analyzed in vitro and in vivo ; pCEAMR expressed only in CEA-producing GAOK cells and not in non-CEA-producing HeLa cells. The drug resistance to doxorubicin (DOX) decreased 91.5% in the infected GAOK cells and did not change in the infected HeLa cells. In nude mice, DOX could obviously inhibit the growth of the infected GAOK tumors, and had no effect on the growth of the infected HeLa cells. These results indicated that MDR1 ribozyme gene regulated by CEA promoter expressed only in human adenocarcinoma cells and reversed their drug resistance selectively. This gene-drug therapy might serve as an effe
LIU Rui-jun; ZHONG Hong
Objective: To study the relationship between the methylation status of multi-drug resistance protein (MRP) gene and the expression of its mRNA and protein in lung cancer cell lines. Methods: Human embryo lung cell line WI-38, lung adenocarcinoma cell line SPCA-1 and its drug-resistant cells induced by different concentrations of doxorubicin were treated with restriction endonuclease Eco47Ⅲ. The methylation status of MRP was examined by PCR, and the expressions of its mRNA and protein were evaluated by in situ hybridization and immunohistochemistry. Results: MRP gene promoter region of WI-38 cells was in hypermethylation status, but the promoter region of MRP in SPCA-1 cells and their resistant derivatives induced by different concentrations of doxorubicin were in hypomethylation status. There were significant differences in the expression of MRP mRNA among WI-38 cell line, SPCA-1 cells and their drug-resistant derivatives induced by different concentration of doxorubicin. Consistently, MRP immunostaining presented similar significant differences. Conclusion: The promoter region of MRP in SPCA-1 lung adenocarcinoma cells was in hypomethylation status. The hypomethylation status of 5' regulatory region of MRP promoter is an important structural basis that can increase the activity of transcription and results in the development of drug resistance in lung cancer.
Full Text Available Because of the absence of a clear therapeutic target for triple negative breast cancer (TNBC, conventional chemotherapy is the only available systemic treatment option for these patients. Despite chemotherapy treatment, TNBC patients still have worse prognosis when compared with other breast cancer patients. The study is to investigate unique phosphorylated proteins expressed in chemoresistant TNBC cell lines. In the current study, twelve TNBC cell lines were subjected to drug sensitivity assays against chemotherapy drugs docetaxel, doxorubicin, gemcitabine, and cisplatin. Based on their half maximal inhibitory concentrations, four resistant and two sensitive cell lines were selected for further analysis. The phosphopeptides from these cells were enriched with TiO2 beads and fractionated using strong cation exchange. 1,645 phosphoprotein groups and 9,585 unique phosphopeptides were identified by a high throughput LC-MS/MS system LTQ-Orbitrap. The phosphopeptides were further filtered with Ascore system and 1,340 phosphoprotein groups, 2,760 unique phosphopeptides, and 4,549 unique phosphosites were identified. Our study suggested that differentially phosphorylated Cdk5, PML, AP-1, and HSF-1 might work together to promote vimentin induced epithelial to mesenchymal transition (EMT in the drug resistant cells. EGFR and HGF were also shown to be involved in this process.
Abdelkareem, Mohammad Z; Sayed, Mohamed; Hassuna, Noha A; Mahmoud, Mahmoud S; Abdelwahab, Sayed F
The prevalence of Enterococcus faecalis (E. faecalis) infections among Egyptians with urinary tract infection (UTI), their antimicrobial susceptibility and mechanisms of resistance are under investigated. In this study, 300 urine samples were collected from UTI patients to identify E. faecalis. Antimicrobial susceptibility to 18 antimicrobial agents was tested. The presence of aac(6)-Ie-aph(2)Ia, erm(B) and mef(A/E) genes was examined by PCR. Fifty-seven (19%) isolates were identified as E. faecalis. All isolates were sensitive to teicoplanin and were completely resistant to nalidixic acid, cefotaxime and cefadroxil. Multi-drug-resistant (MDR) was found to be 100% with 45 different antibiotypes. The aac(6)Ia-aph(2)Ia gene was found in 100 and 90% of the isolates resistant to gentamicin at concentrations of 120 and 10 μg, respectively. erm(B) and mef(A/E) genes were present in 92.5% (37/40) and 2.5% (1/40) of erythromycin-resistant isolates, respectively. We conclude that there is a high prevalence of E. faecalis in UTI cases with a 100% MDR rate indicating a serious problem in treating infections by this organism in Egypt.
Obejcitve To investigate drug-resistance status and changing tendency of Escherichia coli in my hospital to provide the evidence for reasonable use of antibiotics.Me thods Pathogenic bacteria were isolated and identified according to the national clinical laboratory operation rules .Resu lt The resistance to commonly used antibiotics in Escherichia coli was on the rise the resistance rate to ampicillin was great .Conclusion We must investigate drug-resistance status and changing tendency of Escherichia coli.We should strengthen the management of antibiotil use and control the spread and prevalence of the drug -resistant bacteria.%目的：通过对我院1264株大肠埃希菌的耐药性监测，了解大肠埃希菌药敏现状。为临床医师合理用药提供实验数据。提高临床医师对合理使用抗菌药物的重要性的认识。方法病原菌的分离鉴定药敏按《全国临床检验操作规程》进行。结果大肠埃希菌对多种抗菌药物的耐药率呈上升趋势，以氨苄西林耐药率最高。产超光谱B-內酰胺酶大肠埃希菌的检出率也呈上升趋势。结论临床对病原菌应及时监测，合理使用抗菌药物，减少耐药菌的产生，防止发生院内感染。
Charlotte Jane Houldcroft
Full Text Available Human cytomegalovirus (HCMV is a significant pathogen in immunocompromised individuals, with the potential to cause fatal pneumonitis and colitis, as well as increasing the risk of organ rejection in transplant patients. With the advent of new anti-HCMV drugs there is therefore considerable interest in using virus sequence data to monitor emerging resistance to antiviral drugs in HCMV viraemia and disease, including the identification of putative new mutations. We used target-enrichment to deep sequence HCMV DNA from 11 immunosuppressed paediatric patients receiving single or combination anti-HCMV treatment, serially sampled over 1-27 weeks. Changes in consensus sequence and resistance mutations were analysed for three ORFs targeted by anti-HCMV drugs and the frequencies of drug resistance mutations monitored. Targeted-enriched sequencing of clinical material detected mutations occurring at frequencies of 2%. Seven patients showed no evidence of drug resistance mutations. Four patients developed drug resistance mutations a mean of 16 weeks after starting treatment. In two patients, multiple resistance mutations accumulated at frequencies of 20% or less, including putative maribavir and ganciclovir resistance mutations P522Q (UL54 and C480F (UL97. In one patient, resistance was detected 14 days earlier than by PCR. Phylogenetic analysis suggested recombination or superinfection in one patient. Deep sequencing of HCMV enriched from clinical samples excluded resistance in 7 of eleven subjects and identified resistance mutations earlier than conventional PCR-based resistance testing in 2 patients. Detection of multiple low level resistance mutations was associated with poor outcome.
Houldcroft, Charlotte J.; Bryant, Josephine M.; Depledge, Daniel P.; Margetts, Ben K.; Simmonds, Jacob; Nicolaou, Stephanos; Tutill, Helena J.; Williams, Rachel; Worth, Austen J. J.; Marks, Stephen D.; Veys, Paul; Whittaker, Elizabeth; Breuer, Judith
Human cytomegalovirus (HCMV) is a significant pathogen in immunocompromised individuals, with the potential to cause fatal pneumonitis and colitis, as well as increasing the risk of organ rejection in transplant patients. With the advent of new anti-HCMV drugs there is therefore considerable interest in using virus sequence data to monitor emerging resistance to antiviral drugs in HCMV viraemia and disease, including the identification of putative new mutations. We used target-enrichment to deep sequence HCMV DNA from 11 immunosuppressed pediatric patients receiving single or combination anti-HCMV treatment, serially sampled over 1–27 weeks. Changes in consensus sequence and resistance mutations were analyzed for three ORFs targeted by anti-HCMV drugs and the frequencies of drug resistance mutations monitored. Targeted-enriched sequencing of clinical material detected mutations occurring at frequencies of 2%. Seven patients showed no evidence of drug resistance mutations. Four patients developed drug resistance mutations a mean of 16 weeks after starting treatment. In two patients, multiple resistance mutations accumulated at frequencies of 20% or less, including putative maribavir and ganciclovir resistance mutations P522Q (UL54) and C480F (UL97). In one patient, resistance was detected 14 days earlier than by PCR. Phylogenetic analysis suggested recombination or superinfection in one patient. Deep sequencing of HCMV enriched from clinical samples excluded resistance in 7 of 11 subjects and identified resistance mutations earlier than conventional PCR-based resistance testing in 2 patients. Detection of multiple low level resistance mutations was associated with poor outcome. PMID:27667983
Lumb, Richard; Bastian, Ivan; Dawson, David; Gilpin, Chris; Havekort, Frank; Howard, Peter; Sievers, Aina
The Australian Mycobacterium Reference Laboratory Network collected and analysed laboratory data on new diagnoses of disease caused by Mycobacterium tuberculosis complex in the year 2000. A total of 765 cases were identified, representing an annual reporting rate of 4.0 cases of laboratory-confirmed tuberculosis (TB) per 100,000 population. Pulmonary disease was diagnosed in 64.9 per cent of cases with a male:female ratio of 1.5:1. Smears were positive for 209/365 (57.3%) of sputum isolates and 39/117 (33.3%) bronchoscopy isolates. Sputum from males was more likely to be smear-positive (63.3%) than from females (47.5%). Isolates from lymph node accounted for 136 (17.7%) of all cases; only 28.7 per cent were smear-positive. Eighty-four (11.0%) isolates, comprising 82 M. tuberculosis and 2 M. bovis strains, demonstrated in vitro resistance to at least one of the standard anti-TB medications. Resistance to at least isoniazid and rifampicin (defined as multidrug-resistant TB) was observed for only 8 (1.0%) strains, a rate similar to previous years. Almost all (96.3%) of patients with drug resistant strains were classified as having initial resistance. The country of birth was known for 76 (92.7%) of 82 patients with a drug resistant strain of M. tuberculosis; 6 were Australian-born and 70 (92.1%) had migrated from a total of 17 countries. Of these 70 migrants with drug-resistant disease, 68.6 per cent had migrated from one of the following countries: Vietnam (n=15), China (n=11), Philippines (n=11), India (n=6), and Indonesia (n=5).
Full Text Available Drug-resistant HIV are more prevalent and persist longer than previously demonstrated by bulk sequencing due to the ability to detect low-frequency variants. To clarify a clinical benefit to monitoring minority-level drug resistance populations as a guide to select active drugs for salvage therapy, we retrospectively analyzed the dynamics of low-frequency drug-resistant population in antiretroviral (ARV-exposed drug resistant individuals.Six HIV-infected individuals treated with ARV for more than five years were analyzed. These individuals had difficulty in controlling viremia, and treatment regimens were switched multiple times guided by standard drug resistance testing using bulk sequencing. To detect minority variant populations with drug resistance, we used a highly sensitive allele-specific PCR (AS-PCR with detection thresholds of 0.3-2%. According to ARV used in these individuals, we focused on the following seven reverse transcriptase inhibitor-resistant mutations: M41L, K65R, K70R, K103N, Y181C, M184V, and T215F/Y. Results of AS-PCR were compared with bulk sequencing data for concordance and presence of additional mutations. To clarify the genetic relationship between low-frequency and high-frequency populations, AS-PCR amplicon sequences were compared with bulk sequences in phylogenetic analysis.The use of AS-PCR enabled detection of the drug-resistant mutations, M41L, K103N, Y181C, M184V and T215Y, present as low-frequency populations in five of the six individuals. These drug resistant variants persisted for several years without ARV pressure. Phylogenetic analysis indicated that pre-existing K103N and T215I variants had close genetic relationships with high-frequency K103N and T215I observed during treatment.Our results demonstrate the long-term persistence of drug-resistant viruses in the absence of drug pressure. The rapid virologic failures with pre-existing mutant viruses detectable by AS-PCR highlight the clinical importance of
Full Text Available African trypanosomes are unicellular flagellated parasites causing trypanosomiases in Africa, a group of severe diseases also known as sleeping sickness in human and nagana in cattle. These parasites are almost exclusively transmitted by the bite of the tsetse fly. In this review, we describe and compare the three development programs of the main trypanosome species impacting human and animal health, with focus on the most recent observations. From here, some reflections on research issues on the trypanosome developmental biology in the tsetse fly to be addressed in the future are given.
