ArticleClinical infectious diseases : an official publication of the Infectious Diseases Society of America2016
Drug Concentration Thresholds Predictive of Therapy Failure and Death in Children With Tuberculosis: Bread Crumb Trails in Random Forests.
Article in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 84 papers, 2 of them syntheses that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
84 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Effectiveness and Pharmacokinetic Exposures of First-Line Drugs Used to Treat Drug-Susceptible Tuberculosis in Children: A Systematic Review and Meta-Analysis.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2023Pooled it
- Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis.The European respiratory journal · 2023Pooled it
- Effect of HIV on bedaquiline and delamanid pharmacokinetics in patients with multidrug-resistant TB.The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease · 2025Trial
- Artificial intelligence-derived 3-Way Concentration-dependent Antagonism of Gatifloxacin, Pyrazinamide, and Rifampicin During Treatment of Pulmonary Tuberculosis.Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2018Trial
- Evaluation of the Adequacy of WHO Revised Dosages of the First-Line Antituberculosis Drugs in Children with Tuberculosis Using Population Pharmacokinetic Modeling and Simulations.Antimicrobial agents and chemotherapy · 2018Trial
- Quality assurance of rifampicin-containing fixed-drug combinations in South Africa: dosing implications.The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease · 2018Trial
- Supervised Machine-Learning Reveals That Old and Obese People Achieve Low Dapsone Concentrations.CPT: pharmacometrics & systems pharmacology · 2017Trial
- Fractal Geometry-Based Decrease in Trimethoprim-Sulfamethoxazole Concentrations in Overweight and Obese People.CPT: pharmacometrics & systems pharmacology · 2016Trial
- Population pharmacokinetics of pyrazinamide and ethambutol in children with tuberculosis with or without HIV.Antimicrobial agents and chemotherapy · 2026Article
- Eravacycline pharmacokinetics/pharmacodynamics in the hollow fiber system model ofMicrobiology spectrum · 2026Article
- Tuberculosis treatment failure: what are the risk factors? A comprehensive literature review.Multidisciplinary respiratory medicine · 2025Article
- Examining effective monotherapy hypothesis for TB therapy failure and resistance emergence.The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease · 2024Article
- The impact of alcohol and illicit substance use on the pharmacokinetics of first-line TB drugs.The Journal of antimicrobial chemotherapy · 2024Article
- Clinical applications of artificial intelligence in identification and management of bacterial infection: Systematic review and meta-analysis.Saudi journal of biological sciences · 2024Review
- Model-Informed Precision Dosing of Isoniazid: Parametric Population Pharmacokinetics Model Repository.Drug design, development and therapy · 2024Article
- Push forward LC-MS-based therapeutic drug monitoring and pharmacometabolomics for anti-tuberculosis precision dosing and comprehensive clinical management.Journal of pharmaceutical analysis · 2024Review
- Meropenem-vaborbactam restoration of first-line drug efficacy and comparison of meropenem-vaborbactam-moxifloxacin versus BPaL MDR-TB regimen.International journal of antimicrobial agents · 2023Article
- Low rifampicin levels in plasma associated with a poor clinical response in patients with abdominal TB.The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease · 2023Article
- Rifampin urinary excretion to predict serum targets in children with tuberculosis: a prospective diagnostic accuracy study.Archives of disease in childhood · 2023Article
- Estimating the prevalence of poor-quality anti-TB medicines: a neglected risk for global TB control and resistance.BMJ global health · 2023Article
24 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
backgroundThe role of drug concentrations in clinical outcomes in children with tuberculosis is unclear. Target concentrations for dose optimization are unknown.
methodsPlasma 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.
resultsAmong 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).
conclusionsWe have identified new antibiotic target concentrations, which are potential biomarkers associated with treatment failure and death in children with tuberculosis.
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