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Mechanism of protective effect of fosfomycin against aminoglycoside ototoxicity
Abstract:
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.
Insights
Fosfomycin (FOM) protects against dibekacin (DKB)-induced inner ear damage by reducing DKB accumulation in the kidneys. This lowers overall DKB levels, decreasing its transfer to the inner ear and mitigating ototoxicity.
Area of Science:
- Pharmacology
- Ototoxicity Research
- Nephrology
Background:
- Aminoglycosides like dibekacin (DKB) are essential antibiotics but can cause ototoxicity.
- Fosfomycin (FOM) is known to have a protective effect against DKB-induced inner ear damage.
- The precise mechanism underlying this protective effect requires further elucidation.
Purpose of the Study:
- To investigate the pharmacokinetic mechanism of fosfomycin's protective effect against dibekacin-induced ototoxicity.
- To determine how co-administration of FOM influences DKB levels in serum and kidneys.
Main Methods:
- Rats were administered dibekacin (DKB) alone or in combination with fosfomycin (FOM).
- Serum peak levels and area under the curve (AUC) of DKB were measured.
- DKB concentrations in kidney tissue were quantified.
Main Results:
- Co-administration of FOM did not significantly alter DKB's serum peak levels or AUC.
- Significantly lower DKB levels were observed in the kidneys of rats receiving both FOM and DKB compared to DKB alone.
- FOM administration reduced kidney DKB accumulation.
Conclusions:
- Fosfomycin (FOM) mitigates dibekacin (DKB)-induced ototoxicity by inhibiting DKB accumulation in the kidneys.
- Reduced kidney DKB concentration leads to decreased serum levels and subsequently lowers DKB transfer into the inner ear.
- This mechanism highlights FOM as a potential adjunctive therapy to reduce aminoglycoside-induced ototoxicity.