Fluoroquinolones impair tendon healing in a rat rotator cuff repair model: a preliminary study.

BACKGROUND: Recent studies suggest that fluoroquinolone antibiotics predispose tendons to tendinopathy and/or rupture. However, no investigations on the reparative capacity of tendons exposed to fluoroquinolones have been conducted. HYPOTHESIS: Fluoroquinolone-treated animals will have inferior biochemical, histological, and biomechanical properties at the healing tendon-bone enthesis compared with controls. STUDY DESIGN: Controlled laboratory study. METHODS: Ninety-two rats underwent rotator cuff repair and were randomly assigned to 1 of 4 groups: (1) preoperative (Preop), whereby animals received fleroxacin for 1 week preoperatively; (2) pre- and postoperative (Pre/Postop), whereby animals received fleroxacin for 1 week preoperatively and for 2 weeks postoperatively; (3) postoperative (Postop), whereby animals received fleroxacin for 2 weeks postoperatively; and (4) control, whereby animals received vehicle for 1 week preoperatively and for 2 weeks postoperatively. Rats were euthanized at 2 weeks postoperatively for biochemical, histological, and biomechanical analysis. All data were expressed as mean ± standard error of the mean (SEM). Statistical comparisons were performed using either 1-way or 2-way ANOVA, with P < .05 considered significant. RESULTS: Reverse transcriptase quantitative polymerase chain reaction (RTqPCR) analysis revealed a 30-fold increase in expression of matrix metalloproteinase (MMP)-3, a 7-fold increase in MMP-13, and a 4-fold increase in tissue inhibitor of metalloproteinases (TIMP)-1 in the Pre/Postop group compared with the other groups. The appearance of the healing enthesis in all treated animals was qualitatively different than that in controls. The tendons were friable and atrophic. All 3 treated groups showed significantly less fibrocartilage and poorly organized collagen at the healing enthesis compared with control animals. There was a significant difference in the mode of failure, with treated animals demonstrating an intrasubstance failure of the supraspinatus tendon during testing. In contrast, only 1 of 10 control samples failed within the tendon substance. The healing enthesis of the Pre/Postop group displayed significantly reduced ultimate load to failure compared with the Preop, Postop, and control groups. There was no significant difference in load to failure in the Preop group compared with the Postop group. Pre/Postop animals demonstrated significantly reduced cross-sectional area compared with the Postop and control groups. There was also a significant reduction in area between the Preop and control groups. CONCLUSION: In this preliminary study, fluoroquinolone treatment negatively influenced tendon healing. CLINICAL RELEVANCE: These findings indicate that there was an active but inadequate repair response that has potential clinical implications for patients who are exposed to fluoroquinolones before tendon repair surgery.

Quantitative comparison of the convulsive activity of combinations of twelve fluoroquinolones with five nonsteroidal antiinflammatory agents.

Concomitant administration of certain fluoroquinolone antimicrobials and nonsteroidal antiinflammatory agents (NSAIDs) induces serious convulsion in humans. There are differences in convulsive activity among fluoroquinolones and in the potentiation of fluoroquinolone-induced convulsion among NSAIDs, but a comprehensive, quantitative comparison has not been carried out. This study evaluates the inhibitory effects of twelve fluoroquinolones (ciprofloxacin, enoxacin, fleroxacin, gatifloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, pazufloxacin, prulifloxacin, sparfloxacin, and tosufloxacin) alone or in the presence of an NSAID (4-biphenylacetic acid, diclofenac sodium, loxoprofen, lornoxicam or zaltoprofen) on the GABA(A) receptor binding of [(3)H]muscimol in an in vitro study using mice synaptic plasma membrane. The rank order of inhibitory effects of the fluoroquinolones was prulifloxacin asymptotically equal to norfloxacin > ciprofloxacin > or = enoxacin > gatifloxacin > or = ofloxacin asymptotically equal to tosufloxacin asymptotically equal to lomefloxacin > levofloxacin > or = sparfloxacin > or = pazufloxacin asymptotically equal to fleroxacin. 4-Biphenylacetic acid most potently enhanced the inhibitory effects of the fluoroquinolones, while zaltoprofen, loxoprofen, lornoxicam and diclofenac had essentially no effect. The clinical risk of convulsion for each combination was estimated using a pharmacodynamic model based on receptor occupancy using the in vitro data set obtained and pharmacokinetic parameters in humans collected from the literature. The combinations of 4-biphenylacetic acid with prulifloxacin and enoxacin were concluded to be the most hazardous.

