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Original Investigation |

Empirical Atypical Coverage for Inpatients With Community-Acquired Pneumonia:  Systematic Review of Randomized Controlled Trials FREE

Daphna Shefet, MD; Eyal Robenshtok, MD; Mical Paul, MD; Leonard Leibovici, MD
[+] Author Affiliations

Author Affiliations: Department of Medicine E, Beilinson Campus, Rabin Medical Center, Petah-Tiqva, Israel (Drs Shefet, Robenshtok, Paul, and Leibovici); and Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Tel Aviv, Israel (Drs Paul and Leibovici).


Arch Intern Med. 2005;165(17):1992-2000. doi:10.1001/archinte.165.17.1992.
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Background  Current guidelines of empirical antibiotic treatment for inpatients with community-acquired pneumonia recommend antibiotics whose spectrum covers intracellular (atypical) pathogens. No sufficient evidence exists to support the necessity of such coverage, whereas limiting it may reduce toxic effects, resistance, and expense. Our goal was to assess the efficacy of empirical coverage of atypical pathogens in terms of mortality and clinical and bacteriological success.

Methods  Systematic review and meta-analysis of randomized, controlled trials comparing treatment regimens with and without coverage of atypical pathogens. We searched MEDLINE, EMBASE, the Cochrane Library, and references. Relative risks (RRs) with 95% confidence intervals (CIs) were pooled using the fixed-effects model. The primary outcome assessed was all-cause mortality.

Results  We included 24 trials encompassing 5015 patients. We found no studies of a drug without atypical coverage that compared it with the same drug supplemented with a drug with atypical coverage; nearly all compared a β-lactam with a single quinolone or macrolide. There was no difference in mortality between the 2 arms (RR, 1.13 [95% CI, 0.82-1.54]). Regimens with coverage of atypical pathogens showed a trend toward clinical success and a significant advantage to bacteriological eradication. Both disappeared when evaluating methodologically high-quality studies alone. These regimens further showed a significant advantage in clinical success for Legionella pneumophila, whereas no advantage for pneumococcal pneumonia was seen. There was no difference between study arms in the frequency of total adverse events.

Conclusion  Empirical antibiotic coverage of atypical pathogens in hospitalized patients with community-acquired pneumonia showed no benefit of survival or clinical efficacy in this synthesis of randomized trials.

Figures in this Article

Major guidelines for the treatment of community-acquired pneumonia (CAP) generally differentiate between outpatients, inpatients, and patients hospitalized in intensive care units.14 Suggested antibiotic regimens for inpatients include a β-lactam combined with macrolides, or monotherapy with a respiratory fluoroquinolone. Although Streptococcus pneumoniae remains the leading pathogen in CAP, the rationale for a macrolide supplement or fluoroquinolone monotherapy lies in its ability to cover intracellular (atypical) pathogens such as Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila.

Coverage of the latter pathogen is recommended explicitly for patients in intensive care units. To our knowledge, no randomized, controlled trial has compared, as an objective, the superiority of antibiotic regimens containing coverage of atypical pathogens with regimens lacking such coverage. A systematic review of nonrandomized studies found a significant reduction in mortality when the antibiotic spectrum covered atypical pathogens in 6 of its 8 selected studies.5 However, all studies were cohort studies, and 2 were restricted to bacteremic pneumococcal pneumonia.6,7 In the largest study,8 the choice of such regimens was associated with an initial lower severity score, thus underlining the potential bias of nonrandomized studies. Whereas the advantage of combination therapy is unproved, dual therapy may increase toxic effects, resistance, and cost. Moreover, an antagonism between penicillin and erythromycin has been shown in vitro and in vivo against S pneumoniae isolates,9 the most prevalent pathogen causing CAP.10,11

The present review evaluates the need for empirical antibiotic coverage of atypical pathogens in adults hospitalized owing to CAP. It includes all randomized, controlled trials that compared an antibiotic regimen containing coverage of atypical pathogens with one not containing such coverage. The main outcome was mortality. Secondary outcomes included clinical efficacy, bacteriological failure, and adverse events.

INCLUSION CRITERIA

We included randomized, controlled trials that assessed treatment of CAP in hospitalized adults and in which an antibiotic regimen containing coverage of atypical pathogens was compared with a regimen not containing such coverage. Regimens including a macrolide, fluoroquinolone, tetracycline, doxycycline, or chloramphenicol were considered to afford atypical coverage. Regimens lacking these drugs were considered regimens without atypical coverage. We included oral and intravenous therapies.

Trials that included mainly patients with major immunosuppressive states were not considered for this review. Trials with a dropout rate of more than 30% were excluded.

SEARCH STRATEGY

The search string combined community-acquired infections/pneumonia, inpatients, and antibiotic names and classes of atypical drugs identified in the previous section (string specified at The Cochrane Database of Systematic Reviews 2005, Issue 2).

Databases searched included CENTRAL (Cochrane Library Issue 4, 2004), MEDLINE (to August 2004), and EMBASE (to July 2003). We inspected references of identified studies for more trials and contacted corresponding authors for complementary information.

OUTCOMES

The primary outcome was overall mortality up to 30 days after the end of treatment. Secondary outcomes included clinical treatment failure, bacteriological eradication, and development of superinfections and adverse events, specifically gastrointestinal events or events resulting in treatment discontinuation.

