Pneumonia due to Pseudomonas aeruginosa: the levofloxacin clinical trials experience.

Respiratory infections caused by Pseudomonas aeruginosa present significant treatment challenges, including that of overcoming intrinsic and adaptive resistance by these organisms. The fluoroquinolones may provide an effective option for treating these infections. In this analysis, we report on the efficacy of levofloxacin in the treatment of community-acquired pneumonia (CAP) and nosocomial pneumonia caused by P. aeruginosa using information from nine clinical studies supported by Johnson & Johnson Pharmaceutical Research and Development (Raritan, NJ) or Ortho-McNeil Pharmaceutical (Raritan, NJ). From these studies, a total of 36 patients were identified with pneumonia caused by P. aeruginosa and treated with levofloxacin (750 mg or 500 mg). For patients diagnosed with nosocomial pneumonia, levofloxacin treatment achieved a 64.7% (11/17) clinical success rate, compared with 41.2% (7/17) with comparator treatment (imipenem/cilastatin followed by ciprofloxacin) in the microbiologically evaluable population. Eradication rates were 58.8% with levofloxacin treatment vs. 29.4% with comparator (95% CI, -64.2 to 5.4). For levofloxacin-treated CAP patients with P. aeruginosa infections (n = 19), clinical success and microbiological eradication rates in the microbiologically evaluable population were 89.5% and 78.9%, respectively. Several limitations of this analysis exist including that this was a retrospective evaluation that pooled data from multiple studies with varying protocols, the number of patients included was limited, and the nosocomial pneumonia patients used adjunctive therapy with an antipseudomonal beta-lactam in most cases. Nonetheless, these findings suggest that levofloxacin may play a role in the treatment of these difficult respiratory infections.

Levofloxacin 750-mg for 5 days for the treatment of hospitalized Fine Risk Class III/IV community-acquired pneumonia patients.

BACKGROUND: The efficacy and safety of 750-mg, 5-day levofloxacin was recently shown to be comparable to 500-mg, 10-day levofloxacin in a randomized, double-blind, multicentre clinical trial for mild-to-severe community-acquired pneumonia (CAP). This subgroup analysis attempted to compare the safety and efficacy of a short-course levofloxacin regimen with traditional levofloxacin dosing for PSI Class III/IV patients. METHODS: This retrospective, subgroup analysis focused on Pneumonia Severity Index Class III and IV patients enrolled in the study. Measurements included clinical and microbiological success rates, adverse events, and symptom resolution by day 3 of therapy. RESULTS: Of the 528 patients in the ITT population, 219 (41.5%) were categorized as PSI Class III/IV and included in this analysis. Among the clinically evaluable patients, 90.8% (69/76) of patients treated with the 750-mg regimen achieved clinical success, compared with 85.5% (71/83) treated with 500-mg levofloxacin (95% CI,-15.9 to 5.4). Eradication rates in the microbiologically evaluable population were comparable for the 750- and 500-mg regimens (88.9% vs 87.5%, respectively; 95% CI,-18.3 to 15.6). Both regimens were well tolerated and had comparable safety profiles. A greater proportion of patients in the 750-mg treatment group experienced resolution of fever (48.4% vs 34.0%; P=.046) and purulent sputum (48.4% vs 27.5%; P=.007) by day 3 of therapy. CONCLUSIONS: The 750-mg, 5-day levofloxacin course achieved comparable clinical and microbiologic efficacy to the 500-mg, 10-day regimen. By day 3 of therapy, a greater proportion of patients in the 750-mg group had objective and subjective resolution of fever. Further research is needed to determine the economic significance of short-course levofloxacin therapy.

Levofloxacin for treatment of ventilator-associated pneumonia: a subgroup analysis from a randomized trial.

