Mohammed Khashab

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.

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

SUMMARY 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 ≤ 2% of patients in either treatment group. Among patients diagnosed with atypical CAP, the 750-mg therapy resulted in more rapid symptom resolution, with a significantly greater proportion of patients experiencing resolution of fever by Day 3 of therapy ( p = 0.031). Conclusion: The 750-mg, 5-day course of levofloxacin was at least as effective as the 500-mg, 10-day regimen for atypical CAP. Additionally, the 750-mg, short-course levofloxacin therapy may reduce total antimicrobial drug usage and more rapidly relieve pneumonia symptoms.

A trial of levofloxacin 750 mg once daily for 5 days versus ciprofloxacin 400 mg and/or 500 mg twice daily for 10 days in the treatment of acute pyelonephritis

ABSTRACT Objective: A double-blind, noninferiority trial was conducted to establish the safety and efficacy of a once-daily, 5-day course of levofloxacin 750 mg compared to a twice-daily, 10-day course of ciprofloxacin in complicated urinary tract infections (cUTI) and acute pyelonephritis (AP). This report focuses on subjects with AP. Research design and methods: Adult male and female subjects with clinical signs and symptoms of AP and laboratory confirmation of their diagnosis were randomized to receive one dose of levofloxacin 750 mg once daily intravenously (IV) or orally and one dose of placebo for 5 days, followed by placebo; or ciprofloxacin 400 mg IV and/or 500 mg orally twice daily for 10 days. Main outcome measures: The primary, prospectively defined end point was microbiologic eradication at post-therapy (study days 15–22). Secondary outcomes included clinical response and safety and tolerability. Results: In the modified intent-to-treat (mITT) population (levofloxacin 94, ciprofloxacin 98), 83% of levofloxacin-treated and 79.6% of ciprofloxacin-treated subjects achieved microbiological eradication (difference –3.4, 95% CI –14.4%, 7.6%). In the microbiologically evaluable (ME) population (levofloxacin 80, ciprofloxacin 76), 92.5% of levofloxacin-treated vs. 93.4% of ciprofloxacin-treated subjects (difference –0.9, 95% CI –7.1%, 8.9%) achieved microbiologic eradication. Clinical success was achieved in 86.2% vs. 80.6% (mITT) and in 92.5% vs. 89.5% (ME) of levofloxacin-treated and ciprofloxacin-treated subjects, respectively. Escherichia coli was the most commonly isolated uropathogen. Few (2.1%) of the pathogens were fluoroquinolone-resistant. Adverse events (AEs) were similar to those seen previously with both agents. Potential limitations are that this analysis is based on a subset of subjects from a larger study and, because of different durations of therapy, the results may be biased against levofloxacin. Conclusions: High-dose, short-course therapy with levofloxacin in subjects with AP is at least as effective as standard 10-day therapy with ciprofloxacin.

Identifying Exposure Targets for Treatment of Staphylococcal Pneumonia with Ceftobiprole

ABSTRACT Ceftobiprole is a cephalosporin with potent activity against methicillin (meticillin)-resistant Staphylococcus aureus (MRSA). In order to treat patients with severe staphylococcal pneumonia, it is important to understand the drug exposure required to mediate the killing of multiple log10 cells in a preclinical-infection model. We measured drug exposure in terms of the percentage of penetration of the drug into epithelial lining fluid (ELF) and in terms of the time for which the drug concentration was above the MIC (time>MIC) in plasma and ELF. In a murine model of staphylococcal pneumonia, we demonstrated that ceftobiprole penetrated into ELF from the plasma at a median level of nearly 69% (25th to 75th percentile range, 25 to 187%), as indexed to the ratio of values for the area under the concentration-time curve in ELF and plasma. The total-drug times>MIC in ELF that were required to kill 1 log10 and 2 log10 CFU/g of lung tissue were 15% and 25% of the dosing interval. We also examined the penetration of ELF by ceftobiprole in volunteers, demonstrating mean and median penetration percentages of 25.5% and 15.3%, respectively (25th to 75th percentile range, 8 to 30%). Attainment rates were calculated for kill targets of 1 log10 and 2 log10 CFU/g, taken from the murine model, but using the volunteer ceftobiprole ELF penetration data. The standard dose for ceftobiprole is 0.5 g every 8 h as a 2-h infusion. The attainment rates remained above 90% for 1-log10 and 2-log10 CFU/g kill targets at MICs of 1 and 0.5 mg/liter, respectively. Taking the expectation over the distribution of ceftobiprole MICs for 4,958 MRSA isolates showed an overall target attainment of 85.6% for a 1-log10 CFU/g kill and 79.7% for a 2-log10 CFU/g kill. It is important to derive exposure targets in preclinical-infection models of the infection site so that these targets can be explored in clinical trials in order to optimize the probability of a good clinical outcome.

