Risk of bleeding and antibiotic use in patients receiving continuous phenprocoumon therapy. A case-control study nested in a large insurance- and population-based German cohort.

There is major concern about coumarins interacting with various drug classes and increasing the risk of overanticoagulation. The aim of the study was to assess bleeding risk in patients with concurrent use of antibiotics and phenprocoumon, the most widely prescribed coumarin in many European countries. We conducted a nested-case-control study within a cohort of 513,338 incident and continuous phenprocoumon users ≥ 18 years of age using claims data of the statutory health insurance company AOK, covering 30% of the German population. Bleeding risk associated with current use of antibiotics for systemic use (antibacterials/antimycotics) was calculated using conditional logistic regression in 13,785 cases with a bleeding event and 55,140 risk-set sampling-matched controls. Bleeding risk associated with any antibacterial use in phenprocoumon users was significantly increased [odds ratio (OR) 2.37, 95% confidence interval (CI) 2.20-2.56]. The association was stronger for gastrointestinal than for cerebral bleeding (OR 2.09, 95% CI 1.84-2.38 and OR 1.34, 95% CI 1.03-1.74, respectively) and highest for other/unspecified bleeding (OR 2.92, 95% CI 2.62-3.26). Specific antibiotic classes were strongly associated with bleeding risk, e.g. cotrimoxazole (OR 3.86, 95% CI 3.08-4.84) and fluorquinolones (OR 3.13, 95% CI 2.74-3.59), among those highest for ofloxacin (OR 5.00, 95% CI 3.01-8.32). Combined use of phenprocoumon and antimycotics was not significantly associated with bleeding risk. Risk was not significantly modified by age (pint=0.25) or sex (pint=0.96). The association was stronger the closer the antibiotic exposure was to the bleeding event. Among continuous phenprocoumon users, antibiotics - particularly quinolones and cotrimoxazole - should be prescribed after careful consideration due to an increased bleeding risk. Close monitoring of international normalised ratio levels after prescription is recommended.

Single daily dose of moxifloxacin versus ofloxacin plus metronidazole as a new treatment approach to uncomplicated pelvic inflammatory disease: a multicentre prospective randomized trial.

OBJECTIVES: To evaluate the efficacy and safety of moxifloxacin versus ofloxacin plus metronidazole in patients with uncomplicated pelvic inflammatory disease (uPID; defined as PID symptoms and signs, but no complications such as septicemia, perihepatitis, and tubo-ovarian abscess) in Turkey. STUDY DESIGN: This was a multicenter, prospective, randomized, parallel-group study conducted between June 2010 and March 2013 in four hospitals in Turkey. Women received a 14-day course of either oral moxifloxacin at 400mg once daily (n = 560) or oral ofloxacin at 400mg twice daily plus oral metronidazole at 500 mg twice daily (n = 543). RESULTS: A total of 1156 women were randomized to the study. Total compliance was achieved in 1103 patients. For the primary measure of efficacy (clinical cure), moxifloxacin showed no difference compared with ofloxacin plus metronidazole (445/560 [79.5%] vs. 449/543 [82.7%]; p = 0.172). Bacteriological cure rates were high and comparable between treatment arms (99/119 [83.2%] vs. 93/110 [84.5%]; p = 0.781). Drug-related adverse events occurred less frequently with moxifloxacin than with ofloxacin plus metronidazole (210/560 [37.5%] vs. 252/543 [46.4%]; p = 0.003). Furthermore, moxifloxacin treatment was lower in cost and achieved higher patient compliance compared with ofloxacin plus metronidazole (31.4 Euros vs. 23.4 Euros and 7/578 (1.2%) vs. 22/578 (3.8%), respectively; p = 0.005). CONCLUSIONS: In patients with uPID, once-daily moxifloxacin monotherapy was clinically and microbiologically as efficacious as twice-daily ofloxacin plus metronidazole therapy and was associated with fewer drug-related adverse events, lower patient non-compliance, and a lower treatment cost.