DATA EXTRACTION

Outcomes were extracted by intention to treat (ITT), including all individuals randomized in the outcome assessment. When data for ITT analysis were unavailable, available cases were assessed. Two reviewers (D.S. and E.R.) independently extracted data from included trials. Methodological assessment was performed using a component approach, including allocation generation and concealment, blinding, and analysis by ITT. Allocation generation and concealment were classified as adequate, unclear, or inadequate, using criteria from the Cochrane Reviewers’ Handbook 4.2.2.12 We did not assess a composite quality scale, because different scales may lead to discordant results.13 Sensitivity analyses were performed to assess the robustness of the findings per the following trial methods: allocation concealment, allocation generation, and blinding.

DATA ANALYSIS

Relative risks (RRs) with 95% confidence intervals (CIs) are reported. We used a fixed-effects model and compared it with a random-effects model when significant heterogeneity between trials was observed. Heterogeneity of trial results was assessed by calculating a χ2 test of heterogeneity and the I2 measure of inconsistency. Significant heterogeneity was predefined as a χ2 test P value smaller than .1 or an I2 measure larger than 50%. We had anticipated between-trial variation in the estimation of morbidity and mortality for different geographic areas, age groups, sample size, and the drug affording atypical coverage (macrolides or fluoroquinolones). Subgroup analyses to assess the impact of these factors on the main results were performed. A funnel plot estimating the trial precision (logarithm of the RR for efficacy against sample size) was examined to estimate potential asymmetry.

DESCRIPTION OF STUDIES

Our search resulted in 994 references. Fifty-six publications were retrieved for full-text inspection,1469 of which 26 fulfilled the inclusion criteria. Two were withdrawn from analysis owing to unavailable data,44,45 and thus 24 trials are included in the review4669 (Figure 1 and Table 1).

Place holder to copy figure label and caption
Figure 1.

Selection process for randomized controlled trials (RCTs). CAP indicates community-acquired pneumonia.

Graphic Jump Location

Included studies were performed between 1982 and 2004 and encompassed 5015 patients. Inclusion criteria in all studies consisted of adults hospitalized with CAP. The number of participants was 100 or fewer in 8 trials and more than 100 in 16 trials (range, 40-808 participants). All trials were restricted to adults, with a mean age less than 65 years in 12 studies and 65 years or greater in 9. Among the latter, 2 studies were performed in nursing homes,54,62 and 1 exclusively included patients older than 70 years.65 Three studies did not report mean age. Ten studies provided the percentage of patients with chronic obstructive pulmonary disease, ranging from 25% to 52.5%.64 None analyzed separately results for patients with chronic obstructive pulmonary disease and/or smokers.

Pneumonia was defined by a combination of clinical signs, radiological confirmation (the sole criteria in 2 studies), laboratory values, and/or bacteriological evidence. Thirteen trials further included outpatients, patients with nosocomial pneumonia, and/or patients with bronchitis. In all cases, most of the patients had CAP or could undergo separate analysis.

The antibiotic regimens, dosages, and routes of administration are detailed in Table 1. In nearly all studies, the comparison was between monotherapy in the arm covering atypical pathogens and a β-lactam. We found no comparison of a β-lactam–macrolide combination with β-lactam monotherapy. Treatment duration was conveyed in 14 studies and was almost uniformly 10 days, with no difference between the arms. The main outcome in all studies was clinical treatment failure. Six studies mandated radiological resolution for success definition, and 1 required bacteriological eradication. None chose mortality as the primary outcome.

Eighteen trials assessed bacteriological failure (per patient or per pathogen). Only 8 performed serologic tests for atypical pathogens, of which 1 study found negative results for all tests,68 and 4 others did not fully report eradication rates. Superinfection and colonization rates were reported in only 5 studies each, precluding further evaluation.

Adverse events were addressed in all studies, although 2 did not specify the number of events per treatment arm.

METHODOLOGICAL QUALITY OF INCLUDED STUDIES

Of the 24 included studies, adequate allocation concealment was reported in 6 and adequate allocation generation in 9. No information was available for the remaining studies. All studies of adequate allocation concealment were also of adequate allocation generation.

Seven studies reported results by ITT. Another 13 reported the number of dropouts per study arm, permitting reanalysis by ITT by assuming failure for all dropouts. Four studies did not refer to dropouts and were analyzed only by patients undergoing evaluation.

Follow-up duration was specified in 21 studies, of which 16 defined a specific time for outcome measurement. Follow-up ranged from the end of treatment to 3 months after. Overall mortality was assessed at the end of treatment or at follow-up in all studies. Data at the furthest point in time, up to 30 days, was chosen for analysis. At least 18 of the 24 studies were sponsored by pharmaceutical companies, all of which manufactured the drug with atypical coverage.

OVERALL MORTALITY

Twenty-three of the 24 studies could be evaluated for mortality, encompassing 4846 of 5015 randomized patients (96.6%) (Figure 2). Six studies reported no deaths, whereas 10 reported mortality rates of 0.4% to 5%; 6, 5% to 8%, and 1, 25%.51 There was no significant difference between the arms in the overall mortality rate (RR, 1.13 [95% CI, 0.82-1.54]) (Figure 2). The difference was nonsignificant when evaluating quinolones (RR, 0.98; 95% CI, 0.69-1.41) and macrolides (RR, 1.25 [95% CI, 0.52-3.01]). No heterogeneity was seen for the overall comparison.

Place holder to copy figure label and caption
Figure 2.

