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Abstract: Background: Roflumilast is a newly approved phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis and a history of exacerbations. Objective: The objective of this article is to review the pharmacology, clinical efficacy, and tolerability of roflumilast in the treatment of COPD. Methods: Articles were identified using MEDLINE (1966–August 1, 2011) and EMBASE (1947–August 1, 2011). Searches were conducted using the terms roflumilast and COPD. Included in the search were all English-language clinical trials that were randomized, had durations of >6 weeks, and studied the effects of roflumilast on the forced expiratory volume in 1 second (FEV1) or rates of exacerbations in patients with COPD. Abstracts from the annual meetings of the American Thoracic Society, American College of Chest Physicians, and European Respiratory Society were also searched to identify relevant publications. In addition, all pertinent studies evaluating the pharmacokinetics and pharmacodynamics of roflumilast were included. Results: A total of 6 clinical trials (4 publications) evaluating the efficacy of roflumilast were identified and included. For the treatment of COPD, roflumilast was associated with a significant improvement in lung function (increase in FEV1 of 36–88 mL) when compared with placebo. Roflumilast also reduced the rate of exacerbations in subsets of patients with chronic cough and a history of exacerbations. Overall, health-related quality of life was not significantly affected. Adverse effects were common in clinical trials, with 9% to 16% of patients discontinuing therapy as a result. The most frequently reported adverse effects were gastrointestinal issues, headache, and weight loss. Suicide-related adverse effects have occurred in 5 patients receiving roflumilast and 1 patient receiving placebo. Conclusion: Roflumilast significantly improved FEV1 in clinical trials but had inconsistent reductions in the rates of exacerbations. Comparative studies with recommended therapies for COPD, particularly inhaled corticosteroids, are needed to better assess the role of roflumilast in the management of COPD. [Copyright &y& Elsevier]

Abstract: Background:: Bronchoalveolar lavage (BAL) is an established technique for measuring antibiotic concentrations in the epithelial lining fluid (ELF) of the bronchiolar and alveolar regions; however, the results may not reflect concentrations in bronchial regions. Bronchoscopic microsampling (BMS) is a technique that makes it possible to obtain multiple samples from bronchial ELF. Objective:: BMS and BAL were used to analyze the pharmacokinetics of gatifloxacin in bronchial ELF from healthy young adult subjects and adult patients with chronic bronchitis. Methods:: Bronchial ELF samples were obtained by BMS at 1, 2, 3, 4, 6, 10, and 24 hours after administration of a single oral dose of gatifloxacin 200 mg in healthy young adult (aged 20–25 years) subjects, and at 1, 2, 4, and 10 hours after a single dose in patients with chronic bronchitis (aged ≥20 years). At least 1 month after the initial BMS, alveolar (BAL) and bronchial (BMS) ELF samples were obtained from another group of healthy subjects 2 hours after administration of a single oral dose of gatifloxacin 200 mg for comparison of gatifloxacin concentrations in samples obtained by the 2 techniques. Results:: Bronchial ELF samples were obtained from 8 healthy subjects and 5 patients with chronic bronchitis; alveolar ELF samples were obtained from a separate group of 5 healthy subjects. For the healthy subjects, the mean (SD) AUC0–24 in serum and bronchial ELF, corrected for mg/kg doses, was 4.6 (1.1) and 7.6 (3.5) mg · h/L, respectively. In the patients with chronic bronchitis, the AUC0–10 in serum and bronchial ELF, corrected for mg/kg doses, was 3.9 (0.8) and 4.1 (1.5) mg · h/L. The Cmax in serum and bronchial ELF, corrected for mg/kg doses, was 0.6 (0.2) and 1.4 (0.8) mg/L in healthy subjects and 0.7 (0.2) and 0.7 (0.2) mg/L in patients with chronic bronchitis. In healthy subjects, the Cmax and AUC0–24 were significantly higher in bronchial ELF than in serum (both, P < 0.05). Gatifloxacin concentrations were significantly lower in bronchial ELF obtained by BMS than in alveolar ELF obtained by BAL (P < 0.05). Conclusions:: Based on the findings of this study in small numbers of healthy young adult volunteers and patients with chronic bronchitis, BMS appears to be a promising method for measuring drug concentrations and determining the pharmacokinetic profile of gatifloxacin in bronchial ELF. Additional studies are needed to correlate measured concentrations obtained by BMS with clinical and/or microbiologic outcomes in larger populations. [Copyright &y& Elsevier]

Abstract: 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 (FEV1) <50% of the predicted value, or (FEV1) of 50% to 65% of the predicted value plus comorbidities, or ≥4 exacerbations per year. A total of 369 patients were included in the intent-totreat (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). [Copyright &y& Elsevier]