[Infectious exacerbation of chronic obstructive pulmonary disease: prospects for high-dose levofloxacin therapy].

This open comparative randomized study of efficacy, safety, and pharmacoeconomic characteristics of hilifox-750 (750 mg daily for 5 days) and amoxiclav 2X (875/125 mg twice daily for 10 days) included 60 patients with chronic obstructive pulmonary disease (COPD). Duration of the study was 6 months. Medians of age and smoking index in the group treated with hilifox-750 were 63.5 yr (59, 67) and 30 packs/yr (15, 60) respectively. The treatment reduced cough, apnea, sputum volume and pyoptysis with comparative rates of normalization of body temperature and peripheral leukocyte counts in both groups. Helifox-750 promoted decrease in coughing and apnea within the first three days of therapy. 28 (93%) and 26 (87%) patients recovered by day 4 of helifox and amoxiclav therapy (F-test p = 0.67). Both drugs showed comparable bacteriological efficacy. They were not different in terms of side effect frequency that were mild, resolved spontaneously and did not require withdrawal of therapy. Helifox had advantages over amoxiclav in that it reduced duration of antibacterial therapy to 5 days and of temporary incapacity to 12 days (vs 14); moreover, it needs to be taken only once daily.

Evaluation of efficacy and tolerability of fixed dose combination of ofloxacin with ornidazole infusion (infusion O2) in the management of diarrhoea and dysentery.

Acute diarrhoea in adults is one of the most commonly encountered medical emergency in general practice and is responsible for considerable morbidity around the world. To evaluate the efficacy and tolerability of fixed dose combination of ofloxacin with ornidazole infusion (infusion O2) in the management of diarrhoea and dysentery, a study was carried out among 290 patients, age group from 18 to 65 years suffering from diarrhoea, dysentery, gastro-enteritis. Study drug infusion O2, (Medley Pharmaceutical, Mumbai) containing ofloxacin 200 mg + ornidazole 500 mg was administrated twice daily for a duration of 5 days. Number of soft or watery stool, body temperature, nausea, abdominal pain, gas and flatulence were recorded at baseline and at the end of the study. Tolerability and efficacy was evaluated based on the global assessment by the investigator based on a 3-point scale marked as excellent/good/poor. Two hundred and fifty-six-patients (160 male and 96 female) were included for final analysis, 34 patients lost to follow-up. Mean number of watery stool per day was reduced from 9.273 +/- 0.4537 to 1.375 +/- 0.07001 (p < 0.0001) by infusion O2. Body temperature was significantly reduced from 38.055 +/- 0.045 degrees C to 36.778 +/- 0.016 degrees C (p < 0.0001) at the end of the study. Pretreatment symptom nausea was significantly reduced in 90.34% of patients. Improvement in vomiting symptoms was reported in 72.35% of patients after administration of anti-emetic drug; 96.84% and 77.25% of patients reported improvement in abdominal pain and gas/flatulence respectively at the end of the trial by infusion O2. As per investigators' assessment about efficacy of trial drug, 98.43% of patients reported good to excellent and 1.56% reported poor efficacy. As per investigators' assessment about tolerability 98.43% of patients reported good to excellent and 1.17% reported poor tolerability. Minor incidences of nausea, gastritis, metallic taste were reported in 7.42%, 7.14%, and 5.85% of patients respectively. No serious adverse events were reported which led to withdrawal of patient from the study. Result of this study shows that, combination of ofloxacin with ornidazole infusion (infusion O2) significantly reduces number of watery stool and associated symptoms like nausea, abdominal pain, flatulence/gas with excellent tolerability.

Fluoroquinolones in the management of community-acquired pneumonia in primary care.

