AB For CAP

Antibiotics for community acquired pneumonia in adult outpatients (Review)
Bjerre LM, Verheij TJM, Kochen MM
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2004, Issue 2 http://www.thecochranelibrary.com
Antibiotics for community acquired pneumonia in adult outpatients (Review) Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS HEADER . . . . . . . . . . ABSTRACT . . . . . . . . . PLAIN LANGUAGE SUMMARY . BACKGROUND . . . . . . . OBJECTIVES . . . . . . . . METHODS . . . . . . . . . RESULTS . . . . . . . . . . DISCUSSION . . . . . . . . AUTHORS CONCLUSIONS . . ACKNOWLEDGEMENTS . . . REFERENCES . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 2 2 3 3 5 6 7 7 7 9
[Intervention Review]
Antibiotics for community acquired pneumonia in adult outpatients

Lise M Bjerre1 , Theo JM Verheij2 , Michael M Kochen1
1 Department of General Practice/Family Medicine, University of Gttingen, Gttingen, Germany. 2 Julius Center for General Practice and Patient-Oriented Research, University Medical Center Utrecht, Utrecht, Netherlands
Contact address: Lise M Bjerre, Department of General Practice/Family Medicine, University of Gttingen, Humboldtallee 38, Gttingen, D-37073 , Germany. lbjerre@hotmail.com. lbjerre@gwdg.de. Editorial group: Cochrane Acute Respiratory Infections Group. Publication status and date: Unchanged, published in Issue 3, 2009. Review content assessed as up-to-date: 24 February 2004. Citation: Bjerre LM, Verheij TJM, Kochen MM. Antibiotics for community acquired pneumonia in adult outpatients. Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD002109. DOI: 10.1002/14651858.CD002109.pub2. Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT Background Community-acquired pneumonia (CAP) is a common condition representing a signicant disease burden for the community, particularly for the elderly. Because antibiotics are helpful in treating CAP, they are the standard treatment and CAP thus contributes signicantly to antibiotic use, which is associated with the development of bacterial resistance and side-effects. Although several studies have been published concerning CAP and its treatment, the available data arises mainly from studies conducted in hospitalized patients and outpatients. There is no concise summary of the available evidence that can help clinicians in choosing the most appropriate antibiotic. Objectives To summarize the evidence currently available from randomized controlled trials (RCTs) concerning the efcacy of alternative antibiotic treatments for CAP in ambulatory patients above 12 years of age. Search strategy We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2003, issue 2) which contains the Cochrane Acute Respiratory Infections Groups Specialized Register; MEDLINE (January 1966 to September week 3, 2003), and EMBASE (January 1974 to March 2003). Selection criteria We included all randomized controlled trials (RCTs) in which one or more antibiotics were tested for the treatment of CAP in ambulatory adolescent or adult patients. Studies testing one or more antibiotic and reporting the diagnostic criteria used in selecting patients as well as the clinical outcomes achieved were included. No language restrictions were applied. Data collection and analysis Data were extracted and study reports assessed by two independent reviewers (LMB and TJMV). Authors of studies were contacted as needed to resolve any ambiguities in the study reports. The data were analyzed using the Cochrane Collaborations RevMan 4.2.2 Software. Differences between reviewers were resolved by discussion and consensus.
Antibiotics for community acquired pneumonia in adult outpatients (Review) Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1
Main results Three randomized controlled trials involving a total of 622 patients aged 12 years and older diagnosed with community acquired pneumonia were included. The quality of the studies and of the reporting was variable. A variety of clinical, radiological and bacteriological diagnostic criteria and outcomes were reported. Overall there was no signicant difference in the efcacy of the various antibiotics under study. Authors conclusions Currently available evidence from RCTs is insufcient to make evidence-based recommendations for the choice of antibiotic to be used for the treatment of community acquired pneumonia in ambulatory patients. Pooling of study data was limited by the very low number of studies. Individual study results do not reveal signicant differences in efcacy between various antibiotics and antibiotic groups. Multi-drug comparisons using similar administration schedules are needed to provide the evidence necessary for practice recommendations.
PLAIN LANGUAGE SUMMARY Not enough evidence from trials on the comparative effects of different antibiotics for community-acquired pneumonia Pneumonia, or infection involving the lungs, is responsible for a signicant number of deaths worldwide. Pneumonia is especially lifethreatening in older people and people with other illnesses that may affect the immune system (such as diabetes). Antibiotics are the most commonly used treatment for pneumonia, and these can vary in their effectiveness and adverse effects. The review studied the effects of antibiotics for patients with pneumonia acquired and treated in the community (as opposed to people acquiring pneumonia while in hospital, and/or being treated for pneumonia in hospital). There were not enough trials to compare the effects of different antibiotics for pneumonia acquired and treated in the community.
BACKGROUND
Description of the condition

Community acquired pneumonia (CAP) is a common condition that carries a high burden of mortality and morbidity, particularly in elderly populations. Prospective studies carried out in the UK, Finland and the USA have estimated the annual incidence of CAP in community-dwelling adults at 5 to 11 cases per 1000 adult population; the incidence is known to vary markedly with age, being higher in the very young and the elderly (Foy 1979; Woodhead 1987; Jokinen 1993). It is the most important cause of death from infectious causes in the industrialized world and the sixth most important cause of death overall (IDSA 2000). CAP can be caused by a broad range of pathogens including bacteria, atypical agents and viruses (IDSA 2000). In fact, more than 100 different microorganisms have been associated with CAP (Loeb 2002). Furthermore, a patient with CAP can be befallen by more than one microbe, as in the case of a bacterial superinfection of an underlying inuenza infection. The
most common pathogens include, depending on the patient population tested, Streptococcus pneumoniae (S. pneumoniae) (usually by far the most common), Chlamydia pneumoniae (C. pneumoniae), Haemophilus inuenzae (H. inuenzae), Mycoplasma pneumoniae (M. pneumoniae) and inuenza viruses (IDSA 2000; Loeb 2002).
Description of the intervention

