Ototoxic potential of ACHN-490 compared to gentamicin and amikacin in the guinea pig
Abstract number: P1249
Kostrub C.F., Dolan D.F., Altschuler R.A., Baird T.J., Tapp R.L., Boggs J.A., Bruss J.B.
Objectives: ACHN-490 is a "neoglycoside", a next-generation aminoglycoside (AG), currently being advanced through clinical development by Achaogen, Inc. ACHN-490 shows broad-spectrum bactericidal activity in vitro, and its potency is unaffected by most types of AG-modifying enzymes that confer resistance to AGs. In the present studies, the ototoxic potential of ACHN-490 relative to the AG comparators gentamicin and amikacin was investigated over 28 days in guinea pigs. The relative ototoxicity of shorter duration gentamicin treatment (1, 3, or 5 days) was also studied.
Methods: In the guinea pig model, compounds were administered once-daily for 14 days, and both structural and functional evaluations for ototoxicity were employed. Auditory function was quantified by comparing pre-dose and terminal auditory brainstem response (ABR) values at each of 3 stimulus frequencies (4, 10, and 20 kHz). In addition, cochleas were removed and examined histologically for evidence of hair cell damage. Short-term dosing was investigated by dosing separate cohorts of animals for 1, 3, or 5 days, and assessing ABRs both 1 day after the last dose for each cohort and again 28 days after the initial dose for all cohorts.
Results: Gentamicin at 80 or 100 mg/kg/day for 14 days produced substantial hearing loss. Amikacin, with less antibacterial potency but roughly an equivalent therapeutic index in comparison to gentamicin, was associated with profound hearing loss at a therapeutically comparable dose of 300 mg/kg/day. In both cases, histological analyses showed cochlear hair cell loss consistent with the functional ABR shift. By contrast, ACHN-490 demonstrated no significant effects on ABR thresholds up to a dose of 80 mg/kg/day, with no hair cell loss, as determined by cytocochleogram analyses. Gentamicin administration (80 mg/kg/day) for 1, 3, or 5 days did not result in significant functional ABR shift or histopathological evidence of ototoxicity.
Conclusions: The absence of ototoxicity observed for ACHN-490 in this 28-day guinea pig model suggests a lower ototoxic potential for ACHN-490 compared to gentamicin. The absence of hearing loss with shorter courses of gentamicin may support the hypothesis that the risk of AG-induced ototoxicity could be mitigated by avoiding extended treatment regimens. Taken together, these studies provide rationale for the continued clinical investigation of ACHN-490 in high-dose, short-course antimicrobial therapy.
|Session name:||Abstracts 20th European Congress of Clinical Microbiology and Infectious Diseases|
|Location:||Vienna, Austria, 10 - 13 April 2010|
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