Fluoroquinolones in the management of community-acquired pneumonia.

AIMS: Review of the current guidelines for the use of respiratory fluoroquinolones in the management of community-acquired pneumonia (CAP). METHODS: Data were collected from recent clinical trials on fluoroquinolone therapy in patients with CAP and from updated recommendations of antimicrobial therapy in managing CAP, with a focus on current North American guidelines. RESULTS: Randomised clinical trials of respiratory fluoroquinolones (moxifloxacin, levofloxacin and gemifloxacin) in the treatment of CAP were identified and analysed. The bacteriology of CAP, and susceptibility rates, resistance rates and pharmacokinetic and pharmacodynamic properties of fluoroquinolones against causative pathogens in CAP, and adverse event profiles of these agents were described. Respiratory fluoroquinolones have broad-spectrum antibacterial activities against common causative pathogens in CAP and provide an important treatment option as monotherapy for outpatients with comorbidities and inpatients who are not admitted to the intensive care unit (ICU), including those with risk factors of drug-resistant Streptococcus pneumoniae. For treatment of ICU patients with severe CAP, it is recommended that fluoroquinolones be used in combination with a beta-lactam. Recent studies also demonstrated a more rapid resolution of clinical symptoms with the use of highly potent respiratory fluoroquinolones. DISCUSSION: Appropriate use of fluoroquinolone agents may shorten the duration of antimicrobial therapy and the length of hospital stay and contribute to the decreased development of resistance in patients with CAP. Adverse event profiles of these agents should be considered to facilitate the selection of an appropriate fluoroquinolone for appropriate CAP patients. CONCLUSION: The fluoroquinolone class, specifically those with adequate activity against respiratory pathogens, represents an important and convenient treatment option for patients with CAP.

Levofloxacin penetration into epithelial lining fluid as determined by population pharmacokinetic modeling and monte carlo simulation.

Levofloxacin was administered orally to steady state to volunteers randomly in doses of 500 and 750 mg. Plasma and epithelial lining fluid (ELF) samples were obtained at 4, 12, and 24 h after the final dose. All data were comodeled in a population pharmacokinetic analysis employing BigNPEM. Penetration was evaluated from the population mean parameter vector values and from the results of a 1,000-subject Monte Carlo simulation. Evaluation from the population mean values demonstrated a penetration ratio (ELF/plasma) of 1.16. The Monte Carlo simulation provided a measure of dispersion, demonstrating a mean ratio of 3.18, with a median of 1.43 and a 95% confidence interval of 0.14 to 19.1. Population analysis with Monte Carlo simulation provides the best and least-biased estimate of penetration. It also demonstrates clearly that we can expect differences in penetration between patients. This analysis did not deal with inflammation, as it was performed in volunteers. The influence of lung pathology on penetration needs to be examined.

Steady-state plasma and intrapulmonary concentrations of levofloxacin and ciprofloxacin in healthy adult subjects.

STUDY OBJECTIVE: To determine the steady-state plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of levofloxacin and ciprofloxacin. DESIGN: Multiple-dose, open-label, randomized pharmacokinetic study. PARTICIPANTS: Thirty-six healthy, nonsmoking adult subjects were randomized either to oral levofloxacin, 500 or 750 mg once daily for five doses, or ciprofloxacin, 500 mg q12h for nine doses. INTERVENTIONS: Venipuncture, bronchoscopy, and BAL were performed in each subject at 4 h, 12 h, or 24 h after the last administered dose of antibiotic. MEASUREMENT AND RESULTS: Mean plasma concentrations of levofloxacin and ciprofloxacin were similar to those previously reported. For once-daily dosing of levofloxacin, 500 mg, the mean (+/- SD) steady-state concentrations at 4 h, 12 h, and 24 h in ELF were 9.9 +/- 2.7 microg/mL, 6.5 +/- 2.5 microg/mL, and 0.7 +/- 0.4 microg/mL, respectively; AM concentrations were 97.9 +/- 80.0 microg/mL, 36.7 +/- 23.4 microg/mL, and 13.8 +/- 16.0 microg/mL, respectively. For levofloxacin, 750 mg, the mean steady-state concentrations in ELF were 22.1 +/- 14.9 microg/mL, 9.2 +/- 5.3 microg/mL, and 1.5 +/- 0.8 microg/mL, respectively; AM concentrations were 105.1 +/- 65.5 microg/mL, 36.2 +/- 26.1 microg/mL, and 15.1 +/- 2.0 microg/mL, respectively. The concentrations of ciprofloxacin at 4 h and 12 h in ELF were 1.9 +/- 0.9 microg/mL and 0.4 +/- 0.1 microg/mL, respectively; AM concentrations were 34.9 +/- 23.2 microg/mL and 6.8 +/- 5.9 microg/mL, respectively. The differences in the ELF concentrations of the two levofloxacin groups vs those of the ciprofloxacin group were significant (p < 0.05) at each sampling time. CONCLUSIONS: Levofloxacin was more extensively distributed into intrapulmonary compartments than ciprofloxacin and achieved significantly higher steady-state concentrations in plasma and ELF during the 24 h after drug administration.

