A total of 201 critically ill patients were studied during 267 courses of gentamicin or tobramycin treatment (139 gentamicin courses and 128 tobramycin courses). Of these 267 courses, pharmacokinetic and clinical data were obtained for 240 (120 gentamicin and 120 tobramycin). The data collected for pharmacokinetic analysis included measurements of serial blood and urine levels, urinary excretion of beta 2-microglobulin, protein levels, and granular casts. A two-compartment model was used to assess tissue accumulation, and in 89 courses the predicted accumulation was confirmed by cumulative urine collection or postmortem tissue analysis. As groups, the patients given gentamicin and tobramycin did not differ in age, weight, creatine clearance, total dose given, duration of treatment, initial aminoglycoside through serum levels, number of dosage adjustments, concurrent use of furosemide, or concurrent cephalosporins. Previous aminoglycoside treatment (usually gentamicin) had occurred more frequently in the tobramycin treated patients (P less than 0.01), and more males than females received tobramycin (P less than 0.05). Pharmacokinetic assessments of renal damage were based on both changes in glomerular filtration rate (serum creatinine levels, creatinine clearance) and renal tubular damage (beta 2-microglobin, casts), but only patients with elevated aminoglycoside tissue levels leading to renal tubular damage and subsequent creatinine clearance decreases were considered to have experienced aminoglycoside nephrotoxicity. In the pharmacokinetic analysis of nephrotoxicity, 29 gentamicin courses (24%) and 12 tobramycin courses (10%) were complicated by nephrotoxicity (P less than 0.01). The 201 study patients were also evaluated independently for clinical nephrotoxicity (defined as a serum creatinine level increase of 0.5 mg/dl or more). Clinical nephrotoxicity occurred at rates of 37% in the gentamicin-treated group and 22% in the tobramycin-treated group (P less than 0.02). In these similar groups of critically ill patients, tobramycin was less nephrotic than gentamicin.

Comparative nephrotoxicity of gentamicin and tobramycin: pharmacokinetic and clinical studies in 201 patients.

The 50% lethal dose (LD50) of vancomycin for rodents was higher than that of tobramycin but much lower than that of cefamandole nafate. The rodents died in clonic convulsions immediately after receiving vancomycin. The LD50 for dogs similar to that for rodents; however, deaths occurred several days after administration of vancomycin and resulted from renal failure. Rapid intravenous administration of vancomycin to dogs produced a significant decrease in blood pressure that was prevented by pretreatment with the antihistamine methapyrilene. Subchronic administration of vancomycin to laboratory animals in doses of 12.5-400 mg/kg caused no systemic toxicity. Concomitant administration of vancomycin and tobramycin to rats resulted in significantly increased nephrotoxicity compared to that caused by either agent alone. The nephrotoxic response of rats receiving vancomycin was only partially reversed by large volumes of water given orally before and after the drug.

Toxicology of Vancomycin in Laboratory Animals

We studied 201 critically ill patients during 267 courses of gentamicin (139 courses) or tobramycin (128 courses) therapy. Clinical and pharmacokinetic data were obtained on 240 of 267 courses (120 courses each of gentamicin and tobramycin). Two judgments of nephrotoxicity and its cause were made independently in this study, using a clinical and a pharmacokinetic definition of nephrotoxicity. The two sets of criteria were generally in good agreement, as all but 10 of 41 patients who were judged nephrotoxic by pharmacokinetic criteria were independently judged nephrotoxic by the clinical definition. Groups of patients judged nontoxic did not differ from groups judged nephrotoxic in age, sex, weight, initial creatinine clearance, total dose given, duration of treatment, initial aminoglycoside trough serum levels, number of dosage adjustments, concurrent use of furosemide, or concurrent cephalosporins. Prior aminoglycosides (usually gentamicin) had been used more frequently in the nontoxic group (P less than 0.05). Two major conclusions of this study are at variance with those of previous investigators; (i) we found no clinical parameters of value in predicting nephrotoxicity in critically ill patients; and (ii) aminoglycoside serum concentrations, once in the therapeutic range, were of limited value in prevention of aminoglycoside nephrotoxicity in our patients.

Clinical and pharmacokinetic characteristics of aminoglycoside nephrotoxicity in 201 critically ill patients.

The nephrotoxicity and auditory toxicity of high-dose (mean, 28.6 g) and prolonged (mean, 61.6 days) courses of gentamicin and tobramycin were monitored in 15 patients receiving 17 courses of treatment for pseudomonas endocarditis. Doses were adjusted in a manner that maintained peak levels of aminoglycoside in serum at 12-15 micrograms/ml and trough levels at less than 2 micrograms/ml. Drug-related renal dysfunction and auditory toxicity occurred in 63% and 44%, respectively, of gentamicin-treated patients and in 43% and 25%, respectively, of tobramycin-treated patients. Mean maximal rises (+/- SEM) in serum creatinine levels were 0.8 (+/- 0.4) mg/dl in the group given gentamicin and 1.6 (+/- 0.7) mg/dl in the group given tobramycin. Mean maximal decreases in pure-tone hearing threshold levels were greater in gentamicin-treated patients (58.3 dB) than in those given tobramycin (22.5 dB). Both forms of toxicity appeared earlier and at a smaller dose with gentamicin than with tobramycin.

https://www.jstor.org/stable/pdfplus/30109716.pdf

Renal and Auditory Toxicity of High-Dose, Prolonged Therapy with Gentamicin and Tobramycin in Pseudomonas Endocarditis

Most investigations of the comparative nephrotoxicities of aminoglycosides in animals have utilized large multiples of the human dose. Furthermore, many of these assessments have used only one or two dose levels and have not described a dose-response comparison among antibiotics. Because of this lack of comparative dose-response data over a range of low multiples of the human dose, the nephrotoxicities of gentamicin, tobramycin, and amikacin were investigated in 180 rats, utilizing doses ranging from one to seven times the equivalent human clinical doses. Histopathological evaluations of both kidneys from each rat were scored without knowledge of the treatment, and statistical analyses of the results indicated that a linear and parallel dose-response relationship existed for each drug, the relative nephrotoxicity over the range of doses analyzed was gentamicin > tobramycin > amikacin (P = 0.0001), and, unlike amikacin, the human dose equivalents (milligrams per kilogram) of gentamicin and tobramycin were significantly nephrotoxic in rats (P < 0.05).

R. A. Parker

Papers

Comparison of the nephrotoxic potential of gentamicin, tobramycin and netilmicin in the rat