James B. Kahn

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.

Surveillance of antimicrobial resistance in Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States in 1996-1997 respiratory season

A U.S. surveillance study of antimicrobial resistance in respiratory tract pathogens in the respiratory season (1996-1997) is reported that included 11,368 isolates from 434 institutions in 45 states and the District of Columbia. beta-lactamase was produced by 33.4% of Haemophilus influenzae and 92.7% of Moraxella catarrhalis. Of the 9,190 Streptococcus pneumoniae isolates tested, 33.5% were not susceptible to penicillin (MIC > or = 0.12 microgram/mL), with 13.6% having high-level resistance (MICs > 1 microgram/mL). For H. influenzae, the most active antimicrobials (based on percent of strains susceptible) were levofloxacin (100%) and ceftriaxone (99.9%); the least active were ampicillin (67.2%) and clarithromycin (58.1%). For M. catarrhalis, the most active drugs were amoxicillin-clavulanate, ceftriaxone, and levofloxacin (100%); the least active was ampicillin. The order of the activity of the drugs against S. pneumoniae were levofloxacin (97.3%) > ceftriaxone (87.1%) > amoxicillin-clavulanate (81.7%) = clarithromycin (80.9%) > cefuroxime (74.5%) > penicillin (66.5%). The activity of the beta-lactams and clarithromycin against isolates of S. pneumoniae was closely associated with the resistance to penicillin. Levofloxacin was more active against S. pneumoniae overall, because it exhibited no cross-resistance. These data indicate that the incidence of beta-lactamase production in H. influenzae (33.4%) and M. catarrhalis (92.7%) is similar to other recent studies, and that the incidence of penicillin-intermediate and -resistant S. pneumoniae is increasing, particularly the high-level penicillin-resistant (MICs > 1 microgram/mL) strains, which were often multi-resistant.

Application of a mathematical model to prevent in vivo amplification of antibiotic-resistant bacterial populations during therapy

The worldwide increase in the prevalence of multi-antibiotic-resistant bacteria has threatened the physicians ability to provide appropriate therapy for infections. The relationship between antimicrobial drug concentration and infecting pathogen population reduction is of primary interest. Using data derived from mice infected with the bacterium Pseudomonas aeruginosa and treated with a fluoroquinolone antibiotic, a mathematical model was developed that described relationships between antimicrobial drug exposures and changes in drug-susceptible and -resistant bacterial subpopulations at an infection site. Dosing regimens and consequent drug exposures that amplify or suppress the emergence of resistant bacterial subpopulations were identified and prospectively validated. Resistant clones selected in vivo by suboptimal regimens were characterized. No mutations were identified in the quinolone resistance-determining regions of gyrA/B or parC/E. However, all resistant clones demonstrated efflux pump overexpression. At base line, MexAB-OprM, MexCD-OprJ, and MexEF-OprN were represented in the drug-resistant population. After 28 hours of therapy, MexCD-OprJ became the predominant pump expressed in the resistant clones. The likelihood of achieving resistance-suppression exposure in humans with a clinically prescribed antibiotic dose was determined. The methods developed in this study provide insight regarding how mathematical models can be used to identify rational dosing regimens that suppress the amplification of the resistant mutant population.

Levofloxacin compared with imipenem/cilastatin followed by ciprofloxacin in adult patients with nosocomial pneumonia: a multicenter, prospective, randomized, open-label study.