A Trial of High-Dose, Short-Course Levofloxacin for the Treatment of Acute Bacterial Sinusitis

OBJECTIVES: Compare two dosage strengths of levofloxacin in the treatment of acute bacterial sinusitis. STUDY DESIGN AND SETTING: Multicenter clinical trial comparing levofloxacin 750 mg for 5 days vs levofloxacin 500 mg for 10 days. RESULTS: Sinus fluid samples were obtained by antral puncture (59.2%) or by sinus endoscopy (40.8%). Among microbiologically evaluable patients, 91.4% (139/152) of patients receiving levofloxacin 750 mg achieved clinical success vs 88.6% (132/149) of patients receiving levofloxacin 500 mg (95% CI −10.0, 4.2). Clinical success rates by pathogen were above 90% in both treatment groups for the 3 typical pathogens of acute sinusitis: Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. The safety profile of the 2 dosage strengths was similar. CONCLUSION: Levofloxacin 750 mg for 5 days is noninferior to levofloxacin 500 mg for 10 days. SIGNIFICANCE: Levofloxacin 750 mg for 5 days represents a safe and effective treatment regimen for acute bacterial sinusitis. EBM rating: A-1b

Impact of Different Carbapenems and Regimens of Administration on Resistance Emergence for Three Isogenic Pseudomonas aeruginosa Strains with Differing Mechanisms of Resistance

ABSTRACT We compared drugs (imipenem and doripenem), doses (500 mg and 1 g), and infusion times (0.5 and 1.0 [imipenem], 1.0 and 4.0 h [doripenem]) in our hollow-fiber model, examining cell kill and resistance suppression for three isogenic strains of Pseudomonas aeruginosa PAO1. The experiments ran for 10 days. Serial samples were taken for total organism and resistant subpopulation counts. Drug concentrations were determined by high-pressure liquid chromatography-tandem mass spectrometry (LC/MS/MS). Free time above the MIC (time > MIC) was calculated using ADAPT II. Time to resistance emergence was examined with Cox modeling. Cell kill and resistance emergence differences were explained, in the main, by differences in potency (MIC) between doripenem and imipenem. Prolonged infusion increased free drug time > MIC and improved cell kill. For resistance suppression, the 1-g, 4-h infusion was able to completely suppress resistance for the full period of observation for the wild-type isolate. For the mutants, control was ultimately lost, but in all cases, this was the best regimen. Doripenem gave longer free time > MIC than imipenem and, therefore, better cell kill and resistance suppression. For the wild-type organism, the 1-g, 4-h infusion regimen is preferred. For organisms with resistance mutations, larger doses or addition of a second drug should be studied.

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

SUMMARY Objective: To evaluate the time to symptom resolution and IV-to-PO 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 IV-to-PO 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 IV ( N = 108) transitioned to PO in an average of 2.68 days while those starting on 500 mg IV ( N = 124) transitioned in 2.95 days ( P = 0.144). The median time for IV-to-PO 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 IV to PO 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 PO, potentially resulting in lower overall drug costs. Time to switch from IV to PO 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.

Comparison of the adverse event profiles of levofloxacin 500 mg and 750 mg in clinical trials for the treatment of respiratory infections.

