BMJ 2014;348:g1469 doi: 10.1136/bmj.g1469 (Published 13 February 2014)
Page 1 of 2
Editorials
EDITORIALS Which antibiotic for hospital acquired pneumonia caused by MRSA? Vancomycin is as safe and effective as newer alternatives John Muscedere associate professor of medicine Queen’s University, Kingston, ON, Canada, K7L 2V7
Hospital acquired pneumonia is associated with increased patient morbidity, mortality, and healthcare costs. Outcome is greatly influenced by aspects of antibiotic treatment including the agent chosen, the timing of initiation, adequacy, and duration.1 Gram negative organisms were traditionally thought to be the causal pathogens, but there has been an increasing shift towards Gram positive organisms, particularly Staphylococcus aureus. Surveillance studies have found that 50–60% are meticillin resistant S aureus (MRSA).2 Clinicians treating hospital acquired pneumonia, which is known or suspected to be secondary to MRSA, need to know which antimicrobial agent works best and is least harmful. Vancomycin was traditionally considered the mainstay of treatment for MRSA, but in the past few years the number of available antimicrobials active against MRSA has increased substantially. Newly available drugs include linezolid, telavancin, tigecycline, quinupristin-dalfopristin, daptomycin, and ceftaroline. Given these available alternatives, how can we optimise the treatment of hospital acquired pneumonia caused by MRSA? Or, to paraphrase, are the newer antibiotics any better or any safer than the old standby vancomycin?
For hospital acquired pneumonia, the seemingly large number of options is quickly reduced because of the pharmacology, inadequate evaluation, possible harm, or known lack of efficacy. Daptomycin is contraindicated for the treatment of pneumonia because it is inactivated by surfactant. Ceftaroline has not been studied as a treatment for hospital acquired pneumonia. Only one randomised controlled trial has looked at quinupristin-dalfopristin for the treatment of hospital acquired pneumonia, but only a small proportion of patients were documented to have MRSA. Numerical cure rates for documented MRSA were higher in the vancomycin arm, although the small number of patients precludes any firm conclusions.3 Tigecycline was inferior to vancomycin plus imipenem-cilastatin for patients with hospital acquired pneumonia. This was driven largely by lower success rates for ventilator acquired pneumonia and lower cure rates for MRSA, although further studies of tigecycline are under way.4 Two randomised controlled trials
compared telavancin with vancomycin for the treatment of hospital acquired pneumonia. Clinical outcomes were found to be equivalent for both drugs, except that mortality was increased with telavancin in patients who had renal insufficiency, defined as a glomerular filtration rate less than 50%.5 By far the best studied comparator to vancomycin has been linezolid. The development of linezolid was anticipated with much excitement. Linezolid was promoted as a drug with many potential advantages over vancomycin for the treatment of pneumonia—better penetration into pulmonary tissue, improved pharmacokinetic profile, no need for therapeutic drug monitoring, availability in oral and parenteral formulations, and lack of requirement for dose adjustment in renal failure.6 7 This new antibiotic was also of interest because of concerns that MRSA was becoming increasingly resistant to vancomycin. On the basis of these considerations and subgroup analyses of two trials, which found that linezolid was associated with superior significantly higher cure rates and improved mortality, the superiority of linezolid was widely disseminated.8 9
This was followed by two meta-analyses, which both concluded that linezolid had no advantage over vancomycin.10 11 Continued controversy led to an industry funded randomised controlled trial, which was meant to answer the question once and for all.12 This trial also found no mortality advantage for linezolid, but it concluded that cure rates at the end of the study were higher with linezolid in a per protocol analysis, which included only 348 (28%) of the 1225 patients randomised. Many methodological problems have been raised about this trial, including the lack of an intention to treat analysis and involvement of the sponsor in the conduct of the trial. Given the history, the recent systematic review and meta-analysis by Khalil and colleagues, which synthesised the trial evidence comparing vancomycin and linezolid for the treatment of hospital acquired pneumonia caused by MRSA, is timely and goes a long way towards settling the question of which agent to use.13 The authors conducted a thorough search of the literature including databases of abstracts. They identified nine trials that enrolled more than 4000 patients who met their prespecified criteria. The studies were scored for quality using
