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ZAIA

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Background  The ongoing epidemic of multidrug-resistant tuberculosis (MDR-TB) in Georgia highlights the need for more effective control strategies. A new regimen to treat MDR-TB that includes pyrazinamide (PZA) is currently being evaluated and PZA resistance status will largely influence the success of current and future treatment strategies. PZA susceptibility testing was not routinely performed at the National Reference Laboratory (NRL) in Tbilisi between 2010 and September 2015. We here provide a first insight into the prevalence of PZA resistant TB in this region.    Methods  Phenotypic susceptibility to PZA was determined in a convenience collection of well-characterised TB patient isolates collected at the NRL in Tbilisi between 2012 and 2013. In addition, the  pncA  gene was sequenced and whole genome sequencing was performed on two isolates.    Results  Out of 57 isolates tested 33 (57.9%) showed phenotypic drug resistance to PZA and had a single  pncA  mutation. All of these 33 isolates were MDR-TB strains.  pncA  mutations were absent in all but one of the 24 PZA susceptible isolate. In total we found 18 polymorphisms in the  pncA  gene. From the two major MDR-TB clusters represented (94–32 and 100–32), 10 of 15, 67.0% and 13 of 14, 93.0% strains, respectively were PZA resistant. We also identified a member of the potentially highly transmissive clade A strain carrying the characteristic I6L substitution in PncA. Another strain with the same MLVA type as the clade A strain acquired a different mutation in  pncA  and was genetically more distantly related suggesting that different branches of this particular lineage have been introduced into this region.    Conclusion  In this high MDR-TB setting more than half of the tested MDR-TB isolates were resistant to PZA. As PZA is part of current and planned MDR-TB treatment regimens this is alarming and deserves the attention of health authorities. Based on our typing and sequence analysis results we conclude that PZA resistance is the result of primary transmission as well as acquisition within the patient and recommend prospective genotyping and PZA resistance testing in high MDR-TB settings. This is of utmost importance in order to preserve bacterial susceptibility to PZA to help protect (new) second line drugs in PZA containing regimens.

Pyrazinamide resistance-conferring mutations in pncA and the transmission of multidrug resistant TB in Georgia