Effectiveness of lactam antibiotics compared with antibiotics active
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《英国医生杂志》
1 Respiratory and Infectious Diseases Department, Waikato Hospital, Private Bag 3200, Hamilton 2001, New Zealand, 2 University of Auckland School of Medicine, New Zealand, 3 Department of General Practice and Primary Health Care, University of Auckland, New Zealand
Correspondence to: G D Mills millsg@waikatodhb.govt.nz
Abstract
The optimal antibiotic therapy for community acquired pneumonia remains unclear. One of the barriers to better define treatment is the inability to accurately determine the part that the various micro-organisms play.1 In only a few cases is the causative organism identified, due to the poor yield from routine microbiological tests. Since it was first identified in 1881, Streptococcus pneumoniae has been considered the major cause of community acquired pneumonia.2 Its importance was supported by the reduction in mortality observed after the introduction of sulphonamides3 and later lactam antibiotics.4
With improvements in diagnostic microbiology, it became apparent that other organisms seemed causative in community acquired pneumonia. Three of the more recently recognised ones (Mycoplasma pneumoniae, Legionella species, and Chlamydia pneumoniae) are now associated with the term atypical pathogen. Their major distinguishing feature is a lack of in vitro response to lactam and sulphonamide antibiotics, rather than any differences to pneumococcal pneumonia in clinical presentation.5 6
The part that atypical organisms play and the need to provide specific antibiotic coverage for them in community acquired pneumonia is contentious. Recent guidelines vary.1 7-10 The single most important factor in this variance is the failure to produce level 1 evidence on which to base treatment recommendations. We carried out a meta-analysis to compare the efficacy of lactam antibiotics with antibiotics active against atypical pathogens in adults with community acquired pneumonia to produce the level 1 evidence currently lacking.
Methods
We screened over 2000 studies and retrieved over 100 potentially eligible ones. We identified 20 studies that met our inclusion criteria.11-26 Four of the studies (30% of participants) were unpublished as at November 2004 and were obtained from the sponsoring pharmaceutical companies either directly or secondary to the finding of a conference proceedings (see bmj.com). Two small studies concerned children.11 12 We decided to exclude these from our meta-analysis given the distinct clinical context. Three blinded studies were also excluded, as the protocol included the option of adding an agent active against atypical pathogens to the lactam therapy.27-29
The 18 included trials were carried out in more than 30 countries between 1980 and 2000 and included 6749 analysable participants (table). Overall, the trials used nine different fluoroquinolones, two macrolides, and one ketolide. Most study drugs were given orally, with only two of the earlier studies using intravenous therapy initially. Most of the studies listed specific exclusion criteria; a standard feature in most trials of community acquired pneumonia sponsored by pharmaceutical companies. Common exclusions included the requirement for parenteral antimicrobials at study entry in trials of oral antibiotics, hospital acquired or aspiration pneumonia, immunocompromised patients, and major hepatic or renal dysfunction. The specific inclusion and exclusion criteria resulted in participants who were younger and with a better prognostic risk profile than observational pneumonia cohorts.30
Characteristics of included studies comparing lactam antibiotics with antibiotics active against atypical pathogens in patients with community acquired pneumonia
Primary outcome of interest
All trials reported the proportion of patients who failed to achieve clinical cure or improvement, an overall rate of 18%. We found no significant difference between treatments in any study or significant heterogeneity between studies. From a combined analysis of the studies (fig 1) we found no evidence that antibiotics active against atypical pathogens were superior to lactam antibiotics (relative risk 0.97, 95% confidence interval 0.87 to 1.07). The same conclusion was drawn from separate analyses of the studies on macrolides and ketolides (0.81, 0.58 to 1.14) and fluoroquinolones (0.99, 0.88 to 1.11). We also compared the relative risk of the 10 published studies on fluoroquinolones (0.90, 0.77 to 1.04) with the four unpublished studies on fluoroquinolones (1.15, 0.96 to 1.37).
Fig 1 Number of patients failing to achieve clinical cure or improvement with lactam antibiotics compared with antibiotics active against atypical pathogens in all cause community acquired pneumonia
We analysed the data on all cause mortality separately; 130 deaths were reported (mortality 1.9%). We observed no differences in mortality between the study arms (relative risk 1.20, 0.84 to 1.71). This low mortality is in keeping with most patients having mild to moderate (non-severe) community acquired pneumonia.
