Abstract
Pyrazinamide (PZA) is a key antituberculosis drug, yet no rapid susceptibility test is commercially available. PZA drug susceptibility testing (DST) was performed directly on sputum samples from 327 patients and compared with the indirect method by using the Bactec MGIT 960 system in the context of patient screening for participation in a drug trial. Compared to standard indirect PZA DST, direct DST was successful in only 59% of cases, but results obtained were highly accurate and available faster. Agreement between the direct and indirect methods varied from 90 to 100% in each laboratory. The median times for obtaining PZA results from the time when the specimen was collected ranged from 11 to 16 days for the direct test and 18 to 95 days for the indirect test across laboratories. The direct method is accurate and reproducible across laboratories. It can be expected to accelerate results in >50% of cases, but it cannot replace indirect DST for PZA. Phenotypic methods remain the gold standard for DST in drug trials. If future studies can optimize the method to decrease the number of uninterpretable results, direct MGIT DST could be the new phenotypic DST standard for clinical trials, providing more rapid detection of resistance to new drugs in experimental regimens.
Highlights
Pyrazinamide (PZA) is a key antituberculosis drug that has recently been shown to substantially enhance the activity of the novel agents bedaquiline (BDQ) and pretomanid (Pa) (PA-824) in murine models of TB [1,2,3] and phase II studies [4,5,6]
PZA susceptibility testing was performed on sputum samples from 327 patients: 398 tests were performed by the direct method, and 207 were performed by the indirect method (Table 1)
Compared to standard indirect PZA drug susceptibility testing (DST), direct DST was successful in 59% of cases
Summary
Pyrazinamide (PZA) is a key antituberculosis (anti-TB) drug that has recently been shown to substantially enhance the activity of the novel agents bedaquiline (BDQ) and pretomanid (Pa) (PA-824) in murine models of TB [1,2,3] and phase II studies [4,5,6]. Most reports cite problems of false PZA resistance detection with the MGIT 960 system, which is attributed to the inoculum concentration being too high [13] Another limitation of the phenotypic method is the long time to completion [15]. As an alternative to the indirect method, the test can be set up directly from the clinical specimen This eliminates the initial culture, speeding up the availability of test results, but such an abbreviated procedure can lead to invalid results due to culture contamination or insufficient growth if the inoculum contains too few viable bacteria [15, 16]. MGIT 960 liquid culture system (Becton Dickinson Diagnostic Systems, Sparks, MD) directly from sputum specimens is feasible and accurate and expedites the availability of PZA susceptibility results compared to the standard indirect method
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