Abstract: Background:: The 3-day course of azithromycin (AZM) 500 mg/d was introduced to the US market in June 2002. Objective:: The objective of this study was to evaluate changes in health-related quality of life (HRQOL) as measured by the St. George''s Respiratory Questionnaire (SGRQ) over a 1-month period in patients receiving a 3-day course of AZM for bacterial acute exacerbation of chronic bronchitis (AECB). Methods:: This was a prospective, multicenter, observational study evaluating outpatient adults with AECB who received either 3 days of AZM 500 mg/d or 5- to 14-day courses of other antibiotics (usual care [UC]) as directed by the clinician. Patients completed 2 HRQOL instruments—the SGRQ and Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36)—at baseline, day 14, and end of study (EOS) at days 24 to 28. In addition, patients kept a diary for the first 14 days after initiating antibiotic therapy. Results:: One hundred twenty-eight patients (57 AZM, 71 UC) were clinically evaluable. There were no significant differences between treatment groups in clinical presentation or baseline demographics, with the exception of a higher percentage of patients with diabetes mellitus in the UC group compared with the AZM group (16.9% vs 3.5%; P = 0.02). Both groups reported similar improvements in signs and symptoms, absenteeism, concomitant respiratory medication use, resource utilization, compliance, and treatment satisfaction as reported in the patient diary. The AZM group reported statistically significant improvement (simple contrasts for end of study vs baseline) in SGRQ measures (total score, P &#60; 0.001; symptoms, P = 0.031; activity, P &#60; 0.001; impacts, P &#60; 0.001) and the SF-36 mental and physical summary components, compared with baseline (both, P &#60; 0.001). Similarly, the UC group reported significant improvement in all SGRQ measures and in the SF-36 physical component score (P &#60; 0.01), but not in the SF-36 mental component score, compared with baseline. At EOS, 80.0% of AZM patients and 59.0% of UC patients had a ≥4-point improvement on the SGRQ total score; however, this difference was not statistically significant in the multivariate analysis. In addition, 89.5% of AZM patients and 89.9% of UC patients were satisfied or very satisfied with their treatment (P = NS). Resource utilization was similar between the groups. Conclusions:: In this observational study, patients with AECB treated with a 3-day course of AZM experienced significant improvements in HRQOL as measured by a change of ≥4 points on the SGRQ and SF-36 physical and mental component scores versus baseline. [Copyright &y& Elsevier]

Background: Short-term use of antibiotics has become a common component of the management of acute exacerbations of chronic bronchitis (AECB), particularly in complex cases with productive cough or purulent phlegm. The macrolide antibiotics, particularly second-generation agents such as dirithromycin and azithromycin, are among the antibiotic classes frequently recommended and used to treat upper and lower respiratory infections, including AECB.Objective: This study compared the clinical efficacy and tolerability of 5-day courses of dirithromycin and azithromycin given once daily for the treatment of acute exacerbations of chronic obstructive pulmonary disease (COPD).Methods: This randomized, investigator-blinded, parallel-group clinical trial was conducted at 5 centers in the United States. Eligible patients were adult (age > 35 years) smokers or ex-smokers (smoking history of at least 10 pack-years) with chronic bronchitis and an acute exacerbation, defined by the occurrence of increased dyspnea and/or productive cough and feverishness within 48 hours of enrollment. Before randomization, an attempt was made to obtain a sputum specimen from each patient for Gram''s staining and culture. Patients were randomized to receive dirithromycin 500 mg QD for 5 days or azithromycin 500 mg QD on day 1 and 250 mg QD on days 2 to 5. Clinical efficacy was assessed separately by patients and physicians at early (days 7–10) and late (days 25–35) posttreatment visits.Results: Eighty-six patients (48 women, 38 men; mean age, 55 years) with a mean smoking history of 31 pack-years were included in the intent-to-treat analysis. Forty-six (54%) patients were randomized to dirithromycin and 40 (47%) patients to azithromycin. Clinical efficacy was reported in a high proportion of patients in both treatment groups, both at the early posttreatment visit (84.8% dirithromycin, 75.7% azithromycin; difference dirithromycin - azithromycin, 9.1%; 95% CI, −8.2 to 26.4) and the late posttreatment visit (95.5% and 86.5%, respectively; difference dirithromycin - azithromycin, 9.0%; 95% CI, −3.7to 21.6). A similar proportion of patients required a second course of antibiotics over the study period (20.5% dirithromycin, 27.0% azithromycin; difference dirithromycin - azithromycin, −6.6%; 95% CI, −25.2 to 12.1). Only 42 (48.8%) patients were able to produce a sputum sample before receiving study treatment, and of these, only 20 (47.6%) demonstrated a preponderance of neutrophils on Gram''s staining. Both treatments were well tolerated.Conclusions: The results of this study suggest comparable clinical efficacy between 5-day courses of once-daily dirithromycin and azithromycin in acute exacerbations of COPD. There were insufficient data to permit meaningful comparison of the bacteriologic efficacy of these macrolide antibiotics. [Copyright &y& Elsevier]