A randomized clinical trial to compare fleroxacin-rifampicin with flucloxacillin or vancomycin for the treatment of staphylococcal infection.

BACKGROUND: Oral combination therapy with fluoroquinolones plus rifampicin is a promising alternative to standard parenteral therapy for staphylococcal infections. METHODS: In a multicenter, randomized trial, we compared the efficacy, safety, and length of hospital stay for patients with staphylococcal infections treated either with an oral combination of a fluoroquinolone (fleroxacin) plus rifampicin or with standard parenteral treatment (flucloxacillin or vancomycin). Patients were included if cultures showed the presence of bacteremia or deep-seated infections with Staphylococcus aureus (104 patients) or catheter-related bacteremia due to drug-susceptible, coagulase-negative staphylococci (23 patients). RESULTS: The cure rate in the intention-to-treat analysis was 78% for the fleroxacin-rifampicin group (68 patients) and 75% for the standard therapy group (59 patients; 47 received flucloxacillin, and 12 received vancomycin); in the population of clinically evaluable patients (n=119), the cure rate was 82% and 80%, respectively; and in the population of microbiologically evaluable patients (n=103), the cure rate was 86% and 84%, respectively. Clinical and bacteriological failures after S. aureus infections were documented in similar proportions of patients. The median length of hospital stay after study entry was 12 days in the fleroxacin-rifampicin group, compared with 23 days in the standard treatment group (P=.006). More adverse events probably related to the study drug were reported in the fleroxacin-rifampicin group than in the standard therapy group (15 of 68 vs. 5 of 59 patients; P=.05). CONCLUSIONS: This study suggests that an oral regimen containing a fluoroquinolone plus rifampicin may be effective for treating staphylococcal infections, allowing earlier discharge from the hospital.

The pharmacokinetics of oral fleroxacin and ciprofloxacin in plasma and sputum during acute and chronic dosing.

AIMS: To examine the pharmacokinetics of ciprofloxacin and fleroxacin in plasma and sputum of patients with an acute exacerbation of chronic bronchitis or bronchiectasis following the first dose and again during the third day of treatment. METHODS: Twelve patients, aged >35 years, with acute infective exacerbation of bronchitis or bronchiectasis were allocated randomly to treatment with either fleroxacin 400 mg daily or ciprofloxacin 500 mg twice daily in an open, parallel group design. Plasma and sputum were collected during the first and third days of treatment. The time course of concentrations in sputum was modelled assuming that it acted as a negligibly small compartment of distribution. RESULTS: The mean sputum to plasma ratios of both ciprofloxacin and fleroxacin were approximately 1 on both days 1 and 3. Peak concentrations of ciprofloxacin in sputum were achieved 1.6 (95% CI on mean difference 0.8-2.3) and 1.2 (0.4-1.9) h later than in plasma on day 1 and day 3, respectively (mean difference +/- 95% confidence interval). For fleroxacin, the corresponding delay in time to peak concentrations was less marked and not significant. Fleroxacin accumulated in plasma (accumulation index 1.52+/-0.07) and sputum (accumulation index 1.79+/-0.39) from day 1 to day 3. Accumulation did not occur for ciprofloxacin because the dose interval (12 h) was considerable longer than its half life (3-4 h). CONCLUSIONS: The sputum to plasma ratio of ciprofloxacin and fleroxacin is approximately 1. The time to peak concentrations of ciprofloxacin in sputum is slightly delayed compared with plasma. Fleroxacin accumulates over time in both plasma and sputum consistent with its longer half-life.

[Fluoroquinolones as etiology of tendinopathy]. / Fluoroquinolone als Ursache von Tendinopathien.

