Redefining multidrug-resistant tuberculosis based on clinical response to combination therapy

Area of Science:

• Pharmacology
• Infectious Diseases
• Clinical Microbiology

Background:

• Current tuberculosis drug susceptibility testing relies on epidemiologic cutoff methods.
• Established breakpoints for rifampin (1.0 mg/liter) and isoniazid (0.2 or 1.0 mg/liter) may not optimize clinical outcomes.
• Pharmacokinetics-pharmacodynamics (PK-PD) simulations suggest lower, more clinically relevant breakpoints.

Purpose of the Study:

• To evaluate the clinical utility of revised rifampin and isoniazid minimum inhibitory concentration (MIC) cutoffs.
• To determine if MIC values improve prediction of treatment outcomes in tuberculosis patients.
• To compare MIC-based cutoffs with existing epidemiologic cutoffs and PK-PD derived breakpoints.

Main Methods:

• Prospective cohort study of 36 patients with drug-susceptible tuberculosis in Western Cape, South Africa.
• Measurement of minimum inhibitory concentrations (MICs) for rifampin and isoniazid.
• Assessment of plasma drug concentrations and 2-year clinical outcomes, including sputum conversion, failure, relapse, and death.
• Classification and regression tree analysis to identify predictive factors for treatment success.

Main Results:

• Peak drug concentrations and area under the concentration-time curve were primary predictors of outcomes.
• Rifampin MICs improved predictive capacity by 20%; isoniazid MICs improved it by 17%.
• Therapy failure occurred with rifampin MICs >0.125 mg/liter and isoniazid MICs >0.0312 mg/liter, aligning with PK-PD simulations.

Conclusions:

• Revised MIC breakpoints for rifampin and isoniazid demonstrate better correlation with clinical outcomes than current epidemiologic cutoffs.
• Incorporating MIC values into susceptibility testing can enhance prediction of tuberculosis treatment success.
• Clinical decision-making for multidrug resistance should consider patient outcomes and pharmacodynamic principles.