Two-day versus seven-day course of levofloxacin in acute COPD exacerbation: a randomized controlled trial.

INTRODUCTION: Duration of antibiotic treatment in acute exacerbation of COPD (AECOPD) is most commonly based on expert opinion. Typical administration periods range from 5 to 7 days. A 2-day course with levofloxacin was not previously assessed. We performed a randomized clinical trial to evaluate the efficacy of 2-day versus 7-day treatment with levofloxacin in patients with AECOPD. METHODS AND ANALYSIS: Patients with AECOPD were randomized to receive levofloxacin for 2 days and 5 days placebo (n = 155) or levofloxacin for 7 days (n = 155). All patients received a common dose of intravenous prednisone daily for 5 days. The primary outcome measure was cure rate, and secondary outcomes included need for additional antibiotics, ICU admission rate, re-exacerbation rate, death rate, and exacerbation-free interval (EFI) within 1-year follow-up. The study protocol has been prepared in accordance with the revised Helsinki Declaration for Biomedical Research Involving Human Subjects and Guidelines for Good Clinical Practice. The study was approved by ethics committees of all participating centers prior to implementation (Monastir and Sousse Universities).
RESULTS: 310 patients were randomized to receive 2-day course of levofloxacin (n = 155) or 7-day course (n = 155). Cure rate was 79.3% (n = 123) and 74.2% (n = 115), respectively, in 2-day and 7-day groups [OR 1.3; 95% CI 0.78-2.2 (p = 0.28)]. Need for additional antibiotics rate was 3.2% and 1.9% in the 2-day group and 7-day group, respectively; (p = 0.43). ICU admission rate was not significantly different between both groups. One-year re-exacerbation rate was 34.8% (n = 54) in 2-day group versus 29% (n = 45) in 7-day group (p = 0.19); the EFI was 121 days (interquartile range, 99-149) versus 110 days (interquartile range, 89-132) in 2-day and 7-day treatment groups, respectively; (p = 0.73). One-year death rate was not significantly different between the 2 groups, 5.2% versus 7.1% in the 2-day group and 7-day group, respectively; (p = 0.26). No difference in adverse effects was detected.
CONCLUSION: Levofloxacin once daily for 2 days is not inferior to 7 days with respect to cure rate, need for additional antibiotics and hospital readmission in AECOPD. Our findings would improve patient compliance and reduce the incidence of bacterial resistance and adverse effects.

Introduction

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is defined as worsening of COPD symptoms characterized by a change in the patient’s baseline dyspnea, cough or sputum, or both, beyond day-to-day variability sufficient to warrant a change in management. Exacerbations carry a major economic burden as they are responsible of the majority of health costs related to COPD. Most of these exacerbations are triggered by infectious agents, and their treatment by antibiotics is a common practice. The use of antibiotics was shown to reduce short-term mortality and significantly reduce the recurrence of exacerbations.[2,3] While most of AECOPD episodes are treated with antibiotics, up to half of them are thought to be caused by a bacterial infection.[4-6] Combined with the large number of individuals with COPD, this overuse of antibiotics may lead to increased levels of bacterial resistance.[7,8] Reduction of unnecessary antibiotic use is one of the most important strategies to contain resistance. Shortening the duration of antimicrobial therapy has been advocated as a potentially effective measure for decreasing the emergence of antimicrobial resistance and minimizing the costs associated with various respiratory tract infections. Available guidelines stated that antibiotic treatment should be maintained at an average of 7–10 days while the latest systematic review including 10 randomized controlled trials showed no clinical inferiority of shorter courses. While the shortest antibiotic treatment assessed was 3 days,[10-12] further reduction of the duration of antibiotherapy warrants consideration in order to reduce the risk of adverse events and the pressure that drives bacterial resistance. The aim of our study was to evaluate the efficacy of short-course antibiotic therapy of 2 days compared with 7-day regimen in AECOPD.

