Drug Concentration Thresholds Predictive of Therapy Failure and Death in Children With Tuberculosis: Bread Crumb Trails in Random Forests

Abstract

Background. The role of drug concentrations in clinical outcomes in children with tuberculosis is unclear. Target concentrations for dose optimization are unknown.Methods. Plasma drug concentrations measured in Indian children with tuberculosis were modeled using compartmental pharmacokinetic analyses. The children were followed until end of therapy to ascertain therapy failure or death. An ensemble of artificial intelligence algorithms, including random forests, was used to identify predictors of clinical outcome from among 30 clinical, laboratory, and pharmacokinetic variables.Results. Among the 143 children with known outcomes, there was high between-child variability of isoniazid, rifampin, and pyrazinamide concentrations: 110 (77%) completed therapy, 24 (17%) failed therapy, and 9 (6%) died. The main predictors of therapy failure or death were a pyrazinamide peak concentration <38.10 mg/L and rifampin peak concentration <3.01 mg/L. The relative risk of these poor outcomes below these peak concentration thresholds was 3.64 (95% confidence interval [CI], 2.28–5.83). Isoniazid had concentration-dependent antagonism with rifampin and pyrazinamide, with an adjusted odds ratio for therapy failure of 3.00 (95% CI, 2.08–4.33) in antagonism concentration range. In regard to death alone as an outcome, the same drug concentrations, plus z scores (indicators of malnutrition), and age <3 years, were highly ranked predictors. In children <3 years old, isoniazid 0- to 24-hour area under the concentration-time curve <11.95 mg/L × hour and/or rifampin peak <3.10 mg/L were the best predictors of therapy failure, with relative risk of 3.43 (95% CI, .99–11.82).Conclusions. We have identified new antibiotic target concentrations, which are potential biomarkers associated with treatment failure and death in children with tuberculosis.

Concentration-Dependent Antagonism and Culture Conversion in Pulmonary Tuberculosis

“…Similarly, Swaminathan et al [34] showed in Indian children with pyrazinamide C max ≤38.10 and rifampin C max ≤6.20 mg/L, isoniazid AUC 0–24 >31.80 mg × hour/L led to higher proportions of children with poor outcomes. Supplementary Figure 1 shows the percentage of culture conversion stratified by AUC 0–24 /MIC quartile for isoniazid, rifampicin, and pyrazinamide.…”

Sterilizing Effect of Ertapenem-Clavulanate in a Hollow-Fiber Model of Tuberculosis and Implications on Clinical Dosing

“…In TB patients, pharmacokinetic variability is one of the most important drivers of sterilizing effect (23)(24)(25)(26)(27)(28)(29). Therefore, in order to identify the optimal ertapenem dose for pulmonary TB, we performed Monte Carlo simulations of 10,000 patients with pulmonary TB, using the pharmacokinetic parameter estimates and between-patient variability indices shown in Table 2 based on previous studies (30)(31)(32).…”

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

“…The pharmacokinetic parameters for standard first-line drugs and for drugs used in both MDR and XDR tuberculosis are shown in table 9, mainly based on publications from South Africa, India, and the USA. [404][405][406][407][408][409][410][411][412][413][414][415][416] Predicting what concentration a patient will achieve is difficult, given the multiple determinants of pharmacokinetic variability. 191 Therefore, to identify the specific concentration-time profile, the drug concentrations should be measured in the patient directly.…”