Comparison of 5-day, short-course gatifloxacin therapy with 7-day gatifloxacin therapy and 10-day clarithromycin therapy for acute exacerbation of chronic bronchitis.

BACKGROUND: The ideal duration of antibiotic therapy for acute exacerbation of chronic bronchitis (AECB) remains controversial. OBJECTIVE: This study compared short-course, 5-day gatifloxacin treatment with standard 10-day clarithromycin treatment in patients with AECB; 7-day gatifloxacin therapy was a secondary comparator. METHODS: This was a multicenter, prospective, randomized, double-blind study in which adult outpatients with AECB were randomized to 1 of 3 treatment groups: 5 days of gatifloxacin, 7 days of gatifloxacin, or 10 days of clarithromycin. Clinical cure and microbiologic eradication rates were determined 7 to 14 days after the completion of antibiotic treatment. RESULTS: A total of 527 patients with AECB were enrolled and treated with study drug (174, gatifloxacin 5-day; 175, gatifloxacin 7-day; 178, clarithromycin 10-day). Most patients (82%) had type 1 (severe) exacerbations, and a bacterial pathogen was isolated from pretreatmer, sputum samples in 59% of patients. The overall clinical cure rates among clinically evaluable patients were comparable between groups: 89% (135/151 patients) in the gatifloxacin 5-day group; 88% (136/154) in the gatifloxacin 7-day group; and 89% (145/163) in the clarithromycin 10-day group. The 95% CIs for the differences in response rates were -6.1 to 7.0 for gatifloxacin 5-day versus clarithromycin, -8.9 to 5.0 for gatifloxacin 7-day versus clarithromycin, and -5.5 to 8.0 for gatifloxacin 5-day versus 7-day. These observations did not appear to be affected by use of corticosteroids or smoking status, type of exacerbation, or duration of current episode. The microbiologic eradication rate among microbiologically evaluable pathogens was >90% in all treatment groups. No clinically meaningful differences were noted in the incidence of drug-related adverse events. CONCLUSION: Short-course, 5-day gatifloxacin therapy in patients with AECB resulted in clinical cure and microbiologic eradication rates comparable to those of standard 7- and 10-day therapies.

Epidemiology of clinically diagnosed community-acquired pneumonia in the primary care setting: results from the 1999-2000 respiratory surveillance program.

