Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)

Chicago, Illinois / September 17-20, 2011

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

In early 2011, the Infectious Diseases Society of America (IDSA) issued new guidelines for the management of methicillin-resistant Staphylococcus aureus (MRSA) (Liu et al. Clin Infect Dis 2011;52:285-92). The guidelines collated the available evidence to provide specific recommendations for a broad array of clinical scenarios using ratings for the quality of the evidence behind the recommendation. These ranged from A-I to C-III. For most indications, vancomycin was included among A-I choices, but new data challenge this agent for at least some indications when other A-I therapies are available. A relatively narrow therapeutic window and uncertainty about the optimal serum concentrations are among the criticisms of this agent.

Optimal Serum Concentrations

“One of the biggest issues with vancomycin is that we still do not know the optimal serum concentrations. The IDSA recommends serum trough concentrations between 15 and 20 µg/L for treatment of MRSA bacteremia, but there are limited data supporting this target,” reported Dr. Marcus J. Zervos, Head of Infectious Diseases, Henry Ford Hospital, Detroit, Michigan. Senior author of a study led by Dr. Samia Arshad Kaskar at his institution, Dr. Zervos presented retrospective data on 200 patients with MRSA bacteremia who received vancomycin. The goal was to evaluate clinical failure in relation to serum concentrations. Clinical failure was defined as death or MRSA recurrence within 30 days or positive blood culture =7 days after treatment.

Drug trough levels in MRSA bacteremia were available for 86 of the 200 patients and definitive vancomycin levels (>72 hours after initiation of therapy) were available for 78 patients after excluding those with acute renal failure on admission, on dialysis or who did not achieve a steady state vancomycin concentration within 72 hours on therapy. Stratifying patients by a trough vancomycin level below or above 15 µg/mL, the investigators found a lower clinical failure rate at a greater trough level initially (13% vs. 21%; P=0.413). However, the opposite was observed when the definitive measure was taken 72 hours after therapy initiation. In this case, the clinical failure rate was higher at the greater trough level (18% vs. 9%; P=0.276). Nephrotoxicity was also more common with definitive trough levels >15 µg/mL (27% vs. 15%; P=0.224). Although none of these differences reached statistical significance, it led the investigators to emphasize that controlled data are needed to guide vancomycin concentration targets.

“Vancomycin is clearly an effective drug for MRSA, but there appears to be substantial variability between patients in drug concentrations and not enough information about optimal serum concentration targets,” stated Dr. Zervos, who did not provide reasons for the greater rate of failure at higher definitive trough levels, although increased risk of adverse events leading to discontinuation of therapy may have played a role.

Greater Predictability

In fact, the current IDSA recommendations identify the level of support for vancomycin in the treatment of MRSA bacteremia as A-II. The only agent with an A-I designation is daptomycin even though vancomycin remains a common choice at many institutions. The potential for greater efficacy with daptomycin was reflected in a retrospective study that compared it to vancomycin or sequential use of these 2 agents. Of the 101 patients treated at 5 participating centres in this study, 70 received vancomycin only. Of the remainder, 17 received daptomycin only and 14 patients were treated with vancomycin followed by daptomycin. Importantly, standard IDSA-recommended dosing was employed for both agents.

Regarding MRSA bacteremia treatment, “All of the outcomes we measured trended for a better response with daptomycin,” reported Dr. Brent W. Footer, State University of New York, Buffalo. While serum concentrations were not measured or compared as part of this study protocol, the efficacy of daptomycin was overall more predictable.

Specifically, the mean time to pathogen eradication was 4.2 days for daptomycin and 5.8 days (P=0.16) for vancomycin. Failure to achieve eradication (16% vs. 0%; P=0.11) and mortality (34% vs. 12%; P=0.08) were higher on vancomycin. The 30-day readmission rate was 13% for vancomycin and 0% for daptomycin. The sequential use of vancomycin and daptomycin produced results comparable to vancomycin alone. Although the mean time to eradication was shorter on sequential therapy relative to vancomycin alone, it still remained greater than that of daptomycin alone.

