AMINOGLYCOSIDE - CEPHALOSPORIN SYNERGISTIC NEPHROTOXICITY: A RABBIT MODEL
Abstract
The rabbit was evaluated as a model to study aminoglycoside-cephalosporin synergistic nephrotoxicity as experienced by man. Gentamicin was the aminoglycoside studied, alone and in combination with the cephalosporins, cephalothin and cefamandole. Treatments were given IM twice a day. Gentamicin dosages ranging from 20 to 80 mg/kg/day produced negligible to mild kidney damage when administered for 14 days. Treatment with cephalothin or cefamandole, 500 mg/kg/day, for 14 days resulted in minimal kidney damage. Concurrent administration of gentamicin, 20 or 40 mg/kg/day, with either cephalothin or cefamandole, 500 mg/kg/day, for 14 days resulted in significant nephrotoxity detected by elevations in serum creatinine, blood urea nitrogen, urinary protein and urinary (gamma)-glutamyl transferase. Histopathological analysis of kidney tissue documented the damage as primarily in the proximal tubule, the same anatomical site damaged in man. Gentamicin-cephalosporin combinations were also administered for 7 days, resulting in histopathological damage similar, but of less severity, than after 14 days of treatment. Statistical analysis of blood urea nitrogen, urinary protein and urinary (gamma)-glutamyl transferase data demonstrated a significant interaction effect between gentamicin and cephalosporin treatments on kidney dysfunction. Orthogonal comparisons of urinary protein data indicated a nephrotoxic insult one to three days after treatment initiation. Transmission electron microscopy indicated the presence of myeloid bodies in rabbit kidney after gentamicin administration, and the presence of an unidentified rod-like structure in the proximal tubule of rabbits treated with gentamicin-cephalosporin combinations. Whole kidney levels of gentamicin indicated that gentamicin kidney tissue accumulation increased with higher dosages, administered for longer periods of time. Cephalosporin administration did not effect gentamicin accumulation within the kidney. This research demonstrated that the rabbit is an appropriate animal model in which to study aminoglycoside-cephalosporin synergistic nephrotoxicity as experienced by man. Gentamicin-cephalothin and gentamicin-cefamandole combinations each effected a synergistic nephrotoxity in the rabbit functionally and morphologically similar to that of man. Urinary protein and BUN measurements were the most useful indicators of kidney dysfunction.
Degree
Ph.D.
Subject Area
Pharmacology
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.