A literature search was conducted to evaluate the pharmacokinetic and pharmacodynamic profile of the respiratory fluoroquinolones (gemifloxacin, levofloxacin and moxifloxacin) and their efficacy and safety in the management of community-acquired pneumonia (CAP). Data show that CAP is a common presentation in primary care practice, and is associated with high rates of morbidity and mortality, particularly in the elderly. Although the causative pathogens differ depending on treatment setting and patient factors, Streptococcus pneumoniae is the primary pathogen in all treatment settings. As a class, the respiratory fluoroquinolones have a very favorable pharmacokinetic and pharmacodynamic profile. Pharmacodynamic criteria suggest that moxifloxacin and gemifloxacin are more potent against S. pneumoniae, which may have the added benefit of reducing resistance selection and enhancing bacterial eradication. The respiratory fluoroquinolones are also generally well tolerated, and are first-line options for outpatient treatment of CAP in patients with comorbidities or previous antibiotic use.

Empirical levofloxacin-containing versus clarithromycin-containing sequential therapy for Helicobacter pylori eradication: a randomised trial.

BACKGROUND AND AIMS: Antimicrobial drug resistance is a major cause of the failure of Helicobacter pylori eradication and is largely responsible for the decline in eradication rate. Quadruple therapy has been suggested as a first-line regimen in areas with clarithromycin resistance rate >15%. This randomised trial aimed at evaluating the efficacy of a levofloxacin-containing sequential regimen in the eradication of H pylori-infected patients in a geographical area with >15% prevalence of clarithromycin resistance versus a clarithromycin containing sequential therapy. METHODS: 375 patients who were infected with H pylori and naïve to treatment were randomly assigned to one of the following treatments: (1) 5 days omeprazole 20 mg twice daily + amoxicillin 1 g twice daily followed by 5 days omeprazole 20 mg twice daily +clarithromycin 500 mg twice daily + tinidazole 500 mg twice daily; or (2) omeprazole 20 mg twice daily +amoxicillin 1 g twice daily followed by omeprazole 20 mg twice daily + levofloxacin 250 mg twice daily +tinidazole 500 mg twice daily; or (3) omeprazole 20 mg twice daily + amoxicillin 1 g twice daily followed by omeprazole 20 mg twice daily + levofloxacin 500 mg twice daily + tinidazole 500 mg twice daily. Antimicrobial resistance was assessed by the E-test. Efficacy, adverse events and costs were determined for each group. RESULTS: Eradication rates in the intention-to-treat analyses were 80.8% (95% CI, 72.8% to 87.3%) with clarithromycin sequential therapy, 96.0% (95% CI, 90.9%to 98.7%) with levofloxacin-250 sequential therapy, and 96.8% (95% CI, 92.0% to 99.1%) with levofloxacin-500 sequential therapy. No differences in prevalence of antimicrobial resistance or incidence of adverse events were observed between groups. Levofloxacin-250 therapy was cost-saving compared with clarithromycin sequential therapy. CONCLUSION: In an area with >15% prevalence of clarithromycin resistant H pylori strains, a levofloxacin containing sequential therapy is more effective, equally safe and cost-saving compared to a clarithromycin containing sequential therapy.

Retrospective assessment of potential interaction between levofloxacin and warfarin.

OBJECTIVE: There is currently a controversy regarding interactions between levofloxacin and warfarin. The aim of this study was to determine the clinical relevance of this interaction in our setting. SETTING: A university hospital in Barcelona, Spain. METHODS: We carried out a retrospective evaluation of all patients hospitalized in our hospital during the period 2000-2005, selecting all those concomitantly treated with levofloxacin and warfarin for the study. The following data were compiled: demographic information, concomitant medication, comorbid conditions, and relevant analytical parameters, particularly the international normalized ratio (INR), including values taken before, during, and after concomitant administration of the two study drugs. Patients for whom INR values during concomitant administration were not available were excluded. Differences in INR before and during the potential interaction, and before and after the interaction were analyzed with the Wilcoxon t test using SPSS (V12.0). In addition, patients were stratified according to presence or not of toxic habits (smoking/alcohol consumption) to investigate the possible impact of these factors on the interaction under study. RESULTS: Among the 30 patients identified, 9 were excluded because INR data during concomitant administration of warfarin and levofloxacin were not available. Statistical analysis demonstrated significant increase in INR (P = 0.001) following addition of levofloxacin to warfarin therapy. CONCLUSIONS: The results of this study reaffirm the hypothesis that concomitant administration of levofloxacin and warfarin leads to INR increase; hence close monitoring of INR is advisable when patients are prescribed this combination of drugs.

