The Role of Fluoroquinolones in the Treatment of Tuberculosis in 2019

Abstract

The inability to use powerful antituberculosis drugs in an increasing number of patients seems to be the biggest threat towards global tuberculosis (TB) elimination. Simplified, shorter and preferably less toxic drug regimens are being investigated for pulmonary TB to counteract emergence of drug resistance. Intensified regimens with high-dose anti-TB drugs during the first weeks of treatment are being investigated for TB meningitis to increase the survival rate among these patients. Moxifloxacin, gatifloxacin and levofloxacin are seen as core agents in case of resistance or intolerance against first-line anti-TB drugs. However, based on their pharmacokinetics (PK) and pharmacodynamics (PD), these drugs are also promising for TB meningitis and might perhaps have the potential to shorten pulmonary TB treatment if dosing could be optimized. We prepared a comprehensive summary of clinical trials investigating the outcome of TB regimens based on moxifloxacin, gatifloxacin and levofloxacin in recent years. In the majority of clinical trials, treatment success was not in favour of these drugs compared to standard regimens. By discussing these results, we propose that incorporation of extended PK/PD analysis into the armamentarium of drug-development tools is needed to clarify the role of moxifloxacin, gatifloxacin and levofloxacin for TB, using the right dose. In addition, to prevent failure of treatment or emergence of drug-resistance, PK and PD variability advocates for concentration-guided dosing in patients at risk for too low a drug-exposure.

Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline

“…“Target” ranges for the injectable drugs and cycloserine have been proposed, and research continues on refining these. Fluoroquinolones display concentration-dependent efficacy, and higher doses of moxifloxacin and levofloxacin are being studied (174, 248). Currently, avoiding low serum concentrations seems advisable.…”

A multi-scale pipeline linking drug transcriptomics with pharmacokinetics predicts in vivo interactions of tuberculosis drugs

“…Recent phase III clinical trials have investigated the impact of introducing fluoroquinolones into treatment regimens to treat drug-susceptible TB, some with the additional intent of shortening treatment time from six months to four. Many of these trials have failed to show improvement in TB treatment, and often led to higher rates of unfavorable outcomes at the trial's endpoints [36][37][38] . These trends are reflected in our analysis of the drug interactions for various drug combinations.…”

“…Simulated regimen rankings were ranked by average sterilization time, FIC, and average iDIS for non-replicating Mtb. Further, we compared our predicted treatment sterilization times for fluoroquinolone-containing regimens with clinical endpoints (up to 6 months) from recent phase III clinical trials that include fluoroquinolones for treating drug-susceptible TB [36][37][38] .…”

Cinnamic Derivatives as Antitubercular Agents: Characterization by Quantitative Structure–Activity Relationship Studies

“…One of the approaches being used for this purpose is the identification of new therapeutic uses (repurposing) for molecules that were already approved to treat a specific disease or were previously synthesized but were not found to have a clinical application [6]. This is the case of the fluoroquinolones gatifloxacin and moxifloxacin, marketed in 1999 for the treatment of respiratory tract infections, and which are presently the most valuable second-line anti-TB agents according to the WHO guidelines [7].…”