Population pharmacokinetics of daptomycin in vancomycin-resistant Enterococcus bloodstream infections

Posted on by kcairns

Background: Vancomycin-resistant Enterococcus faecium (VREfm) bloodstream infections (BSIs) are challenging to manage, with limited treatment options available. Daptomycin, a cyclic lipopeptide antibiotic is a key treatment agent, however optimal dosing regimens are uncertain. Daptomycin is highly protein bound (~93%) and has been reported to have significant between patient variability, including based on sex.

Aims: This study aimed to (i) develop a population pharmacokinetic (popPK) model to describe daptomycin exposure in adult patients with an underlying haematological malignancy receiving contemporary doses of daptomycin for treatment of VREfm BSIs; and (ii) perform Monte Carlo simulations to predict daptomycin exposures and probabilities of target attainment (PTA) for different dosing regimens.

Methods: Total daptomycin steady-state concentrations were measured at three time points following the 30-minute infusion (0 to 3, 3 to 12 and 12 to 24 hours). Blood samples were collected after a median of 5 doses (range: 5 to 10 doses). Population pharmacokinetic (popPK) modelling was performed using non-linear mixed-effects methods in NONMEM v7.4. Model evaluation included prediction corrected visual predictive checks (pcVPC) and goodness of fit plots. Monte Carlo simulations were then performed to determine probability of target attainment (PTA) for various fixed and weight-based dosing regimens at steady-state. Target exposures were identified from published literature, defined as fAUC0-24/MIC >27.43 [1] for efficacy and Cmin ≥24.3 mg/L [2] and Cmin ≥60 mg/L [3]. fAUC was estimated using an unbound fraction of 0.07 [4].

Results: Patients received a median daptomycin dose of 11.7 mg/kg (range: 9.1 – 12.9 mg/kg). Thirty daptomycin concentrations from 10 patients (50% male, median 63 years, IQR: 56.3 – 71.8 years) were analysed. A two-compartment model, with creatinine clearance and lean body weight identified as significant covariates, best described the data. Population parameter estimates included renal clearance (CLR) at 0.411 L/h/(88.9 mL/min CLCR) and non-renal clearance (CLNR) at 0.2 L/h/(54.0 kg lean body weight)0.75, whilst V1 was 6.48L/54.0 kg, Q1 was 1.16 L/h and V2 was 5.12 L/54.0 kg. Sex did not significantly influence the PK parameters in this study. Subsequent simulations demonstrated marked interindividual variability in exposure, with fixed daptomycin doses of 1200 mg daily being the only dosing regimen to achieve PTA > 90% for VREfm with an MIC of 2 mg/L when targeting fAUC0-24>27.43 (efficacy). 15.5% of patients would be expected to achieve a Cmin ≥60 mg/L (toxicity).

Conclusions: The developed popPK model and subsequent Monte Carlo simulations support the need for individualised daptomycin dosing strategies to optimise efficacy and minimise potential toxicity in adult haematology patients with VREfm BSIs.

References:

  1. Avery LM, Kuti JL, Weisser M, Egli A, Rybak MJ, Zasowski EJ, et al. Pharmacodynamic Analysis of Daptomycin-treated Enterococcal Bacteremia: It Is Time to Change the Breakpoint. Clin Infect Dis. 2019;68(10):1650-7.
  2. Bhavnani SM, Rubino CM, Ambrose PG, Drusano GL. Daptomycin exposure and the probability of elevations in the creatine phosphokinase level: data from a randomized trial of patients with bacteremia and endocarditis. Clin Infect Dis. 2010;50(12):1568-74.
  3. Vellat C, Garreau R, Millet A, Piron C, Bourguignon L, Roux S, et al. Risk factors of daptomycin overexposure: a case-control study. Antimicrob Agents Chemother. 2025;69(12):e0113925.
  4. Benvenuto M, Benziger DP, Yankelev S, Vigliani G. Pharmacokinetics and tolerability of daptomycin at doses up to 12 milligrams per kilogram of body weight once daily in healthy volunteers. Antimicrob Agents Chemother. 2006;50(10):3245-9.

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