A comparison of levofloxacin and moxifloxacin use in hospitalized community-acquired pneumonia (CAP) patients in the US: focus on length of stay.

OBJECTIVE: Length of stay (LOS) and hospitalization costs were compared among patients admitted for community-acquired pneumonia (CAP) and initially treated with either levofloxacin 750 mg intravenous (IV) or with moxifloxacin 400 mg IV. Hospital-related complications and relationship of LOS and comorbidities were descriptively examined. METHODS: A retrospective database study was conducted of adult patients admitted for CAP and given levofloxacin 750 mg IV or moxifloxacin 400 mg IV through the first 3 days of hospitalization, using the Premier Perspective comparative database. Cohorts were matched 1:1 by hospital geographic location, by coarse caliper propensity scores using all baseline covariates, and by Mahalanobis metric matching based on age and severity (All Patient Refined-Diagnosis-related Groups Severity of Illness (APR-DRG SOI) index). Comparisons between groups were further adjusted for characteristics that remained imbalanced after matching using generalized estimating equation methodology. RESULTS: The initial sample of 3868 patients (levofloxacin = 827; moxifloxacin = 3041) was reduced to 1594 (797 patients per treatment group) after matching. Analyses of matched cohorts showed that the mean hospital LOS was significantly shorter for patients treated with levofloxacin 750 mg IV than for those patients treated with moxifloxacin 400 mg IV (5.8 vs. 6.4 days, respectively; least squares mean difference = 0.54 days; p = 0.020). Hospitalization costs were also lower for the levofloxacin 750 mg IV-treated patients (least squares mean difference = US$129; p = 0.753). There were no significant differences in the percentage of patients experiencing complications. LIMITATIONS: Although claims databases provide large sample sizes and reflect routine care, they do have several inherent limitations. Since randomization of subjects is not possible, adequate statistical techniques must be used to ensure treatment groups are balanced with respect to patient and clinical characteristics. In addition, data may be missing or miscoded. CONCLUSIONS: This retrospective study suggests that among patients hospitalized with CAP, initial treatment with levofloxacin 750 mg IV is associated with a significantly shorter mean hospital LOS compared with treatment with moxifloxacin 400 mg IV. The clinical implications of a shorter hospital LOS include improved patient and economic outcomes.

Patient stratification in the management of acute bacterial exacerbation of chronic bronchitis: the role of levofloxacin 750 mg.

This is the first prospective clinical trial in which patients with acute bacterial exacerbation of chronic bronchitis have been stratified by degree of underlying illness. Uncomplicated patients were randomised to levofloxacin 750 mg once daily (q.d.) for 3 days or azithromycin q.d. for 5 days. Complicated patients were randomised to levofloxacin 750 mg q.d. for 5 days or amoxicillin 875 mg/clavulanate 125 mg twice daily for 10 days. Regardless of therapy, complicated patients demonstrated lower clinical and microbiological success than uncomplicated patients. Clinical success for clinically evaluable patients was similar for levofloxacin and azithromycin (93.0 versus 90.1%, respectively), and levofloxacin and amoxicillin/clavulanate (79.2 versus 81.7%, respectively). For microbiologically evaluable patients, clinical response to levofloxacin for 3 days was superior to azithromycin for 5 days (96.3 versus 87.4%, respectively), and levofloxacin for 5 days was similar to amoxicillin/clavulanate for 10 days (81.4 versus 80.9%, respectively). Microbiological eradication was superior for levofloxacin for 3 days compared with azithromycin for 5 days (93.8 versus 82.8%, respectively), and similar for levofloxacin and amoxicillin/clavulanate for 10 days (81.4 versus 79.8%, respectively). In conclusion, levofloxacin 750 mg for 3 days was comparable to azithromycin for 5 days for uncomplicated patients with acute bacterial exacerbation of chronic bronchitis, while 5 days of 750 mg levofloxacin was comparable to 10 days of amoxicillin/clavulanate for complicated acute bacterial exacerbation of chronic bronchitis.

