Drug Exposure and Susceptibility of Pyrazinamide Correlate with Treatment Response in Pyrazinamide-Susceptible Patients with Multidrug-Resistant Tuberculosis

Abstract

Exploring the influence of pyrazinamide exposure and susceptibility on treatment response is crucial for optimizing the management of multidrug-resistant tuberculosis (MDR-TB). This study aimed to investigate the association between pyrazinamide exposure, susceptibility, and response to MDR-TB treatment, as well as find clinical thresholds for pyrazinamide. A prospective multi-center cohort study of participants with MDR-TB using pyrazinamide was conducted in three TB-designated hospitals in China. Univariate and multivariate analyses were applied to investigate the associations. Classification and Regression Tree (CART) analysis was used to identify clinical thresholds, which were further evaluated by multivariate analysis and receiver operating characteristic (ROC) curves. The study included 143 patients with MDR-TB. The exposure/susceptibility ratio of pyrazinamide was associated with two-month culture conversion (adjusted risk ratio (aRR), 1.1; 95% confidence interval (CI), 1.07-1.20), six-month culture conversion (aRR, 1.1; 95% CI, 1.06-1.16), treatment success (aRR, 1.07; 95% CI, 1.03-1.10), as well as culture conversion time (adjusted hazard ratio (aHR) 1.18; 95% CI,1.14-1.23). The threshold for optimal improvement in sputum culture results at the sixth month of treatment was determined to be a pyrazinamide AUC_0-24h/MIC ratio of 7.8. In conclusion, the exposure/susceptibility ratio of pyrazinamide is associated with the treatment response of MDR-TB, which may change in different Group A drug-based regimens.

Keywords: minimum inhibitory concentration; multidrug-resistant tuberculosis; pharmacokinetics; pyrazinamide; treatment outcome.

Figure 1

The enrolment process of participants with multidrug-resistant tuberculosis. MDR-TB: Multidrug-Resistant Tuberculosis; HIV: Human Immunodeficiency Virus.

Figure 2

The distribution of MIC (A), AUC_0–24h (B), and AUC_0–24h/MIC ratio (C) of pyrazinamide in participants with multidrug-resistant tuberculosis.

Figure 3

Treatment responses in participants with multidrug-resistant tuberculosis receiving different Group A drug-based regimes.

Figure 4

The distribution of MIC (A), AUC_0–24h, (B,D), and AUC_0–24h/MIC ratio (C,E) of pyrazinamide with different treatment responses in patients with multidrug-resistant tuberculosis. MFX: moxifloxacin; LZD: linezolid; BDQ: bedaquiline.

Figure 5

Time to culture conversion among patients with multidrug-resistant tuberculosis grouped by MIC levels, AUC_0–24h, and AUC_0–24h/MIC ratio quartiles of pyrazinamide. First quartile: 25% of smallest numbers; Second quartile: between 25.1% and 50%; Third quartile: 50.1% to 75%; Fourth quartile: 25% of the largest numbers. Dotted line: median survival time at which 50% of the participants had still not achieved sputum culture conversion.

Figure 6

Random forest and Classification and Regression Tree (CART) analysis for two-month sputum culture results (A), six-month sputum culture results (B), and treatment outcome (C).

Figure 7

Time to culture conversion in patients with multidrug-resistant tuberculosis grouped by CART-derived thresholds of pyrazinamide AUC_0–24h/MIC. MFX: moxifloxacin; LZD: linezolid; BDQ: bedaquiline. Dotted line: median survival time at which 50% of participants did not achieve sputum culture conversion.

Figure 8

ROC curves for different thresholds to treatment responses with all patients with MDR-TB. ROC: receiver operating characteristic; AUC: the area under the receiver operating characteristic (ROC) curves.