Azithromycin antagonizes aminoglycoside-induced ototoxicity in a zebrafish model. (A) Response seen when fish were exposed to increasing concentrations of azithromycin (AZM) and neomycin (NEO) in checkerboard format, as quantified by PEPITA in relative fluorescence units (RFU). Fish exposed to a combination of AZM and NEO experienced less ototoxic damage than those exposed to NEO alone, at all significantly ototoxic doses of NEO (i.e., ≥1.6 μM) and AZM doses up through 190 μM. In an extreme case, a dose of 6.4 μM NEO, causing 90% HC damage (10% RFU), is reduced to minimal damage (88% RFU) by the addition of 96 μM AZM. (B) excess over Bliss values calculated for the previous checkerboard data: positive numbers indicate synergy, negative numbers antagonism. The trend of reduced damage seen in the checkerboard translates to consistent antagonism, with an overall wEOB of −0.36 for this experiment. (C) Comparison of lateral line HC ototoxic dose response elicited by NEO with vs. without AZM co-administration (96 μM). (D) Comparison of lateral line HC damage in response to ototoxic drug exposure with vs. without AZM co-administration (96 μM). Drugs tested: AMK = amikacin, GEN = gentamicin, KAN = kanamycin, NEO = neomycin, TOB = tobramycin, CAP = capreomycin, CIS = cisplatin. Doses of drugs tested were selected to elicit 70%–95% hair cell damage in the absence of AZM co-administration. Aminoglycosides as a group are more antagonized than the non-aminoglycoside drugs tested (p < 0.0001).
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