SAN DIEGO (FRONTLINE MEDICAL NEWS) – Among patients with vancomycin-resistant Enterococcus bloodstream infections, delay of treatment with linezolid or daptomycin for three days or more increased the morality risk by 39%, a nationwide retrospective cohort study demonstrated.

In addition, propensity score matching revealed that treatment with linezolid was associated with an increased mortality, compared with daptomycin.

“Based on these findings, we believe daptomycin should be the treatment of choice for patients with vancomycin-resistant Enterococcus (VRE) bacteremia and that early initiation is associated with improved survival,” lead study author Nicholas S. Britt, Pharm.D., said in an interview in advance of the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.

Prior to the current study, linezolid and daptomycin were considered equivalent in terms of clinical outcomes for vancomycin-resistant Enterococcal (VRE) bacteremia, said Dr. Britt, of Barnes-Jewish Hospital/Washington University Medical Center, St. Louis, Mo. “However, the studies that had compared these agents were small and may not have had enough patients enrolled to find an outcomes difference between the two agents if one existed.”

In an effort to evaluate the effect of time to treatment with linezolid or daptomycin on 30-day mortality and to compare clinical outcomes between linezolid and daptomycin while accounting for time to treatment and potential treatment selection bias, the researchers conducted a nationwide retrospective cohort study of hospitalized Veterans Affairs patients treated with linezolid or daptomycin for VRE BSI between 2004 and 2014. They included all adult patients with at least one blood culture positive for VRE who were treated with at least one dose of linezolid or daptomycin. Classification and regression tree (CART) analysis was performed to identify the most significant time to treatment breakpoint for the primary outcome, which was 30-day mortality. To account for treatment selection bias, propensity scores were derived and 1:1 matching was performed.

A total of 851 patients were evaluated: 426 in the linezolid group and 425 in the daptomycin group. CART analysis demonstrated a significant time to treatment breakpoint for 30-day mortality of 80 hours or more (RR 1.39; P less than .001). After propensity score matching, treatment with linezolid was significantly associated with 30-day mortality (RR 1.16; P =.018). This association persisted in propensity score adjusted binomial regression (adjusted RR, 1.25; P =.014) and Cox regression (hazard ratio 1.73; P less than .001). There was no difference between the two agents in terms of adverse effects.

“In this evaluation, we found that every hour delay in initiation of anti-VRE therapy was associated with an increased risk of death,” Dr. Britt said. “Delays in therapy of greater than 3 days were associated with the greatest risk of mortality, but overall, the sooner anti-VRE therapy was initiated, the better the patients did.” He went on to note that some debate exists among clinicians “as far as the virulence of VRE and the true impact of VRE bacteremia on patient outcomes. We were surprised that the time to treatment effect was so pronounced and that this effect persisted independent of other patient factors.”

Dr. Britt acknowledged certain limitations of the study, including the potential for bias due to its retrospective design. “However, attempts at clinical trials comparing these two agents have failed in the past due to poor enrollment,” he said. “Other potential limitations are with regard to generalizability to non-VA patient populations. This study featured a relatively low number of stem cell and solid organ transplant recipients and further research in these populations are warranted.”

The study was funded in part by the National Institutes of Health and the Department of Veterans Affairs. The researchers reported having no financial disclosures.


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