Fifteen of the trials provided data on either the intention to treat population or the modified intention to treat population. Three studies reported only on the clinically evaluable population, although the overall dropout rate was less than 17%.13 18 26 As all the studies were blinded, we did not consider the lack of intention to treat data in these three studies as critical and we therefore included the data. The treatment effect (relative risk 0.97) was not altered when we excluded trials that did not use an intention to treat or modified intention to treat method. Similar results (0.93, 0.81 to 1.06) were obtained from a separate analysis on the clinically evaluable per protocol population (n = 5639), with the failure to achieve clinical cure or improvement reduced to 13%.
We decided to include one study (weighting 3.3%) where a small proportion (< 10%) of patients had nosocomial pneumonia.14 The result was not altered (relative risk 0.97) when we carried out a sensitivity analysis with these data excluded. The time point for assessment varied between studies. Sixteen of the studies had visits for end of treatment or for test of cure within 10 days of completion of the study drug, whereas two studies assessed patients at the end of follow up. We found no evidence of a secular trend of decreasing treatment effect in the lactam arms, suggesting that there was no impact on treatment effect from the worldwide trend for increasing pneumococcal resistance.
Subgroup analysis
Overall, 311 patients (13 studies) were diagnosed as having M pneumoniae, 115 (seven studies) as having C pneumoniae, and 75 (10 studies) as having Legionella species (fig 2). We found no significant treatment effect in patients with M pneumoniae (relative risk 0.60, 0.31 to 1.17) or C pneumoniae (2.32, 0.67 to 8.03). In contrast, the failure rate from antibiotics active against atypical pathogens in patients with legionella was statistically lower (0.40, 0.19 to 0.85).
Fig 2 Number of patients failing to achieve clinical cure or improvement with lactam antibiotics compared with antibiotics active against atypical pathogens in confirmed cases of community acquired pneumonia related to Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella species
Discussion
British Thoracic Society Standards of Care Committee. BTS guidelines for the management of community acquired pneumonia in adults. Thorax 2001;56(suppl 4): IV1-64.
Watson DA, Musher DM, Jacobson JW, Verhoef J. A brief history of the pneumococcus in biomedical research: a panoply of scientific discovery. Clin Infect Dis 1993;17: 913-24.
Evans GM, Gaisford WF. Treatment of pneumonia with 2-(-aminobenzenesulphonamido) pyridine. Lancet 1938;2: 14-9.
Tillett WS, Cambier MJ, McCormack JE. The treatment of lobar pneumonia and pneumococcal empyema with penicillin. Bull NY Acad Sci 1944;20: 142-78.
Farr BW, Kaiser DL, Harrison BDW, Connolly CK. Prediction of microbial aetiology at admission to hospital for pneumonia from the presenting clinical features. Thorax 1989;44: 1031-5.
File TM, Jr, Plouffe JF, Breiman RF, Skelton SK. Clinical characteristics of Chlamydia pneumoniae infection as the sole cause of community-acquired pneumonia. Clin Infect Dis 1999;29: 426-8.
Niederman MS, Mandell LA, Anzueto A, Bass JB, Broughton WA, Campbell GD, et al. Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy and prevention. Am J Respir Crit Care Med 2001;163: 1730-54.
ERS Taskforce Report. Guidelines for the management of adults with community-acquired lower respiratory tract infections. Eur Resp J 1998;11: 986-91.
Bartlett JG, Dowell SF, Mandell LA, File TM, Musher DM, Fine MJ. Practice guidelines for the management of community-acquired pneumonia in adults. Clin Infect Dis 2000;31: 347-82.
Mandell LA, Marrie TJ, Grossman RF, Chow AW, Hyland RH. 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. Clin Infect Dis 2000;31: 383-421.
Harris JA, Kolohathis A, Campbell M, Cassell GH, Hammerschlag MR. Safety and efficacy of azithromycin in the treatment of community-acquired pneumonia in children. Pediatr Infect Dis J 1998;17: 865-71.
