Authors: Harrison Yoon, PharmD Candidate 2020 and Julianne Yeary, Pharm.D.
Vancomycin-resistant enterococcus (VRE) is an emerging drug-resistant organism responsible for increasing numbers of hospital-acquired infections. It readily colonizes the intestines without any symptoms, which can serve as an infection reservoir and spread quickly among hospitalized patients.1 In 2013, the Centers for Disease Control and Prevention (CDC) estimated 20,000 cases of nosocomial VRE infections in the United States with 1,300 cases resulting in death.2
VRE bacteremia is associated with significant mortality rates and prolonged hospital stays.3,4 Limited treatment options are available for VRE bacteremia. IDSA Guidelines recommend both daptomycin and linezolid as first-line agents for the treatment of VRE bacteremia,5 but clear distinction of therapeutic outcomes between the two therapies is still lacking.
Risk Factors for VRE Bacteremia
Patient populations at risk for VRE bacteremia include those with previous VRE colonization, hematologic malignancy, hemodialysis, neutropenia, mucositis, recent surgery, indwelling catheters, previous antibiotic therapy, use of immunosuppressive agents, and organ transplantation.6
Toxicity Profile of Linezolid and Daptomycin
Linezolid is known to have a number of toxicities and drug interactions with its use. Notable toxicities include thrombocytopenia, neutropenia, lactic acidosis, peripheral and optic neuropathy, and increased liver enzymes.7 Serotonin syndrome can also be seen in patients receiving concomitant serotonergic agents because linezolid exhibits low monoamine oxidase (MAO) inhibition.
Daptomycin is associated with increases in creatine kinase (CK) levels which can result in muscle pain/weakness and rhabdomyolysis. Cases of eosinophilic pneumonia have also been reported with prolonged daptomycin use.8
Clinical Efficacy of Linezolid and Daptomycin
A 2015 multicenter, retrospective cohort study by Britt and colleagues compared the effectiveness of linezolid vs. daptomycin in the Veteran Affairs healthcare system. The primary outcome was clinical failure defined as a composite of 30-day all-cause mortality, microbiologic failure, and 60-day recurrence of VRE bacteremia. Linezolid was associated with a higher risk of treatment failure (risk ratio: 1.37; 95% CI 1.13-1.67; p=0.011), higher 30-day mortality rates (42.9% vs. 33.5%; RR: 1.17; 95% CI: 1.02-1.30; p=0.026), and higher microbiologic failure rates (RR: 1.10; 95% CI: 1.02-1.18; p=0.011) compared to daptomycin. No difference in 60-day VRE bacteremia recurrence was observed between the two therapies. Standard daptomycin dosing of 6 mg/kg was used in the majority of patients. Duration of treatment differed between the groups, as the linezolid group received a median treatment duration of 7 days and daptomycin group received a median treatment duration of 11 days, but the results discussed above were controlled for treatment duration.9
A single-center, retrospective cohort study by Narayanan and colleagues evaluated the clinical effectiveness of linezolid and daptomycin in 93 patients with VRE bacteremia between 2012 and 2016. The primary outcome was clinical failure defined as a composite of 14-day mortality, microbiologic failure, or relapse of VRE bacteremia. Overall, patients treated with daptomycin had a significantly higher rate of clinical failure compared to patients treated with linezolid (74.2% vs. 46.8%, p=0.01). Individual outcomes of 14-day mortality, microbiologic failure, and relapse of VRE bacteremia were worse in patients treated with daptomycin, but not statistically significant. Daptomycin dosing remained stable throughout the patient population at a standard dose of 6 mg/kg, and the treatment duration was undisclosed for both therapies.10
A systematic review and meta-analysis of ten retrospective studies that does not include the studies discussed previously was published in 2014 by Balli and colleagues. A total of 967 patients were identified, and the primary outcome was 30-day all-cause mortality. Patients treated with daptomycin showed significantly higher 30-day all-cause mortality (OR: 1.61; 95% CI: 1.08-2.40) and overall mortality (OR: 1.41; 95% CI: 1.06-1.89) compared to linezolid patients. The median daptomycin dose was 6 mg/kg in six studies, 5.5 mg/kg in one study, and not reported in the remaining three studies.11
High-Dose vs. Standard-Dose Daptomycin
Therapeutic outcome differences between high-dose daptomycin and standard-dose daptomycin in VRE bacteremia should also be addressed. A 2016 prospective cohort study compared mortality rates of VRE bacteremia treated with high-dose daptomycin (>9 mg/kg) vs. standard dose daptomycin (6 mg/kg) vs. linezolid. Use of high-dose daptomycin correlated to a significantly lower all-cause 14-day mortality compared to standard dose daptomycin (OR: 0.76; 95% CI: 0.59-0.98; p=0.03). There were no significant differences in adverse events between the high-dose and the standard-dose daptomycin groups. The study also found had lower mortality rates in the linezolid group compared to the standard-dose daptomycin group (aOR: 0.34; 95% CI: 0.14-0.79; p=0.01) and compared to all patients receiving daptomycin regardless of dose (aOR: 0.39; 95% CI: 0.18-0.85; p=0.02). The linezolid group did not show a statistically significant difference in terms of mortality when compared with high-dose daptomycin patients alone (aOR: 0.98; 95% CI: 0.14-7.03; p=0.99).12
In contrast to other literature discussed, Britt and colleagues found that linezolid use was associated with higher treatment failure compared to daptomycin. This may be due to a number of reasons. The linezolid group had a higher percentage of ICU admissions compared to the daptomycin group (83.5% vs. 70.5%), indicating that linezolid may have been used in more critically ill patients. Also, a higher percentage of linezolid patients were above the age of 65 compared to daptomycin group (54.9% vs. 46.2%),12 which likely contributed to the higher mortality and microbiologic failure rates seen. As stated, both retrospective cohort studies discussed utilized a standard daptomycin dose of 6 mg/kg for a majority of their patients.
Optimal daptomycin dosing in VRE bacteremia is critical. Daptomycin exhibits dose-dependent bactericidal activity, so the standard daptomycin dose of 6 mg/kg may not be sufficient to induce sustained bactericidal activity to eradicate enterococcal bloodstream infections. Further studies to elucidate daptomycin dose-efficacy relationships may be an important step towards suggesting high-dose daptomycin as initial therapy for VRE bacteremia.
Linezolid and daptomycin are first-line options for VRE bacteremia. Although linezolid and daptomycin have notable differences in toxicities, literature regarding their comparative clinical efficacy is somewhat conflicting. A meta-analysis suggests slightly more favorable outcomes with linezolid compared to daptomycin, but definitive conclusions are difficult to make due to the insufficient daptomycin dosing in the majority of the studies included.
In summary, current literature favors linezolid over daptomycin in the treatment of VRE bacteremia, but clear evidence to support one agent over the other is lacking. High-dose daptomycin and linezolid have shown similar results, and both seem to be superior to standard-dose daptomycin. Choosing between high-dose daptomycin and linezolid should be individualized based on patient-specific factors such as severity of illness, concomitant infections, drug interactions, and tolerability to therapy.