Migliori, Giovanni Battista; Pontali, Emanuele; Sotgiu, Giovanni; Centis, Rosella; D’Ambrosio, Lia; Tiberi, Simon; Tadolini, Marina; Esposito, Susanna
The new drugs delamanid and bedaquiline are increasingly being used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB). The World Health Organization, based on lack of evidence, recommends their use under specific conditions and not in combination. No systematic review has yet evaluated the efficacy, safety, and tolerability of delamanid and bedaquiline used in combination. A search of peer-reviewed, scientific evidence was carried out, aimed at evaluating the efficacy/effectiveness, safety, and tolerability of delamanid and bedaquiline-containing regimens in individuals with pulmonary/extrapulmonary disease, which were bacteriologically confirmed as M/XDR-TB. We used PubMed to identify any relevant manuscripts in English up to the 23 December 2016, excluding editorials and reviews. Three out of 75 manuscripts retrieved satisfied the inclusion criteria, whilst 72 were excluded for dealing with only one drug (three studies), being recommendations (one study) or identifying need for their use (one study), focusing on drug resistance aspects (six studies) or being generic reviews/other studies (61 papers). The studies retrieved reported two XDR-TB cases observed for six months and achieving consistent sputum smear and culture conversion. Case 2 experienced a short break of bedaquiline, which was re-started after introducing verapamil. After a transient and symptom-free increase of the QT interval from week 5 to 17, it then decreased below the 500 ms threshold. PMID:28178199
Hupalo, Daniel N; Luo, Zunping; Melnikov, Alexandre; Sutton, Patrick L; Rogov, Peter; Escalante, Ananias; Vallejo, Andrés F; Herrera, Sócrates; Arévalo-Herrera, Myriam; Fan, Qi; Wang, Ying; Cui, Liwang; Lucas, Carmen M; Durand, Salomon; Sanchez, Juan F; Baldeviano, G Christian; Lescano, Andres G; Laman, Moses; Barnadas, Celine; Barry, Alyssa; Mueller, Ivo; Kazura, James W; Eapen, Alex; Kanagaraj, Deena; Valecha, Neena; Ferreira, Marcelo U; Roobsoong, Wanlapa; Nguitragool, Wang; Sattabonkot, Jetsumon; Gamboa, Dionicia; Kosek, Margaret; Vinetz, Joseph M; González-Cerón, Lilia; Birren, Bruce W; Neafsey, Daniel E; Carlton, Jane M
Plasmodium vivax is a major public health burden, responsible for the majority of malaria infections outside Africa. We explored the impact of demographic history and selective pressures on the P. vivax genome by sequencing 182 clinical isolates sampled from 11 countries across the globe, using hybrid selection to overcome human DNA contamination. We confirmed previous reports of high genomic diversity in P. vivax relative to the more virulent Plasmodium falciparum species; regional populations of P. vivax exhibited greater diversity than the global P. falciparum population, indicating a large and/or stable population. Signals of natural selection suggest that P. vivax is evolving in response to antimalarial drugs and is adapting to regional differences in the human host and the mosquito vector. These findings underline the variable epidemiology of this parasite species and highlight the breadth of approaches that may be required to eliminate P. vivax globally. PMID:27348298
Lee Sue J
Full Text Available Abstract Background Preventing the emergence of anti-malarial drug resistance is critical for the success of current malaria elimination efforts. Prevention strategies have focused predominantly on qualitative factors, such as choice of drugs, use of combinations and deployment of multiple first-line treatments. The importance of anti-malarial treatment dosing has been underappreciated. Treatment recommendations are often for the lowest doses that produce "satisfactory" results. Methods The probability of de-novo resistant malaria parasites surviving and transmitting depends on the relationship between their degree of resistance and the blood concentration profiles of the anti-malarial drug to which they are exposed. The conditions required for the in-vivo selection of de-novo emergent resistant malaria parasites were examined and relative probabilities assessed. Results Recrudescence is essential for the transmission of de-novo resistance. For rapidly eliminated anti-malarials high-grade resistance can arise from a single drug exposure, but low-grade resistance can arise only from repeated inadequate treatments. Resistance to artemisinins is, therefore, unlikely to emerge with single drug exposures. Hyperparasitaemic patients are an important source of de-novo anti-malarial drug resistance. Their parasite populations are larger, their control of the infection insufficient, and their rates of recrudescence following anti-malarial treatment are high. As use of substandard drugs, poor adherence, unusual pharmacokinetics, and inadequate immune responses are host characteristics, likely to pertain to each recurrence of infection, a small subgroup of patients provides the particular circumstances conducive to de-novo resistance selection and transmission. Conclusion Current dosing recommendations provide a resistance selection opportunity in those patients with low drug levels and high parasite burdens (often children or pregnant women. Patients with
Abu Hena Hasanoor Reja
Full Text Available Background: The current strategy for leprosy control depends mainly on early case detection and providing the recommended multidrug therapy (MDT dosage. Understanding the molecular mechanisms of drug resistance to each of these drugs is essential in providing effective treatment and preventing the spread of resistant strains in the community. The progress of molecular biology research provides a very efficient opportunity for the diagnosis of drug resistance by in vitro method. Aim: We aimed to investigate the point mutations within the rpoB gene region of the Mycobacterium leprae genome, which are responsible for resistance to rifampicin, in order to determine the emergence of drug resistance in leprosy in the Kolkata region of West Bengal. Methods: A total of 50 patients with a relapse of leprosy were enrolled in the study. Skin smears were obtained for estimation of bacillary index and biopsies were obtained in 70% alcohol for extraction of DNA. The extracted DNA was amplified by M. leprae-polymerase chain reaction (PCR targeting rpoB gene region. Every single nucleotide base in the sequence is aligned to reference sequence and identity gaps were determined by NCBI - BLAST. Later in-silico analysis was done to identify the changes in the translated protein sequences. Results: A mutation at the base pair position 2275405 where G is replaced by C in the M. leprae genome, which corresponds to the coding region of rpoB gene (279 bp - 2275228 to2275506, was observed in two patients. This missense mutation in CAC codon brings about a glutamic acid to histidine change in the amino acid sequence of RNA polymerase beta subunit at the position 442 (Glu442His, a region specific for rifampicin interaction, which might be responsible for unresponsiveness to rifampicin by manifesting a stable bacteriological index in these 2 patients even after completion of 24 months of multibacillary multi-drug therapy (MB-MDT. Limitations: The major limitations of
Full Text Available Abstract Background The Malanga sleeping sickness focus of the Democratic Republic of Congo has shown an epidemic evolution of disease during the last century. However, following case detection and treatment, the prevalence of the disease decreased considerably. No active survey has been undertaken in this focus for a couple of years. To understand the current epidemiological status of sleeping sickness as well as the animal African trypanosomiasis in the Malanga focus, we undertook the identification of tsetse blood meals as well as different trypanosome species in flies trapped in this focus. Methods Pyramidal traps were use to trap tsetse flies. All flies caught were identified and live flies were dissected and their mid-guts collected. Fly mid-gut was used for the molecular identification of the blood meal source, as well as for the presence of different trypanosome species. Results About 949 Glossina palpalis palpalis were trapped; 296 (31.2% of which were dissected, 60 (20.3% blood meals collected and 57 (19.3% trypanosome infections identified. The infection rates were 13.4%, 5.1%, 3.5% and 0.4% for Trypanosoma congolense savannah type, Trypanosoma brucei s.l., Trypanosoma congolense forest type and Trypanosoma vivax, respectively. Three mixed infections including Trypanosoma brucei s.l. and Trypanosoma congolense savannah type, and one mixed infection of Trypanosoma vivax and Trypanosoma congolense savannah type were identified. Eleven Trypanosoma brucei gambiense infections were identified; indicating an active circulation of this trypanosome subspecies. Of all the identified blood meals, about 58.3% were identified as being taken on pigs, while 33.3% and 8.3% were from man and other mammals, respectively. Conclusion The presence of Trypanosoma brucei in tsetse mid-guts associated with human blood meals is indicative of an active transmission of this parasite between tsetse and man. The considerable number of pig blood meals combined
Simo, Gustave; Silatsa, Barberine; Flobert, Njiokou; Lutumba, Pascal; Mansinsa, Philemon; Madinga, Joule; Manzambi, Emile; De Deken, Reginald; Asonganyi, Tazoacha
The Malanga sleeping sickness focus of the Democratic Republic of Congo has shown an epidemic evolution of disease during the last century. However, following case detection and treatment, the prevalence of the disease decreased considerably. No active survey has been undertaken in this focus for a couple of years. To understand the current epidemiological status of sleeping sickness as well as the animal African trypanosomiasis in the Malanga focus, we undertook the identification of tsetse blood meals as well as different trypanosome species in flies trapped in this focus. Pyramidal traps were use to trap tsetse flies. All flies caught were identified and live flies were dissected and their mid-guts collected. Fly mid-gut was used for the molecular identification of the blood meal source, as well as for the presence of different trypanosome species. About 949 Glossina palpalis palpalis were trapped; 296 (31.2%) of which were dissected, 60 (20.3%) blood meals collected and 57 (19.3%) trypanosome infections identified. The infection rates were 13.4%, 5.1%, 3.5% and 0.4% for Trypanosoma congolense savannah type, Trypanosoma brucei s.l., Trypanosoma congolense forest type and Trypanosoma vivax, respectively. Three mixed infections including Trypanosoma brucei s.l. and Trypanosoma congolense savannah type, and one mixed infection of Trypanosoma vivax and Trypanosoma congolense savannah type were identified. Eleven Trypanosoma brucei gambiense infections were identified; indicating an active circulation of this trypanosome subspecies. Of all the identified blood meals, about 58.3% were identified as being taken on pigs, while 33.3% and 8.3% were from man and other mammals, respectively. The presence of Trypanosoma brucei in tsetse mid-guts associated with human blood meals is indicative of an active transmission of this parasite between tsetse and man. The considerable number of pig blood meals combined with the circulation of Trypanosoma brucei gambiense in this focus
Brouwer-Visser, Jurriaan; Lee, Jiyeon; McCullagh, KellyAnne; Cossio, Maria J; Wang, Yanhua; Huang, Gloria S
Drug resistance is an obstacle to the effective treatment of ovarian cancer. We and others have shown that the insulin-like growth factor (IGF) signaling pathway is a novel potential target to overcome drug resistance. The purpose of this study was to validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and to determine the efficacy of targeting IGF2 in vivo. An analysis of The Cancer Genome Atlas (TCGA) data in the serous ovarian cancer cohort showed that high IGF2 mRNA expression is significantly associated with shortened interval to disease progression and death, clinical indicators of drug resistance. In a genetically diverse panel of ovarian cancer cell lines, the IGF2 mRNA levels measured in cell lines resistant to various microtubule-stabilizing agents including Taxol were found to be significantly elevated compared to the drug sensitive cell lines. The effect of IGF2 knockdown on Taxol resistance was investigated in vitro and in vivo. Transient IGF2 knockdown significantly sensitized drug resistant cells to Taxol treatment. A Taxol-resistant ovarian cancer xenograft model, developed from HEY-T30 cells, exhibited extreme drug resistance, wherein the maximal tolerated dose of Taxol did not delay tumor growth in mice. Blocking the IGF1R (a transmembrane receptor that transmits signals from IGF1 and IGF2) using a monoclonal antibody did not alter the response to Taxol. However, stable IGF2 knockdown using short-hairpin RNA in HEY-T30 effectively restored Taxol sensitivity. These findings validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and show that directly targeting IGF2 may be a preferable strategy compared with targeting IGF1R alone.
Olusoji Daniel; Eltayeb Osman
Objective:To determine the prevalence and risk factors associated with drug resistant tuberculosis(TB) in South West Nigeria.Methods: A retrospective study conducted among pulmonary tuberculosis (PTB) patients from Oyo and Osun States in South West Nigeria who had their culture and drug susceptibility test performed at the institute of tropical medicine Antwerp, Belgium between2007 and2009. Data on the patient’s characteristics were retrieved from the TB treatment card. Univariate analysis was performed to assess the risk factors for drug resistant tuberculosis. The Level of significance was atP<0.05.Results:Among the88 patients who had drug-susceptibility test result, there were50 males and38 females. Of the88patients,55 (62.5%) had strains resistant to at least one or more anti-drugs. The proportion ofTBcases with resistance to a single drug was12.7%. The multi-drug resistantTB (MDR-TB) rate was76.4%. The only significant factor for the development of drug resistance andMDR was the history of previous anti TB treatment (P<0.01). Other factors such as age[OR 0.86 (0.35-2.13);P=0.72] and gender[OR 1.24 (0.49-3.14);P=0.62] were not significantly associated with drug resistanceTB.Conclusions: The study highlighted a high prevalence ofMDR-TBamong the study population. History of previous TB treatment was associated withMDR-TB. There is an urgent need to conduct a nationalTB drug resistance survey to determine the actual burden and risk factors associated with drug resistance TB in the country.
Babiker, Hamza A; Hastings, Ian M; Swedberg, Göte
Malaria, a leading parasitic disease, inflicts an enormous toll on human lives and is caused by protozoal parasites belonging to the genus Plasmodium. Antimalarial drugs targeting essential biochemical processes in the parasite are the primary resources for management and control. However, the parasite has established mutations, substantially reducing the efficacy of these drugs. First-line therapy is faced the with the consistent evolution of drug-resistant genotypes carrying these mutations. However, drug-resistant genotypes are likely to be less fit than the wild-type, suggesting that they might disappear by reducing the volume of drug pressure. A substantial body of epidemiological evidence confirmed that the frequency of resistant genotypes wanes when active drug selection declines. Drug selection on the parasite genome that removes genetic variation in the vicinity of drug-resistant genes (hitch-hiking) is common among resistant parasites in the field. This can further disadvantage drug-resistant strains and limit their variability in the face of a mounting immune response. Attempts to provide unequivocal evidence for the fitness cost of drug resistance have monitored the outcomes of laboratory competition experiments of deliberate mixtures of sensitive and resistant strains, in the absence of drug pressure, using isogenic clones produced either by drug selection or gene manipulation. Some of these experiments provided inconclusive results, but they all suggested reduced fitness of drug-resistant clones in the absence of drug pressure. In addition, biochemical analyses provided clearer information demonstrating that the mutation of some antimalarial-targeted enzymes lowers their activity compared with the wild-type enzyme. Here, we review current evidences for the disadvantage of drug-resistance mutations, and discuss some strategies of drug deployment to maximize the cost of resistance and limit its spread.
Full Text Available The objective of this study was to isolate pathogenic bacteria in neo-natal septicaemia cases, and to know their antibiograms. Under aseptic precautions, blood was drawn from 140 neonates with sus-pected septicaemia and inoculated in brain heart infusion (BHI broth. Isolates obtained were identified as per standard protocol and antibi-otic susceptibility was done by Kirby Bauer disc diffusion method (as per CLSI guidelines. A total number of 62 (44.2% patients had positive blood cultures. The most common pathogens isolated were Klebsiella pneumoniae (n=22, 35% followed by Staphylococcus aureus (n=15, 24.1%, Escherichia coli (n=14, 22.5%, CONS (n=7, 11.2% and Pseudomonas aeruginosa (n=4, 6.4%. The Gram nega-tive organisms showed high resistance to commonly used antibiotics and were highly sensitive to Meropenem. The Gram positive bacteria showed high resistance to Ampicillin, Erythromycin and Amoxycillin; but they were highly susceptible to Linizolid and Vancomycin. As the Gram negative organisms were the most common isolates in neona-tal septicemia, their resistance pattern should be considered essen-tial for deciding the empirical treatment. Prompt treatment of neonatal sepsis with judicious use of appropriate antibiotics can minimize the morbidity and mortality, besides reducing the emergence of multi-drug resistant organisms in intensive care units (ICUs.
Shobrak, Mohammed Y; Abo-Amer, Aly E
Emergence and distribution of multi-drug resistant (MDR) bacteria in environments pose a risk to human and animal health. A total of 82 isolates of Escherichia spp. were recovered from cloacal swabs of migrating and non-migrating wild birds. All bacterial isolates were identified and characterized morphologically and biochemically. 72% and 50% of isolates recovered from non-migrating and migrating birds, respectively, showed positive congo red dye binding (a virulence factor). Also, hemolysin production (a virulence factor) was showed in 8% of isolates recovered from non-migrating birds and 75% of isolates recovered from migrating birds. All isolates recovered from non-migrating birds were found resistant to Oxacillin while all isolates recovered from migrating birds demonstrated resistance to Oxacillin, Chloramphenicol, Oxytetracycline and Lincomycin. Some bacterial isolates recovered from non-migrating birds and migrating birds exhibited MDR phenotype. The MDR isolates were further characterized by API 20E and 16S rRNA as E. coli and E. vulneris. MDR Escherichia isolates contain ~1-5 plasmids of high-molecular weights. Accordingly, wild birds could create a potential threat to human and animal health by transmitting MDR bacteria to water streams and other environmental sources through their faecal residues, and to remote regions by migration.
Furin, J; Alirol, E; Allen, E; Fielding, K; Merle, C; Abubakar, I; Andersen, J; Davies, G; Dheda, K; Diacon, A; Dooley, K E; Dravnice, G; Eisenach, K; Everitt, D; Ferstenberg, D; Goolam-Mahomed, A; Grobusch, M P; Gupta, R; Harausz, E; Harrington, M; Horsburgh, C R; Lienhardt, C; McNeeley, D; Mitnick, C D; Nachman, S; Nahid, P; Nunn, A J; Phillips, P; Rodriguez, C; Shah, S; Wells, C; Thomas-Nyang'wa, B; du Cros, P
Drug-resistant tuberculosis (DR-TB) is a growing public health problem, and for the first time in decades, new drugs for the treatment of this disease have been developed. These new drugs have prompted strengthened efforts in DR-TB clinical trials research, and there are now multiple ongoing and planned DR-TB clinical trials. To facilitate comparability and maximise policy impact, a common set of core research definitions is needed, and this paper presents a core set of efficacy and safety definitions as well as other important considerations in DR-TB clinical trials work. To elaborate these definitions, a search of clinical trials registries, published manuscripts and conference proceedings was undertaken to identify groups conducting trials of new regimens for the treatment of DR-TB. Individuals from these groups developed the core set of definitions presented here. Further work is needed to validate and assess the utility of these definitions but they represent an important first step to ensure there is comparability in clinical trials on multidrug-resistant TB.
Full Text Available Our previous studies showed that several sipholane triterpenes, sipholenol A, sipholenone E, sipholenol L and siphonellinol D, have potent reversal effect for multidrug resistance (MDR in cancer cells that overexpressed P-glycoprotein (P-gp/ABCB1. Through comparison of cytotoxicity towards sensitive and multi-drug resistant cell lines, we identified that the semisynthetic esters sipholenol A-4-O-acetate and sipholenol A-4-O-isonicotinate potently reversed P-gp-mediated MDR but had no effect on MRP1/ABCC1 and BCRP/ABCG2-mediated MDR. The results from [3H]-paclitaxel accumulation and efflux studies suggested that these two triterpenoids were able to increase the intracellular accumulation of paclitaxel by inhibiting its active efflux. In addition, western blot analysis revealed that these two compounds did not alter the expression levels of P-gp when treated up to 72 h. These sipholenol derivatives also stimulated the ATPase activity of P-gp membranes, which suggested that they might be substrates of P-gp. Moreover, in silico molecular docking studies revealed the virtual binding modes of these two compounds into human homology model of P-gp. In conclusion, sipholenol A-4-O-acetate and sipholenol A-4-O-isonicotinate efficiently inhibit the P-gp and may represent potential reversal agents for the treatment of multidrug resistant cancers.
Rong WANG; Shangwei WU; Xue LI; Ping HE; Yunde LIU
In order to provide useful information for effective control and clinical therapy of infection, the resistance status and the rate of carrying AmpC β-1actamase of Enterobacter cloacae (E. cloacae) were investigated. By VITEK (Bacterial automatic biochemical analyzer), the isolates of E. cloacae were identified and the drag resistance was measured. The AmpC enzyme was detected by the five-disk diffusion test. Antibiotic sensitivity test showed that the resistance effects of E. cloacae to cefazolin, cefoxitin and ampicillin were more serious, with resistant rates of 80.5%, 75.3% and 70.1%, respectively. However, it was more sensitive to Sulperazone (cefoperazone/sulbactam, 13.0%), amikacin (16.9%) and ciprofloxacin (19.5%). Meanwhile, the phenotype detection showed that 35.06% (27/77) isolates of E. cloacae produced AmpC β-1actamase. Most of E. cloacae are multi-drug resistant strains. Sulperazone (cefoperazone/sulbactam), a kind of component β-1actamase, is a more effective antibiotic for treating infection caused by E. cloacae. Unreasonable application of the third generation cephalosporins plays an important role in leading to emergence of high-yield AmpC β-1actamase strains, so antibiotics should be used wisely.