The number of patients who died within the follow-up period (overall mortality). The left side depicts arms with atypical coverage; the right side, arms without atypical coverage. A value of less than 1 favors atypical coverage. Studies are subdivided by the antibiotic used as the atypical regimen, including quinolone therapy (01), macrolide therapy (02), and combined macrolide and quinolone therapy (03). The total indicates the total number of patients (sum of groups 01-03). CAP indicates community-acquired pneumonia; CI, confidence interval; I2, measure of inconsistency (see “Methods” section); n/N, number of patients/total number of patients in the study; RR, relative risk; and solid oblong diamond, total events.

Graphic Jump Location

Mortality was further analyzed by age, geographic area, and sample size, and the results disclosed no significant difference. Overall mortality in both arms was similar when analyzing studies per allocation generation, allocation concealment, blinding, and the ITT analysis (Table 2). In the funnel plot for overall mortality, results are symmetrically centered around the combined RR.

Table Graphic Jump LocationTable 2. Sensitivity Analyses for Individual Methodological Quality Components*
CLINICAL FAILURE

Clinical failure was the primary outcome in all studies, encompassing 4682 patients. No significant difference between study arms was observed (RR, 0.92 [95% CI, 0.82-1.03]) (Figure 3).

Place holder to copy figure label and caption
Figure 3.

The number of patients considered to have a clinical treatment failure. The left side depicts arms with atypical coverage; the right side, arms without atypical coverage. Studies are subdivided by the antibiotic used as the atypical regimen, including quinolone therapy (01), macrolide therapy (02), and combined macrolide and quinolone therapy (03). Total indicates the total number of patients (sum of groups 01-03). CAP indicate community-acquired pneumonia; CI, confidence interval; I2, measure of inconsistency (see “Methods” section); n/N, number of patients/total number of patients in the study; RR, relative risk; and solid oblong diamond, total events.

Graphic Jump Location

When we evaluated the different drug regimens, opposing trends were noticeable, with an advantage for quinolone monotherapy (RR, 0.89 [95% CI, 0.77-1.02]) and a disadvantage for macrolide monotherapy (RR, 1.17 [95% CI, 0.77-1.77]). Clinical failure with macrolide treatment was the only comparison in which heterogeneity was detected (χ23 = 6.68; P = .08; I2 = 55.1%). Reanalysis by the random-effects model did not alter the results. Relative risks were similar regardless of age or sample size. An advantage for coverage of atypical pathogens was statistically significant in the 13 European studies (RR, 0.82 [95% CI, 0.70-0.95]), but not in studies performed elsewhere.

When we analyzed studies by methodological quality, an advantage toward coverage of atypical pathogens was accentuated in studies of unclear or inadequate allocation concealment and allocation generation. In the analysis of studies of high methodological quality, the effect was nearly identical in the 2 arms (for adequate allocation generation, RR, 0.99 [95% CI, 0.82-1.19]; for adequate allocation concealment, RR, 0.98 [95% CI, 0.81-1.19]) (Table 2). In an ITT vs per-protocol design sensitivity analysis, no significant difference was found.

Clinical treatment failure rates were evaluated among patients with microbiologically documented infections. No significant difference between the study arms in the treatment of documented pneumococcal infections was detected (RR, 1.15 [95% CI, 0.81-1.63] among 16 studies and 906 patients). Data were insufficient to analyze cases of pneumococcal bacteremia. For atypical pathogens, a trend in favor of atypical coverage did not reach statistical significance (RR, 0.52 [95% CI, 0.24-1.10] among 4 studies and 158 patients). A significant advantage to coverage of atypical pathogens was found for eradication of Legionella species, with an RR of 0.17 and narrow 95% CIs (0.05-0.63), based on relatively few cases (n = 43). Sixty-one of 78 atypical cases and 9 of 20 cases of L pneumophila were successfully resolved in the arm without coverage of atypical pathogens.

BACTERIOLOGICAL ERADICATION

Eighteen studies reported bacteriological eradication rates, encompassing 1968 patients and/or isolates. There was a statistically significant advantage to bacteriological eradication for the arm covering atypical pathogens (RR, 0.73 [95% CI, 0.59-0.91]), with no heterogeneity seen. However, in an analysis restricted to studies of adequate allocation generation and concealment, this advantage disappeared (RR, 0.96 [95% CI, 0.61-1.52]) (Table 2).

ADVERSE EVENTS

Adverse events per treatment arm were reported for 4261 patients. Total adverse events (RR, 1.02 [95% CI, 0.91-1.13]) and events requiring treatment discontinuation (RR, 0.98 [95% CI, 0.67-1.42]) were similar in both treatment arms, with no heterogeneity seen. Gastrointestinal events were reported in 15 studies and were significantly more common in the arm without atypical coverage (which consisted mainly of β-lactams) (RR, 0.73 [95% CI, 0.54-0.99]). However, the definitions of gastrointestinal events differed, some including abdominal pain and some diarrhea alone, thereby precluding an accurate comparison of antibiotic-associated diarrhea.

The objective of our review was to assess empirical antibiotic coverage of atypical pathogens in hospitalized patients with CAP, in terms of mortality and successful treatment. We found no difference in mortality between regimens with coverage of atypical pathogens and regimens without such coverage, persisting in all subgroup analyses. There was a nonsignificant trend toward clinical success to coverage of atypical pathogens, accentuated with quinolone monotherapy. The advantage disappeared when we evaluated high-quality methodological studies alone. A significant advantage in bacteriological eradication was detected in the coverage of atypical pathogens, especially in reference to Legionella species. This advantage was not demonstrated in an analysis restricted to studies of adequate allocation generation and concealment. There was no difference in the frequency of total adverse events between the 2 groups, although more gastrointestinal events (but not explicitly diarrhea) were noted in the arm without atypical coverage.

