Elsevier

The Lancet

Volume 358, Issue 9298, 15 December 2001, Pages 2020-2025
The Lancet

Articles
Once daily oral ofloxacin in chronic obstructive pulmonary disease exacerbation requiring mechanical ventilation: a randomised placebo-controlled trial

https://doi.org/10.1016/S0140-6736(01)07097-0Get rights and content

Summary

Background

The role of antibiotics in treatment of patients with moderate exacerbations of chronic obstructive pulmonary disease (COPD) is uncertain, but such treatment might be useful in very severe episodes. Our objective was to assess the effects of ofloxacin in patients with exacerbations of COPD who required mechanical ventilation.

Methods

We did a prospective, randomised, double-blind, placebo-controlled trial in 93 patients with acute exacerbation of COPD who required mechanical ventilation. Patients were randomly assigned to receive oral ofloxacin 400 mg once daily (n=47) or placebo (46) for 10 days. Primary endpoints were death in hospital and need for an additional course of antibiotics, both separately and in combination. Analysis was by intention to treat.

Findings

Three patients dropped out of the study. Two (4%) patients receiving ofloxacin died in hospital and ten (22%) did so in the placebo group (absolute risk reduction 17·5%, 95% Cl 4·3–30·7, p=0·01). Treatment with ofloxacin significantly reduced the need for additional courses of antibiotics (28·4%, 12·9–43·9, p=0·0006). The combined frequency of death in hospital and need for additional antibiotics was significantly lower in patients assigned to ofloxacin than in those receiving placebo (45·9%, 29·1–62·7, p<0·0001). The duration of mechanical ventilation and hospital stay was significantly shorter in the ofloxacin group than in the placebo group (absolute difference 4·2 days, 95% Cl 2·5–5·9; and 9·6 days, 3·4–12·8, respectively).

Interpretation

New fluoroquinolones, such as ofloxacin, are beneficial in the treatment of COPD exacerbation requiring mechanical ventilation.

Introduction

Chronic obstructive pulmonary disease (COPD) is seen worldwide. The frequency of COPD and number of resulting deaths continues to increase.1, 2 Since patients with COPD have one to four acute exacerbations a year, and many of them have to be admitted, the economic burden of this disease is very high.3 In the USA, about US$7 billion are attributable to direct costs, and US$8 billion to loss of productivity.4 Among patients requiring treatment in hospital, 20–60% will need endotracheal intubation and admission to an intensive-care unit (ICU) with a median cost of hospital stay of US$7400 per patient (range 4100–16000).2, 5

Although most guidelines recommend antibiotics for patients with acute exacerbations of COPD, the fundamental question about their effectiveness remains unanswered. Most studies are not placebo-controlled trials—mainly done for new product registration—and they are unlikely to be valuable in assessment of the role of antibiotics in the treatment of acute exacerbation of COPD.6, 7, 8, 9, 10, 11 Of nine placebo-controlled trials included in one meta-analysis,12 five did not show a significant benefit in the group treated with antibiotics. The overall results favoured antibiotics, but the benefit was clinically unimportant. Although inpatients seemed to benefit more from antibiotics than outpatients, extrapolation of the marginal effect seen in this meta-analysis12 to severely ill patients, such as those managed in ICUs, might be hazardous. Nonetheless, use of antibiotics in severely ill patients with COPD requiring mechanical ventilation remains usual practice, although this treatment is not yet evidence based. Whether antibiotic treatment is effective in severely ill patients with COPD requiring mechanical ventilation is, indeed, an issue that has not been well investigated. The few data in this specialty, and current concern about use of antibiotics and their contribution to selection of resistant bacteria, show that a placebo-controlled study is needed.

Choice of antimicrobial agent is another difficult clinical decision when antibiotic treatment is considered. Indeed, conventional first-line agents—including ampicillin, amoxicillin, doxycycline, and trimethoprim-sulfa-methoxazole—were associated with a low number of treatment failures in early studies.6, 7, 13 However, the increasing proportion of resistant respiratory pathogens to these antibiotics prompted evaluation of new agents, such as fluoroquinolones.14, 15, 16 The susceptibility of common respiratory pathogens to fluoroquinolones, and the good pharmacokinetic characteristics of these antibiotics, is shown in the favourable outcome rate compared with traditional agents.8, 9, 10, 11, 17 However, most therapeutic trials with fluoroquinolones have been done in moderate exacerbations of COPD, and little is known about the usefulness of these drugs in patients with severe COPD.

We therefore designed a randomised, placebo-controlled clinical trial to assess the efficacy of oral ofloxacin in the treatment of patients admitted to the ICU for severe acute exacerbation of COPD requiring mechanical ventilation.

Section snippets

Patients

From January, 1996, to December, 1999, consecutive patients aged 40 years or older, who were admitted to the medical ICUs of Fattouma Bourguiba Hospital (Monastir, Tunisia) and Farhat Hached Hospital (Sousse, Tunisia) for acute exacerbation of COPD, were included in the study. Patients were eligible if they were admitted to the ICU with acute exacerbation of COPD—diagnosed on the basis of clinical history, physical examination, and chest radiograph—and had an acute respiratory failure requiring

Results

From January, 1996, to December, 1999, 213 patients with COPD were admitted to one of the two participating ICUs with acute respiratory failure; 120 patients (56%) were excluded from the trial before randomisation (figure 1). The most common reasons for exclusion were pneumonia, antibiotic treatment at admission to ICU, and serious comorbidity. Of the 93 participants randomly assigned, three were removed (two on ofloxacin and one on placebo) because they required non-invasive ventilation for

Discussion

Our results show that in patients with severe acute exacerbation of COPD requiring mechanical ventilation, 400 mg ofloxacin given enterally once daily reduced the mortality rate in hospital and the need for additional antibiotic therapy. Duration of mechanical ventilation and length of hospital stay were also shortened. Our data lend support to the clinical benefit of antibiotic administration to patients with severe acute exacerbation of COPD requiring mechanical ventilation, and show that

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