Fleroxacin

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Abstract
The fluoroquinolone antibacterial agent fleroxacin has a broad spectrum of in vitro activity which encompasses most Gram-negative species (particularly Enterobacteriaceae) and a number of Gram-positive organisms, including methicillin-sensitive staphylococci. It is available as oral and intravenous formulations. In clinical trials, fleroxacin has been evaluated in the treatment of uncomplicated urinary tract infections (single or multiple once-daily oral doses of 200 or 400mg), gonorrhoea and chancroid (single oral doses of 200 or 400mg), complicated urinary tract, nonpneumococcal lower respiratory tract and skin and soft tissue infections and typhoid fever (multiple once-daily oral or intravenous regimens, usually 400 mg/day), bacterial enteritis, and traveller’s diarrhoea (single or multiple once-daily oral doses of 400mg). Bacteriological cure rates were generally around 90% or higher in complicated and uncomplicated urinary tract infections, uncomplicated gonorrhoea (≈100%), pyelonephritis, bacterial enteritis and typhoid fever, and exceeded 80% in lower respiratory tract, and skin and soft tissue infections and chancroid. These cure rates were similar to, or better than, those achieved with standard comparator antibacterial agents such as penicillins, cephalosporins, cotrimoxazole, or other quinolones. Fleroxacin 400mg once daily also achieved bacteriological cure in approximately 80% of patients with bone and joint infections in preliminary studies. In Japanese studies using a lower dosage of 200 or 300 mg/day, fleroxacin was reported to be bacteriologically effective in a range of infections, including urinary tract and upper and lower respiratory tract infections. Fleroxacin has a relatively long elimination half-life, which allows once-daily administration, and it appears to have less propensity for interactions with other medications in comparison to many other fluoroquinolones. Its tolerability profile is typical of this class of compound, with adverse events mostly relating to the gastrointestinal tract, CNS, and skin and appendages (including phototoxicity). Recent pooled tolerability data from worldwide clinical trials indicate that adverse events are reported by approximately 27% of patients receiving 200 mg/day orally or 400 mg/day orally or intravenously, and 17% of those receiving a single oral dose of 400mg. These exceed incidences reported for established fluoroquinolones, possibly indicating recent trends towards increased rates of reported adverse effects with these agents. However, in direct comparative studies with twice-daily fluoroquinolones, fleroxacin 400mg once daily produced a similar incidence of adverse effects to ofloxacin 800 mg/day and a slightly higher incidence than ciprofloxacin 1000 mg/day, while fleroxacin 200mg once daily produced a similar incidence to norfloxacin 800 mg/day. Fleroxacin may provide an alternative to other fluoroquinolones for the treatment of a variety of infections, offering a once-daily dosage regimen and a relative lack of clinically significant drug interactions. The efficacy of fleroxacin is established in urinary tract infections and gonorrhoea, but clinical experience with this compound is limited in other infections, particularly bone and joint infections, typhoid fever and chancroid. Postmarketing studies will further clarify the efficacy and tolerability of fleroxacin in routine clinical settings. Fleroxacin is a trifluoroquinolone antibacterial agent available for oral or intravenous use. In common with other quinolone antibacterials, its primary mechanism of action appears to be inhibition of bacterial DNA gyrase (a topoisomerase II enzyme), which disrupts bacterial DNA replication. As with other fluoroquinolones, its spectrum of activity encompasses most Gram-negative bacteria, including Acinetobacter, Aeromonas, Bordetella, Campylobacter, Citrobacter, Enterobacter, Haemophilus, Klebsiella, Legionella, Neisseria, Proteus, Providencia, Salmonella, and Shigella spp., Escherichia coli, Morganella morganii, Serratia marcescens, Vibrio cholerae and Yersinia enterocolitica. Pseudomonas aeruginosa strains are generally moderately susceptible or resistant. Fleroxacin has poor activity against streptococci and enterococci, but is active against methicillin-sensitive S. aureus and coagulase-negative staphylococci. Other susceptible, or moderately susceptible, Grampositive bacteria include Corynebacterium jeikeium and some mycobacterial species. The activity of fleroxacin against most of these organisms was broadly