ABSTRACT Objective: To compare safety data with levofloxacin 500 mg and 750 mg from clinical trials for the treatment of respiratory infections. Methods: We compared adverse event data for levofloxacin 500 mg and 750 mg from clinical trials in acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, and community-acquired pneumonia. Adverse events occurring after the initiation of therapy were classified as treatment-emergent adverse events (TEAE); drug-related adverse events (DRAE) were TEAE assessed by the clinical investigator as definitely/very likely or probably related to levofloxacin therapy. Results: Overall, the safety profile of the two doses was similar but not identical. TEAE occurred in 49.0% (1601/3268) of those treated with 500 mg and in 45.5% (519/1141) of those treated with 750 mg ( p = 0.042); the corresponding rates of DRAE were 7.6% (248/3268) and 8.0% (91/1141) ( p = 0.699). There was no statistically significant difference in terms of overall TEAE and DRAE rates within each of the three infectious conditions, but there were in specific events, all of which are expected with levofloxacin therapy. The limitations of this analysis include that it utilized a subset of available safety data, that it includes data only from clinical trials, and that we report primarily on events occurring in ≥ 2% of patients. Conclusions: Given similar adverse event profiles and the advantages of higher dose therapy, including shorter courses of therapy and potential impact on preventing resistance, clinicians should consider utilizing the 750 mg dose of levofloxacin when choosing between dosage strengths for treatment of indicated infections.

Study entry microbiology in patients with acute bacterial exacerbation of chronic bronchitis in a clinical trial stratifying by disease severity.

ABSTRACT Objective: To examine study entry microbiology in patients stratified by disease severity in a clinical trial in acute bacterial exacerbation of chronic bronchitis (ABECB). Methods: Patients were assigned to differing antibiotic therapies based on stratification by disease severity using parameters including forced expiratory volume in 1 second (FEV1) as a percentage of predicted value, number of exacerbations during the previous 12 months, and defined co-morbidities. All patients were required to have sputum Gram stain and culture at study entry. Results: There was no statistically significant difference in overall microbiology between patients with less severe and more severe clinical presentations. Typical ABECB pathogens (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis) were found in 46.2% (147/318) of patients with less severe presentations and 41.9% (143/341) of patients with more severe presentations. Gram-negative organisms and Staphylococcus aureus were also found in both groups. Pneumococcal susceptibilities to the three antibiotics utilized in the trial revealed marked resistance to azithromycin. Limitations of this analysis include that the clinical trial was designed to examine clinical outcomes rather than microbiology, and that we do not correlate study entry microbiology with clinical outcomes. Conclusions: Stratification of patients by disease severity did not reveal a statistically significant difference in overall microbiological profile. Gram-negative organisms and S. aureus were recovered even from patients with less severe clinical presentations. Pneumococcal resistance varied with the agent tested. These findings may have implications for the selection of appropriate antibiotic therapy.

Levofloxacin 750 mg QD for five days versus amoxicillin/clavulanate 875 mg/125 mg BID for ten days for treatment of acute bacterial exacerbation of chronic bronchitis: A post hoc analysis of data from severely ill patients

This post hoc analysis of data from a previous randomized, blinded, multicenter, parallel, noninferiority study assessed the bacterial etiology, symptom resolution, and tolerability of severe acute bacterial exacerbation of chronic bronchitis (ABECB) patients treated with either levofloxacin 750 mg QD for 5 days or amoxicillin/clavulanate 875 mg/125 mg BID for 10 days. Severe ABECB was defined as ABECB and forced expiratory volume in 1 second (FEV(1)) <50% of the predicted value, or (FEV(1)) of 50% to 65% of the predicted value plus comorbidities, or > or =4 exacerbations per year. A total of 369 patients were included in the intent-to-treat (ITT) population (187 treated with levofloxacin and 182 treated with amoxicillin/clavulanate), and 175 patients were microbiologically assessable (MA) (86 treated with levofloxacin and 89 treated with amoxicillin/clavulanate). In the ITT population, the mean age was 58.7 years, 49.1 % were male, and 48.2% were current smokers. At the on-treatment visit, a significantly higher proportion of MA patients in the levofloxacin group resolved purulent sputum production (57.5% vs 35.6%; P < 0.006), sputum production (65.4% vs 45.3%; P < 0.013), and cough (60.0% vs 44.0%; P < 0.045), compared with the amoxicillin/clavulanate group. However, no significant between-group differences were observed at posttreatment. A total of 341 pathogens were isolated, of which 143 (41.9%) were traditional ABECB flora, 181 (53.1%) were other gram-negative organisms, and 17 (5.0%) were gram-positive organisms. Overall susceptibility of the pathogens was 97.1% for levofloxacin and 90.6% for amoxicillin/clavulanate (P < 0.001). The prevalence of treatment-emergent adverse events was 42.1 % in patients who received levofloxacin and 48.6 % in those who received amoxicillin/clavulanate (95% CI,-4.0 to 17.0).