vancomycin treatment

August 25, 2008 — Lower minimal inhibitory concentrations (MICs) than the US Food and Drug Administration (FDA) has used as breakpoints may predict vancomycin treatment failure against methicillin-resistant Staphylococcus aureus (MRSA) infections, according to the results of an observational cohort study published online June 30, 2008, for the September print issue of Antimicrobial Agents and Chemotherapy. Lowering these breakpoints could encourage needed research and development of new antimicrobial agents.

"Physicians are mistakenly of the belief that vancomycin is the most powerful, most potent drug available for gram-positive infections," Barry Eisenstein, MD, clinical professor of medicine at Harvard University Medical School in Boston, Massachusetts, and senior vice president of scientific affairs at Cubist Pharmaceuticals, Lexington, Massachusetts, said in a teleconference August 21, 2008. "This study was truly the smoking gun showing us that we must be much more careful about how we use drugs like vancomycin."

Although vancomycin became the drug of choice for MRSA and is still widely used for this indication, previous studies suggest that when vancomycin MIC values are at the high end of the susceptibility range (≥1.5 mg/L), vancomycin is less effective against MRSA. However, these studies have been criticized on the grounds that patients with vancomycin MIC values of 1.5 mg/L or higher may have been sicker than those with lower MIC values.

"Our study is the first to rigorously control for confounding variables," said lead author Thomas P. Lodise, MD, associate professor of Pharmacy Practice at Albany College of Pharmacy, New York. "We looked at patients with MRSA treated appropriately within 48 hours with vancomycin, stratified them based on vancomycin MIC [values] less than or equal to 1 or greater than or equal to 1.5, and compared outcomes."

Between January 2005 and May 2007, data regarding demographic factors, comorbid conditions, microbiology, and antibiotic exposure data were collected on 105 adult patients with MRSA bloodstream infections who met inclusion criteria. Etest was used to determine vancomycin MICs, and stepwise logistic regression identified independent predictors of high vancomycin MICs.

Vancomycin MIC values were 1.5 mg/L or higher in 73.3% of patients (77 of 105). Independent predictors of high MICs were prior vancomycin exposure within 30 days of index culture collection (15 patients [19.5%] vs 1 patient [3.6%]; P = .05) and being in an intensive care unit (ICU) at the onset of infection (27 patients [35.1%] vs 3 patients [10.7%]; P = .02).

The only variable differing between the 2 groups at baseline with a P value of less than .2 that predicted treatment failure with vancomycin was baseline creatinine clearance levels of 33 mL/min or lower, which was actually more prevalent in the low-MIC group. This would actually tend to bias the findings toward seeing no difference in outcomes between groups with vancomycin MIC values of 1 or lower or 1.5 or higher.

"Outcomes were significantly worse in the higher vancomycin MIC group, even though the groups were very well matched for clinical factors at baseline," Dr. Lodise said. "If anything, some of the factors usually associated with treatment failure were more pronounced in the low MIC group."

Compared with patients with MRSA bloodstream infection and vancomycin MIC values less than 1, those patients with MIC values of 1.5 or higher had a greater likelihood of treatment failure, longer duration of bacteremia, greater likelihood of recurrence, and longer duration of hospital length of stay. Treatment success rates were no better in patients with higher vancomycin troughs of 15 mg/L or more.

"Even patients with adequate vancomycin trough levels in the higher MIC group had a very low probability of success, which tells us there is something special about these organisms," Dr. Lodise said. "The organisms with higher MIC are less responsive to vancomycin, so pushing the dose is not really an option because of decreased efficacy and increased nephrotoxicity."

On the basis of these findings, the investigators concluded that patients with MRSA bloodstream infections in the ICU or who had a history of vancomycin exposure should be considered at high risk for infection with MRSA strains having high vancomycin MICs and should receive appropriate and aggressive empirical therapy.

"Within the susceptibility range there is a gradient of response," Dr. Eisenstein said. "There is an extraordinarily large range of organisms that by current criteria look like they are susceptible, but in terms of treatment success, they are ineffective."

The investigators therefore recommend considering nonvancomycin anti-MRSA treatment for patients with vancomycin MIC values of 1.5 mg/L or higher and lowering the vancomycin susceptibility breakpoint for MRSA bloodstream infection from MIC values of 2.0 mg/L or lower to 1.0 mg/L or lower.

Limitations of this study include collection of MRSA blood culture data from a single site, potentially reducing generalizability of the findings; exclusion of patients with neutropenia; and large number of bivariate tests performed, increasing the likelihood that 1 or more of the "significant" results are false-positive. In addition, most strains had MIC values of 1.5 mg/L, suggesting that 1 or several clones could be driving the observed relationship between vancomycin MIC and treatment failure at the study institution.

In response to questions posed by Medscape Infectious Diseases, Dr. Eisenstein described a "perverse paradox" acting on 2 fronts to suppress research and development of new antimicrobial agents — both supply versus demand and regulatory policies regarding new drug approval.

"We need to practice antibiotic stewardship and reserve the best and most potent antibiotics for those patients who truly need them," Dr. Eisenstein said. "This helps on the demand side but hurts on the supply side, because the tendency of physicians not to use newly developed antibiotics with fewer resistance issues means that pharmaceutical companies will take too many years to recoup their initial investment."

The second front also tends to suppress pharmaceutical development of new antimicrobials: because the FDA recognizes growing issues with resistance to vancomycin, it now requires that new antibiotics seeking approval must show a vanishingly small degree of inferiority to vancomycin in clinical trials. The smaller the required noninferiority margin, the larger the size and the higher the costs of the needed clinical trial.

"Studies like this can be used to awaken Congress to not be complacent about the value of old antibiotics, which is depreciating, and can also be used to encourage pharmaceutical companies to invest in new drugs," Dr. Eisenstein concluded.

Cubist Pharmaceuticals, makers of daptomycin, supported this study via a grant for which Dr. Lodise was the principal investigator. The other authors have disclosed no relevant financial relationships.

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