Short-course Fluoroquinolones in Acute Exacerbations of Chronic Bronchitis

Mark H Gotfried; Ronald F Grossman

Disclosures

Expert Rev Resp Med. 2010;4(5):661-672. 

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Among 994 AECB-related articles, 177 articles reported the use of fluoroquinolones for AECB treatment. From these, a list of 23 randomized controlled clinical studies that used a short-course fluoroquinolone regimen to treat AECB was compiled. Overall, 18 of these trials studied the effectiveness of short-course respiratory fluoroquinolones on clinical and microbiological outcomes in AECB. Data from these studies are described later in the section 'Comparative studies on efficacy.' Five clinical trials studying the effects of short-course fluoroquinolones on the speed of recovery are described later in 'Comparative studies on speed of recovery.' Unless specified, most of the medications described in the following studies were administered orally.

Comparative Studies on Efficacy

Table 1 presents comparative studies of short-course fluoroquinolone treatment and standard therapy (≥7 days) of antimicrobial agents on clinical and bacteriological outcomes in patients with AECB.[7,26–35,37–44]

Levofloxacin A randomized, double-blind study was conducted to compare patients with AECB who received 500 mg levofloxacin once daily using a 5-day (268 patients) or standard 7-day regimen (264 patients).[37] Equivalent clinical success rates in the primary PP analysis were observed in patients who received a 5-day (82.8%) or 7-day (84.8%) course of levofloxacin treatment. Bacteriological eradication rates also were similar between groups: 82.1% for 5 days and 83.2% for 7 days of treatment. This study demonstrates that a 5-day, short course of levofloxacin 500 mg once daily is both clinically and microbiologically as effective as standard 7-day treatment and suggests that short-course therapy should be considered as an alternative treatment for AECB.

The role of high-dose, short-course levofloxacin in the management of AECB was studied in patients stratified by severity of illness.[38] Uncomplicated patients with FEV1 50% or more and less than four exacerbations per year were randomized to levofloxacin 750 mg once daily for 3 days or azithromycin 500 mg on day 1 followed by 250 mg once daily for days 2–5. Complicated patients (FEV1 < 50%, or FEV1 50–65% and significant comorbidity, or ≥4 exacerbations per year) were randomized to levofloxacin 750 mg once daily for 5 days or amoxicillin 875 mg/clavulanate 125 mg twice daily for 10 days. Martinez and colleagues demonstrated that the clinical success rates for clinically evaluable patients in both uncomplicated and complicated groups were similar for levofloxacin and azithromycin (93.0 vs 90.1%, respectively) and for levofloxacin and amoxicillin/clavulanate (co-amoxiclav; 79.2 vs 81.7%, respectively).[38] In addition, the microbiological eradication rate in uncomplicated cases was superior for 3 days of levofloxacin compared with 5 days of azithromycin (93.8 vs 82.8%, respectively), and similar for 5 days of levofloxacin and 10 days of co-amoxiclav (81.4 vs 79.8%, respectively) in complicated cases. The authors concluded that high-dose, short-course levofloxacin therapy at 750 mg once daily was at least as effective as traditional antimicrobial regimens, such as azithromycin and co-amoxiclav, for patients with varied severity of AECB.[38]

Furthermore, a post hoc analysis of data from a previous randomized, noninferiority study of patients with severe AECB further confirmed that high-dose, short-course levofloxacin therapy (750 mg once daily for 5 days) was at least as effective in symptom resolution as co-amoxiclav 875/125 mg twice daily for 10 days.[26] A significantly higher proportion of 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 co-amoxiclav group in the ITT population. Overall susceptibility of the pathogens was higher with levofloxacin therapy (97.1 vs 90.6%; p < 0.001).[26] In addition, levofloxacin was as effective in the resolution of other symptoms, such as shortness of breath, fever and chills, both at the on-treatment visit and the post-treatment visit, compared with co-amoxiclav therapy.