Tendinopathies as a result of fluoroquinolone therapy represent a new clinical entity. We report on tendinitis and tendon rupture in six fluoroquinolone treated patients of our outpatient and dialysis service between 1995 and 1997. The most important risk factors for tendinopathies were renal failure in all cases, glucocorticosteroid therapy in five patients, secondary hyperparathyroidism in three patients, advanced age in two patients, and diabetes mellitus in another patient. Latency periods of 2 to 60 days between onset of fluoroquinolone therapy and emergence of symptoms suggest significant involvement of these agents and are compatible with previously published case reports. Therefore, care should be used in prescribing fluoroquinolones to older renal transplant or hemodialysis patients with additional risk factors for tendinopathies. These drugs should be stopped when symptoms of tendinitis occur, particularly to prevent tendon rupture. The incidence of fluoroquinolone induced tendinopathies in patients without renal diseases is unknown.

[Encephalopathy induced by fleroxacin in a patient with Machado-Joseph disease].

Convulsive seizure with unconciousness is an adverse effect of new quinolone antibiotics including fleroxacin. A block of GABA receptor in CNS has been reported as pathomechanism. A 48-year-old female patient with Machado-Joseph disease (MJD) had encephalopathy induced by fleroxacin. She revealed unconsciousness after the administration of fleroxacin (200mg/day) for three days. Electroencephrogram (EEG) showed diffuse slow waves. The administration was discontinued and her consciousness became clear after a day. The abnormal findings on EEG disappeared gradually. The concentrations of fleroxacin were within normal limits in serum and cerebrospinal fluid. The patient with MJD might have a tendency to develop encephalopathy by fleroxacin, because the GABA-ergic nervous system could be involved in MJD.

Fleroxacin 400 mg once daily versus ofloxacin 400 mg twice daily in skin and soft tissue infections.

The efficacy and safety of 10 days' oral treatment with fleroxacin 400 mg once daily were compared with those of ofloxacin 400 mg twice daily in adults with skin and soft tissue infections. The most common diagnoses were skin abscess, cellulitis and wound infection. The most commonly-isolated pathogens were Staphylococcus aureus, Staphylococcus epidermidis and other coagulase-negative staphylococci. Overall bacteriological cure rates in patients with susceptible pathogens were 89% for 158 fleroxacin-treated patients and 97% for 157 ofloxacin-treated patients (treatment difference 8%; 95% confidence intervals 2-14%; p < 0.05). Clinical cure rates were 78% for fleroxacin and 83% for ofloxacin (treatment difference 5%; 95% confidence intervals-5-14%, not statistically significant). The overall safety profiles were similar and the most frequently reported events were insomnia, headache, dizziness, and digestive system disorders. More fleroxacin-treated patients experienced phototoxicity and treatment-limiting adverse events. In conclusion, compared to twice-daily ofloxacin, fleroxacin had similar clinical efficacy and the advantage of once-a-day dosing, but with slightly lower bacteriological cure rate and a higher rate of treatment-limiting adverse events.

Atypical pneumonia in the Nordic countries: aetiology and clinical results of a trial comparing fleroxacin and doxycycline. Nordic Atypical Pneumonia Study Group.

Community-aquired pneumonia caused by atypical bacteria or viruses was studied in a double-blind trial comparing fleroxacin 400 mg od and doxycycline 100 mg bd for 10 days. The aetiology was confirmed in 258 of 411 cases (66%), of which 133 were caused by Mycoplasma spp., Chlamydia spp. or Legionella spp.; 30 patients had viral infection, nine had pneumococcal or Haemophilus influenzae infection and 93 had mixed aetiology. In intention-to-treat analyses clinical response rates in fleroxacin-treated patients were 86% (157/182) and 75% (137/182) 2-8 days and 3-5 weeks after therapy, respectively. Corresponding results with doxycycline were 93% (177/191) and 85% (162/190), respectively. Differences between treatments seemed to be due to the lower activity of fleroxacin compared with doxycycline against mycoplasma and pneumococci. Drug-related adverse events were reported in 39% of 204 fleroxacin patients and in 34% of 207 doxycycline patients. The null hypothesis that fleroxacin was <15% inferior to doxycycline was accepted at early follow-up but rejected at later review.