Mortality data were obtained for 96.6% of randomized patients. The overall mortality rate (adjusted mean mortality rate, 3.7%) was lower than that reported in the literature (eg, MedisGroups, 10.6%70; validation cohort inpatient mortality for the Pneumonia Patient Outcome Research Team, 8.0%71). This is surprising because nearly half of the studies target relatively severe pneumonia cases. Thus, patients recruited to randomized trials may not adequately represent all patients hospitalized with CAP.

Although mortality is the most significant outcome in a potentially lethal infection, all studies chose clinical failure as their primary outcome. This end point is subjective and should be studied with care. Our review clearly demonstrates its potential for bias. A trend in favor of clinical success for the arm covering atypical pathogens originated in studies with unclear allocation generation. Similarly, the clear statistical advantage of that arm, found in the overall analysis of bacteriological eradication rates, did not exist in an analysis restricted to studies of adequate allocation generation. Thus, we should be wary about relying solely on subjective outcomes when comparing treatment regimens for pneumonia, especially because pharmaceutical companies sponsored most studies and many studies were nonblinded.

The similar response of the young and old is somewhat surprising, as an advantage to atypical coverage would be expected in younger people with a higher prevalence of atypical pneumonia. Perhaps this prevalence diminishes in the hospitalized population. The clear advantage of the arm with atypical pathogen coverage in the successful treatment of L pneumophila infections is not surprising, although cases of atypical pneumonia (including L pneumophila) often resolved without such coverage. Coinfections with typical pathogens may explain some of these cases.

We had set out to investigate the contribution of coverage of atypical pathogens to empirical treatment of CAP in hospitalized patients. The most suitable study for our purpose would have been one comparing a drug without atypical coverage (eg, β-lactam) with a combination of that drug and a drug with atypical coverage (eg, β-lactam and a macrolide). None was found, although the need to add a macrolide to β-lactam therapy is a common dilemma manifested within the guidelines themselves. Furthermore, many studies included treatment arms that do not adhere to current guidelines. Therefore, our meta-analysis is chiefly based on comparison of various regimens without coverage of atypical pathogens to monotherapy, mainly quinolone monotherapy. Regarding this comparison, we found no advantage to coverage of atypical pathogens in terms of mortality or clinical success.

Our conclusion of no benefit might be due to lack of power when using available randomized trials. Large observational studies showed benefit for atypical coverage. However, correction for the baseline differences between patients given or not given atypical coverage in these studies may be impossible.

Studies designed specifically to evaluate the necessity of atypical coverage are needed. The optimal design would be a randomized controlled trial comparing the same β-lactam in both study arms with and without the addition of antibiotics against atypical pathogens. Studies must be of adequate generation concealment and allocation, and patients included should resemble more closely the general population of inpatients with CAP.

Correspondence: Daphna Shefet, MD, Department of Medicine E, Beilinson Campus, Rabin Medical Center, Petah-Tiqva, Israel (dshefet@yahoo.com).

Accepted for Publication: May 2, 2005.

Financial Disclosure: None.

Funding/Support: This study was supported by a European Union Fifth Framework Information Society Technologies program (TREAT), Brussels, Belgium.

Additional Information: A detailed protocol of the methodology used for this study was published in The Cochrane Library, where the full review has been accepted for publication.

Acknowledgment: We thank Claude Carbon, MD, Christian Chuard, MD, Francois Fourrier, MD, Daniel Genne, MD, Hartmut Lode, MD, Phillip Peterson, MD, Patrick Petitpretz, MD, and Jose Sifuentes Osornio, MD, for supplying complementary information for their trials; Karla Soares-Weiser, MD, PhD, for her guidance; Gabriel Izbicki, MD, for translation from German; and Rika Fujia for obtaining and translating the Japanese articles.

