Population pharmacokinetics of vancomycin delivered from active calcium sulfate bone graft substitute.
P. André (1), P. Wahl (2, 3), F. Livio (1), T. Buclin (1), M. Guidi (1, 4)
(1) Division of Clinical Pharmacology, University Hospital Center, University of Lausanne, Lausanne, Switzerland; (2) Department for Orthopaedic Surgery, HFR Fribourg - Cantonal Hospital, Fribourg, Switzerland; (3) Division for Orthopaedic and Trauma Surgery, Cantonal Hospital Winterthur, Winterthur, Switzerland; (4) School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
Objectives: Resorbable bone graft substitutes such as calcium sulfate (CaSO4) can be used as carrier material for local antimicrobial therapy in orthopedic surgery [1]. Vancomycin (VA) is an antibiotic of choice to treat bone infections caused by Gram-positive bacteria and offers many advantages for this type of administration. However, VA is known to induce nephrotoxicity when high blood levels (>25 mg/L) are maintained over a prolonged period (>10 days) [2]. On the other hand, subinhibitory VA plasma levels (0.4-4 mg/L) may induce the emergence of VA-resistant bacterial strains [3]. The aim of our analysis was to develop a population pharmacokinetic model of VA release in blood from active CaSO4, to predict ensuing systemic VA exposure and to infer about the risks for patients to develop nephrotoxicity or carriage of VA-resistant bacteria.
Methods: A total of 651 VA plasma levels collected from 86 patients treated for bone and joint infections of various sites were available for this pharmacokinetic analysis (NONMEM®). Patients received 2 (23%), 4 (21%) or 6 g (38%) of VA added into variable quantities of CaSO4 pellets. Age, body weight, sex, creatinine clearance estimated by the Cockcroft-Gault formula (CLCG) and number of days after intervention were tested as covariates. 1000 patients with various CLCG (15 to 120 mL/min) receiving 2-6 g were simulated using the final pharmacokinetic model to assess the percentage of patients at risk of nephrotoxicity and how long patients would exhibit VA concentrations in the critical interval for VA-resistant bacteria induction.
Results: A one-compartment model with first-order absorption best described VA pharmacokinetics. Average clearance (CL) was 8 L/h, volume of distribution (V) 61 L and absorption rate constant (Ka) 0.0025 h-1. CLCG on CL and number of days after intervention on Ka were retained as covariates. Only 0.2% of the simulated patients maintained blood levels above 25 mg/L during 10 days under the worst conditions (6 g with CLCG of 15 mL/min). The persistence of VA plasma concentrations in the subinhibitory range was observed for an overall mean of 29 days, which reduced to 13 days in the best conditions (2 g with CLCG of 120 mL/min).
Conclusions: Clinical and microbiological follow up studies should be conducted to confirm the low nephrotoxicity risk and to evaluate the consequences on patient's bacterial flora before recommending the widespread use of VA-loaded CaSO4 pellets in orthopedic surgery.
References:
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