title: Primary Capreomycin Resistance Is Common and Associated With Early Mortality in Patients With Extensively Drug-Resistant Tuberculosis in KwaZulu-Natal, South Africa.
abstract: BACKGROUND
  Capreomycin is a key antimycobacterial drug in treatment of extensively drug-resistant tuberculosis (XDR-TB). Drug-susceptibility testing (DST) for capreomycin is not routinely performed in newly diagnosed XDR-TB in South Africa. We performed this study to assess the prevalence, clinical significance, and molecular epidemiology of capreomycin resistance in newly diagnosed patients with XDR-TB in KwaZulu-Natal, South Africa.
  
  
  METHODS
  Retrospective cohort study of consecutive patients with XDR-TB admitted to a TB referral hospital without previous XDR-TB treatment. A subset of isolates had extended DST (including capreomycin), mutational analysis, and IS6110 restriction fragment length polymorphism assays.
  
  
  RESULTS
  A total of 216 eligible patients with XDR-TB were identified. The majority were treated with capreomycin (72%), were young (median age: 35.5 years), and were female (56%). One hundred five (76%) were HIV+, and 109 (66%) were on antiretroviral therapy. A subset of 52 patients had full DST. A total of 47/52 (90.4%) patients with XDR-TB were capreomycin resistant. Capreomycin-resistant patients experienced worse mortality and culture conversion than capreomycin susceptible, although this difference was not statistically significant. The A1401G mutation in the rrs gene was associated with capreomycin resistance. The majority of capreomycin-resistant strains were F15/LAM4/KZN lineage (80%), and clustering was common in these isolates (92.5%).
  
  
  CONCLUSIONS
  Capreomycin resistance is common in patients with XDR-TB in KwaZulu-Natal, is predominantly because of ongoing province-wide transmission of a highly resistant strain, and is associated with high mortality. Capreomycin should be included in routine DST in all patients with XDR-TB. New drug regimens that do not include injectable agents should be operationally tested as empiric treatment in XDR-TB.
authors.affiliation: *Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, New York, NY; †Department of Epidemiology, Columbia Mailman School of Public Health, New York, NY; ‡Centre for AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa; §Department of Microbiology, National Health Laboratory Service (NHLS), Durban, South Africa; ‖Department of Medical Microbiology, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa; ¶DR-TB Department, King Dinuzulu Hospital, Department of Health, Sydenham, South Africa; and #Department of Epidemiology, Boston University School of Public Health, Boston, MA.
authors.forename: Max R
authors.initials: MR
authors.lastname: OʼDonnell
authors.forename: Melendhran
authors.initials: M
authors.lastname: Pillay
authors.forename: Manormoney
authors.initials: M
authors.lastname: Pillay
authors.forename: Lise
authors.initials: L
authors.lastname: Werner
authors.forename: Iqbal
authors.initials: I
authors.lastname: Master
authors.forename: Allison
authors.initials: A
authors.lastname: Wolf
authors.forename: Barun
authors.initials: B
authors.lastname: Mathema
authors.forename: Yacoob M
authors.initials: YM
authors.lastname: Coovadia
authors.forename: Koleka
authors.initials: K
authors.lastname: Mlisana
authors.forename: Charles Robert
authors.initials: CR
authors.lastname: Horsburgh
authors.forename: Nesri
authors.initials: N
authors.lastname: Padayatchi
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000494:pharmacology*; D002207:Capreomycin / Q000008:administration & dosage / Q000494:pharmacology*; D015331:Cohort Studies; D004352:Drug Resistance, Microbial; D024901:Drug Resistance, Multiple, Bacterial; D054908:Extensively Drug-Resistant Tuberculosis / Q000453:epidemiology* / Q000401:mortality*; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000150:complications* / Q000453:epidemiology; D006801:Humans; D008297:Male; D009169:Mycobacterium tuberculosis / Q000145:classification / Q000187:drug effects / Q000235:genetics; D012189:Retrospective Studies; D013019:South Africa / Q000453:epidemiology
chemical_list: D019380:Anti-HIV Agents; D000904:Antibiotics, Antitubercular; D002207:Capreomycin