BACKGROUND Therapy of nosocomial pneumonia is usually empiric and includes > or = 1 broad-spectrum antimicrobial agent. When considering the use of fluoroquinolones in these difficult-to-treat infections--in which drug delivery to the site of infection may be impaired or organisms with higher minimum inhibitory concentrations may be present--an agent should be chosen whose pharmacodynamics ensure maximal drug exposure. Use of the 750-mg dose of levofloxacin should enhance therapeutic benefit in patients with nosocomial pneumonia. OBJECTIVE The goal of this study was to compare the efficacy and safety of levofloxacin 750 mg and imipenem/cilastatin followed by ciprofloxacin in adult patients with nosocomial pneumonia. METHODS This was a multicenter, prospective, randomized, open-label trial conducted in North America. Patients were randomly assigned to 1 of 2 treatment arms: levofloxacin 750 mg QD given i.v. and then orally for 7 to 15 days or imipenem/cilastatin 500 mg to 1 g i.v. every 6 to 8 hours, followed by oral ciprofloxacin 750 mg every 12 hours for 7 to 15 days. Adjunctive antibacterial therapy was mandatory in patients with documented or suspected Pseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus infection. The primary predefined outcome measure was the clinical response (cure, improvement, failure, or unable to evaluate) in microbiologically evaluable patients 3 to 15 days after the end of therapy. RESULTS The study enrolled 438 adult patients (315 men, 123 women; mean [SD] age, 55.7 [20.04] years). Two hundred twenty patients received levofloxacin, and 218 received the comparator regimen. Demographic and baseline clinical characteristics were similar in the intent-to-treat and clinically evaluable populations. In patients evaluable for microbiologic efficacy, clinical success (cure or improvement) was achieved in 58.1% (54/93) of patients who received levofloxacin, compared with 60.6% (57/94) of patients who received the comparator regimen (95% CI, -12.0 to 17.2). Similar clinical results were seen in patients evaluable for clinical efficacy and in the intent-to-treat population. In the 187 patients evaluable for microbiologic efficacy, eradication was achieved in 66.7% (62/93) of patients receiving levofloxacin and 60.6% (57/94) of patients receiving the comparator regimen (95% CI, -20.3 to 8.3). CONCLUSION In this study, levofloxacin was at least as effective and was as well tolerated as imipenem/cilastatin followed by ciprofloxacin in adult patients with nosocomial pneumonia, as demonstrated by comparable clinical and microbiologic success rates.

A Multicenter, Open-Label, Randomized Comparison of Levofloxacin and Azithromycin Plus Ceftriaxone in Hospitalized Adults with Moderate to Severe Community-Acquired Pneumonia

BACKGROUND Changing etiologic patterns and the growing problem of antimicrobial resistance, particularly an increase in macrolide-resistant pneumococcal bacteremia, are causing physicians to adopt new approaches to the treatment of community-acquired pneumonia (CAP). OBJECTIVE The relative efficacy and tolerability of levofloxacin monotherapy and azithromycin and ceftriaxone combination therapy were assessed in hospitalized adults with moderate to severe CAP. METHODS This Phase IV, multicenter, open-label, randomized trial compared 2 treatment regimens: (1) levofloxacin 500 mg PO or IV q24h, and (2) azithromycin 500 mg IV q24h for > or = 2 days plus ceftriaxone 1 g IV q24h for 2 days, followed by an optional transition to azithromycin 500 mg PO q24h at the investigators discretion. The total duration of therapy was to be a minimum of 10 days in both treatment groups. Ceftriaxone was included in the initial azithromycin regimen to ensure coverage against pneumococcal bacteremia. RESULTS Of 236 patients in the intent-to-treat population, completion or withdrawal information was available for 110 patients in the levofloxacin group and 114 in the azithromycin group. Baseline demographic and disease characteristics were comparable between groups. At the end of treatment, the clinical success rate (cured + improved) in clinically evaluable patients was 94.1% in the levofloxacin group and 92.3% in the azithromycin group. The respective posttherapy microbiologic eradication rates were 89.5% and 92.3%. Levofloxacin was as well tolerated as azithromycin, with an incidence of drug-related adverse events (AEs) for all body systems of 5.3% and 9.3%, respectively. None of the drug-related AEs were considered serious [corrected]. CONCLUSIONS In this study in hospitalized patients with moderate to severe CAP, levofloxacin monotherapy was at least as effective as a combination regimen of azithromycin and ceftriaxone in providing coverage against the current causative pathogens in CAP. In addition, levofloxacin was as well tolerated as the combination of azithromycin and ceftriaxone.