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PubMed Link to Article
Allegra  LBerni  FBoisisio  E  et al.  Efficacy of the teicoplanin-ciprofloxacin combination in high risk community acquired pneumonia: comparison to ceftriaxone in a multicenter study. Internista 1995;3139- 43
Johnson  RH Sequential intravenous/oral ciprofloxacin compared with parenteral ceftriaxone in the treatment of hospitalized patients with community-acquired pneumonia. Infect Dis Clin Pract 1996;5265- 272
Lode  HWiley  EOlschewski  P  et al.  Prospective randomized clinical trials of new quinolones versus beta-lactam antibiotics in lower respiratory tract infections. Scand J Infect Dis Suppl 1990;6850- 55
PubMed
Aubier  MVerster  RRegamey  CGeslin  PVercken  JBSparfloxacin European Study Group, Once-daily sparfloxacin versus high-dosage amoxicillin in the treatment of community-acquired, suspected pneumococcal pneumonia in adults. Clin Infect Dis 1998;261312- 1320
PubMed Link to Article
Bohte  Rvan’t Wout  JWLobatto  S  et al.  Efficacy and safety of azithromycin versus benzylpenicillin or erythromycin in community-acquired pneumonia. Eur J Clin Microbiol Infect Dis 1995;14182- 187
PubMed Link to Article
Carbon  CLephonte  PPetitpretz  PChauvin  JPHazebroucq  J Efficacy and safety of temafloxacin versus those of amoxicillin in hospitalized adults with community-acquired pneumonia. Antimicrob Agents Chemother 1992;36833- 839
PubMed Link to Article
Chuard  CRegamey  C Effect and tolerance of ofloxacin in bronchopulmonary infections in comparison with amoxicillin [in German]. Schweiz Med Wochenschr 1989;1191913- 1916
PubMed
Feldman  CWhite  HO’Grady  JFlitcroft  ABriggs  ARichards  G An open, randomised, multi-centre study comparing the safety and efficacy of sitafloxacin and imipenem/cilastatin in the intravenous treatment of hospitalised patients with pneumonia. Int J Antimicrob Agents 2001;17177- 188
PubMed Link to Article
Fourrier  FChopin  CLestavel  PhSavage  C Initial antibiotherapy in severe bacterial bronchopneumopathies: randomized study of a new quinolone: pefloxacin [in French]. Presse Med 1986;151240
PubMed
Genne  DSiegrist  HHJanin-Jaquat  Bde Torrente  A Clarithromycin versus amoxicillin-clavulanic acid in the treatment of community-acquired pneumonia. Eur J Clin Microbiol Infect Dis 1997;16783- 788
PubMed Link to Article
Gleadhill  ICFerguson  WPLowry  RC Efficacy and safety of ciprofloxacin in patients with respiratory infections in comparison with amoxycillin. J Antimicrob Chemother 1986;18 ((suppl D)) 133- 138
PubMed
Hirata-Dulas  CAStein  DJGuay  DRGruninger  RPPeterson  PK A randomized study of ciprofloxacin versus ceftriaxone in the treatment of nursing home-acquired lower respiratory tract infections. J Am Geriatr Soc 1991;39979- 985
PubMed
Kalbermatter  VBagilet  DDiab  MJavkin  E Oral levofloxacin versus intravenous ceftriaxone and amoxicillin/clavulanic acid in the treatment of community-acquired pneumonia that requires hospitalization [in Spanish]. Med Clin (Barc) 2000;115561- 563
PubMed Link to Article
Khan  FABasir  R Sequential intravenous-oral administration of ciprofloxacin vs ceftazidime in serious bacterial respiratory tract infections. Chest 1989;96528- 537
PubMed Link to Article
Kobayashi  HTakamura  KKono  K  et al.  Comparison of DL-8280 and amoxicillin in the treatment of respiratory tract infections [in Japanese]. Kansenshogaku Zasshi 1984;58525- 555
PubMed
Leophonte  PFile  TFeldman  C Gemifloxacin once daily for 7 days compared to amoxicillin/clavulanic acid thrice daily for 10 days for the treatment of community-acquired pneumonia of suspected pneumococcal origin. Respir Med 2004;98708- 720
PubMed Link to Article
Lode  HGarau  JGrassi  C  et al.  Treatment of community-acquired pneumonia: a randomized comparison of sparfloxacin, amoxycillin-clavulanic acid and erythromycin. Eur Respir J 1995;81999- 2007
PubMed Link to Article
Miki  FSaito  ATomizawa  M  et al.  Comparative study of the effectiveness of enoxacin and amoxicillin in bacterial pneumonia by a double blind method [in Japanese]. Kansenshogaku Zasshi 1984;581083- 1113
PubMed
Norrby  SRPetermann  WWillcox  PAVetter  NSalewski  E A comparative study of levofloxacin and ceftriaxone in the treatment of hospitalized patients with pneumonia. Scand J Infect Dis 1998;30397- 404
PubMed Link to Article
Peterson  PKStein  DGuay  DR  et al.  Prospective study of lower respiratory tract infections in an extended-care nursing home program: potential role of oral ciprofloxacin. Am J Med 1988;85164- 171
PubMed Link to Article
Petitpretz  PArvis  PMarel  MMoita  JUrueta  JCAP5 Moxifloxacin Study Group, Oral moxifloxacin vs high-dosage amoxicillin in the treatment of mild-to-moderate, community-acquired, suspected pneumococcal pneumonia in adults. Chest 2001;119185- 195
PubMed Link to Article
Rizzato  GAllegra  LMulticentre Italian Study Group (Coordinated by Centro Thorax), Efficacy and tolerability of teicoplanin-ciprofloxacin combination in severe community-acquired pneumonia: comparison with ceftriaxone in a multicentre Italian study. Clin Drug Invest 1997;14337- 345
Link to Article
Romanelli  GCravarezza  PPozzi  A  et al.  Carbapenems in the treatment of severe community-acquired pneumonia in hospitalized elderly patients: a comparative study against standard therapy. J Chemother 2002;14609- 617
PubMed Link to Article
Tremolieres  Fde Kock  FPluck  NDaniel  R Trovafloxacin versus high-dose amoxicillin (1 g three times daily) in the treatment of community-acquired bacterial pneumonia. Eur J Clin Microbiol Infect Dis 1998;17447- 453
PubMed Link to Article
Vanderdonckt  J Comparison of pefloxacin with ceftazidime in severe bronchopulmonary infections. J Antimicrob Chemother 1990;26 ((suppl B)) 111- 116
PubMed Link to Article
Vogel  FLode  H The use of oral temafloxacin compared with a parenteral cephalosporin in hospitalized patients with pneumonia. J Antimicrob Chemother 1991;28 ((suppl C)) 81- 86
PubMed Link to Article
Zeluff  BJLowe  PKoorhof  HJGentry  LO Evaluation of roxithromycin (RU-965) versus cephradine in pneumococcal pneumonia. Eur J Clin Microbiol Infect Dis 1988;769- 71
PubMed Link to Article
Iezzoni  LIMoskowitz  MA A clinical assessment of MedisGroups. JAMA 1988;2603159- 3163
PubMed Link to Article
Fine  MJAuble  TEYealy  DM  et al.  A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997;336243- 250
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Selection process for randomized controlled trials (RCTs). CAP indicates community-acquired pneumonia.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

