Reduction of cisplatin ototoxicity by fosfomycin in animal model

The protective effect of fosfomycin against cisplatin-induced ototoxicity was studied in rats. Sixty-four Fischer rats were injected intravenously with daily doses of 1, 2, 5, and 10 mg/kg of cisplatin with or without 300 mg/kg of fosfomycin for a varying period from 1 to 10 days. The total dose of 10 mg/kg of cisplatin was given equally in all animals. Inner ear damage appeared to be more reduced histopathologically in animals given both cisplatin and fosfomycin than in animals given cisplatin alone. Similarly, renal damage appeared to be reduced histopathologically and functionally by the combined administration of cisplatin and fosfomycin.     

Protective effect of fosfomycin against aminoglycoside ototoxicity

The protective effect of fosfomycin against aminoglycoside (dibekacin)-induced ototoxicity was studied in rats. Rats were injected with 100 or 50 mg/kg of dibekacin with or without 500 mg/kg of fosfomycin for 60 or 120 consecutive days. Inner ear damage appeared to be more reduced histopathologically in animals given both dibekacin and fosfomycin than in animals given dibekacin alone. Similarly, renal damage appeared to be reduced histopathologically and functionally by the combined administration of dibekacin and fosfomycin. The mechanism of reduced ototoxicity may be as follows: fosfomycin inhibits the accumulation of dibekacin in the kidney, and reduces its concentration in the kidney and serum. Consequently, the amounts of dibekacin reaching the inner ear are decreased, and ototoxicity is reduced.     

Effect of topical fosfomycin on polymyxin B ototoxicity

Fosfomycin is an antibiotic that has been found to reduce the ototoxicity of aminoglycoside antibiotics and cisplatin when systemically coadministered. Polymyxin B, an antibiotic frequently used in ototopical preparations, has been shown to be ototoxic in experimental studies. To investigate the effect of fosfomycin on polymyxin B ototoxicity, topical administration of the two agents into the middle ear cavity was performed. Two groups of chinchillas were used. One group received applications of polymyxin B alone, and the second group received polymyxin B combined with fosfomycin. It was found that application of polymyxin B produces severe damage to the cochlea. However, when polymyxin B was given in combination with fosfomycin, cochlear damage was dramatically reduced. It is likely that in clinical use, a combination of polymyxin B and fosfomycin would demonstrate reduced risk of ototoxicity.     

Mechanism of protective effect of fosfomycin against aminoglycoside ototoxicity

The purpose of this study was to clarify the mechanism of the protective effect of fosfomycin (FOM) against inner ear damage induced by an aminoglycoside dibekacin (DKB), when administered concurrently DKB and FOM. Rats were treated with 50 mg/kg of DKB with or without 500 mg/kg of FOM for short-term administration. No significant difference was seen in the serum peak level and in the area under the curve between the group receiving DKB alone and the combined administration group of DKB and FOM. On the other hand, the DKB level in the kidney was significantly lower in the combined administration group than in the group receiving DKB alone. The mechanism of protective effect of FOM against DKB-induced ototoxicity may be considered as follows: FOM inhibits the accumulation of DKB in the kidney and reduces its concentration in the kidney and serum. Consequently, the transferability of DKB into the inner ear is decreased, and finally inner ear damage is reduced.     

Potentiation of ototoxicity by glutathione depletion

The combination of 10 mg/kg ethacrynic acid (ETA) and 100 mg/kg kanamycin (KA) caused neither morphologic damage to the cochlea nor change in the auditory brain stem response of the chinchilla. However, after pretreatment with a single dose of buthionine sulfoximine (BSO; 800 mg/kg intraperitoneally) to reduce intracellular glutathione (gamma-glutamylcysteinylglycine; GSH) levels, the above single administration of ETA and KA resulted in complete deafness and severe morphologic damage. The kidney, which has a rapid GSH turnover and is therefore especially susceptible to GSH depletion by BSO, also demonstrated severe damage after this treatment. A similar rapid turnover of GSH and resulting limited capacity to detoxify reactive metabolites and free radicals may determine cochlear and renal vulnerability to this toxicity. These findings may explain the clinical observations of enhanced ototoxicity in patients administered amino-glycoside antibiotics concomitantly with loop diuretics.     

Abolition of optokinetic afternystagmus by aminoglycoside ototoxicity

We studied optokinetic afternystagmus in eight subjects with loss of or impairment of vestibular function due to ototoxic antibiotics. We found that the initial amplitude, the time constant, and the slow-phase cumulative eye position of optokinetic afternystagmus were significantly reduced in the patients. Slow-phase cumulative eye position most reliably distinguished our patients' responses from those of a normal group.     

Prophylaxis of kanamycin-induced ototoxicity by a radioprotectant

S-2 (3-aminopropylamino)ethylphosphorothioate ameliorates hearing losses due to ototoxic doses of kanamycin sulfate in the guinea pig when administered one hour before the antibiotic. Since this radioprotectant is believed to operate as a free-radical scavenger, kanamycin ototoxicity may involve free radicals.     

Bromocriptine-associated ototoxicity

Three patients treated with bromocriptine for chronic hepatic encephalopathy showed audiometric evidence of bilateral sensori-neural hearing-loss. Audiometrically, the hearing improved in all three patients when the bromocriptine dosage was reduced, thus suggesting that this drug may produce a reversible ototoxicity.     

