Division of Infectious Diseases

What is the optimal dosing of daptomycin for VRE bacteremia?

This month’s #PharmToExamTable question was answered by Xiaoxiao (Monica) Qi, PharmD 2020 UNMC graduate who is pursuing a PGY1 Pharmacy Residency at Avera McKennan Hospital and University Health Center in Sioux Falls, SD.
It was reviewed by:
Scott Bergman, PharmD, BCPS, BCIDP – Antimicrobial Stewardship Coordinator at Nebraska Medicine and Clinical Associate Professor at UNMC College of Pharmacy
Andrew Watkins, PharmD – PGY2 Infectious Diseases Pharmacy Resident at Nebraska Medicine

In healthcare settings, infections due to vancomycin-resistant enterococci (VRE) are commonly encountered. Up to 31% of all enterococcal isolates are vancomycin-resistant in U.S. hospitals(1-4). Bloodstream infection caused by vancomycin-resistant enterococci (VRE) has been associated with higher morbidity, mortality, and prolonged hospital stay(2). Given that very few antibiotics with activity against VRE have been evaluated in the treatment of bacteremia clinically, the options for VRE bloodstream infection are limited. Thus, vancomycin-resistant enterococcal bloodstream infections (VRE-BSIs) are uniquely difficult to treat (5). Currently, only linezolid is approved by the US FDA for treating such a condition, but it does have a few limitations: linezolid resistance has emerged; prolonged use can lead to thrombocytopenia; it’s mechanism of action is bacteriostatic and the clinical success rate of treating VRE bacteremia varies. Recent clinical studies have shown improved clinical and microbiologic outcomes associated with daptomycin over linezolid in VRE-BSI (6).

Daptomycin is an antibiotic that is approved by the FDA for the treatment of bacteremia and right-sided infective endocarditis caused by Staphylococcus aureus (7). Daptomycin exhibits concentration-dependent bactericidal activity against gram-positive pathogens. The pharmacodynamic parameters of such activities are maximum concentration (Cmax)/minimum inhibitory concentration (MIC) or area under the concentration-time curve (AUC)/MIC ratios.5 Although it is not approved by the FDA for the treatment of bacteremia caused by Enterococcus spp., it has both in vitro and in vivo activity against this organism. It could be used in certain conditions, such as prolonged VRE bacteremia endocarditis, where a bactericidal agent is preferred. The usual dose of daptomycin for MRSA bloodstream infections is 6 mg/kg/day (7). However, VRE isolates generally demonstrate MICs 2- to 4-fold higher than those of S. aureus (5). The susceptible breakpoint of daptomycin for Enterococcus spp. has been ≤4 mg/L compared to <1 mg/L for Staphylococci (1). In 2019, The Clinical and Laboratory Standards Institute (CLSI) revised the interpretive criteria of daptomycin for Enterococcus faecium to be called “susceptible dose-dependent” (SDD) at MICs ≤4 mg/L. This is because of the epidemiological profile of the organism, new PK/PD data, emergence of daptomycin-resistant Enterococci, and clinical studies that rendered the previous interpretation of susceptible no longer appropriate for this species. The susceptible dose-dependent (SDD) category is used when susceptibility of an isolate depends on the dosing regimen used (8). For E. faecium, an increased daptomycin dosage of 8–12 mg/kg/day is recommended to treat the organism since it has naturally higher MICs and the pharmacokinetics(PK)/pharmacodynamics (PD) of daptomycin can be optimized with peak serum concentrations increasing linearly with the dose. 

Both in-vivo and in-vitro studies have demonstrated that using higher dosages of daptomycin increased both the degree and speed of bactericidal activity (1,5,7). One study compared in vitro activity of daptomycin at 6 vs. 10 mg/kg/day towards vancomycin-resistant Enterococcus faecium and showed that the higher dosage achieved a more rapid and greater reduction in bacteria (p 6 mg/kg) in two-hundred and forty-five patients were evaluated. Overall, 204 (83%) of all identified Enterococcus faecium were VRE. One-hundred and seventy-three patients (70.3%) had enterococcal bloodstream Infection. The median dose and duration of high dose-daptomycin was 8.2 mg/kg/day (IQR 7.7-9.7) and 10 days (IQR 6-15), respectively. The overall clinical success rate was 89% and microbiological eradication was observed in 93% of patients. This study showed that a high frequency of clinical success and microbiological eradication in patients treated with high-dose daptomycin for enterococcal infections, even in patients with complicated and difficult to treat infections. In terms of safety, no high-dose daptomycin regimen was discontinued due to an elevated CPK and all patients were asymptomatic (10).

