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 fl2-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, creatinine clearance, total dose given, duration of treatment, initial aminoglycoside trough serum levels, number of dosage adjustments, concurrent use of furosemide, or concurrent cephalosporins. Previous aminoglycoside treatment (usually gentamicin) had occurred more frequently in the tobramycintreated patients (P < 0.01), and more males than females received tobramycin (P < 0.05). Pharmnacokinetic assessments of renal damage were based on both changes in glomerular filtration rate (serum creatinine levels, creatinine clearance) and renal tubular damage (,82-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 pharnacokinetic analysis of nephrotoxicity, 29 gentamicin courses (24%) and 12 tobramycin courses (10%) were complicated by nephrotoxicity (P < 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 < 0.02). In these similar groups of critically ill patients, tobramycin was less nephrotoxic than gentamicin.

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In 64 adults treated with gentamicin sulfate, peak and trough serum concentrations rose gradually and declined in two phases after the final dose. Seventeen patients experienced renal damage. The 17 patients had greater amounts of gentamicin in tissues even after the first dose and before any renal effects were noted. This pharmacokinetics analysis provided evidence that patients who experience gentamicin-related nephrotoxic effects while receiving recommended doses of gentamicin could be distinguished from patients with no toxic effects because they experienced abnormal tissue accumulation before detectable changes in renal function occurred.

Aminoglycoside antibiotics are relatively mild nephrotoxins, but their action is site-specific to the proximal tubule. Therefore, use of these drugs presents a unique opportunity to study the temporal relation between the damage to the cells lining the renal proximal tubule and the subsequent rise in the serum creatinine concentration. Our study of 52 aminoglycoside-treated patients included measurements of daily serum creatinine, daily 24-hour urinary beta 2-microglobulin (beta 2M) excretion, and determination of aminoglycoside tissue accumulation. An elevation in beta 2M excretion above the baseline value occurred in 37 of 52 (71%), whereas the serum creatinine concentration rose in only 17 of 52 (33%) of patients. Even fewer patients (10 of 52) demonstrated all three criteria for aminoglycoside nephrotoxicity. These 10 patients had elevated tissue accumulation, evidence of renal tubular damage, and a rise in serum creatinine concentration. The increased beta 2M excretion greater than 50 mg/day preceded the serum creatinine rise by 2 to 7 days. An abnormal baseline beta 2M was not a risk factor for a subsequent rise in creatinine concentration or vice versa. Although each test is primarily site specific, widespread and severe renal proximal tubular damage, regardless of cause, will eventually lead to an elevation of serum creatinine. Thus, serial monitoring of proximal tubular function with urinary beta 2M excretion has potential value in the assessment of insults to this site, but cannot be expected to explain all changes in serum creatinine.