The number of patients who died within the follow-up period (overall mortality). The left side depicts arms with atypical coverage; the right side, arms without atypical coverage. A value of less than 1 favors atypical coverage. Studies are subdivided by the antibiotic used as the atypical regimen, including quinolone therapy (01), macrolide therapy (02), and combined macrolide and quinolone therapy (03). The total indicates the total number of patients (sum of groups 01-03). CAP indicates community-acquired pneumonia; CI, confidence interval; I2, measure of inconsistency (see “Methods” section); n/N, number of patients/total number of patients in the study; RR, relative risk; and solid oblong diamond, total events.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

The number of patients considered to have a clinical treatment failure. The left side depicts arms with atypical coverage; the right side, arms without atypical coverage. Studies are subdivided by the antibiotic used as the atypical regimen, including quinolone therapy (01), macrolide therapy (02), and combined macrolide and quinolone therapy (03). Total indicates the total number of patients (sum of groups 01-03). CAP indicate community-acquired pneumonia; CI, confidence interval; I2, measure of inconsistency (see “Methods” section); n/N, number of patients/total number of patients in the study; RR, relative risk; and solid oblong diamond, total events.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 2. Sensitivity Analyses for Individual Methodological Quality Components*

References

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PubMed Link to Article
Ailani  RKAgastya  GAilani  RKMukunda  BNShekar  R Doxycycline is a cost-effective therapy for hospitalized patients with community-acquired pneumonia. Arch Intern Med 1999;159266- 270
PubMed Link to Article
Aubier  MLode  HGialdroni-Grassi  G  et al.  Sparfloxacin for the treatment of community-acquired pneumonia: a pooled data analysis of two studies. J Antimicrob Chemother 1996;37 ((suppl A)) 73- 82
PubMed Link to Article
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PubMed Link to Article
Fass  RJPlouffe  JFRussell  JA Intravenous/oral ciprofloxacin vs ceftazidime in the treatment of serious infections. Am J Med 1989;87164S- 168S
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File  TMSegreti  JDunbar  L  et al.  A multicenter, randomized study comparing the efficacy and saftey of intravenous and/or oral levofloxacin versus cerftriaxone and/or cefuroxime axetil in treatment of adults with community-acquired pneumonia. Antimicrob Agents Chemother 1997;411965- 1972
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Fink  MPSnydman  DRNiederman  MS  et al. Severe Pneumonia Study Group, Treatment of severe pneumonia in hospitalized patients: results of a multicenter, randomized, double-blind trial comparing intravenous ciprofloxacin with imipenem-cilastatin. Antimicrob Agents Chemother 1994;38547- 557
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Fong  IWLaforge  JDubois  JSmall  DGrossman  RZakhari  RCanadian Bronchitis Study Group, Clarithromycin versus cefaclor in lower respiratory tract infections. Clin Invest Med 1995;18131- 138
PubMed
Hoepelman  AISips  APvan Helmond  JL  et al.  A single-blind comparison of three-day azithromycin and ten-day co-amoxiclav treatment of acute lower respiratory tract infections. J Antimicrob Chemother 1993;31 ((suppl E)) 147- 152
PubMed Link to Article
Khajotia  RDrlicek  MVetter  N A comparative study of ofloxacin and amoxycillin/clavulanate in hospitalized patients with lower respiratory tract infections. J Antimicrob Chemother 1990;26 ((suppl D)) 83- 91
PubMed Link to Article
Kinasewitz  GWood  RG Azithromycin versus cefaclor in the treatment of acute bacterial pneumonia. Eur J Clin Microbiol Infect Dis 1991;10872- 877
PubMed Link to Article
Krumpe  PECohn  SGarreltes  J  et al. Ciprofloxacin Study Group, Intravenous and oral mono- or combination-therapy in the treatment of severe infections: ciprofloxacin versus standard antibiotic therapy. J Antimicrob Chemother 1999;43 ((suppl A)) 117- 128
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Leophonte  PVeyssier  P Levofloxacin in the treatment of community-acquired pneumococcal pneumonia [in French]. Presse Med 1999;281975- 1979
PubMed
Levine  DMcNeil  PLerner  SA Randomized, double-blind comparative study of intravenous ciprofloxacin versus ceftazidime in the treatment of serious infections. Am J Med 1989;87 ((suppl 5A)) 160S- 163S
PubMed Link to Article
Lode  HWiley  RHoffken  G  et al.  Prospective randomized controlled study of ciprofloxacin versus imipenem-cilastatin in severe clinical infections. Antimicrob Agents Chemother 1987;311491- 1496
PubMed Link to Article
Lode  HAubier  MPortier  HOrtquist  A Sparfloxacin as alternative treatment to standard therapy for community-acquired bacteremic pneumococcal pneumonia. Clin Microbiol Infect 1998;4135- 143