Materials and methods

Study design

This was a prospective, randomized, double-blind controlled study including patients admitted to the emergency department (ED) with AECOPD. The study was carried out from February 2018 to January 2021. The study protocol has been prepared in accordance with the revised Helsinki Declaration for Biomedical Research Involving Human Subjects and Guidelines for Good Clinical Practice. The study was approved by ethics committees of all participating centers prior to implementation (Monastir and Sousse Universities), and all included patients provided their written informed consent. The study was registered at www.clinicaltrials.gov (NCT03698682).

Settings and participants

This study included adult patients admitted to four EDs (Fattouma Bourguiba University Hospital Monastir, Sahloul University Hospital Sousse, Farhat Hached University Hospital Sousse, and Taher Sfar University Hospital Mahdia). Patients were eligible for inclusion if they were 45 years or older; had a smoking history of at least 10 pack-years; had a clinical diagnosis of mild-to-severe COPD, defined as a postbronchodilator forced expiratory volume in 1 s (FEV1) to forced vital capacity ratio of 0:7 or lower and a postbronchodilator FEV1 of at least 30%, according to Global Initiative of Chronic Obstructive Lung Disease (GOLD). AECOPD was defined as acute worsening of respiratory symptoms that result in additional therapy. Patients were excluded if they presented one of the following conditions: clinical evidence of hemodynamic compromise with need to vasoactive drugs, immediate need for endotracheal intubation, pneumonia, previous adverse reactions to study drug, antibiotic treatment in the previous days, pregnancy or lactation, severe renal (creatinine clearance < 40 ml/min) or hepatic impairment, and lung disease other than COPD that could affect the clinical evaluation of the treatments. Patients with active alcohol or drug abuse were also excluded.

Randomization and intervention

After verification of inclusion and exclusion criteria as well the informed consent, demographic, clinical, and biological data were collected at baseline. These included patient’s comorbidities, number of exacerbations in the past year, physical examination findings, blood gas analysis, and standard laboratory test results. Sputum samples were collected for pathogen culture. All data were recorded in standardized electronic case report forms (DACIMA Tunisia; https://www.dacimasoftware.com). Noninvasive ventilation (NIV) was performed for patients with an arterial carbon dioxide partial pressure > 45 mmHg and arterial pH < 7.35 with supplemental oxygen in order to obtain a pulse oxygen saturation > 90%. Included patients were then randomized into 2 groups: short-course group (2-day group) in which patients received one tablet of 500 mg of levofloxacin per day for 2 days followed by one tablet of placebo per day for the subsequent 5 days; standard course group (control group) in which patients received one tablet of 500mg of levofloxacin per day for 7 days. The randomization list was provided by a software using a block size so that an equal number of patients were allocated to each treatment group in each block, and patients were assigned sequential ascending random numbers within each center. This randomization list was not accessible to any individual involved in the study conduct, and patient codes were only allowed to be broken in case of emergency. In order to ensure blinding, active drug and placebo tablets were encapsulated for identical appearance and placed in sealed envelopes. All patients received a dose of 40 mg of intravenous prednisone daily for 5 days for hospitalized patients or 40 mg of oral prednisone if patients were discharged home, nebulized bronchodilator therapy, and fluid therapy. All other medications were prescribed at the attending physician’s discretion. All patients were treated in the ED during the first 48 h as a part of the study. After 48-h ED stay, the decision to discharge was held by the treating physician; patients with marginal improvement were hospitalized in the ward or in the ICU if they required mechanical ventilation. All patients were clinically monitored until hospital discharge. Long-term follow-up was made with phone contact at months 1, 3, 6, and 12 after study treatment. If the patient was not reachable, the next of kin or the patient’s general practitioner, or both, were contacted. Physicians who collected outcome data were blinded to the treatment allocation list. Vital status, the time to next acute exacerbation, and the exacerbation-free interval (EFI) were also recorded.

