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Background
and Objectives: Interest in the use of aminoglycosides
is becoming more prevalent in clinical practice with the emergence of
Gram-negative infections resistant to contemporary antibiotics. For patients
undergoing chronic hemodialysis, aminoglycosides are usually administered at a
low dose at the end of their hemodialysis session, but this approach remains
controversial. Intradialytic infusion (IDI) of high dose of
tobramycin could yield better exposure when administered early in the
hemodialysis session. This study sought to characterize the pharmacokinetic profile
of tobramycin IDI dosed in infected patients receiving chronic intermittent
hemodialysis and to determine whether it is possible to achieve favorable
pharmacokinetic targets using this approach.

Design,
setting, participants, and measurements: In this prospective
pharmacokinetic study, a single dose (5 mg/kg) of tobramycin was administered IDI
to eleven non-critically ill patients undergoing chronic intermittent
hemodialysis. Blood samples were collected at selected time to determine tobramycin
serum concentrations. Pharmacokinetic analysis, modelling and Monte Carlo
simulations (MCS) were performed using PhoenixTM NLME. The efficacy
exposure target for non-severe Gram-negative infections and CMI≤1 were maximum concentration
(Cmax≥10 mg/L) and area under the curve (AUC24h>30
mg*h/L). For toxicity, the goal was to identify plasma trough concentrations <2
mg/L.

Results: Tobramycin disposition was best described by a zero-order input
one-compartment model with two clearances. Tobramycin mean (SD) Cmax,
trough levels and AUC24h were 13.1(1.3) mg/L, 1.32(0.47) mg/L and
61(23) mg*h/L, respectively. MCS run with 1000 virtual patients showed that a 5
mg/kg dose of tobramycin IDI outperformed the usual post-dialysis dosing (80%
meeting all targets vs < 1%, respectively).

Conclusions: A single high-dose of tobramycin can achieve favorable pharmacokinetic
endpoints when administered using IHI in hemodialysis patients. This dosing
regimen may represent an effective and safer alternative to the usual dosing in
the treatment of non-severe Gram-negative infection.