Ferwerda A, Moll HA, Hop WCJ, Kouwenberg JM, Gi CVTP, Robben SGF, et al. Efficacy, safety and tolerability of 3 day azithromycin versus 10 day co-amoxiclav in the treatment of children with acute lower respiratory tract infections. J Antimicrob Chemother 2001;47: 441-6.
Kinasewitz G, Wood RG. Azithromycin versus cefaclor in the treatment of acute bacterial pneumonia. Eur J Clin Microbiol Infect Dis 1991;10: 872-7.
Johnson RH, Levine S, Traub SL, Echols RM, Haverstock D, Arnold E, et al. Sequential intravenous/oral ciprofloxacin compared with parenteral ceftriaxone in the treatment of hospitalised patients with community-acquired pneumonia Infectious. Dis Clin Pract 1996;5: 265-72.
Macfarlane JT, Finch RG, Ward MJ, Rose DH. Erythromycin compared with a combination of ampicillin and amoxycillin as initial therapy for adults with pneumonia including Legionnaires disease. J Infect 1983;7: 111-7.
Lode H, Magyar P, Muir JF, Loos U, Kleutgens K, on behalf of the International 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;10: 512-20.
Leophonte P, File T, Feldman 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 2004:198: 708-20.
O'Doherty B, Dutchman DA, Pettit R, Maroli A. Randomised, 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.
Carbon C, Ariza H, Rabie W, Salvarezza C, Elkharrat D, Rangaraj M, et al. Comparative study of levofloxacin and amoxycillin/clavulanic acid in adults with mild-to moderate community acquired pneumonia. Clin Microbiol Infect 1999;5: 724-32.
Petitpretz PA, Arvis P, Marel M, Moita J, Urueta J, and the CAP5 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;119: 185-95.
Lode HG, Garau J, Grassi C, Hosie J, Huchon G, Legakis N, et al. Treatment of community-acquired pneumonia: a randomized comparison of sparfloxacin, amoxycillin-clavulanic acid and erythromycin. Eur Respir J 1995;8: 1999-2007.
Aubier M, Verster R, Regamey C, Geslin P, Vercken J. Once daily sparfloxacin versus high dosage amoxicillin in the treatment of community-acquired pneumococcal pneumonia in adults. Clin Infect Dis 1998;26: 1312-20.
Donowitz GRB, Salisbury ML, Harman JP, Tipping CP, Urick DM, Talbot AE. Sparfloxacin versus cefaclor in the treatment of patients with community-acquired pneumonia: a randomized, double-masked, comparative, multicenter study. Clin Ther 1997;19: 936-53.
Hagberg L, Torres A, van Rensburg D, Leroy B, Rangaraju M, Ruuth E. Efficacy and tolerability of once-daily telithromycin compared with high-dose amoxicillin for treatment of community-acquired pneumonia. Infection 2002;30: 378-86.
Carbon C, Leophonte P, Petitpretz P, Chauvin J, Hazebroucq J. Efficacy and safety of temafloxacin versus those of amoxicillin in hospitalized adults with community-acquired pneumonia. Antimicrob Agents Chemother 1992;36: 833-9.
Trémolières F, de Kock F, Pluck N, Daniel 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;17: 447-53.
Fogarty C, Dowell ME, Ellison T, Vrooman PS, White BJ, Mayer H. Treating community-acquired pneumonia in hospitalised patients: gatifloxacin vs ceftriaxone/clarithromycin. J Respir Dis 1999;20: 11(suppl):60-9.
Food and Drug Administration new drug application file. Medical Officer review of CAP study 154-111. www.fda.gov/cder/foi/nda/97/020760a.htm (accessed 20 Nov 2004).
Food and Drug Administration new drug application file. Medical Officer review of CAP study 154-112. www.fda.gov/cder/foi/nda/97/020760a.htm (accessed 20 Nov 2004).
Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997;336: 243-50.
Lim WS, van der Eerden MM, Laing R, Boersma WG, Karalus N, Town GI, et al. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 2003;58: 377-82.
Ferraro MJ. Limitations in laboratory diagnosis of community-acquired pneumonia and acute exacerbations of chronic bronchitis. Hosp Med 1997;33 (suppl 2): 14-7.