To evaluate the prevalence of typical pathogens, level of resistance, and risk factors associated with community-acquired pneumonia (CAP) in the outpatient primary care setting and define current antibiotic treatment for office-based CAP, the Respiratory Surveillance Program (RESP) recruited 1,200 primary care clinics during the 1999-2000 respiratory infection season. Participating community-based physicians submitted sputum samples from patients presenting with a community-acquired respiratory infection including community-acquired pneumonia (CAP). All patients were aged > or =18 years. Patient demographics and risk factors were collected. Physicians express-mailed the specimens to a central laboratory for identification and susceptibility testing. All isolates were tested against a select panel of antimicrobial agents that are used to treat CAP. Patients with CAP were diagnosed by the treating physicians. Chest radiographs were not required as part of the study. A total of 610 specimens were submitted from patients with CAP. A smoking history or reported history of chronic obstructive pulmonary disease were present in >50% of those diagnosed with CAP. The most common pathogens were, in order of prevalence, Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis. During the study period, a variety of antibiotics were prescribed for the treatment of outpatient CAP. The top 3 prescribed antibiotics include levofloxacin (23%), clarithromycin (19%), and azithromycin (10%). Gatifloxacin, which was approved in December 1999 and therefore available for only part of the study, accounted for 4% of the prescriptions. Of S pneumoniae isolates, 8% demonstrated high-level resistance to penicillin (> or =2 microg/mL) and 33% were found resistant to macrolides and trimethoprim/sulfamethoxazole. All S pneumoniae isolates were sensitive to gatifloxacin, vancomycin, and levofloxacin. Other less common organisms isolated were staphylococci, streptococci, Enterobacteriaceae, Pseudomonas spp, and Acinetobacter spp. The choice of antibiotic to treat outpatient CAP varies from practice to practice and does not appear to be influenced by the patient's age, the patient's history of smoking, or comorbidity.

Long-term clarithromycin decreases prednisone requirements in elderly patients with prednisone-dependent asthma.

Prolonged use of prednisone is associated with serious side effects, such as osteoporosis, particularly among elderly individuals. Macrolide antibiotics exhibit anti-inflammatory effects that are distinct from their antimicrobial properties. Thus, the purpose of this case report is to describe the effects of prolonged treatment with clarithromycin, 500 mg bid, in reducing prednisone requirements in three elderly patients with prednisone-dependent asthma. Three patients (one woman and two men) aged 63 to 69 years, who had been treated with 5 to 10 mg prednisone daily for at least the last 12 months, were given clarithromycin, 500 mg bid. They were followed regularly for changes in daily prednisone dose, spirometry, quality of life, and adverse events. The prednisone dose was tapered in a stepwise fashion at each clinic visit. Within 3 to 6 months of initiation of treatment with clarithromycin, and throughout the 12-month follow-up, two of three patients discontinued prednisone therapy, while the third patient displayed increased spirometry readings and noted an increasingly better quality of life. Pulmonary function tests were stable or improved over this time period, with no reported adverse events, including increased rate of infections. One patient relapsed upon discontinuation of clarithromycin therapy but has since responded to re-initiation of treatment. Long-term oral clarithromycin may have a role in reducing prednisone requirements in elderly patients with prednisone-dependent asthma.

Tobramycin solution for inhalation reduces sputum Pseudomonas aeruginosa density in bronchiectasis.

We conducted a placebo-controlled, double-blind, randomized study to evaluate the microbiological efficacy and safety of inhaled tobramycin for treatment of patients with bronchiectasis and Pseudomonas aeruginosa. Patients were randomly assigned to receive either tobramycin solution for inhalation (TSI) (n = 37) or placebo (n = 37), which was self-administered twice daily for 4 wk and followed by 2-wk off-drug. At Week 4, the TSI group had a mean decrease in P. aeruginosa density of 4.54 log(10) colony-forming units (cfu)/g sputum compared with no change in the placebo group (p < 0.01). At Week 6, P. aeruginosa was eradicated in 35% of TSI patients but was detected in all placebo patients. Investigators indicated that 62% of TSI patients showed an improved medical condition compared with 38% of placebo patients (odds ratio = 2.7, 95% confidence interval [CI] 1.1 to 6.9). Tobramycin-resistant P. aeruginosa strains developed in 11% of TSI patients and 3% of placebo patients (p = 0.36). The mean percent change in FEV(1) percent predicted from Week 0 to Week 4 was similar for the TSI and placebo groups (p = 0.41). More TSI-treated patients than placebo patients reported increased cough, dyspnea, wheezing, and noncardiac chest pain, but the symptoms did not limit therapy. Additional study is warranted to further evaluate TSI in bronchiectasis patients.

