Our results showed that in patients admitted with AECOPD, a 2-day course of Levofloxacin was not clinically inferior to a standard 7-day course in terms of cure rate, need for additional antibiotics or ICU admission, hospital readmissions rate, and exacerbation free interval.
The purpose behind shortening antibiotherapy duration was mainly to limit bacterial resistance and reduce healthcare cost provided that their clinical efficacy is not impaired.[11] A systematic review of many common infections, including acute respiratory and urinary infections found that, in general, shorter treatments of antibiotics were as effective as longer [12]. In AECOPD, numerous studies have been performed to evaluate this possibility particularly with fluoroquinolones. They showed that short course fluoroquinolone therapy was as effective as the standard course and, in some studies, it was associated with faster recovery, fewer relapses, prolonged duration between episodes, and less hospitalization.[13] The recent meta-analysis conducted by Stolbrink et al. [6] included 10 randomized controlled trials evaluating short and standard antibiotic course with the same antibiotic classes. The total number of patients in this study was 3979 patients, of which 1990 patients received an antibiotic course of 6 days or fewer, and 1989 received that of 7 days or more. Three of the studies involving fluoroquinolones were in favour of short course treatment and all of them defined the short course regimen as 5-day duration.[14–16] In a prospective trial stratifying patients with AECOPD into uncomplicated or complicated groups, Martinez et al advocated the use of high dose levofloxacin (750 mg) for 3 days in uncomplicated group and for 5 days in complicated group.[17] In our study, we reduced the course to two days which is the shortest antibiotic duration so far in acute exacerbations of COPD but without patients’ stratification and without increasing the dose of levofloxacin. The main strengths of our trial were that it was large, double blind, and multicentre and was conducted over more than three years covering all four seasons with a minimal loss to follow up and good adherence to treatment.
How can an antibiotherapy as short as two days be as effective as a longer one? The fact that some acute bacterial infections are cured with 1 day of antibiotics would support the principle that, if antibiotics are useful, their positive effects are mainly observed within the early infection period.[18] This implies that the effect of antibiotics are particularly important in the acute phase of infection; it accelerates the decrease of the bacterial growth rate allowing the immune system to acquire an enhanced ability to fight the microorganism.[19] Except in a few key circumstances, sterility of the infection site is not necessary for clinical healing. In addition, the dogma that stopping antibiotic treatment early encourages resistance to antibiotics is not evidence based. [6, 9] On the contrary, reducing the exposure of patients to antibiotics will reduce the risk of selective pressure that drives bacterial resistance.[20] Furthermore, besides antibiotic treatment duration, timing of treatment is an important factor of success. In a recent study using a mathematical model of a generic bacterial infection, Paupério et al showed that the difference between the short and the standard treatments strongly depends on the timing of treatment.[21] Another important consideration in pharmacodynamics is the presence of post antibiotic effect (PAE), which refers to the ability to suppress bacterial growth after a scripted exposure to an antibiotic. Similar to the aminoglycosides, fluoroquinolones have concentration-dependent bactericidal activity and a prolonged PAE against gram positive and gram-negative bacteria.[22, 23]
One could further investigate the optimal antibiotic duration using the kinetics of serum inflammatory markers. Many studies assessed the effects of implementation of procalcitonin guidelines on antibiotic prescription in cases of AECOPD. However, it seems that procalcitonin-guided antibiotic strategy could reduce antibiotic prescriptions, but is unable to diminish antibiotic exposure duration compared to standard course.[24, 25]
The findings of the present study must be interpreted in the context of several potential limitations. First, we excluded patients with hemodynamic or respiratory instability requiring intensive care unit and mechanical ventilation upon their admission. Therefore, our findings cannot be extrapolated to unstable patients with such severe COPD exacerbations. Second, while we advocate shortening courses of fluoroquinolones therapy, particularly in light of their concentration dependent killing activity, extrapolating these results to other antibiotic classes is presumptive. Third, it may be argued that shorter course was found to be as effective as longer one because antibiotics are largely ineffective at any dose. This could be true; however, in our study we only included patients belonging to type 1 and 2 of Anthonisen classification and most of our patients had a high level of C-reactive protein which is an accepted marker for antibiotic treatment.
As a conclusion, our study showed that a 2-day course of levofloxacin was as effective as 7-day course in AECOPD. Our findings should probably be considered if we want to avoid antibiotic overuse and antibiotic resistance.