Antibiotics are the mainstay in the treatment of CAP, since the causative organisms usually respond to this them. Consequently, CAP contributes signicantly to antibiotic use, which is associated with the development of bacterial resistance. In treating patients with CAP, the choice of antibiotic is a difcult one. Factors to be considered are the possible etiologic pathogen, the efcacy of the substance, potential side-effects, the treatment schedule and its effect on adherence to treatment, the particular regional resistance prole of the causative organism, and co-morbidities that might inuence the range of potential pathogens (such as in cystic brosis) or the dosage (as in the case of renal insufciency). Signicant costs are associated with the diagnosis and management
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of CAP. In the UK, 22% to 42% of adults with CAP are admitted to hospital (Woodhead 1987; Guest 1997), and of those, 5% to 10% need to be admitted to an intensive care unit (Torres 1991; BTS 1992).
Criteria for considering studies for this review
Types of studies All randomised trials of antibiotics in adolescent and adult outpatients with CAP reporting on clinical parameters, cure rates or mortality were included.
How the intervention might work

Many clinical trials have been performed to evaluate and compare the efcacy of antibiotics for CAP, however the vast majority of them were conducted in hospitalized patients. These patients usually suffer from more severe manifestations of the disease and often have other co-morbid conditions that affect their response to treatment and their time to recovery. Consequently, it is unclear to what extent results comparing the efcacy of different antibiotics in hospitalized patients can be extrapolated to outpatients.
Types of participants Outpatients of either gender over 12 years of age with: 1. Symptoms and signs consistent with an acute lower respiratory tract infection associated with new radiographic shadowing for which there is no other explanation (e.g. not pulmonary oedema or infarction) 2. The illness is the primary clinical problem and is managed as pneumonia (modied from the criteria for CAP as dened by the British Thoracic Society )
Why it is important to do this review