Little, D; Flowers, J R; Hammerberg, B H; Gardner, S Y
Possible anthelmintic resistance on a breeding farm where a rapid rotation anthelmintic programme had been implemented for 9 years was investigated. Cyathostomins resistant to fenbendazole and pyrantel were documented by faecal worm egg count reduction test (FWECRT). To 1) manage small strongyle transmission in a herd of horses in which resistance to both pyrantel pamoate and fenbendazole was identified and thereby reduce the risk of clinical disease in the individual animal, 2) monitor the change in resistance patterns over time and 3) monitor the efficacy of ivermectin over the study period. Targeted ivermectin treatment of horses on the farm was instituted for mature horses with faecal worm egg counts (FWEC) > 200 eggs/g (epg) and for horses 100 epg. Over a 30 month period, targeted ivermectin treatment achieved acceptable control in mares, as judged by FWEC, and improved control of patent cyathostome infection in consecutive foal crops. Egg reappearance time (ERT) after treatment with ivermectin was managing multiple drug resistant cyathostominosis. Use of ivermectin should be monitored closely for development of resistance.
Oymak Sema F
Full Text Available Abstract Backround The emergence of Mycobacterium tuberculosis strains resistant to antituberculosis agents has recently received increased attention owing largely to the dramatic outbreaks of multi drug resistance tuberculosis (MDR-TB. Methods Patients residing in Zonguldak and Kayseri provinces of Turkey with, pulmonary tuberculosis diagnosed between 1972 and 1999 were retrospectively identified. Drug susceptibility tests had been performed for isoniazid (INH, rifampin (RIF, streptomycin (SM, ethambutol (EMB and thiacetasone (TH after isolation by using the resistance proportion method. Results Total 3718 patients were retrospectively studied. In 1972–1981, resistance rates for to SM and INH were found to be 14.8% and 9.8% respectively (n: 2172. In 1982–1991 period, resistance rates for INH, SM, RIF, EMB and TH were 14.2%, 14.4%, 10.5%, 2.7% and 2.9% (n: 683, while in 1992–1999 period 14.4%, 21.1%, 10.6%, 2.4% and 3.7% respectively (n: 863. Resistance rates were highest for SM and INH in three periods. MDR-TB patients constituted 7.3% and 6.6% of 1982–1991 and 1992–1999 periods (p > 0.05. Conclusion This study demonstrates the importance of resistance rates for TB. Continued surveillance and immediate therapeutic decisions should be undertaken in order to prevent the dissemination of such resistant strains.
Mehta, Manjula; Sood, Shaveta; Sharma, Jyoti
Introduction Enterococci are an important cause of opportunistic nosocomial infections and several multidrug resistant strains have emerged. The severity of periodontal diseases is managed by reduction in the pathogenic bacteria. There is a need to assess the prevalence and antibiotic susceptibility of enterococci colonizing the periodontal pocket and correlate its biofilm formation ability because oral biofilms provide a protective environment and are a reservoir of bacterial colonization of the gingival crevice. Aim To investigate possible association between antibiotic susceptibility and biofilm formation in enterococci isolates from chronic periodontitis patients. Materials and Methods This retrospective study was conducted at Dr. Harvansh Singh Judge Institute of Dental Sciences and Hospital, Punjab University, Chandigarh from January 2015 to October 2015. Sterile paper points were inserted in the periodontal pocket of 100 subjects and put in a transport media. Forty -six isolates were identified as enterococci. The isolates were further examined for their ability to form biofilm by microtitre plate assay and antimicrobial susceptibility testing was done by disc diffusion method for clinically relevant antibiotics. Results Significant relationship (p<0.001) was found between biofilm production with antibiotic resistance to Vancomycin, Erythromycin, Ciprofloxacin, Tiecoplanin, Amoxycillin and Gentamycin. Conclusion The study demonstrates a high propensity among the isolates of Enterococci to form biofilm and a significant association of biofilm with multiple drug resistance. PMID:28273964
Power, Robert A.; Davaniah, Siva; Derache, Anne; Wilkinson, Eduan; Tanser, Frank; Pillay, Deenan; de Oliveira, Tulio
Background Genome-wide association studies (GWAS) have considerably advanced our understanding of human traits and diseases. With the increasing availability of whole genome sequences (WGS) for pathogens, it is important to establish whether GWAS of viral genomes could reveal important biological insights. Here we perform the first proof of concept viral GWAS examining drug resistance (DR), a phenotype with well understood genetics. Method We performed a GWAS of DR in a sample of 343 HIV subtype C patients failing 1st line antiretroviral treatment in rural KwaZulu-Natal, South Africa. The majority and minority variants within each sequence were called using PILON, and GWAS was performed within PLINK. HIV WGS from patients failing on different antiretroviral treatments were compared to sequences derived from individuals naïve to the respective treatment. Results GWAS methodology was validated by identifying five associations on a genetic level that led to amino acid changes known to cause DR. Further, we highlighted the ability of GWAS to identify epistatic effects, identifying two replicable variants within amino acid 68 of the reverse transcriptase protein previously described as potential fitness compensatory mutations. A possible additional DR variant within amino acid 91 of the matrix region of the Gag protein was associated with tenofovir failure, highlighting GWAS’s ability to identify variants outside classical candidate genes. Our results also suggest a polygenic component to DR. Conclusions These results validate the applicability of GWAS to HIV WGS data even in relative small samples, and emphasise how high throughput sequencing can provide novel and clinically relevant insights. Further they suggested that for viruses like HIV, population structure was only minor concern compared to that seen in bacteria or parasite GWAS. Given the small genome length and reduced burden for multiple testing, this makes HIV an ideal candidate for GWAS. PMID:27677172
Full Text Available The human aldo-keto reductase AKR1B10, originally identified as an aldose reductase-like protein and human small intestine aldose reductase, is a cytosolic NADPH-dependent reductase that metabolizes a variety of endogenous compounds, such as aromatic and aliphatic aldehydes and dicarbonyl compounds, and some drug ketones. The enzyme is highly expressed in solid tumors of several tissues including lung and liver, and as such has received considerable interest as a relevant biomarker for the development of those tumors. In addition, AKR1B10 has been recently reported to be significantly up-regulated in some cancer cell lines (medulloblastoma D341 and colon cancer HT29 acquiring resistance towards chemotherapeutic agents (cyclophosphamide and mitomycin c, suggesting the validity of the enzyme as a chemoresistance marker. Although the detailed information on the AKR1B10-mediated mechanisms leading to the drug resistance process is not well understood so far, the enzyme has been proposed to be involved in functional regulations of cell proliferation and metabolism of drugs and endogenous lipids during the development of chemoresistance. This article reviews the current literature focusing mainly on expression profile and roles of AKR1B10 in the drug resistance of cancer cells. Recent developments of AKR1B10 inhibitors and their usefulness in restoring sensitivity to anticancer drugs are also reviewed.
Helke, Kristi L; McCrackin, M A; Galloway, Ashley M; Poole, Ann Z; Salgado, Cassandra D; Marriott, Bernadette P
Controversy continues concerning antimicrobial use in food animals and its relationship to drug-resistant infections in humans. We systematically reviewed published literature for evidence of a relationship between antimicrobial use in agricultural animals and drug-resistant meat or dairy-borne non-typhoidal salmonellosis in humans. Based on publications from the United States (U.S.), Canada, and Denmark from January 2010 to July 2014, 858 articles received title and abstract review, 104 met study criteria for full article review with 68 retained for which data are presented. Antibiotic exposure in both cattle and humans found an increased likelihood of Salmonella colonization, whereas in chickens, animals not exposed to antibiotics (organic) were more likely to be Salmonella positive and those that had antibiotic exposure were more likely to harbor antimicrobial resistant Salmonella organisms. In swine literature, only tylosin exposure was examined and no correlation was found among exposure, Salmonella colonization, or antimicrobial resistance. No studies that identified farm antimicrobial use also traced antimicrobial-resistant Salmonella from farm to fork.
Full Text Available BACKGROUND: Adherence to effective malaria medication is extremely important in the context of Cambodia's elimination targets and drug resistance containment. Although the public sector health facilities are accessible to the local ethnic minorities of Ratanakiri province (Northeast Cambodia, their illness itineraries often lead them to private pharmacies selling "cocktails" and artemether injections, or to local diviners prescribing animal sacrifices to appease the spirits. METHODS: The research design consisted of a mixed methods study, combining qualitative (in-depth interviews and participant observation and quantitative methods (household and cross-sectional survey. RESULTS: Three broad options for malaria treatment were identified: i the public sector; ii the private sector; iii traditional treatment based on divination and ceremonial sacrifice. Treatment choice was influenced by the availability of treatment and provider, perceived side effects and efficacy of treatments, perceived etiology of symptoms, and patient-health provider encounters. Moreover, treatment paths proved to be highly flexible, changing mostly in relation to the perceived efficacy of a chosen treatment. CONCLUSIONS: Despite good availability of anti-malarial treatment in the public health sector, attendance remained low due to both structural and human behavioral factors. The common use and under-dosage of anti-malaria monotherapy in the private sector (single-dose injections, single-day drug cocktails represents a threat not only for individual case management, but also for the regional plan of drug resistance containment and malaria elimination.
Ipsaro, Jonathan J; Shen, Chen; Arai, Eri; Xu, Yali; Kinney, Justin B; Joshua-Tor, Leemor; Vakoc, Christopher R; Shi, Junwei
Genetic alterations conferring resistance to the effects of chemical inhibitors are valuable tools for validating on-target effects in cells. Unfortunately, for many therapeutic targets such alleles are not available. To address this issue, we evaluated whether CRISPR-Cas9-mediated insertion/deletion (indel) mutagenesis can produce drug-resistance alleles at endogenous loci. This method takes advantage of the heterogeneous in-frame alleles produced following Cas9-mediated DNA cleavage, which we show can generate rare alleles that confer resistance to the growth-arrest caused by chemical inhibitors. We used this approach to identify novel resistance alleles of two lysine methyltransferases, DOT1L and EZH2, which are each essential for the growth of MLL-fusion leukemia cells. We biochemically characterized the DOT1L mutation, showing that it is significantly more active than the wild-type enzyme. These findings validate the on-target anti-leukemia activities of existing DOT1L and EZH2 inhibitors and reveal a simple method for deriving drug-resistance alleles for novel targets, which may have utility during early stages of drug development.
Ipsaro, Jonathan J.; Shen, Chen; Arai, Eri; Xu, Yali; Kinney, Justin B.; Joshua-Tor, Leemor; Vakoc, Christopher R.
Genetic alterations conferring resistance to the effects of chemical inhibitors are valuable tools for validating on-target effects in cells. Unfortunately, for many therapeutic targets such alleles are not available. To address this issue, we evaluated whether CRISPR-Cas9-mediated insertion/deletion (indel) mutagenesis can produce drug-resistance alleles at endogenous loci. This method takes advantage of the heterogeneous in-frame alleles produced following Cas9-mediated DNA cleavage, which we show can generate rare alleles that confer resistance to the growth-arrest caused by chemical inhibitors. We used this approach to identify novel resistance alleles of two lysine methyltransferases, DOT1L and EZH2, which are each essential for the growth of MLL-fusion leukemia cells. We biochemically characterized the DOT1L mutation, showing that it is significantly more active than the wild-type enzyme. These findings validate the on-target anti-leukemia activities of existing DOT1L and EZH2 inhibitors and reveal a simple method for deriving drug-resistance alleles for novel targets, which may have utility during early stages of drug development. PMID:28231254
Kevin, Dion A; Meujo, Damaris AF; Hamann, Mark T
Background As multidrug-resistant (MDR) pathogens continue to emerge, there is a substantial amount of pressure to identify new drug candidates. Carboxyl polyethers, also referred to as polyether antibiotics, are a unique class of compounds with outstanding potency against a variety of critical infectious disease targets including protozoa, bacteria and viruses. The characteristics of these molecules that are of key interest are their selectivity and high potency against several MDR etiological agents. Objective Although many studies have been published about carboxyl polyether antibiotics, there are no recent reviews of this class of drugs. The purpose of this review is to provide the reader with an overview of the spectrum of activity of polyether antibiotics, their mechanism of action, toxicity and potential as drug candidates to combat drug-resistant infectious diseases. Conclusion Polyether ionophores show a high degree of promise for the potential control of drug-resistant bacterial and parasitic infections. Despite the long history of use of this class of drugs, very limited medicinal chemistry and drug optimization studies have been reported, thus leaving the door open to these opportunities in the future. Scifinder and PubMed were the main search engines used to locate articles relevant to the topic presented in the present review. Keywords used in our search were specific names of each of the 88 compounds presented in the review as well as more general terms such as polyethers, ionophores, carboxylic polyethers and polyether antibiotics. PMID:23480512
Taylor, Matthew; McCollister, Bruce; Park, Daewon
The battle against the prevalence of hospital-acquired infections has underscored the importance of identifying and maintaining the cleanliness of possible infection transmission sources in the patient's environment. One of the most crucial lines of defense for mitigating the spread of pathogens in a healthcare facility is the removal of microorganisms from the environment by air filtration systems. After removing the pathogenic microorganisms, the filters used in these systems can serve as reservoirs for the pathogens and pose a risk for secondary infection. This threat, combined with the ever-growing prevalence of drug-resistant bacterial strains, substantiates the need for an effective bactericidal air filter. To this end, a broad-spectrum bactericidal polyurethane incorporating immobilized quaternary ammonium groups was developed for use as an air filter coating. In this study, the bactericidal activity of the polymer coating on high-efficiency particulate air (HEPA) filter samples was quantified against eight bacterial strains commonly responsible for nosocomial infection-including drug-resistant strains, and confirmed when applied as a filter coating in conditions mimicking those of its intended application. The coated HEPA filter samples exhibited high bactericidal activity against all eight strains, and the polyurethane was concluded to be an effective coating in rendering HEPA filters bactericidal.
Wilson, John W; Tsukayama, Dean T
Extensively drug-resistant (XDR) tuberculosis (TB) is an unfortunate by-product of mankind's medical and pharmaceutical ingenuity during the past 60 years. Although new drug developments have enabled TB to be more readily curable, inappropriate TB management has led to the emergence of drug-resistant disease. Extensively drug-resistant TB describes Mycobacterium tuberculosis that is collectively resistant to isoniazid, rifampin, a fluoroquinolone, and an injectable agent. It proliferates when established case management and infection control procedures are not followed. Optimized treatment outcomes necessitate time-sensitive diagnoses, along with expanded combinations and prolonged durations of antimicrobial drug therapy. The challenges to public health institutions are immense and most noteworthy in underresourced communities and in patients coinfected with human immunodeficiency virus. A comprehensive and multidisciplinary case management approach is required to optimize outcomes. We review the principles of TB drug resistance and the risk factors, diagnosis, and managerial approaches for extensively drug-resistant TB. Treatment outcomes, cost, and unresolved medical issues are also discussed.
González-Escalante, Laura; Peñuelas-Urquides, Katia; Said-Fernández, Salvador; Silva-Ramírez, Beatriz; Bermúdez de León, Mario
Understanding drug resistance in Mycobacterium tuberculosis requires an integrated analysis of strain lineages, mutations and gene expression. Previously, we reported the differential expression of esxG, esxH, infA, groES, rpmI, rpsA and lipF genes in a sensitive M. tuberculosis strain and in a multidrug-resistant clinical isolate. Here, we have evaluated the expression of these genes in 24 clinical isolates that belong to different lineages and have different drug resistance profiles. In vitro, growth kinetics analysis showed no difference in the growth of the clinical isolates, and thus drug resistance occurred without a fitness cost. However, a quantitative reverse transcription PCR analysis of gene expression revealed high variability among the clinical isolates, including those with similar drug resistance profiles. Due to the complexity of gene regulation pathways and the wide diversity of M. tuberculosis lineages, the use of gene expression as a molecular signature for drug resistance is not straightforward. Therefore, we recommend that the expression of M. tuberculosis genes be performed individually, and baseline expression levels should be verified among several different clinical isolates, before any further applications of these findings.
Full Text Available Objective: Pathogen distribution characteristics of nephrology patients with urinary tract infections are studied, and drug resistance of nephrology and urinary tract infection disease are analyzed, so as to provide sufficient evidence for treatment of patients. Methods: Conduct randomized control study of 3500 cases of nephrology patients with urinary tract infections treated in different hospitals from December 2013 to December 2015, isolate pathogens in patients’ urine samples, perform identification and drug sensitive test and then conduct detailed analysis of drug resistance of pathogens. Results: Through isolation of pathogens, it can be found that all pathogens include Escherichia coli, Gram-positive cocci, gram-negative bacteria, fungi, Acinetobacter baumannii, Enterococcus faecalis, and urinary Enterococcus. Among them, proportion of E. coli is the largest. Patients have relatively high drug resistance to ceftriaxone, gentamicin, ciprofloxacin and cotrimoxazole. Conclusion: For nephrology patients with urinary tract infection, the main pathogen is E. coli, which has had some drug resistance. Drug resistance detection of pathogen should be strengthened in clinics, so as to provide strong guidance for clinical treatment and promote effective treatment of patients.
