Gentamicin in hemodialyzed critical care patients: early dialysis after administration of a high dose should be considered

Abstract

Gentamicin is a widely used antibiotic in the intensive care unit (ICU). Its dosage is difficult to adapt to hemodialyzed ICU patients. The FDA-approved regimen consists of the administration of 1 to 1.7 mg/kg of gentamicin at the end of each dialysis session. Better pharmacokinetic management could be obtained if gentamicin were administered just before the dialysis session. We performed Monte Carlo simulations (MCS) to determine the best gentamicin pharmacokinetic profile (high peak and low trough concentrations). Then, 6 mg/kg of gentamicin was infused into 10 ICU patients over a period of 30 min. A 4-h-long hemodialysis session was started 30 min after the end of the infusion. Pharmacokinetic samples were regularly collected over 24 h. A one-compartment model with zero-order input and first-order elimination was developed in Nonmem version VI to analyze patients' measured gentamicin concentration-versus-time profiles. Finally, additional MCS were performed to compare the regimen chosen with the FDA-approved gentamicin regimen. High peak concentrations (C(max), 31.8 ± 16.8 mg/liter) were achieved. The estimated C(24) and C(48) values (concentrations 24 and 48 h, respectively, after the beginning of the infusion) were 4.1 ± 2.3 and 1.8 ± 1.2 mg/liter, respectively. The volume of distribution was 0.21 ± 0.06 liter/kg. MCS confirmed that the dosing regimen chosen achieved the target C(max) whereas the FDA-approved regimen did not (31.0 ± 10.9 versus 8.8 ± 3.1 mg · liter(-1)). Moreover, the C(24) values were similar while the AUC(0-24) values were moderately increased (190.8 ± 65.0 versus 135 ± 42.2 mg · h · liter(-1)). Therefore, administration of 6 mg/kg of gentamicin before hemodialysis to critically ill patients achieves a high C(max) and an acceptable AUC, maximizing pharmacokinetic/pharmacodynamic endpoints.

Figures

Fig 1

Goodness-of-fit plots for the final population PK model. (a) Observed concentrations versus individual predicted concentrations. The line x = y is the identity line. (b) Weighted residuals versus time. (c) Gentamicin concentration-versus-time profiles of the patients enrolled in this study (ID1 to ID10). Each black square represents a measured concentration. The line represents the individual estimate from the final population PK model.

Fig 2

Simulated gentamicin concentrations versus time for a 6-mg/kg dose administered at the beginning of the hemodialysis session (thin line) or at 1 h (bold line) or 20 h (dotted line) before hemodialysis commenced.

Fig 3

Simulated gentamicin concentrations versus time for a 6-mg/kg dose administered at the beginning of the hemodialysis session (bold line) and for a 1.7-mg/kg dose (dotted line) administered at the end of the hemodialysis period.