Moxifloxacin The use of short-course therapy with moxifloxacin has been extensively studied. The Bronchitis Study was a randomized, multicenter study involving 936 patients with AECB that was conducted to compare the efficacy of 5 and 10 days of moxifloxacin 400 mg daily with clarithromycin 500 mg twice daily for 10 days.[39] In 420 efficacy-valid patients, overall clinical resolution was 89, 91 and 91% for 5-day moxifloxacin, 10-day moxifloxacin and 10-day clarithromycin, respectively. Bacteriological eradication rates at the end of therapy were 94, 95 and 91%, respectively, for the three treatment groups. Short-course moxifloxacin therapy was recommended as a more convenient treatment than a standard course of moxifloxacin or clarithromycin for patients with AECB.[39]

In a randomized, multicenter study involving a Latin American cohort, short-course, 5-day moxifloxacin treatment was reported to be clinically and microbiologically equivalent to a standard therapy using another respiratory fluoroquinolone, levofloxacin 500 mg, for 7 days. Clinical success rate was achieved in 91.0 and 94.0% of patients in the moxifloxacin and levofloxacin groups, respectively. Bacteriological eradication rate was also similar in the two treatment groups: 92.8 and 93.8% in the moxifloxacin and levofloxacin groups, respectively. The authors suggested that short-course, once-daily moxifloxacin therapy has compliance advantages over other currently used therapies.[40]

Comparable clinical and bacteriological outcomes were also reported in a randomized multicenter study of patients treated with 5 days of moxifloxacin versus 7 days of co-amoxiclav in patients with AECB.[27,28] Schaberg et al. reported that clinical success rates for moxifloxacin and co-amoxiclav among evaluable patients were 96.2 and 91.6%, and eradication rates at 14 days were 87.7 and 89.6%, respectively.[27] Similar observations were reported by Starakis and colleagues.[28]

A randomized study comparing two short-course antibiotic therapies, 5-day moxifloxacin versus 5-day azithromycin (500 mg once daily for 1 day, then 250 mg once daily for 4 days) in 567 outpatients with mild-to-moderate AECB demonstrated equivalent clinical (both 88%) and bacteriological (95 and 94%) effectiveness in these regimens for patients with AECB.[29] When a 5-day course of moxifloxacin therapy was compared with a 3-day course of azithromycin in 342 outpatients with AECB, comparable clinical success rates were observed in these short-course regimens at days 10 and 12 (90 vs 90%, respectively) and at follow-up days 22 and 26 (82 vs 81%, respectively).[33]

Statistical noninferiority was confirmed in a study conducted in Italy that compared the efficacy of short-course, 5-day moxifloxacin (400 mg once daily) with a 7-day intramuscular injection of ceftriaxone (1000 mg once daily).[30] Comparable clinical success rates and bacteriological eradication rates were observed in both PP and ITT populations. Moreover, moxifloxacin was associated with lower relapse rates (23.3 vs 28.3%) and a reduced number of hospitalization days in inpatient and day-hospital settings (1864 vs 2001 days), contributing to reduced costs.

In the MOSAIC study, short-course, 5-day moxifloxacin treatment demonstrated superior clinical cure rates[32] and higher bacteriological success rates[31,32,41] than treatment with standard therapy with amoxicillin (500 mg three-times daily for 7 days), clarithromycin (500 mg twice daily for 7 days) or cefuroxime-axetil (250 mg twice daily for 7 days). At 7–10 days after therapy, clinical success rates were similar between these treatment groups in both the ITT and PP populations. In addition, moxifloxacin showed superior clinical cure rates over standard therapy in both the ITT population (70.9 vs 62.8%; 95% CI: 1.4–14.9) and PP population (69.7 vs 62.1%; 95% CI: 0.3–15.6), as well as higher bacteriological eradication rates in the ITT population (76.8 vs 67.5%; 95% CI: -1.8–20.4) and microbiologically valid population (91.5 vs 81.0%; 95% CI: 0.4–22.1).[32] Multivariate analyses further confirmed the positive influence of short-course moxifloxacin compared with standard therapy on clinical cure (odds ratio [OR]: 1.49; 95% CI: 1.08–2.04) in patients with AECB.[41]