WANG Sheng Fen; ZHOU Yang; PANG Yu; ZHENG Hui Wen; ZHAO Yan Lin
ObjectiveTo investigatetheprevalence of primary drug-resistant tuberculosis (TB) and associated risk factors in China.We also explored factors contributing tothe transmission of multidrug-resistant tuberculosis (MDR-TB). MethodsA total of 2794 representative,Mycobacterium tuberculosis isolates from treatment-naive patients were subjected to drug susceptibility testing, and risk factors for drug-resistant TBwere analyzed. We also analyzed MDR-TB strain sublineages, drug-resistance-conferring mutations, and risk factors associated with clustered primary MDR strains. ResultsAmong 2794Mycobacterium tuberculosis isolates from treatment-naive patients, the prevalence of any resistance to first-line drugs was 33.2%andthe prevalence of MDR-TB was 5.7%. We did not find any risk factors significantly associated with resistance to first-line drugs.The93 primary MDR-TB isolates were classified into six sublineages, of which, 75 (80.6%) isolates were the RD105-deleted Beijing lineage.The largest sublineage included 65 (69.9%) isolates with concurrent deletions of RD105, RD207, and RD181.Twenty-nine (31.2%) primary MDR strains grouped in clusters;MDR isolates in clusters were more likely to have S531LrpoBmutation. ConclusionThis study indicates that primary drug-resistantTBand MDR-TBstrains are prevalent in China,and multiplemeasures should be taken toaddress drug-resistant TB.
Rho, Jin Kyung; Choi, Yun Jung; Lee, Jin Kyung; Ryoo, Baek-Yeol; Na, Im Ii; Yang, Sung Hyun; Kim, Cheol Hyeon; Yoo, Young Do; Lee, Jae Cheol
Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcriptional factor which is activated by hypoxia and associated with cell survival, proliferation and drug resistance. Recent studies have shown that the down-stream molecules of the epidermal growth factor receptor (EGFR) signal are involved in the hypoxia-dependent or -independent HIF-1alpha protein accumulation. Thus, we hypothesized that an EGFR-TK inhibitor, gefitinib, might circumvent the hypoxia-induced drug resistance via the regulation of HIF-1alpha expression. In our data, treatment of gefitinib suppressed induced HIF-1alpha by hypoxia. This action of gefitinib was caused by reduced protein stability without any change in the level of HIF-1alpha mRNA. The effect of gefitinib on down-regulation of HIF-1alpha was reversed by transfection of constitutively active form of Akt. The cellular response to gefitinib was similar in both normoxia and hypoxia condition. However, the response to conventional chemotherapeutic drugs decreased >50% under hypoxia condition and they did not change HIF-1alpha expression. In addition, the suppression of HIF-1alpha using siRNA overcame partially hypoxia-induced drug resistance. In conclusion, gefitinib was able to circumvent hypoxia-induced drug resistance suggesting that the effective suppression of HIF-1alpha by the inhibition of EGFR-Akt pathway may overcome the hypoxia-induced drug resistance.
Full Text Available Background: Multidrug-resistant tuberculosis (MDR-TB has emerged as an important global health concern and is on the rise throughout the world. Objective: The aim of this study was to examine the epidemiology and pattern of TB drug resistance. Methods: In this cross-sectional study, 180 pulmonary TB patients from two Northwestern provinces of Iran were selected. The first and second line drug susceptibility testing was carried out using the 1% proportion method on the Lφwenstein-Jensen medium. Full demographic, environmental and clinical history was evaluated. Results: Prevalence of resistance to any TB drug was 13.8%. Eight (4.4% patients had MDR-TB (2.4% in the province of East Azerbaijan and 9.3% in the province of Ardabil and one patient had extensively drug-resistant TB. Patient resistance to both isoniazid and streptomycin was the most prevalent at a rate of 8.3%. Patients showed the least resistance to ethambutol (2.8%. There was a significant relationship between the previous history of TB drug treatment and TB drug resistance. Migrants from rural to urban areas were in high-risk groups for the occurrence of TB drug resistance. Conclusion: In our study, prevalence of MDR was less than the global average. It is essential to monitor the patients with previous history of TB treatment and migrants by rapid and accurate techniques in terms of drug-resistance odds.
Full Text Available HAART has dramatically improved survival and quality of life among people living with HIV and AIDS globally. However, drug resistant mutations of HIV are a great challenge to the benefits of HAART. Antiviral resistance can be mediated either by changes in the molecular target of therapy (the primary mechanism observed in HIV-1 or in other viral proteins that indirectly interfere with a drug′s activity. Drug resistant mutations easily evolve in the presence of sub-optimal adherence. With the introduction of generic HAART, there has been a steep increase in the number of patients put on HAART in India. It should also be noted that since most patients pay for medications out of their own pockets, interruptions in therapy due to monetary constraints are not uncommon. There is little information on HIV drug resistance in resource constrained settings like India where the predominant circulating HIV-1 sub-type is C. The transmissibility of drug-resistant forms of the virus is also a major concern especially when formulating treatment guidelines. This article reviews published data available on the patterns of HIV-1 drug resistance among treatment naοve in India.
Piao, Ji-Gang; Gao, Feng; Yang, Lihua
How to destroy drug-resistant tumor cells remains an ongoing challenge for cancer treatment. We herein report on a therapeutic nanoparticle, aHLP-PDA, which has an acid-activated hemolytic polymer (aHLP) grafted onto photothermal polydopamine (PDA) nanosphere via boronate ester bond, in efforts to ablate drug-resistant tumors. Upon exposure to oxidative stress and/or near-infrared laser irradiation, aHLP-PDA nanoparticle responsively releases aHLP, likely via responsive cleavage of boronate ester bond, and thus responsively exhibits acid-facilitated mammalian-membrane-disruptive activity. In vitro cell studies with drug-resistant and/or thermo-tolerant cancer cells show that the aHLP-PDA nanoparticle demonstrates preferential cytotoxicity at acidic pH over physiological pH. When administered intravenously, the aHLP-PDA nanoparticle exhibits significantly prolonged blood circulation lifetime and enhanced tumor uptake compared to bare PDA nanosphere, likely owing to aHLP's stealth effects conferred by its zwitterionic nature at blood pH. As a result, the aHLP-PDA nanoparticle effectively ablates drug-resistant tumors, leading to 100% mouse survival even on the 32nd day after suspension of photothermal treatment, as demonstrated with the mouse model. This work suggests that a combination of nanotechnology with lessons learned in bacterial antibiotic resistance may offer a feasible and effective strategy for treating drug-resistant cancers often found in relapsing patients.
Dheda, Keertan; Gumbo, Tawanda; Gandhi, Neel R; Murray, Megan; Theron, Grant; Udwadia, Zarir; Migliori, G B; Warren, Robin
Extensively drug-resistant tuberculosis is a burgeoning global health crisis mainly affecting economically active young adults, and has high mortality irrespective of HIV status. In some countries such as South Africa, drug-resistant tuberculosis represents less than 3% of all cases but consumes more than a third of the total national budget for tuberculosis, which is unsustainable and threatens to destabilise national tuberculosis programmes. However, concern about drug-resistant tuberculosis has been eclipsed by that of totally and extremely drug-resistant tuberculosis—ie, resistance to all or nearly all conventional first-line and second-line antituberculosis drugs. In this Review, we discuss the epidemiology, pathogenesis, diagnosis, management, implications for health-care workers, and ethical and medicolegal aspects of extensively drug-resistant tuberculosis and other resistant strains. Finally, we discuss the emerging problem of functionally untreatable tuberculosis, and the issues and challenges that it poses to public health and clinical practice. The emergence and growth of highly resistant strains of tuberculosis make the development of new drugs and rapid diagnostics for tuberculosis—and increased funding to strengthen global control efforts, research, and advocacy—even more pressing. PMID:24717628
Prevalence of Pre-Extensively Drug-Resistant Tuberculosis (Pre XDR-TB) and Extensively Drug-Resistant Tuberculosis (XDR-TB) among Pulmonary Multidrug Resistant Tuberculosis (MDR-TB) at a Tertiary Care Center in Mumbai
Unnati D. Desai; Joshi, Jyotsna M
Background: India is a high burden country for Tuberculosis (TB). As per the World Health Organization (WHO) statistics, 24000 cases of Multi Drug Resistant (MDR) TB were diagnosed in India in 2014. MDR-TB patients consist of a heterogeneous cohort and management has its challenges. Aims and objectives: We studied the prevalence of PreExtensively Drug Resistant TB (Pre XDR-TB) and Extensively Drug Resistant TB (XDR-TB) among patients of pulmonary MDR-TB not previous...
Full Text Available The brown-banded cockroach, Supella longipalpa is known as a carrier of pathogenic bacteria in urban environments, but its role is not well documented regarding the carriage of antibiotic-resistant pathogenic bacteria in Iran. The aim of this study was to determine the resistance bacteria isolated from the brown-banded cockroach in Ahvaz, south west of Iran.Totally 39 cockroaches were collected from kitchen area of houses and identified. All specimens were cultured to isolate the bacterial agents on blood agar and MacConky agar media. The microorganisms were identified using necessary differential and biochemical tests. Antimicrobial susceptibility tests were performed for isolated organisms by Kirby-Bauer's disk diffusion according to NCLI guideline, using 18 antibiotics.From the 39 collected S. langipalpa, 179 bacterial agents were isolated, 92 of alimentary ducts and 87 of external body surfaces. Isolated bacteria from cockroaches were identified as Enterobacter spp., Klebsiella spp., Citrobacter spp., Escherichia coli, Salmonella spp., Proteus spp., coagulase negative staphylococci, Serratia marcescens, Staphylococcus aureus, and Bacillus species. The pattern resistance rates were determined for gram negative bacilli and gram positive cocci regarding 18 antibiotics.The brown-banded cockroach can be involved in the spread of drug resistant bacteria and increases the possibility of contacting human environment to drug resistant bacteria. Therefore, the potential of removing this insect should be improved. This is the first original report of drug resistant bacteria isolated from the brown-banded cockroach of Iran.
Full Text Available BACKGROUND: Pharmacoresistance is a major issue in the treatment of epilepsy. However, the mechanism underlying pharmacoresistance to antiepileptic drugs (AEDs is still unclear, and few animal models have been established for studying drug resistant epilepsy (DRE. In our study, spontaneous recurrent seizures (SRSs were investigated by video-EEG monitoring during the entire procedure. METHODS/PRINCIPAL FINDINGS: In the mouse pilocarpine-induced epilepsy model, we administered levetiracetam (LEV and valproate (VPA in sequence. AED-responsive and AED-resistant mice were naturally selected after 7-day treatment of LEV and VPA. Behavioral tests (open field, object exploration, elevated plus maze, and light-dark transition test and a microRNA microarray test were performed. Among the 37 epileptic mice with SRS, 23 showed significantly fewer SRSs during administration of LEV (n = 16, LEV sensitive (LS group or VPA (n = 7, LEV resistant/VPA sensitive (LRVS group, while 7 epileptic mice did not show any amelioration with either of the AEDs (n = 7, multidrug resistant (MDR group. On the behavioral assessment, MDR mice displayed distinctive behaviors in the object exploration and elevated plus maze tests, which were not observed in the LS group. Expression of miRNA was altered in LS and MDR groups, and we identified 4 miRNAs (miR-206, miR-374, miR-468, and miR-142-5p, which were differently modulated in the MDR group versus both control and LS groups. CONCLUSION: This is the first study to identify a pharmacoresistant subgroup, resistant to 2 AEDs, in the pilocarpine-induced epilepsy model. We hypothesize that modulation of the identified miRNAs may play a key role in developing pharmacoresistance and behavioral alterations in the MDR group.
Lane-Serff, Harriet; MacGregor, Paula; Carrington, Mark
African trypanosomes have complex life cycles comprising at least ten developmental forms, variously adapted to different niches in their tsetse fly vector and their mammalian hosts. Unlike many other protozoan pathogens, they are always extracellular and have evolved intricate surface coats that allow them to obtain nutrients while also protecting them from the immune defenses of either insects or mammals. The acquisition of macromolecular nutrients requires receptors that function within the context of these surface coats. The best understood of these is the haptoglobin–hemoglobin receptor (HpHbR) of Trypanosoma brucei, which is used by the mammalian bloodstream form of the parasite, allowing heme acquisition. However, in some primates it also provides an uptake route for trypanolytic factor-1, a mediator of innate immunity against trypanosome infection. Recent studies have shown that during the evolution of African trypanosome species the receptor has diversified in function from a hemoglobin receptor predominantly expressed in the tsetse fly to a haptoglobin–hemoglobin receptor predominantly expressed in the mammalian bloodstream. Structural and functional studies of homologous receptors from different trypanosome species have allowed us to propose an evolutionary history for how one receptor has adapted to different roles in different trypanosome species. They also highlight the challenges that a receptor faces in operating on the complex trypanosome surface and show how these challenges can be met. PMID:28125726
Vecht, Charles; Duran-Peña, Alberto; Houillier, Caroline; Durand, Thomas; Capelle, Laurent; Huberfeld, Gilles
International audience; Drug-resistant epilepsy (DRE) occurs commonly in gliomas, possibly due to a shared mechanism of AMPA-activation involving both seizure activity and tumor growth. We tested the AMPA-receptor blocker perampanel (PER) in patients with DRE in low- and high-grade gliomas. Seizure response was defined as 50% drop in seizure frequency or as seizure-freedom. Cognitive function was examined by computerized test on cognitive speed (CTCS), which is sensitive to the type of cognit...
Pinto, C Miguel; Ocaña-Mayorga, Sofía; Tapia, Elicio E; Lobos, Simón E; Zurita, Alejandra P; Aguirre-Villacís, Fernanda; MacDonald, Amber; Villacís, Anita G; Lima, Luciana; Teixeira, Marta M G; Grijalva, Mario J; Perkins, Susan L
The generalist parasite Trypanosoma cruzi has two phylogenetic lineages associated almost exclusively with bats-Trypanosoma cruzi Tcbat and the subspecies T. c. marinkellei. We present new information on the genetic variation, geographic distribution, host associations, and potential vectors of these lineages. We conducted field surveys of bats and triatomines in southern Ecuador, a country endemic for Chagas disease, and screened for trypanosomes by microscopy and PCR. We identified parasites at species and genotype levels through phylogenetic approaches based on 18S ribosomal RNA (18S rRNA) and cytochrome b (cytb) genes and conducted a comparison of nucleotide diversity of the cytb gene. We document for the first time T. cruzi Tcbat and T. c. marinkellei in Ecuador, expanding their distribution in South America to the western side of the Andes. In addition, we found the triatomines Cavernicola pilosa and Triatoma dispar sharing shelters with bats. The comparisons of nucleotide diversity revealed a higher diversity for T. c. marinkellei than any of the T. c. cruzi genotypes associated with Chagas disease. Findings from this study increased both the number of host species and known geographical ranges of both parasites and suggest potential vectors for these two trypanosomes associated with bats in rural areas of southern Ecuador. The higher nucleotide diversity of T. c. marinkellei supports a long evolutionary relationship between T. cruzi and bats, implying that bats are the original hosts of this important parasite.