Comparison of bacteriologic eradication of Streptococcus pneumoniae by clarithromycin and reports of increased antimicrobial resistance.

OBJECTIVE: To determine whether reported increases in Streptococcus pneumoniae resistance, as determined by in vitro antimicrobial susceptibility testing, correlate with the clinical efficacy of clarithromycin in treating patients with acute exacerbations of chronic bronchitis (AECB) or community-acquired pneumonia (CAP). BACKGROUND: Surveillance data on antimicrobial resistance suggest that the overall rate of S. pneumoniae resistance in vitro in the United States has increased to approximately 45% during the past decade. S. pneumoniae is showing increased resistance to penicillin, other beta-lactams, and macrolides. Despite this increased resistance, the clinical efficacy of clarithromycin does not appear to be diminished to the degree suggested by reported resistance rates. The author examined several studies of clarithromycin in patients with AECB or CAP that demonstrate S. pneumoniae eradication rates in vivo of approximately 92%. The discordance between reported increases in resistance of S. pneumoniae isolates in vitro and the eradication rate with clarithromycin in vivo is discussed in light of 5 observations. RESULTS: First, surveillance data on S. pneumoniae resistance rates to clarithromycin may be overestimated. Second, efflux mutant strains may not be clinically resistant. Third, host immune defenses play a role in treatment outcomes. Fourth, in vitro resistance may not correlate with in vivo clinical success. Finally, clarithromycin and its active metabolite, 14-OH-clarithromycin, attain high concentrations in patients. CONCLUSION: Reported increases in the prevalence of S. pneumoniae resistance do not appear to have had proportional effects on the clinical efficacy of clarithromycin in the treatment of patients with AECB or CAP caused by S. pneumoniae.

Penetration of levofloxacin into lung tissue after oral administration to subjects undergoing lung biopsy or lobectomy.

STUDY OBJECTIVE: To evaluate the pulmonary tissue distribution of levofloxacin, the new once-daily fluoroquinolone, after a single 500-mg oral dose. DESIGN: Open-label study. SETTING: One pulmonary clinic and two university-affiliated teaching hospitals. PATIENTS: Eighteen adults undergoing lung biopsy or lobectomy. INTERVENTIONS: Levofloxacin plasma and lung tissue concentrations were determined by high-performance liquid chromatography with fluorescence detection. Lung tissue levofloxacin concentrations were corrected for blood contamination by measuring hemoglobin. MEASUREMENTS AND MAIN RESULTS: After a single 500-mg oral dose, concentrations of levofloxacin in lung tissue consistently exceeded those in plasma at every time point over the 24-hour sampling period, with tissue:plasma penetration ratios of 2.02 (2-3 hrs), 5.02 (4-6 hrs), 5.13 (11-17 hrs), and 4.13 (22-25 hrs). The mean penetration ratio over the 24-hour sampling period was 3.95 (range 1.06-9.98). Lung tissue concentrations of levofloxacin also exceeded minimum inhibitory concentration values for most community-acquired respiratory tract pathogens over the 24 hours. CONCLUSION: This study supports clinical evaluation of levofloxacin as once-daily oral therapy for community-acquired lower respiratory tract infections.

Intrapulmonary steady-state concentrations of clarithromycin and azithromycin in healthy adult volunteers.

The steady-state concentrations of clarithromycin and azithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained in intrapulmonary samples during bronchoscopy and bronchoalveolar lavage from 40 healthy, nonsmoking adult volunteers. Mean plasma clarithromycin, 14-(R)-hydroxyclarithromycin, and azithromycin concentrations were similar to those previously reported. Clarithromycin was extensively concentrated in ELF (range of mean +/- standard deviation concentrations, 34.4 +/- 29.3 microg/ml at 4 h to 4.6 +/- 3.7 microg/ml at 24 h) and AM (480 +/- 533 microg/ml at 4 h to 99 +/- 50 microg/ml at 24 h). The concentrations of azithromycin in ELF were 1.01 +/- 0.45 microg/ml at 4 h to 1.22 +/- 0.59 microg/ml at 24 h, and those in AM were 42.7 +/- 28.7 microg/ml at 4 h to 41.7 +/- 12.1 microg/ml at 24 h. The concentrations of 14-(R)-hydroxyclarithromycin in the AM ranged from 89.3 +/- 52.8 microg/ml at 4 h to 31.3 +/- 17.7 microg/ml at 24 h. During the period of 24 h after drug administration, azithromycin and clarithromycin achieved mean concentrations in ELF and AM higher than the concomitant concentrations in plasma.