Environmental risk assessment of six human pharmaceuticals: are the current environmental risk assessment procedures sufficient for the protection of the aquatic environment?

In this study, exposure and ecotoxicity data of six human pharmaceuticals (carbamazepine, clofibric acid, diclofenac, ofloxacin, propranolol, and sulfamethoxazole) were collected, including our own experimental data and literature data. From this data collection, the two-tiered European draft guideline on the environmental risk assessment of human pharmaceuticals was tested. Measured environmental concentrations in effluents from France and in effluents and surface waters from Germany were compared to the predicted environmental concentrations (PECs) in both countries. In a similar manner, predicted no-effect concentrations (PNECs) derived from acute data and PNECs derived from chronic data were estimated for each pharmaceutical and corresponding PEC/PNEC ratios then were compared in both countries. Globally, results demonstrated that all environmental concentrations (predicted or measured) for each considered pharmaceutical exceeded the 10-ng/L cutoff value, which requires the implementation of the second-tier assessment based on ecotoxicity data. Moreover, the six pharmaceuticals showed a relatively limited acute toxicity, and carbamazepine and propranolol were inaccurately identified as having negligible risks under the current European draft procedure. Such results lead to discussion of the actual procedure on pharmaceuticals, especially on the need of appropriate ecotoxicity tests.

Ofloxacin plus rifampicin versus doxycycline plus rifampicin in the treatment of brucellosis: a randomized clinical trial [ISRCTN11871179].

BACKGROUND: The combination therapies recommended by the World Health Organization for treatment of brucellosis are doxycycline plus rifampicin or doxycycline plus streptomycin. Although highly successful results have been obtained with these two regimens, relapse rates as high as 14.4%. The most effective and the least toxic chemotherapy for human brucellosis is still undetermined. The aim of the present study was to investigate the efficacy, adverse effects and cost of ofloxacin plus rifampicin therapy, and doxycycline plus rifampicin therapy and evaluate in the treatment of brucellosis. METHODS: The open trial has been carried out prospectively by the two medical centers from December 1999 to December 2001 in Duzce region Turkey. The diagnosis was based on the presence of signs and symptoms compatible with brucellosis including a positive agglutination titre (>/=1/160) and/or a positive culture. Doxycycline and rifampicin group consisted of 14 patients who were given doxycycline 200 mg/day plus rifampicin 600 mg/day during 45 days and this group Ofloxacin plus rifampicin group was consisted of 15 patients who were given ofloxacin 400 mg/day plus rifampicin 600 mg/day during 30 days. RESULTS: Regarding clinical and/or demographic characteristics no significant difference was found between two groups of patients that underwent two different therapeutic regimens. At the end of the therapy, two relapses were seen in both groups (p = 0.695). Although duration of therapy was two weeks shorter in group treated with rifampicin plus ofloxacin, the cure rate was similar in both groups of examinees. Fever dropped more rapidly in the group that treated with rifampicin plus ofloxacin, 74 +/- 30 (ranges 48-216) vs. 106 +/- 26 (ranges 48-262) hours (p = 0.016). CONCLUSIONS: Ofloxacin plus rifampicin therapy has advantages of shorter treatment duration and provided shorter course of fever with treatment than in doxycycline plus rifampicin therapy. However, cost of ofloxacin plus rifampicin treatment is higher than doxycycline plus rifampicin treatment. Because of the similar effects, adverse effects and relapses rates between two regimens, we still advice doxycycline plus rifampicin for the treatment of brucellosis for countries, which have limited resources.

Drug costs and bacterial susceptibility after implementing a single-fluoroquinolone use policy at a university hospital.