comparable to that of ofloxacin, and less than that of ciprofloxacin. However, it should be noted that ciprofloxacin has a lower susceptibility breakpoint than either fleroxacin or ofloxacin (1 vs 2 mg/L). The activity of fleroxacin was decreased in urine and acidic media, by addition of Mg++or Ca++ to the growth medium, and by increasing the size of the inoculum. Fleroxacin is bactericidal at concentrations equal to, or within 2 dilutions of, the minimum inhibitory concentration (MIC) against most susceptible organisms, and exerts a postantibiotic effect against Gram-positive and Gram-negative bacteria in vitro. As with other fluoroquinolones, development of resistance to fleroxacin has been found to occur in several bacterial species during administration of the drug in clinical and preclinical studies. Cross-resistance between fleroxacin and other fluoroquinolones has been confirmed. As with other fluoroquinolones, fleroxacin was found to markedly suppress Enterobacteriaceae in the gastrointestinal tract, but did not affect anaerobic flora or faecal streptococci. Fleroxacin did not demonstrate any mutagenic effects in mammalian cells in vitro, and only produced cytotoxic effects or inhibited mammalian topoisomerases at very high concentrations (> 100 times MIC against susceptible bacteria). As with other quinolones, fleroxacin has been found in animal toxicology studies to induce articular cartilage damage in young animals, and adverse effects on male reproductive function. It also has photosensitising effects. In preliminary animal studies, fleroxacin appeared to have less propensity than ciprofloxacin and several other fluoroquinolones for inducing convulsions at high doses. Following oral administration of fleroxacin, absorption is almost complete and is not significantly affected by the presence of food or calcium-containing antacids. Maximum plasma fleroxacin concentrations generally occur within 1 to 2 hours, with a value of 2 to 3 and 4 to 7 mg/L following a 200 and 400mg dose, respectively. Mean peak and trough plasma fleroxacin concentrations of approximately 7 and 1 mg/L, respectively, were achieved by the third day of repeated administration of fleroxacin 400mg once daily. The oral and intravenous dosage forms are bioequivalent. Fleroxacin is not extensively bound to plasma proteins (approximately 23 to 50%) and has a high apparent volume of distribution (1.2 to 1.5 L/kg in healthy volunteers), reflecting its extensive extravascular penetration. Following oral administration, concentrations of fleroxacin similar to, or higher than, concomitant plasma concentrations were found in most human tissues and fluids, including urine (the major excretion route), bile, liver, bronchial mucosa, lung and palatine tonsil tissues, bone and synovial fluid, female reproductive tissue, testis, epididymis or prostatic tissue, seminal fluid, lymph and nasal secretions. Lower penetration (6 to 70% of plasma concentrations) of the drug occurred into brain and ocular lens tissue, saliva, tears, sweat, prostatic secretions, cerebrospinal fluid, aqueous humour, peritoneal dialysate and breast milk. Fleroxacin concentrations exceeded 1 mg/L at 24 hours following a 400mg dose in the majority of tissues and fluids sampled at this time point. The drug was concentrated 2- to 4-fold within polymorphonuclear neutrophils in vitro. Fleroxacin and its metabolites are eliminated primarily (approximately 60 to 70%) by the renal route, and the plasma elimination half-life of fleroxacin is approximately 9 to 15 hours in healthy volunteers. Pharmacokinetic studies identified age, creatinine clearance, gender, body-weight and chronic heart failure as factors which influence fleroxacin disposition. For infections normally treated with multiple doses of 400mg, dosage reduction is recommended for elderly patients (male ≥75 years, female ≥65 years), patients with creatinine clearance Urinary tract infections. Single oral doses of fleroxacin 200 or 400mg were bacteriologically effective (eradicated causative pathogens) in approximately 90% or more of female patients with uncomplicated urinary tract infections in most studies. The 400mg dose of fleroxacin appeared to be as effective as a single dose of trimethoprim 600mg or a 3-day course of ofloxacin 100mg twice daily and was significantly more effective than a single dose of amoxicillin 3g. Three-or 7-day courses of fleroxacin 200mg once daily were as effective as 7-day courses of ciprofloxacin 250mg twice daily. In those with complicated urinary tract infections (including pyelonephritis), oral fleroxacin 200 to 400mg once daily or