The Continued Search for Optimal Daptomycin Dosing Strategies in VRE Bloodstream Infections

A wide range of daptomycin doses have been evaluated for the treatment of vanco­mycin-resistant Enterococcus bloodstream infections (VRE-BSIs). The US Food and Drug Administration—approved dose of 6 mg/kg/ day is derived from Staphylococcus aureus infection treatment, but has been shown to be inadequate for the treatment of VRE-BSIs.^1-3

A key determinant of poor outcomes is higher daptomycin minimum inhibitory concentrations (MICs) of Enterococci (4 μg/mL), compared with Staphylococci (1 μg/mL), that decrease the probability of achieving optimal pharmacody­namic targets associated with clinical efficacy.⁴ In vitro study results show MIC90 of 0.5 μg/mL and 4 μg/mL for S aureus and Enterococcus faecium, respectively.⁵ Indeed, clinical study results have shown that BSIs due to VRE with higher MICs (>2 μg/mL) are associated with higher rates of microbiologic and clinical failure when treated with standard dosing strategies.^6,7

At MICs >3 μg/mL, Enterococci may harbor mutations in the LiaFSR 3-component system, which is involved in the cell envelopes’ response to antibiotics, and may result in the emer­gence of daptomycin resistance during treatment or reduced potency.^6,8 Higher MICs may also be a by-product of the testing method since there is variability in MIC results regardless of testing method utilized. This variability may pose problems for clinical interpretation.^9-12 In the 2019 Clinical and Laboratory Standards Institute (CLSI) update, daptomycin breakpoints for Enterococci were changed to reflect the dose-dependent susceptibility observed from previous studies and differentiate E faecium from other species (Table 1).

DAPTOMYCIN DOSING IN ADULTS WITH VRE-BSI

Although data support higher daptomycin doses, it is unclear what dose is needed to optimally treat VRE-BSIs.^1-3 Studies have classified “high-dose” daptomycin with various definitions, including the 8 to 12 mg/kg recommendation by CSLI, leading to the question of what is the optimal dose for VRE-BSIs.

In vitro pharmacokinetic (PK)/pharmacodynamic study results have shown that the dose-dependent effects of dapto­mycin vary based on the MIC, with a minimum AUC0-24 of 1540 to maintain bactericidal activity.¹³ Models of simulated endocarditis predicted a daptomycin dose >10 mg/kg is neces­sary to obtain AUC24/MIC targets for successful treatment and suppression of resistance development.^13,14

A retrospective, multicenter review of adult patients treated with daptomycin doses >6 mg/kg for VRE-BSIs found high rates of overall clinical success and microbiological eradication of 89% and 93%, respectively. The median daptomycin dose was 8.2 mg/kg. As predicted from in vitro models, rates of clinical success decreased as the daptomycin MIC increased.¹⁵ Although these results indicate that higher daptomycin doses may be more effective, the study lacked a comparator group and failed to define high-dose.

Chuang and colleagues conducted a prospective, observa­tional study comparing daptomycin doses utilized for treat­ment of VRE-BSIs.¹⁶ Investigators compared mortality rates across 3 patient groups based on daptomycin dosing strategy. After dose rounding, higher doses (>9 mg/kg) were associ­ated with lower mortality and better outcomes compared with lower doses (Table 2^16,17). The study results did not show an association between MIC and mortality.¹⁶

Britt and colleagues further stratified dosing by standard (6 mg/kg), medium (8 mg/kg), and high ( > 10 mg/kg) in a retrospective review of VRE-BSIs among Department of Veterans Affairs patients.¹⁷ The patients were divided into 3 groups: standard dose (n = 709), medium dose (n = 142), and high dose (n = 60). High-dose daptomycin was associated with an overall survival benefit compared with medium-dose daptomycin after adjusting for confounders. However, there were no differences in the rate of microbiological clearance between the 2 groups (Table 2).