Numerous guidelines exist to aid clinicians with the treatment of CAP: in recent years, guidelines have been published, among others, by the American Thoracic Society (ATS 2001), the Infectious Diseases Society of America (IDSA 2000, updated December 2003: IDSA 2003), the British Thoracic Society (BTS 2001), and the Canadian Community-Acquired Pneumonia Working Group (CCAPWG 2000). All these guidelines include recommendation for the choice of antibiotic treatment for CAP in ambulatory patients, however the evidence on which these recommendations are based stems from studies carried out almost exclusively in hospitalized patients. Thus, although many studies have been published concerning CAP and its treatment, there is no concise summary of the available evidence concerning its treatment in ambulatory outpatients. This review addresses the comparative efcacy of antibiotic treatments for community acquired pneumonia (CAP) in outpatients above 12 years of age.
Types of interventions All double-blind randomized controlled comparisons of one antibiotic and a placebo or at least two antibiotics used to treat community acquired pneumonia were included. Trials comparing two doses or two different application forms of the same drug were not included. Most of the available studies compare the effects of two antibiotics. Comparisons involving intravenous drugs are usually carried out in a hospital setting. However, as this might occasionally be performed in an ambulatory setting, we did not a priori exclude studies dealing with intravenous drug applications. Trials allowing concurrent use of other medications such as antitussives, antipyretics, bronchodilators, or mucolytics were included if they allowed equal access to such medications for patients in both arms of the trial.
OBJECTIVES
The objectives of this review are: 1. To assess and compare the efcacy of individual antimicrobial therapies with respect to clinical, radiological and bacteriological outcomes in adult outpatients with CAP; 2. To assess and compare the efcacy of antibiotic drugs across drug groups.
Types of outcome measures 1. Clinical response: improvement of signs and symptoms. Where possible, duration of clinical signs and symptoms were used as outcome measures. We used a clinical denition of cure as the primary outcome since radiographic resolution lags behind clinical improvement (Macfarlane 1984). 2. Radiologic response: resolution or improvement of a new nding on chest x-ray after antibiotic therapy 3. Bacteriologic response: negative sputum culture in patients previously found to have had pathogens in their sputum. 4. Hospitalization. 5. Mortality.
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METHODS
Search methods for identication of studies
Electronic searches We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2003, issue 2, 2003) which contains the Cochrane Acute Respiratory Infections Group Specialized Register; MEDLINE (January 1966 to week 3, September 2003), and EMBASE (January 1974 to March 2003). MEDLINE (SilverPlatter) #1 explode Antibiotics- / all subheadings in MIME,MJME #2 antibiotic* #3 #1 or #2 #4 explode Community-Acquired-Infections / all subheadings in MIME,MJME #5 explode Pneumonia- / all subheadings in MIME,MJME #6 #4 and #5 #7 community acquired pneumonia #8 #6 or #7 #9 #3 and #8 #10 Randomized-Controlled-Trial in pt #11 controlled-clinical-trial in pt #12 explode Randomized-Controlled-Trials / all subheadings in MIME,MJME #13 explode Random-Allocation / all subheadings in MIME,MJME #14 explode Single-Blind-Method / all subheadings in MIME,MJME #15 explode Double-Blind-Method / all subheadings in MIME,MJME #16 #10 or #11 or #12 or #13 or #14 or #15 #17 (TG=animal) not ((TG=animal) and (TG=human)) #18 #16 not #17 #19 clinical-trial in pt #20 explode Clinical-Trials / all subheadings in MIME,MJME #21 (clin* near trial*) in ti #22 (clin* near trial*) in ab #23 explode Placebos- / all subheadings in MIME,MJME #24 placebo* in ti #25 placebo* in ab #26 random* in ti #27 random* in ab #28 (singl* or doubl* or tripl* or trebl*) near (blind* or mask*) #29 #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or # 27 or #28 #30 #29 not #17 #31 #18 or #30 #32 #9 and #31
Studies were also identied by checking the bibliographies of studies and review articles retrieved, and if necessary by contacting the rst or corresponding authors of included studies. To identify any additional published or unpublished studies we contacted the following manufacturers: Abbott, AstraZeneca, Aventis, Boehringer-Ingelheim, Bristol-Myers-Squibb, GlaxoSmithKline Beecham, Hoffmann-LaRoche, Lilly, Merck, Merck Sharp & Dohme, Novartis, Pzer, Pharmacia, Sano, and Yamanouchi. No language restrictions were applied to the search and selection processes. This search strategy yielded a total of 1828 references, some of which were double entries, due to the overlapping content of databases.
Data collection and analysis
Selection of studies Two review authors (MMK and LMB) used the titles and abstracts of the identied citations to exclude trials which clearly did not meet the inclusion criteria of the review. If the reviewers felt that the trial might possibly full the criteria, the full paper was obtained for further study. The most common reason for exclusion was that studies were conducted exclusively in hospitalized patients. Articles having passed this initial screen (n = 34) were then reviewed independently by two reviewers (LMB and TJMV) to determine whether they met the inclusion criteria of the review. The selection process is shown graphically in Figure 1. Studies could be excluded for any one of the following reasons: if they were not truly randomized; if they only compared two doses or two application forms of the same substance; if the results were not reported separately for in- and outpatients; if the indication for treatment consisted of a mix of diagnoses (most commonly: acute bronchitis, exacerbation of chronic bronchitis, and pneumonia) and the results were not reported separately for each diagnostic group. Studies including only bacteriologically evaluated patients were excluded, because these studies typically included only patients with positive cultures of pathogens susceptible to study antibiotics. A priori excluding patients with resistant strains as well as patients with non-bacterial causes of CAP (such as Mycoplasma pneumoniae) would falsely increase the treatment success rate to levels that would be unrealistic in real practice. Studies were also excluded if the diagnosis of pneumonia was not conrmed by chest x-ray. This exclusion criteria was necessary to ensure that only patients with a very high likelihood of having pneumonia be included in the review, since this was the patient population in which the efcacy of various treatment alternatives was to be tested. Finally, studies were excluded if the total number of patients was less than
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Searching other resources
30, because below this limit, the estimate of a binomial parameter (in this case, proportion of patients cured or improved) becomes too unstable (Armitage 1994).
Data extraction and management The following data were extracted from each study whenever possible: - description of participants (outpatients over 12 years) - description of potential pathogens identied and their antimicrobial resistance proles - description of intervention - description of control therapy - total number of participants in each arm of the trial - study setting - mean duration of symptoms in each arm of the trial - clinical, radiographic and bacteriologic cure rates in each arm of the trial - proportion of patients admitted to hospital in each arm of the trial - mortality rates in each arm of the trial - study sponsor The studies were assessed by two reviewers (LMB and TJMV). Disagreements were resolved by discussion and consensus. There were no unreconcilable disagreements. Reviewers were not blinded to the identity and afliation of the study authors.
Unit of analysis issues For dichotomous outcome data, an estimate of the common odds ratios with approximate 95% condence intervals was estimated using the Mantel-Haenzel approach. This was done by means of the Cochrane Collaborations Review Manager software, version 4.2.2.
RESULTS
1993; Ramirez 1999). The trials included varying numbers of patients, the largest having 342 patients (Ramirez 1999), the smallest 107 (Anderson 1991). The median trial size in the analysis was 173 patients, the mean size 207. Diagnoses All three trials exclusively enrolled outpatients with community acquired pneumonia. Diagnostic criteria In all trials, the diagnosis of community acquired pneumonia was based on clinical signs and symptoms as well as radiographic ndings in all patients. The signs and symptoms used as diagnostic criteria included combinations of the following: fever, chills, recent onset of productive cough, pleuritic chest pain, dyspnoea, pyrexia, tachypnoea, dullness to percussion, egophony, rales, localized reduced breath sounds and bronchial breath sounds. Out- versus Inpatient treatment In all three trials, patients were treated exclusively as outpatients. Patient inclusion and exclusion criteria Two trials included only adult patients, one (Chien 1993) also included adolescents (12 years of age and older). One trials reported including patients as old as 90 and none used older age as an exclusion criterion. Overall, the trials excluded patients with conditions that could have affected the treatment or interfered with follow-up. Exclusion criteria were reported in more or less detail in the study reports. The most common criteria reported were: pregnancy and lactation, women not using adequate contraception (usually oral contraceptives or a barrier method), history of allergic reaction to the study drugs, recent treatment with or concommitant use of an antimicrobial agent, concurrent medication with ergotamine, cyclosporin, antacids (except H2-antagonists) or digitalis, conditions affecting GI absorption, severe renal or hepatic impairment, terminal illness or conditions precluding study completion, infectious mononucleosis, HIV/AIDS, and prior participation in the study. Antibiotics The trials varied with respect to the antibiotics studied (see Fig. 2). Two trials (Anderson 1991; Chien 1993) studied the same antibiotic pair (clarithromycin and erythromycin). The other trial (Ramirez 1999) studied a different antibiotic pair, namely clarithromycin versus sparoxacin.
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies.
Risk of bias in included studies

