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Higher doses of daptomycin associated with lower mortality among VRE patients

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February 6, 2017

The mortality rate of patients with vancomycin-resistant enterococci bloodstream infections who were treated with daptomycin was lower among those who received a dose greater than 9 mg/kg compared with those who received a smaller dose, according to recent study findings.

“A higher daptomycin dose remained significantly associated with lower mortality even when adjusted for steroid use, disease severity and platelet counts,” Yu-Chung Chuang, MD, MS, of the Graduate Institute of Clinical Medicine, College of Medicine at the National Taiwan University and the department of internal medicine at the National Taiwan University Hospital, and colleagues wrote in Clinical Infectious Diseases. “These findings suggest that daptomycin doses greater than the customary dose of 6 mg/kg should be considered for the treatment of [vancomycin-resistant enterococci (VRE)] bacteremia.”

Since they were first described in 1986, VRE have emerged as critical pathogens for nosocomial infections, but treatment options remain limited, according to the researchers. They reported that daptomycin has become an “attractive treatment option” and is frequently used even though it is not approved by the FDA for this indication. An optimal dose, however, has yet to be determined. Therefore, Chuang and colleagues conducted a prospective observational cohort study to compare the outcomes of patients receiving different doses of daptomycin.

The study included 112 adult patients infected with Enterococcus faecium who were treated at the National Taiwan University or its Yun-Lin branch from January 2010 to July 2015. The primary outcome was 14-day mortality. Secondary outcomes included microbiological failure (defined as VRE isolated 4 days or more after onset or death within 7 days without VRE clearance), clinical failure (defined as 14-day mortality or microbiological failure) and creatinine kinase elevation.  

Most VRE isolates collected from patients were susceptible to daptomycin at a MIC of 4 mg/L (69.6%). The remainder were susceptible at a MIC of 2 mg/L or less. The overall 14-day mortality rate was 35.7%, and approximately half of patients experienced microbiological failure (55.4%) or clinical failure (50.0%).

The unadjusted mortality rate was 20% among those who received a dose of daptomycin greater than 9 mg/kg vs. 33.3% among those who received 7 mg/kg to 9 mg/kg and 50% among those who received less than 7 mg/kg (P = .05). Additional analyses further demonstrated that the best outcomes were observed with doses greater than 9 mg/kg vs. doses less than 7 mg/kg (adjusted odds ratio [aOR] = 10.57; 95% CI, 2.25-49.62) and 7 mg/kg to 9 mg/kg (aOR = 5.01; 95% CI, 1.14-21.98). The odds of VRE-related mortality decreased 40% with each dose increase (aOR = 0.60; 95% CI, 0.42-0.87), but daptomycin MIC did not have a significant impact, according to the researchers.

“Theoretically, both the daptomycin dose and the daptomycin MIC should affect the [pharmacodynamic] parameter of AUC/MIC,” they noted. “In this study, however, we did not find an independent association between the daptomycin MIC and patient mortality.”

Median daptomycin doses were similar between the microbiological failure group and the nonfailure group (7.8 mg/kg vs. 7.6 mg/kg). In addition, there was no significant relationship between daptomycin dosing and elevated creatine kinase (CK) levels, but the researchers urged physicians to monitor CK levels until an optimal dose is officially established.

“High-dose daptomycin appeared to be safe and should be considered for the treatment of bacteremia caused by daptomycin-susceptible VRE,” they concluded. “Further studies, including controlled clinical trials, are needed to ensure the safety and efficacy of a daptomycin dose of ≥9 mg/kg compared to the customary dose (6 mg/kg) used for the treatment of VRE bacteremia.” – by Stephanie Viguers

Disclosure: The researchers report no relevant financial disclosures.

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PERSPECTIVE
Jason Burnham
Jason Burnham

In this interesting prospective observational cohort study from Taiwan, Chuang and colleagues demonstrate that high-dose daptomycin (≥9 mg/kg) was associated with lower mortality in patients with vancomycin-resistant enterococci bloodstream infections. Previous studies have suggested that daptomycin doses of 10 mg/kg/day might be required to prevent the emergence of daptomycin resistance in enterococci. Additionally, prior studies have suggested that elevated daptomycin minimum inhibitory concentrations (MIC) might be associated with worse clinical outcomes. However, daptomycin MICs are notoriously difficult to determine due to heterogeneity of confirmatory testing methods. Fortunately in the present study, the authors used broth microdilution for daptomycin MIC determination, which is less prone to errors.

The authors evaluated whether daptomycin MIC was related to clinical outcome and found that only daptomycin dose, not daptomycin MIC, was associated with mortality. This is interesting and may be a reflection of an increased barrier to daptomycin resistance with higher doses of daptomycin.

Prospective trials are required to compare the effect of daptomycin dose on clinical outcomes, but this study is informative and may be a gateway to major practice changes for daptomycin dosing. As a segue to prospective clinical trials, the authors of this study found no increase in daptomycin-related side effects at higher doses, which should reassure clinicians in the future.


Jason Burnham, MD
Infectious disease fellow, department of internal medicine, Washington University School of Medicine, Barnes-Jewish Hospital
Disclosure: Burnham reports no relevant financial disclosures.