Population-based resistance of Mycobacterium tuberculosis isolates to pyrazinamide and fluoroquinolones: results from a multicountry surveillance project

Matteo Zignol, Anna S. Dean, Natavan Alikhanova, Sonke Andres, Andrea Maurizio Cabibbe, Daniela Maria Cirillo, Andrei Dadu, Andries Dreyer, Michele Driesen, Christopher Gilpin, Rumina Hasan, Zahra Hasan, Sven Hoffner, Ashaque Husain, Alamdar Hussain, Nazir Ismail, Mostofa Kamal, Mikael Mansjo, Lindiwe Mvusi, Stefan NiemannShaheed V. Omar, Ejaz Qadeer, Leen Rigouts, Sabine Ruesch-Gerdes, Marco Schito, Mehriban Seyfaddinova, Alena Skrahina, Sabira Tahseen, William A. Wells, Ya Diul Mukadi, Michael Kimerling, Katherine Floyd, Karin Weyer, Mario C. Raviglione

Research output: Contribution to journalA1: Web of Science-article

Abstract

Background Pyrazinamide and fluoroquinolones are essential antituberculosis drugs in new rifampicin-sparing regimens. However, little information about the extent of resistance to these drugs at the population level is available.

Methods In a molecular epidemiology analysis, we used population-based surveys from Azerbaijan, Bangladesh, Belarus, Pakistan, and South Africa to investigate resistance to pyrazinamide and fluoroquinolones among patients with tuberculosis. Resistance to pyrazinamide was assessed by gene sequencing with the detection of resistance-conferring mutations in the pncA gene, and susceptibility testing to fluoroquinolones was conducted using the MGIT system.

Findings Pyrazinamide resistance was assessed in 4972 patients. Levels of resistance varied substantially in the surveyed settings (3.0-42.1%). In all settings, pyrazinamide resistance was significantly associated with rifampicin resistance. Among 5015 patients who underwent susceptibility testing to fluoroquinolones, proportions of resistance ranged from 1.0-16.6% for ofloxacin, to 0.5-12.4% for levofloxacin, and 0.9-14.6% for moxifloxacin when tested at 0.5 mu g/mL. High levels of ofloxacin resistance were detected in Pakistan. Resistance to moxifloxacin and gatifloxacin when tested at 2 mu g/mL was low in all countries.

Interpretation Although pyrazinamide resistance was significantly associated with rifampicin resistance, this drug may still be effective in 19-63% of patients with rifampicin-resistant tuberculosis. Even though the high level of resistance to ofloxacin found in Pakistan is worrisome because it might be the expression of extensive and unregulated use of fluoroquinolones in some parts of Asia, the negligible levels of resistance to fourth-generation fluoroquinolones documented in all survey sites is an encouraging finding. Rational use of this class of antibiotics should therefore be ensured to preserve its effectiveness.

Original languageEnglish
JournalLancet Infectious Diseases
Volume16
Issue number10
Pages (from-to)1185-1192
Number of pages8
ISSN1473-3099
DOIs
Publication statusPublished - 2016

Keywords

  • ANTITUBERCULOSIS DRUG-RESISTANCE
  • PULMONARY TUBERCULOSIS
  • MOXIFLOXACIN
  • REGIMEN
  • GATIFLOXACIN
  • COMBINATION
  • BREAKPOINT
  • MUTATIONS
  • PA-824
  • MGIT

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