All three trials were randomized, double-blind evaluations comparing two antibiotics. The extent of reporting was variable between studies. None of the studies clearly stated the randomization method used. None of the articles reported any test of effectiveness of the blinding procedures used. Compliance with treatment was assessed by pill count in two studies (Anderson 1991; Chien 1993); neither reported any difference in the number of pills remaining between the two groups, however in the Chien study, forty patients were excluded because they received less than the mini5
Results of the search See: Table of studies Number of trials and trial size Three randomized controlled trials involving a total of 622 patients aged 12 years and older diagnosed with community acquired pneumonia were included in the analysis (Anderson 1991; Chien
mum therapy (seven days) and these patients were distributed unevenly across the two groups (10 in the clarithromycin group and 30 in the erythromycin group). The third study (Ramirez 1999) reports having assessed patient compliance but does not state how. Regarding co interventions with other medications, most studies excluded patients whose co medication included certain drugs such as other antibiotics, chemotherapeutics or anti retrovirals. Only one study (Chien 1993) reported how many patients were excluded because of forbidden co-medication. Withdrawals were reported by all studies with varying degree of detail as to the reasons for withdrawal. One study (Ramirez 1999) reported only the number of withdrawals without specifying any reason for these. The number of patients lost to follow-up was reported in all but one study (Ramirez 1999). In the other studies (Anderson 1991; Chien 1993), losses to follow-up appeared to be minor, amounting to a maximum of 10% of the initially randomized patients. One study (Chien 1993) did not present intention-to-treat analysis results.
ing positive for Haemophilus Inuenzae (H. inuenzae) (62% of positive cultures) with Streptococcus pneumoniae (S. pneumoniae) (18%) being second most common, whereas Chien predominantly identied S. pneumoniae as causative organism in 56% of cultures, with H. inuenzae taking second place at 40%. On the contrary, Haemophilus parainuenzae (H. parainuenzae) (31%) was the most commonly identied pathogen in the study by Ramirez, with H. inuenzae (23%) in second place. Serologically identied pathogens Only two of the three studies carried out serologic tests to identify putative pathogens (Anderson 1991; Chien 1993; see Table 4). In both these studies, the most frequently identied pathogen was Mycoplasma pneumoniae (M. pneumoniae) which represented 69% (Anderson 1991) and 74% (Chien 1993) of positive serology results. Chlamydia pneumonia (C. pneumonia) accounted for the remainder with 38% (Anderson 1991) and 26% (Chien 1993) respectively. There were no samples positive for Legionella pneumoniae (L. pneumoniae) or for Chlamydia psittaci (C. psittaci ) in either study.
Effects of interventions
Efcacy The success rates for each of the treatment arms of the three trials are shown in Table 1. Success was dened as cure or improvement, be it clinical, bacteriological or radiological, as assessed at a predened follow-up visit. None of the clinical, bacterial or radiological success rates differed signicantly among treatment arms within each of the studies, nor did they achieve clinical - or statistical - signicance when the results of the two studies of clarythromycin vs erythromycin were pooled together (Fig. 3, 4 and 5). Comparisons across antibiotic groups The only comparison across antibiotic groups is provided by the study by Ramirez et al., whereby a macrolide (clarithromycin) and a quinolone (sparoxacin) are compared. Again, there was no signicant difference in clinical or bacteriological success; radiological outcomes were not reported separately for the two treatment arms. Side-effects There were, however, signicant differences in the occurrence of side-effects attributed to the study drug in the two studies comparing clarithromycin with erythromycin (Anderson 1991; Chien 1993) (Table 2). In both cases, there were signicantly more sideeffects in the erythromycin group, the majority being gastrointestinal side-effects. This was not, however, reected in the rate of side-effects leading to withdrawal from the study, which was not signicantly different across treatment arms. Bacterial pathogen Various pathogens were identied with varying frequency across studies (see Table 3). The proportion of samples yielding an identiable pathogen ranged from 19% (Anderson 1991) to 43% (Ramirez 1999). Anderson reported on a majority of cases be-
DISCUSSION
The overwhelming feature of this review is the utter paucity of relevant evidence that could be identied and included in the review. Given this current state of affairs, it is not possible to make evidence-based recommendations regarding the choice of antibiotic to be used for the treatment of community acquired pneumonia in ambulatory outpatients. One important reason for this lack of evidence is that a large number of the trials originally identied were conducted in hospitalized patients and therefore are not directly relevant to the treatment of ambulatory patients. It could be argued that the inclusion/exclusion criteria for this review were too strict and that this is the reason why so few studies were retained. We do, however, believe that the criteria we applied were necessary in order to validly address the question of the efcacy of treatment of CAP in ambulatory patients. In particular, it could be argued that the decision to exclude studies based on size is not desirable, since one aim of the review is to pool results and that each study therefore would contribute some information. We felt however that this criterion was necessary to exclude studies where the number of patients with pneumonia was so small that randomization could no longer be expected to achieve a balanced distribution of confounders, both known and unknown, across study groups. Finally, arguing retrospectively, it can be seen that dropping size as an exclusion criteria would not have made much difference to the results we obtained: the study by Fong et al. would have been excluded because it was not double-blinded and the two remaining studies would have contributed a total of six (Gris 1996) and eight (Tilyard 1992) patients respectively.
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As for the requirement that the diagnosis of CAP be conrmed by a chest radiograph, we felt that this was necessary to avoid diagnostic misclassication, which could for example have led to inclusion of patients with bronchitis into the review. This could have biased the estimation of the efcacy of various antibiotic treatments, either differentially or non-differentially, depending on the distribution of non-CAP cases across treatment groups. Indeed, most recent clinical guidelines recommend the routine use of chest x-rays to conrm a suspected pneumonia (ATS 2001, CCAPWG 2000, IDSA 2000), however, we are aware that this diagnostic test is often not used in practice and that patients are therefore treated empirically according to the severity of the clinical picture.
in the treatment of community acquired pneumonia in ambulatory patients. At most, it can be stated that individual study results do not reveal signicant differences in efcacy between various antibiotics and antibiotic groups.
Implications for research

Multi-drug, multi-drug-group blinded comparisons using similar administration schedules are needed to provide the evidence necessary for practice recommendations if these are to be applicable in the ambulatory setting. Study conditions should ensure that diagnosis and management of patients with community acquired pneumonia is as similar as possible to real practice, while still ensuring that the study question is addressed in a valid way.
AUTHORS CONCLUSIONS Implications for practice

Currently available evidence from RCTs is insufcient to make evidence-based recommendations for choice of antibiotic to be used
ACKNOWLEDGEMENTS
Many thanks to Dr. Frederike Behn (Hamburg) for precious help with parts of the data extraction process.
REFERENCES
References to studies included in this review