PubMed Link to Article
Lode  HMagyar  PMuir  JFLoos  UKleutgens  KInternational Gatifloxacin Study Group, Once-daily oral gatifloxacin vs three-times-daily co-amoxiclav in the treatment of patients with community-acquired pneumonia. Clin Microbiol Infect 2004;10512- 520
PubMed Link to Article
Mouton  YBeuscart  CLeroy  OAjana  FCharrel  JGroupe Multicentrique, Evaluation of ciprofloxacin versus amoxicillin + clavulanic acid or erythromycin for the empiric treatment of community-acquired pneumonia [in French]. Pathol Biol (Paris) 1991;3934- 37
PubMed
O’Doherty  BDutchman  DAPettit  RMaroli  A Randomized, double blind, comparative study of grepafloxacin and amoxycillin in the treatment of patients with community-acquired pneumonia. J Antimicrob Chemother 1997;40 ((suppl A)) 73- 81
PubMed Link to Article
Peacock  JE  JrPegram  SPWeber  SFLeone  PA Prospective, randomized comparison of sequential intravenous followed by oral ciprofloxacin with intravenous ceftazidime in the treatment of serious infections. Am J Med 1989;87185S- 190S
PubMed Link to Article
Plouffe  JFHerbert  MTFile  TM  Jr  et al.  Ofloxacin versus standard therapy in treatment of community-acquired pneumonia requiring hospitalization. Antimicrob Agents Chemother 1996;401175- 1179
PubMed
Rahav  GFidel  JGibor  YShapiro  M Azithromycin versus comparative therapy for the treatment of community acquired pneumonia. Int J Antimicrob Agents 2004;24181- 184
PubMed Link to Article
Siami  GAWilkins  WTBess  DTChristman  JW Comparison of ciprofloxacin with imipenem in the treatment of severe pneumonia in hospitalised geriatric patients. Drugs 1995;49 ((suppl 2)) 436- 438
PubMed Link to Article
Sifuentes-Osornio  JMacias  AAmieva  RIRamos  ARuiz-Palacios  GM Intravenous ciprofloxacin and ceftazidime in serious infections: a prospective, controlled clinical trial with third-party blinding. Am J Med 1989;87202S- 205S
PubMed Link to Article
Snydman  DFink  FNiederman  MReinhart  H Treatment of severe pneumonia in hospitalised patients: results of a multicentre trial comparing IV ciprofloxacin with imipenem/cilastatin. Drugs 1995;49 ((suppl 2)) 439- 441
PubMed Link to Article
Stocks  JMWallace  RJ  JrGriffith  DEGarcia  JGKohler  RB Ofloxacin in community-acquired lower respiratory infections: a comparison with amoxicillin or erythromycin. Am J Med 1989;8752S- 56S
PubMed Link to Article
Torres  AMuir  JFCorris  P  et al.  Effectiveness of oral moxifloxacin in standard first-line therapy in community-acquired pneumonia. Eur Respir J 2003;21135- 143
PubMed Link to Article
Trenholme  GMSchmitt  BASpear  JGvazdinskas  LC Randomized study of intravenous/oral ciprofloxacin versus ceftazidime in the treatment of hospital and nursing home patients with lower respiratory tract infections. Am J Med 1989;87116S- 118S
PubMed Link to Article
Wollschlager  CMRaoof  SKhan  FAGuarneri  JJLaBombardi  VAfzal  Q Controlled, comparative study of ciprofloxacin versus ampicillin in treatment of bacterial respiratory tract infections. Am J Med 1987;82164- 168
PubMed
Jardim  JRRico  Gde la Roza  C  et al. Grupo de Estudio Latinoamericano CAP, A comparison of moxifloxacin and amoxicillin in the treatment of community-acquired pneumonia in Latin America: results of a multicenter clinical trial [in Spanish]. Arch Bronconeumol 2003;39387- 389
PubMed Link to Article
Allegra  LBerni  FBoisisio  E  et al.  Efficacy of the teicoplanin-ciprofloxacin combination in high risk community acquired pneumonia: comparison to ceftriaxone in a multicenter study. Internista 1995;3139- 43
Johnson  RH Sequential intravenous/oral ciprofloxacin compared with parenteral ceftriaxone in the treatment of hospitalized patients with community-acquired pneumonia. Infect Dis Clin Pract 1996;5265- 272
Lode  HWiley  EOlschewski  P  et al.  Prospective randomized clinical trials of new quinolones versus beta-lactam antibiotics in lower respiratory tract infections. Scand J Infect Dis Suppl 1990;6850- 55
PubMed
Aubier  MVerster  RRegamey  CGeslin  PVercken  JBSparfloxacin European Study Group, Once-daily sparfloxacin versus high-dosage amoxicillin in the treatment of community-acquired, suspected pneumococcal pneumonia in adults. Clin Infect Dis 1998;261312- 1320
PubMed Link to Article
Bohte  Rvan’t Wout  JWLobatto  S  et al.  Efficacy and safety of azithromycin versus benzylpenicillin or erythromycin in community-acquired pneumonia. Eur J Clin Microbiol Infect Dis 1995;14182- 187
PubMed Link to Article
Carbon  CLephonte  PPetitpretz  PChauvin  JPHazebroucq  J Efficacy and safety of temafloxacin versus those of amoxicillin in hospitalized adults with community-acquired pneumonia. Antimicrob Agents Chemother 1992;36833- 839
PubMed Link to Article
Chuard  CRegamey  C Effect and tolerance of ofloxacin in bronchopulmonary infections in comparison with amoxicillin [in German]. Schweiz Med Wochenschr 1989;1191913- 1916
PubMed
