D-Methionine reduces tobramycin-induced ototoxicity without antimicrobial interference in animal models Daniel J. Fox, Morris D. Cooper, Cristian A.

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d-Methionine reduces tobramycin-induced ototoxicity without antimicrobial interference in animal models Daniel J. Fox, Morris D. Cooper, Cristian A. Speil, Melissa H. Roberts, Susan C. Yanik, Robert P. Meech, Tim L. Hargrove, Steven J. Verhulst, Leonard P. Rybak, Kathleen C.M. Campbell Journal of Cystic Fibrosis Volume 15, Issue 4, Pages 518-530 (July 2016) DOI: 10.1016/j.jcf.2015.06.005 Copyright © 2015 Terms and Conditions

Fig. 1 Baseline ABR thresholds for 4, 8, 14, and 20kHz tone-burst frequencies for all tobramycin-treated control and d-met dosing groups. Journal of Cystic Fibrosis 2016 15, 518-530DOI: (10.1016/j.jcf.2015.06.005) Copyright © 2015 Terms and Conditions

Fig. 2 ABR threshold shifts at 2, 4, and 6weeks for 4, 8, 14 and 20kHz tone-burst frequencies for all tobramycin-treated control and d-met dosing groups. Six guinea pig groups (n=10) were treated daily with 100mg/kg/day tobramycin sulfate for 21days. Five experimental groups received doses of 240, 300, 360, 420 or 480mg/kg/day d-met 15min prior to and 7h after each tobramycin administration. Significant results differing from the control group at an α-level of 0.05 or 0.01 as determined by a Dunnett's post-hoc test are indicated by one or two closed stars, respectively. Significant results differing from d-met-treated groups at an α-level of 0.05 or 0.01 as determined by a Tukey's post-hoc test are indicated by one or two open stars, respectively. Error bars represent +/−1 SD. Journal of Cystic Fibrosis 2016 15, 518-530DOI: (10.1016/j.jcf.2015.06.005) Copyright © 2015 Terms and Conditions

Fig. 3 Remaining outer and inner hair cell percentages at sacrifice for treatment groups at 4, 8, 14 and 20kHz tone-burst frequencies. Three weeks after a 21day treatment course, cochleae were harvested and prepared for OHC viewing and analysis. Significant results differing from the control group at an α-level of 0.05 using Dunnett's test are indicated with one star. Error bars represent +/−1 SD. Journal of Cystic Fibrosis 2016 15, 518-530DOI: (10.1016/j.jcf.2015.06.005) Copyright © 2015 Terms and Conditions

Fig. 4 Cochlear outer hair cell SEM micrographs of animals treated with tobramycin and saline (left) or tobramycin and d-met (420mg/kg/dose; right) in the 4kHz (middle), 8kHz (basal), and 14kHz (hook) cochlear regions. Three weeks after a 21day treatment course, cochleae were harvested and prepared for OHC viewing and analysis. d-Met treatment significantly increased remaining OHC counts only in the 20kHz region (p≤0.05). However, increased OHC counts were observed throughout the cochlea. Scale for each image ranges from 20 to 25μm. Journal of Cystic Fibrosis 2016 15, 518-530DOI: (10.1016/j.jcf.2015.06.005) Copyright © 2015 Terms and Conditions

Fig. 5 Mean Fractional Inhibitory Index (FIC) for tobramycin and d-met concentrations. A checkerboard assay was used to determine MIC values of tobramycin (128–0.25μg/ml) in combination with a serial dilution of d-met (6400–100μg/ml). FIC values were calculated using previously determined MIC results for tobramycin and d-met and E. coli, S. aureus, or P. aeruginosa (n=6 for E. coli and S. aureus; n=5 for P. aeruginosa). Journal of Cystic Fibrosis 2016 15, 518-530DOI: (10.1016/j.jcf.2015.06.005) Copyright © 2015 Terms and Conditions

Fig. 6 Clinical isolate time course inhibition assays for tobramycin/d-met combinations. Graphs show optical density plotted over time during bacterial log growth phase. Tobramycin (at MIC) was combined with serial d-met dilutions (6400–100μg/ml) and compared to clinical isolate growth. Studies were performed in triplicate. d-Met did not significantly inhibit antimicrobial efficacy (p≤0.05). Clinical isolates tested were: A) E. coli; B) S. aureus; and C) P. aeruginosa. Journal of Cystic Fibrosis 2016 15, 518-530DOI: (10.1016/j.jcf.2015.06.005) Copyright © 2015 Terms and Conditions

Fig. 7 Post antibiotic effect (PAE) assays of an E. coli clinical isolate with tobramycin (2μg/ml). E. coli was exposed to tobramycin alone and in combination with serially diluted d-met (6400–400μg/ml) for 2h at 37°C. Tobramycin/d-met combinations were compared to isolate and d-met (6400μg/ml d-met and media) controls. Studies were performed in triplicate. All tobramycin/d-met growth curves were significantly inhibited (p≤0.05) when compared with isolate controls and d-met controls. Journal of Cystic Fibrosis 2016 15, 518-530DOI: (10.1016/j.jcf.2015.06.005) Copyright © 2015 Terms and Conditions