The University of Kentucky Hospital investigated the feasibility of choosing a sole fluoroquinolone for its formulary in an effort to reduce costs without affecting clinical outcomes. A three-step process was used to plan, implement, and monitor the selection program. Based on the range of clinical indications, safety profile, local susceptibility, cost, and dosing convenience, levofloxacin was chosen over ciprofloxacin and gatifloxacin as the sole fluoroquinolone. Since the implementation of the program in May 2001, susceptibility to levofloxacin has been maintained or increased for the most common pathogens. In addition, University Hospital has saved nearly 100,000 dollars in antibiotic acquisition costs during the first 12 months after the switch. This assessment did not take into account effects in clinical outcomes, such as clinical failures (such as readmission rates), mortality, and adverse events, or measure changes in overall medical expenditures beyond drug acquisition costs. In the future, monitoring of overall patient care and medical care costs, in addition to susceptibility patterns and drug costs, will allow for a better understanding of the long-term benefits of this switch.

Characterization of the onset and consequences of pneumonia due to fluoroquinolone-susceptible or -resistant Pseudomonas aeruginosa.

OBJECTIVES: This study was conducted to identify and compare the microbiological and clinical outcomes among hospitalized adults with pneumonia caused by fluoroquinolone-susceptible or -resistant strains of Pseudomonas aeruginosa. Antibiotic regimens used prior to, as well as those used to treat, the infections were characterized. PATIENTS AND METHODS: This non-randomized multicentre study included 100 consecutively identified patients with pneumonia caused by fluoroquinolone-susceptible (n = 50) or fluoroquinolone-resistant (n = 50) strains of P. aeruginosa. Medical records were examined for demographic, clinical and treatment variables including antibiotics received in the 30 days before the index respiratory or blood culture; AUICs were calculated for each patient using reported or derived MICs. Multivariate logistic and linear regressions were used to identify factors associated with successful clinical and microbiological outcomes. RESULTS: The study population was primarily elderly, frequently in a critical care unit, with low serum albumin and with a high probability of failure and mortality. Patients with pneumonia caused by fluoroquinolone-resistant P. aeruginosa were more likely to have received antibiotics within 7 days before the infection (P = 0.027); the antibiotic regimen was more likely to be of a weak potency (mean AUIC of 58 versus 169, P = 0.001) and to include levofloxacin (P < 0.0001) than what was administered to patients who became infected with a fluoroquinolone-susceptible strain. Regardless of susceptibility, a mean of between 2 and 3 weeks of directed antibiotic therapy was administered to each patient. CONCLUSIONS: Pneumonia caused by fluoroquinolone-resistant P. aeruginosa is frequently associated with prior exposure to levofloxacin. Treatment of P. aeruginosa pneumonia is difficult and usually consists of combination regimens with multiple modifications.

A benefit-risk assessment of ofloxacin otic solution in ear infection.

Ofloxacin is a fluoroquinolone antibacterial with potent bactericidal activities and the topical otological preparation of this drug has been clinically utilised since the late 1980s. The rate of eradication with ofloxacin ranges from 83.3% to 100% for all pathogens commonly isolated from middle ear effusions in cases of otitis media and otitis externa. Despite the significant length of its usage, emergence of resistant pathogens has been rarely encountered in clinical trials; only two strains of Pseudomonas aeruginosa have been documented with decreased susceptibility to ofloxacin following the use of the otic solution.Ear infections, including otitis externa, chronic suppurative otitis media and otorrhoea associated with tympanostomy tubes, are common problems in clinical practice. The potential complications associated with ear infection can be otological, extratemporal, or even psychosocial. They are sometimes fatal and the effect can be long-lasting and detrimental. The use of an effective topical antibacterial with high cost-effectiveness is definitely warranted. As regards various clinical aspects, including overall success rate, symptomatic relief of otalgia and otorrhoea, ofloxacin otic solution was found to be more effective than comparator agents, be it a topical antibacterial, a systemic antibacterial or combination drugs. The systemic absorption of fluoroquinolones is minimal after topical application. Ofloxacin otic solution 0.3% has been shown to have a low rate of adverse drug reactions. Adverse reactions to ofloxacin otic solution were generally mild. The lack of ototoxic effect from ofloxacin eardrops, even in the concentration higher than 0.3%, has been demonstrated in animal studies. In the clinical setting, no increase in bone-conduction threshold has been shown after the treatment of topical ofloxacin otic solution. There have not been any reports of ototoxicity with ofloxacin otic solution since its approval. To conclude, ofloxacin otic solution 0.3% is clinically effective in the treatment of otitis externa and chronic suppurative otitis media in particular with respect to the overall cure rate, relief of otalgia and otorrhoea. It is well tolerated, with minimal adverse effects. It is not associated with any ototoxicity both experimentally and clinically.