Anderson 1991 {published data only} Anderson G, Esmonde TS, Coles S, Macklin J, Carnegie C. A comparative safety and efcacy study of clarithromycin and erythromycin stearate in community-acquired pneumonia. Journal of Antimicrobial Chemotherapy 1991;27 (Suppl A):11724. Chien 1993 {published data only} Chien SM, Pichotta P, Siepman N, Chan CK and the Canada-Sweden Clarithromycin-Pneumonia Group. Treatment of Community-Acquired Pneumonia: A multicenter, double-blind, randomized study comparing clarithromycin with erythromycin. Chest 1993;103: 697701. Ramirez 1999 {published data only} Ramirez J, Unowsky J, Talbot GH, Zhang H, Townsend L. Sparoxacin vs clarithromycin in the treatment of community acquired pneumonia. Clinical Therapeutics 1999;21(1):10317.
Ball 1994 {published data only} Ball P. Efcacy and safety of cefprozil versus other betalactam antibiotics in the treatment of lower respiratory tract infections. European Journal of Clinical Microbiology and Infectious Diseases 1994;13(10):8516. Balmes 1991 {published data only} Balmes P, Clerc G, Dupont B, Labram C, Pariente P, Poirier R. Comparative study of azithromycin and amoxicillin/clavulanic acid in the treatment of lower respiratory tract infections. European Journal of Clinical Microbiology and Infectious Diseases 1991;10:4379. Bantz 1987 {published data only} Bantz PM, Grote J, Peters-Haertel W, Stahmann J, Timm J, Kasten R, et al.Low-dose ciprooxacin in respiratory tract infections: a randomized comparison with doxycycline in general practice. American Journal of Medicine 1987;82 (Suppl 4A):20810. Biermann 1988 {published data only} Biermann C, Loken A, Riise R. Comparison of spiramycin and doxycycline in the treatment of lower respiratory infections in general practice. Journal of Antimicrobial Chemotherapy 1988;22(Suppl B):1558. Chodosh 1991 {published data only} Chodosh S. Temaoxacin compared with ciprooxacin in mild to moderate lower respiratory tract infections in ambulatory patients. Chest 1991;100:1497502. Dark 1991 {published data only} Dark D. Multicenter evaluation of azithromycin and cefaclor in acute lower respiratory tract infections. American
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References to studies excluded from this review

