Title

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

Authors

Matteo Zignol, World Health Organization
Anna S. Dean, World Health Organization
Sönke Andres, National and Supranational Reference Laboratory for Mycobacterium
Natavan Alikhanova, Scientific Research Institute of Lung Diseases
Andrea Maurizio Cabibbe, IRCCS San Raffaele Scientific Institute
Daniela Maria Cirillo, IRCCS San Raffaele Scientific Institute
Andrei Dadu, Regional Office for Europe, World Health Organization
Andries Dreyer, National Institute for Communicable Diseases, Sandringham,
Michèle Driesen, Mycobacteriology Unit, Institute of Tropical Medicine
Christopher Gilpin, World Health Organization
Rumina Rumina, Aga Khan University
Zahra Hasan, Agha Khan UniversityFollow
Sven Hoffner, Public Health Agency of Sweden
Ashaque Husain, National Tuberculosis Control Programme
Alamdar Hussain, National Tuberculosis Control Programme
Nazir Ismail, National Institute for Communicable Diseases
Mostofa Kamal, National Institute of Diseases of the Chest and Hospital
Mikael Mansjö, Public Health Agency of Sweden
Lindiwe Mvusi, National Department of Health
Stefan Niemann, National and Supranational Reference Laboratory for Mycobacterium
Shaheed V. Omar, National Institute for Communicable Diseases
Ejaz Qadeer, Ministry of National Health Services
Leen Rigouts, Institute of Tropical Medicine
Sabine Ruesch Gerdes, National and Supranational Reference Laboratory for Mycobacterium
Marco Schito, Critical Path Institute
Mehriban Seyfaddinova, Scientific Research Institute of Lung Diseases
Alena Skrahina, Republican Research and Practical Centre for Pulmonology and Tuberculosis
Sabira Tahseen, National Tuberculosis Reference Laboratory, National Tuberculosis Control Programme
William A. Wells, US Agency for International Development
Ya Diul Mukadi, US Agency for International Development
Michael Kimerling, KNCV Tuberculosis Foundation
Katherine Floyd, World Health Organization, Geneva
Karin Weyer, World Health Organization
Mario C. Raviglione, World Health Organization

Document Type

Article

Department

AKU-Pakistan; Medical College Pakistan

Abstract

Background Pyrazinamide and fl uoroquinolones 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 fl uoroquinolones 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 fl uoroquinolones 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 signifi cantly associated with rifampicin resistance. Among 5015 patients who underwent susceptibility testing to fluoroquinolones, proportions of resistance ranged from 1·0–16·6% for ofl oxacin, to 0·5–12·4% for levofl oxacin, and 0·9–14·6% for moxifl oxacin when tested at 0·5 μg/mL. High levels of ofl oxacin resistance were detected in Pakistan. Resistance to moxifl oxacin and gatifl oxacin when tested at 2 μg/mL was low in all countries. Interpretation Although pyrazinamide resistance was signifi cantly 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 ofl oxacin found in Pakistan is worrisome because it might be the expression of extensive and unregulated use of fl uoroquinolones in some parts of Asia, the negligible levels of resistance to fourth-generation fl uoroquinolones documented in all survey sites is an encouraging fi nding. Rational use of this class of antibiotics should therefore be ensured to preserve its eff ectiveness. Funding Bill & Melinda Gates Foundation, United States Agency for International Development, Global Alliance for Tuberculosis Drug Development.