المؤلفون: Walker, Timothy M, Miotto, Paolo, Köser, Claudio U, Fowler, Philip W, Knaggs, Jeff, Iqbal, Zamin, Hunt, Martin, Chindelevitch, Leonid, Farhat, Maha R, Cirillo, Daniela Maria, Comas, Iñaki, Posey, James, Omar, Shaheed V, Peto, Timothy EA, Suresh, Anita, Uplekar, Swapna, Laurent, Sacha, Colman, Rebecca E, Nathanson, Carl-Michael, Zignol, Matteo, Walker, Ann Sarah, Crook, Derrick W, Ismail, Nazir, Rodwell, Timothy C, Consortium, the SeqTreat Consortium CRyPTIC, Walker, A Sarah, Steyn, Adrie JC, Lalvani, Ajit, Baulard, Alain, Christoffels, Alan, Mendoza-Ticona, Alberto, Trovato, Alberto, Skrahina, Alena, Lachapelle, Alexander S, Brankin, Alice, Piatek, Amy, Cruz, Ana Gibertoni, Koch, Anastasia, Cabibbe, Andrea Maurizio, Spitaleri, Andrea, Brandao, Angela P, Chaiprasert, Angkana, Barbova, Anna, Van Rie, Annelies, Ghodousi, Arash, Bainomugisa, Arnold, Mandal, Ayan, Roohi, Aysha, Javid, Babak, Zhu, Baoli, Letcher, Brice, Rodrigues, Camilla, Nimmo, Camus, NATHANSON, Carl-Michael, Duncan, Carla, Coulter, Christopher, Utpatel, Christian, Liu, Chunfa, Grazian, Clara, Kong, Clare, Wilson, Daniel J, Matias, Daniela, Jorgensen, Danielle, Zimenkov, Danila, Chetty, Darren, Moore, David AJ, Clifton, David A, van Soolingen, Dick, Liu, Dongxin, Kohlerschmidt, Donna, Barreira, Draurio, Ngcamu, Dumisani, Lazaro, Elias David Santos, Kelly, Ellis, Borroni, Emanuele, Roycroft, Emma, Andre, Emmanuel, Böttger, Erik C, Robinson, Esther, Menardo, Fabrizio, Mendes, Flavia F, Jamieson, Frances B, Coll, Francesc, Gao, George Fu, Kasule, George W, Rossolini, Gian Maria, Rodger, Gillian, Smith, E Grace, Meintjes, Graeme, Thwaites, Guy, Hoffmann, Harald, Albert, Heidi, Cox, Helen, Laurenson, Ian F, Arandjelovic, Irena

المصدر: The Lancet Microbe. 3(4)

مصطلحات موضوعية: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Microbiology, Clinical Sciences, Tuberculosis, Infectious Diseases, Rare Diseases, Antimicrobial Resistance, Orphan Drug, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Infection, Good Health and Well Being, Antitubercular Agents, Drug Resistance, Ethambutol, Microbial Sensitivity Tests, Mutation, Mycobacterium tuberculosis, World Health Organization, CRyPTIC Consortium, Seq&Treat Consortium, Immunology, Medical microbiology

الوصف: BackgroundMolecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for Mycobacterium tuberculosiscomplex (MTBC). We aimed to generate a WHO endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction.MethodsA candidate gene approach was used to identify mutations as associated with resistance, or consistent with susceptibility, for 13 WHO endorsed anti-tuberculosis drugs. 38,215 MTBC isolates with paired whole-genome sequencing and phenotypic drug susceptibility testing data were amassed from 45 countries. For each mutation, a contingency table of binary phenotypes and presence or absence of the mutation computed positive predictive value, and Fisher's exact tests generated odds ratios and Benjamini-Hochberg corrected p-values. Mutations were graded as Associated with Resistance if present in at least 5 isolates, if the odds ratio was >1 with a statistically significant corrected p-value, and if the lower bound of the 95% confidence interval on the positive predictive value for phenotypic resistance was >25%. A series of expert rules were applied for final confidence grading of each mutation.Findings15,667 associations were computed for 13,211 unique mutations linked to one or more drugs. 1,149/15,667 (7·3%) mutations were classified as associated with phenotypic resistance and 107/15,667 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was >80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were classified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs.InterpretationThis first WHO endorsed catalogue of molecular targets for MTBC drug susceptibility testing provides a global standard for resistance interpretation. Its existence should encourage the implementation of molecular diagnostics by National Tuberculosis Programmes.FundingUNITAID, Wellcome, MRC, BMGF.

الوصول الحر: https://escholarship.org/uc/item/7xp7418cTest

المؤلفون: Kigozi, Edgar, Kasule, George W., Musisi, Kenneth, Lukoye, Deus, Kyobe, Samuel, Katabazi, Fred Ashaba, Wampande, Eddie M., Joloba, Moses L., Kateete, David Patrick

المساهمون: Hasnain, Seyed Ehtesham, Fogarty International Center, Wellcome Trust

المصدر: PLOS ONE ; volume 13, issue 5, page e0198091 ; ISSN 1932-6203

الإتاحة: https://doi.org/10.1371/journal.pone.0198091Test

المؤلفون: Kasule, George W., Kateete, David P., Joloba, Moses L.

