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

Abstract

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.

Increased renal DNA synthesis in vivo after administration of low doses of gentamicin to rats

“…Healthy volunteers (<40 years of age) have shown no significant alteration of kidney function upon a 10-day exposure to gentamicin (29). Conversely, elevation of serum creatinine was seen in 10 to 37% of ill patients (average age, >60 years) treated for the same time period or less (7,26,30). Other situations in which kidney regeneration rates might differ from normal would be worthy of investigation.…”

Clinical Pharmacokinetics, Toxicity and Cost Effectiveness Analysis of Aminoglycosides and Aminoglycoside Dosing Services

“…Smith et al, defined nephrotoxicity as an increase in serum creatinine concentration of 0.5 mg/dl(50 pmol/l) or more if initial serum creatinine concentration was less than 3.0 mg/dl (300 pmol/l), or a rise of 1.0 mg/dl (10 pmol/l) or more if serum creatinine concentration was 3.0 mg/dl(300 pmol/l) or above (62). Others defined nephrotoxicity as an increase of 0.5 mg/dl(50 pmol/l) or more during therapy or within seven days of the last dose (63,64). Matzke et al, defined nephrotoxicity as an increase in serum creatinine of 0.5 mg/l (50 pmol/l) or more if the initial concentration was less than 2.0mg/dl (200pmol/l), or as a rise of 30% of the initial value or more if the initial concentration was greater than or equal to 2.0 mg/dl(200 pmol/l) (65).…”

Discovery of Metabolomics Biomarkers for Early Detection of Nephrotoxicity

“…Administration of gentamicin, the prototype aminoglycoside antibiotic, induces proximal tubular necrosis in rodents (Houghton et al 1986). Tobramycin belongs to the aminoglycoside antibiotics, as well, and induces tubular necrosis, although generally less severe than gentamicin (Kahlmeter et al 1984;Kepczyk et al 1990;Schentag et al 1981). Cisplatin is an antineoplastic agent, used in the treatment of a variety of solid tumors, that induces severe tubular toxicity (Dobyan et al 1980).…”