Comparative ototoxicity of gentamicin and sisomicin in the cat

The authors compared the ototoxicity of gentamicin and sisomicin in cats to augment earlier studies dealing with the ototoxicity of gentamicin in experimental animals. They likewise evaluated the vestibular toxicity of both aminoglycosides in cats. Twenty-four male and female cats with intact ear drums and normal hearing were randomly assigned to treatment groups after they had had suitable conditioning. No Siamese or albino cats were included in the study. All animals were conditioned to respond to three different test frequencies (2000, 8000, and 14 000 hertz). The pure tone thresholds for each frequency were determined by gradually attenuating the signal to the point that the animal no longer responded. Failure to respond to two or more successive trials at the same sound intensity level was recorded as nonhearing. The last three measurements were averaged to obtain a mean threshold for each test frequency. During drug injections, two of the three frequencies were tested daily for five days a week. Ataxia was evaluated from the animal's voluntary locomotion and from the integrity of the righting reflex in a fivefoot drop. The tests for ataxia were performed before the administration of the study drug, daily on the 10th to 21st days of drug administration and, finally, one day after injection. Cardiac blood samples for determination of blood urea nitrogen (BUN) and serum creatinine levels were obtained terminally. All surviving animals were killed under general anesthesia by perfusion with 0.9% sodium chloride solution, followed immediately by exchange perfusion with 10% formalin. Temporal bones were then removed and stained sections were studied by light microscopy. Also, all cochlear spirals were graphically reconstructed to evaluate hair cell pathology. (The temporal bones of one cat that died during the experiment were also studied, but cardiac perfusion could not be done.) The cats were randomly allotted to one of six groups of four animals each; the groups received either gentamicin or sisomicin at 20, 30 or 40 mg/kg/day (MPK) subcutaneously for 21 consecutive days. Hearing loss was defined as a reduction in pure tone thresholds of more than 20 dB from pretest levels. On this basis, no cat in either the sisomicin 20 MPK or gentarnicin 20 MPK groups showed hearing loss. On the other hand, heating loss and moderate to severe ataxia were seen in all animals that received either drug at 40 MPK and in two animals each in both drug groups receiving 30 MPK dosages. The overall difference between the two drugs in this respect was not significant, but there was a significant difference between the dosage levels used. No significant difference was found between levels of the test tone frequency factor (collapsed across drugs and dosage levels). To sort out differences between individual levels, tests for multiple comparisons of the treatment group means were done. From the test for drug dosage levels, collapsing across the test tone frequency factor, the only differences found to be significant were gentamicin 40 MPK versus gentamicin 30 MPK, sisomicin 20 MPK or gentamicin 20 MPK. There was no statistically significant difference in the results of behavioral audiometry at the three test frequencies, although microscopic studies showed the most extensive sensory hair cell loss and damage to supporting structures (such as the limbus spiralis in some animals) at the basal turn of the cochlea, which, according to others, may be the portion of the cochlea most susceptible to aminoglycoside toxicity. The mean overall extent of hair cell damage over the cochlear spiral ranged from a high of 40% (40 MPK gentamicin group) to zero. The gentamicin-treated animals showed slightly greater cochlear damage at both 40 and 30 MPK. On the basis of behavior, three animals in each of the 30 and 40 MPK groups were judged to have a hearing deficit without, however, any histological evidence of cochlear damage. No signs of ataxia were found in either drug group at the 20 MPK level, but one animal in each group showed slight to moderate ataxia at 30 MPK. All animals in both groups showed variable degrees of ataxia at 40 MPK, with no significant difference in the time of onset for the two drugs (15.8 days for gentamicin, 16.5 for sisomicin). In both treatment groups, the onset of ataxia preceded the mean onset of heating loss by a few days. Histological evidence of crista ampullaris damage was found, to some extent, in both drug groups and it was always more severe than the damage to the maculae. Moderate to severe hair cell loss, flattening of sensory epithelium, collapse of the membranous ampulla and eosinophilic inner ear precipitates were frequent findings. The distribution of vestibular end organ pathology was similar for the two drug groups. Renal impairment, which may have indirectly influenced both hearing and ataxia, occurred at the 30 and 40 MPK dosages of both drugs. Evidence of renal impairment included BUN and serum creatinine values, as well as antibiotic levels in terminal blood samples. A comparison of the ototoxicity of gentamicin and sisomicin in cats showed no significant differences between the two drugs. Behavioral audiometry response and tests for