The pyrazinamide susceptibility breakpoint above which combination therapy fails

Abstract

ObjectivesTo identify the pyrazinamide MIC above which standard combination therapy fails.MethodsMICs of pyrazinamide were determined for Mycobacterium tuberculosis isolates, cultured from 58 patients in a previous randomized clinical trial in Cape Town, South Africa. The MICs were determined using BACTEC MGIT 960 for isolates that were collected before standard treatment with isoniazid, rifampicin, pyrazinamide and ethambutol commenced. Weekly sputum collections were subsequently made for 8 weeks in order to culture M. tuberculosis in Middlebrook broth medium. Classification and regression tree (CART) analysis was utilized to identify the pyrazinamide MIC predictive of sputum culture results at the end of pyrazinamide therapy. The machine learning-derived susceptibility breakpoints were then confirmed using standard association statistics that took into account confounders of 2 month sputum conversion.ResultsThe pyrazinamide MIC range was 12.5 to >100 mg/L for the isolates prior to therapy. The epidemiological 95% cut-off value was >100 mg/L. The 2 month sputum conversion rate in liquid cultures was 26% by stringent criteria and 48% by less stringent criteria. CART analysis identified an MIC breakpoint of 50 mg/L, above which patients had poor sputum conversion rates. The relative risk of poor sputum conversion was 1.5 (95% CI: 1.2–1.8) for an MIC >50 mg/L compared with an MIC ≤50 mg/L.ConclusionsWe propose a pyrazinamide susceptibility breakpoint of 50 mg/L for clinical decision making and for development of rapid susceptibility assays. This breakpoint is identical to that identified using computer-aided simulations of hollow fibre system output.

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…Confirmation of these lower critical concentrations have come from clinical studies [209][210][211][212][213] and several investigations [214][215][216][217][218][219][220][221] of drug resistance-associated mutations in isolates with MICs below the standard breakpoint. Clinical studies using assumption-free methods such as machine learning have confirmed that these values (table 3) are in fact the MICs above which tuberculosis patients fail combination therapy.…”

“…208 The problem with this definition is logical and mathematical: what do the parameters of the Gaussian curve of the MIC distribution have to do with how well a patient will respond to therapy? 209 Wild-type MIC distributions of any organism vary between regions because of local evolutionary drivers, so it in unclear which to use. 210 The idea that all wild-type distributions are the same is assumed in general microbiology-but they aren't the same, and data show that M tuberculosis is no exception.…”

“…Clinical studies using assumption-free methods such as machine learning have confirmed that these values (table 3) are in fact the MICs above which tuberculosis patients fail combination therapy. 209,212,213 As an example, on the basis of an analysis of 207 patients with MDR tuberculosis in China, Zheng and colleagues 213 identified the same proposed susceptibility breakpoint for pyrazinamide as the pharmacokinetic-pharmaco dynamic break point (table 3), and calculated a sensitivity of 89% and a specificity of 93% for treatment success. Thus, the proposed breakpoints are relevant in terms of patient outcomes.…”

Mycobacterium tuberculosis pncA Polymorphisms That Do Not Confer Pyrazinamide Resistance at a Breakpoint Concentration of 100 Micrograms per Milliliter in MGIT

“…In a recent report, an MIC of Ͼ50 g/ml and Ͻ100 g/ml was associated with a poor 2 month sputum conversion (relative risk of 1.5 [95% confidence interval, 1.2 to 1.8]) compared with that of an MIC of Յ50 g/ml (23). Accordingly, the authors concluded that a PZA susceptibility breakpoint of ϳ50 g/ml should be used for clinical decision making.…”

“…Accordingly, the authors concluded that a PZA susceptibility breakpoint of ϳ50 g/ml should be used for clinical decision making. However, one cannot exclude other factors that may have contributed to the observed delayed treatment response (23).…”