Pérez, Lissette; Kourí, Vivian; Alemán, Yoan; Abrahantes, Yeisel; Correa, Consuelo; Aragonés, Carlos; Martínez, Orlando; Pérez, Jorge; Fonseca, Carlos; Campos, Jorge; Álvarez, Delmis; Schrooten, Yoeri; Dekeersmaeker, Nathalie; Imbrechts, Stijn; Beheydt, Gertjan; Vinken, Lore; Soto, Yudira; Álvarez, Alina; Vandamme, Anne-Mieke; Van Laethem, Kristel
In Cuba, antiretroviral therapy rollout started in 2001 and antiretroviral therapy coverage has reached almost 40% since then. The objectives of this study were therefore to analyze subtype distribution, and level and patterns of drug resistance in therapy-naive HIV-1 patients. Four hundred and one plasma samples were collected from HIV-1 therapy-naive patients in 2003 and in 2007-2011. HIV-1 drug resistance genotyping was performed in the pol gene and drug resistance was interpreted according to the WHO surveillance drug-resistance mutations list, version 2009. Potential impact on first-line therapy response was estimated using genotypic drug resistance interpretation systems HIVdb version 6.2.0 and Rega version 8.0.2. Phylogenetic analysis was performed using Neighbor-Joining. The majority of patients were male (84.5%), men who have sex with men (78.1%) and from Havana City (73.6%). Subtype B was the most prevalent subtype (39.3%), followed by CRF20-23-24_BG (19.5%), CRF19_cpx (18.0%) and CRF18_cpx (10.3%). Overall, 29 patients (7.2%) had evidence of drug resistance, with 4.0% (CI 1.6%-4.8%) in 2003 versus 12.5% (CI 7.2%-14.5%) in 2007-2011. A significant increase in drug resistance was observed in recently HIV-1 diagnosed patients, i.e. 14.8% (CI 8.0%-17.0%) in 2007-2011 versus 3.8% (CI 0.9%-4.7%) in 2003 (OR 3.9, CI 1.5-17.0, p=0.02). The majority of drug resistance was restricted to a single drug class (75.8%), with 55.2% patients displaying nucleoside reverse transcriptase inhibitor (NRTI), 10.3% non-NRTI (NNRTI) and 10.3% protease inhibitor (PI) resistance mutations. Respectively, 20.7% and 3.4% patients carried viruses containing drug resistance mutations against NRTI+NNRTI and NRTI+NNRTI+PI. The first cases of resistance towards other drug classes than NRTI were only detected from 2008 onwards. The most frequent resistance mutations were T215Y/rev (44.8%), M41L (31.0%), M184V (17.2%) and K103N (13.8%). The median genotypic susceptibility score for the
Vandamme, Anne-Mieke; Camacho, Ricardo J; Ceccherini-Silberstein, Francesca
) consider testing earliest detectable plasma RNA when a successful nonnucleoside reverse transcriptase inhibitor-containing therapy was inappropriately interrupted; (v) genotype source patient when postexposure prophylaxis is considered; for HIV-2, (vi) consider resistance testing where treatment change......The European HIV Drug Resistance Guidelines Panel, established to make recommendations to clinicians and virologists, felt that sufficient new information has become available to warrant an update of its recommendations, explained in both pocket guidelines and this full paper. The Panel makes...... the following recommendations concerning the indications for resistance testing: for HIV-1 (i) test earliest sample for protease and reverse transcriptase drug resistance in drug-naive patients with acute or chronic infection; (ii) test protease and reverse transcriptase drug resistance at virologic failure...
A. L. Khanin
Full Text Available The results of the dispensary control for 188 patients with drug-resistant tuberculosis having been analysed during 3—5 years; those patients hadn’t received the adequate chemical therapy: 50% — died because of growing more serious tuberculosis in the first 2 years of the control, 33% — the process became cronic, 7,4% — self-recovered, 9,6% — left for other places or for the prison hospitals. Some patients are known to infect with drug-resistant strains MBT nearly 1 500 people every year, thus keeping the circulation among town population DR/MBT as well as the high level of drug-resistant tuberculosis cases.
Mounsey, Kate E; Holt, Deborah C; McCarthy, James; Currie, Bart J; Walton, Shelley F
Limited effective treatments, coupled with recent observations of emerging drug resistance to oral ivermectin and 5% permethrin, raise concerns regarding the future control of scabies, especially in severe cases and in endemic areas where repeated community treatment programs are in place. There is consequently an urgent need to define molecular mechanisms of drug resistance in scabies mites and to develop and assess alternative therapeutic options, such as tea tree oil, in the event of increasing treatment failure. Molecular studies on scabies mites have, until recently, been restricted; however, recent advances are providing new insights into scabies mite biology and genetic mechanisms underlying drug resistance. These may assist in overcoming many of the current difficulties in monitoring treatment efficacy and allow the development of more sensitive tools for monitoring emerging resistance.
Ghaderpour, Aziz; Ho, Wing Sze; Chew, Li-Lee; Bong, Chui Wei; Chong, Ving Ching; Thong, Kwai-Lin; Chai, Lay Ching
E.coli, an important vector distributing antimicrobial resistance in the environment, was found to be multi-drug resistant, abundant, and genetically diverse in the Matang mangrove estuaries, Malaysia. One-third (34%) of the estuarine E. coli was multi-drug resistant. The highest antibiotic resistance prevalence was observed for aminoglycosides (83%) and beta-lactams (37%). Phylogenetic groups A and B1, being the most predominant E. coli, demonstrated the highest antibiotic resistant level and prevalence of integrons (integron I, 21%; integron II, 3%). Detection of phylogenetic group B23 downstream of fishing villages indicates human fecal contamination as a source of E. coli pollution. Enteroaggregative E. coli (1%) were also detected immediately downstream of the fishing village. The results indicated multi-drug resistance among E. coli circulating in Matang estuaries, which could be reflective of anthropogenic activities and aggravated by bacterial and antibiotic discharges from village lack of a sewerage system, aquaculture farms and upstream animal husbandry.
Hao, Xiao-ting; Wong, Irina S M; Kwan, Patrick
We evaluated the interrater reliability of the consensus definition of drug-resistant epilepsy proposed by the International League Against Epilepsy. According to the definition framework, outcome of each antiepileptic drug (AED) trial was categorized as "seizure freedom" or "treatment failure." This level 1 assessment was used to determine the level 2 classification, which defined drug-resistant epilepsy as the failure of adequate trials of two or more AED schedules to achieve sustained seizure freedom. Two raters classified treatment outcomes of 150 patients independently. The patients had received a total of 428 trials of AEDs. Categorization of level 1 outcome to individual AED trials by the raters was consistent in 413 (96.5%). For the level 2 classification of drug-resistant or drug-responsive epilepsy, there was absolute agreement between the raters in 141 patients (94%), with a κ index of 0.91 (Pdefinition appeared to have a high degree of interrater reliability in this setting.
Full Text Available FLT3 is the most frequently mutated kinase in acute myeloid leukemia (AML. Internal tandem duplications (ITDs in the juxta-membrane region constitute the majority of activating FLT3 mutations. Several FLT3 kinase inhibitors were developed and tested in the clinic with significant success. However, recent studies have reported the development of secondary drug resistance in patients treated with FLT3 inhibitors. Since FLT3-ITD is an HSP90 client kinase, we here explored if targeting the stability of drug-resistant FLT3 mutant protein could be a potential therapeutic option. We observed that HSP90 inhibitor treatment resulted in the degradation of inhibitor-resistant FLT3-ITD mutants and selectively induced toxicity in cells expressing FLT3-ITD mutants. Thus, HSP90 inhibitors provide a potential therapeutic choice to overcome secondary drug resistance following TKI treatment in FLT3-ITD positive AML.
López, Beatriz; Ambroggi, Marta; Palmero, Domingo; Salvadores, Bernardo; Gravina, Elida; Mazzeo, Eduardo; Imaz, Susana; Barrera, Lucía
During 2003–2009, the National Tuberculosis (TB) Laboratory Network in Argentina gave 830 patients a new diagnosis of multidrug-resistant (MDR) TB and 53 a diagnosis of extensively drug- resistant (XDR) TB. HIV co-infection was involved in nearly one third of these cases. Strain genotyping showed that 7 major clusters gathered 56% of patients within restricted geographic areas. The 3 largest clusters corresponded to epidemic MDR TB strains that have been undergoing transmission for >10 years. The indigenous M strain accounted for 29% and 40% of MDR and XDR TB cases, respectively. Drug-resistant TB trends in Argentina are driven by spread of a few strains in hotspots where the rate of HIV infection is high. To curb transmission, the national TB program is focusing stringent interventions in these areas by strengthening infection control in large hospitals and prisons, expediting drug resistance detection, and streamlining information-sharing systems between HIV and TB programs. PMID:23092584
de la Puente, Pilar; Azab, Feda; Muz, Barbara; Luderer, Micah; Arbiser, Jack; Azab, Abdel Kareem
Despite recent progress in novel and targeted therapies, multiple myeloma (MM) remains a therapeutically challenging incurable disease. The regulation of important cellular processes and its link to cancer presented Src as an attractive target for MM. We suggest a novel strategy to improve the treatment of MM and overcome the drug resistance for the current therapeutic agents by specific inhibition of Src in MM cells by Tris (Dibenzylideneacetone) dipalladium (Tris DBA). Tris DBA reduces proliferation, induces G1 arrest and apoptosis in MM cells. Tris DBA showed additive effect with proteasome inhibitors reducing proliferation, cell cycle signaling, and increasing apoptosis more than each drug alone. Tris DBA overcame hypoxia-induced effects such as enhanced chemotaxis or drug resistance to proteasome inhibitors by inhibition of HIF1α expression. Moreover, we found that Tris DBA is an effective anti-myeloma agent alone or in combination with other targeted drugs and that it reverses hypoxia-induced drug resistance in myeloma.
Yamamoto, T; Echeverria, P; Yokota, T
Clinical isolates of enteroaggregative Escherichia coli (EAggEC) were tested for their in vitro susceptibilities to 27 antimicrobial agents. Marked drug resistance was observed with sulfamethoxazole, ampicillin, and chloramphenicol in contrast to such antimicrobial agents as cefixime, sparfloxacin, and ciprofloxacin. One of the EAggEC strains carried a plasmid that conferred on its host resistance to ampicillin, tetracycline, sulfamethoxazole, streptomycin, and spectinomycin and an ability to adhere to child ileal villi or HeLa cells in the characteristic aggregative pattern. This plasmid also mediated D-mannose-resistant hemagglutinin production and bacterial clump formation (autoagglutination). The data demonstrate appearance of marked drug resistance and an intestine-adherence and drug-resistance plasmid in the newest category of diarrheagenic E. coli.
Vandamme, Anne-Mieke; Camacho, Ricardo J; Ceccherini-Silberstein, Francesca;
The European HIV Drug Resistance Guidelines Panel, established to make recommendations to clinicians and virologists, felt that sufficient new information has become available to warrant an update of its recommendations, explained in both pocket guidelines and this full paper. The Panel makes...... the following recommendations concerning the indications for resistance testing: for HIV-1 (i) test earliest sample for protease and reverse transcriptase drug resistance in drug-naive patients with acute or chronic infection; (ii) test protease and reverse transcriptase drug resistance at virologic failure......) consider testing earliest detectable plasma RNA when a successful nonnucleoside reverse transcriptase inhibitor-containing therapy was inappropriately interrupted; (v) genotype source patient when postexposure prophylaxis is considered; for HIV-2, (vi) consider resistance testing where treatment change...
Assefa, E; Abebe, G
A three-part study was conducted to determine the efficacy of isometamidium chloride in donkey populations naturally infected with trypanosomes in north Omo Zone, southern Ethiopia. In the first, 373 randomly selected donkeys from four villages were examined for trypanosome infections by the dark ground/phase contrast buffy coat technique (BCT) in November 1999. The trypanosome prevalence was 18.2% (95% confidence interval (CI): 14.4, 22.5) and Trypanosoma congolense was the most common species accounting for 66.2% of the overall infections. In the second part, 40 infected donkeys were selected and treated with a prophylactic dose of 1.0mg/kg of isometamidium chloride and thereafter monitored every 14 days for 90 days. Trypanosomes were detected in eight donkeys within 1 month and in 20 donkeys within 2 months of treatment. About 16% (5/32) of donkeys infected with T. congolense were detected parasitemic 1 month after treatment. In addition, the result also revealed that all relapse/breakthrough infections were due to T. congolense. In the third part of this study mice were infected with two T. congolense field isolates from donkeys that were found to be parasitemic within 1 or 2 months after isometamidium treatment. The mice were treated with ranges of doses of isometamidium chloride or diminazene aceturate and thereafter followed for relapse infection. Isometamidium chloride at doses 0.5-4 mg/kg body weight and diminazene aceturate at doses of 3.5-28 mg/kg body weight failed completely to cure T. congolense infections in any of the mice.
Hannan, Abdul; Ikram Ullah, Muhammad; Usman, Muhammad; Hussain, Shahid; Absar, Muhammad; Javed, Khursheed
Emergence of multi-drug resistant (MDR) and extensively drug resistant (XDR) TB throughout the developing world is very disturbing in the present scenario of TB management. There is a fundamental need to explore alternative anti-TB agents. Hence natural plants should be investigated to understand their antimicrobial properties and safety. Garlic (Allium sativum) is one of natural plant which possesses variety of biological properties like anti-tumor, anti-hyperlipedemic and anti-microbial etc. The present study was evaluated for anti-bacterial activity of garlic against non-MDR and MDR isolates of M. tuberculosis. A total of 20 clinical isolates of MTB including 15 MDR and 5 non-MDR were investigated. Ethanolic extract of garlic was prepared by maceration method. Minimum inhibitory concentration (MIC) was performed by using 7H9 middle brook broth dilution technique. MIC of garlic extract was ranged from 1 to 3 mg/ml; showing inhibitory effects of garlic against both non-MDR and MDR M. tuberculosis isolates. Alternate medicine practices with plant extracts including garlic should be considered to decrease the burden of drug resistance and cost in the management of diseases. The use of garlic against MDR-TB may be of great importance regarding public health.
Yi Hu; Barun Mathema; Weili Jiang; Barry Kreiswirth; Weibing Wang; Biao Xu
OBJECTIVE: Transmission patterns of drug-resistant Mycobacterium tuberculosis (MTB) may be influenced by differences in socio-demographics, local tuberculosis (TB) endemicity and efficaciousness of TB control programs. This study aimed to investigate the impact of DOTS on the transmission of drug-resistant TB in eastern rural China. METHODS: We conducted a cross-sectional study of all patients diagnosed with drug-resistant TB over a one-year period in two rural Chinese counties with varying l...
Artzy-Randrup, Yael; Alonso, David; Pascual, Mercedes
Although the spread of drug resistance and the influence of climate change on malaria are most often considered separately, these factors have the potential to interact through altered levels of transmission intensity. The influence of transmission intensity on the evolution of drug resistance has been addressed in theoretical studies from a population genetics' perspective; less is known however on how epidemiological dynamics at the population level modulates this influence. We ask from a theoretical perspective, whether population dynamics can explain non-trivial, non-monotonic, patterns of treatment failure with transmission intensity, and, if so, under what conditions. We then address the implications of warmer temperatures in an East African highland, where, as in other similar regions at the altitudinal edge of malaria's distribution, there has been a pronounced increase of cases from the 1970s to the 1990s. Our theoretical analyses, with a transmission model that includes different levels of immunity, demonstrate that an increase in transmission beyond a threshold can lead to a decrease in drug resistance, as previously shown, but that a second threshold may occur and lead to the re-establishment of drug resistance. Estimates of the increase in transmission intensity from the 1970s to the 1990s for the Kenyan time series, obtained by fitting the two-stage version of the model with an explicit representation of vector dynamics, suggest that warmer temperatures are likely to have moved the system towards the first threshold, and in so doing, to have promoted the faster spread of drug resistance. Climate change and drug resistance can interact and need not be considered as alternative explanations for trends in disease incidence in this region. Non-monotonic patterns of treatment failure with transmission intensity similar to those described as the 'valley phenomenon' for Uganda can result from epidemiological dynamics but under poorly understood assumptions.
Rhee, Soo-Yon; Jordan, Michael R; Raizes, Elliot; Chua, Arlene; Parkin, Neil; Kantor, Rami; Van Zyl, Gert U; Mukui, Irene; Hosseinipour, Mina C; Frenkel, Lisa M; Ndembi, Nicaise; Hamers, Raph L; Rinke de Wit, Tobias F; Wallis, Carole L; Gupta, Ravindra K; Fokam, Joseph; Zeh, Clement; Schapiro, Jonathan M; Carmona, Sergio; Katzenstein, David; Tang, Michele; Aghokeng, Avelin F; De Oliveira, Tulio; Wensing, Annemarie M J; Gallant, Joel E; Wainberg, Mark A; Richman, Douglas D; Fitzgibbon, Joseph E; Schito, Marco; Bertagnolio, Silvia; Yang, Chunfu; Shafer, Robert W
The increasing prevalence of acquired and transmitted HIV-1 drug resistance is an obstacle to successful antiretroviral therapy (ART) in the low- and middle-income countries (LMICs) hardest hit by the HIV-1 pandemic. Genotypic drug resistance testing could facilitate the choice of initial ART in areas with rising transmitted drug resistance (TDR) and enable care-providers to determine which individuals with virological failure (VF) on a first- or second-line ART regimen require a change in treatment. An inexpensive near point-of-care (POC) genotypic resistance test would be useful in settings where the resources, capacity, and infrastructure to perform standard genotypic drug resistance testing are limited. Such a test would be particularly useful in conjunction with the POC HIV-1 viral load tests that are currently being introduced in LMICs. A POC genotypic resistance test is likely to involve the use of allele-specific point mutation assays for detecting drug-resistance mutations (DRMs). This study proposes that two major nucleoside reverse transcriptase inhibitor (NRTI)-associated DRMs (M184V and K65R) and four major NNRTI-associated DRMs (K103N, Y181C, G190A, and V106M) would be the most useful for POC genotypic resistance testing in LMIC settings. One or more of these six DRMs was present in 61.2% of analyzed virus sequences from ART-naïve individuals with intermediate or high-level TDR and 98.8% of analyzed virus sequences from individuals on a first-line NRTI/NNRTI-containing regimen with intermediate or high-level acquired drug resistance. The detection of one or more of these DRMs in an ART-naïve individual or in a individual with VF on a first-line NRTI/NNRTI-containing regimen may be considered an indication for a protease inhibitor (PI)-containing regimen or closer virological monitoring based on cost-effectiveness or country policy.
