Safety Concerns with Fluoroquinolones

A 4-month regimen of gatifloxacin with rifampin, isoniazid, and pyrazinamide is being evaluated for the treatment of tuberculosis in a phase 3 randomized controlled trial (OFLOTUB). A prior single-dose study found that gatifloxacin exposure increased by 14% in the combination. The aims of the study are to evaluate the initial and steady-state pharmacokinetics of gatifloxacin when daily doses are given to patients with newly diagnosed drug-sensitive pulmonary tuberculosis as part of a combination regimen and to evaluate the gatifloxacin dose with respect to the probability of attaining a pharmacokinetic/pharmacodynamic target. We describe the population pharmacokinetics of gatifloxacin from the first dose to a median of 28 days in 169 adults enrolled in the OFLOTUB trial in Benin, Guinea, Senegal, and South Africa. The probability of achieving a ratio of >125 for the area under the concentration time curve to infinity (AUC 0 -ؕ ) for the free fraction of gatifloxacin over the MIC (fAUC/MIC) was investigated using Monte Carlo simulations. The median AUC 0 -ؕ of 41.2 g · h/ml decreased on average by 14.3% (90% confidence interval [CI], ؊90.5% to ؉61.5%) following multiple 400-mg daily doses. At steady state, 90% of patients achieved an fAUC/MIC of >125 only when the MIC was <0.125 g/ml. We conclude that systemic exposure to gatifloxacin declines with repeated daily 400-mg doses when used together with rifampin, isoniazid, and pyrazinamide, thus compensating for any initial increase in gatifloxacin levels due to a drug interaction. (The OFLOTUB study has been registered at ClinicalTrials.gov under registration no. NCT00216385.) F luoroquinolones represent a promising class of drug for the treatment of tuberculosis. Gatifloxacin distributes widely throughout the body (1), achieving MICs for Mycobacterium tuberculosis observed in vitro of 0.031 to 0.5 g/ml (2, 3, 4), and demonstrates strong bactericidal activity in the mouse model (2, 5). Furthermore, gatifloxacin displays excellent early bactericidal activity (EBA), only slightly lower than that of isoniazid (6); replacing ethambutol with gatifloxacin in the standard first-line regimen resulted in accelerated killing of M. tuberculosis in the sputum of patients with pulmonary tuberculosis (7). A single-dose crossover study in healthy volunteers showed a reduction in the elimination rate of gatifloxacin resulting in a 14% increase in the area under the concentration time curve to infinity (AUC 0 -ϱ ) when it was given together with rifampin, isoniazid, and pyrazinamide (8). Reports of dysglycemia related to the use of gatifloxacin in elderly patients with renal insufficiency (9, 10, 11, 12) have raised concerns that pharmacokinetic interactions may lead to an increased risk of toxicity related to higher gatifloxacin exposure. On the other hand, in vitro and in vivo studies suggest a target ratio of Ն125 for the free drug area under the concentration versus time curve to MIC (fAUC/MIC) for maximal bactericidal effect and prevention of resistance to fluoroquinolones (13...

Abstract:Completing its initial phases of drug development in the mid 1990s as the one of the fi rst fl uoroquinolones that could be used with confi dence to treat respiratory tract infections, levofl oxacin went on to become one of the most widely prescribed antibiotics in the world. Available in both oral (po) and intravenous (IV) formulations and with characteristics of over 90% bioavailability, distribution into both extracellular and intracellular pulmonary compartments, highly predictable pharmacokinetics with over 90% of the drug being excreted unchanged in urine, and reliable activity against a broad spectrum of clinically important pathogens, levofl oxacin has been used successfully to treat patients with a variety of serious infectious diseases as well as common infections most often treated outside of the hospital setting. Results of clinical trials involving patients with respiratory tract, urinary tract, and skin infections have consistently shown rates of clinical success and bacteriological eradication that were comparable to other widely used broad-spectrum agents. Regimens of levofl oxacin, initially involving total daily doses of 250 mg to 500 mg, but more recently regimens involving 750 mg doses, have been shown to be safe and effective. Nearly a decade and a half of clinical experience has defi ned a safety and tolerability profi le that permits data-driven assessment of the risks and benefi ts of using levofl oxacin. As resistance to currently available fl uoroquinolones has emerged, the clinical value of levofl oxacin deserves continued evaluation. However, consistently high rates of susceptibility of clinically important bacteria, especially among those bacteria that commonly cause respiratory tract infections, such as Streptococcus pneumoniae and Haemophilus infl uenzae, suggest that this agent will continue to be a widely used well past the 20-year anniversary of its introduction into the antibacterial armamentarium.

Fluoroquinolones are substantially safe antibiotics. Although fluoroquinolone-related hepatic injury occurs infrequently, its consequences can be severe. Patients should also be cautioned to avoid re-exposure to other members of the fluoroquinolone class.