Balgos 1999 {published data only} Balgos AA, Rodriguez-Gomez G, Nasnas R, Mahasur AA, Margono BP, Tinoco-Favila JC. Efcacy of twicedaily amoxycillin/clavulanate in lower respiratory tract infections. International Journal of Clinical Practice 1999;53 (5):32530.
Journal of Medicine 1991;91(Suppl 3A):315. Dautzenberg 1992 {published data only} Dautzenberg B, Scheimberg A, Brambilla C, Camus P, Godard P, Guerin JC. Comparison of two oral antibiotics, roxithromycin and amoxicillin plus clavulanic acid, in lower respiratory tract infections. Diagnostic Microbiology and Infectious Disease Diagnostic Microbiology and Infectious Disease 1992;15(Supplement):859. De Cock 1988 {published data only} De Cock L, Poels R. Comparison of spiramycin with erythromycin for lower respiratory tract infections. Journal of Antimicrobial Chemotherapy 1988;22(Suppl B):15963. Fong 1995 {published data only} Fong IW, Laforge J, Dubois J, Small D, Grossman R, Zakhari R, et al.Clarithromycin versus cefaclor in lower respiratory tract infections. Clinical and Investigative Medicine 1995;18:1318. Gris 1996 {published data only} Gris P. Once-daily, 3-day azithromycin versus a threetimes-daily, 10-day course of co-amoxiclav in the treatment of adults with lower respriatory tract infections: results of a randomized, double-blind comparative study. Journal of Antimicrobial Chemotherapy 1996;37(Suppl C):93101. Higuera 1996 {published data only} Higuera F, Hidalgo H, Feris J, Giguere G, Collins JJ. Comparison of oral cefuroxime axetil and oral amoxycillin/ clavulanate in the treatment of community-acquired pneumonia. Journal of Antimicrobial Chemotherapy 1996; 37:55564. Hoepelman 1993 {published data only} Hoepelman AIM, Sips AP, van Helmond JLM, van Barneveld PWC, Neve AJ, et al.A single-blind comparison of three-day azithromycin and ten-day co-amoxiclav treatment of acute lower respiratory tract infections. Journal of Antimicrobial Chemotherapy 1993;31(Suppl E):14752. Hoepelman 1998 {published data only} Hoepelman IM, Mllers MJ, van Schie MH, Greefhorst APM, Schlsser NJJ, Sinninghe Damst EJ, et al.A short (3-day) course of azithromycin tablets versus a 10-day course of amoxycillin-clavulanic acid (co-amoxiclav) in the treatment of adults with lower respiratory tract infections and effects on long-term outcome. International Journal of Antimicrobial Agents 1998;9:1416. Kammer 1991 {published data only} Kammer RB, Ress R. Randomized comparative study of ceftibuten versus cefaclor in the treatment of acute lower respiratory tract infections. Diagnostic Microbiology and Infectious Disease 1991;14:1015. Kiani 1990 {published data only} Kiani R, Coulson L, Johnson D, Hammershaimb L. Comparison of once-daily and twice-daily cexime regimens with amoxicillin in the treatment of acute lower respiratory tract infections. Current Therapeutic Research, Clinical and Experimental 1990;48(5):84152.
Lacny 1972 {published data only} Lacny J. A comparison of oral therapy with clindamycin and penicillin G in common gram-positive infections. Current Therapeutic Research, Clinical and Experimental 1972;14(1):2630. Laurent 1996 {published data only} Laurent K. Efcacy, safety and tolerability of azithromycin versus roxithromycin in the treatment of acute lower respiratory tract infections. Journal of Antimicrobial Chemotherapy 1996;37(Suppl C):11524. Liipo 1994 {published data only} Liippo K, Tala E, Puolijoki H, Brckner OJ, Rodrig J, Smits JPH. A comparative study of dirithromycin and erythromycin in bacterial pneumonia. Journal of Infectious Diseases 1994;28:1319. Lode 1995 {published data only} Lode H, Garau J, Grassi C, Hosie J, Huchon G, Legakis N, et al.Treatment of community-acquired pneumonia: a randomized comparison of sparoxacin, amoxycillinclavulanic acid and erythromycin. European Respiratory Journal 1995;8:19992007. Lode 1998 {published data only} Lode H, Aubier M, Portier H, Ortqvist A and the Sparoxacin Study Group. Sparoxacin as alternative treatment to standard therapy for community-acquired bacteremic pneumococcal pneumonia. Clinical Microbiology and Infection 1998;4(3):13543. Mller 1992 {published data only} Mller O, Wettich K. Comparison of loracarbef (LY 163892) versus amoxicillin in the treatment of bronchopneumonia and lobar pneumonia. Infection 1992; 20(3):17682. NAPSG 1997 {published data only} The Nordic Atypical Pneumona Study Group. Atypical pneumona in the Nordic countires: aetiology and clincal results of a trial comparing eroxacin and doxycyclin. Journal of Antimicrobial Chemotherapy 1997;39:499508. Neu 1993 {published data only} Neu HC, Chick TW. Efcacy and safety of clarithromycin compared to cexime as outpatient treatment of lower respiratory tract infections. Chest 1993;104:13939. ODoherty 1998 {published data only} ODoherty B, Muller O and the Azithromycin Study Group. Randomized, multicentre study of the efcacy and tolerance of Azithromycin versus clarithromycin in the treatment of adults with mild to moderate communityacquired pneumonia. European Journal of Clinical Microbiology and Infectious Diseases 1998;17:82833. Peugeot 1991 {published data only} Peugeot RL, Lipsky BA, Hooton TM, Pecoraro RE. Treatment of lower respiratory infections in outpatients with ooxacin compred with erythromycin. Drugs in Experimental and Clinical Research 1991;17(5):2537.
8
Rayman 1996 {published data only} Rayman J, Krchnav M, Balciar P, Duchon J, Fortunk J, Faith L, et al.Ooxacin once daily versus twice daily in community-acquired pneumonia and acute exacerbation of chronic bronchitis. Chemotherapy 1996;42:22730. Salvarezza 1998 {published data only} Salvarezza CR, Mingrone H, Fachinelli H, Kijanczuk S. Comparison of roxithromycin with cexime in the treatment of adults with community-acquired pneumonia. Journal of Antimicrobial Chemotherapy 1998;41(Suppl B): 7580. Schleupner 1988 {published data only} Schleupner CJ, Anthony WC, Tan J, File TM, Liand P, Craig W, Vogelman B. Blinded comparison of cefuroxime to cefaclor for lower respiratory tract infections. Archives of Internal Medicine 1988;148:3438. Tilyard 1992 {published data only} Tilyard MW, Dovey SM. A randomized double-blind controlled trial of roxithromycin and cefaclor in the treatment of acute lower respiratory tract infections in general practice. Diagnostic Microbiology and Infectious Disease 1992;15:97101. rtqvist 1996 {published data only} rtqvist A, Valtonen M, Cars O, Wahl M, Saikku P, Jean C, et al.Oral empiric treatment of community-acquired pneumonia: a multicenter, double-blind, randomized study comparing sparoxacin with roxithromycin. Chest 1996; 110:1499506.
