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PRIORITY PRESS - 31st International Symposium on Intensive Care and Emergency Medicine (ISICEM)

Brussels, Belgium / March 22-25, 2011

According to data from a double-blind, randomized, multicentre comparison, the two most commonly recommended antibiotics for control of methicillin-resistant Staphylococcus aureus (MRSA) in the intensive-care unit (ICU) did not appear to be equally effective. The ZEPHyR study was conducted in 156 centres worldwide and compared the oxazolidinone linezolid and the glycopeptide vancomycin, both of which are currently listed as acceptable MRSA treatments in several current guidelines or consensus statements. For the primary end point of clinical response (57.6% vs. 46.6%; P=0.042) and for the secondary end point of microbiological response (81.9% vs. 60.6%; P<0.001), linezolid appeared more effective.

“The conclusion from this study is that linezolid provided a statistically significant higher success rate. The relative advantage was similar for clinical and microbiological outcomes. The advantage of linezolid was achieved with an acceptable safety and tolerability profile,” reported Dr. Jordi Rello, Hospital Vall d’Hebron Research Unit, Universitat Autónoma de Barcelona, Spain, here at ISICEM. He noted that the trend for greater rates of renal failure in patients treated with vancomycin is consistent with previous reports of the relative safety profile of these 2 agents. Most importantly, the study provides objective data on which to base therapeutic decisions.

Emerging Evidence

Up until now, “the limits of vancomycin have been well recognized, but there was no basis on which to indicate a preference. ZEPHyR may have a major influence on treatment guidelines,” Dr. Tobias Welte, Department of Respiratory Medicine, Hannover Medical School, Germany, told ISICEM delegates. He cited a discussion from a published study comparing quinupristin/dalfopristin to vancomycin in nosocomial pneumonia that included MRSA (Fagon et al. Am J Respir Crit Care Med 2000;163:1759-60). He noted that although vancomycin is often used for highly treatment-resistant infections, several studies have indicated that it may not have ideal pharmacodynamics for lung infections.

There is already other evidence that linezolid may be superior in MRSA pneumonia, including a recent meta-analysis that showed a trend for superior outcomes (Walkey AJ, O’Donnell MR, Wieners RS. Chest 2010 Sep 23;epub ahead of print), but there has been no prospective evidence from a major controlled study until now.

In ZEPHyR, complete data are available on 342 of the 348 evaluable patients. All had culture-positive MRSA pneumonia. The 172 patients randomized to linezolid received 600 mg every 12 hours. The 170 randomized to vancomycin received 15 mg/kg every 12 hours. Treatment was continued for 7 to 14 days. Of the patients, 67% were male, 70% were ventilated, nearly 10% had bacteremia and the median APACHE score was approximately 17 in both arms, which were similar for most other significant characteristics. Target plasma concentrations of drug therapy were monitored to ensure that vancomycin patients achieved target minimum inhibitory concentrations (MICs).

During the ISICEM symposium in which Dr. Rello presented the ZEPHyR results, which were characterized as “preliminary” (a summary of the as-yet unpublished study were also presented at the 2010 meeting of the Infectious Diseases Society of America), Dr. Welte noted that several guidelines had already indicated that linezolid might be preferable for MRSA pneumonia on the basis of better lung tissue penetration, but these were expert opinions and not evidence-based.

Burden of Pneumonias

One reason that guidelines and consensus statements regarding treatment of MRSA pneumonia have emerged in advance of controlled trials is the high toll in morbidity and mortality from this disease. Citing one surveillance study (Wiersma et al. Epidemiol Infect 2009;137:1674-8), Dr. Welte noted that mortality rates even for community-acquired MRSA were more than tenfold greater in patients who developed a pneumonia relative to those with a skin or soft tissue MRSA infection. Currently, one of the most significant risks for MRSA pneumonia is a viral infection, particularly H1N1 influenza, for which MRSA is a common secondary bacterial infection. Dr. Welte cautioned that this might be an increasingly important public health concern in the years ahead.

The only European guidelines for the management of MRSA infections were developed in the UK (Nathwani et al. J Antimicrob Chemother 2008;61:976-94). For severe community-acquired MRSA pneumonia, either linezolid or vancomycin is recommended with a “very weak” mention of teicoplanin and daptomycin as potential alternatives, according to Dr. Welte. For nosocomial MRSA, the guidelines recommend a combination of linezolid and clindamycin as first-line. He explained that the reason for the addition of clindamycin is that it has anti-inflammatory effects that may lessen the cytokine release that can sometimes adversely affect the clinical course in serious MRSA pneumonia.

In ventilator-associated pneumonias, the consequences of MRSA infection are even greater, raising the mortality rates by more than twofold, according to Dr. Welte, who cited several studies including one from his own centre (Gastmeier et al. Infect Control Hosp Epidemiol 2007;28:446-52).

Rationale for Evidence-based Guidelines

“The problem is not the pathogen. The problem is us,” Dr. Andrew F. Shorr, Pulmonary and Critical Care Medicine, Washington Hospital Center, Washington, D.C., emphasized. He indicated that delayed or inappropriate therapy, not the absence of an effective therapy, is the major hurdle to infection control. He agreed with Dr. Welte that results of a controlled trial in this field could provide clinicians with objective guidance for a major challenge in infectious disease.

Dr. Welte cited several studies, including one from Canada, suggesting that S. aureus infections in general and MRSA infections specifically are often poorly treated. This promotes the need for better guidelines, but Dr. Welte noted that, except for the UK guidelines, only consensus statements are available.

“In general, these expert opinions have determined that either linezolid or vancomycin can be considered, often without preference,” Dr. Welte told delegates. One exception was the German Sepsis Society, “which was a little bit more in favour of linezolid. It is mentioned that there are some problems with tissue penetration with vancomycin, and this has been seen by several groups.” In contrast, linezolid typically reaches the lungs in adequate concentrations.

“What initially drove the interest in linezolid as a molecule for pneumonia was the lung penetration,” reported Dr. Shorr. “There is some good data that linezolid, relative to glycopeptides, is a good drug for respiratory pathogens.” Citing 2 retrospective subgroup analyses that favoured this agent over vancomycin in ventilator-associated MRSA pneumonia, Dr. Shorr said that this provided the “biologic plausibility” that made the ZEPHyR trial appropriate.

“One of the main reasons we need these data is that past studies often included patients treated before the pathogen was known, so many did not, in fact, have MRSA. In addition, the studies did not focus on patients with nosocomial MRSA pneumonia,” Dr. Shorr explained.

Importance of Objective Guidance

There are other issues, including the “MIC creep” that is making previously recommended doses of vancomycin potentially less appropriate in the current era. This issue is underlined by evidence that increasing vancomycin MICs are associated with rising rates of failure, according to Dr. Shorr, but the key goal is to develop controlled data that can direct evidence-based decisions.

Summary

A recently completed prospective study has provided data to guide treatment decisions in patients with MRSA culture-positive pneumonia. High rates of efficacy were observed with both linezolid and vancomycin, which are widely regarded as the 2 antibiotics most appropriate for this infection, but the former provided a significantly higher rate of clinical and microbiological cure. The differences in efficacy are relevant for informing clinical decisions but also provide potential insight into characteristics, such as lung tissue penetration, that determine likelihood of infection control.