Comparison of First-Line With Second-Line Antibiotics for Acute Exacerbations of Chronic Bronchitis

George Dimopoulos, MD, FCCP; Ilias I. Siempos, MD; Ioanna P. Korbila, MD; Katerina G. Manta, MD; Matthew E. Falagas, MD, MSc, DSc


CHEST. 2007;132(2):447-455. 

In This Article

Materials and Methods

Literature Search

To identify the randomized controlled trials (RCTs) that were appropriate for inclusion in the metaanalysis, we conducted a systematic search of the PubMed and the Cochrane Central Register of Controlled Trials. We used the following search terms: "acute exacerbations"; "COPD"; and "chronic bronchitis" combined with "amoxicillin," "clavulanic acid," "ampicillin," "sulfamethoxazole," "trimethoprim", "doxycycline," "quinolones," "macrolides," "Haemophilus influenzae," "Moraxella catarrhalis," and "Streptococcus pneumoniae." The reference lists of all retrieved articles were reviewed as well. The search was limited to articles written in English, French, and German.

Study Selection and Data Extraction

Two reviewers (IPK and KGM) independently searched the aforementioned databases to identify potentially eligible trials. To be included in our analysis, a trial had to be an RCT, and to focus on the comparison of the effectiveness and/or toxicity between a first-line antibiotic and a second-line (advanced) antibiotic.

From each of the selected studies, the following data were extracted: year of publication; study design; patient population; dosage and duration of antimicrobial treatment as well as treatment success in the intention-to-treat (ITT), the clinically evaluable (CE), and the microbiologically evaluable (ME) patients; all-cause mortality; and toxicity (ie, any adverse effect, diarrhea, and the number of patients who were withdrawn from the RCTs due to drug-related adverse effects). In addition, the methodological quality of the RCTs included in the analysis was assessed according to a modified Jadad score.[12] In detail, the existence of randomization, blinding, and information on withdrawals in each RCT was examined, and the appropriateness of randomization and blinding, if present, was evaluated. One point was awarded for the presence of each of the first three criteria, whereas the last two criteria could take the values of -1 (inappropriate), 0 (no data), and + 1 (appropriate). Thus, the maximum score for a study was 5, and a score ≥ 3 points denoted a good-quality RCT.


First-Line and Second-Line Antibiotics. Amoxicillin, ampicillin, pivampicillin, TMP/SMX, and doxycycline were considered to be first-line antibiotics for the management of patients with AECB. On the other hand, amoxicillin/clavulanic acid, macrolides (ie, roxithromycin, clarithromycin, and azithromycin), second-generation or third-generation cephalosporins (ie, cefaclor), and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines.[8,13]

CB and AECB. The diagnosis of CB in all RCTs included in this metaanalysis was based on the history of cough and expectoration on most days during a period of at least 3 consecutive months for 2 consecutive years, as the authors stated. We classified AECBs according to the criteria of Anthonisen et al,[14] based on the information provided by the investigators. The exacerbation classified as type I by Anthonisen et al[14] met all three of the following criteria: increases in amount of sputum; purulence of sputum; and dyspnea. Type II met two of the above three criteria, and type III met only one criterion.[14]

Outcomes of This Metaanalysis. Treatment success (defined as remission of all baseline symptoms of acute infection [clinical cure] or amelioration of symptoms without their complete disappearance [improvement]) in both ITT and CE patients and adverse effects probably or possibly related to study antibiotics were considered as outcome measures for this metaanalysis. In addition, all-cause mortality in the ITT population during the study period, the number of patients who experienced diarrhea or were withdrawn from the RCTs due to drug-related adverse effects, treatment success in ME patients (ie, the absence of a baseline pathogen or the absence of adequate culturable material from a patient exhibiting clinical cure or improvement), and pathogen eradication (documented or presumed) of H influenzae, M catarrhalis, and S pneumoniae isolates were also regarded as outcomes for this metaanalysis.

Statistical Analysis

Statistical analyses were performed using a statistical software package (S-PLUS, version 6.1; Insightful Corp; Seattle, WA). Using a χ2 test, we assessed the heterogeneity among RCTs. Publication bias was assessed by the funnel plot method using the test of Egger et al.[15] Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for all primary and secondary outcomes were calculated by using both the Mantel-Haenszel fixed effects model (FEM)[16] and the DerSimonian-Laird[17] random-effects models (REMs). For all analyses, results from the FEM are presented only when there was no statistically significant heterogeneity among RCTs; otherwise, results from the REM are presented.


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