a sequential intravenous/oral fleroxacin regimen produced bacteriological cure in around 90% or more of patients. Fleroxacin 200 or 400 mg once daily appeared at least as effective as oral norfloxacin 400mg twice daily or ofloxacin 200mg twice or 3 times daily, while intravenous fleroxacin 400mg once daily for 4 to 21 days was as effective as intravenous ceftazidime 0.5 to 2g 3 times daily or 1 to 2g twice daily. In Japanese patients, fleroxacin 200 or 300mg once daily appeared to be as effective as ofloxacin 200mg 3 times daily. Sexually transmitted diseases. Single oral doses of fleroxacin 200 or 400mg produced bacteriological and clinical cure in approximately 100% of patients with acute uncomplicated gonorrhoea, and the 400mg dose was as effective as a single intramuscular dose of ceftriaxone 250mg. Variable results were achieved in preliminary studies with single oral doses of fleroxacin 200 or 400mg in patients with chancroid, with bacteriological cure in 83 to 100%, and clinical cure in 52 to 93%, of patients. While fleroxacin was also studied in chlamydial infections, few data relating to the recommended dosage range are available. Lower respiratory tract infections. Multiple once-daily oral or intravenous regimens of fleroxacin 400mg achieved bacteriological cure in 84 to 96% of patients with acute exacerbations of chronic bronchitis caused by susceptible organisms and 84 to 100% of those with nonpneumococcal pneumonia/pneumonitis or tracheobronchitis. Fleroxacin 400mg once daily appeared to be at least as effective as oral amoxicillin 500mg 3 times daily or ciprofloxacin 500mg twice daily in acute exacerbations of chronic bronchitis, and comparable to intravenous or oral erythromycin 500mg 4 times daily with or without intravenous ceftazidime 1g 3 times daily in nonpneumococcal community-acquired pneumonia. Intravenous fleroxacin 400mg once daily appeared to be at least as effective as intravenous ceftazidime 0.5 to 2g 2 to 3 times daily in acute nonpneumococcal lower respiratory tract infections. In Japanese patients with chronic lower respiratory tract infections, oral fleroxacin 300 mg/day produced similar cure rates to oral ofloxacin 200mg 3 times daily. Skin and soft tissue infections. In the treatment of skin and soft tissue infections, oral fleroxacin 400mg once daily generally achieved clinical and bacteriological cure rates of 75 to 90%, and 76 to 95%, respectively, and appeared to be at least comparable to oral amoxicillin/clavulanate 500/125mg 3 times daily. Fleroxacin 400mg once daily achieved a significantly lower rate of bacteriological cure than ofloxacin 400mg twice daily, although clinical cure rates were similar for the 2 regimens. Intravenously administered fleroxacin 400mg once daily produced a similar cure rate and appeared to be at least as effective as intravenous ceftazidime 0.5 to 2g 2 to 3 times daily. Gastrointestinal infections. Fleroxacin 400mg once daily orally for 1 to 3 days shortened the clinical course of diarrhoea, in patients with bacterial enteritis (mainly caused by V. cholerae/parahaemolyticus) or traveller’s diarrhoea (caused by enterotoxigenic E. coli and various protozoal organisms). Causative pathogens were eliminated from more than 90% of those with bacterial enteritis. Typhoid Fever. When given once daily for 7 to 14 days, fleroxacin 400mg was at least as effective as a 14-day course of chloramphenicol 50 mg/kg/day in patients with typhoid fever, achieving bacteriological cure in over 90% of patients. Moreover, no relapses occurred in patients who received 10 or 14 days’ treatment with fleroxacin. Bone and joint infections. Fleroxacin 400mg once daily orally for 2 to 12 weeks achieved bacteriological eradication in approximately 80% of 49 patients with bone and joint infections in a preliminary study. Otorhinolaryngological infections. A 7-day regimen of fleroxacin 200 to 300 mg/day was reported to be bacteriologically effective in over 90% of Japanese patients with various acute otorhinolaryngological infections, and approximately 80% of those with chronic otitis media or acute exacerbations of chronic sinusitis. The tolerability profile of fleroxacin is characteristic of this class of compound. Analysis of pooled manufacturer’s tolerability data from 8893 patients treated with fleroxacin in worldwide clinical trials indicated that treatment-related adverse events occurred in approximately 27% of patients treated with multiple oral doses of 200 or 400mg, or intravenous or sequential intravenous/oral doses of 400mg, and 17% of those who received a single oral dose of 400mg. Among 6777 patients