Using Mycobacterium tuberculosis Single-Nucleotide Polymorphisms To Predict Fluoroquinolone Treatment Response

Area of Science:

• Microbiology
• Pharmacology
• Genetics

Background:

• Current fluoroquinolone susceptibility testing for Mycobacterium tuberculosis relies on a single critical concentration, offering limited clinical insight.
• There is a need for more precise methods to guide fluoroquinolone treatment decisions in tuberculosis.

Purpose of the Study:

• To develop a novel method using gyrA mutations and pharmacokinetic/pharmacodynamic (PK/PD) modeling to predict fluoroquinolone resistance in Mycobacterium tuberculosis.
• To inform fluoroquinolone dosing strategies based on predicted resistance levels.

Main Methods:

• Sequencing of the gyrA resistance-determining region in 138 clinical Mycobacterium tuberculosis isolates.
• Determination of Minimum Inhibitory Concentrations (MICs) against four fluoroquinolones (ofloxacin, moxifloxacin, levofloxacin, gatifloxacin).
• Grouping strains by gyrA single-nucleotide polymorphisms (SNPs) into high or low resistance categories and applying population PK/PD modeling.

Main Results:

• Specific gyrA SNPs correlated with empirically measured MICs, allowing prediction of drug resistance phenotypes.
• Modeling suggested that increased dosing of gatifloxacin and moxifloxacin could improve therapeutic target attainment in low-level resistance cases.
• Increased fluoroquinolone dosing did not significantly improve therapeutic target attainment in high-level resistance cases.

Conclusions:

• Quantifiable fluoroquinolone resistance phenotypes can be predicted from readily detectable gyrA SNPs.
• This SNP-based approach can support optimized fluoroquinolone dosing decisions for tuberculosis treatment.
• Findings support the recently established WHO clinical breakpoint for moxifloxacin.