Skin and Soft-tissue MRSA

In MRSA skin and soft-tissue infections (SSTI) among hospitalized patients, IDSA recognizes 4 agents with an A-I designation. These are intravenous (i.v.) vancomycin, oral or i.v. linezolid 600 mg b.i.d., i.v. daptomycin 4 mg/kg q.d. and i.v. telavancin 10 mg/kg q.d. This was another indication where new data makes it unclear whether vancomycin, a long recognized standard, remains the best choice among A-I options. The predictability of standard doses both in regard to efficacy and safety is an important issue. This was raised in several studies that considered alternative agents in the treatment of diabetic foot MRSA.

“In a multicentre but non-comparative study, linezolid achieved excellent rates of cure or improvement even at first evaluation, which was supported by high microbiologic eradication rates,” reported Dr. Rafael Zaragoza, Intensive Care Unit, Hospital Universitario Dr. Peset, Valencia, Spain. In this prospective evaluation, 87 patients with documented diabetic foot MRSA were enrolled at 10 participating centres. At 60 days, 85.1% had cure or improvement and 80.5% had microbiological eradication. The mean duration of treatment was 28.5 days.

“Linezolid was a safe drug despite the prolonged period of treatment,” Dr. Zaragoza maintained. He suggested that relative to the nephrotoxicity associated with vancomycin, which is a particular risk in diabetic patients, the safety and efficacy of linezolid makes this an attractive alternative.

A similar but broader study was conducted with daptomycin. In this study, 277 patients with diabetic foot infections of any pathogen were studied retrospectively. All were participating in the European Cubicin Outcomes Registry and Experience (EU-CORE) program, which is an ongoing effort to collect safety and efficacy data on daptomycin in a real-world setting. One of the strengths of this study is that it includes all comers, including complicated patients. For example, a small proportion of patients in this series had concomitant bacteremia or osteomyelitis and more than half of the patients were over the age of 65.

Of the pathogens in this series, S. aureus was the most common, representing 54% of culture results. In contrast, the next most common pathogen, S. epidermidis, only represented 7%. Of the S. aureus infections, 69% were MRSA. No pathogen could be identified in 12% of this series. The most frequent initial dose of daptomycin, as recommended by the IDSA, was 4 mg/kg q.d. The mean duration was 6 days for outpatients and 12 days for inpatients. Additional antibiotics used in combination with daptomycin were permitted. The most common types and the proportion of patients who received them were fluoroquinolones (23.5%), carbapenem (17.7%), penicillin (9.7%) and cephalosporin (4.7%).

The overall clinical success rate was 85.6%. This included a cure rate of 30.7% and improvement of 54.9%. While these rates of success are encouraging in the context of challenging patients with multiple comorbidities, the tolerability of daptomycin was an important asset, particularly in this population. The rate of adverse events attributed to daptomycin was 1.4%.

“In comparison to other MRSA agents recommended by IDSA, including vancomycin, linezolid and telavancin, daptomycin has the most potent bactericidal activity against staphylococci, which is the most common diabetic foot infection,” reported senior author of this study, Dr. Alberto Cogo, Casa Di Cura V Berica, Vicenza, Italy. Based on these results he called daptomycin an “attractive option,” which are terms similar to those used by Dr. Zaragoza in discussing linezolid. While direct comparisons of these agents have not been carried out, both investigators suggested that a high rate of efficacy and a low risk of adverse events provide a reason to revisit the use of vancomycin as an automatic choice in MRSA.

Summary

The IDSA guidelines are a useful evidence-based tool for identifying the most effective therapies in the treatment of MRSA. However, when multiple therapies are given the highest evidence-based designation, it is appropriate to consider relative differences, particularly when infections are life-threatening. Vancomycin has been a standard in MRSA since this infection was first identified, but there are now multiple alternatives for specific types of MRSA, many of which appear to be at least as effective, safer and may provide more predictable benefits. Studies at this year’s ICAAC involving MRSA bacteremia and MRSA diabetic foot infections, 2 common and challenging types of such infections, underscore evolving treatment choices and a reason to consider newer agents.