Latest industry information on the safety profile of levofloxacin in the US.

This paper reviews the safety data for levofloxacin utilizing reports from clinical and post-marketing surveillance trials. The side effect incidence rates are 1.3% for nausea, 0.1% for anxiety, 0.3% for insomnia, and 0.1% for headache. No levofloxacin-related adverse events were reported at a rate higher than 1.3%, and most were lower. Four clinical trials were reported. Levofloxacin achieved superior clinical and microbiological results compared to ceftriaxone/macrolide combination, and was better tolerated. Results comparing IV azithromycin plus ceftriaxone versus 500 mg levofloxacin in hospitalised CAP demonstrated that levofloxacin performed better, with more adverse events associated with the comparators (levofloxacin 5.3%, comparators 9.3%). High-dose levofloxacin (750 mg) was also evaluated and found to be well tolerated. Surveillance data reported low ADR rates for levofloxacin: nausea 0.8%, rash 0.5%, abdominal pain 0.4%, and diarrhoea, dizziness, and vomiting 0.3%. Worldwide and US surveillance data confirmed that tendon rupture occurred in less than 4 per million prescriptions, taste perversion in less than 3 per million, convulsions in 2 per million, and photosensitivity, hepatitis, hepatic failure, QT prolongation, torsade de pointes or empyema all in less than 1 per million.

Latest industry information on the safety profile of levofloxacin in Japan.

This paper focuses on the development of four major adverse drug reactions (ADRs) associated with some fluoroquinolones: convulsions, phototoxicity, cardiac effects, and hepatotoxicity. CNS adverse events have been linked to fluoroquinolone administration, including seizures, which are more likely with co-administration of NSAIDs. Only 61 cases of convulsions have been reported with levofloxacin, with 33 of those affected having received NSAIDs. The assumed rate of serious convulsions was as low as 1/65,000 with NSAIDs and 1/260,000 without NSAIDs. Levofloxacin has a very low phototoxicity-inducing potential confirmed by pre-clinical animal studies and the results of post-marketing surveillance (PMS). Pre-clinical results demonstrated that levofloxacin was 20 times less phototoxic than sparfloxacin and PMS data show that serious phototoxicity develops in only 1 in 1.8 million cases treated with levofloxacin. While many fluoroquinolones are associated with cardiac effects, pre-clinical data has shown that compared with sparfloxacin and grepafloxacin, levofloxacin has no effect on myocardial conduction. PMS data further support the safety of levofloxacin in this regard. While trovafloxacin is associated with serious hepatic problems, PMS data demonstrates that levofloxacin has a very low incidence of 1/100,000 hepatic effects. These results were confirmed in a prospective study that confirmed a low 1.3% incidence rate for all ADRs associated with levofloxacin.

Open-label assessment of levofloxacin for the treatment of acute bacterial sinusitis in adults.