Moreover, moxifloxacin significantly improved long-term outcomes of patients with AECB in the MOSAIC trial. Fewer ITT patients required additional antimicrobial agents after treatment with moxifloxacin than standard therapy (p < 0.01). Median and mean time to next exacerbation was longer with moxifloxacin, at 131.0 days and 132.8 days, respectively, compared with 103.5 days and 118.0 days with standard therapy (p = 0.03), respectively. The occurrence of failure, new exacerbation or any further antimicrobial treatment was less frequent in patients treated with moxifloxacin for up to 5 months of follow-up compared with standard regimens (p = 0.03).[32]

Gemifloxacin A short 5-day course of gemifloxacin (320 mg once daily) also demonstrates clinical efficacy and bacteriological success comparable with that of standard therapy in the treatment of AECB. In a randomized double-blind study, gemifloxacin 320 mg once daily for 5 days was compared with levofloxacin 500 mg once daily for 7 days in patients with AECB. Sethi and colleagues reported that short-course gemifloxacin therapy was at least as effective as 7-day levofloxacin treatment in both ITT and PP populations.[42] In the PP patients, clinical success rates at days 14 and 21 were 88.2% with gemifloxacin and 85.1% with levofloxacin, and were 83.7 and 78.4% at days 28 and 35, respectively.

In a randomized double-blind multinational study, efficacy of short-course, once-daily gemifloxacin therapy on clinical and bacteriological cure of AECB was shown to be as good as that of another fluoroquinolone regimen, trovafloxacin. Clinical success rates for gemifloxacin and trovafloxacin groups were 91.5 and 87.6%, respectively, and bacteriological success rates were 86.8 and 82.4%.[44]

A 5-day course of gemifloxacin (320 mg once daily) was also reported to be at least as effective as a 7-day clarithromycin regimen (500 mg twice daily) in treating AECB.[43] Investigators reported clinical success rates of 85.4 and 84.6% for gemifloxacin and clarithromycin, respectively, and bacteriological success rates of 86.7 and 73.1%. Furthermore, significantly more patients receiving gemifloxacin remained free of AECB recurrence after 26 weeks compared with those receiving clarithromycin (71.0 vs 58.5%, respectively; p = 0.016).[43]

The efficacy of short-course oral gemifloxacin (320 mg once daily for 5 days) was compared with sequential intravenous ceftriaxone (1 g once daily, for a maximum of 3 days) followed by oral cefuroxime axetil (500 mg twice daily, for a maximum of 7 days) in 274 hospitalized adult patients with AECB.[34] The clinical success rates at 21–28 days post-therapy were 86.8% for gemifloxacin and 81.3% for the ceftriaxone/cefuroxime regimen in the clinical PP population (95% CI: -3.9–14.9) and 82.6 and 72.1%, respectively, in the clinical ITT population (95% CI: 0.7–20.4). In addition, the median time to discharge was shorter in the gemifloxacin group than in the ceftriaxone/cefuroxime group (9 vs 11 days; p = 0.04, Wilcoxon test). At follow-up, 120 out of 138 gemifloxacin-treated patients (87.0%) had been discharged from the hospital, compared with 111 out of 136 ceftriaxone/cefuroxime-treated patients (81.6%) in the clinical ITT population. These observations suggest that short-course oral gemifloxacin treatment is at least as effective as sequential ceftriaxone/cefuroxime therapy in patients with AECB who require hospital treatment.[34]

The efficacy and safety of short-course gemifloxacin (320 mg once daily for 5 days) was compared with that of co-amoxiclav (500/125 mg three-times daily for 7 days) in a randomized double-blind study.[34] The two drugs were shown to be equally effective, with clinical success rates of 93.6% for gemifloxacin and 93.2% for co-amoxiclav (95% CI: -3.9–4.6). However, bacteriological success rates favored gemifloxacin (90.9%, compared with 79.5% for co-amoxiclav; 95% CI: -3.3–26.0).

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