Gentamicin and Ampicillin in Human Bile

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...

Section: Methodsmentioning

confidence: 74%

Pharmacokinetics of tobramycin and gentamicin in abusers of intravenous drugs

King

Creger

Ellner

1985

“…A number of reports (1,2,4) have shown that levels of gentamicin in the biliary tract were lower than serum levels in the same patients. However, these reports have been limited since only a few patients were studied.…”

mentioning

confidence: 96%

Pharmacology of Gentamicin in the Biliary Tract of Humans

Mendelson

Portnoy

Sigman

1973

“…The limited eradication rate with ampicillin-tobramycin can most likely be explained by the fact that 51% of the bacteria isolated from the biliary tree were resistant to ampicillin. Although most pathogens (96%) were susceptible to tobramycin, the poor penetration of aminoglycosides into the bile may explain the persistence of pathogens within the bile (19,31,39). In contrast, only 1% of the pathogens were resistant to cefoperazone.…”

Section: Discussionmentioning

confidence: 99%

“…Maximum biliary levels of 3.0 jxg/ml were observed after high doses of gentamicin (25,39). The extremely high biliary levels of cefoperazone, coupled with its excellent in vitro activity, which resulted in a very high concentration over MIC ratio within the infected biliary tree, have certainly played a determinant role in the outcome of therapy in these patients with severe biliary tract infections and were probably responsible for the elimination of the biliary pathogens in 18 of the 19 patients.…”

Section: Discussionmentioning

confidence: 99%

Cefoperazone compared with ampicillin plus tobramycin for severe biliary tract infections

Bergeron

Mendelson

Harding

et al. 1988

In a prospective, randomized, multicenter study, the efficacy and safety of cefoperazone and the combination ampicillin-tobramycin as initial therapy for patients with severe acute biliary tract infections were compared. Of 77 patients initially entered in the study, definite severe biliary tract infection was confirmed in 67. Sixty-four patients completed treatment. At the end of treatment, 35 of 36 (97%) patients given cefoperazone and 23 of 28 (82%) given ampicillin-tobramycin were cured of their infection (P = 0.07). Pathogens were recovered from the bile in 32 patients; microbiological cures were observed in 18 of 19 (94%) patients receiving cefoperazone and 8 of 13 (62%) receiving ampicillin-tobramycin (P = 0.03). Thirteen patients had septicemia. None (0%) of the eight septicemic patients from the cefoperazone group, but two of five (40%) from the ampicillin-tobramycin group, were clinical failures. Of the isolated pathogens, 51% were resistant to ampicillin, while the resistance rate was 4% for tobramycin and 1% for cefoperazone (P < 0.001). Biliary concentrations of cefoperazone were maintained at high levels-236 ± 87