Pharmacokinetics of tobramycin and gentamicin in abusers of intravenous drugs

Abstract

The kinetics of aminoglycoside elimination were determined in 18 hospitalized narcotics abusers receiving gentamicin or tobramycin for treatment of severe infection. Rapid aminoglycoside elimination (requiring doses of >5 mg/kg per day to maintain adequate drug levels) was noted in 12 of the 18 patients (18 of 27 clearance studies). Patients found to have rapid elimination were younger (P < 0.01) and had larger drug distribution volumes (P < 0.005), greater measured creatinine clearances (P < 0.05), and lower creatinine levels in serum (P < 0.001) than those with normal elimination. Nevertheless, by regression analysis, age, creatinine levels in serum, creatinine clearances, and drug distribution volumes proved to be unreliable predictors of individual aminoglycoside clearance. Measured drug half-life in serum appeared to be the only reliable predictor of drug clearance (r = 0.93). Patients with rapid drug elimination had aminoglycoside clearances 16 to 43% greater than measured creatinine clearances, suggesting an extraglomerular route of drug elimination. We conclude that in drug abuse patients a significant and clinically unpredictable interpatient variation occurs in aminoglycoside elimination and that accurate serum kinetics are needed to determine therapeutic dosing. In addicts younger than 35 years, with a creatinine level of <1.0 mg/100 ml in serum, the risk of inadequate therapy is high if standard dosing guidelines are followed. For this group, initial dosing of 8 mg/kg per day, with a drug half-life determination on the first dose, is recommended. Pharmacokinetic analysis is critical for all drug abusers treated with aminoglycosides for serious infection.For heroin addicts, successful medical therapy of Pseudomonas aeruginosa endocarditis has required empirical use of gentamicin in doses of -8 mg/kg per day (21,22). Although such doses are well above the maximum recommended daily regimen of 5 mg/kg (1, 11), it is not known why addicts require supranormal doses of aminoglycoside for therapy.While reviewing several recent cases of severe Pseudomonas infection among Cleveland drug abusers, we noted that 60% of our addict patients required gentamicin or tobramycin therapy above 5 mg/kg per day to maintain therapeutic drug concentrations in serum. To define the pharmacokinetics of gentamicin and tobramycin elimination in a population of hospitalized addicts, we have undertaken this prospective study to determine the drug kinetics in a mixed group of addicts with Pseudomonas and non-Pseudomonas infections. We determined the prevalence of rapid drug elimination in a sequential group of hospitalized addicts with normal renal function and correlated individual kinetic data with clinical attributes previously postulated to affect aminoglycoside elimination (i.e., renal function, fluid balance, age, anemia, hypopioteinemia, and duration of aminoglycoside therapy [6,8,12,15,16,17,20,25,28]) to identify individuals at risk for undertreatment with standard therapy. We also tested the hypothesis that addicts, like b...

Population pharmacokinetics of tobramycin.

“…We should like to point out, however, that in our study population (which was an unselected population of patients treated with tobramycin) only few patients were morbidly obese. It has been reported that younger patients require a higher loading dose on a mg kg-l basis than older patients (King et al, 1985), a trend seen in our studies. The reason for this age effect is not clear but it may reflect the different distribution of tissue masses as a function of age.…”

Vancomycin pharmacokinetics in burn patients and intravenous drug abusers

“…The mechanism for enhanced aminoglycoside elimination that results in increased dosage requirements'for burn patients appears to be related to an increased glomerular filtration rate (12,(23)(24)(25). Intravenous drug abusers (IVDA) have also been reported to eliminate aminoglycosides at a rate which necessitates more aggressive aminoglycoside dosage regimens (10). This observation has not been reported with vancomycin' a'dministration in this patient population.…”

Antibiotic Pharmacokinetics in Cystic Fibrosis

“…Induction of a new metabolic route of elimination may be related to the basic bio-246 chemical defect, the result of repeated infection, or a consequence of long term administration of drugs which induce the activity of the hepatic cytochrome P-450 enzyme system. It was recently suggested that increased aminoglycoside clearance in young drug addicts was a consequence of induction of hepatic metabolism (King et al 1985). This potential elimination route needs further exploration.…”