Penetration of clarithromycin into lung tissues from patients undergoing lung resection.

The concentrations of clarithromycin and its active principal metabolite, 14-(R)-hydroxy-clarithromycin, were determined in lung tissue obtained during lung resection and compared with concomitant concentrations in plasma. Concentrations of the parent and metabolite were determined by high-performance liquid chromatography. The 15 patients studied were given 500 mg orally every 12 h for a minimum of five doses to achieve steady-state concentrations. The mean concentrations of clarithromycin and 14-(R)-hydroxy-clarithromycin in plasma just prior to the final dose were 1.38 and 0.67 micrograms/ml, respectively, and those 4 h after the final dose (at the time of lung resection) were 1.89 and 0.80 microgram/mL, respectively. The concentrations of the parent and metabolite in lung tissue at the time of lung resection averaged 54.3 and 5.12 micrograms/g, respectively, with a mean calculated ratio of concentrations of the parent to metabolite being 11.3 in lung tissue and 2.4 in plasma. Clarithromycin and its active metabolite are extensively distributed into human lung tissue.

Safety and efficacy of lomefloxacin versus cefaclor in the treatment of acute exacerbations of chronic bronchitis.

In two multicenter trials, lomefloxacin and cefaclor were compared as treatments for acute bacterial exacerbations of chronic bronchitis. In total, 522 adult outpatients were enrolled at 50 centers in the United States. Patients were randomized to treatment groups receiving either 400 mg lomefloxacin orally once daily (n = 259) or 250 mg cefaclor every 8 hours (n = 263) for 7-10 days. Both groups were comparable in terms of age, severity of exacerbation, smoking history, theophylline use, and baseline pathogens. The most common baseline pathogens were Haemophilus influenzae, found in 32% of patients in the lomefloxacin group and in 29% in the cefaclor group, Pseudomonas aeruginosa (13% and 16%, respectively), Moraxella (Branhamella) catarrhalis (12% and 13%), and Streptococcus pneumoniae (10% in both groups). Bacterial eradication rates 1-4 days after the completion of treatment for all patients with baseline pathogens were 81.8% in the lomefloxacin group and 62.7% in the cefaclor group (p less than 0.001). Clinical success (disappearance or improvement of presenting signs and symptoms) was noted in 80.0% of patients in the lomefloxacin group and 64.7% in the cefaclor group (p = 0.002). Eradication rates for the subgroup of patients who had pathogens susceptible in vitro to both study drugs and who completed treatment were 97.1% for lomefloxacin and 84.6% for cefaclor (p = 0.002). Clinical success rates in this subgroup were 92.4% for lomefloxacin and 90.1 for cefaclor (p = 0.585). Treatment-related adverse events were reported for 7% of patients in the lomefloxacin group and 5% in the cefaclor group. The most common adverse events in both groups were nausea and diarrhea. Six patients were withdrawn from treatment with lomefloxacin and four from the cefaclor group because of adverse events. There was no clinical or laboratory evidence of theophylline interaction with either treatment. Once-daily oral administration of 400 mg lomefloxacin was an effective, well-tolerated alternative to 250 mg of cefaclor three times daily in the treatment of acute exacerbations of chronic bronchitis.

Diffuse epithelial pleural mesothelioma presenting as a solitary lung mass.

We report the occurrence of a malignant pleural epithelial mesothelioma which presented radiographically and at surgery as a localized solitary mass, but was found microscopically to involve grossly normal pleura. Clinically diffuse mesothelioma recurred 19 months later. Localized malignant mesothelioma has been associated with the same poor prognosis as the diffuse form and, as suggested by this case, may represent an early phase of diffuse disease.