Outcomes analysis

Clinical cure rate was considered as the primary outcome. It was defined as a complete resolution of acute signs and symptoms associated with the exacerbation (nonexacerbated state) and no recurrences nor relapse at 30 days of follow up. Secondary outcome included need for additional antibiotics, EFI and ICU admission rate. The decision to initiate new antibiotics was left to the discretion of the treating physician. One-year re-exacerbation and death rates were also considered as secondary outcomes. A subgroup analysis including patients with CRP > 50mg/l was also considered.

Safety assessment

Adverse events were evaluated in all patients who received at least one dose of the study medication and had one post-inclusion assessment. Adverse events were defined as treatment-emergent adverse events if they developed or worsened during the on-treatment period, defined as the time from the first drug intake (levofloxacin or placebo) up to 7 days after the last drug intake.

Statistical analysis

All statistical analysis was performed using SPSS software, version 20.0. The primary objective was to demonstrate that levofloxacin treatment for 2 days was noninferior to 7 days of treatment. Sample size calculation was based on noninferiority testing for clinical cure. The noninferiority margin is 10%. Assuming an underlying clinical cure rate of 80% in the 7-day treatment group, 300 evaluable patients (150 per treatment group) were required to give a power of 80% to detect that the lower bound of the two-sided 95% confidence interval (CI) for the difference in rates (2-day group minus 7-day group) was no less than −10%. Qualitative data were described with frequencies and percentages; quantitative data were described with mean and standard error or with median, interquartile range (IQR). Baseline characteristics of patients were compared with the unpaired t-test or nonparametric tests for continuous variables, depending on their distributions. Percentage differences were compared with the Fisher exact test (or the Chi-square test, when appropriate). In case of skewed distributions, continuous variables were logarithmically transformed for further analysis. Differences between both groups in cure rate and secondary outcomes were assessed with odds ratio (OR). Comparisons of the incidence rates of AEs between the two study drug groups were performed descriptively. No interim analyses were planned or performed for this study. All statistical tests were two-sided and performed at the 0.05 significance level.

Results

A total of 712 patients were screened, and 310 patients were randomized to receive 2-day course of levofloxacin (n = 155) or 7-day course (n = 155). (Figure 1). Description of baseline characteristics of the patients is given in Table 1. Both treatment groups had similar baseline demographics and clinical findings (Table 1). Most patients were treated as outpatients. They were also similar with respect to severity criteria of the episode assessed by the number of exacerbations during the previous year and Anthonisen classification. Adequate sputum sampling was obtained from 58.3% of the overall population. The two treatment groups were similar in the number of pathogens isolated at pre-therapy (44 versus 37, respectively, in 2-day course and 7-day course groups). S pneumoniae, the most common pathogen found, was isolated from 20 patients. The other most common pathogens identified at pre-therapy were C pneumoniae (n = 18) and Haemophilus influenzae (n = 16) (Table 2).

Figure 1.

Flow diagram.

Table 1.

Patients’ demographic and clinical characteristics at admission.

	2-day groupn = 155	7-day groupn = 155	p
Age years, mean (SD)	68.2 (10.5)	67.1 (10.0)	0.34
Sex ratio, M/F	132/23	136/19	0.51
Smoking (pack-years), mean (SD)	42.8 (15.9)	44.6 (15.7)	0.39
Peak Expiratory Flow (L/min), mean (SD)	54 (72.7)	41.5 (60.8)	0.33
Body mass index (kg/m2), mean (SD)	26.5 (4.3)	26.5 (5.8)	0.91
Exacerbations within the past year, mean (SD)	2.4 (1.5)	2.1 (0.9)	0.17
Past medical history, n (%)
Hypertension	42 (27)	50 (32.2)	0.39
Heart failure	5 (3.2)	5 (3.2)	0.96
Diabetes	29 (18.7)	36 (32.2)	0.37
Anthonisen classification, n (%)			0.74
Type 1	69 (44.5)	66 (42.5)
Type 2	74 (47.6)	82 (57.5)
Blood pressure
Systolic mmHg, mean (SD)	142 (25)	138 (22)	0.71
Diastolic mmHg, mean (SD)	71 (21)	73 (22)	0.63
Temperature (°C), mean (SD)	37.1 (0.5)	37.1 (0.6)	0.99
Pulse rate (b/min), mean (SD)	104 (26)	110 (20)	0.97
Respiratory rate (c/min), mean (SD)	27 (10)	29 (11)	0.87
Blood gas
pH, median (IQR)	7.35 (7.30–7.42)	7.34 (7.29–7.40)	0.18
PaCO2 (mmHg), median (IQR)	42 (37–49)	43 (37–50)	0.39
White blood cells (x103/mm3)	13.8 ± 8.8	13.9 ± 8.8	0.93
C-reactive protein (mg/l), median (IQR)	43 (21–95)	47 (24–101)	0.62
Oxygen supplementation, n (%)	81 (52.2)	76 (49)	0.32
Noninvasive ventilation, n (%)	6 (3.8)	5 (3.2)	0.09
Need for hospitalization beyond 2 days, n (%)	34 (22)	49 (31.1)	0.11

