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Lineage 1 is the odd one out for pretomanid and pyrazinamide – implications for antimicrobial susceptibility testing and treatment

C U Köser(1) S Battaglia(2) M Chiacchiaretta(2) A Spitaleri(2) V Stenback Gabro(3) J Werngren(4) M Mansjö(4) J E Posey(5) D M Cirillo(2) P Miotto(2) T Schön(3)

1:University of Cambridge; 2:IRCCS San Raffaele Scientific Institute; 3:Linköping University Hospital; 4:Public Health Agency of Sweden; 5:Centers for Disease Control and Prevention

The TB Alliance has shown that lineage 1 (L1) strains of the Mycobacterium tuberculosis complex (MTBC) have intrinsically elevated MICs to pretomanid (PMD) compared with lineages 2-7 (L2-7). Two recent studies have raised the possibility that L1 may also be intrinsically less susceptible to pyrazinamide (PZA). We reviewed categorical phenotypic antimicrobial susceptibility testing (pAST) results for PZA from a multicentre study and the Swedish national surveillance system, which we complemented by carrying out systematic PZA MIC testing of a phylogenetically diverse collection of 78 MTBC strains that lacked pncA resistance mutations. The phylogenetic relationship of the strains was also considered when analysing the data. We found that the PZA MICs of L1 strains (mode 64 mg/L; range 8-256 mg/L) were also significantly higher than for L2-7 strains (mode 16 mg/L; range 4-64 mg/L). As a result, the current PZA breakpoint of 100 mg/L divides the upper end of the L1 MIC distribution. Although some L1 strains exist at the upper end of the MIC distribution may have secondary mutations, it appears that up to approximately 10% of L1 strains without pncA resistance mutations test resistant at the current breakpoint because of the inherent technical variability in MIC testing, which explains why an initial resistant pAST result is usually not confirmed upon retesting. The current breakpoints for PMD and PZA must be re-evaluated taking pharmacokinetic/pharmacodynamic and clinical outcome data into consideration. Moreover, the phylogenetic diversity within MTBC has to be considered at early stages of drug development.

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