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.

48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/Infectious Disease Society of America 46th Annual Meeting

Washington, DC / October 25-28, 2008

According to the US Centers for Disease Control data as recent as August 2007, upwards of 63% of hospital- and healthcare-associated S. aureus infections now fall into the methicillin-resistant S. aureus (MRSA) category. Dr. Robert C. Moellering, Jr., retired Harvard Medical School Herrman Ludwig Blumgardt Professor of Medicine and former Physician-in-Chief and Chair, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, noted that MRSA’s pathogenic “success” is attributed to its genetic diversity and ability to acquire new exogenous genes. It has the ability to establish asymptomatic carriage, thus permitting widespread dissemination among human hosts, and a remarkable propensity to acquire resistance to multiple antimicrobial agents.

Vancomycin Reduced Susceptibility

According to a study presented here by Lewis et al., the minimum inhibitory concentration (MIC) value of vancomycin is an important factor for choice of antibiotic treatment for MRSA bacteremia. Findings showed that in adult patients with MRSA bacteremia treated with vancomycin, a MIC <u>></u>1 µg/mL was associated with microbiologic failure and overall failure with the same MIC and mechanical ventilation.

A study led by Yamamura and colleagues determined that reduced suceptibility to vancomycin increased from 2006 to 2007 in four regions in Ontario and observed that tolerance occurred at 12.6% and was more frequent in isolates with vancomycin MIC of 2 µg/mL.

MRSA Canadian Prevalence Data

It is established that community-acquired (CA) and hospital-acquired (HA)-MRSA differ in their genotypic and phenotypic characteristics. According to the national CANWARD study 2007, from 385 MRSA isolates collected, CA-MRSA accounted for 19.2% of all MRSA and 95.9% were Panton-Valentine leukocidin (PVL)-positive while all HA-MRSA were PVL-negative. The study authors concluded that CA-MRSA is an emerging pathogen in Canadian hospitals.

At the Hospital for Sick Children in Toronto, Ontario, Phongsamart and colleagues reviewed medical records of patients with MRSA from 1996 to 2007. The first detected case of CA-MRSA occurred in 1998 and now accounts for 34.1% of new MRSA in 2007. Over the study period, the HA-MRSA rate increased from 0.09 to 0.87 cases per 1000 admissions. This study echoes the increase of both CA- and HA-MRSA in healthcare institutions. However, the authors noted that CA-MRSA strains are predominantly CMRSA-10 clones and cause more skin and skin structure infections (SSSIs) in healthy children.

New MRSA Treatment Guidelines

New MRSA treatment guidelines are scheduled to be released in the summer of 2009. Dr. Catherine Liu, Assistant Clinical Professor, University of California, San Francisco, and co-chair of the IDSA panel developing these recommendations, previewed the direction the new treatment guidelines are taking.

To address vancomycin reduced susceptibility and efficacy, other agents are being recommended as first-line therapies for moderate to severe MRSA infections.

• Complicated MRSA SSSIs and necrotizing fasciitis. Along with surgical evaluation and debridement, empiric therapy is recommended awaiting culture data. Recommended therapies for adults are vancomycin, daptomycin or linezolid, with no significant difference in primary outcome of clinical cure. Clinical outcomes for daptomycin used to treat complicated SSSIs were reported by Arbeit et al. (Clin Infect Dis 2004;38(12):1673-81).

• Recurrent MRSA SSSIs. Education, wound draining and coverage, and education focusing on personal and environmental hygiene are recommended along with a possible role for decolonization in selected individuals. Oral antibiotics are not routinely recommended; the draft guidelines cite lack of evidence of benefit and potential for toxicity and resistance.

• MRSA bacteremia and endocarditis. The draft recommendations call for vancomycin or daptomycin 6 mg/kg i.v. once daily, the latter based on efficacy established in a phase III clinical trial reported by Fowler et al. (N Engl J Med 2006;355: 653-65). Higher doses of daptomycin 8 to 10 mg/kg i.v. once daily are given a weak recommendation, backed by evidence that doses of up to 12 mg/kg were tolerated in healthy volunteers over a two-week duration (Heart Lung 2006;35(3):207-11, Antimicrob Agents Chemother 2006;50:3245-9). The draft guidelines specifically recommend against combination therapy—adding gentamicin or rifampicin to vancomycin—due to lack of benefit and increased risk of nephrotoxicity or hepatotoxicity.