Objective: The aim of this study was to compare the efficacy and safety of clarithromycin extended-release (ER) tablets and immediate-release (IR) tablets.Methods: This was a Phase III, open-label, randomized, multicenter, comparative study in ambulatory patients with a diagnosis of acute exacerbation of chronic bronchitis (AECB). Eligible patients were randomized 1:1 to receive either 1 clarithromycin ER 500-mg tablet QD for 7 days or 1 clarithromycin IR 250-mg tablet BID for 7 days. Clinical and bacteriologic responses were assessed within 48 hours after the last dose of study drug and at a test-of-cure visit 21 ± 2 days posttreatment.Results: Of 233 patients randomized, 162 (86/117 [73.5%] in the ER group and 76/115 [66.1%] in the IR group) completed the study protocol. Compliance did not differ significantly between the treatment groups; however, significantly fewer patients in the ER group reported missing doses of study medication than in the IR group (7/118 [5.9%] vs 16/115 [13.9%]; P = 0.04). The clinical cure rates for the clarithromycin ER and IR groups were 81.0% (68/84) and 82.1% (64/78) and the clinical success (clinical cure plus clinical improvement) rates were 94.0% [79/84] and 89.7% [70/78], respectively. There were insufficient data for analysis of bacteriologic efficacy. However, bacteria were eradicated or presumed eradicated in 71.4% (10/14) and 79.2% (19/24) of patients in the ER and IR groups, respectively. The number of adverse events (AEs) considered to be possibly or probably related to study drug (23.4% [52/222] of patients receiving clarithromycin ER and 24.4% [43/176] of patients receiving clarithromycin IR) was similar between groups, as was the severity of these events (94.2% [49/52] in the ER group classified as mild or moderate vs 93.0% [40/43] in the IR group). Overall, the most commonly reported AEs were diarrhea, nausea, abdominal pain, headache, and taste disturbance.Conclusion: Clarithromycin ER 500-mg tablets QD for 7 days were as effective and well tolerated as clarithromycin IR 250-mg tablets BID for 7 days in treating adults with AECB. [Copyright &y& Elsevier]

Background: In the absence of a confirmed pathogen, empiric antimicrobial treatment of patients with acute exacerbations of chronic bronchitis and acute bacterial exacerbations of chronic bronchitis (ABECB) is accepted as standard practice and recommended in treatment guidelines.Objective: This study compared the efficacy and tolerability of a 10-day course of 3 antimicrobial regimens commonly used to treat adults with ABECB.Methods: This prospective, open-label, randomized study assessed clarithromycin 500 mg twice daily, levofloxacin 500 mg once daily, and cefuroxime axetil 250 mg twice daily, each administered for 10 days with food, in patients with ABECB. Efficacy was determined on the basis of the clinical response to treatment and need for hospitalization and/or further antimicrobial therapy.Results: A total of 283 patients (150 men, 133 women) with a mean age of 55 years (range, 29 to 86 years) were randomized to receive clarithromycin (n = 97), levofloxacin (n = 94), or cefuroxime axetil (n = 92). Of 262 clinically assessable patients, clinical cure or improvement occurred in 87.9% (80/91) of those treated with clarithromycin, 87.4% (76/87) of those treated with levofloxacin, and 79.8% (67/84) of those treated with cefuroxime axetil. Eight (8.8%) clarithromycin-treated patients, 6 (6.9%) levofloxacin-treated patients, and 12 (14.3%) cefuroxime axetil—treated patients required a change in antimicrobial therapy to achieve clinical cure/improvement; between-group differences were not significant. No patients treated with clarithromycin required hospitalization for further antimicrobial treatment, compared with 3.4% (3/87) of levofloxacin-treated and 3.6% (3/84) of cefuroxime axetil—treated patients (P = NS). A total of 6.2% (6/97) of clarithromycin-treated patients were prematurely discontinued from treatment due to adverse events, compared with 7.4% (7/94) and 8.7% (8/92) of levofloxacin- and cefuroxime axetil—treated patients, respectively.Conclusion: A high rate of clinical efficacy and tolerability was observed in this population of patients with ABECB treated with clarithromycin 500 mg twice daily, levofloxacin 500 mg once daily, or cefuroxime axetil 250 mg twice daily for 10 days. [Copyright &y& Elsevier]