Once daily fleroxacin and twice daily ciprofloxacin are both effective in the treatment of complicated urinary tract infections

In a multicenter randomized double-blind, trial, 90 patients received either fleroxacin 400mg po once/day or ciprofloxacin 500mg po twice/day for treatment of complicated urinary tract infections (UTI). Treatment was administered orally and presumptively. Bacteriological efficacy was assessed 7 days post-treatment. In total, 78 patients were available for efficacy testing: 40 in the fleroxacin group and 38 in the ciprofloxacin group. The bacteriological cure rate was 92.5 percent and 94.7 and in the fleroxacin and ciprofloxacin groups, respectively. The most commonly isolated pathogen (E. coli) was erradicated in 94.1 percent and 95.8 percent of the cases in fleroxacin and ciprofloxacin groups, respectively. Eight patients in the fleroxacin group had some adverse events, two of them severe (insomnia and photodermatitis). In the ciprofloxacin group, 11 patients had adverse events of mild to moderate intensity, mainly affecting the digestive system. In conclusion, fleroxacin 400mg po once/day and ciprofloraxin 500mg po twice/day were both effective in the treatment of complicated urinary tract infections.

Complicated urinary infection in spinal injury patients: fleroxacin compared with ciprofloxacin.

The efficacy and safety of fleroxacin and ciprofloxacin were evaluated in a single-centre, prospective, randomised, blinded study of patients with complicated urinary infection in a spinal injury unit. Patients were randomised to receive oral fleroxacin 400 mg once daily (n = 68) or oral ciprofloxacin 500 mg twice daily (n = 65) for 10 days. Clinical cure assessed 5-9 days after therapy was obtained in 41 of 42 (98%) assessable patients in the fleroxacin group, and in 41 of 43 (95%) of the ciprofloxacin group, and was maintained at the 6-week follow-up visit in all but 1 patient in each group. Bacteriological eradication rates 5-9 days after therapy exceeded 88% in the fleroxacin group and 86% in the ciprofloxacin group, and 69 and 65%, respectively, 6 weeks after completion of therapy. Adverse events occurred in a similarly low percentage of patients (19 and 20%) in both treatment groups, and consisted primarily of nausea. Once daily fleroxacin appears to be as safe and effective as twice daily ciprofloxacin and both represent efficacious treatment in complicated urinary infection in spinal injury patients.

Fleroxacin overview.

Fleroxacin is a new oral and intravenous trifluorinated 4-quinolone, which acts by inhibiting the essential bacterial enzyme DNA gyrase. Fleroxacin exhibits a broad spectrum of action, characterized by pronounced activity against aerobic gram-negative bacteria, but also against gram-positive pathogens such as staphylococci. Fleroxacin is distinguished by its excellent bioavailability, high concentrations in the plasma and other body fluids, good tissue penetration, and a long half-life of 10-12 h, thus allowing once-a-day administration. A single oral dose of 400 mg fleroxacin is effective in uncomplicated cystitis in women, uncomplicated gonococcal infections, bacterial enteritis, and traveler's diarrhea. A single daily dose of 200 mg administered for 3 days is effective in uncomplicated urinary tract infection (UTI), while longer treatment and higher doses may be required in acute uncomplicated pyelonephritis and complicated UTI. Skin, soft tissue, bone and joint infections, and lower respiratory tract infections including exacerbation of chronic bronchitis and non-pneumococcal pneumonia are further indications for fleroxacin.

Quinolones in everyday clinical practice: respiratory tract infections and nosocomial pneumonia.

Currently available fluoroquinolones have established their value in the treatment of lower respiratory tract infections due to gram-negative rods and Staphylococcus aureus. The fact that these drugs are absorbed (and well tolerated) when given orally is a major positive feature. The once daily dosage of fleroxacin [400 mg once daily intravenously (i.v.) for 2-4 days followed by oral doses of 400 mg for up to 10 days] was compared with twice daily ciprofloxacin (400 mg twice daily i.v. for 2-4 days followed by oral doses of 2 x 500 mg for up to 10 days) for treatment of inpatients with pneumonia confirmed by clinical signs and chest X ray. To date, 93 evaluable patients have been enrolled in this study. Clinical cure and improvement rates were 73.3% in the fleroxacin group and 79.2% in the ciprofloxacin group. The rate of adverse clinical or laboratory events was similar in both study groups.