Probability of Target Attainment for Ceftobiprole as Derived from a Population Pharmacokinetic Analysis of 150 Subjects

ABSTRACT Ceftobiprole is a broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) that is undergoing phase III trials for the treatment of complicated skin and skin structure infections and nosocomial pneumonia. The objectives were to describe the pharmacodynamic profiles of ceftobiprole given at 500 mg intravenously (i.v.) every 8 h (q8h) (2-h infusion) and 500 mg i.v. every 12 h (q12h) (1-h infusion) to determine the overall probability of target attainment (PTA) by weighting for the expected distributions of renal function in the populations of interests, to determine the PTA against representative pathogens encountered in clinical trials, and to determine the optimal renal dose adjustment for ceftobiprole at 500 mg i.v. q8h (2-h infusion). Data for a total of 150 subjects in phase I/II trials were analyzed by using the population pharmacokinetic modeling program BigNPOD (nonparametric optimal design). Monte Carlo simulation was performed with the ADAPT II program to estimate the PTA at which the free drug concentrations exceed the MIC for 30 to 60% of the dosing interval (30 to 60% fT > MIC). For ceftobiprole at 500 mg i.v. q12h, the probabilities of achieving 30% and 50% fT > MIC exceeded 90% for MICs ≤2 mg/liter and ≤1 mg/liter, respectively, For ceftobiprole at 500 mg i.v. q8h, the probabilities of achieving 40 and 60% fT > MIC exceeded 90% for MICs ≤4 mg/liter and ≤2 mg/liter, respectively. For ceftobiprole at both 500 mg i.v. q12h and 500 mg i.v. q8h, the probability of achieving a nearly bactericidal effect (50% fT > MIC) exceeded 90% for methicillin-susceptible S. aureus and MRSA. For gram-negative pathogens, the PTA for achieving a nearly maximal bactericidal effect (60% fT > MIC) for ceftobiprole at 500 mg i.v. q8h exceeded 90% for non-AmpC-producing gram-negative organisms. Ceftobiprole at 500 mg i.v. q12h, for patients who had a creatinine clearance rate of ≤50 ml/min, was identified as the most appropriate treatment regimen for patients who require renal dose adjustment for mild to moderate renal impairment.

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 Multicenter, Investigator-Blinded, Randomized Comparison of Oral Levofloxacin and Oral Clarithromycin in the Treatment of Acute Bacterial Sinusitis

A multicenter, investigator‐blinded, randomized, parallel‐group study was conducted to compare oral levofloxacin 500 mg once/day for 14 days with clarithromycin 500 mg twice/day for 14 days in the treatment of acute bacterial sinusitis. Of 216 adult outpatients randomized to treatment, 190 were evaluable for efficacy. The primary efficacy measure was clinical response, based on resolution of signs and symptoms 2–5 days after therapy. A secondary efficacy measure was relapse rate 1 month after therapy. Among evaluable patients, clinical success rates (cured or improved) were 96.0% and 93.3% for levofloxacin (L) and clarithromycin (C), respectively (95% CI −9.2%, 3.7%). The confidence interval (CI) for treatment difference (C‐L) included zero and its upper limit was less than 15%, indicating that levofloxacin was as effective as clarithromycin. In all, 4.1% of patients receiving levofloxacin and 7.2% receiving clarithromycin had a relapse of symptoms 1 month after therapy (95% CI −12.2%, 3.2%). Long‐term success (initial success, absence of relapse at 1 month, no further antibacterial therapy 2–5 days after therapy) was 79.2% in the levofloxacin group and 76.4% in the clarithromycin group (95% CI −14.7%, 9.0%). Based on investigator‐assessed treatment‐emergent adverse events, overall tolerability of the drugs was similar, except for a higher frequency of taste perversion and diarrhea in the clarithromycin group. Levofloxacin had an advantage over clarithromycin based on two quality‐of‐life (QOL) parameters: number of times taking other drugs for targeted medical conditions and mean total cost of these drugs. No statistical significance was found in other QOL variables. These findings suggest that the efficacy and tolerability of levofloxacin 500 mg once/day are comparable with those of clarithromycin 500 mg twice/day in the treatment of acute bacterial sinusitis.

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