Ventilator-associated pneumonia (VAP) remains a significant challenge in critical care. We conducted a secondary analysis of a multicenter, prospective, randomized trial comparing levofloxacin (750 mg iv q24h) with imipenem-cilastatin (500-1000 mg iv q6-8h) for treatment of nosocomial pneumonia and focused on the subgroup of patients with VAP. The study cohort included 222 patients, with half (111) of the patients assigned to each treatment group. The patients in both groups were similar with respect to age, severity of illness, and duration of mechanical ventilation before the onset of VAP. Among the intention-to-treat population, clinical success was achieved in 58.6% of patients receiving levofloxacin, compared with 63.1% of patients receiving imipenem-cilastatin (P=.49; 95% confidence interval for the difference, -8.77% to 17.79%). Microbiological success and 28-day mortality rates were also comparable. Multivariate analysis demonstrated that assignment to antibiotic treatment (i.e., levofloxacin vs. imipenem-cilastatin) was not predictive of outcomes, thus suggesting that the treatment regimens were equivalent. Both levofloxacin and imipenem-cilastatin regimens were well tolerated and had similar adverse event profiles.

A multicenter, randomized, double-blind, retrospective comparison of 5- and 10-day regimens of levofloxacin in a subgroup of patients aged > or =65 years with community-acquired pneumonia.

OBJECTIVE: This subgroup analysis sought to determine the efficacy and tolerability of a 5-day regimen of levofloxacin 750 mg/d compared with a 10-day regimen of levofloxacin 500 mg/d in the treatment of community-acquired pneumonia (CAP) in elderly patients (aged > or =65 years). METHODS: This subgroup analysis was based on the outcomes in patients aged > or =65 years from a randomized, double-blind, controlled trial conducted at 70 US centers. Patients in Pneumonia Severity Index (PSI) class I/II and III/IV were randomized to receive levofloxacin 750 mg/d for 5 days or levofloxacin 500 mg/d for 10 days. Study investigators assessed clinical and microbiologic outcomes 7 to 14 days after administration of the last dose of medication and collected adverse events for 30 days after the last dose. RESULTS: This analysis included 177 elderly patients, 80 receiving levofloxacin 750 mg/d for 5 days and 97 receiving levofloxacin 500 mg/d for 10 days. Although most demographic and baseline clinical characteristics were comparable between the 2 groups, the group that received levofloxacin 500 mg/d was older than the group that received levofloxacin 750 mg/d (median age, 76.0 vs 72.5 years, respectively; P = 0.029) and had a higher mean PSI score (90.7 vs 83.1; P = 0.017). Despite the halved duration of therapy, unadjusted clinical success rates were comparable between the 2 groups (89.0% and 91.9% in the 750- and 500-mg arms, respectively; 95% CI, -7.1 to 12.7). Microbiologic eradication rates were 90.3% (28/31) in the 750-mg arm and 87.5% (14/16) in the 500-mg arm (P = NS). Multivariate analysis adjusting for baseline PSI score indicated that treatment assignment was not statistically associated with clinical success (adjusted odds ratio for clinical success with 500-mg dose, 1.92; 95% CI, 0.62 to 5.99). The incidence of treatment-emergent adverse events did not differ between the 2 study treatments. The most common adverse events in both groups were insomnia, constipation, and headache. CONCLUSIONS: This subgroup analysis found that levofloxacin 750 mg/d for 5 days was well tolerated in the treatment of CAP in elderly patients. Undajusted and adjusted rates of clinical success were statistically similar between levofloxacin 750 mg/d for 5 days and levofloxacin 500 mg/d for 10 days.

High-dose, short-course levofloxacin for community-acquired pneumonia: a new treatment paradigm.

Levofloxacin demonstrates concentration-dependent bactericidal activity most closely related to the pharmacodynamic parameters of the ratio of area under the concentration-time curve (AUC) to minimum inhibitory concentration (MIC) and the ratio of peak plasma concentration (C(max)) to MIC. Increasing the dose of levofloxacin to 750 mg exploits these parameters by increasing peak drug concentrations, allowing for a shorter course of treatment without diminishing therapeutic benefit. This was demonstrated in a multicenter, randomized, double-blind investigation that compared levofloxacin dosages of 750 mg per day for 5 days with 500 mg per day for 10 days for the treatment of mild to severe community-acquired pneumonia (CAP). In the clinically evaluable population, the clinical success rates were 92.4% (183 of 198 persons) for the 750-mg group and 91.1% (175 of 192 persons) for the 500-mg group (95% confidence interval, -7.0 to 4.4). Microbiologic eradication rates were 93.2% and 92.4% in the 750-mg and 500-mg groups, respectively. These data demonstrate that 750 mg of levofloxacin per day for 5 days is at least as effective as 500 mg per day for 10 days for treatment of mild-to-severe CAP.