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Subscribe: http://www.bmj.com/subscribe
BMJ 2014;348:g1469 doi: 10.1136/bmj.g1469 (Published 13 February 2014)
Page 2 of 2
EDITORIALS
Jadad criteria. Khalil and colleagues found no difference in mortality between the groups, with low heterogeneity, and no difference in clinical response rate based on intention to treat principles. There were also no significant differences in microbiological eradication or MRSA eradication. In safety analyses, they found a non-significant trend towards increased risk of gastrointestinal events and thrombocytopenia in the linezolid group, but no differences in the occurrence of renal failure or discontinuation secondary to adverse events. Sensitivity analyses, including analyses confined to high or low quality trials, upheld the overall findings. After a power calculation, Khalil and colleagues concluded that, with the number of patients included in their meta-analysis, a significant difference in mortality or clinical response rates was unlikely to have been missed. Overall, the meta-analysis seemed to be well conducted and complied with PRISMA guidelines for reporting. Given the findings of this well conducted meta-analysis, and because additional trial evidence comparing linezolid with vancomycin is unlikely to become available, clinicians can conclude with confidence that these agents have similar clinical efficacy for adults with hospital acquired pneumonia caused by MRSA. Similarly, although less well studied, current available evidence suggests that, in those without renal insufficiency, vancomycin and telavancin have similar clinical efficacy. The choice of one agent over another will be driven by availability, drug costs, the costs of therapeutic drug monitoring, potential to switch from parenteral to oral therapy, and drug resistance rates. Further cost effectiveness studies incorporating these variables would be valuable and should now be done. In conclusion, newer is not necessarily better, and clinicians can continue to prescribe vancomycin for MRSA hospital acquired pneumonia with the confidence that it is as equally efficacious and safe as any of the newer alternatives.
Competing interests: I have read and understood the BMJ Group policy on declaration of interests and declare the following interests: None. Provenance and peer review: Not commissioned; not externally peer reviewed. 1 2 3
4 5 6 7 8 9
10 11 12 13
Kuti EL, Patel AA, Coleman CI. Impact of inappropriate antibiotic therapy on mortality in patients with ventilator-associated pneumonia and blood stream infection: a meta-analysis. J Crit Care 2008;23:91-100. Jones RN. Microbial etiologies of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. Clin Infect Dis 2010;51(suppl 1):S81-7. Fagon J, Patrick H, Haas DW, Torres A, Gibert C, Cheadle WG, et al. Treatment of Gram-positive nosocomial pneumonia. Prospective randomized comparison of quinupristin/dalfopristin versus vancomycin. Nosocomial Pneumonia Group. Am J Respir Crit Care Med 2000;161:753-62. Freire AT, Melnyk V, Kim MJ, Datsenko O, Dzyublik O, Glumcher F, et al. Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia. Diagn Microbiol Infect Dis 2010;68:140-51. Corey GR, Kollef MH, Shorr AF, Rubinstein E, Stryjewski ME, Hopkins A, et al. Telavancin for hospital-acquired pneumonia: clinical response and 28-day survival. Antimicrob Agents Chemother 2014; published online 13 Jan. Pletz MW, Burkhardt O, Welte T. Nosocomial methicillin-resistant Staphylococcus aureus (MRSA) pneumonia: linezolid or vancomycin? Comparison of pharmacology and clinical efficacy. Eur J Med Res 2010;15:507-13. Stalker DJ, Jungbluth GL. Clinical pharmacokinetics of linezolid, a novel oxazolidinone antibacterial. Clin Pharmacokinet 2003;42:1129-40. Wunderink RG, Rello J, Cammarata SK, Croos-Dabrera RV, Kollef MH. Linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia. Chest 2003;124:1789-97. Kollef MH, Rello J, Cammarata SK, Croos-Dabrera RV, Wunderink RG. Clinical cure and survival in Gram-positive ventilator-associated pneumonia: retrospective analysis of two double-blind studies comparing linezolid with vancomycin. Intens Care Med 2004;30:388-94. Kalil AC, Murthy MH, Hermsen ED, Neto FK, Sun J, Rupp ME. Linezolid versus vancomycin or teicoplanin for nosocomial pneumonia: a systematic review and meta-analysis. Crit Care Med 2010;38:1802-8. Walkey AJ, O’Donnell MR, Wiener RS. Linezolid vs glycopeptide antibiotics for the treatment of suspected methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a meta-analysis of randomized controlled trials. Chest 2011;139:1148-55. Wunderink RG, Niederman MS, Kollef MH, Kollef MH, Shorr AF, Kunkel MJ, Baruch A, et al. Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. Clin Infect Dis 2012;54:621-9. Kalil AC, Klompas M, Haynatzki G, Rupp ME. Treatment of hospital-acquired pneumonia with linezolid or vancomycin: a systematic review and meta-analysis. BMJ Open 2013;3:e003912.