PURPOSE: To evaluate the efficacy and safety of levofloxacin (500 mg orally once daily for 10 to 14 days) in treating adult outpatients with acute bacterial sinusitis. PATIENTS AND METHODS: A total of 329 patients enrolled in the study at 24 centers. All patients had a pre-therapy Gram's stain and culture of sinus exudate obtained by antral puncture or nasal endoscopy. Clinical response was assessed on the basis of signs and symptoms and sinus radiograph or computed tomography results. Microbiologic cure rates were determined on the basis of presumed plus documented eradication of the pre-therapy pathogen(s). RESULTS: The most common pathogens were Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, and Moraxella catarrhalis. Of 300 clinically evaluable patients, 175 (58%) were cured and 90 (30%) were improved at the post-therapy evaluation, resulting in a clinical success rate of 88%. Thirty-five patients (12%) clinically failed treatment. The microbiologic eradication rate (presumed plus documented) among 138 microbiologically evaluable patients was 92%. Microbiologic eradication rates (presumed plus documented) of the most common pathogens ranged from 93% (M. catarrhalis) to 100% (S. pneumoniae) at the post-therapy visit. All but one of the 265 patients who were cured or improved at post-therapy returned for a long-term follow-up visit; 243 (92%) remained well 4 to 6 weeks after therapy; and 21 (8%) had a relapse of symptoms. Adverse events considered to be related to levofloxacin administration were reported by 29 patients (9%). The most common drug-related adverse events were diarrhea, flatulence, and nausea; most adverse events were mild to moderate in severity. CONCLUSION: The results of this study indicate that levofloxacin 500 mg once daily is an effective and safe treatment for acute bacterial sinusitis.

A comparison of ciprofloxacin, norfloxacin, ofloxacin, azithromycin and cefixime examined by observational cohort studies.

1. The safety in everyday clinical usage of three 4-quinolone antibiotics, (ciprofloxacin, norfloxacin and ofloxacin), was compared with similar data for azithromycin and cefixime, each agent being examined by Prescription-Event Monitoring (PEM) during the early post-marketing period. 2. In PEM the exposure data are derived from general practitioner prescriptions confidentially provided by the Prescription Pricing Authority. Outcome data are provided by questionnaires (green forms) on which the prescribing medical practitioner records event data. When necessary, further information is obtained from a number of sources which include follow-up of all pregnancies and the patients' life-time medical record. 3. The main outcome measures were demographic information, including the patient's date of birth and sex; the indication for prescribing the drug being monitored; the reason for stopping treatment; the start and stop dates of treatment and the events recorded during and after treatment. 4. The final cohort for each of the five antibiotics exceeded 11000 patients. The only event significantly related to the use of all five antibiotics was nausea/vomiting. This was also the most frequent adverse event causing treatment to be discontinued with norfloxacin, ofloxacin and azithromycin (relevant information was not requested in the studies of ciprofloxacin and cefixime). Vaginal candidiasis was significantly more frequently associated with the use of the three 4-quinolones than with azithromycin and cefixime but it was frequently delayed until the week or two after the cessation of therapy. Within each event, as recorded in these studies, the highest event rates (the number of events per 1000 patients) in the week following the start of therapy were: 9.2 for diarrhoea with cefixime; 4.9 for nausea/vomiting with ofloxacin; 2.4 for rash with azithromycin; 2.2 for abdominal pain with norfloxacin; 1.5 for headache/migraine with ofloxacin; 1.4 for malaise/lassitude with ofloxacin; 1.2 for dizziness with norfloxacin. Uncommon events (reported in less than 1:1000 patients) included rare cases of allergic phenomena, convulsions and pseudomembranous colitis. There were no reports of tendinitis, tenosynovitis or tendon rupture in children but tendon disorders were reported in the two months following the start of treatment in 20 adults. A total of 307 pregnancies were reported. Thirty-eight of the 55 women who received these drugs during the first trimester of pregnancy gave birth to healthy babies. No congenital abnormalities were reported. Apart from one case of unconfirmed pseudomembranous colitis, none of the other 2468 deaths that occurred in these studies was attributed to the antibiotics. 5. These five antibiotics are acceptably safe antimicrobial agents when used in general medical practice. PEM is an effective method for monitoring the safety of recently introduced antimicrobial agents.