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PRIORITY PRESS - Association of Medical Microbiology and Infectious Disease Canada- Canadian Association for Clinical Microbiology and Infectious Diseases (AMMI-CACMID) Annual Conference

Montreal, Quebec / April 7-9, 2011

Staphylococcus aureus is the most common cause of pneumonia among patients in Canadian intensive care units (ICUs) or surgical wards, accounting for about a quarter of cases. Methicillin-resistant S. aureus (MRSA), which demonstrates resistance to penicillins, cephalosporins, monobactams and carbapenems, is an increasingly frequent cause of nosocomial infections worldwide. In the US, the proportion of isolates from ICU patients identified as MRSA has increased steeply in the last 4 decades: from 2% in 1974 to 22% in 1995 and 64% in 2004 (Klevens et al. Clin Infect Dis 2006;42:389-91). “Today, it’s somewhere around 75% to 80%,” noted Dr. Ethan Rubenstein, Head, Infectious Diseases, University of Manitoba, Winnipeg, here at AMMI-CACMID.

Although clinicians have traditionally distinguished community- and hospital-acquired MRSA, “the epidemiologic distinction between [the strains] is blurring and we now have transmission of community-acquired strains in hospital and we often see hospital-acquired strains circulating in the community,” remarked Dr. Andrew Simor, Head, Microbiology and Infectious Diseases, Sunnybrook Health Sciences Centre, Toronto, Ontario. Added Dr. Rubenstein, “It’s likely in the future some other nomenclature will come out which will truncate the connection to where the infection was acquired.”

Early Empiric Therapy Crucial

The risks and complications associated with hospital-acquired pneumonia (HAP) or MRSA pneumonia call for early therapy covering all possible pathogens. Treatment should be modified once the causative organism is identified. Treatments with lower incidences of bacterial resistance can help minimize delays in therapeutic efficacy, complications of add-on therapy such as increased toxicity and drug interactions, overall costs, adverse outcomes and further transmission, commented Dr. Daniel Thirion, Clinical Associate Professor of Pharmacy, Université de Montréal, Quebec. Several studies have demonstrated that mortality in critically ill ICU patients with infections is approximately doubled when initial antimicrobial therapy is inappropriate. Canadian investigators recently determined that the mortality risk of patients in septic shock increases with each hour of delay in appropriate therapy by 6.8% (Kumar et al. Crit Care Med 2006;34:1589-96). “You don’t have the luxury of waiting for culture results before initiating appropriate therapy in patients who are at high risk of complications,” emphasized Dr. Thirion.

Guidelines issued this year by the Infectious Diseases Society of America (Clin Infect Dis 2011;52:285-92) confirm that coverage for MRSA is appropriate for any patient entering the ICU, as well as those who have necrotizing pneumonia or cavitary infiltrates or empyema. The guidelines recommend vancomycin (15 to 20 mg/kg/q 8-12h, aiming for trough levels of 15 to 20 µg/mL) or linezolid (600 mg q 12h) for HAP or MRSA pneumonia, Dr. Thirion stated. Some studies have indicated rifampin may be of use in HAP, particularly in combination with vancomycin. This agent should not be used as monotherapy due to rapid emergence of resistance, he remarked. Evidence for the use of clindamycin is weaker and primarily from pediatric sources. Tigecycline is effective in HAP but not ventilator-associated pneumonia; it comes with a warning of an increase in all-cause mortality of 0.6% (95% CI, 0.1-1.2) over comparator-treated patients determined from a pooled analysis of 13 phase III and IV studies, Dr. Rubenstein added. Telavancin, a new agent, is approved in Canada for treatment of skin and soft tissue infection caused by gram-positive organisms, but not for pneumonia.

Some data suggest that there may be advantages to the use of linezolid over vancomycin, at least in certain patients, Dr. Thirion commented. A phenomenon known as “MIC creep,” the gradual increase in the minimum drug concentration able to inhibit S. aureus, has been reported with vancomycin. “There has been a steady increase in the number of strains with a MIC of 1 and a decrease of the more sensitive strains,” he told delegates. Increasing MIC may lead to unfavourable outcomes, including an increased risk of mortality. The use of vancomycin at the higher dose and trough levels now recommended may increase the risk of nephrotoxicity, he added.