CCAPWG 2000 Canadian Community-Acquired Pneumonia Working Group. Canadian guidelines for the initial management of community-acquired pneumonia: an evidence-based update by the Canadian Infectious Diseases Society and the Canadian Thoracic Society. Clinical Infectious Diseases 2000;31:383421. Foy 1979 Foy HM, Cooney MK, Allan I, et al.Rates of pneumonia during inuenza epidemics in Seattle, 1964 to 1975. JAMA 1979;241:2538. Guest 1997 Guest JF, Morris A. Community-acquired pneumonia: the annual cost to the National Health Service in the United Kingdom. Eur Respir J 1997;10:15304. IDSA 2000 Infectious Dieseases Society of America. Practice guidelines for the management of community-acquired pneumonia in adults. Clinical Infectious Diseases 2000;31:34782. IDSA 2003 Infectious Dieseases Society of America. Update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults. Clinical Infectious Diseases 2003;37:140533. Jokinen 1993 Jokinen C, Heiskanen L, Juvonen H, et al.Incidence off community-acquired pneumonia in the population of four municipalities in eastern Finland. Am J Epidemiol 1993; 137:97788. Loeb 2002 Loeb M. Community-acquired pneumonia. Clinical Evidence. Vol. 8, London: BMJ Publishing Group, 2002. Macfarlane 1984 Macfarlane JT, Miller AC, Smith WHR, et al.Comparative radiographic features of community-acquired legionnaires disease, pneumococcal pneumonia, mycoplasma pneumonia and psittacosis. Thorax 1984;39:2833. Torres 1991 Torres A, Serra-Batlles J, Ferrer A, et al.Severe communityacquired pneumonia. Epidemiology and prognostic factors. Am Rev Respir Dis 1991;144:3128. Woodhead 1987 Woodhead MA, Macfarlane JT, McCracken JS, et al.Prospective study of the aetiology and outcome of pneumonia in the community. Lancet 1987;i:6714. Indicates the major publication for the study
Additional references
Armitage 1994 Armitage P, Berry G. Statistical Methods in Medical Research. 3rd Edition. Oxford: Blackwell Scientic Publications, 1994. ATS 2001 American Thoracic Society. Guidelines for the management of adults with community-acquired pneumonia. American Journal of Critical Care 2001;163:173054. BTS 1992 British Thoracic Society Research Committee and Public Health Laboratory Service. The aetiology, management and outcome of severe community-acquired pneumonia on the intensive care unit. Respir Med 1992;86:713. BTS 2001 British Thoracic Society. British Thoracic Society Guidelines for the management of adults with communityacquired pneumonia. Thorax 2001;56(Suppl IV):164.
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Anderson 1991 Methods Study period: ? Follow-up: 6 to 8 weeks Parallel trial Patients were included from 57 general practitioners in the UK Double-blind, double-dummy technique Intention-to-treat results provided Drop-outs: total: 48% (33% clarithro, 61% erythro) due to failure to conrm the diagnosis on the pretreatment CXR, premature discontinuation, no post-treatment evaluation, less than minimum therapy, no post-treatment CXR, concomitant medication, lost of follow-up Exclusion criteria clear 3 of 5 authors from Abbott Laboratories Patients with CAP older than 18 years CAP diagnosis conrmed by: 3 of the following features: pyrexia, dyspnoea, tachypnoea, rales, localized reduced breath sounds and cough Diagnosis of CAP was later conrmed radiographically Total: n = 208 Evaluable for efcacy: n = 108 (Exclusion usually due to failure to conrm initial Dx on CXR) n = 64 (clarithro), n = 44 (erythro) Mean age 53.5 yrs Male: 65% Clarithromycin (clarithro)250 mg bid for 14 days or Erythromycin (erythro) 500 mg qid for 14 days, each given at least 1h before or 2h after meals Mean treatment duration: 13 days (clarithro), or 10 days (erythro) Compliance assessment: tablet count 1. Clinical cure rate 2. Clinical success rate (cured and improved) 3. Radiographic success rate 4. Bacteriological cure rate Clinical response at 2 weeks: cure: 52% (clarithro), 41% (erythro) success: 98% (clarithro), 91% (erythro) At 6 to 8 weeks: cure: 77% (clarithro), 80% (erythro), success: 89% (clarithro), 98% (erythro)
Participants
Interventions
Outcomes
Notes Risk of bias
10
Anderson 1991
(Continued)
Item Allocation concealment?
Authors judgement Yes
Description A - Adequate
Chien 1993 Methods Duration: January 1989 to June 1990 Follow-up: 4-6 weeks Parallel trial Multicenter study (15 centers of the Canada-Sweden ClarithromycinPneumonia Study Group) Double-blind, double-dummy technique No intention-to-treat results provided Drop-outs: 35% (due to less than minimum therapy, premature discontinuation, unavailable for followup, misdiagnosis, inadequate data collection, concomitant medication, underlying condition) Exclusion criteria clear Research supported by Abbott Laboratories, Chicago Ambulatory patients older than 12 yrs with CAP CAP diagnosis based on pretreatment CXR (new inltrate consistent with pneumonia), a positive bacterial culture of bronchopulmonary secretions before treatment or a history and clinical ndings consistent with a diagnosis of bacterial or atypical pneumonia to be conrmed subsequently by positive culture or serologic result n = 268 all patients, exclusions, 173 evaluable patients: n = 92 (clarithro), n = 81 (erythro) Patients with mild or moderate infection Mean age: 47.2 yrs (clarithro), 48.2 yrs (erythro) Male: 47% (clarithro), 56% (erythro) Clarithromycin: 250 mg every 12h, or Erythromycin stearate: 500 mg every 6 h Mean treatment duration not specied (minimum duration: 7 days, intended duration: 7-14 days) Compliance assessment: tablet count Clinical response: 1. Cure: resolution of all signs and symptoms 2. Improvement: partial resolution 3. Failure: no improvement 4. Relapse: deterioration observed at the rst posttherapy visit after initial improvement Radiologic response: 1. Resolution 2. Improvement 3. Unchanged 4. Worsening
11
Participants
Interventions
Outcomes
Chien 1993
(Continued)
Bacteriologic responses: 1. Cure: absence of the pretreatment pathogen in the posttreatment culture 2. Failure: persistence of the pretreatment pathogen in the posttreatment culture 3. Reinfection: presence of a pathogen in the posttreatment culture that was different from that in the pretreatment culture 4. Recurrence: reappearance on the follow-up culture of a pathogen that was previously eradicated Clinical response: Success (cure and improvement) 97% clarithro, 96% erythro Radiological response: 96% in both groups Bacteriological response: 88% clarithro, 100% erythro (not signicant) Overall adverse events: 31% clarithro, 59% erythro (p<0.001) Notes Risk of bias Item Allocation concealment? Authors judgement Yes Description A - Adequate
Ramirez 1999 Methods Duration: February 3rd to October 31st 1996 Follow-up: 28 days post-treatment Parallel trial Multicenter study (56 centers in the USA) Investigator and patients blinded, use of double dummy technique to blind the different dosing regimens Intention-to-treat results provided About 25% drop-outs in each group, due to treatment failure, adverse events, protocol deviations and loss to follow-up Exclusion criteria clear Study funded by Rhne-Poulenc-Rorer Patients: presumed to have CAP, 18-91 years Pts withdrawn or excluded if nosocomial pneumonia CAP diagnosis conrmed by: - CXR and - at least 2 of the following: fever (oral temp >38C), cough, sputum production, evidence of pulmonary consolidation, hemoptysis, rigors, pleuritic chest pain n = 167 (sparoxacin) n = 175 (clarithromycin) Total = 342 150 sparox and 162 clarithro clinically evaluable as per-protocol patients 48 sparox and 50 clarithro patients bacteriologically evaluable Sparoxacin 400 mg loading dose on day 1, then 200mg qd x 10 d or Clarithromycin 250 mg bid x 10 d Mean and median treatment duration not reported Compliance not assessed
