Difference in persistent tuberculosis bacteria between in vitro and sputum from patients: implications for...

Area of Science:

• Microbiology
• Pharmacokinetics
• Translational Science

Background:

• Tuberculosis (TB) treatment relies on accurate prediction of drug efficacy.
• In vitro studies often form the basis for predicting drug response in humans.
• Differences between in vitro and human physiology can impact treatment outcomes.

Purpose of the Study:

• To quantify persistent bacteria in sputum from TB patients compared to in vitro.
• To propose a model-based approach for translating in vitro to human drug response.
• To assess the impact of phenotypic differences on clinical trial simulations.

Main Methods:

• Sputum samples from 25 smear-positive TB patients were analyzed pre-chemotherapy.
• Bacterial quantification used colony forming unit (CFU) and most probable number (MPN) assays.
• Persistent bacteria were defined as the difference between MPN with Rpf supplementation and CFU.

Main Results:

• Persistent bacteria in sputum were 17% of in vitro levels, indicating phenotypic resistance differences.
• No significant difference was observed in multiplying bacterial subpopulations.
• Model-based simulations showed a 3-day delay in predicted treatment time if phenotypic differences were ignored.

Conclusions:

• Phenotypic differences exist between in vitro and human sputum bacterial populations prior to chemotherapy.
• These differences can affect the translation of preclinical data to human drug response.
• A model-based approach can account for these variations, improving translational efforts in TB drug development.