Yu VL, Greenberg RN, Zadeikis N, Stout JE, Khashab MM, Olson WH, et al. Levofloxacin efficacy in the treatment of community-acquired legionellosis. Chest 2004;125: 2135-9.
Lieberman D, Schlaeffer F, Boldur I, Lieberman D, Horowitz S, Friedman MG, et al. Multiple pathogens in adult patients admitted with community-acquired pneumonia: a one-year prospective study of 346 consecutive patients. Thorax 1996;51: 179-84.
File TM Jr, Garau J, Blasi F, Chidiac C, Klugman K, Lode H, et al. Guidelines for empiric antimicrobial prescribing in community-acquired pneumonia. Chest 2004;125: 1888-901.
Kauppinen MT, Saikku P, Kujala P, Herva E, Syrjala H. Clinical picture of community acquired Chlamydia pneumoniae pneumonia requiring hospital treatment: a comparison between chlamydial and pneumococcal pneumonia. Thorax 1996;51: 185-9.
Mundy LM, Oldach D, Auwaerter PG, Gaydos CA, Moore RD, Bartlett JG, et al. Implications for macrolide treatment in community-acquired pneumonia. Hopkins CAP Team. Chest 1998;113: 1201-6.
Oosterheert JJ, Bonten MJM, Hak E, Schneider MME, Hoepelman IM. How good is the evidence for the recommended empirical antimicrobial treatment of patients hospitalized because of community-acquired pneumonia? A systematic review. J Antimicrob Chemother 2003;52: 555-63.
Hedlund J, Ortqvist A. Management of patients with community-acquired pneumonia treated in hospital in Sweden. Scand J Infect Dis 2002;34: 887-92.
Gleason PP, Meehan TP, Fine JM, Galusha DH, Fine MJ. Associations between initial antimicrobial therapy and medical outcomes for hospitalized elderly patients with pneumonia. Arch Intern Med 1999;159: 2562-72.
Houck PM, MacLehose RF, Niederman MS, Lowery JK. Empiric antibiotic therapy and mortality among Medicare pneumonia inpatients in 10 western states: 1993, 1995, and 1997. Chest 2001;119: 1420-6.(Graham D Mills, consultant physician1, M)
Correspondence to: G D Mills millsg@waikatodhb.govt.nz
Abstract
The optimal antibiotic therapy for community acquired pneumonia remains unclear. One of the barriers to better define treatment is the inability to accurately determine the part that the various micro-organisms play.1 In only a few cases is the causative organism identified, due to the poor yield from routine microbiological tests. Since it was first identified in 1881, Streptococcus pneumoniae has been considered the major cause of community acquired pneumonia.2 Its importance was supported by the reduction in mortality observed after the introduction of sulphonamides3 and later lactam antibiotics.4
With improvements in diagnostic microbiology, it became apparent that other organisms seemed causative in community acquired pneumonia. Three of the more recently recognised ones (Mycoplasma pneumoniae, Legionella species, and Chlamydia pneumoniae) are now associated with the term atypical pathogen. Their major distinguishing feature is a lack of in vitro response to lactam and sulphonamide antibiotics, rather than any differences to pneumococcal pneumonia in clinical presentation.5 6
The part that atypical organisms play and the need to provide specific antibiotic coverage for them in community acquired pneumonia is contentious. Recent guidelines vary.1 7-10 The single most important factor in this variance is the failure to produce level 1 evidence on which to base treatment recommendations. We carried out a meta-analysis to compare the efficacy of lactam antibiotics with antibiotics active against atypical pathogens in adults with community acquired pneumonia to produce the level 1 evidence currently lacking.