Limited-isolate MICs were available to further stratify outcomes based on MIC.¹⁷ The association with daptomycin MICs and clinical outcomes was evaluated by Shukla and colleagues. This study found that at higher MICs (3-4 μg/mL), there were increased rates of microbiological failure (P = .014). Findings did not support the antici­pated increased daptomycin doses and improved outcomes in this study.⁶

Although not discussed here, the combination of daptomycin with high PBP5 binding affinity β-lactams has shown increased binding affinity of daptomycin through adjustments to the overall charge of the bacterial surface and has shown promising outcomes through in vitro studies and case reports.^18-20

Daptomycin is generally well tolerated, with elevations of creatinine phosphokinase and rhab­domyolysis being the primarily reported adverse drug events (ADRs). Based on the available data, there does not seem to be an association with increased dose and muscle toxicity.^16,17,21 Concomitant statin use and increased risk of ADRs remain uncertain.^22-26

DOSING IN SPECIAL POPULATIONS

Obesity

Considerations for dosing weight selection in patients considered obese become significant as higher doses are used. The daptomycin package insert recommends dosing based on actual body weight (ABW) in obesity; however, this is based on a 6 mg/kg analysis.²⁷ The concerns are that using ABW may put patients at greater risk for ADRs, given the inherently higher total doses, and using adjusted body weight (AdjBW) or ideal body weight (IBW) could have a negative impact on clinical outcomes. Limited data are available that show the effect of dosing weight on clinical outcomes. A 500-mg fixed dose has been studied, but the investigators did not evaluate outcomes.²⁸ Two studies that eval&shy;uated clinical and safety outcomes in patients clas&shy;sified as obese using ABW versus AdjBW or IBW found no difference in clinical outcomes, and ADRs were similar between groups. Most patients in the 2 studies received <6 mg/kg; few patients received doses >6 mg/kg.^29,30 Based on available data, dosing based on AdjBW in obesity is reasonable for VRE; however, further studies are warranted.

Renal Replacement Therapy (RRT)

Dosing varies by type of RRT. In patients receiving continuous renal replacement therapy (CRRT) daily dosing is necessary to achieve similar plasma concentrations and overall exposure as do patients with a creatinine clearance >30 mL/min. In patients receiving CRRT, a 48-hour dosing interval could result in lower systemic concentrations after the first 24 hours, as drug concentrations are likely to fall below the optimal concentrations needed to maintain bactericidal activity.³¹ Daptomycin is typically dosed after hemodialysis (HD), and on the longer-interval HD days, the dose should be increased by 50% to account for the 72-hour interval in order to maintain adequate serum levels.32,33 A high dose has not been shown to result in excessive drug exposures or elevated trough levels associated with increased creatine phos&shy;phokinase and therefore should still be utilized in patients receiving RRT.^31,33

Pediatrics

To date, no studies have evaluated outcomes of high-dose daptomycin for VRE-BSIs in pediatric patients. Available studies are limited to PKs and case series of mixed gram-positive infections.

PK study results demonstrate that serum concen&shy;trations are age-dependent with younger children (2 to 6 years old) and infants (< 24 months) who require higher doses in order to achieve peak serum concentrations similar to those gained with the 4 to 6 mg/kg/day dose used in adult patients, which is reflected in the current dosing recommendations.^34-38 In younger children doses of 8 to 10 mg/kg/day result in concentrations similar to 4 to 6 mg/kg/d in adults.³⁶ Whereas a dose of up to 15mg/kg every 12 hours has been used safely in infants.³⁹

Given the variation between pediatric and adults patients, high-dose daptomycin in pediatrics is likely to be different than in adults. In the absence of pediatric clinical outcome data for VRE-BSIs, daptomycin therapeutic drug monitoring may be prudent.⁴⁰ It is important to note that the updated CLSI susceptible dose-dependent recommenda&shy;tions do not apply to pediatrics.

CONCLUSIONS

The current evidence regarding optimal dapto&shy;mycin dosing for the treatment of VRE-BSIs favors the use of high-dose regimens; however, such doses are not well defined in the literature. Targeting strategies to prevent daptomycin resis&shy;tance remain critical to preserve future utiliza&shy;tion in an already limited antimicrobial setting for VRE-BSI treatment. Collaborations between infectious diseases and microbiology teams are necessary for susceptibility interpretations.

Based upon the available literature, a minimum daptomycin dose of 8mg/kg/d should be utilized for the treatment of VRE-BSIs, with higher doses encouraged based upon patient-specific character&shy;istics, including MIC value. Routine monitoring of ADRs is required in the setting of increased doses as well as patients considered obese. Robust studies assessing the optimal dosing of daptomycin are needed for both adult and pediatric populations.

Hanretty is an antimicrobial stewardship pharmacist at Cooper University Healthcare in Camden, New Jersey. *She is an active member of the Society of Infectious Diseases Pharmacists.

Marini is an antimicrobial stewardship pharmacist at the University of Pittsburgh Medical Center (UPMC) Presbyterian Hospital in Pittsburgh, Pennsylvania. *She is an active member of the Society of Infectious Diseases Pharmacists.

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