Dr. Simor agreed that linezolid may be a better first-line choice for patients with renal failure or fluctuating renal function. “Whenever you are in that kind of setting you know you are at much higher risk of vancomycin toxicity and it is much harder to ensure that you have adequate dosing... So I think that is a subset [of patients] who would clearly benefit from treatment with linezolid.” Other patients who might benefit are those with community-acquired pneumonia, in which the Panton-Valentine leukocidin (PVL) genotype is a concern. This protein contributes to tissue necrotization and is widely believed to increase MRSA mortality. Dr. Simor explained to delegates, “PVL is a protein or toxin that is mediated through ribosomal protein production and by inhibiting it, you might actually reduce levels of PVL and thereby come up with a better outcome.... This is purely theoretical but it is something to consider.”

MRSA Trials

A recent large-scale, double-blind phase IV study, ZEPHyR, compared the efficacy and safety of linezolid and vancomycin given for 7 to 14 days in patients with severe HAP. It evaluated 448 patients with culture-positive MRSA, 348 of whom were evaluable at end of study. The primary end point was clinical response in the evaluable MRSA subjects at the end-of-study visit (7 to 30 days after the end of antibiotic treatment). At the end of the study, significantly more linezolid-treated patients than those receiving vancomycin were deemed to have been treated successfully or cured (57.6% vs. 46.6%, P=0.042). Microbiological analysis confirmed that eradication or presumed eradication of MRSA was higher in patients receiving linezolid. Mortality over 60 days did not differ in the 2 treatment groups. Safety findings were also similar. Given the relatively short treatment duration, the adverse effects associated with linezolid (e.g. anemia, thrombocytopenia, neuropathy) were not observed. “It looks like up to 2 weeks of therapy with linezolid is fairly safe,” Dr. Rubenstein remarked.

The ATTAIN studies of telavancin (Rubenstein et al. Clin Infect Dis 2011;52:31-40) demonstrated that this agent is non-inferior to vancomycin in the treatment of HAP. These double-blind, international, multicentre phase III trials compared the clinical efficacy and safety of telavancin and vancomycin, given for up to 21 days, in 1503 patients with gram-positive HAP (especially MRSA, which was identified in 56% of telavancin-treated patients and 65% of vancomycin-treated subjects). The investigators reported that results at the test-of-cure visit, conducted up to 2 weeks after antibiotic treatment ended, were not statistically or clinically different in the 2 treatment groups. Among clinically evaluable patients (n=654), for example, 82.4% and 80.7% of patients in the telavancin and vancomycin groups, respectively, had a clinical response. In patients with confirmed MRSA, 74.8% and 74.7% of the groups had treatment success/cure. Subpopulation analysis suggested that telavancin may have been slightly more effective in sicker patients (e.g. those with an APACHE score >20, acute lung injury or respiratory distress syndrome, or bacteremia) but none of these results were statistically significant. Higher cure rates were observed with telavancin in patients with a vancomycin MIC =1 mg/mL (P=0.03). There was no survival advantage to either agent. Although the incidence of common adverse events was generally similar, renal impairment was more frequent in the telavancin group, as was discontinuation due to adverse events.

A common finding in these recent studies was that increasing vancomycin dose to reach higher trough levels for patients with S. aureus with MIC >1.5 was ineffective, Dr. Rubenstein stressed. “Antibiotic failure was more common in those with higher trough levels of vancomycin... the death rate was doubled and the cure rate was correspondingly low. So we could not confirm the fact that increasing the dose and having high vancomycin troughs would be accompanied by better results for MRSA pneumonia.”

Summary

“MRSA continues to be responsible for an absolutely enormous burden of disease in Canada. It is on the rise both in hospital settings and in the community.... We need to take advantage of improved treatment modalities, and that includes newer drugs.... And we need to ensure that we use these drugs wisely and appropriately, as indicated. Likewise, we need to be doing a better job of trying to reduce the risk in terms of better preventive measures,” commented Dr. Simor.