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

Disclosures

CHEST. 2007;132(2):447-455.

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(ME) patients; all-cause mortality; and toxicity (ie, any adverse effect, diarrhea, and the number of patients who were withdrawn from the RCTs due to drug-related adverse effects).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.

Definitions

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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Table 1. Main Characteristics of RCTs Included in the Metaanalysis*
Study/Year/Country	Study Design	Study Population	Mean Age, yr/Proportion of Women Among Enrolled Patients, %^†	Regimen (Duration of Treatment)		Use of Systemic Corticosteroid Before AECB	Enrolled Patients, No.	ITT Patients, No.^†	Study Quality Score^‡
Study/Year/Country	Study Design	Study Population		1	2	Use of Systemic Corticosteroid Before AECB	Enrolled Patients, No.	ITT Patients, No.^†	Study Quality Score^‡
Schouenbourg et al¹⁹/2000/Denmark	MC, SB, RCT	Outpatients ≥ 18 yr old with CB and an Anthonisen type II or III AECB	61 vs 59/49 vs 49	Pivampicillin, 700 mg q12h (10 d)	Azithromycin, 500 mg q24h (3 d)	NA	239	98 vs 138	3
Chodosh²⁰/1993/United States	MC, DB, RCT	Hospitalized patients and outpatients ≥ 18 yr old with CB and an Anthonisen type I AECB	65 vs 65/23 vs 41	Amoxicillin, 500 mg q8h (7 d)	Fleroxacin, 400 mg q24h (7 d)	NA	194	92 vs 102	4
Ulmer²¹/1993/Germany	MC, DB, RCT	Hospitalized patients and outpatients ≥ 18 yr old with CB and an Anthonisen type II AECB	63 vs 63/34 vs 35	Amoxicillin, 500 mg q8h (7 d)	Fleroxacin, 400 mg q24h (7 d)	Permitted	625	310 vs 313	4
De Vlieger et al²²/1992/Belgium	MC, DB, RCT	Patients > 18 yr old with CB and an Anthonisen type II AECB	58 vs 62/48 vs 37	Doxycycline, 200 mg q24h (714 d)	Roxithromycin, 300 mg q24h (714 d)	Permitted	76	33 vs 41	4
Guay and Craft²³/1992/United States	MC, SB, RCT	Outpatients ≥ 18 yr old with CB and an Anthonisen type II or III AECB	54 vs 58/46 vs 42	Ampicillin, 500 mg q6h (up to 14 d)	Clarithromycin, 500 mg q12h (maximum of 14 d)	NA	103	50 vs 53	1
Mertens et al²⁴/1992/the Netherlands	DB, RCT	Hospitalized patients and outpatients (adults) with CB and an Anthonisen type I, II AECB	58 vs 65/56 vs 79	Amoxicillin, 500 mg q8h (5 d)	Azithromycin, 500 mg q24h ( 3 d)	NA	50	25 vs 25	4
Aldons²⁵/1991/Australia	MC, DB, RCT	Outpatients ≥ 18 yr old with CB and an Anthonisen type I, II or III AECB	58 vs 60/43 vs 45	Ampicillin, 250 mg q6h (714 d)	Clarithromycin, 250 mg q12h (714 d)	NA	125	65 vs 60	5
Bachand²⁶/1991/United States	MC, DB, RCT	Outpatients ≥ 18 yr old with COPD, asthma, emphysema, bronchiectasis, and AECB^§	56 vs 55/42 vs 41	Ampicillin, 250 mg q6h (10 d)	Clarithromycin, 250 mg q12h (10 d)	Permitted	225	114 vs 111	4
Trigg et al²⁷/1991/United Kingdom	DB, RCT	Hospitalized patients ≥ 46 yr old with COPD and an Anthonisen type II AECB	71 vs 68/79 vs 30	Amoxicillin, 500 mg q8h (7 d)	Cefaclor, 500 mg q8h (7 d)	NA	51	25 vs 26	2
McGhie et al²⁸/1986/United Kingdom	SB, RCT	Patients ≥ 18 yr old with CB and AECB^§	49 vs 52/50 vs 43	Pivampicillin, 250 mg, plus pivmecillinam, 200 mg q12h (10 d)	Amoxicillin, 250 mg, plus clavulanic acid, 125 mg q8h (10 d)	NA	454	230 vs 224	3
Law et al²⁹/1983/United Kingdom	DB, RCT	Hospitalized patients and outpatients ≥ 55 yr old with CB and an Anthonisen type II AECB	66 vs 65/20 vs 15	Amoxicillin, 500 mg q8h (10 d)	Cefaclor, 500 mg q8h (10 d)	NA	80	40 vs 40	3
Anderson et al³⁰/1981/United Kingdom	DB, RCT	Hospitalized patients ≥ 48 yr old with CB and AECB^§	66 vs 64/16 vs 25	TMP, 80 mg/SMX, 400 mg q24h (7 d)	Cefaclor, 500 mg q8h (7 d)	NA	39	19 vs 20	3

