title: The nitrate reductase assay for the rapid detection of isoniazid and rifampicin resistance in Mycobacterium tuberculosis: a systematic review and meta-analysis.
abstract: OBJECTIVE
  The reference standard methods for drug susceptibility testing (DST) of M. tuberculosis are very slow to give results, and due to the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis, there is an urgent demand for new, rapid and accurate DST methods, particularly in low-income countries. The nitrate reductase assay (NRA) has been proposed as a rapid method for the detection of resistance to rifampicin and isoniazid, but its accuracy has not been systematically evaluated.
  
  
  METHODS
  We performed a systematic review and meta-analysis to evaluate the accuracy of the NRA for the detection of rifampicin- and isoniazid-resistant tuberculosis. We searched Medline PubMed (NCBI), Global Health-CAB, EJS-E (EbscoHost), ISI Web, Web of Science and IFCC and contacted authors if additional information was required. Fifteen studies met our inclusion criteria for rifampicin resistance detection and 13 for isoniazid. Of these, the majority of the studies used culture isolates on solid medium, four used culture isolates on liquid medium and three used sputum samples. We applied the summary receiver operating characteristic (SROC) curve to perform meta-analysis and to summarize diagnostic accuracy.
  
  
  RESULTS
  For rifampicin, the majority of the studies that applied NRA to isolates had a sensitivity and specificity >94% and for isoniazid, >92%. The three studies that applied NRA directly on sputum samples had a sensitivity and specificity that ranged between 88% and 100%. The SROC curve had an area of >0.99 for both drugs.
  
  
  CONCLUSIONS
  There is evidence that NRA is highly sensitive and specific for the rapid detection of rifampicin and isoniazid resistance in culture isolates. More evidence is required for the NRA applied directly on sputum samples, but preliminary results appear promising and show a good sensitivity and specificity. Additional studies are required in countries with a high prevalence of MDR-TB and also cost-effectiveness analysis in order to obtain a complete picture on the utility of this method for rapid drug resistance detection in tuberculosis.
authors.affiliation: Mycobacteriology Unit, Institute of Tropical Medicine, Antwerp, Belgium. amartin@itg.be
authors.forename: Anandi
authors.initials: A
authors.lastname: Martin
authors.forename: Stefan
authors.initials: S
authors.lastname: Panaiotov
authors.forename: Françoise
authors.initials: F
authors.lastname: Portaels
authors.forename: Sven
authors.initials: S
authors.lastname: Hoffner
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Palomino
authors.forename: Kristian
authors.initials: K
authors.lastname: Angeby
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D006801:Humans; D007538:Isoniazid / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests / Q000379:methods; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D050901:Nitrate Reductase / Q000032:analysis*; D012293:Rifampin / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D014376:Tuberculosis / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D050901:Nitrate Reductase; D007538:Isoniazid; D012293:Rifampin