title: High frequency of resistance, lack of clinical benefit, and poor outcomes in capreomycin treated South African patients with extensively drug-resistant tuberculosis.
abstract: BACKGROUND
  There are limited data about the epidemiology and treatment-related outcomes associated with capreomycin resistance in patients with XDR-TB. Capreomycin achieves high serum concentrations relative to MIC but whether capreomycin has therapeutic benefit despite microbiological resistance remains unclear.
  
  
  METHODS
  We reviewed the susceptibility profiles and outcomes associated with capreomycin usage in patients diagnosed with XDR-TB between August 2002 and October 2012 in two provinces of South Africa. Patients whose isolates were genotypically tested for capreomycin resistance were included in the analysis.
  
  
  RESULTS
  Of 178 XDR-TB patients 41% were HIV-infected. 87% (154/178) isolates contained a capreomycin resistance-conferring mutation [80% (143/178) rrs A1401G and 6% (11/178) were heteroresistant (containing both the rrs A1401G mutation and wild-type sequences)]. Previous MDR-TB treatment, prior usage of kanamycin, or strain type was not associated with capreomycin resistance. 92% (163/178) of XDR-TB patients were empirically treated with capreomycin. Capreomycin resistance decreased the odds of sputum culture conversion. In capreomycin sensitive and resistant persons combined weight at diagnosis was the only independent predictor for survival (p=<0.001). By contrast, HIV status and use of co-amoxicillin/clavulanic acid were independent predictors of mortality (p=<0.05). Capreomycin usage was not associated with survival or culture conversion when the analysis was restricted to those whose isolates were resistant to capreomycin.
  
  
  CONCLUSIONS
  In South Africa the frequency of capreomycin conferring mutations was extremely high in XDR-TB isolates. In those with capreomycin resistance there appeared to be no therapeutic benefit of using capreomycin. These data inform susceptibility testing and the design of treatment regimens for XDR-TB in TB endemic settings.
authors.affiliation: Lung Infection and Immunity Unit, Division of Pulmonology and University of Cape Town Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Elize
authors.initials: E
authors.lastname: Pietersen
authors.affiliation: Lung Infection and Immunity Unit, Division of Pulmonology and University of Cape Town Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Jonny
authors.initials: J
authors.lastname: Peter
authors.affiliation: Department of Science and Technology/National Research Foundation Centre for Excellence for Biomedical Tuberculosis Research/South African Medical Research Council Centre for TB Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Science, Stellenbosch University, Tygerberg, South Africa.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Streicher
authors.affiliation: Department of Science and Technology/National Research Foundation Centre for Excellence for Biomedical Tuberculosis Research/South African Medical Research Council Centre for TB Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Science, Stellenbosch University, Tygerberg, South Africa.
authors.forename: Frik
authors.initials: F
authors.lastname: Sirgel
authors.affiliation: Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Neesha
authors.initials: N
authors.lastname: Rockwood
authors.affiliation: Gordonia Provincial Hospital, Upington, South Africa.
authors.forename: Barbara
authors.initials: B
authors.lastname: Mastrapa
authors.affiliation: Brooklyn Chest Hospital, Cape Town, South Africa.
authors.forename: Julian
authors.initials: J
authors.lastname: Te Riele
authors.affiliation: Lung Infection and Immunity Unit, Division of Pulmonology and University of Cape Town Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Malika
authors.initials: M
authors.lastname: Davids
authors.affiliation: Department of Science and Technology/National Research Foundation Centre for Excellence for Biomedical Tuberculosis Research/South African Medical Research Council Centre for TB Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Science, Stellenbosch University, Tygerberg, South Africa.
authors.forename: Paul
authors.initials: P
authors.lastname: van Helden
authors.affiliation: Department of Science and Technology/National Research Foundation Centre for Excellence for Biomedical Tuberculosis Research/South African Medical Research Council Centre for TB Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Science, Stellenbosch University, Tygerberg, South Africa.
authors.forename: Robin
authors.initials: R
authors.lastname: Warren
authors.affiliation: Lung Infection and Immunity Unit, Division of Pulmonology and University of Cape Town Lung Institute, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Keertan
authors.initials: K
authors.lastname: Dheda
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D060085:Coinfection; D024901:Drug Resistance, Multiple, Bacterial; D054908:Extensively Drug-Resistant Tuberculosis / Q000188:drug therapy* / Q000453:epidemiology*; D005260:Female; D015658:HIV Infections; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics; D012189:Retrospective Studies; D013019:South Africa / Q000453:epidemiology; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D000995:Antitubercular Agents