Feldman  CWhite  HO’Grady  JFlitcroft  ABriggs  ARichards  G An open, randomised, multi-centre study comparing the safety and efficacy of sitafloxacin and imipenem/cilastatin in the intravenous treatment of hospitalised patients with pneumonia. Int J Antimicrob Agents 2001;17177- 188
PubMed Link to Article
Fourrier  FChopin  CLestavel  PhSavage  C Initial antibiotherapy in severe bacterial bronchopneumopathies: randomized study of a new quinolone: pefloxacin [in French]. Presse Med 1986;151240
PubMed
Genne  DSiegrist  HHJanin-Jaquat  Bde Torrente  A Clarithromycin versus amoxicillin-clavulanic acid in the treatment of community-acquired pneumonia. Eur J Clin Microbiol Infect Dis 1997;16783- 788
PubMed Link to Article
Gleadhill  ICFerguson  WPLowry  RC Efficacy and safety of ciprofloxacin in patients with respiratory infections in comparison with amoxycillin. J Antimicrob Chemother 1986;18 ((suppl D)) 133- 138
PubMed
Hirata-Dulas  CAStein  DJGuay  DRGruninger  RPPeterson  PK A randomized study of ciprofloxacin versus ceftriaxone in the treatment of nursing home-acquired lower respiratory tract infections. J Am Geriatr Soc 1991;39979- 985
PubMed
Kalbermatter  VBagilet  DDiab  MJavkin  E Oral levofloxacin versus intravenous ceftriaxone and amoxicillin/clavulanic acid in the treatment of community-acquired pneumonia that requires hospitalization [in Spanish]. Med Clin (Barc) 2000;115561- 563
PubMed Link to Article
Khan  FABasir  R Sequential intravenous-oral administration of ciprofloxacin vs ceftazidime in serious bacterial respiratory tract infections. Chest 1989;96528- 537
PubMed Link to Article
Kobayashi  HTakamura  KKono  K  et al.  Comparison of DL-8280 and amoxicillin in the treatment of respiratory tract infections [in Japanese]. Kansenshogaku Zasshi 1984;58525- 555
PubMed
Leophonte  PFile  TFeldman  C Gemifloxacin once daily for 7 days compared to amoxicillin/clavulanic acid thrice daily for 10 days for the treatment of community-acquired pneumonia of suspected pneumococcal origin. Respir Med 2004;98708- 720
PubMed Link to Article
Lode  HGarau  JGrassi  C  et al.  Treatment of community-acquired pneumonia: a randomized comparison of sparfloxacin, amoxycillin-clavulanic acid and erythromycin. Eur Respir J 1995;81999- 2007
PubMed Link to Article
Miki  FSaito  ATomizawa  M  et al.  Comparative study of the effectiveness of enoxacin and amoxicillin in bacterial pneumonia by a double blind method [in Japanese]. Kansenshogaku Zasshi 1984;581083- 1113
PubMed
Norrby  SRPetermann  WWillcox  PAVetter  NSalewski  E A comparative study of levofloxacin and ceftriaxone in the treatment of hospitalized patients with pneumonia. Scand J Infect Dis 1998;30397- 404
PubMed Link to Article
Peterson  PKStein  DGuay  DR  et al.  Prospective study of lower respiratory tract infections in an extended-care nursing home program: potential role of oral ciprofloxacin. Am J Med 1988;85164- 171
PubMed Link to Article
Petitpretz  PArvis  PMarel  MMoita  JUrueta  JCAP5 Moxifloxacin Study Group, Oral moxifloxacin vs high-dosage amoxicillin in the treatment of mild-to-moderate, community-acquired, suspected pneumococcal pneumonia in adults. Chest 2001;119185- 195
PubMed Link to Article
Rizzato  GAllegra  LMulticentre Italian Study Group (Coordinated by Centro Thorax), Efficacy and tolerability of teicoplanin-ciprofloxacin combination in severe community-acquired pneumonia: comparison with ceftriaxone in a multicentre Italian study. Clin Drug Invest 1997;14337- 345
Link to Article
Romanelli  GCravarezza  PPozzi  A  et al.  Carbapenems in the treatment of severe community-acquired pneumonia in hospitalized elderly patients: a comparative study against standard therapy. J Chemother 2002;14609- 617
PubMed Link to Article
Tremolieres  Fde Kock  FPluck  NDaniel  R Trovafloxacin versus high-dose amoxicillin (1 g three times daily) in the treatment of community-acquired bacterial pneumonia. Eur J Clin Microbiol Infect Dis 1998;17447- 453
PubMed Link to Article
Vanderdonckt  J Comparison of pefloxacin with ceftazidime in severe bronchopulmonary infections. J Antimicrob Chemother 1990;26 ((suppl B)) 111- 116
PubMed Link to Article
Vogel  FLode  H The use of oral temafloxacin compared with a parenteral cephalosporin in hospitalized patients with pneumonia. J Antimicrob Chemother 1991;28 ((suppl C)) 81- 86
PubMed Link to Article
Zeluff  BJLowe  PKoorhof  HJGentry  LO Evaluation of roxithromycin (RU-965) versus cephradine in pneumococcal pneumonia. Eur J Clin Microbiol Infect Dis 1988;769- 71
PubMed Link to Article
Iezzoni  LIMoskowitz  MA A clinical assessment of MedisGroups. JAMA 1988;2603159- 3163
PubMed Link to Article
Fine  MJAuble  TEYealy  DM  et al.  A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997;336243- 250
PubMed Link to Article

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Community-Acquired Pneumonia

Users' Guides to the Medical Literature
Some prediction rules require, by their very nature, evidence of clinical impact as a...