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.
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.
Full Text Available Introduction: Epilepsy is one of the most common neurological illnesses occurring in children. In approximately 20–30% of cases it is drug-resistant. Aim of the research: To assess the already-known risk factors, analyse the rarely described ones, and find new causes of epilepsy drug resistance in children, taking into account the level of impact of each factor. Material and methods : The study comprised 152 of all 383 children hospitalised in 2012 at the Neurology Department of the Polish Mother’s Memorial Hospital in Lodz due to epilepsy. Based on medical documentation, neurological examination, and our own questionnaire, we divided patients into two groups: drug-resistant epilepsy or drug-sensitive epilepsy. We compared the type, level of influence, and prevalence of different factors. For statistical analysis, the 2 test was used. Statistical significance was set at p < 0.05. Results: Drug-resistant epilepsy was found in 64 patients (42.1%, and drug-sensitive epilepsy was found in 88 patients (57.9%. Factors that were most probable to cause drug resistance included: high prevalence of seizures (Cramer’s V = 0.66, type of epileptic syndrome (V = 0.62, psychomotor developmental delay (V = 0.62, and occurrence of status epilepticus (V = 0.6. Factors such as infections of CNS in early childhood, repeated severe infections of airways in childhood, and mother’s infectious diseases with high fever during pregnancy were rare or non occurring (Cramer’s V = 0.41, 0.32, and 0.31, respectively. Conclusions : The study confirmed the previously known causes of drug resistance and indicated the significance of underestimated inflammatory and infectious factors involving pyrexia, in children and also in mothers during pregnancy.
Xia, Hongping; Hui, Kam M
Drug resistance is one of the major reasons for the failure of cancer therapies. Although our understanding of resistance to targeted cancer drugs remains incomplete, new and more creative approaches are being exploited to intercept this phenomenon. Considerable advances have been made in our understanding that cancer drug resistance can be caused by alterations of drug efflux, increases in drug metabolism, mutations of drug targets, alterations in DNA repair and cell cycle, changes in cell apoptosis and autophagy, induction of epithelial-mesenchymal transition (EMT) and the generation of cancer stem cells (CSCs). Furthermore, intracellular signalling pathways have been shown to play key physiological roles and the abnormal activation of signalling pathways may be correlated with drug resistance. Recently, noncoding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have emerged as important regulators of gene expression and alternative splicing, which provides cells with yet another mode to greatly increase regulatory complexity and fine-tune their transcriptome and can rapidly adjust their proteome in response to stimuli. Consequently, a wide variety of biological functions have been shown to depend on the coordinated interactions between noncoding RNAs and cellular signalling networks to achieve a concerted desired physiological outcome, whereas mutations and dysregulation of ncRNAs have been linked to diverse human diseases, including cancer drug resistance. In this review, we will discuss recent findings on the multiple molecular roles of regulatory ncRNAs on the signalling pathways involved in cancer drug resistance and the therapeutic potential of reverse drug resistance.
Mac-Arthur, A; Gloyd, S; Perdigão, P; Noya, A; Sacarlal, J; Kreiss, J
The rate of human immunodeficiency virus (HIV) seroprevalence among tuberculosis patients varies between 2% and 53% in Mozambique, depending on the region. Drug resistance surveillance has been performed in only a few cities in Mozambique. To establish the extent of drug resistance in areas of Mozambique with different levels of HIV prevalence, to estimate the prevalence of HIV among tuberculosis (TB) patients, and to examine the association between drug resistance and HIV infection. All tuberculosis patients diagnosed at randomly selected health facilities over 9 months (September 1998 to June 1999) were enrolled in the study. Sputum was collected, smeared and cultured, and drug susceptibility tests were performed. Blood was tested for HIV in the respective provinces, and patients received pre-test and post-test counselling. Of 709 culture-positive cases, 25.5% were HIV-positive. HIV-positive patients were significantly more likely to have a prior history of treatment (OR 2.2; 95% CI 1.9-3.6) and resistance to both isoniazid and streptomycin (OR 2.3; 95% CI 1.3, 4.5). In patients with no history of prior tuberculosis treatment, the multidrug resistance rate was 3.4% and resistance to isoniazid and streptomycin (HS) was 5.2%. Any drug resistance was significantly more common among those with a history of prior treatment (OR 3.1; 95% CI 2.1-4.7), particularly resistance to HS (OR 4.5; 95% CI 2.6-7.9). This study demonstrates substantial levels of drug resistance in Mozambique. Differences in drug resistance between high and low HIV prevalence areas may be related to prior treatment.
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.
Scott E Hensley
Full Text Available Drugs inhibiting the influenza A virus (IAV neuraminidase (NA are the cornerstone of anti-IAV chemotherapy and prophylaxis in man. Drug-resistant mutations in NA arise frequently in human isolates, limiting the therapeutic application of NA inhibitors. Here, we show that antibody-driven antigenic variation in one domain of the H1 hemagglutinin Sa site leads to compensatory mutations in NA, resulting in NA antigenic variation and acquisition of drug resistance. These findings indicate that influenza A virus resistance to NA inhibitors can potentially arise from antibody driven HA escape, confounding analysis of influenza NA evolution in nature.
Full Text Available A mathematical model of HIV/AIDS transmission incorporating treatment and drug resistance was built in this study. We firstly calculated the threshold value of the basic reproductive number (R0 by the next generation matrix and then analyzed stability of two equilibriums by constructing Lyapunov function. When R0<1, the system was globally asymptotically stable and converged to the disease-free equilibrium. Otherwise, the system had a unique endemic equilibrium which was also globally asymptotically stable. While an antiretroviral drug tried to reduce the infection rate and prolong the patients’ survival, drug resistance was neutralizing the effects of treatment in fact.
Conclusions: Reliable and timely detection of drug-resistant TB is needed, which is best achieved with molecular assays. In this author's opinion, rapid detection of resistance to isoniazid should be included with rifampicin resistance examination. In MDR, timely detection of the XDR defining agents and PZA is urgently needed. Development and validation of such tests should be a priority, as well as establishing QMS for the implementation and routine use of molecular rapid diagnostics. Each country should develop national diagnostic algorithms for how, when and where rapid molecular assays should be used for early detection of drug-resistant TB.
Fernández-Galindo, D A; Sánchez-Ávila, F; Bobadilla-Morales, L; Gómez-Quiróz, P; Bueno-Topete, M; Armendáriz-Borunda, J; Sánchez-Orozco, L V
Long-term treatment with retrotranscriptase (RT) inhibitors eventually leads to the development of drug resistance. Drug-related mutations occur naturally and these can be found in hepatitis B virus (HBV) carriers who have never received antiviral therapy. HBsAg are overlapped with RT domain, thus nucleot(s)ide analogues (NAs) resistance mutations and naturally-occurring mutations can cause amino acid changes in the HBsAg. Twenty-two patients with chronic hepatitis B were enrolled; three of them were previously treated with NAs and 19 were NAs-naïve treated. HBV reverse transcriptase region was sequenced; genotyping and analysis of missense mutations were performed in both RT domain and HBsAg. There was predominance of genotype H. Drug mutations were present in 18.2% of patients. Classical lamivudine resistance mutations (rtM204V/rtL180M) were present in one naïve-treatment patient infected with genotype G. New amino acid changes were identified in drug resistance sites in HBV strains from patients infected with genotype H; rtQ215E was present in two naïve-NAs treatment patients and rtI169M was identified in a patient previously treated with lamivudine. Mutations at sites rt169, rt204, and rt215 resulted in the Y161C, I195M, and C206W mutations at HBsAg. Also, new amino acid changes were identified in B-cell and T-cell epitopes and were more frequent in HBsAg compared to RT domain. In conclusion, new amino acid changes at antiviral resistance sites, B-cell and T-cell epitopes in HBV genotype H were identified in Mexican patients.
Abstract Background Combating the spread of drug resistant tuberculosis is a global health priority. Whole genome association studies are being applied to identify genetic determinants of resistance to anti-tuberculosis drugs. Protein structure and interaction modelling are used to understand the functional effects of putative mutations and provide insight into the molecular mechanisms leading to resistance. Methods To investigate the potential utility of these approaches, we analysed the genomes of 144 Mycobacterium tuberculosis clinical isolates from The Special Programme for Research and Training in Tropical Diseases (TDR) collection sourced from 20 countries in four continents. A genome-wide approach was applied to 127 isolates to identify polymorphisms associated with minimum inhibitory concentrations for first-line anti-tuberculosis drugs. In addition, the effect of identified candidate mutations on protein stability and interactions was assessed quantitatively with well-established computational methods. Results The analysis revealed that mutations in the genes rpoB (rifampicin), katG (isoniazid), inhA-promoter (isoniazid), rpsL (streptomycin) and embB (ethambutol) were responsible for the majority of resistance observed. A subset of the mutations identified in rpoB and katG were predicted to affect protein stability. Further, a strong direct correlation was observed between the minimum inhibitory concentration values and the distance of the mutated residues in the three-dimensional structures of rpoB and katG to their respective drugs binding sites. Conclusions Using the TDR resource, we demonstrate the usefulness of whole genome association and convergent evolution approaches to detect known and potentially novel mutations associated with drug resistance. Further, protein structural modelling could provide a means of predicting the impact of polymorphisms on drug efficacy in the absence of phenotypic data. These approaches could ultimately lead to novel
Background Combating the spread of drug resistant tuberculosis is a global health priority. Whole genome association studies are being applied to identify genetic determinants of resistance to anti-tuberculosis drugs. Protein structure and interaction modelling are used to understand the functional effects of putative mutations and provide insight into the molecular mechanisms leading to resistance. Methods To investigate the potential utility of these approaches, we analysed the genomes of 144 Mycobacterium tuberculosis clinical isolates from The Special Programme for Research and Training in Tropical Diseases (TDR) collection sourced from 20 countries in four continents. A genome-wide approach was applied to 127 isolates to identify polymorphisms associated with minimum inhibitory concentrations for first-line anti-tuberculosis drugs. In addition, the effect of identified candidate mutations on protein stability and interactions was assessed quantitatively with well-established computational methods. Results The analysis revealed that mutations in the genes rpoB (rifampicin), katG (isoniazid), inhA-promoter (isoniazid), rpsL (streptomycin) and embB (ethambutol) were responsible for the majority of resistance observed. A subset of the mutations identified in rpoB and katG were predicted to affect protein stability. Further, a strong direct correlation was observed between the minimum inhibitory concentration values and the distance of the mutated residues in the three-dimensional structures of rpoB and katG to their respective drugs binding sites. Conclusions Using the TDR resource, we demonstrate the usefulness of whole genome association and convergent evolution approaches to detect known and potentially novel mutations associated with drug resistance. Further, protein structural modelling could provide a means of predicting the impact of polymorphisms on drug efficacy in the absence of phenotypic data. These approaches could ultimately lead to novel resistance
Full Text Available Infection with influenza virus is a major public health problem, causing serious illness and death each year. Emergence of drug-resistant influenza virus strains limits the effectiveness of drug treatment. Importantly, a dual H275Y/I223R mutation detected in the pandemic influenza A 2009 virus strain results in multidrug resistance to current neuraminidase (NA drugs. Therefore, discovery of new agents for treating multiple drug-resistant (MDR influenza virus infections is important. Here, we propose a parallel screening strategy that simultaneously screens wild-type (WT and MDR NAs, and identifies inhibitors matching the subsite characteristics of both NA-binding sites. These may maintain their potency when drug-resistant mutations arise. Initially, we analyzed the subsite of the dual H275Y/I223R NA mutant. Analysis of the site-moiety maps of NA protein structures show that the mutant subsite has a relatively small volume and is highly polar compared with the WT subsite. Moreover, the mutant subsite has a high preference for forming hydrogen-bonding interactions with polar moieties. These changes may drive multidrug resistance. Using this strategy, we identified a new inhibitor, Remazol Brilliant Blue R (RB19, an anthraquinone dye, which inhibited WT NA and MDR NA with IC(50 values of 3.4 and 4.5 µM, respectively. RB19 comprises a rigid core scaffold and a flexible chain with a large polar moiety. The former interacts with highly conserved residues, decreasing the probability of resistance. The latter forms van der Waals contacts with the WT subsite and yields hydrogen bonds with the mutant subsite by switching the orientation of its flexible side chain. Both scaffolds of RB19 are good starting points for lead optimization. The results reveal a parallel screening strategy for identifying resistance mechanisms and discovering anti-resistance neuraminidase inhibitors. We believe that this strategy may be applied to other diseases with high
Pettigrew, Jonathan; Miller-Day, Michelle; Krieger, Janice; Hecht, Michael L.
This study seeks to identify how rural adolescents make health decisions and utilize communication strategies to resist influence attempts in offers of alcohol, tobacco, and other drugs (ATOD). Semi-structured interviews were conducted with 113 adolescents from rural school districts to solicit information on ATOD norms, past ATOD experiences, and…
Timothy F Brewer
Full Text Available BACKGROUND: Multiple drug-resistance in new tuberculosis (TB cases accounts for the majority of all multiple drug-resistant TB (MDR-TB worldwide. Effective control requires determining which new TB patients should be tested for MDR disease, yet the effectiveness of global screening recommendations of high-risk groups is unknown. METHODS: Sixty MDR-TB cases with no history of previous TB treatment, 80 drug-sensitive TB and 80 community-based controls were recruited in Lima, Peru between August and December, 2008 to investigate whether recommended screening practices identify individuals presenting with MDR-TB. Odd ratios (OR and 95% confidence intervals (CI were calculated using logistic regression to study the association of potential risk factors with case/control variables. RESULTS: MDR-TB cases did not differ from drug-sensitive TB and community controls in rates of human immunodeficiency virus infection, reported hospital or prison visits in the 3 years prior to diagnosis. MDR-TB cases were more likely than drug-sensitive TB controls to have had a recent MDR-TB household contact (OR 4.66, (95% CI 1.56-13.87; however, only 15 cases (28.3% reported this exposure. In multivariate modeling, recent TB household contact, but not contact with an MDR-TB case, remained predictive of MDR-TB, OR 7.47, (95% CI 1.91-29.3. Living with a partner rather than parents was associated with a lower risk of MDR-TB, OR 0.15, (95% CI 0.04-0.51. CONCLUSION: Targeted drug susceptibility testing (DST linked to reported MDR-TB contact or other high-risk exposures does not identify the majority of new TB cases with MDR disease in Lima where it is endemic. All new TB cases should be screened with DST to identify MDR patients. These findings are likely applicable to other regions with endemic MDR-TB.
Joel L Bargul
Full Text Available African trypanosomes thrive in the bloodstream and tissue spaces of a wide range of mammalian hosts. Infections of cattle cause an enormous socio-economic burden in sub-Saharan Africa. A hallmark of the trypanosome lifestyle is the flagellate's incessant motion. This work details the cell motility behavior of the four livestock-parasites Trypanosoma vivax, T. brucei, T. evansi and T. congolense. The trypanosomes feature distinct swimming patterns, speeds and flagellar wave frequencies, although the basic mechanism of flagellar propulsion is conserved, as is shown by extended single flagellar beat analyses. Three-dimensional analyses of the trypanosomes expose a high degree of dynamic pleomorphism, typified by the 'cellular waveform'. This is a product of the flagellar oscillation, the chirality of the flagellum attachment and the stiffness of the trypanosome cell body. The waveforms are characteristic for each trypanosome species and are influenced by changes of the microenvironment, such as differences in viscosity and the presence of confining obstacles. The distinct cellular waveforms may be reflective of the actual anatomical niches the parasites populate within their mammalian host. T. vivax displays waveforms optimally aligned to the topology of the bloodstream, while the two subspecies T. brucei and T. evansi feature distinct cellular waveforms, both additionally adapted to motion in more confined environments such as tissue spaces. T. congolense reveals a small and stiff waveform, which makes these parasites weak swimmers and destined for cell adherence in low flow areas of the circulation. Thus, our experiments show that the differential dissemination and annidation of trypanosomes in their mammalian hosts may depend on the distinct swimming capabilities of the parasites.
