The results from this study provide estimates of the occurrence of cochleotoxicity in the CF patient group following repeated administration of AG therapy. They also raise broader questions about the mechanism of AG cochleotoxicity in the normal and CF genotype.
This study found that in 70 screened CF patients, the incidence of ototoxicity, judged from the degree of threshold elevation in the standard PTA, was 12 in 70 or ca. 17%. This loss was likely to be irreversible in at least eight of these patients. The range of loss in the standard PTA varied from 20 to 85 dB HL. There was also clear evidence in these 12 patients of significant threshold elevations (measured in decibels SPL) in the high-frequency (10- to 16-kHz) part of the audiogram compared to the control groups. The proportion of patients in this study identified as having sustained hearing loss by the appearance of their standard PTA is in line with two earlier reports (30
; Morgan et al., Abstr. 1987 BTS Meet.). These authors found that 7 (16%) of 43 and 8 (30%) of 26 CF patients had at least one standard PTA threshold over a range of 4 to 8 kHz in excess of 30 dB HL with repeated courses of AG therapy.
Distinct differences in the G:T use ratio between the normal-hearing pediatric group and the adult group were seen, with use of tobramycin predominating in CF adults by 20 versus 80%. Since 11 of the 12 subjects in the CF hearing-loss group were adults, the G:T use ratio in this group would have perhaps been expected to be closer to 20 versus 80% rather than the actual one of 41 versus 59%. This could be taken as evidence that gentamicin use may be associated with greater cochleotoxic risk although, based on the small data set presented here, it would be premature to consider one drug to be more cochleotoxic than the other.
There was no evidence that the overall median peak levels in plasma within the CF hearing-loss group were significantly elevated above that of the adult group. Moreover, single incidences of peak or trough levels in plasma above the therapeutic range were not associated with the development of the hearing loss seen in this study.
There was an increased risk of threshold elevations in the standard audiogram related to the median number of courses of AG therapy. However, this risk did not appear to be related in a linear manner to the number of courses received. The results from Fig. suggest an idiosyncratic response to repeated AG exposure. This absence of a linear relationship is likely to reflect the multifactorial contribution to the onset and progression of AG-induced hearing loss (2
). This idea is supported by a number of distinct pharmacokinetic and biochemical processes identified from experimentally induced cochleotoxicity outlined below.
Clinically, the patients in this study were asymptomatic and apparently unaware of any hearing loss, even when it had substantially progressed into the mid-frequencies of less than 6 kHz involved in speech perception. This indicates that CF patients cannot be expected to self-report hearing loss and that questioning alone is likely to miss the onset and progression of hearing loss. By the time the CF patient would be aware of any hearing loss, it would be too late to attempt to ameliorate or limit the progression by changing the antibiotic therapy. However, it is also important to note from this study that, for about the first 10 courses of AGs, the therapeutic benefit could be deemed to outweigh the risk of cochleotoxicity.
From a mechanistic point of view, the patient group who did not have any measurable elevation in standard PTA thresholds, compared with controls, are of equal interest to those who did. In this group, the absence of any threshold elevation suggests that repeated cochleotoxic challenge was consistently dealt with. This protective response appeared to extend through to the higher frequencies, which are normally considered to be particularly vulnerable to AG insult (2
). In fact, the success of CF patients in dealing with repeated cochleotoxic challenge is further supported by a number of previous studies (33
). These studies reported that no evidence of threshold elevation over the standard PTA took place in patients who had received multiple courses of AG therapy.
Taken together, the results presented here, along with those of previous reports, suggest that there is an apparent contrast in the incidence of cochleotoxicity in CF patients compared with that in non-CF patients. The estimates for cochleotoxicity in non-CF groups of 5 to 10% are typically for short single courses of AG therapy (10
). This incidence is further contrasted by the longer courses, higher dosing, and higher peak AG concentrations in plasma required in CF patients. On these grounds alone, a doubling of the per-course risk in CF patients could be expected.
The interpretation of these results depends on whether the primary features of the AG pharmacokinetics and toxicology derived from animal models also extend to humans. The key features from this experimental work include the following: AG penetration of cochlear endolymph and perilymph in the micromolar range; selective uptake by cochlear outer and inner hair cells (OHCs and IHCs, respectively); acceleration in uptake by OHCs and IHCs with increasing length of exposure; a biphasic release from these cells, a fast phase (t1/2 measured in days) and a second slow phase (t1/2 measured in months).
