Detecting mutations in the mycobacterium tuberculosis pyrazinamidase gene pnca to improve infection control and decrease drug resistance rates in human immunodeficiency virus coinfection

Matthew Z. Dudley, Patricia Sheen, Robert H. Gilman, Eduardo Ticona, Jon S. Friedland, Daniela E. Kirwan, Luz Caviedes, Richard Rodriguez, Lilia Z. Cabrera, Jorge Coronel, Louis Grandjean, David A.J. Moore, Carlton A. Evans, Luz Huaroto, Víctor Chávez-Pérez, Mirko Zimic

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Hospital infection control measures are crucial to tuberculosis (TB) control strategies within settings caring for human immunodeficiency virus (HIV)-positive patients, as these patients are at heightened risk of developing TB. Pyrazinamide (PZA) is a potent drug that effectively sterilizes persistent Mycobacterium tuberculosis bacilli. However, PZA resistance associated with mutations in the nicotinamidase/pyrazinamidase coding gene, pncA, is increasing. A total of 794 patient isolates obtained from four sites in Lima, Peru, underwent spoligotyping and drug resistance testing. In one of these sites, the HIV unit of Hospital Dos de Mayo (HDM), an isolation ward for HIV/TB coinfected patients opened during the study as an infection control intervention: circulating genotypes and drug resistance pre-and postintervention were compared. All other sites cared for HIV-negative outpatients: genotypes and drug resistance rates from these sites were compared with those from HDM. HDM patients showed high concordance between multidrug resistance, PZA resistance according to the Wayne method, the two most common genotypes (spoligotype international type [SIT] 42 of the Latino American-Mediterranean (LAM)-9 clade and SIT 53 of the T1 clade), and the two most common pncA mutations (G145A and A403C). These associations were absent among community isolates. The infection control intervention was associated with 58-92% reductions in TB caused by SIT 42 or SIT 53 genotypes (odds ratio [OR] = 0.420, P = 0.003); multidrug-resistant TB (OR = 0.349, P < 0.001); and PZA-resistant TB (OR = 0.076, P < 0.001). In conclusion, pncA mutation typing, with resistance testing and spoligotyping, was useful in identifying a nosocomial TB outbreak and demonstrating its resolution after implementation of infection control measures.

Original languageEnglish
Pages (from-to)1239-1246
Number of pages8
JournalAmerican Journal of Tropical Medicine and Hygiene
Issue number6
StatePublished - Dec 2016

Bibliographical note

Funding Information:
Financial support: We acknowledge financial support from the Wellcome Trust (awards 057434/Z/99/Z, 070005/Z/02/Z, 078340/Z/05/Z, 099805/Z/12/Z, 105788/Z/14/Z, and 201251/Z/16/Z); the Joint Global Health Trials consortium (MRC, DFID, and Wellcome Trust award MR/K007467/1); the charity Innovation For Health And Development (IFHAD); DFID-CSCF; the Bill & Melinda Gates Foundation (award OPP1118545); the Imperial College National Institutes of Health Research Biomedical Research Centre; and the National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States, under the terms of Award 1R01TW008669-01. Patricia Sheen was funded by a Wellcome Trust Intermediate Fellowship, Daniela E. Kirwan was funded by a National Institute for Health Research Academic Clinical Fellowship, and Louis Grandjean was funded by a Wellcome Trust Tropical Clinical Research Training Fellowship.

Publisher Copyright:
Copyright © 2016 by The American Society of Tropical Medicine and Hygiene.


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