Another retrospective cohort study on comparison of different doses for daptomycin has been done in patients hospitalized at Veterans Affairs facilities with VRE-BSI. Britt et al. compared standard-dose (6 mg/kg total body weight), medium-dose (8 mg/kg total body weight), or high-dose (≥10 mg/kg total body weight) daptomycin. A total of 911 patients were included (standard dose, n = 709; medium dose, n = 142; high dose, n = 60). Compared to high-dose daptomycin, both standard-dose and medium-dose daptomycin were associated with worse survival (adjusted HR [aHR], 2.58; P = 0.004). This association persists after adjustments of confounders. High-dose daptomycin was associated with significantly improved microbiological clearance. There was no difference in the risk of CPK elevation among the treatment groups. Despite the comparatively low number of patients that received high-dose daptomycin, the authors concluded that it was associated with improved survival and microbiological clearance in VRE-BSI (5).

A systematic review and meta-analysis was performed on the efficacy and safety of daptomycin versus linezolid in 2019. According to the sub-group analysis, high-dose daptomycin showed an increase in use from 6% in 2006 to 34% in 2012 and corresponding improved mortality benefits, which supports that a high-dose may be beneficial for the treatment of VRE bacteremia (11).

In conclusion, VRE isolates generally have MICs 2- to 4-fold higher than those of S. aureus and are now classified as “Susceptible Dose-Dependent” up to an MIC of 4 mg/L by the CLSI. Based on its concentration-dependent bactericidal activity, high-dose daptomycin (8-12 mg/kg) is needed to optimize pharmacodynamic (PD) parameters of Cmax and AUC over MIC. Current clinical data have shown that high-dose daptomycin is beneficial for the treatment of VRE bacteremia. Although high-dose daptomycin may raise a concern of more CPK elevation, it does not necessarily lead to more severe skeletal muscle toxicity or discontinuation of daptomycin.

References:
1. King EA, McCoy D, Desai S, Nyirenda T, Bicking K. Vancomycin-resistant enterococcal bacteremia and daptomycin: are higher doses necessary? J Antimicrob Chemother 2011 Sep 1;66(9):2112-8.
2. Sader HS, Jones RN. Antimicrobial susceptibility of Gram-positive bacteria isolated from US medical centers: results of the Daptomycin Surveillance Program (2007–2008). Diagn Microbiol Infect Dis. 2009;65:158-62.
3. Casapao AM, Kullar R, Davis SL, Levine DP, Zhao JJ, Potoski, B, et al. Multicenter study of high-dose daptomycin for treatment of enterococcal infections. Antimicrob Agents Chemother 2013 Sep 1;57(9):4190-6.
4. Wisplinghoff H, Bischoff T, Tallent SM, et al. Nosocomial Bloodstream Infections in US Hospitals: Analysis of 24,179 Cases from a Prospective Nationwide Surveillance Study. Clin Infect Dis 2004; 39: 309–17. https://doi.org/10.1086/421946
5. Britt NS, Potter EM, Patel N, Steed ME. Comparative Effectiveness and Safety of Standard-, Medium-, and High-Dose Daptomycin Strategies for the Treatment of Vancomycin-Resistant Enterococcal Bacteremia Among Veterans Affairs Patients. Clin Infect Dis 2017;64(5):605–13.
6. McKinnell JA, Arias CA. Editorial commentary: linezolid vs daptomycin for vancomycin-resistant enterococci: the evidence gap between trials and clinical experience. Clin Infect Dis 2015; 61:879–82.
7. Daptomycin. [Clinical pharmacology]. Elsevier. Tampa (FL): Daptomycin indications. [cited 2020 Mar 13]
8. Satlin MJ, Nicolau DP, Humphries RM, et al. Clinical and Laboratory Standards Institute Subcommittee on Antimicrobial Susceptibility Testing and Ad Hoc Working Group on Revision of Daptomycin Enterococcal Breakpoints, Development of Daptomycin Susceptibility Breakpoints for Enterococcus faecium and Revision of the Breakpoints for Other Enterococcal Species by the Clinical and Laboratory Standards Institute, Clin Infect Dis 2020; 70:1240–46, https://doi.org/10.1093/cid/ciz845.
9. Akins RL, Rybak MJ. Bactericidal Activities of Two Daptomycin Regimens against Clinical Strains of Glycopeptide Intermediate-Resistant Staphylococcus aureus, Vancomycin-Resistant Enterococcus faecium, and Methicillin-Resistant Staphylococcus aureus Isolates in an In Vitro Pharmacodynamic Model with Simulated Endocardial Vegetations. Antimicrob Agents Chemother. 2001 Feb; 45 (2): 454-459.
10. Gonzalez-Ruiz A, Seaton A, Hamed K. Daptomycin: an evidence-based review of its role in the treatment of Gram-positive infections. Infect Drug Resist. 2016;9:47-58. https://doi.org/10.2147/IDR.S99046
11. Shi C, Jin W, Xie Y, Zhou D, Xu S, Li Q, et al. Efficacy and safety of daptomycin versus linezolid treatment in patients with vancomycin-resistant enterococcal bacteraemia: an updated systematic review and meta-analysis. J Glob Antimicrob Resist 2019 Oct 17.

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