Pharmacokinetics of oral fleroxacin in male and premenopausal female volunteers.

The pharmacokinetics of oral fleroxacin were compared in men and premenopausal women. The total volume of distribution of the drug was significantly smaller in women in the single-dose trial. No difference in other pharmacokinetic parameters was noted. Since adverse events appear to occur in women more commonly than in men, dose-response studies of fleroxacin in women may be appropriate.

Photosensitivity induced by fleroxacin.

A case of photosensitivity induced by fleroxacin (FLRX) is reported. A 71-year-old man had erythema on sun-exposed areas after 5 months FLRX treatment for prostatitis. The minimal erythema dose to UVA was reduced at the initial examination and became normal 4 weeks after he stopped taking FLRX. Oral photo-challenge with FLRX 100 mg was positive, but photopatch testing was negative. Fleroxacin (FLRX), in use since 1992, is a fluoroquinolone antibacterial derived from quinoline. Photosensitivity induced by FLRX is not uncommon, but a photobiological study has not been reported. The mechanism of action of photosensitivity induced by the fluoroquinolones is considered to be phototoxic in origin in that in vitro technique studies are positive. FLRX, a quinoline derivative may be a photosensitizer as well as enoxacin, lomefloxacin and sparfloxacin.

Influence of rifampin on fleroxacin pharmacokinetics.

Staphylococcus aureus infections have been successfully treated in animal models with the combination of fleroxacin and rifampin. We studied the influence of rifampin, a potent cytochrome P-450 inducer, on the pharmacokinetics and biotransformation of fleroxacin in 14 healthy young male volunteers. Subjects were given 400 mg of fleroxacin orally once a day for 3 days to reach steady state. After a wash-out period of 2 days, the same subjects received 600 mg of rifampin orally once daily for 7 days. On days 5 to 7 of rifampin treatment, 400 mg of fleroxacin was again administered once daily. Concentrations of fleroxacin as well as its two major urinary metabolites, N-demethyl- and N-oxide-fleroxacin, in plasma and urine were determined by reverse-phase high-performance liquid chromatography. The extent of hepatic enzyme induction by rifampin was confirmed by a significant increase of 6-beta-hydroxycortisol urinary output from 160.8 +/- 41.4 to 544.8 +/- 120.7 micrograms/4 h. There were no significant changes in the peak fleroxacin concentration in plasma (6.3 +/- 1.2 versus 6.2 +/- 1.9 mg/liter), time to maximum concentration of fleroxacin in plasma (1.1 +/- 0.9 versus 1.3 +/- 1.1 h), or renal clearance (58.3 +/- 16.4 versus 61.9 +/- 19.2 ml/min). The area under the curve AUC (71.4 +/- 15.8 versus 62.2 +/- 13.7 mg.h/liter) and the terminal half-life of fleroxacin (11.4 +/- 2.2 versus 9.2 +/- 1.1 h) decreased (P < 0.05), while the total plasma clearance increased from 97.7 +/- 21.6 to 112.3 +/- 25.8 ml/min (P < 0.01). Despite being statistically significant, this 15% increase in total plasma clearance does not appear to be clinically relevant. Metabolic clearance by N demethylation was increased ( 6.9 +/- 2.4 versus 12.5 +/- 3.2 ml/min; P < 0.01), whereas clearance by N oxidation did not change (5.8 +/- 1.1 versus 5.8 +/- 1.5 ml/min). Fleroxacin elimination was slightly increased (about 15%) through induction of metabolic clearance to N-demethyl-fleroxacin. Since fleroxacin levels remained above the MIC for 90% of the tested isolates of methicillin-susceptible S. aureus for at least 24 h, dose adjustment does not appear necessary, at least for short-term treatments.