Within the OHCs and IHCs, the main features determining cochleotoxicity are (i) an AG “storage” threshold, below which AG remains as a dormant “protoxin” and, when this threshold is exceeded, AG is involved in the generation of an “active toxin” species (2
) and (ii) detoxicant processes involving free-radical scavengers that may ameliorate the severity of damage. This suggests that the active toxin is a free-radical species (37
Of these features, perhaps the most important in modeling repeated-course cochleotoxic risk is the prolonged half-life of AGs in the hair cells. If this also applies in humans, then repeat courses, separated by intervals shorter than this half-life, would be expected to result in the accumulation of the drug in the sensory cells.
If, however, the AG half-life in OHCs and IHCs in humans was much shorter than estimated from the experimental model (2
) (i.e., days instead of months), then appreciable accumulation of the drug following multiple courses would be unlikely to occur. In this case, the simplest estimation of cochleotoxic risk would be provided by a single exponential model similar to that used in the equation described above. This model is based on the assumption that in any given course, AG levels in the hair cells will exceed a simple “toxic threshold” in a probabilistic manner. If we assume there is a much shorter half-life of AGs in cochlear sensory cells, then the residual AG levels from previous exposure would be negligible. Consequently, the probability of crossing this cochleotoxic threshold in any given course would then effectively be independent of any previous exposure. If this is true, then the per-course cochleotoxic risk returned for CF patients of about 1.7% in this particular study, and this probably represents a reasonable preliminary estimate.
If, on the other hand, the characteristics of AG pharmacokinetics from the animal model do apply in humans, then these preliminary estimates of ototoxic risk would require a fundamentally different interpretation. In CF patients receiving courses of AGs every 6 to 12 months, substantial accumulation of the drug in the OHCs and IHCs would be expected to occur. If we assume that a threshold concentration of the protoxin AG has to be reached prior to the generation of an active toxin, the probability of crossing this threshold would increase with every subsequent course. This would mean that the overall per-course estimate of 1.7% returned here would not realistically reflect the repeated-course cochleototoxic risk. Instead, there would be an increase in risk with each subsequent course. The calculation of this incremental risk would lead to a much lower single-course value.
If this latter scheme is generally correct, it would have relevance to the broader understanding of the mechanisms for AG cochleotoxicity in both CF and non-CF groups. The most conservative interpretation would be to assume that cochleototoxic risk in these groups is generally similar. The results presented here, which are likely to be cases of irreversible ototoxicity, although interesting, would be clinically unremarkable. This would then suggest that the previously reviewed reports of single-course ototoxicity of between 5 and 10% (10
) were composed of estimates of both reversible and irreversible cochleotoxicity, which were not sufficiently differentiated between by longer-term serial audiometry. The figures of ca. 1.7% reported here would then be in line with some of the more conservative reports of single-course cochleotoxicity (14
Mechanistically, the extent of cochleotoxicity in any one individual would be explained by the dynamic balance between the factors outlined above, a balance between generation of the toxin and the detoxicant systems removing the toxin. For example, repeated AG exposure could cause “upregulation” of detoxicant systems in the OHCs and/or IHCs. Upregulation of these systems in response to moderate ototrauma has already been demonstrated experimentally (22
Alternatively, these results could be explained by the possibility that the CF condition itself is responsible for significantly attenuating the progression of AG cochleotoxicity. There is clinical and experimental evidence to support this idea. It is already known that the CF condition results in a more rapid renal elimination of other drugs, including AGs (14
). It has been proposed that the defective or absent CF transmembrane regulator protein (a cyclic AMP-activated chloride transporter) may underlie this accelerated elimination of some of these xenobiotics (46
). This defect could also conceivably result in reduced cochleotoxicity, due to similarly enhanced outward transport of AGs from the OHC and/or IHCs. Alternatively, the CF defect may underlie an increase in the activity or efficiency of detoxicant pathways within the OHC and/or IHCs.
If these ideas are at least partly correct, then they may yield important clues as to the mediation of and protection against AG cochleotoxicity in humans. Apart from any theoretical utility, the results reported here are of direct clinical relevance, providing new estimates of cochleotoxic risk with repeated-course AG therapy in CF patients. These estimates suggest that during the first 10 courses or so, the balance is toward therapeutic benefit with a relatively low risk of cochleotoxicity.