Nicolas Garbez (1,5), Litaty Mbatchi (1), Emilio Maseda (2), Sonia Luque (3), Steven C. Wallis (4), Laurent Muller (5), Jeffrey Lipman (6), Jason A. Roberts (6), Jean-Yves Lefrant (5), Claire Roger (5)
(1) Laboratoire de Pharmacocinétique, Faculté de Pharmacie, Université de Montpellier, Montpellier, France, (2) Department of Anesthesia and Surgical Intensive Care, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain, (3) Pharmacy Department, Hospital del Mar, Barcelona, Spain, (4) UQ Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia, (5) Service des Réanimations, Pôle Anesthésie Réanimation Douleur Urgence, CHU Nîmes, Nîmes, France, (6) Department of Intensive Care Medicine, Royal Brisbane and Womens’ Hospital, Brisbane, QLD, Australia
Objectives: In intensive care units (ICUs), one third of patients are admitted for sepsis [1]. Among these, fungal infections have been implicated in 20 % of cases, mostly Candida species, leading it to be the third leading cause of infection in ICU [2]. Fungi-related sepsis greatly increases morbidity and mortality in ICU patients [3]. Echinocandins, like micafungin, are recommended as first-line treatment for invasive candidiasis or candidemia in critically ill patients [4]. However, PK parameters of antifungal agents can be altered by sepsis [5] and continuous renal replacement therapy (CRRT [6], where continuous-veno-veno hemofiltration (CVVH) and continuous veno-veno hemodiafiltration (CVVHDF) are the most widely used techniques [7]. Thus, the aim of the study is to compare the population PK of micafungin in critically ill patients receiving continuous veno-venous hemofiltration (CVVH, 30 mL/kg/h) to those receiving equidoses of hemodiafiltration (CVVHDF, 15 mL/kg/h + 15 mL/kg/h).
Methods: Eight critically ill patients in septic shock undergoing CRRT and receiving 100 mg micafungin once daily were eligible for inclusion. Total micafungin plasma concentrations were analyzed using a non parametric adaptive grid (NPAG) algorithm within the freely available Pmetrics software package for R [8]®. External validation of the model was performed using a different dataset [9]. Probability of PK/PD target attainment (PTA) was calculated from Monte Carlo simulations using 24-hour area under curve/minimum inhibitory concentration (AUC0-24/MIC) cut-offs 285 (C. parapsilosis), 3000 (all Candida species) and 5000 (C. non parapsilosis) [10]. Daily dosing regimens of 100, 150 and 200 mg were simulated for the first 2 days of treatment. A micafungin dosing regimen was considered optimal if the PTA was ≥ 90 %.
Results: TMicafungin concentrations were best described by a two-compartmental PK model and no covariate, including CRRT modality (CVVH and CVVHDF), was retained in the final model. The validity of the model was assessed by both internal and external validation. The mean parameter estimates (standard deviation) were 0.96 (0.32) L/h for clearance (CL), 14.84 (5.33) L for the volume of the central compartment (Vc), 0.36 (0.33) 1/h for rate constant from central to peripheral compartment (Kcp) and 0.53 (0.24) 1/h for rate constant from central to peripheral compartment (Kpc). The standard 100 mg daily dosing was unable to reach 90 % of PTA for all Candida species except C. albicans on the second day of therapy.
Conclusions: There was no difference in micafungin PK between equidoses of CVVH and CVVHDF. A dose escalation to 200 mg is suggested to achieve the PK/PD target of Candida species with MICs exceeding 0.016 mg/L in this population. These “off-label” dosing regimens should be further investigated in clinical trials knowing the favourable toxicity profile and the post-antifungal effect of micafungin. Indeed, optimal dosing regimen could ensure efficacy and prevent the emergence of resistance due to an inadequate initial antifungal dosing regimen.
References:
[1] Vincent J-L, Sakr Y, Sprung CL, et al. Sepsis in European intensive care units: Results of the SOAP study*: Crit Care Med 2006; 34: 344–53.
[2] Vincent J-L. International Study of the Prevalence and Outcomes of Infection in Intensive Care Units. JAMA 2009; 302: 2323.
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[4] Pappas PG, Rotstein CMF, Betts RF, et al. Micafungin versus Caspofungin for Treatment of Candidemia and Other Forms of Invasive Candidiasis. Clin Infect Dis 2007; 45: 883–93.
[5] Roberts DM, Roberts JA, Roberts MS, et al. Variability of antibiotic concentrations in critically ill patients receiving continuous renal replacement therapy: A multicentre pharmacokinetic study*. Crit Care Med 2012; 40: 1523–8.
[6] Uchino S, Bellomo R, Morimatsu H, et al. Continuous renal replacement therapy: A worldwide practice survey: The Beginning and Ending Supportive Therapy for the Kidney (B.E.S.T. Kidney) Investigators. Intensive Care Med 2007; 33: 1563–70.
[7] Friedrich JO, Wald R, Bagshaw SM, Burns KE, Adhikari NK. Hemofiltration compared to hemodialysis for acute kidney injury: systematic review and meta-analysis. Crit Care 2012; 16: R146.
[8] Neely MN, van Guilder MG, Yamada WM, Schumitzky A, Jelliffe RW. Accurate Detection of Outliers and Subpopulations With Pmetrics, a Nonparametric and Parametric Pharmacometric Modeling and Simulation Package for R: Ther Drug Monit 2012; 34: 467–76.
[9] Maseda E, Grau S, Villagran M-J, et al. Micafungin pharmacokinetic/pharmacodynamic adequacy for the treatment of invasive candidiasis in critically ill patients on continuous venovenous haemofiltration. J Antimicrob Chemother 2014; 69: 1624–32.
[10] Andes D, Ambrose PG, Hammel JP, et al. Use of Pharmacokinetic-Pharmacodynamic Analyses To Optimize Therapy with the Systemic Antifungal Micafungin for Invasive Candidiasis or Candidemia. Antimicrob Agents Chemother 2011; 55: 2113–21.
Reference: PAGE () Abstr 9404 [www.page-meeting.org/?abstract=9404]
Poster: Clinical Applications