Methods
We screened over 2000 studies and retrieved over 100 potentially eligible ones. We identified 20 studies that met our inclusion criteria.11-26 Four of the studies (30% of participants) were unpublished as at November 2004 and were obtained from the sponsoring pharmaceutical companies either directly or secondary to the finding of a conference proceedings (see bmj.com). Two small studies concerned children.11 12 We decided to exclude these from our meta-analysis given the distinct clinical context. Three blinded studies were also excluded, as the protocol included the option of adding an agent active against atypical pathogens to the lactam therapy.27-29
The 18 included trials were carried out in more than 30 countries between 1980 and 2000 and included 6749 analysable participants (table). Overall, the trials used nine different fluoroquinolones, two macrolides, and one ketolide. Most study drugs were given orally, with only two of the earlier studies using intravenous therapy initially. Most of the studies listed specific exclusion criteria; a standard feature in most trials of community acquired pneumonia sponsored by pharmaceutical companies. Common exclusions included the requirement for parenteral antimicrobials at study entry in trials of oral antibiotics, hospital acquired or aspiration pneumonia, immunocompromised patients, and major hepatic or renal dysfunction. The specific inclusion and exclusion criteria resulted in participants who were younger and with a better prognostic risk profile than observational pneumonia cohorts.30
Characteristics of included studies comparing lactam antibiotics with antibiotics active against atypical pathogens in patients with community acquired pneumonia
Primary outcome of interest
All trials reported the proportion of patients who failed to achieve clinical cure or improvement, an overall rate of 18%. We found no significant difference between treatments in any study or significant heterogeneity between studies. From a combined analysis of the studies (fig 1) we found no evidence that antibiotics active against atypical pathogens were superior to lactam antibiotics (relative risk 0.97, 95% confidence interval 0.87 to 1.07). The same conclusion was drawn from separate analyses of the studies on macrolides and ketolides (0.81, 0.58 to 1.14) and fluoroquinolones (0.99, 0.88 to 1.11). We also compared the relative risk of the 10 published studies on fluoroquinolones (0.90, 0.77 to 1.04) with the four unpublished studies on fluoroquinolones (1.15, 0.96 to 1.37).
Fig 1 Number of patients failing to achieve clinical cure or improvement with lactam antibiotics compared with antibiotics active against atypical pathogens in all cause community acquired pneumonia
We analysed the data on all cause mortality separately; 130 deaths were reported (mortality 1.9%). We observed no differences in mortality between the study arms (relative risk 1.20, 0.84 to 1.71). This low mortality is in keeping with most patients having mild to moderate (non-severe) community acquired pneumonia.
Fifteen of the trials provided data on either the intention to treat population or the modified intention to treat population. Three studies reported only on the clinically evaluable population, although the overall dropout rate was less than 17%.13 18 26 As all the studies were blinded, we did not consider the lack of intention to treat data in these three studies as critical and we therefore included the data. The treatment effect (relative risk 0.97) was not altered when we excluded trials that did not use an intention to treat or modified intention to treat method. Similar results (0.93, 0.81 to 1.06) were obtained from a separate analysis on the clinically evaluable per protocol population (n = 5639), with the failure to achieve clinical cure or improvement reduced to 13%.
We decided to include one study (weighting 3.3%) where a small proportion (< 10%) of patients had nosocomial pneumonia.14 The result was not altered (relative risk 0.97) when we carried out a sensitivity analysis with these data excluded. The time point for assessment varied between studies. Sixteen of the studies had visits for end of treatment or for test of cure within 10 days of completion of the study drug, whereas two studies assessed patients at the end of follow up. We found no evidence of a secular trend of decreasing treatment effect in the lactam arms, suggesting that there was no impact on treatment effect from the worldwide trend for increasing pneumococcal resistance.
Subgroup analysis
Overall, 311 patients (13 studies) were diagnosed as having M pneumoniae, 115 (seven studies) as having C pneumoniae, and 75 (10 studies) as having Legionella species (fig 2). We found no significant treatment effect in patients with M pneumoniae (relative risk 0.60, 0.31 to 1.17) or C pneumoniae (2.32, 0.67 to 8.03). In contrast, the failure rate from antibiotics active against atypical pathogens in patients with legionella was statistically lower (0.40, 0.19 to 0.85).
Fig 2 Number of patients failing to achieve clinical cure or improvement with lactam antibiotics compared with antibiotics active against atypical pathogens in confirmed cases of community acquired pneumonia related to Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella species
Discussion
British Thoracic Society Standards of Care Committee. BTS guidelines for the management of community acquired pneumonia in adults. Thorax 2001;56(suppl 4): IV1-64.