* All study antibiotics were administered orally. The use of antimicrobial agents other than those studied was not allowed. MC = multicenter; SB = single-blind; DB = double-blind; NA = not applicable.

^† Values are reported for patients receiving first-line antimicrobial agents vs patients receiving second-line antimicrobial agents.

^‡ According to a modified Jadad score.

^§ The data did not allow us to classify AECBs according to the Anthonisen criteria.

Table 1. Main Characteristics of RCTs Included in the Metaanalysis*
Study/Year/Country	Study Design	Study Population	Mean Age, yr/Proportion of Women Among Enrolled Patients, %^†	Regimen (Duration of Treatment)		Use of Systemic Corticosteroid Before AECB	Enrolled Patients, No.	ITT Patients, No.^†	Study Quality Score^‡
Study/Year/Country	Study Design	Study Population		1	2	Use of Systemic Corticosteroid Before AECB	Enrolled Patients, No.	ITT Patients, No.^†	Study Quality Score^‡
Schouenbourg et al¹⁹/2000/Denmark	MC, SB, RCT	Outpatients ≥ 18 yr old with CB and an Anthonisen type II or III AECB	61 vs 59/49 vs 49	Pivampicillin, 700 mg q12h (10 d)	Azithromycin, 500 mg q24h (3 d)	NA	239	98 vs 138	3
Chodosh²⁰/1993/United States	MC, DB, RCT	Hospitalized patients and outpatients ≥ 18 yr old with CB and an Anthonisen type I AECB	65 vs 65/23 vs 41	Amoxicillin, 500 mg q8h (7 d)	Fleroxacin, 400 mg q24h (7 d)	NA	194	92 vs 102	4
Ulmer²¹/1993/Germany	MC, DB, RCT	Hospitalized patients and outpatients ≥ 18 yr old with CB and an Anthonisen type II AECB	63 vs 63/34 vs 35	Amoxicillin, 500 mg q8h (7 d)	Fleroxacin, 400 mg q24h (7 d)	Permitted	625	310 vs 313	4
De Vlieger et al²²/1992/Belgium	MC, DB, RCT	Patients > 18 yr old with CB and an Anthonisen type II AECB	58 vs 62/48 vs 37	Doxycycline, 200 mg q24h (714 d)	Roxithromycin, 300 mg q24h (714 d)	Permitted	76	33 vs 41	4
Guay and Craft²³/1992/United States	MC, SB, RCT	Outpatients ≥ 18 yr old with CB and an Anthonisen type II or III AECB	54 vs 58/46 vs 42	Ampicillin, 500 mg q6h (up to 14 d)	Clarithromycin, 500 mg q12h (maximum of 14 d)	NA	103	50 vs 53	1
Mertens et al²⁴/1992/the Netherlands	DB, RCT	Hospitalized patients and outpatients (adults) with CB and an Anthonisen type I, II AECB	58 vs 65/56 vs 79	Amoxicillin, 500 mg q8h (5 d)	Azithromycin, 500 mg q24h ( 3 d)	NA	50	25 vs 25	4
Aldons²⁵/1991/Australia	MC, DB, RCT	Outpatients ≥ 18 yr old with CB and an Anthonisen type I, II or III AECB	58 vs 60/43 vs 45	Ampicillin, 250 mg q6h (714 d)	Clarithromycin, 250 mg q12h (714 d)	NA	125	65 vs 60	5
Bachand²⁶/1991/United States	MC, DB, RCT	Outpatients ≥ 18 yr old with COPD, asthma, emphysema, bronchiectasis, and AECB^§	56 vs 55/42 vs 41	Ampicillin, 250 mg q6h (10 d)	Clarithromycin, 250 mg q12h (10 d)	Permitted	225	114 vs 111	4
Trigg et al²⁷/1991/United Kingdom	DB, RCT	Hospitalized patients ≥ 46 yr old with COPD and an Anthonisen type II AECB	71 vs 68/79 vs 30	Amoxicillin, 500 mg q8h (7 d)	Cefaclor, 500 mg q8h (7 d)	NA	51	25 vs 26	2
McGhie et al²⁸/1986/United Kingdom	SB, RCT	Patients ≥ 18 yr old with CB and AECB^§	49 vs 52/50 vs 43	Pivampicillin, 250 mg, plus pivmecillinam, 200 mg q12h (10 d)	Amoxicillin, 250 mg, plus clavulanic acid, 125 mg q8h (10 d)	NA	454	230 vs 224	3
Law et al²⁹/1983/United Kingdom	DB, RCT	Hospitalized patients and outpatients ≥ 55 yr old with CB and an Anthonisen type II AECB	66 vs 65/20 vs 15	Amoxicillin, 500 mg q8h (10 d)	Cefaclor, 500 mg q8h (10 d)	NA	80	40 vs 40	3
Anderson et al³⁰/1981/United Kingdom	DB, RCT	Hospitalized patients ≥ 48 yr old with CB and AECB^§	66 vs 64/16 vs 25	TMP, 80 mg/SMX, 400 mg q24h (7 d)	Cefaclor, 500 mg q8h (7 d)	NA	39	19 vs 20	3