treated with multiple oral doses of fleroxacin 200 or 400mg, the most frequently reported adverse events related to the gastrointestinal tract (nausea, vomiting, diarrhoea, constipation; 13% of patients) or the CNS (insomnia, headache, dizziness; 14%). Injection site disorders were documented in <3% of patients who received intravenous fleroxacin. Adverse events were generally mild to moderate in severity and reversible on discontinuation of the drug, but were classed as severe in approximately 3% of patients treated with single or multiple oral doses of 200 or 400mg, and <2% of those who received multiple intravenous or intravenous/oral doses of 400mg. Serious adverse events (including seizure, confusion, psychosis, phototoxicity and pseudomembranous colitis) were documented in 0.6% of patients who received multiple oral and/or intravenous doses. Less than 6% of patients withdrew from clinical trials because of adverse events. Rates of reported adverse events vary considerably between individual studies and centres, ranging from 0 to 69% of patients receiving fleroxacin 400mg once daily. The incidence of adverse events during treatment with fleroxacin is influenced by various factors. It increases with dose and AUC and was greater among female versus male, and Caucasian versus Black, patients. The incidence of phototoxicity reactions to fleroxacin appears to increase with dose (0.07% with a single dose of 400mg, and 0.7% at 200mg, 2% at 400mg, 5.5% at 600mg, and 22% at 800mg, per day with oral formulations) and degree and intensity of exposure to ultraviolet light. Phototoxicity is less common with intravenous formulations (0.5%), consistent with less exposure to UV light (as patients were generally hospitalised). To date, fleroxacin has not been associated with adverse events indicative of ‘multi-system’ syndrome/hypoglycaemia that led to the withdrawal of temafloxacin. Achilles tendinitis (without rupture) or similar symptoms of indeterminate aetiology occurred at a rate of 0.08% among 12 502 fleroxacin recipients. On the basis of recent manufacturers’ prescribing information and figures reported in the literature, fleroxacin appears to produce a greater incidence of adverse events than other established fluoroquinolones, including ciprofloxacin and ofloxacin, perhaps to some extent reflecting increasing reporting rates of adverse events to this class of compound in recent years and the need for fleroxacin dosage adjustment in some patients. However, in direct comparative studies, oral fleroxacin 400mg once daily was generally associated with a similar number of adverse events to amoxicillin/clavulanic acid 500/125mg 3 times daily or oral ofloxacin 400mg twice daily, but more than oral amoxicillin 500mg 3 times daily and slightly more than oral ciprofloxacin 500mg twice daily. In comparisons with norfloxacin 400mg twice daily, fleroxacin 200mg once daily produced a similar incidence and fleroxacin 400mg once daily a higher incidence. The most common laboratory abnormalities occurring during fleroxacin treatment were increased blood urea nitrogen or urea and fasting blood glucose, most of which were related to underlying diseases or state of infection. Small elevations in creatinine levels which occur in some patients appear to reflect competition between fleroxacin and creatinine for tubular secretion. Fleroxacin is distinguished from most other fluoroquinolones by a relative absence of clinically relevant drug interactions with commonly administered comedications. It had little effect on the pharmacokinetics of theophylline, caffeine or warfarin, and the pharmacokinetics of fleroxacin were not altered to a clinically significant degree by coadministration of calcium-containing antacids, ranitidine or rifampicin (rifampin). Coadministration with cimetidine decreased the clearance of fleroxacin, resulting in a 32% increase in plasma elimination half-life. Although absorption of fleroxacin was decreased when the drug was coadministered with aluminium- or magnesium-containing antacids or sucralfate, the magnitude of these interactions was substantially less than those reported for various other fluoroquinolones and is not sufficient to warrant special precautions or dosage adjustments. The recommended dosage and duration of fleroxacin therapy varies according to the type and severity of infection, the susceptibility of the causative pathogen, the patient’s general condition and the country of prescribing. It is given in single-dose or multiple once-daily regimens, either orally, or as a 0.5 hour...

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