Full Text Available The relationship between extensively drug-resistant tuberculosis (XDR-TB and multidrug-resistant Gram-negative bacilli (MDR-GNB is unclear. Identification of the relationship between XDR-TB and MDR-GNB would have important implications for patient care.We conducted a retrospective study reviewing the records of patients admitted with a confirmed pulmonary TB from 2011 to 2014. To identify the relationship between XDR-TB and MDR-GNB, univariable comparison and multivariable logistic regression were performed.Among 2962 pulmonary TB patients, 45(1.5% patients had a diagnosis of XDR-TB. A total of 165 MDR-GNB strains were detected in 143 (4.8% pulmonary TB patients. XDR-TB patients had a significantly higher occurrence of MDR-GNB than non-XDR-TB patients (24.4% vs. 4.5%; P<0.001. Age (OR 1.02, 95% CI 1.01-1.03, hypoalbuminemia (OR 1.48, 95% CI 1.18-1.85, chronic renal failure (OR 6.67, 95% CI 1.42-31.47, chronic hepatic insufficiency (OR 1.99, 95% CI 1.15-3.43, presence of XDR-TB (OR 6.56, 95% CI 1.61-26.69, and duration of TB diagnostic delay (OR 1.01, 95% CI 1.00-1.02 were the independent risk factors for MDR-GNB infection.Patients with XDR-TB have a significantly higher risk of being affected by MDR-GNB pathogen. The underlying mechanism association warrant further studies.
Full Text Available This study was designed to find the clinical, neuropsychologic, EEG and TMS (Transcranial Magnetic Stimulation characteristics of patients with treatment resistant Juvenile Myoclonic Epilepsy (JME. JME diagnosis was according to the criteria defined by Classification and Terminology Commission of the International League Against Epilepsy. For the purpose of this study, ‘treatment resistance’ was defined as having two or more generalized tonic - clonic sei zures (GTCS or disabling myoclonus resulting in falls, while on optimal dose of a first - line anti - epileptic drug for JME, with proper compliance. All the patients with JME presenting during the study period underwent detailed clinical and EEG evaluation. Hospital Anxiety and Depression score (HADS was used to screen for anxiety and depression. Single and paired pulse (TMS parameters were used to measure cortical excitability. We identified 190 patients with JME during the study period, of which 30 (15.8% were diagnosed as having treatment resistance JME. Patients with drug resistant JME were found to have statistically significant markers in the form of - later age of onset of myoclonic jerks, absence of typical early morning myoclonia, higher scores for depression and anxiety, low IQ scores and persistent EEG abnormalities while on treatment. Frequency of GTCS showed inverse correlation with IQ scores and direct correlation to the anxiety/depression scores. These patients also had paradoxically decreased cortical excitability, probably related to the high antiepileptic drug doses they were taking. We conclude that treatment resistance in JME is not very rare and that such patients form a distinct subtype with certain atypical clinical and electrophysiolog ical characteristics, with a higher risk of developing anxiety and depression
Arya, Ravindra; Leach, James L; Horn, Paul S; Greiner, Hansel M; Gelfand, Michael; Byars, Anna W; Arthur, Todd M; Tenney, Jeffrey R; Jain, Sejal V; Rozhkov, Leonid; Fujiwara, Hisako; Rose, Douglas F; Mangano, Francesco T; Holland, Katherine D
Lack of a potentially epileptogenic lesion on brain magnetic resonance imaging (MRI) is a poor prognostic marker for epilepsy surgery. We present a single-center series of childhood-onset MRI-negative drug-resistant epilepsy (DRE) and analyze surgical outcomes and predictors. Children with MRI-negative DRE who had resective surgery from January 2007 to December 2013 were identified using an institutional database. Relevant clinical, neurophysiological, imaging, and surgical data was extracted. The primary outcome measure was seizure freedom. Predictors of seizure freedom were obtained using multivariate logistic regression. Out of 47 children with MRI-negative DRE, 12 (25.5%) were seizure free (International League Against Epilepsy [ILAE] outcome class I), after mean follow-up of 2.75 (±1.72) years. Seizure-free proportion was significantly higher in patients with single seizure semiology and concordant ictal EEG (50.0% vs. 15.2%, p=0.025). Multivariate analysis using only non-invasive pre-surgical data showed that children with daily seizures (OR 0.02, 95% CIseizures (OR 0.72, 95% CI 0.52-0.99) were less likely to be seizure-free. Also, each additional anti-epileptic drug (AED) tried before surgery decreased the probability of seizure-free outcome (OR 0.16, 95% CI 0.04-0.63). Repeat multivariate analysis after including surgical variables found no additional significant predictors of seizure-freedom. Cortical dysplasia (ILAE type IB) was the commonest histopathology. Surgical outcomes in children with MRI-negative DRE are determined by clinical factors including seizure frequency, age of onset of seizures, and number of failed AEDs. Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Full Text Available The increasing prevalence of multi-drug-resistant (MDR strains of Pseudomonas aeruginosa among critically ill humans is of significant concern. In the current study, we show that MDR clinical isolates of P. aeruginosa representing three distinct genotypes that display high virulence against intestinal epithelial cells, form novel appendage-like structures on their cell surfaces. These appendages contain PstS, an extracellular phosphate binding protein. Using anti-PstS antibodies, we determined that the PstS-rich appendages in MDR strains are involved in adherence to and disruption of the integrity of cultured intestinal epithelial cell monolayers. The outer surface-expressed PstS protein was also identified to be present in P. aeruginosa MPAO1, although to a lesser degree, and its role in conferring an adhesive and barrier disruptive phenotype against intestinal epithelial cells was confirmed using an isogenic DeltaPstS mutant. Formation of the PstS rich appendages was induced during phosphate limitation and completely suppressed in phosphate-rich media. Injection of MDR strains directly into the intestinal tract of surgically injured mice, a known model of phosphate limitation, caused high mortality rates (60%-100%. Repletion of intestinal phosphate in this model completely prevented mortality. Finally, significantly less outer surface PstS was observed in the MPAO1 mutant DeltaHxcR thus establishing a role for the alternative type II secretion system Hxc in outer surface PstS expression. Gene expression analysis performed by RT-PCR confirmed this finding and further demonstrated abundant expression of pstS analogous to pa5369, pstS analogous to pa0688/pa14-55410, and hxcX in MDR strains. Taken together, these studies provide evidence that outer surface PstS expression confers a highly virulent phenotype of MDR isolates against the intestinal epithelium that alters their adhesive and barrier disrupting properties against the intestinal
Mathieu, Véronique; Chantôme, Aurélie; Lefranc, Florence; Cimmino, Alessio; Miklos, Walter; Paulitschke, Verena; Mohr, Thomas; Maddau, Lucia; Kornienko, Alexander; Berger, Walter; Vandier, Christophe; Evidente, Antonio; Delpire, Eric; Kiss, Robert
Despite the recent advances in the treatment of tumors with intrinsic chemotherapy resistance, such as melanoma and renal cancers, their prognosis remains poor and new chemical agents with promising activity against these cancers are urgently needed. Sphaeropsidin A, a fungal metabolite whose anticancer potential had previously received little attention, was isolated from Diplodia cupressi and found to display specific anticancer activity in vitro against melanoma and kidney cancer subpanels in the National Cancer Institute (NCI) 60-cell line screen. The NCI data revealed a mean LC50 of ca. 10 μM and a cellular sensitivity profile that did not match that of any other agent in the 765,000 compound database. Subsequent mechanistic studies in melanoma and other multidrug-resistant in vitro cancer models showed that sphaeropsidin A can overcome apoptosis as well as multidrug resistance by inducing a marked and rapid cellular shrinkage related to the loss of intracellular Cl− and the decreased HCO3− concentration in the culture supernatant. These changes in ion homeostasis and the absence of effects on the plasma membrane potential were attributed to the sphaeropsidin A-induced impairment of regulatory volume increase (RVI). Preliminary results also indicate that depending on the type of cancer, the sphaeropsidin A effects on RVI could be related to Na–K–2Cl electroneutral cotransporter or Cl−/HCO3− anion exchanger(s) targeting. This study underscores the modulation of ion-transporter activity as a promising therapeutic strategy to combat drug-resistant cancers and identifies the fungal metabolite, sphaeropsidin A, as a lead to develop anticancer agents targeting RVI in cancer cells. PMID:25868554
Asmundsdottir, Lena Ros; Erlendsdottir, Helga; Gottfredsson, Magnus
Candidemia is often a life-threatening infection, with highly variable incidence among countries. We conducted a nationwide study of candidemia in Iceland from 2000 to 2011, in order to determine recent trends in incidence rates, fungal species distribution, antifungal susceptibility patterns, and concurrent antifungal consumption. A total of 208 infection episodes in 199 patients were identified. The average incidence during the 12 years was 5.7 cases/100,000 population/year, which was significantly higher than that from 1990 to 1999 (4.3/100,000/year; P = 0.02). A significant reduction in the use of blood cultures was noted in the last 3 years of the study, coinciding with the economic crisis in the country (P 60 years, and varied by gender. Age-specific incidence among males >80 years old was 28.6/100,000/year, and it was 8.3/100,000/year for females in this age group (P = 0.028). The 30-day survival rate among adult patients remained unchanged compared to that from 1990 to 1999 (70.4% versus 69.5%, P = 0.97). Candida albicans was the predominant species (56%), followed by C. glabrata (16%) and C. tropicalis (13%). The species distribution remained stable compared to that from previous decades. Fluconazole use increased 2.4-fold from 2000 to 2011, with no increase in resistance. In summary, the incidence of candidemia in Iceland has continued to increase but may have reached a steady state, and no increase in antifungal drug resistance has been noted. Decreased use of blood cultures toward the end of the study may have influenced detection rates.
Full Text Available Background: Acinetobacter baumannii is usually multi-drug resistant (MDR, including third generation cephalosporins, amino glycosides and fluoroquinolone. Resistance to these antibiotics is mediated by multiple factors such as: lactamases, efflux pumps and other mechanisms of resistance. Pulsed-field gel electrophoresis (PFGE was then used to investigate the genetic relationships among the MDR isolates. Aim: The aim of this study was to determine MDR isolates and the existence of OXAs genes among MDR isolates of A. baumannii collected from Kermanshah hospitals in west of Iran. Materials and Methods: Forty-two MDR A. baumannii were collected from patients at Kermanshah hospitals. The isolates were identified by biochemical tests and API 20NE kit. The susceptibility to different antibiotics by disk diffusion method was determined. Polymerase chain reaction (PCR was performed for detection of blaOXA-23-like , blaOXA-24-like , blaOXA-51-like and blaOXA-58-like betalactamase genes in isolates and clonal relatedness was done by PFGE (with the restriction enzyme ApaI and patterns analyzed by Bionumeric software. Results: This study showed high resistant to ciprofloxacin, piperacillin, ceftazidime and also resistant to other anti-microbial agents and more spread blaOXA-23-like gene (93% in MDR isolate. The PFGE method obtained six clones: A (10, B (9, C (5, D (4, E (11 and F (3 that clone E was outbreak and dominant in different wards of hospitals studied. Conclusion: An isolate from the emergency ward of these hospitals had indistinguishable isolates PFGE profile and similar resistance profile to isolates from intensive care unit (ICU, suggesting likely transmission from ICU to emergency via patient or hospital staff contact.
McKenzie F Ellis
Full Text Available Abstract Background The evolution of drug resistance in malaria parasites highlights a need to identify and evaluate strategies that could extend the useful therapeutic life of anti-malarial drugs. Such strategies are deployed to best effect before resistance has emerged, under conditions of great uncertainty. Methods Here, the emergence and spread of resistance was modelled using a hybrid framework to evaluate prospective strategies, estimate the time to drug failure, and weigh uncertainty. The waiting time to appearance was estimated as the product of low mutation rates, drug pressure, and parasite population sizes during treatment. Stochastic persistence and the waiting time to establishment were simulated as an evolving branching process. The subsequent spread of resistance was simulated in simple epidemiological models. Results Using this framework, the waiting time to the failure of artemisinin combination therapy (ACT for malaria was estimated, and a policy of multiple first-line therapies (MFTs was evaluated. The models quantify the effects of reducing drug pressure in delaying appearance, reducing the chances of establishment, and slowing spread. By using two first-line therapies in a population, it is possible to reduce drug pressure while still treating the full complement of cases. Conclusions At a global scale, because of uncertainty about the time to the emergence of ACT resistance, there was a strong case for MFTs to guard against early failure. Our study recommends developing operationally feasible strategies for implementing MFTs, such as distributing different ACTs at the clinic and for home-based care, or formulating different ACTs for children and adults.
Lau Susanna KP
Full Text Available Abstract Background Laribacter hongkongensis is associated with community-acquired gastroenteritis and traveler's diarrhea. In this study, we performed an in-depth annotation of the genes in its genome related to the various steps in the infective process, drug resistance and mobile genetic elements. Results For acid and bile resistance, L. hongkongensis possessed a urease gene cassette, two arc gene clusters and bile salt efflux systems. For intestinal colonization, it possessed a putative adhesin of the autotransporter family homologous to those of diffusely adherent Escherichia coli (E. coli and enterotoxigenic E. coli. To evade from host defense, it possessed superoxide dismutase and catalases. For lipopolysaccharide biosynthesis, it possessed the same set of genes that encode enzymes for synthesizing lipid A, two Kdo units and heptose units as E. coli, but different genes for its symmetrical acylation pattern, and nine genes for polysaccharide side chains biosynthesis. It contained a number of CDSs that encode putative cell surface acting (RTX toxin and hemolysins and intracellular cytotoxins (patatin-like proteins and enzymes for invasion (outer membrane phospholipase A. It contained a broad variety of antibiotic resistance-related genes, including genes related to β-lactam (n = 10 and multidrug efflux (n = 54. It also contained eight prophages, 17 other phage-related CDSs and 26 CDSs for transposases. Conclusions The L. hongkongensis genome possessed genes for acid and bile resistance, intestinal mucosa colonization, evasion of host defense and cytotoxicity and invasion. A broad variety of antibiotic resistance or multidrug resistance genes, a high number of prophages, other phage-related CDSs and CDSs for transposases, were also identified.
Jones, Lim S; Carvalho, Maria J; Toleman, Mark A; White, P Lewis; Connor, Thomas R; Mushtaq, Ammara; Weeks, Janis L; Kumarasamy, Karthikeyan K; Raven, Katherine E; Török, M Estée; Peacock, Sharon J; Howe, Robin A; Walsh, Timothy R
The blaNDM-1 gene is associated with extensive drug resistance in Gram-negative bacteria. This probably spread to Enterobacteriaceae from Acinetobacter spp., and we characterized plasmids associated with blaNDM-1 in Acinetobacter spp. to gain insight into their role in this dissemination. Four clinical NDM-1-producing Acinetobacter species strains from India and Pakistan were investigated. A plasmid harboring blaNDM-1, pNDM-40-1, was characterized by whole-genome sequencing of Acinetobacter bereziniae CHI-40-1 and comparison with related plasmids. The presence of similar plasmids in strains from Pakistan was sought by PCR and sequencing of amplicons. Conjugation frequency was tested and stability of pNDM-40-1 investigated by real-time PCR of isolates passaged with and without antimicrobial selection pressure. A. bereziniae and Acinetobacter haemolyticus strains contained plasmids similar to the pNDM-BJ01-like plasmids identified in Acinetobacter spp. in China. The backbone of pNDM-40-1 was almost identical to that of pNDM-BJ01-like plasmids, but the transposon harboring blaNDM-1, Tn125, contained two short deletions. Escherichia coli and Acinetobacter pittii transconjugants were readily obtained. Transconjugants retained pNDM-40-1 after a 14-day passage experiment, although stability was greater with meropenem selection. Fragments of pNDM-BJ01-like plasmid backbones are found near blaNDM-1 in some genetic contexts from Enterobacteriaceae, suggesting that cross-genus transfer has occurred. pNDM-BJ01-like plasmids have been described in isolates originating from a wide geographical region in southern Asia. In vitro data on plasmid transfer and stability suggest that these plasmids could have contributed to the spread of blaNDM-1 into Enterobacteriaceae.
Ferro, B.E.; Garcia, P.K.; Nieto, L.M.; Soolingen, D. van
Previous evaluations of the molecular GenoType tests have promoted their use to detect resistance to first- and second-line antituberculosis drugs in different geographical regions. However, there are known geographic variations in the mutations associated with drug resistance in Mycobacterium
Bannister, Wendy P; Cozzi-Lepri, Alessandro; Kjær, Jesper
Estimating the prevalence of accumulated HIV drug resistance in patients receiving antiretroviral therapy (ART) is difficult due to lack of resistance testing at all occasions of virological failure and in patients with undetectable viral load. A method to estimate this for 6498 EuroSIDA patients...
... 21 Food and Drugs 8 2010-04-01 2010-04-01 false In vitro human immunodeficiency virus (HIV) drug... OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological Reagents § 866.3950 In vitro human immunodeficiency virus (HIV) drug resistance genotype assay....