Levofloxacin efficacy in the treatment of community-acquired legionellosis.

BACKGROUND: Although fluoroquinolones possess excellent in vitro activity against Legionella, few large-scale clinical trials have examined their efficacy in the treatment of Legionnaires disease. Even fewer studies have applied rigorous criteria for diagnosis of community-acquired Legionnaires disease, including culture of respiratory secretions on selective media. METHODS: Data from six clinical trials encompassing 1,997 total patients have been analyzed to determine the efficacy of levofloxacin (500 mg qd or 750 mg qd) in treating patients with community-acquired pneumonia (CAP) due to Legionella. RESULTS: Of the 1,997 total patients with CAP from the clinical trials, 75 patients had infection with a Legionella species. Demographics showed a large portion of these patients were < 55 years of age and nonsmokers. More than 90% of mild-to-moderate and severe cases of Legionella infection resolved clinically at the posttherapy visit, 2 to 14 days after treatment termination. No deaths were reported for any patient with Legionnaires disease treated with levofloxacin during the studies. CONCLUSIONS: Levofloxacin was efficacious at both 500 mg for 7 to 14 days and 750 mg for 5 days. Legionnaires disease is not associated only with smokers, the elderly, and the immunosuppressed, but also has the potential to affect a broader demographic range of the general population than previously thought.

Clinical implications of 750 mg, 5-day levofloxacin for the treatment of community-acquired pneumonia.

OBJECTIVE: To evaluate the time to symptom resolution and i.v.-to-p.o. transition in community-acquired pneumonia (CAP) patients treated with 750 mg or 500 mg levofloxacin. RESEARCH DESIGN: A retrospective, subset analysis of a multicenter, randomized, double-blind, controlled trial comparing 750 mg levofloxacin for 5 days to 500 mg levofloxacin for 10 days for the treatment of CAP. PATIENTS AND METHODS: A total of 528 CAP patients were included. Baseline symptoms were re-evaluated on Day 3 of therapy, and time to i.v.-to-p.o. transition was recorded for inpatients. RESULTS: For the overall population, 67.4% of patients receiving 750 mg levofloxacin had resolution of fever by Day 3 of therapy, compared to 54.6% of 500 mg treated patients (P = 0.006). Patients who started on 750 mg levofloxacin i.v. (N = 108) transitioned to p.o. in an average of 2.68 days while those starting on 500 mg i.v. (N = 124) transitioned in 2.95 days (P = 0.144). The median time for i.v.-to-p.o. switch was 2.35 days and 2.75 days for patients receiving 750 mg and 500 mg levofloxacin, respectively (P = 0.098, log rank test). By Day 3 of therapy, 68% of patients receiving the 750 mg dose had transitioned from i.v. to p.o. levofloxacin, compared with 61% of the 500 mg group (P = 0.280). The safety profiles were comparable for the two regimens. CONCLUSIONS: The 750 mg levofloxacin dose resulted in a greater proportion of patients with resolution of CAP symptoms by Day 3 when compared with 500 mg therapy. Consequently, the 750 mg regimen trended toward more rapid transition to p.o., potentially resulting in lower overall drug costs. Time to switch from i.v. to p.o. was determined by the investigators' discretion rather than a set protocol. Additionally, length of stay data was not collected in this study, which can significantly impact overall healthcare costs. Further research is required to fully understand the economic impact of the 750 mg, 5-day levofloxacin regimen.

Efficacy of 750-mg, 5-day levofloxacin in the treatment of community-acquired pneumonia caused by atypical pathogens.

BACKGROUND: Current recommended durations for treatment of atypical community-acquired pneumonia (CAP) range from 10 to 21 days. However, antibiotics such as the fluoroquinolones may allow for effective, short-course regimens. OBJECTIVE: This study evaluated the efficacy of 750 mg levofloxacin for 5 days compared to a 500-mg, 10-day levofloxacin regimen for the treatment of atypical CAP. METHODS: A randomized, active-controlled, double-blind, multicenter study was conducted within the United States. Of the 528 patients enrolled in the study, 149 were diagnosed with CAP due to Legionella pneumophila, Chlamydia pneumoniae, or Mycoplasma pneumoniae. Patients' baseline symptoms were re-evaluated on Day 3 of therapy. Clinical efficacy and resolution of CAP symptoms were evaluated at the posttherapy visit (7-14 days after the last dose of active drug). RESULTS: This report represents a subgroup analysis of a previous clinical study. Among the 123 clinically evaluable patients diagnosed with atypical CAP (26 patients were unevaluable), the clinical success rates were 95.5% (63 of 66 patients) for the 750-mg group and 96.5% (55 of 57 patients) for the 500-mg group (95% CI for success rate of the 500-mg group minus that of the 750-mg group, -6.8 to 8.8). At the poststudy evaluation (31-38 days after treatment began), relapse occurred in