Background: Recognizing acute exacerbations of chronic bronchitis (AECB) and selecting appropriate antibiotic treatment for patients who would benefit most is a challenge for community-based physicians.Objective: The Tequin Clinical Experience Study, an open-label, noncomparative, post-marketing trial, assessed the efficacy and tolerability of gatifloxacin, an 8-methoxy fluoroquinolone, in the treatment of AECB in the community-practice setting.Methods: Consecutive patients with respiratory tract infections in community-based settings were eligible for participation. Treated patients (N = 2512) included 1107 men (44.1%) and 1405 women (55.9%) aged ≥18 years with a clinical diagnosis of chronic bronchitis. All participants received oral gatifloxacin 400 mg once daily for 7 to 10 days. Clinical response was determined via telephone contact conducted by the investigator or study coordinator using case-report forms or during an office visit after the last dose. The investigator or coordinator collected expectorated or induced sputum specimens that were then smeared on a microscope slide, stored in a tube, and transported to a central reference laboratory for Gram-staining and culture. Of 1388 pretreatment sputum specimens submitted, pathogens were isolated from 424.Results: The most frequently detected pathogens were Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. All H influenzae and 99% of S pneumoniae isolates tested were susceptible to gatifloxacin. Of the 2267 patients with a determinable clinical response, 2084 (91.9% [95% CI, 90.8%–93.0%]) were cured (all acute symptoms improved or returned to baseline level, no new symptoms present, no additional antibiotic required). The 95.8% cure rate in 166 patients with H influenzae included 100% of those with beta-lactamase-positive strains. Overall, 89.2% of 111 patients with M catarrhalis were cured; rates were similar regardless of beta-lactamase production. The clinical cure rate in 74 patients with S pneumoniae was 98.6% and was independent of the degree of penicillin resistance (minimum inhibitory concentration ≥2.0 μg/mL). All 6 patients infected with S pneumoniae fully resistant to penicillin were cured. Gatifloxacin was generally well tolerated, and the majority of adverse events were mild to moderate; only 11 drug-related adverse events in 10 patients (0.4%) were serious. Drug-related nausea (3.0%), dizziness (1.5%), diarrhea (1.2%), and vomiting (0.9%) were the most common adverse events.Conclusions: The high clinical cure rate and favorable tolerability support gatifloxacin as a rational choice for the treatment of AECB in patients such as those in this community-based study. [Copyright &y& Elsevier]

Background: Gemifloxacin is an enhanced-affinity quinolone with potent activity against lower respiratory tract pathogens.Objective: The efficacy and safety of a 5-day course of gemifloxacin were compared with those of a standard 7-day regimen of clarithromycin in patients with an acute exacerbation of chronic bronchitis (AECB). The impact of treatment on the long-term (26 weeks) clinical outcome was also assessed.Methods: The acute phase of this randomized, double-blind study was performed in 93 centers in 7 countries. Adult patients (age >40 years) with a history of chronic bronchitis and an Anthonisen type 1 acute exacerbation (increased dyspnea, cough, and sputum purulence) were eligible. Patients receiving systemic steroids at a dose of >10 mg prednisone or the equivalent were excluded. Patients were randomized to receive gemifloxacin 320 mg once daily for 5 days or clarithromycin 500 mg twice daily for 7 days. Clinical and bacteriologic response rates were assessed at the end-of-therapy visit (days 8–12), the week 2–3 follow-up visit (days 13–24), and the week 4–5 follow-up visit (days 25–38). The long-term phase (26 weeks), which included US and Canadian participants only, evaluated the proportion of patients who remained free of a recurrence of AECB requiring additional antimicrobial therapy after resolution of the initial episode.Results: Seven hundred twelve patients were randomized to treatment, 351 to gemifloxacin and 361 to clarithromycin. The long-term study included 438 patients, 214 receiving gemifloxacin and 224 receiving clarithromycin. Clinical success rates at the 2–3 week follow-up visit were 85.4% for gemifloxacin and 84.6% for clarithromycin. Bacteriologic success rates were 86.7% for gemifloxacin and 73.1% for clarithromycin. Significantly more patients receiving gemifloxacin than clarithromycin remained free of AECB recurrences (71.0% vs 58.5%, respectively; P = 0.016). Both treatments were well tolerated.Conclusions: In the acute treatment of Anthonisen type 1 AECB, a 5-day course of gemifloxacin was at least as effective as a 7-day regimen of clarithromycin. In this population, significantly more patients receiving gemifloxacin remained free of AECB recurrence after 26 weeks compared with those receiving clarithromycin. [Copyright &y& Elsevier]