Absence of cochleotoxicity measured by standard and high-frequency pure tone audiometry in a trial of once- versus three-times-daily tobramycin in cystic fibrosis patients

Abstract

We undertook assessment of hearing in patients with cystic fibrosis who were taking part in a large randomized controlled trial of once- versus three-times-daily tobramycin for pulmonary exacerbations of cystic fibrosis (the TOPIC study). All patients were eligible to have standard pure tone audiometry performed across the frequency range of 0.25 to 8 kHz. High-frequency pure tone audiometry over 10 to 16 kHz was also performed with a subset of patients. Audiometry was undertaken at the start of tobramycin treatment, at the end of a 14-day course of treatment, and at follow-up 6 to 8 weeks later. We enrolled 244 patients, of whom 219 (125 children and 94 adults) completed treatment. Nineteen patients were excluded from analysis due to abnormal baseline audiometry. Complete pre- and posttreatment standard audiological data were obtained for 168/219 patients. We found no significant differences in hearing thresholds when they were assessed at the baseline, at the end of treatment, and at follow-up 6 to 8 weeks later were compared. In addition, no significant differences in hearing thresholds were detected between treatment regimens. Similar results were obtained for the subset of 63/168 patients who underwent high-frequency audiometry. We conclude that for a single 14-day course of tobramycin treatment in patients with cystic fibrosis with no preexisiting auditory deficit, no measurable effect on hearing was apparent with either once- or three-times-daily treatment. Estimation of the cumulative cochleotoxic risk in cystic fibrosis patients due to repeated aminoglycoside therapy, as evidenced by the patients excluded from this study due to hearing loss, also requires further characterization.

FIG. 1.

Flow diagram summarizing the numbers of patients completing audiometric test procedures within the TOPIC study.

FIG. 2.

Standard PTA threshold means ± 95% confidence intervals on day 14 for the (a) right and (b) left ears (n = 168) for once- versus three-times-daily treatments. Across all frequencies, these were found to be directly comparable to each other. No changes between these values and standard PTA thresholds on entry at day 1 were apparent when they were analyzed by ANCOVA.

FIG. 3.

Standard PTA threshold means ± 95% confidence intervals for once- versus three-times-daily treatments at 6 to 8 weeks after entry into TOPIC for (a) right and (b) left ears (n = 79). No difference in treatment means were evident at 6 to 8 weeks and day 1 when they were analyzed by ANCOVA.

FIG. 4.

HFPTA threshold means in dB SPL ± 95% confidence intervals for once- and three-times-daily treatments on day 14 after entry into TOPIC for the (a) right and (b) left ears (n = 63). There were no differences between the HFPTA means at day 14 and on entry day 1 when they were analyzed by ANCOVA.

FIG. 5.

HFPTA threshold means in dB SPL ± 95% confidence intervals for once- versus three-times-daily administration at 6 to 8 weeks after TOPIC entry for the (a) right and (b) left ears (n = 31). There were no differences between treatment means at 6 to 8 weeks and day 1 when they were analyzed by ANCOVA.