Pepper, John W
Pathogen drug resistance is a central problem in medicine and public health. It arises through somatic evolution, by mutation and selection among pathogen cells within a host. Here, we examine the hypothesis that evolution of drug resistance could be reduced by developing drugs that target the secreted metabolites produced by pathogen cells instead of directly targeting the cells themselves. Using an agent-based computational model of an evolving population of pathogen cells, we test this hypothesis and find support for it. We also use our model to explain this effect within the framework of standard evolutionary theory. We find that in our model, the drugs most robust against evolved drug resistance are those that target the most widely shared external products, or 'public goods', of pathogen cells. We also show that these drugs exert a weak selective pressure for resistance because they create only a weak correlation between drug resistance and cell fitness. The same principles apply to design of vaccines that are robust against vaccine escape. Because our theoretical results have crucial practical implications, they should be tested by empirical experiments.
Po'A-Kekuawela, Ka'Ohinani; Okamoto, Scott K.; Nebre, La Risa H.; Helm, Susana; Chin, Coralee I. H.
This qualitative study examined how Native Hawai'ian youths from rural communities utilized cultural practices to promote drug resistance and/or abstinence. Forty-seven students from five different middle schools participated in gender-specific focus groups that focused on the cultural and environmental contexts of drug use for Native Hawai'ian…
Agusto, F B
Human habitat connectivity, movement rates, and spatial heterogeneity have tremendous impact on malaria transmission. In this paper, a deterministic system of differential equations for malaria transmission incorporating human movements and the development of drug resistance malaria in an [Formula: see text] patch system is presented. The disease-free equilibrium of the model is globally asymptotically stable when the associated reproduction number is less than unity. For a two patch case, the boundary equilibria (drug sensitive-only and drug resistance-only boundary equilibria) when there is no movement between the patches are shown to be locally asymptotically stable when they exist; the co-existence equilibrium is locally asymptotically stable whenever the reproduction number for the drug sensitive malaria is greater than the reproduction number for the resistance malaria. Furthermore, numerical simulations of the connected two patch model (when there is movement between the patches) suggest that co-existence or competitive exclusion of the two strains can occur when the respective reproduction numbers of the two strains exceed unity. With slow movement (or low migration) between the patches, the drug sensitive strain dominates the drug resistance strain. However, with fast movement (or high migration) between the patches, the drug resistance strain dominates the drug sensitive strain.
Kamal Uddin Zaidi
Full Text Available This study was done to assess the antifungal susceptibility of clinical isolates of Candida albicans and to evaluate its total protein profile based on morphological difference on drug resistance. Hundred and twenty clinical isolates of C. albicans from various clinical specimens were tested for susceptibility against four antifungal agents, namely, fluconazole, itraconazole, amphotericin B, and ketoconazole. A significant increase of drug resistance in clinical isolates of C. albicans was observed. The study showed 50% fluconazole and itraconazole resistance at 32 μg mL−1 with a MIC50 and MIC90 values at 34 and 47 and 36 and 49 μg mL−1, respectively. All isolates were sensitive to amphotericin B and ketoconazole. The SDS-PAGE protein profile showed a prevalent band of ~52.5 kDa, indicating overexpression of gene in 72% strains with fluconazole resistance. Since the opportunistic infections of Candida spp. are increasing along with drug resistance, the total protein profile will help in understanding the evolutionary changes in drug resistance and also to characterize them.
Pedro, Heloisa da Silveira Paro; Nardi, Susilene Maria Tonelli; Pereira, Maria Izabel Ferreira; Oliveira, Rosângela Siqueira; Suffys, Philip Noel; Gomes, Harrison Magdinier; Finardi, Amanda Juliane; de Moraes, Eloise Brasil; Baptista, Ida Maria Foschiani Dias; Machado, Ricardo Luiz Dantas; Castiglioni, Lilian
Drug-resistant tuberculosis (TB) is a growing global threat. Approximately 450,000 people developed multidrug-resistant TB worldwide in 2012 and an estimated 170,000 people died from the disease. This paper describes the sociodemographic, clinical-epidemiological and bacteriological aspects of TB and correlates these features with the distribution of anti-TB drug resistance. Mycobacterium tuberculosis (MT) cultures and drug susceptibility testing were performed according to the BACTEC MGIT 960 method. The results demonstrated that MT strains from individuals who received treatment for TB and people who were infected with human immunodeficiency virus were more resistant to TB drugs compared to other individuals (p < 0.05). Approximately half of the individuals received supervised treatment, but most drug-resistant cases were positive for pulmonary TB and exhibited positive acid-fast bacilli smears, which are complicating factors for TB control programs. Primary healthcare is the ideal level for early disease detection, but tertiary healthcare is the most common entry point for patients into the system. These factors require special attention from healthcare managers and professionals to effectively control and monitor the spread of TB drug-resistant cases. PMID:25946248
Zandvliet, M.M.J.M.; Teske, E.
Drug resistance (DR) is the major limiting factor in the successful treatment of systemic neoplasia with cytotoxic chemotherapy. DR can be either intrinsic or acquired, and although the development and clinical implications are different, the underlying mechanisms are likely to be similar. Most caus
Skov, Marianne; Andersen, Jens Strodl; Aabo, Søren
We compared 8,144 Salmonella isolates collected from meat imported to or produced in Denmark, as well as from Danish patients. Isolates from imported meat showed a higher rate of antimicrobial drug resistance, including multidrug resistance, than did isolates from domestic meat. Isolates from hum...
Multi-drug resistant bacteria are a persistent problem in modern health care, food safety and animal health. There is a need for new antimicrobials to replace over-used conventional antibiotics. Staphylococcus aureus (S. aureus) is a notorious pathogen for both animal and human health with multi-d...
Multi-drug resistant bacteria are a persistent problem in modern health care, food safety and animal health. There is a need for new antimicrobials to replace over-used conventional antibiotics. Staphylococcus aureus (S. aureus) is a notorious pathogen for both animal and human health with multi-d...
The emergence of multi-drug resistant bacteria, coupled with the lack of new antibiotics in development, is fast evolving into a global crisis. New strategies utilizing existing antibacterial agents are urgently needed. We propose one such strategy in which four outmoded ß-lactam antibiotics (amp...
Hartz, A.M.; Notenboom, S.; Bauer, B.
Epilepsy affects more than 60 million people worldwide. While most patients can be treated with antiepileptic drugs, up to 40% of patients respond poorly to pharmacotherapy. This drug resistance is not well understood and presents a major clinical problem. In this short review we provide background
The discovery of antibiotics has enabled serious infections to be treated. However, bacteria resistant to several families of antibiotics and the emergence of new highly drug-resistant bacteria constitute a public health issue in France and across the world. Actions to prevent their transmission are being put in place. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
Clément, Agnès; Denis, Christine
The increase in antibiotic-resistant bacteria and emerging highly drug-resistant bacteria is resulting in alarming situations of treatment failure. In hospitals, precautionary measures to control nosocomial infections are put in place through the collaboration between caregivers, the operational hygiene team and the nosocomial infection control committee, in accordance with official recommendations. Copyright © 2015. Published by Elsevier Masson SAS.
Post, Frank A; Grint, Daniel; Efsen, Anne Marie Werlinrud
Observational data from Eastern Europe on the management and outcome of multi-drug-resistant tuberculosis (MDR TB) in HIV positive populations remain sparse in the English-language literature.We compared clinical characteristics and outcomes of 55 patients who were diagnosed with HIV and MDR TB i...
Pranger, A. D.; Alffenaar, J. W. C.; Aarnoutse, R. E.
Fluoroquinolones (FQs) are important drugs to treat drug-resistant tuberculosis. In this review we integrated pharmacokinetic properties (PK) and microbiological susceptibility against M. tuberculosis and eventually evaluated the pharmcodynamic (PD) properties, as well as the influence of co-adminis
Hendriksen, Rene S.; Joensen, Katrine Grimstrup; Lukwesa-Musyani, Chileshe
Two cases of extremely drug-resistant Salmonella enterica serovar Senftenberg isolated from patients in Zambia were investigated by utilizing MIC determinations and whole-genome sequencing. The isolates were resistant to, and harbored genes toward, nine drug classes, including fluoroquinolones...
Pires, Elisabete; Frange, Pierre; Henry, Benoît; Lortholary, Olivier; Reichert, Catherine
Learning that they are a carrier of multi-drug resistant bacteria and being placed in isolation to prevent transmission has significant psychological repercussions for the patient and their families. Through therapeutic education, caregivers adapt their support to the patient's experience, raising their awareness of prevention. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
Kuczynski, Elizabeth A.; Sargent, Daniel J.; Grothey, Axel; Kerbel, Robert S.
The established dogma in oncology for managing recurrent or refractory disease dictates that therapy is changed at disease progression, because the cancer is assumed to have become drug-resistant. Drug resistance, whether pre-existing or acquired, is largely thought to be a stable and heritable process; thus, reuse of therapeutic agents that have failed is generally contraindicated. Over the past few decades, clinical evidence has suggested a role for unstable, non-heritable mechanisms of acquired drug resistance pertaining to chemotherapy and targeted agents. There are many examples of circumstances where patients respond to reintroduction of the same therapy (drug rechallenge) after a drug holiday following disease relapse or progression during therapy. Additional, albeit limited, evidence suggests that, in certain circumstances, continuing a therapy beyond disease progression can also have antitumour activity. In this Review, we describe the anticancer agents used in these treatment strategies and discuss the potential mechanisms explaining the apparent tumour re-sensitization with reintroduced or continued therapy. The extensive number of malignancies and drugs that challenge the custom of permanently switching to different drugs at each line of therapy warrants a more in-depth examination of the definitions of disease progression and drug resistance and the resulting implications for patient care. PMID:23999218
Rieckmann, K. H.; Trenholme, G. M.; Williams, R. L.; Carson, P. E.; Frischer, H.; Desjardins, R. E.
In preliminary studies with mefloquine (WR 142 490) a single dose exerted prolonged suppressive activity against a drug-resistant strain of Plasmodium falciparum. Development of patent parasitaemia was prevented when nonimmune persons were exposed to infected mosquitos 2 weeks after medication, and it was delayed when exposure occurred 3 weeks after drug administration. PMID:4619059
Monteserin, Johana; Camacho, Mirtha; Barrera, Lucía; Palomino, Juan Carlos; Ritacco, Viviana; Martin, Anandi
Bolivia ranks among the 10 Latin American countries with the highest rates of tuberculosis (TB) and multidrug resistant (MDR) TB. In view of this, and of the lacking information on the population structure of Mycobacterium tuberculosis in the country, we explored genotype associations with drug resistance and clustering by analyzing isolates collected in 2010 from 100 consecutive TB patients at risk of drug resistance in seven of the nine departments in which Bolivia is divided. Fourteen isolates were MDR, 29 had other drug resistance profiles, and 57 were pansusceptible. Spoligotype family distribution was: Haarlem 39.4%, LAM 26.3%, T 22.2%, S 2.0%, X 1.0%, orphan 9.1%, with very low intra-family diversity and absence of Beijing genotypes. We found 66 different MIRU-VNTR patterns; the most frequent corresponded to Multiple Locus Variable Analysis (MLVA) MtbC15 patterns 860, 372 and 873. Twelve clusters, each with identical MIRU-VNTR and spoligotypes, gathered 35 patients. We found no association of genotype with drug resistant or MDR-TB. Clustering associated with SIT 50 and the H3 subfamily to which it belongs (pBolivia. However, results should be taken cautiously because the sample is small and includes a particular subset of M. tuberculosis population. Copyright © 2013 Elsevier B.V. All rights reserved.
Miwanda, Berthe; Moore, Sandra; Muyembe, Jean-Jacques; Nguefack-Tsague, Georges; Kabangwa, Ickel Kakongo; Ndjakani, Daniel Yassa; Mutreja, Ankur; Thomson, Nicholas; Thefenne, Helene; Garnotel, Eric; Tshapenda, Gaston; Kakongo, Denis Kandolo; Kalambayi, Guy; Piarroux, Renaud
We analyzed 1,093 Vibrio cholerae isolates from the Democratic Republic of the Congo during 1997-2012 and found increasing antimicrobial drug resistance over time. Our study also demonstrated that the 2011-2012 epidemic was caused by an El Tor variant clonal complex with a single antimicrobial drug susceptibility profile.
Kulis, Stephen; Brown, Eddie F.
This study explored the drug resistance strategies that urban American Indian adolescents consider the best and worst ways to respond to offers of alcohol, cigarettes, and marijuana. Focus group data were collected from 11 female and 9 male American Indian adolescents attending urban middle schools in the southwest. The youth were presented with…
KB-8-5-11 cells are a drug-resistant cervical cell model that overexpresses ABCB1 (P-glycoprotein). KB-8-5-11 has become sensitive to non-ABCB1 substrate cisplatin. Understanding the mechanism of collateral sensitivity to cisplatin may lead to biomarker discovery for platinum sensitivity in patients with cancer.
Eun Kyung Lee
Full Text Available Acquisition of drug resistance leads to failure of anti-cancer treatments and therapies. Although several successive chemotherapies are available, along with efforts towards clinical applications of new anti-cancer drugs, it is generally realized that there is a long way to go to treat cancers. Resistance to anti-cancer drugs results from various factors, including genetic as well as epigenetic differences in tumors. Determining the molecular and cellular mechanisms responsible for the acquisition of drug resistance may be a helpful approach for the development of new therapeutic strategies to overcome treatment failure. Several studies have shown that the acquisition of drug resistance is tightly regulated by post-transcriptional regulators such as RNA binding proteins (RBPs and microRNAs (miRNAs, which change the stability and translation of mRNAs encoding factors involved in cell survival, proliferation, epithelial-mesenchymal transition, and drug metabolism. Here, we review our current understanding of ribonucleoprotein complexes, including RBPs and miRNAs, which play critical roles in the acquisition of drug resistance and have potential clinical implications for cancer.
Kang, Hoin; Kim, Chongtae; Lee, Heejin; Kim, Wook; Lee, Eun Kyung
Acquisition of drug resistance leads to failure of anti-cancer treatments and therapies. Although several successive chemotherapies are available, along with efforts towards clinical applications of new anti-cancer drugs, it is generally realized that there is a long way to go to treat cancers. Resistance to anti-cancer drugs results from various factors, including genetic as well as epigenetic differences in tumors. Determining the molecular and cellular mechanisms responsible for the acquisition of drug resistance may be a helpful approach for the development of new therapeutic strategies to overcome treatment failure. Several studies have shown that the acquisition of drug resistance is tightly regulated by post-transcriptional regulators such as RNA binding proteins (RBPs) and microRNAs (miRNAs), which change the stability and translation of mRNAs encoding factors involved in cell survival, proliferation, epithelial-mesenchymal transition, and drug metabolism. Here, we review our current understanding of ribonucleoprotein complexes, including RBPs and miRNAs, which play critical roles in the acquisition of drug resistance and have potential clinical implications for cancer.
This thesis reports findings of six studies including two tuberculosis (TB) drug resistance surveys, a comparative study of HIV infection rates among patients enrolled in the survey and those under routine TB/HIV surveillance, two TB molecular epidemiological analyses and a systematic review and met
van Altena, Richard
Tuberculosis (TB) caused by bacilli that are resistant to the two major drugs, rifampicin and isoniazid is defined as Multi-Drug Resistant TB or MDRTB. MDRTB kills around 50% of people affected around the world. In contrast, treatment results of MDR-TB in the Netherlands (1985-2013) have consistentl
indication of the degree of phenotypic resistance to a given ... history is often required for accurate interpretations, particularly for patients ... could result in the development of drug resistance with potential ... na"ive HIV-infected pregnant women varies geographically. .... infants is rapidly evolving and increasingly complex.
COVERED 26 September 2011 25 September 2012 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Identification of New Drug Targets in Multi-Drug Resistant...will be necessary for the fragment based screening and subsequent design of new drug lead compounds. To accompany and validate the structural studies
Alffenaar, Jan-Willem C.; Akkerman, Onno W.; Anthony, Richard M.; Tiberi, Simon; Heysell, Scott; Grobusch, Martin P.; Cobelens, Frank G J; van Soolingen, Dick
Introduction: Success rates for treatment of extensively drug resistant tuberculosis (XDR-TB) are low due to limited treatment options, delayed diagnosis and inadequate health care infrastructure.Areas covered: This review analyses existing programmes of prevention, diagnosis and treatment of
Pranger, A.D.; Alffenaar, J.W.C.; Aarnoutse, R.E.
Fluoroquinolones (FQs) are important drugs to treat drug-resistant tuberculosis. In this review we integrated pharmacokinetic properties (PK) and microbiological susceptibility against M. tuberculosis and eventually evaluated the pharmcodynamic (PD) properties, as well as the influence of co-adminis
Full Text Available South Africa has a high and increasing burden of both drugs-susceptible and drug-resistant tuberculosis. This disease has been declared an emergency in Africa. South Africa has committed itself to addressing this national crises by designing...
This thesis reports findings of six studies including two tuberculosis (TB) drug resistance surveys, a comparative study of HIV infection rates among patients enrolled in the survey and those under routine TB/HIV surveillance, two TB molecular epidemiological analyses and a systematic review and