Cite this as: BMJ 2014;348:g1469 © BMJ Publishing Group Ltd 2014
For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
Page 1 of 2
Editorials
EDITORIALS Which antibiotic for hospital acquired pneumonia caused by MRSA? Vancomycin is as safe and effective as newer alternatives John Muscedere associate professor of medicine Queen’s University, Kingston, ON, Canada, K7L 2V7
Hospital acquired pneumonia is associated with increased patient morbidity, mortality, and healthcare costs. Outcome is greatly influenced by aspects of antibiotic treatment including the agent chosen, the timing of initiation, adequacy, and duration.1 Gram negative organisms were traditionally thought to be the causal pathogens, but there has been an increasing shift towards Gram positive organisms, particularly Staphylococcus aureus. Surveillance studies have found that 50–60% are meticillin resistant S aureus (MRSA).2 Clinicians treating hospital acquired pneumonia, which is known or suspected to be secondary to MRSA, need to know which antimicrobial agent works best and is least harmful. Vancomycin was traditionally considered the mainstay of treatment for MRSA, but in the past few years the number of available antimicrobials active against MRSA has increased substantially. Newly available drugs include linezolid, telavancin, tigecycline, quinupristin-dalfopristin, daptomycin, and ceftaroline. Given these available alternatives, how can we optimise the treatment of hospital acquired pneumonia caused by MRSA? Or, to paraphrase, are the newer antibiotics any better or any safer than the old standby vancomycin?
For hospital acquired pneumonia, the seemingly large number of options is quickly reduced because of the pharmacology, inadequate evaluation, possible harm, or known lack of efficacy. Daptomycin is contraindicated for the treatment of pneumonia because it is inactivated by surfactant. Ceftaroline has not been studied as a treatment for hospital acquired pneumonia. Only one randomised controlled trial has looked at quinupristin-dalfopristin for the treatment of hospital acquired pneumonia, but only a small proportion of patients were documented to have MRSA. Numerical cure rates for documented MRSA were higher in the vancomycin arm, although the small number of patients precludes any firm conclusions.3 Tigecycline was inferior to vancomycin plus imipenem-cilastatin for patients with hospital acquired pneumonia. This was driven largely by lower success rates for ventilator acquired pneumonia and lower cure rates for MRSA, although further studies of tigecycline are under way.4 Two randomised controlled trials
compared telavancin with vancomycin for the treatment of hospital acquired pneumonia. Clinical outcomes were found to be equivalent for both drugs, except that mortality was increased with telavancin in patients who had renal insufficiency, defined as a glomerular filtration rate less than 50%.5 By far the best studied comparator to vancomycin has been linezolid. The development of linezolid was anticipated with much excitement. Linezolid was promoted as a drug with many potential advantages over vancomycin for the treatment of pneumonia—better penetration into pulmonary tissue, improved pharmacokinetic profile, no need for therapeutic drug monitoring, availability in oral and parenteral formulations, and lack of requirement for dose adjustment in renal failure.6 7 This new antibiotic was also of interest because of concerns that MRSA was becoming increasingly resistant to vancomycin. On the basis of these considerations and subgroup analyses of two trials, which found that linezolid was associated with superior significantly higher cure rates and improved mortality, the superiority of linezolid was widely disseminated.8 9
This was followed by two meta-analyses, which both concluded that linezolid had no advantage over vancomycin.10 11 Continued controversy led to an industry funded randomised controlled trial, which was meant to answer the question once and for all.12 This trial also found no mortality advantage for linezolid, but it concluded that cure rates at the end of the study were higher with linezolid in a per protocol analysis, which included only 348 (28%) of the 1225 patients randomised. Many methodological problems have been raised about this trial, including the lack of an intention to treat analysis and involvement of the sponsor in the conduct of the trial. Given the history, the recent systematic review and meta-analysis by Khalil and colleagues, which synthesised the trial evidence comparing vancomycin and linezolid for the treatment of hospital acquired pneumonia caused by MRSA, is timely and goes a long way towards settling the question of which agent to use.13 The authors conducted a thorough search of the literature including databases of abstracts. They identified nine trials that enrolled more than 4000 patients who met their prespecified criteria. The studies were scored for quality using
[email protected] For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
BMJ 2014;348:g1469 doi: 10.1136/bmj.g1469 (Published 13 February 2014)
Page 2 of 2
EDITORIALS
Jadad criteria. Khalil and colleagues found no difference in mortality between the groups, with low heterogeneity, and no difference in clinical response rate based on intention to treat principles. There were also no significant differences in microbiological eradication or MRSA eradication. In safety analyses, they found a non-significant trend towards increased risk of gastrointestinal events and thrombocytopenia in the linezolid group, but no differences in the occurrence of renal failure or discontinuation secondary to adverse events. Sensitivity analyses, including analyses confined to high or low quality trials, upheld the overall findings. After a power calculation, Khalil and colleagues concluded that, with the number of patients included in their meta-analysis, a significant difference in mortality or clinical response rates was unlikely to have been missed. Overall, the meta-analysis seemed to be well conducted and complied with PRISMA guidelines for reporting. Given the findings of this well conducted meta-analysis, and because additional trial evidence comparing linezolid with vancomycin is unlikely to become available, clinicians can conclude with confidence that these agents have similar clinical efficacy for adults with hospital acquired pneumonia caused by MRSA. Similarly, although less well studied, current available evidence suggests that, in those without renal insufficiency, vancomycin and telavancin have similar clinical efficacy. The choice of one agent over another will be driven by availability, drug costs, the costs of therapeutic drug monitoring, potential to switch from parenteral to oral therapy, and drug resistance rates. Further cost effectiveness studies incorporating these variables would be valuable and should now be done. In conclusion, newer is not necessarily better, and clinicians can continue to prescribe vancomycin for MRSA hospital acquired pneumonia with the confidence that it is as equally efficacious and safe as any of the newer alternatives.
