Protection from ototoxicity of intraperitoneal gentamicin in guinea pig.
BACKGROUND
Aminoglycoside antibiotics are common to treat peritonitis and exit-site infections in patients on peritoneal dialysis. Ototoxicity (loss of hearing or balance) is a well-documented adverse effect of aminoglycosides, and severe ototoxic reactions have been noted in patients receiving these drugs by intraperitoneal lavage. We have proposed a free-radical hypothesis for the mechanism of aminoglycoside ototoxicity and suggested a therapeutic prevention by the concomitant administration of antioxidants or iron chelators. Here we investigate whether 2, 3-dihydroxybenzoate can prevent the ototoxicity of intraperitoneal gentamicin.


METHODS
Two strains of pigmented guinea pigs received daily intraperitoneal injections of gentamicin. Both strains developed ototoxicity, although different dosages were needed to produce similar auditory deficits (120 mg gentamicin base/kg body weight daily for 19 days vs. 135 mg/kg for 14 days). Dihydroxybenzoate was administered intraperitoneally once or twice daily. Auditory thresholds were measured by evoked brain stem response. Pathology was assessed as a loss of sensory cells in surface preparations of the organ of Corti.


RESULTS
The auditory threshold shifts and hair cell loss were similar to the pathology observed following subcutaneous injections of gentamicin. Animals sustained almost complete loss of outer hair cells in the basal cochlea and a progressive hearing loss with threshold shifts of 60 dB at 18 kHz. The concomitant administration of dihydroxybenzoate significantly attenuated the threshold shift to less than 30 dB and reduced the loss of hair cells. The treatment with dihydroxybenzoate did not affect serum gentamicin levels.


CONCLUSIONS
Antioxidant therapy is a promising approach to prevent aminoglycoside-induced hearing loss following intraperitoneal application.
Sinswat
P
P
Kresge Hearing Research Institute, Department of Otolaryngology, University of Michigan, Ann Arbor, Michigan, USA.
Wu
W J
WJ
Sha
S H
SH
Schacht
J
J
D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology; D001309:Auditory Threshold / Q000187:drug effects; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D005839:Gentamicins / Q000097:blood / Q000633:toxicity*; D006168:Guinea Pigs; D006319:Hearing Loss, Sensorineural / Q000139:chemically induced* / Q000188:drug therapy / Q000517:prevention & control*; D062385:Hydroxybenzoates / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007502:Iron Chelating Agents / Q000494:pharmacology*; D007668:Kidney / Q000502:physiology; D008297:Male; D009925:Organ of Corti / Q000473:pathology; D012709:Serum Albumin; D014722:Vestibule, Labyrinth / Q000473:pathology / Q000502:physiology
D000900:Anti-Bacterial Agents; D000975:Antioxidants; D005839:Gentamicins; D062385:Hydroxybenzoates; D007502:Iron Chelating Agents; D012709:Serum Albumin; C009135:2,3-dihydroxybenzoic acid; D003404:Creatinine