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Quantitative comparison of aminoglycoside nephrotoxicity in rats for effective screening and evaluation of new derivatives, and dosing rationales that minimise toxicity

Abstract number: P1979

Kostrub C.F., Diokno R., Aggen J., Miller G., Judice K., Tulkens P.

Objectives: Aminoglycosides (AG) are a well-known class of antibiotics with an established record of efficacy, but limited in their use because of the risks of oto- and nephrotoxicity. To support the development of the next generation of AGs with an improved antibacterial spectrum and clinical safety (neoglycosides), we have refined a rat toxicity model to effectively quantitate AG nephrotoxic potential. The model was based on integration of extensive past research on AG nephrotoxicity and allows for effective screening of novel AGs with potentially reduced nephrotoxicity.

Methods: Our standard rat nephrotoxicity study design used 14 days of once-daily dosing. We also monitored changes in serum markers of glomerular filtration rate (GFR) and microscopic examination of kidney slices using H&E staining, as well as scoring of cellular necrosis, tubular dilation, and basophilia. This rat model provided a consistent measure of AG nephrotoxicity, as evidenced by the reliable dose-response of serum creatinine changes for gentamicin across a number of independent studies (no change at 10 mg/kg, mild elevation at 30 mg/kg, and >2x elevation/mortality at 100 mg/kg).

Results: Neomycin, sisomicin, gentamicin, apramycin, tobramycin, paromomycin, and amikacin were evaluated. Their nephrotoxic ranking in this rat model (minimum dose that affects GFR) correlates well with their relative clinical nephrotoxicity, where clinical data are available. AG induced kidney changes were detected by H&E at doses many multiples below those that cause a GFR functional deficit (30x for gentamicin). Consistent with prior work and the model that kidney uptake of AGs is a saturable process, once-daily dosing of gentamicin was significantly less toxic than twice- or three-times daily dosing of the same total daily dose. Also, supporting the model that AG nephrotoxicity is correlated to the total duration of treatment, we found that limiting the duration of dosing to 5 days allows for doubling the dose of gentamicin without a significant increase in toxicity compared with 14 days of dosing.

Conclusions: Our rat model allows for a consistent evaluation of the nephrotoxic potential of AGs, and also points to conditions that minimise toxicity. This model should allow for the reliable evaluation of the nephrotoxic potential of new AG derivatives, and guide their selection for further clinical development. This work also provides a rationale for shorter course dosing of AGs to minimise toxicity.

Session Details

Date: 16/05/2009
Time: 00:00-00:00
Session name: 19th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Helsinki, Finland, 16 - 19 May 2009
Presentation type:
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