Competing interests: I have read and understood the BMJ Group policy on declaration of interests and declare the following interests: None. Provenance and peer review: Not commissioned; not externally peer reviewed. 1 2 3
4 5 6 7 8 9
10 11 12 13
Kuti EL, Patel AA, Coleman CI. Impact of inappropriate antibiotic therapy on mortality in patients with ventilator-associated pneumonia and blood stream infection: a meta-analysis. J Crit Care 2008;23:91-100. Jones RN. Microbial etiologies of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. Clin Infect Dis 2010;51(suppl 1):S81-7. Fagon J, Patrick H, Haas DW, Torres A, Gibert C, Cheadle WG, et al. Treatment of Gram-positive nosocomial pneumonia. Prospective randomized comparison of quinupristin/dalfopristin versus vancomycin. Nosocomial Pneumonia Group. Am J Respir Crit Care Med 2000;161:753-62. Freire AT, Melnyk V, Kim MJ, Datsenko O, Dzyublik O, Glumcher F, et al. Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia. Diagn Microbiol Infect Dis 2010;68:140-51. Corey GR, Kollef MH, Shorr AF, Rubinstein E, Stryjewski ME, Hopkins A, et al. Telavancin for hospital-acquired pneumonia: clinical response and 28-day survival. Antimicrob Agents Chemother 2014; published online 13 Jan. Pletz MW, Burkhardt O, Welte T. Nosocomial methicillin-resistant Staphylococcus aureus (MRSA) pneumonia: linezolid or vancomycin? Comparison of pharmacology and clinical efficacy. Eur J Med Res 2010;15:507-13. Stalker DJ, Jungbluth GL. Clinical pharmacokinetics of linezolid, a novel oxazolidinone antibacterial. Clin Pharmacokinet 2003;42:1129-40. Wunderink RG, Rello J, Cammarata SK, Croos-Dabrera RV, Kollef MH. Linezolid vs vancomycin: analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia. Chest 2003;124:1789-97. Kollef MH, Rello J, Cammarata SK, Croos-Dabrera RV, Wunderink RG. Clinical cure and survival in Gram-positive ventilator-associated pneumonia: retrospective analysis of two double-blind studies comparing linezolid with vancomycin. Intens Care Med 2004;30:388-94. Kalil AC, Murthy MH, Hermsen ED, Neto FK, Sun J, Rupp ME. Linezolid versus vancomycin or teicoplanin for nosocomial pneumonia: a systematic review and meta-analysis. Crit Care Med 2010;38:1802-8. Walkey AJ, O’Donnell MR, Wiener RS. Linezolid vs glycopeptide antibiotics for the treatment of suspected methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a meta-analysis of randomized controlled trials. Chest 2011;139:1148-55. Wunderink RG, Niederman MS, Kollef MH, Kollef MH, Shorr AF, Kunkel MJ, Baruch A, et al. Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. Clin Infect Dis 2012;54:621-9. Kalil AC, Klompas M, Haynatzki G, Rupp ME. Treatment of hospital-acquired pneumonia with linezolid or vancomycin: a systematic review and meta-analysis. BMJ Open 2013;3:e003912.
Cite this as: BMJ 2014;348:g1469 © BMJ Publishing Group Ltd 2014
For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