• Pneumonia. Empiric MRSA treatment with vancomycin or linezolid 600 mg b.i.d. are recommended in patients with severe community-acquired pneumonia with preceding influenza-like illness, necrotizing or cavitary infiltrates, or requiring ICU admission. Daptomycin is not indicated for pneumonia because it is inactivated by alveolar surfactant fluid.

The guidelines will also address vancomycin dosing considerations, including the possibility of a loading dose in seriously ill patients. They will seek to determine optimal management of isolates with reduced susceptibility to vancomycin and vancomycin treatment failures.

Elevated MIC in the 1.5 to 2 µg/mL range are associated with vancomycin treatment failures and the guidelines recommend an alternative therapy for isolates with a vancomycin MIC >2 µg/mL. However, as Dr. Liu noted, a “MIC creep” has been observed among MRSA isolates. In light of this development, and given the limitations of current susceptibility testing methods, the guidelines will strongly recommend that MIC results be correlated with clinical and microbiologic data.

CORE Data

Data from the Cubicin Outcomes Registry and Experience (CORE) database reviewed outcomes and clinical factors associated with daptomycin treatment of infective endocarditis from a variety of pathogens in 41 evaluable patients, nine with right-sided and 28 with left-sided disease. The most common primary pathogens were S. aureus (n=20, 85% MRSA), enterococci (n=8, 25% vancomycin-resistant) and viridans group streptococci (n=4). The treatment success rates by valve were aortic (85%), tricuspid only (89%), mitral only (63%) and nonvalvular or unreported (100%). Regardless of the valve infected, none of the cases considered as treatment failures received surgery, and surgically treated patients were classified as successes. Investigators concluded that while daptomycin appears effective against a variety of clinical presentations of infective endocarditis, the data support surgical intervention to optimize outcomes and further studies on left-sided infective endocarditis are warranted.

In another CORE analysis presented here, Forrest et al. reviewed use of daptomycin in 90 evaluable patients with gram-positive catheter-related bacteremia. Enterococci were identified in 40% of blood isolates in this cohort. Overall, 81% of patients had a single gram-positive organism isolated, 19% had <u>></u>2. Clinical success (cure or improvement) was achieved in 93% of patients overall and was similar in patients with monomicrobial vs. polymicrobial infection and among various monomicrobial pathogens: 93% for S. aureus, 97% for coagulase-negative staphylococcus species and 92% for enterococci.

Dr. Donald M. Poretz, Clinical Professor of Internal Medicine, Georgetown University Medical School, Washington, DC, noted that besides efficacy and safety, factors such as tolerability and cost must be considered when selecting an antibiotic. He cited a prospective trial by Davis et al. comparing clinical and economic outcomes of inpatients treated between daptomycin and vancomycin for complicated SSSI. Patients in the daptomycin arm (n=53) achieved a faster clinical cure than did a matched cohort of 212 patients receiving vancomycin treatment. This resulted in both a decreased treatment duration (4 vs. 7 days) and lower cost ($5027 vs. $7552) for daptomycin compared with vancomycin (P<0.001 for both comparisons) (Pharmacotherapy 2007;27(12):1611-8).

In Dr. Poretz’ experience, when compared with vancomycin, daptomycin is very nonirritating to the vein when infused and can be given through smaller lines. “It’s easier to use on an outpatient basis.” It can go in over 30 minutes, whereas vancomycin requires over an hour and has many associated toxicities, he remarked. However, daptomycin while better tolerated, requires monitoring of CPK function.

Summary

The distinction is blurring between CA-MRSA and HA-MRSA and hospitals are now obligated to employ better surveillance and infection control to reduce morbidity, mortality and cost. The published guidelines help direct this effort. New MRSA treatment guidelines will place greater reliance on susceptibility testing and use of alternative treatment agents, including daptomycin, to treat vancomycin treatment failures and refractory disease.