IQR, interquartile range.

Table 2.

Bacteriologic results.

	2-day group	7-day group
Branhamella catarrhalis	2	4
Haemophilus influenzae	9	7
Klebsiella pneumoniae	1	2
Pseudomonas aeruginosa	5	4
Staphylococcus aureus	2	0
Streptococcus pneumoniae	11	9
Chlamydophila pneumonia	8	10
Mycoplasma pneumoniae	4	2
Coxiella burnetii	2	1
Total	44	37

Primary outcome

Clinical outcomes showed that a 2-day regimen of levofloxacin was noninferior to a 7-day regimen (Table 3). Cure rate was similar in the two groups, 79.3% and 74.2% in the 2-day group and 7-day group, respectively [OR 1.3; 95% CI 0.78–2.2 (p = 0.28)].

Table 3.

Clinical outcomes.

Patient outcomes	2-day groupn = 155	7-day groupn = 155	p-value	OR (95% CI)
Primary outcome, n (%)
Cure rate	123/155 (79.3)	115/155 (74.2)	0.28	1.3 (0.78–2.2)
Secondary outcomes
Need for additional antibiotics, n (%)	5 (3.2)	3 (1.9)	0.43	0.59 (0.13–2.5)
ICU Admissions, n (%)	8 (5.1)	5 (3.2)	0.65	0.55 (0.13–2.5)
Exacerbation-free interval days;median (IQR)	121 (99–149)	110 (89–132)	0.73	1 (0.99–1.003)
One-year re-exacerbation rate, n (%)	54 (34.8)	45 (29)	0.19	0.71 (0.42–1.19)
Death rate, n (%)	8 (5.2)	11 (7.1)	0.26	0.51 (0.54–3.59)

IQR, interquartile range; OR, odds ratio.

Secondary outcome

Data regarding secondary outcome are shown in Table 3. Rate of additional antibiotics was similar in both groups, 3.2% and 1.9% in the 2-day group and 7-day group, respectively [OR 0.59; 95% CI 0.13–2.5 (p = 0.43)]. ICU admission rate was 5.1% in the 2-day group and 3.2% in the 7-day group [OR 0.55; 95% CI 0.17–1.8 (p = 0.65)]. One-year re-exacerbation rate was not significantly different between the two groups, 34.8% versus 29% in the 2-day group and 7-day group, respectively [OR 0.71; 95% CI 0.42–1.19 (p = 0.19)]. Median EFI was similar in both treatment groups, 121 days (interquartile range 99–149) versus 110 days (interquartile range 89–132) in the 2-day and 7-day groups, respectively [OR 1; 95% CI 0.9–1 (p = 0.73)]. Survival curves for combined death and re-exacerbation events did not differ significantly in the two groups when compared by the log-rank test (p = 0.78; Figure 2). One-year death rate was not significantly different between the two groups, 5.2% versus 7.1% in the 2-day group and 7-day group, respectively [OR 0.51; 95% CI 0.54–3.59 (p = 0.26)]. In the subgroup of patients with CRP > 50mg/l, cure rate was similar between the two groups, 63.3% and 64.6% in the 2-day group and 7-day group, respectively [OR 0.94; 95% CI 0.41–2.1 (p = 0.89)]. Rate of additional antibiotics was similar in both groups, 6.1% and 4.2% in the 2-day group and 7-day group, respectively [OR 0.66; 95% CI 0.10–4.1 (p = 0.66)]. ICU admission rate was 16.7% in the 2-day group and 9.7% in the 7-day group [OR 0.53; 95% CI, 0.10–2.6 (p = 0.44)]. One-year re-exacerbation rate was not significantly different between the two groups, 39.5% versus 43.9% in the 2-day group and 7-day group, respectively [OR 1.2; 95% CI 0.49–2.9 (p = 0.69)]. Median EFI was similar in both treatment groups, 131 days (IQR 89–173) versus 111 days (IQR 77–145) in the 2-day group and 7-day group, respectively; (p = 0.42).