Aminoglycoside ototoxicity

PURPOSE OF REVIEW: To summarize mechanisms of ototoxicity associated with aminoglycoside antibiotics and discuss possible protective strategies. RECENT FINDINGS: Studies in the past 15 years have demonstrated that aminoglycoside ototoxicity is mediated by an apoptotic form of cell death which employs caspase-dependent pathways. Reactive oxygen species have been demonstrated in the sensory epithelium after aminoglycoside administration and methods of blocking reactive oxygen species in the cochlea have been attempted, but not found to be uniformly effective in protecting against cell loss or threshold shift. Aspirin has recently been studied in a human chemoprevention trial in China, and while data suggest the possibility of protection, there was a significant increase in gastrointestinal bleeds associated with aspirin use. SUMMARY: There are currently no recommendations for pretreatment or posttreatment therapies to attenuate ototoxicity associated with aminoglycoside antibiotics. Our understanding of the mechanisms of ototoxicity has improved and apoptotic pathways are clearly responsible for hair cell demise. Further studies are necessary before significant improvement in hearing outcome can be expected after use of ototoxic antibiotics.     

Aminoglycoside ototoxicity

The author participated in two prospective studies of patients receiving aminoglycoside antibiotics. In the first study, 54 patients received amikacin, and 54 received gentamicin. In the second study, 61 patients received gentamicin, 50 received netilmicin, and 52 received tobramycin. The studies were randomized and the investigator was blinded when evaluating auditory and vestibular toxicity and nephrotoxicity. All patients had pure tone audiometric evaluations, and two thirds of the patients had vestibular function tests consisting of an electronystagmogram performed with 30 degrees C and 44 degrees C water. Nephrotoxicity was measured by changes in serum creatinine levels. The incidence of gentamicin toxicity in the first study was 11 per cent, and it was 18 per cent in the second study. Amikacin was ototoxic 12.9 per cent of the time, whereas the incidence of tobramycin ototoxicity was 11.5 per cent, and the incidence of netilmicin ototoxicity was 2 per cent. Cases of unilateral, delayed-onset, and reversible auditory and vestibular toxicities were seen in all drug treatment groups. Nephrotoxicity was rare with amikacin usage. Gentamicin, on the other hand, produced a 18.6 per cent, tobramycin a 25 per cent, and netilmicin a 21.3 per cent rate of nephrotoxicity.     

Selective inner hair cell ototoxicity induced by carboplatin

Carboplatin is a second-generation platinum antineoplastic agent. It has biological activity similar to cisplatin and is currently recommended for the treatment of ovarian cancer. In clinical use, carboplatin appears less ototoxic than cisplatin. This paper reports the ototoxic effects of carboplatin, in doses equivalent to the clinical use of the drug, in the chinchilla. Intravenous carboplatin 200 to 400 mg/m² by bolus injection caused significant ototoxicity in this model as revealed by brainstem evoked responses (ABR audiometry). The cochlear pathology as seen by scanning electron microscopy revealed predominantly inner hair cell (IHC) stereocilia damage. Furthermore, the extent (grade) of the morphological lesions appears to be well correlated with the auditory brainstem response pattern of threshold elevation.     

Clinical ototoxicity of teicoplanin

No strong evidence of ototoxicity of teicoplanin can be found in the literature, possibly because of conservative definitions of ototoxicity. We performed audiometry over time to compare the ototoxicity of teicoplanin with that of cloxacillin as a non-ototoxic standard. The data were analyzed with a linear mixed-effects model. The hearing thresholds of 12 patients who were treated with teicoplanin for severe staphylococcal infections showed a slight but significant increase over time, whereas the thresholds of 5 patients treated with cloxacillin decreased significantly during treatment. This improvement in hearing with cloxacillin may be attributed to improvement of the clinical condition. This outcome implies that previous reports that suggest a lack of ototoxicity of teicoplanin potentially underestimate the risk and should be interpreted accordingly.     

Mechanisms of salicylate ototoxicity

The ototoxic effects of salicylates, reversible hearing loss and tinnitus, are well documented. However, the pharmacological mechanisms underlying these changes in cochlear function are not well understood. The studies reported here were an investigation of the site and mechanism of salicylate ototoxicity through an examination of its effects on ionic, neural and mechanical aspects of cochlear transduction. Salicylate administration produced an intensity dependent reduction of the AP and SP, with the predominant effects occurring at low stimulus levels. In direct contrast, a significant increase was observed for corresponding CM responses, independent of stimulus intensity. Salicylates also reduced the magnitude of efferent induced shifts in the AP, CM and EP. Cochlear mechanics were altered as evidenced by the reduction in two-tone distortion products, electrically evoked emissions, and electrophonic APs. These changes in cochlear function are attributed to a salicylate mediated increase in the membrane conductance of the outer hair cells. This change in membrane permeability interferes with the reverse transduction process, effectively reducing the gain of the cochlear amplifier. Results of single unit recordings suggest parallels between salicylate intoxication and noise trauma, which are discussed with regard to potential mechanisms of tinnitus generation.