Watson DA, Musher DM, Jacobson JW, Verhoef J. A brief history of the pneumococcus in biomedical research: a panoply of scientific discovery. Clin Infect Dis 1993;17: 913-24.
Evans GM, Gaisford WF. Treatment of pneumonia with 2-(-aminobenzenesulphonamido) pyridine. Lancet 1938;2: 14-9.
Tillett WS, Cambier MJ, McCormack JE. The treatment of lobar pneumonia and pneumococcal empyema with penicillin. Bull NY Acad Sci 1944;20: 142-78.
Farr BW, Kaiser DL, Harrison BDW, Connolly CK. Prediction of microbial aetiology at admission to hospital for pneumonia from the presenting clinical features. Thorax 1989;44: 1031-5.
File TM, Jr, Plouffe JF, Breiman RF, Skelton SK. Clinical characteristics of Chlamydia pneumoniae infection as the sole cause of community-acquired pneumonia. Clin Infect Dis 1999;29: 426-8.
Niederman MS, Mandell LA, Anzueto A, Bass JB, Broughton WA, Campbell GD, et al. Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy and prevention. Am J Respir Crit Care Med 2001;163: 1730-54.
ERS Taskforce Report. Guidelines for the management of adults with community-acquired lower respiratory tract infections. Eur Resp J 1998;11: 986-91.
Bartlett JG, Dowell SF, Mandell LA, File TM, Musher DM, Fine MJ. Practice guidelines for the management of community-acquired pneumonia in adults. Clin Infect Dis 2000;31: 347-82.
Mandell LA, Marrie TJ, Grossman RF, Chow AW, Hyland RH. 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. Clin Infect Dis 2000;31: 383-421.
Harris JA, Kolohathis A, Campbell M, Cassell GH, Hammerschlag MR. Safety and efficacy of azithromycin in the treatment of community-acquired pneumonia in children. Pediatr Infect Dis J 1998;17: 865-71.
Ferwerda A, Moll HA, Hop WCJ, Kouwenberg JM, Gi CVTP, Robben SGF, et al. Efficacy, safety and tolerability of 3 day azithromycin versus 10 day co-amoxiclav in the treatment of children with acute lower respiratory tract infections. J Antimicrob Chemother 2001;47: 441-6.
Kinasewitz G, Wood RG. Azithromycin versus cefaclor in the treatment of acute bacterial pneumonia. Eur J Clin Microbiol Infect Dis 1991;10: 872-7.
Johnson RH, Levine S, Traub SL, Echols RM, Haverstock D, Arnold E, et al. Sequential intravenous/oral ciprofloxacin compared with parenteral ceftriaxone in the treatment of hospitalised patients with community-acquired pneumonia Infectious. Dis Clin Pract 1996;5: 265-72.
Macfarlane JT, Finch RG, Ward MJ, Rose DH. Erythromycin compared with a combination of ampicillin and amoxycillin as initial therapy for adults with pneumonia including Legionnaires disease. J Infect 1983;7: 111-7.
Lode H, Magyar P, Muir JF, Loos U, Kleutgens K, on behalf of the International 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;10: 512-20.
Leophonte P, File T, Feldman 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 2004:198: 708-20.
O'Doherty B, Dutchman DA, Pettit R, Maroli A. Randomised, 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.
Carbon C, Ariza H, Rabie W, Salvarezza C, Elkharrat D, Rangaraj M, et al. Comparative study of levofloxacin and amoxycillin/clavulanic acid in adults with mild-to moderate community acquired pneumonia. Clin Microbiol Infect 1999;5: 724-32.
Petitpretz PA, Arvis P, Marel M, Moita J, Urueta J, and the CAP5 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;119: 185-95.
Lode HG, Garau J, Grassi C, Hosie J, Huchon G, Legakis N, et al. Treatment of community-acquired pneumonia: a randomized comparison of sparfloxacin, amoxycillin-clavulanic acid and erythromycin. Eur Respir J 1995;8: 1999-2007.
Aubier M, Verster R, Regamey C, Geslin P, Vercken J. Once daily sparfloxacin versus high dosage amoxicillin in the treatment of community-acquired pneumococcal pneumonia in adults. Clin Infect Dis 1998;26: 1312-20.