Figure 2.

Survival curves in 2-day and 7-day regimen groups. Both groups did not differ significantly when compared by the log-rank test (p = 0.78).

Safety

The incidence of adverse events was low in this study, three patients in the 2-day course group (1.9%) and six patients in the 7-day course group (3.9%) [OR 0.5; 95% CI 0.12 to1.96 (p = 0.99)]. The most frequently reported treatment-related adverse event was gastrointestinal (two patients in the 2-day group and three patients in the 7-day group). Most adverse events were mild and did not require discontinuation of the treatment study. No serious adverse events were reported in both groups.

Discussion

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, ICU admission rate, hospital readmissions rate, exacerbation-free interval, and 1-year mortality rate. The purpose behind shortening antibiotherapy duration was mainly to limit bacterial resistance and reduce healthcare cost provided that their clinical efficacy is not impaired.[15,16] 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. 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.[18-20] A meta-analysis conducted by Llor et al. showed that a short-course antibiotic treatments were not significantly different from those of long-course treatments regarding clinical cure rate and bacterial eradication. From the eight studies eligible for inclusion in this meta-analysis, five evaluated fluoroquinolones. 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. In our study, we reduced the course to 2 days which is the shortest antibiotic duration so far in AECOPD but without patients’ stratification and without increasing the dose of levofloxacin. The main strengths of our trial were that it was large, double-blind, multicentric and was conducted over more than 3 years covering all four seasons with a minimal loss to follow up and good adherence to treatment.

How can an antibiotherapy as short as 2 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. This implies that the effect of antibiotics is 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. 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. On the contrary, reducing the exposure of patients to antibiotics will reduce the risk of selective pressure that drives bacterial resistance. 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. 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.[27,28]

One could further investigate the optimal antibiotic duration using the kinetics of serum inflammatory markers. Likewise, validating known biomarkers, such as the procalcitonin level, for guiding targeted antibiotic therapy is also a strategy that could help appropriate decisions for antibiotic prescribing. 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 with standard course.

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, we advocate shortening courses of fluoroquinolones therapy, particularly in light of their concentration-dependent killing activity. Meanwhile, except for fluoroquinolones, where the question of short duration course was assessed by a consistent number of studies, it remains uncertain if results similar to ours would be obtained in response to other antibiotics as more data are needed to have conclusive results. 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. Of note, in our study we only included patients belonging to type 1 and 2 of Anthonisen classification and most of had a high level of C-reactive protein which is an accepted marker for antibiotic treatment. Importantly, we found that 2-day course was also effective in the subgroup of patients with CRP level > 50mg/l which is another support to our conclusions. Fourth, we treated all of our patients with systemic corticosteroids and this can explain why statistically significant differences between the two groups were not observed at least for some patients. In this regard, eosinophil counts could play a role because there is increasing evidence that low eosinophil count is associated with higher prevalence of bacterial exacerbations. In the present study, blood eosinophil count was not recorded and procalcitonin was not measured. Consequently, we treated our patients uniformly with the administration of bronchodilators, systemic corticosteroids, and antibiotics as recommended by current guidelines.[14,31]

In 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.