Drug resistance of M. tuberculosis to pyrazinamide among drug-resistant clinical isolates, including MDR/XDR strains in Kazakhstan.

Kazakhstan is among the 30 countries worldwide with the highest rates of MDR-TB. Pyrazinamide is an anti-TB drug that plays an important role in shortening the duration of therapy because it targets persistent bacilli and enhances the effectiveness of combination regimens.

The aim of the study was to determine the frequency of pyrazinamide resistance among drug-resistant (DR) M. tuberculosis isolates from different regions of Kazakhstan and to identify genetic families.

271 drug-resistant clinical isolates of M. tuberculosis were collected, of which 143 (52.8%) were multidrug-resistant, 79 (29.2%) pre-XDR, 21 (7.7%) monoresistant, 19 (7.0%) polyresistant, and 9 (3.3%) XDR. All clinical isolates were tested for drug susceptibility to first/second-line anti-TB drugs and pyrazinamide (PZA) using the BACTEC MGIT-960. All clinical isolates of M. tuberculosis were spoligotyped on the Zeesan automated analysis system, SLAN-96 (Zeesan Biotech, China), using the MeltPro® Mycobacterium Tuberculosis McSpoligotyping kit.

Of the 271 drug-resistant clinical isolates of M. tuberculosis, 158 (58.3%) were phenotypically resistant to pyrazinamide, whereas 113 (41.7%) were susceptible. Spoligotyping results showed a predominance of the Beijing genotype among both pyrazinamide-resistant (n = 135, 85.4%) and pyrazinamide-susceptible (n = 90, 79.6%) clinical isolates of M. tuberculosis.

Analysis of the distribution among drug-resistant isolates showed that among 143 (100%) MDR isolates, 73 (51.0%) were identified as resistant to pyrazinamide, among 79 (100%) pre-XDR isolates, 63 (69.7%) were resistant to pyrazinamide, and among 9 XDRs, 7 were resistant to pyrazinamide. Among 19 polyresistant isolates, 9 (47.4%) were resistant to pyrazinamide. Among all drug-resistant clinical isolates, 225 (83%) were the Beijing genotypes, and 46 (17.0%) were non-Beijing genotypes represented by LAM, T, URAL, H, S, MANU-2, and Unknown.

Among multidrug-resistant and polyresistant strains, nearly half are susceptible to pyrazinamide (49.0% and 52.6%, respectively), which allows PZA to be included in the treatment regimen. PZA kills persistent, slow‑growing bacilli that survive standard therapy, preventing relapse, which makes PZA especially effective. Genotyping results showed that Beijing genetic lines continue to dominate and play a key role in the spread of drug-resistant tuberculosis, including drug resistance to pyrazinamide in Kazakhstan.