Experimental study on the ototoxicity of amikacin at therapeutic doses in infant guinea pig

Objective To clarify the possibility of higher sensitivity to ototoxicity of aminoglycosides and its causes in infant guinea pig by comparing the differences of ototoxicity and pharmacokinetics among different age groups of guinea pig (including premature and neonatal animals) given amikacin with therapeutic doses equal to clinical doses. Methods There were 31 guinea pigs in each of neonatal, infant and adult groups and 10 in premature group. Six guinea pigs in each group were used as control. Amikacin was intramuscularly injected at a dose of 65 mg/kg (which is equal to the clinical therapeutic dose) once a day for 14 days. Five to 8 guinea pigs in each group were sacrificed for histological and scanning electron-microscopic examination of cochlea on the day after the 3rd, 5th, 7th, 10th and 14th day of drug administration, as well as on the 28th day. Pharmacokinetic parameters were investigated in all but premature group with 16 guinea pigs from each by TDx system. Results (1) The Pharmacokinetic parameters were compatible with the model of two compartments in all age groups. There were no significant differences in the peak level and peak time among the groups. The neonatal group had lower plasma clearance than the infant and adult groups [ (0.004 4 ± 0.001 1) , (0.009 7 ± 0.004 2) and (0.008 8 ±0.001 4) L/ (min · kg) , P < 0.01 for all] ; the half-life for elimination was longer [ (71 ± 13) , (53± 11) and (43 ± 8) min, P < 0.05 and P < 0.01 respectively] ; the AUC was larger [ (11 462±4 317) , (8 349 ± 1 470) and (8 166 ± 3 213) , P < 0.01 for all] . There was no statistically significant difference between the infant and adult groups in single-dose pharmacokinetics. The blood levels of amikacin after daily administration in neonatal guinea pigs were predominantly higher than those in infant and adult groups, and were increased markedly since the 10th day. It did so in infant group since 14th day. These results indicated that there was an increased accumulation of amikacin in neonatal and infant guinea pigs. (2) On histological examinations of cochlea, many stereocilia were found lain down or disappeared as early as on the 3rd day and a number of outer hair cells were found disappeared on the 5th day in either premature or neonatal group on scanning electron-microscopy. The change of stereocilia at 5th day in infant and adult groups was similar to that in premature and neonatal groups. Microscopic observation showed that more hair cells were absent in neonatal group than in infant and adult groups after the 7th day (P < 0.05 or P < 0.01) . The hair cell absence was more obvious in premature group than in neonatal group. The hair cell absence in infant group was more severe than in adult group on 28th day (P < 0.05) . The severity of cochlea damage became worse with a prolonged course of amikacin administration. Continuous damage was observed within 2 weeks after the drug administration was stopped in all groups. Conclusions Significant ototoxicity of amikacin to cochlea was well observed in infant guinea pigs with various severity, particularly in premature and neonatal animals at a dose equal to clinical therapeutic dose. The severity of cochlear damage became worse with a prolonged course of the administration. The ototoxicity occurred much earlier and more severe in premature and neonatal animals. The damage to cochlea could continue for quite a longer period after the drug administration was discontinued. The higher sensitivity to ototoxicity of amikacin in young guinea pigs seemed to be related to their much slow clearance and accumulation of amikacin. The results suggest that close attention should be paid to the danger of ototoxicity caused by aminoglycosides in children (especially in premature, neonate or infant) even they are administrated at a dose recommended by pharmacopeia and for a regular course. Auditory electrophysiological eximation should be used to monitor the audition during aminoglycosides administration. Aminoglycosides should be avoided in children as long as possible, esp. in those from families with higher sensitivity to ototoxicity of aminoglycosides. Key words: Amikacin; Dose-response relationship, drug; Guinea pigs; Pharmacokinetics