Animal Models of Aminoglycoside Antibiotic Ototoxicity

Abstract

A model of aminoglycoside antibiotic ototoxicity was developed in the guinea pig for the study of parameters of ototoxicity such as frequency specificity, comparative ototoxic potency, latency of onset, laterality, interaction with other agents, and possible complications arising from the use of aminoglycosides in the middle ear space. In this model it was found that aminoglycoside antibiotics (1) produce their initial ototoxic effects on high-frequency auditory function; (2) differ in ototoxic potency; (3) have a latency of onset independent of drug accumulation; (4) can produce unilateral ototoxicity; (5) can have their ototoxic potential augmented by loop diuretics and loud sounds; and (6) can result in ototoxicity when instilled into the middle ear space in otic drops. The results of these studies are discussed in relation to what is known about ototoxicity due to the aminoglycoside antibiotics in humans. Several arguments support the importance of an animal model of aminoglycoside antibiotic ototoxicity. (1) In the clinical setting patients, of necessity, are administered multiple drugs. When an adverse effect such as ototoxicity occurs, it is difficult to detemine the role of a specific drug. (2) patients cannot purposely be given toxic doses of aminoglycosides. Thus, in the clinical setting the incidence of ototoxicity is low. Therefore, a large number of patients would be required for the study of any variable that might influence the incidence of ototoxicity. (3) In clinical studies it is impossible to separate the potential ototoxic effects of the patient's disease from the ototoxic effect of the drug under study.