Adverse reactions in a dose-ranging study with a new long-acting fluoroquinolone, fleroxacin

Abstract

New fluoroquinolones have generally been well tolerated. In a double-blind evaluation of oral fleroxacin, using 400, 600, or 800 mg once daily for 7 days in an ambulatory setting for treatment of uncomplicated genital infections, we encountered unexpectedly high rates of adverse reactions. The objective of this analysis was to determine whether any factors in addition to dose could be found to account for our observations. Adverse Fluoroquinolones have generally been considered to be relatively safe antimicrobial agents (7, 9). The most frequently reported adverse reactions were gastrointestinal (2.9 to 5.6%), central nervous system (0.9 to 1.7%), and skin (0.4 to 2.2%) reactions, with overall rates of adverse reactions of 4 to 8% (7). Reactions were reversible, not dose dependent, and similar among different fluoroquinolones (7).Our own experience with norfloxacin in a sexually transmitted disease clinic setting was very favorable (3). However, not all quinolones have been well tolerated, and adverse reactions have prevented marketing of some (8,12). In a double-blind clinical trial of fleroxacin, using 400, 600, and 800 mg once daily for 7 days, adverse reactions were dose related, frequent at higher doses, and often reported by the patient as being severe. Especially frequent or troublesome were insomnia, bad dreams or nightmares, and photosensitivity reactions resulting in desquamation. Consequently, in this study we attempted to ascertain what factors might have accounted for our observations. MATERIALS AND METHODSStudy population and protocol. Men and women 18 years of age and older who presented to the Vancouver and Calgary Sexually Transmitted Disease Clinics were eligible for the study. Entrance criteria and study design are described in our companion paper (4). At the initial visit, individuals completed a detailed questionnaire about symptoms, sexual history, prior use of antimicrobial agents, use of other medications (prescribed, over the counter, and recreational), and exclusion criteria. After the initial evaluation, all were then given medication to be taken with or immediately after meals at a similar time each day. All took * Corresponding author.four identical tablets daily, of which two, three, or four contained active medication. Thus, they received 400, 600, or 800 mg daily for 7 days. The patients and the investigators were blind as to the regimen received.Subjects were specifically warned not to use antacids.They were also warned that caffeine might interact unfavorably with fleroxacin. In the last two-thirds of the study, they were urged to avoid sun exposure or else to take more precautions than usual, including use of sunscreens, long sleeves, and hats.

A quantitative in vitro determination of relative phototoxic potential of quinolone antibiotics

“…Subsequently, in the mid-1980's, new fluoroquinolones with improved antibacterial activity and pharmacokinetic parameters were introduced. All these compounds showed varying degrees of phototoxicity and the incidence rates ranged from less than 2.4% for ciprofloxacin (16) to 10-15% for fleroxacin (16,17). There have been many reports on incidence of quinolone phototoxicities in humans: temafloxacin, 0.1% (18); lomefloxacin, 2.4% (19); and sparfloxacin, 1.9% (20).…”

“…In fact, drug-induced phototoxic reactions due to nalidixic acid, a classic prototype quinolone compound, began appearing in the literature soon after its release for human use in the early 1960's (13, 14,15). Since then, essentially every other quinolone in clinical use has been implicated in similar adverse reactions, and the reported incidence of photosensitivity reactions of quinolones ranges from less than 2.4% for ciprofloxacin (16) to as high as 10-15% for a high dose fleroxacin regimen (16,17).…”

Respiratory medications and sleep

“…Macrolide antibiotics, which are used in respiratory disease to treat infections and for their anti-inflammatory effect, have also been reported to cause sleep disturbances. There is a case report of erythromycin as a cause of nightmares [78]. Two cases of hypersomnia secondary to clarithromycin have also been reported [79].…”

“…Ciprofloxacin has been reported to cause nightmares [77]. Fleroxacin, which is no longer on the market in the United States, was also reported to frequently cause insomnia [78]. Macrolide antibiotics, which are used in respiratory disease to treat infections and for their anti-inflammatory effect, have also been reported to cause sleep disturbances.…”

Dose-ranging study of fleroxacin for treatment of uncomplicated Chlamydia trachomatis genital infections

“…Especially frequent or troublesome were sleep disturbances and photosensitivity reactions. Adverse reactions are described in more detail in a companion report (5). (10).…”