المصدر: BMC Infectious Diseases ; volume 16, issue 1 ; ISSN 1471-2334

مصطلحات موضوعية: Infectious Diseases

الإتاحة: https://doi.org/10.1186/s12879-016-1487-1Test

المؤلفون: Lukoye, Deus, Ssengooba, Willy, Musisi, Kenneth, Kasule, George W, Cobelens, Frank G J, Joloba, Moses, Gomez, Gabriela B

مصطلحات موضوعية: Sub-Saharan Africa, Drug resistant tuberculosis, Risk factors, HIV, Survey

الوصف: Background Prevalence of multidrug resistant tuberculosis (MDR-TB), defined as in vitro resistance to both rifampicin and isoniazid with or without resistance to other TB drugs, in sub-Saharan Africa (SSA) is reportedly low compared to other regions. These estimates are based on data reported to the World Health Organization (WHO) on drug resistance surveys, which may suffer from a reporting bias. We set out to evaluate the variation in prevalence of drug resistant tuberculosis (DR-TB) and its determinants across SSA countries among new and previously treated TB patients. Methods The aim was to perform a systematic review and meta-analysis of DR-TB prevalence and associated risk factors in SSA. PubMed, EMBASE, Cochrane and bibliographies of DR-TB studies were searched. Surveys at national or sub-national level, with reported DR-TB prevalence (or sufficient data to calculate a prevalence) to isoniazid (INH), rifampicin (RMP), ethambutol (EMB), and streptomycin (SM) conducted in SSA excluding the Republic of South Africa, published between 2003 and 2013 with no language restriction were considered. Two authors searched and reviewed the studies for eligibility and extracted the data in pre-defined forms. Forest plots of all prevalence estimates by resistance outcome were performed. Summary estimates were calculated using random effects models, when appropriate. Associations between any DR-TB and MDR-TB with potential risk factors were examined through subgroup analyses stratified by new and previously treated patients. Results A total of 726 studies were identified, of which 27 articles fulfilled the inclusion criteria. Studies reported drug susceptibility testing (DST) results for a total of 13,465 new and 1,776 previously treated TB patients. Pooled estimate of any DR-TB prevalence among the new cases was 12.6% (95% CI 10.6-15.0) while for MDR-TB this was 1.5% (95% CI 1.0-2.3). Among previously treated patients, these were 27.2% (95% CI 21.4-33.8) and 10.3% (95% CI 5.8-17.4%), respectively. DR-TB (any ...

العلاقة: http://www.biomedcentral.com/1471-2458/15/291Test

الإتاحة: http://www.biomedcentral.com/1471-2458/15/291Test

المؤلفون: Ezati, Nicholas, Lukoye, Deus, Wampande, Eddie M, Musisi, Kenneth, Kasule, George W, Cobelens, Frank, Kateete, David P, Joloba, Moses L

مصطلحات موضوعية: ■■■

الوصف: Background The global increase in the burden of multidrug-resistant tuberculosis (MDR-TB) underscores an urgent need for data on factors involved in generation and spread of TB drug resistance. We performed molecular analyses on a representative sample of Mycobacterium tuberculosis (MTB) isolates. Basing on findings of the molecular epidemiological study in Kampala, we hypothesized that the predominant MTB strain lineage in Uganda is negatively associated with anti-TB drug resistance and we set out to test this hypothesis. Methods We extracted DNA from mycobacterial isolates collected from smear-positive TB patients in the national TB drug resistance survey and carried out IS6110-PCR. To identify MTB lineages/sub lineages RT-PCR SNP was performed using specific primers and hybridization probes and the ‘melting curve’ analysis was done to distinguish the Uganda II family from other MTB families. The primary outcome was the distribution of the Uganda II family and its associations with anti-TB drug resistance and HIV infection. Results Out of the 1537 patients enrolled, MTB isolates for 1001 patients were available for SNP analysis for identification of Uganda II family, of which 973 (97%) had conclusive RT-PCR results. Of these 422 (43.4%) were of the Uganda II family, mostly distributed in the south west zone (55.0%; OR = 4.6 for comparison with other zones; 95% CI 2.83-7.57; p < 0.001) but occurred in each of the other seven geographic zones at varying levels. Compared to the Uganda II family, other genotypes as a group were more likely to be resistant to any anti-TB drug (OR adj =2.9; 95% CI 1.63-5.06; p = 0.001) or MDR (OR adj 4.9; 95% CI, 1.15-20.60; p = 0.032), even after adjusting for geographic zone, patient category, sex, residence and HIV status. It was commonest in the 25–34 year age group 159/330 (48.2%). No association was observed between Uganda II family and HIV infection. Conclusion The Uganda II family is a major cause of morbidity due to TB in all NTLP zones in Uganda. It is less ...

العلاقة: http://www.biomedcentral.com/1471-2334/14/703Test

الإتاحة: http://www.biomedcentral.com/1471-2334/14/703Test

المؤلفون: Ezati, Nicholas, Lukoye, Deus, Wampande, Eddie M, Musisi, Kenneth, Kasule, George W, Cobelens, Frank GJ, Kateete, David P, Joloba, Moses L

المصدر: BMC Infectious Diseases ; volume 14, issue 1 ; ISSN 1471-2334

مصطلحات موضوعية: Infectious Diseases

الإتاحة: https://doi.org/10.1186/s12879-014-0703-0Test