Fluoroquinolones, the Cornerstone of Treatment of Drug-Resistant Tuberculosis: A Pharmacokinetic and Pharmacodynamic Approach

A.      D. Pranger; J.      W.C. Alffenaar; R.      E. Aarnoutse

doi:10.2174/138161211797470200

Abstract

Fluoroquinolones (FQs) are important drugs to treat drug-resistant tuberculosis. In this review we integrated pharmacokinetic properties (PK) and microbiological susceptibility against M. tuberculosis and eventually evaluated the pharmcodynamic (PD) properties, as well as the influence of co-administered agents on these characteristics, for the currently used FQs (ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin and moxifloxacin) in TB treatment. Future FQs that are being developed may overcome the problems with FQs that are used in daily practice. Therefore PK and pharmacodynamic (PD) properties of novel FQs (clinafloxacin, garenoxacin, lomefloxacin, sitafloxacin, sparfloxacin, trovafloxacin, gemifloxacin, grepafloxacin and DC-159a) were evaluated in TB treatment as well. Integrating both excellent PK and PD properties, moxifloxacin, possibly at a higher dosage, may fulfil a far more important role in the treatment of multi-drug and early-generation FQ resistant TB than proposed in the current WHO guideline. Sparfloxacin, trovafloxacin and sitafloxacin are upcoming novel FQs that may be useful for drug-resistant TB based on their favourable PK properties or microbiological susceptibility against M. tuberculosis. Finally, the 8-methoxy moiety, as present in the chemical structure of MFX, will possibly provide DC- 159a with promising PK/PD characteristics and consequently this FQ may develop into a key FQ in future drug resistant TB treatment.

Keywords: Fluoroquinolones, drug-resistant tuberculosis, pharmacokinetics, pharmacodynamics, drug-drug interactions, M. tuberculosis, cerebrospinal fluid (CSF), DNA gyrase, biotransformation, HIV infection