Table 2. Outcome Data From the Selected RCTs for the Metaanalysis*
Study/Year	Treatment Success		All-Cause Mortality	Adverse Effects
Study/Year	ITT at TOCV	CE at TOCV	All-Cause Mortality	Total	Withdrawn Patients	Diarrhea
Schouenbourg et al^[19]/2000	NA	79/92 (86) vs 124/133 (93)	NA	22/98 (22) vs 20/138 (14)	5/98 (5) vs 3/138 (2)	11/98 (11) vs 7/138 (5)
Chodosh^[20]/1993	NA	22/29 (76) vs 21/22 (95)	NA	14/92 (15) vs 42/102 (41)	5/92 (5) vs 13/102 (13)	NA
Ulmer^[21]/1993	NA	111/136 (81) vs 131/145 (89)	3/310 (1) vs 3/313 (1)	27/310 (9) vs 61/313 (19)	7/310 (2) vs 20/313 (6)	NA
De Vlieger et al^[22]/1992	NA	20/25 (80) vs 30/37 (81)	NA	7/33 (21) vs 4/41 (10)	3/33 (9) vs 0/41 (0)	NA
Guay and Craft^[23]/1992	NA	46/47 (98) vs 53/53 (100)	NA	10/50 (20) vs 8/53 (15)	NA	3/50 (6) vs 3/53 (6)
Mertens et al^[24]/1992	20/25 (80) vs 24/25 (96)	20/25 (80) vs 24/25 (96)	NA	NA	NA	NA
Aldons^[25]/1991	NA	21/23 (91) vs 27/28 (96)	NA	1/65 (2) vs 7/60 (12)	1/65 (2) vs NA	0/65 (0) vs 0/60 (0)
Bachand^[26]/1991	NA	31/34 (91) vs 28/29 (97)	1/114 (1) vs 1/111 (1)	36/114 (32) vs 34/111 (31)	NA	NA
Trigg et al^[27]/1991	NA	13/25 (52) vs 11/23 (48)	2/25 (8) vs 4/26 (15)	NA	NA	1/25 (4) vs 2/26 (8)
McGhie et al^[28]/1986	NA	51/55 (93) vs 49/49 (100)	0/230 (0) vs 2/224 (1)	NA	NA	NA
Law et al^[29]/1983	NA	33/36 (92) vs 36/38 (95)	NA	NA	NA	NA
Anderson et al^[30]/1981	15/19 (79) vs 15/20 (75)	15/17 (88) vs 15/19 (80)	1/19 (5) vs 1/20 (5)	0/19 (0) vs 0/20 (0)	0/19 (0) vs 0/20 (0)	0/19 (0) vs 0/20 (0)