12
Participants
Interventions
Ramirez 1999
(Continued)
Outcomes
Clinical response at visit 3 (10 days after end of treatment) 1. cure: disappearance of all pretreatment clinical signs and symptoms; cxr resolved, improved or stable compared to baseline 2. improvement: resolution or reduction of most pretreatment clinical signs and symptoms; cxr resolved, improved or stable compared to baseline 3. Failure: no resolution or reduction of most signs and symptoms of pneumonia, worsening of one or more signs or sympt., new signs or sympt., or cxr worsened 4. Indeterminate: it was not possible to assess signs and symptoms Clinical results (intent-to-treat): 1. cure or improv: Spar: 79.6% Clarithro: 82.9% no sig diff Adverse events: Spar: 56.3% Clarithro: 65.1%
Notes Risk of bias Item Allocation concealment? Authors judgement Yes Description A - Adequate
Characteristics of excluded studies [ordered by study ID]
Study Balgos 1999
Reason for exclusion Mix of in- and outpatients (unspecied proportions) Mix of diagnoses (chron bronch and CAP), only about 50% with CAP; results reported separately Comparison of two dosage regimens of the same drug (amoxycillin/clavulanic acid 875/125mg bid vs 500/ 125mg tid) Review of a series of unblinded trials Mix of patients of different studies Mix of diagnoses (acute bronchitis and pneumonia) Only 8/110 (7%) patients had a diagnosis of pneumonia Mix of in- and out-patients (unspecied proportions) Mix of diagnoses (bronchitis and pneumonia) Only 15/108 (14%) patients had a diagnosis of pneumonia Data not reported separately No chest x-ray for every patient with suspected pneumonia
13
Ball 1994
Balmes 1991
Bantz 1987
Biermann 1988
(Continued)
Chodosh 1991 Dark 1991
Only bacteriologically evaluable patients were included. Mix of diagnoses (bronchitis and pneumonia) Only 23/272 (8%) patients had a diagnosis of pneumonia Mix of in- and out-patients (unspecied proportions) Open-label study Mix of diagnoses (acute bronchitis, acute superinfection of chronic bronchitis, pneumonia) and results reported separately Only 42/198 (21%) patients had a diagnosis of pneumonia (results not specied for diagnosis groups) Too small (n<30) Too small (n<30) Open-label study Mix of diagnoses (infective exacerbation of chronic obstructive pulmonary disease, purulent bronchitis and pneumonia) and results not reported separately Only 9/99 (9%) patients had pneumonia Pneumonia not necessarily community acquired Mix of diagnoses and results not reported separately Only bacteriologically evaluable patients were included Mix of in and out-patients, results not reported separately Mix of diagnoses (acute bronchitis, pneumonia, acute exacerbation of chronic bronchopulmonary infection) but results reported separately Only 10/110 (9%) patients had a diagnosis of pneumonia Mix of diagnoses (infection of soft tissue, infection of the upper respiratory tract, otitis, skin infection, conjunctivitis, pneumonia) but results not reported separately Only 2/121 (2.6%) patients had a diagnosis of pneumonia Completely institutionalized population 32.5% patients were younger than 16 yrs Mix of diagnoses (acute bronchitis, acute infectious exacerbations of chronic brochitis, or pneumonia) but results reported separately Only 43/204 (21%) patients had a diagnosis of pneumonia Mix of in- and outpatients (unclear in which proportions) Patients recruited from both hospitals and general practice, proportions unclear Only inpatients (personal communication H. Lode), contrary to study report (Patients reportely treated as either in- or outpatients)
14
Dautzenberg 1992 De Cock 1988
Fong 1995 Gris 1996 Higuera 1996 Hoepelman 1993
Hoepelman 1998 Kammer 1991 Kiani 1990
Lacny 1972
Laurent 1996
Liipo 1994 Lode 1995
(Continued)
Lode 1998
Combines patients from four other RCTs, including only those patients with strep pneumoniae pneumonia conrmed by blood culture, i.e. highly select sub-group, generalizability questionable. And the data from the four studies can be obtained from the original reports (one of which is rtqvist 1996, already included in the review) Only bacteriologically evaluable patients were included Study included both in- and out-patients, without providing any information on either of the sub-groups or carrying out sub-group analyses Mix of diagnoses (acute bacterial exacerbation of chronic bronchitis or asthmatic bronchitis and bacterial pneumonia) but results not reported separately Unclear whether in- or outpatients Only 43/213 (20%) had a diagnosis of CAP Open-label study Open-label study Comparison of different dosage regimens of the same drug. Included patients with either CAP or acute exacerbation of chronic bronchitis (i.e. mixed indications) Groups were not similar at baseline (more smokers and more failures of previous treatment in the twice daily group, for which more adverse reactions were reported) Open-label study Mix of diagnoses (bronchitis, pneumonia) Only 34/61 (56%) patients had a diagnosis of pneumonia Mix of in- and out-patients (unspecied proportions) Too small (n<30) Patients had CAP but were treated exclusively as inpatients.
Mller 1992 NAPSG 1997
Neu 1993
ODoherty 1998 Peugeot 1991 Rayman 1996
Salvarezza 1998 Schleupner 1988
Tilyard 1992 rtqvist 1996
15

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Antibiotics for community acquired pneumonia in adult outpatients (Review)

Bjerre LM, Verheij TJM, Kochen MM

Antibiotics for community acquired pneumonia in adult outpatients

Description of the condition

Description of the intervention

Criteria for considering studies for this review

How the intervention might work

Why it is important to do this review

Search methods for identication of studies

Data collection and analysis

Searching other resources

Risk of bias in included studies

Implications for research

AUTHORS CONCLUSIONS Implications for practice

References to studies included in this review

References to studies excluded from this review

Characteristics of included studies [ordered by study ID]

Notes Risk of bias

Item Allocation concealment?

Authors judgement Yes

Characteristics of excluded studies [ordered by study ID]

Study Balgos 1999

Chodosh 1991 Dark 1991

Dautzenberg 1992 De Cock 1988

Fong 1995 Gris 1996 Higuera 1996 Hoepelman 1993

Hoepelman 1998 Kammer 1991 Kiani 1990

Liipo 1994 Lode 1995

Mller 1992 NAPSG 1997

ODoherty 1998 Peugeot 1991 Rayman 1996

Salvarezza 1998 Schleupner 1988

Tilyard 1992 rtqvist 1996

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