Administration of aminoglycosides to hemodialysis patients immediately before dialysis: a new dosing modality

Abstract

We describe a new modality for administering aminoglycosides to hemodialysis (HD) patients, namely, a modification of the once-daily regimen which consists of administering the aminoglycosides over 60 min by drip infusion just before each HD session, with a preplanned peak concentration being reached at the beginning of the session and then with a rapidly decreasing concentration being achieved by the start of HD. The area under the concentration-time curve (AUC), i.e., the accumulation of the drug in the body, is thus minimized by this modality. Arbekacin (ABK) was given at a dose of 2 mg/kg of body weight to 10 HD patients infected with methicillin-resistant Staphylococcus aureus (MRSA) for 2 weeks (six sessions in total), resulting in the complete disappearance of MRSA in 5 patients. A high rate of elimination of ABK was attained for each patient while the patient was on HD (range, 0.20 to 0.42 h-1; mean 0.28 +/- 0.08 h-1) by using high-performance dialyzers provided with membranes made of either polymethylmethacrylate, cellulose triacetate (CTA), or ethylene vinyl alcohol. The best results were obtained with the CTA membrane, as revealed by the overall mass transfer coefficient (Ko). The AUC in the simulation model for the variation in the serum ABK concentration in this modality was calculated to be 40% of that of the conventional post-HD dosing modality, suggesting that a much higher dose could be administered to HD patients who receive HD thrice weekly (4 h per session), giving, e.g., 4 mg/kg initially and before the HD sessions, when there is an interval of 68 h from HD session to HD session, and giving 2 mg/kg before the other sessions.

Development of a Semimechanistic Model to Describe the Pharmacokinetics of Gentamicin in Patients Receiving Hemodialysis

“…9 Toxicity (ototoxicity: vestibular, sensory, and nephrotoxicity) has been the primary concern of aminoglycoside therapy. 3,11 However, our understanding of the pharmacokinetics and pharmacodynamics of gentamicin that supported the change to oncedaily dosing also lends support to the predialysis dosing of gentamicin. 3,11 However, our understanding of the pharmacokinetics and pharmacodynamics of gentamicin that supported the change to oncedaily dosing also lends support to the predialysis dosing of gentamicin.…”

“…7,10 Current practice is to dose gentamicin after a hemodialysis session. 11 Various properties of gentamicin that support intermittent pulse dosing include the following: bactericidal activity is concentration dependent, 9,11,12 adaptive resistance is promoted in the presence of prolonged high residual concentrations, 6,13 and uptake of gentamicin into the renal cortex is thought to be saturable, 6,7 although data regarding ototoxicity are less clear. 11 Various properties of gentamicin that support intermittent pulse dosing include the following: bactericidal activity is concentration dependent, 9,11,12 adaptive resistance is promoted in the presence of prolonged high residual concentrations, 6,13 and uptake of gentamicin into the renal cortex is thought to be saturable, 6,7 although data regarding ototoxicity are less clear.…”

“…11 Using the pharmacokinetic values for arbekacin obtained from the 10 patients in their study, the authors calculated that doses as high as 4 mg/kg could be given predialysis. 11 Using the pharmacokinetic values for arbekacin obtained from the 10 patients in their study, the authors calculated that doses as high as 4 mg/kg could be given predialysis.…”

“…11 Using the pharmacokinetic values for arbekacin obtained from the 10 patients in their study, the authors calculated that doses as high as 4 mg/kg could be given predialysis. 11 The AUC represents the total exposure of the body to the drug and is believed to be reflective of safety. 11 The AUC represents the total exposure of the body to the drug and is believed to be reflective of safety.…”

“…11 Also, the authors simulated concentration-time profiles for dosage regimens involving predialysis and postdialysis dosing, demonstrating that the area under the curve (AUC) produced from administration of a dose predialysis was approximately 60% less than the AUC from the same dose given postdialysis. 11,14 This present study describes the development of a semimechanistic model to describe the pharmacokinetics of aminoglycosides in patients with ESRD during and between periods of hemodialysis. 11,14 This present study describes the development of a semimechanistic model to describe the pharmacokinetics of aminoglycosides in patients with ESRD during and between periods of hemodialysis.…”