Donowitz GRB, Salisbury ML, Harman JP, Tipping CP, Urick DM, Talbot AE. Sparfloxacin versus cefaclor in the treatment of patients with community-acquired pneumonia: a randomized, double-masked, comparative, multicenter study. Clin Ther 1997;19: 936-53.
Hagberg L, Torres A, van Rensburg D, Leroy B, Rangaraju M, Ruuth E. Efficacy and tolerability of once-daily telithromycin compared with high-dose amoxicillin for treatment of community-acquired pneumonia. Infection 2002;30: 378-86.
Carbon C, Leophonte P, Petitpretz P, Chauvin J, Hazebroucq J. Efficacy and safety of temafloxacin versus those of amoxicillin in hospitalized adults with community-acquired pneumonia. Antimicrob Agents Chemother 1992;36: 833-9.
Trémolières F, de Kock F, Pluck N, Daniel 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;17: 447-53.
Fogarty C, Dowell ME, Ellison T, Vrooman PS, White BJ, Mayer H. Treating community-acquired pneumonia in hospitalised patients: gatifloxacin vs ceftriaxone/clarithromycin. J Respir Dis 1999;20: 11(suppl):60-9.
Food and Drug Administration new drug application file. Medical Officer review of CAP study 154-111. www.fda.gov/cder/foi/nda/97/020760a.htm (accessed 20 Nov 2004).
Food and Drug Administration new drug application file. Medical Officer review of CAP study 154-112. www.fda.gov/cder/foi/nda/97/020760a.htm (accessed 20 Nov 2004).
Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997;336: 243-50.
Lim WS, van der Eerden MM, Laing R, Boersma WG, Karalus N, Town GI, et al. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 2003;58: 377-82.
Ferraro MJ. Limitations in laboratory diagnosis of community-acquired pneumonia and acute exacerbations of chronic bronchitis. Hosp Med 1997;33 (suppl 2): 14-7.
Yu VL, Greenberg RN, Zadeikis N, Stout JE, Khashab MM, Olson WH, et al. Levofloxacin efficacy in the treatment of community-acquired legionellosis. Chest 2004;125: 2135-9.
Lieberman D, Schlaeffer F, Boldur I, Lieberman D, Horowitz S, Friedman MG, et al. Multiple pathogens in adult patients admitted with community-acquired pneumonia: a one-year prospective study of 346 consecutive patients. Thorax 1996;51: 179-84.
File TM Jr, Garau J, Blasi F, Chidiac C, Klugman K, Lode H, et al. Guidelines for empiric antimicrobial prescribing in community-acquired pneumonia. Chest 2004;125: 1888-901.
Kauppinen MT, Saikku P, Kujala P, Herva E, Syrjala H. Clinical picture of community acquired Chlamydia pneumoniae pneumonia requiring hospital treatment: a comparison between chlamydial and pneumococcal pneumonia. Thorax 1996;51: 185-9.
Mundy LM, Oldach D, Auwaerter PG, Gaydos CA, Moore RD, Bartlett JG, et al. Implications for macrolide treatment in community-acquired pneumonia. Hopkins CAP Team. Chest 1998;113: 1201-6.
Oosterheert JJ, Bonten MJM, Hak E, Schneider MME, Hoepelman IM. How good is the evidence for the recommended empirical antimicrobial treatment of patients hospitalized because of community-acquired pneumonia? A systematic review. J Antimicrob Chemother 2003;52: 555-63.
Hedlund J, Ortqvist A. Management of patients with community-acquired pneumonia treated in hospital in Sweden. Scand J Infect Dis 2002;34: 887-92.
Gleason PP, Meehan TP, Fine JM, Galusha DH, Fine MJ. Associations between initial antimicrobial therapy and medical outcomes for hospitalized elderly patients with pneumonia. Arch Intern Med 1999;159: 2562-72.
Houck PM, MacLehose RF, Niederman MS, Lowery JK. Empiric antibiotic therapy and mortality among Medicare pneumonia inpatients in 10 western states: 1993, 1995, and 1997. Chest 2001;119: 1420-6.(Graham D Mills, consultant physician1, M)