Abstract
Pyrazinamide (PZA) is a key antibiotic in current anti-tuberculosis regimens. Although the WHO has stressed the urgent need to obtain data on PZA resistance, in high tuberculosis burden countries, little is known about the level of PZA resistance, the genetic basis of such resistance or its link with Mycobacterium tuberculosis families. In this context, this study assessed PZA resistance through the molecular analysis of 260 Vietnamese M. tuberculosis isolates. First-line drug susceptibility testing, pncA gene sequencing, spoligotyping and mycobacterial interspersed repetitive units-variable number of tandem repeats (MIRU-VNTR) typing were performed. Overall, the pncA mutation frequency was 38.1% (99 out of 260 isolates) but was higher than 72% (89 out of 123 isolates) in multidrug and quadruple-drug resistant isolates. Many different pncA mutations (71 types) were detected, of which 55 have been previously described and 50 were linked to PZA resistance. Among the 16 novel mutations, 14 are likely to be linked to PZA resistance because of their mutation types or codon positions. Genotype analysis revealed that PZA resistance can emerge in any M. tuberculosis cluster or family, although the mutation frequency was the highest in Beijing family isolates (47.7%, 62 out of 130 isolates). These data highlight the high rate of PZA resistance-associated mutations in M. tuberculosis clinical isolates in Vietnam and bring into question the use of PZA for current and future treatment regimens of multidrug-resistant tuberculosis without PZA resistance testing.Emerging Microbes & Infections (2017) 6, e86; doi:10.1038/emi.2017.73; published online 11 October 2017
Highlights
As the objective of this study was to evaluate the risk of PZA resistance in sensitive and drug-resistant M. tuberculosis, isolates were chosen according to the first-line drug (FLD) susceptibility patterns and M. tuberculosis families (Table 1)
FLD susceptibility testing and genotyping Among the 260 M. tuberculosis isolates selected for this study, 55 were susceptible and 205 were resistant to at least one FLD (Table 1)
High diversity and frequency of pncA mutations in clinical M. tuberculosis isolates in Vietnam Our molecular analysis indicates that 38.1% of the clinical M. tuberculosis isolates selected in this study carry mutations in the pncA gene or its promoter
Summary
Pyrazinamide (PZA) is a crucial first-line drug (FLD) for tuberculosis (TB) treatment because it shortens the treatment duration in patients with susceptible, multidrug-resistant (MDR, isolates resistant to at least isoniazid and rifampicin) or extensively drug-resistant (XDR, MDR isolates resistant to any fluoroquinolone and at least one second-line injectable drug) TB and reduces TB relapse rates.. Culture-based PZA susceptibility testing is difficult to perform and produces unreliable results due to the need for an acidic pH medium that inhibits bacterial growth and for large inoculum volumes that might reduce PZA activity.. The automated Bactec MGIT 960 liquid culture system (Sparks, MD) is the only method recommended by the World Health Organization (WHO) for phenotypic-PZA susceptibility testing.. The automated Bactec MGIT 960 liquid culture system (Sparks, MD) is the only method recommended by the World Health Organization (WHO) for phenotypic-PZA susceptibility testing.5 This method is difficult to perform, and still produces a high rate of false-positive resistance results.
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