Pharmacokinetic dosing of aminoglycosides: a controlled trial.
OBJECTIVE
To evaluate whether individualized pharmacokinetic dosing of aminoglycosides can reduce nephrotoxicity and improve the outcome of patients with gram-negative sepsis.


METHODS
We conducted a prospective controlled trial at a tertiary care university hospital. Eighty-one patients with suspected or documented gram-negative infections were enrolled. All were treated with either gentamicin or amikacin, according to clinical judgement. Patients were allocated to one of two groups based on the last digit (odd/even) of their identification number. In the study group (pharmacokinetic dosing) of 43 patients, plasma aminoglycoside levels were determined 1 hour after initiation of drug infusion and 8 to 16 hours later to estimate the elimination half-life and volume of distribution, from which the subsequent dosage schedule was calculated. Target peak plasma levels were 20 microg/mL for gentamicin and 60 microg/mL for amikacin. Target trough levels were <1 microg/mL for both drugs. The control group (fixed once-daily dosing) consisted of 38 patients who were prescribed single daily doses of gentamicin or amikacin. The primary endpoints were renal toxicity (> or = 25% increase in serum creatinine level or a serum creatinine level > or = 1.4 mg/dL) and 28-day mortality.


RESULTS
The two study groups were similar in age, sex, indications for therapy, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and clinical assessment at baseline. Although the pharmacokinetic group received significantly greater doses of aminoglycosides than did the once-daily group, the incidence of nephrotoxicity was significantly lower in the pharmacokinetic group (5% [2/43] vs. 21% [8/38], P = 0.03). There was no statistically significant difference in 28-day mortality (27% [12/43] vs. 22% [8/38], P = 0.3).


CONCLUSIONS
These results suggest that individualized pharmacokinetic dosing of aminoglycosides reduces the incidence of nephrotoxicity and allows the use of greater doses of aminoglycosides.
Bartal
Carmi
C
Medical Intensive Care Unit, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Danon
Abraham
A
Schlaeffer
Francisc
F
Reisenberg
Klaris
K
Alkan
Michael
M
Smoliakov
Rosa
R
Sidi
Aviel
A
Almog
Yaniv
Y
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000583:Amikacin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D016903:Drug Monitoring / Q000379:methods; D023381:Endpoint Determination; D005260:Female; D005839:Gentamicins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D016037:Single-Blind Method; D016896:Treatment Outcome
D000900:Anti-Bacterial Agents; D005839:Gentamicins; D000583:Amikacin; D003404:Creatinine