* Values are given as the No. of patients treated/total No. of patients in the group (%) for patients receiving first-line antimicrobial agents vs those receiving second-line antimicrobial agents. TOCV = test-of-cure visit (1 to 7 days after the end of treatment). See Table 1 for abbreviation not used in the text.

Table 3. Microbiological Outcomes From the Selected RCTs for the Metaanalysis*
Study/Year	Treatment Success (Microbiological Evaluation)^†	Pathogen Eradication^‡
Study/Year	Treatment Success (Microbiological Evaluation)^†	H influenzae	M catarrhalis	S pneumoniae
Schouenbourg et al^[19]/2000	32/37 (86) vs 49/54 (91)	NA	NA	NA
Chodosh^[20]/1993	18/30 (60) vs 21/22 (95)	7/11 (64) vs 10/10 (100)	5/5 (100) vs 6/6 (100)	0/1 (0) vs 1/1 (100)
Ulmer^[21]/1993	114/138 (83) vs 142/148 (96)	31/38 (82) vs 59/59 (100)	20/22 (91) vs 19/19 (100)	31/35 (89) vs 15/19 (79)
De Vlieger et al^[22]/1992	6/7 (86) vs 5/5 (100)	NA	NA	NA
Guay and Craft^[23]/1992	12/12 (100) vs 23/23 (100)	10/10 (100) vs 10/10 (100)	11/11 (100) vs 11/11 (100)	20/20 (100) vs 19/19 (100)
Mertens et al^[24]/1992	NA	7/11 (64) vs 8/12 (67)	2/2 (100) vs 6/6 (100)	6/7 (86) vs 3/4 (75)
Aldons^[25]/1991	24/24 (100) vs 28/29 (96)	17/17 (100) vs 19/20 (95)	1/1 (100) vs 6/6 (100)	6/6 (100) vs 2/2 (100)
Bachand^[26]/1991	32/34 (94) vs 25/29 (86)	18/21 (86) vs 7/11 (64)	1/2 (50) vs 6/7 (86)	7/7 (100) vs 11/11 (100)
Trigg et al^[27]/1991	5/15 (33) vs 9/15 (60)	NA	NA	NA
McGhie et al^[28]/1986	NA	NA	NA	NA
Law et al^[29]/1983	NA	NA	NA	NA
Anderson et al^[30]/1981	8/8 (100) vs 4/8 (50)	5/5 (100) vs 4/6 (67)	NA	3/3 (100) vs 0/2 (0)

* See Table 1 for abbreviation not used in the text.

^† Values are given as the No. of patients in whom the specified outcome occurred/total No. of patients in the group (%) for patients receiving first-line antimicrobial agents vs those receiving second-line antimicrobial agents.

^‡ Values are given as the No. of isolates eradicated/total No. of isolates for each microbe (%) in patients receiving first-line antimicrobial agents vs those receiving second-line antimicrobial agents.

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