title: Population-based resistance of Mycobacterium tuberculosis isolates to pyrazinamide and fluoroquinolones: results from a multicountry surveillance project.
abstract: 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.
  
  
  
  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.
  
  
  
  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 μg/mL. High levels of ofloxacin resistance were detected in Pakistan. Resistance to moxifloxacin and gatifloxacin when tested at 2 μg/mL was low in all countries.
  
  
  
  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.
  
  
  
  Bill & Melinda Gates Foundation, United States Agency for International Development, Global Alliance for Tuberculosis Drug Development.
authors.affiliation: Global Tuberculosis Programme, World Health Organization, Geneva, Switzerland. Electronic address: zignolm@who.int.
authors.forename: Matteo
authors.initials: M
authors.lastname: Zignol
authors.affiliation: Global Tuberculosis Programme, World Health Organization, Geneva, Switzerland.
authors.forename: Anna S
authors.initials: AS
authors.lastname: Dean
authors.affiliation: Scientific Research Institute of Lung Diseases, Baku, Azerbaijan.
authors.forename: Natavan
authors.initials: N
authors.lastname: Alikhanova
authors.affiliation: National and Supranational Reference Laboratory for Mycobacterium, Borstel, Germany.
authors.forename: Sönke
authors.initials: S
authors.lastname: Andres
authors.affiliation: IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Andrea Maurizio
authors.initials: AM
authors.lastname: Cabibbe
authors.affiliation: IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Daniela Maria
authors.initials: DM
authors.lastname: Cirillo
authors.affiliation: Regional Office for Europe, World Health Organization, Copenhagen, Denmark.
authors.forename: Andrei
authors.initials: A
authors.lastname: Dadu
authors.affiliation: National Institute for Communicable Diseases, Sandringham, South Africa.
authors.forename: Andries
authors.initials: A
authors.lastname: Dreyer
authors.affiliation: Mycobacteriology Unit, Institute of Tropical Medicine, Antwerp, Belgium.
authors.forename: Michèle
authors.initials: M
authors.lastname: Driesen
authors.affiliation: Global Tuberculosis Programme, World Health Organization, Geneva, Switzerland.
authors.forename: Christopher
authors.initials: C
authors.lastname: Gilpin
authors.affiliation: Department of Pathology and Laboratory Medicine, Aga Khan University, Karachi, Pakistan.
authors.forename: Rumina
authors.initials: R
authors.lastname: Hasan
authors.affiliation: Department of Pathology and Laboratory Medicine, Aga Khan University, Karachi, Pakistan.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Hasan
authors.affiliation: Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden; Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Hoffner
authors.affiliation: National Tuberculosis Control Programme, Dhaka, Bangladesh.
authors.forename: Ashaque
authors.initials: A
authors.lastname: Husain
authors.affiliation: National Tuberculosis Reference Laboratory, National Tuberculosis Control Programme, Islamabad, Pakistan.
authors.forename: Alamdar
authors.initials: A
authors.lastname: Hussain
authors.affiliation: National Institute for Communicable Diseases, Sandringham, South Africa; University of Pretoria, Pretoria, South Africa.
authors.forename: Nazir
authors.initials: N
authors.lastname: Ismail
authors.affiliation: National Institute of Diseases of the Chest and Hospital, Dhaka, Bangladesh.
authors.forename: Mostofa
authors.initials: M
authors.lastname: Kamal
authors.affiliation: Department of Microbiology, Public Health Agency of Sweden, Solna, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Mansjö
authors.affiliation: Tuberculosis Control and Management, National Department of Health, Pretoria, South Africa.
authors.forename: Lindiwe
authors.initials: L
authors.lastname: Mvusi
authors.affiliation: National and Supranational Reference Laboratory for Mycobacterium, Borstel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Niemann
authors.affiliation: National Institute for Communicable Diseases, Sandringham, South Africa.
authors.forename: Shaheed V
authors.initials: SV
authors.lastname: Omar
authors.affiliation: National Tuberculosis Control Programme, Ministry of National Health Services, Regulation and Coordination, Islamabad, Pakistan.
authors.forename: Ejaz
authors.initials: E
authors.lastname: Qadeer
authors.affiliation: Mycobacteriology Unit, Institute of Tropical Medicine, Antwerp, Belgium; Biomedical Sciences, Antwerp University, Antwerp, Belgium.
authors.forename: Leen
authors.initials: L
authors.lastname: Rigouts
authors.affiliation: National and Supranational Reference Laboratory for Mycobacterium, Borstel, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Ruesch-Gerdes
authors.affiliation: Critical Path Institute, Tucson, AZ, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Schito
authors.affiliation: Scientific Research Institute of Lung Diseases, Baku, Azerbaijan.
authors.forename: Mehriban
authors.initials: M
authors.lastname: Seyfaddinova
authors.affiliation: Republican Research and Practical Centre for Pulmonology and Tuberculosis, Minsk, Belarus.
authors.forename: Alena
authors.initials: A
authors.lastname: Skrahina
authors.affiliation: National Tuberculosis Reference Laboratory, National Tuberculosis Control Programme, Islamabad, Pakistan.
authors.forename: Sabira
authors.initials: S
authors.lastname: Tahseen
authors.affiliation: Bureau for Global Health, US Agency for International Development, Washington, DC, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Wells
authors.affiliation: Bureau for Global Health, US Agency for International Development, Washington, DC, USA.
authors.forename: Ya Diul
authors.initials: YD
authors.lastname: Mukadi
authors.affiliation: KNCV Tuberculosis Foundation, The Hague, Netherlands.
authors.forename: Michael
authors.initials: M
authors.lastname: Kimerling
authors.affiliation: Global Tuberculosis Programme, World Health Organization, Geneva, Switzerland.
authors.forename: Katherine
authors.initials: K
authors.lastname: Floyd
authors.affiliation: Global Tuberculosis Programme, World Health Organization, Geneva, Switzerland.
authors.forename: Karin
authors.initials: K
authors.lastname: Weyer
authors.affiliation: Global Tuberculosis Programme, World Health Organization, Geneva, Switzerland.
authors.forename: Mario C
authors.initials: MC
authors.lastname: Raviglione
mesh_terms: D000890:Anti-Infective Agents / Q000627:therapeutic use*; D000995:Antitubercular Agents / Q000627:therapeutic use*; D001208:Asia; D024841:Fluoroquinolones / Q000627:therapeutic use*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000302:isolation & purification*; D011159:Population Surveillance; D011718:Pyrazinamide / Q000627:therapeutic use*; D012189:Retrospective Studies; D012293:Rifampin / Q000494:pharmacology; D013019:South Africa; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy
chemical_list: D000890:Anti-Infective Agents; D000995:Antitubercular Agents; D024841:Fluoroquinolones; D011718:Pyrazinamide; D012293:Rifampin