Treatment of chronic bacterial prostatitis with levofloxacin and ciprofloxacin lowers serum prostate specific antigen.

PURPOSE: We compared baseline and post-therapy prostate specific antigen (PSA) in patients with chronic bacterial prostatitis who were treated with levofloxacin or ciprofloxacin. MATERIALS AND METHODS: Subset analysis was done using a randomized, multicenter, double-blind, active control trial of 500 mg levofloxacin daily for 28 days vs 500 mg ciprofloxacin twice daily in 28 days in men with chronic bacterial prostatitis. RESULTS: Of the 377 men in the intent to treat population, including 197 treated with levofloxacin and 180 treated with ciprofloxacin, 35 on levofloxacin and 37 on ciprofloxacin with baseline PSA greater than 4 ng/ml were included in this analysis. Excluded from analysis were 2 levofloxacin treated patients with extremely high PSA at baseline (62 and 103 ng/ml, respectively). Mean baseline PSA +/- SD in the patients analyzed was 8.33 +/- 4.46 ng/ml, which decreased to 5.36 +/- 3.82 ng/ml after therapy. There was no significant difference in the mean change in PSA between the levofloxacin and ciprofloxacin groups. Approximately 42% of patients with increased baseline PSA had a post-therapy PSA of 4 ng/ml or less. Of patients who were microbiologically evaluable and had normalized PSA after therapy levofloxacin eradicated the pathogen in 90.9% (10 of 11). However, of patients in whom post-therapy PSA remained increased the microbiological eradication rate was 69.2% (9 of 13). Similarly 93.3% of the ciprofloxacin group (14 of 15 patients) with normalized post-therapy PSA experienced microbiological eradication compared with 61.5% (8 of 13) with continued increased PSA after therapy. CONCLUSIONS: Approximately 20% of patients diagnosed with chronic bacterial prostatitis had increased PSA. A significant decrease in PSA was observed in these patients after treatment with levofloxacin or ciprofloxacin. An association was observed between bacterial persistence and the likelihood that PSA would return to normal.

Levofloxacin versus ciprofloxacin in the treatment of chronic bacterial prostatitis: a randomized double-blind multicenter study.

OBJECTIVES: To compare the safety and efficacy of levofloxacin with that of ciprofloxacin for the treatment of chronic bacterial prostatitis. METHODS: In a multicenter, double-blind, active-control trial, 377 men with a history of chronic bacterial prostatitis, current clinical signs and symptoms, and laboratory evidence of prostatitis were randomized to treatment with levofloxacin 500 mg once daily or ciprofloxacin 500 mg twice daily for 28 days. The primary endpoint was microbiologic efficacy in the microbiologically assessable population. The Meares-Stamey "four-glass" procedure was used to obtain prostatic secretions and urine for culture. RESULTS: A total of 377 subjects received the study drug. The clinical success rates, including cured plus improved patients, were similar (75% for levofloxacin and 72.8% for ciprofloxacin; 95% confidence interval for the difference in the success rates: -13.27 to 8.87), as were the microbiologic eradication rates (75% for levofloxacin and 76.8% for ciprofloxacin; 95% confidence interval for the difference -8.98 to 12.58). Enterococcus faecalis and Escherichia coli were the most common isolates. The 6-month relapse rates were similar for both regimens. Both levofloxacin and ciprofloxacin were well tolerated, with similar rates of adverse events. CONCLUSIONS: Levofloxacin 500 mg once daily for 28 days is as effective as ciprofloxacin 500 mg twice daily for 28 days for the treatment of chronic bacterial prostatitis. Isolation of a high proportion of gram-positive organisms, as well as gram-negative pathogens, underscores the necessity of choosing an antimicrobial agent with broad-spectrum activity.