MDR-TB is a growing problem throughout the world [20
]. The selection of drug resistant M. tuberculosis depends on the frequency of the specific drug-resistant mutants in the initially drug-susceptible bacterial population. As a consequence, the chance of selecting such mutants is highest in the case of mono-therapy [4
] and this is the rationale of combination chemotherapy both in case of drug-susceptible as well as MDR-TB even at the cost of adverse drug reactions so that mutants resistant to a single drug are not easily selected by mono-therapy. Adherence to treatment is a critical factor in the management of MDR-TB and adverse events associated with second line drugs could have a severe impact on adherence because long term use of second line drugs is required in MDR-TB ranging from 18–24 months [21
]. A large literature exists on the adverse effects of anti-tuberculosis medications, which range from minor to life threatening [10
The main constraint to the administration of aminoglycosides are risks of nephrotoxicity and ototoxicity [24
]. Ototoxicity is the major irreversible toxicity of aminoglycosides. Cochlear damage can produce permanent hearing loss, while damage to vestibular apparatus results in dizziness, ataxia and/or nystagmus. Aminoglycosides appear to generate free radicals within the inner ear, with subsequent permanent damage to sensory cells and neurons resulting in permanent hearing loss [14
]. The other major limitation to the clinical use of aminoglycosides continues to be concern for the development of nephrotoxicity. Nephrotoxicity has been defined as an increase in the baseline serum creatinine concentration of 0.5 mg/dl or a 50% increase, whichever is greater, on two consecutive occasions any time during therapy or up to 1 week after the cessation of therapy [25
]. Evidence from studies with animals and humans has demonstrated a correlation between the nephrotoxic effect of aminoglycosides and the accumulation of these drugs in the cortex of kidney [26
The present study evaluates the effect of parenteral second line aminoglycosides namely amikacin, kanamycin and capreomycin on hearing status of MDR-TB patients. We report a hearing loss documented by pure tone audiometry in 18.75% patients of MDR-TB using a single parenteral second line aminoglycoside involving higher frequencies (4000 to 8000 Hz) to start with and progressing to involve lower frequencies (500, 1000, 2000 and 3000 Hz) in 6.25% thus affecting the speech comprehension of the patient (n = 64). Speech comprehension can also be affected with hearing loss in the 4000 Hz range and may adversely affect communication especially in situations like environments with back ground noise [29
]. The loss once developed has been found to be irreversible and none of the patients in the present study showed any improvement after stopping the therapy.
Ototoxicity is determined by comparing baseline data, ideally obtained prior to ototoxic drug administration, to the results of subsequent monitoring tests. Detecting changes in pure tone thresholds directly using serial audiograms is considered the most effective indicator of ototoxic hearing loss, particularly when ultra-high frequency thresholds are included [17
]. Monitoring audiological evaluations after the baseline evaluations have been recommended 1–2 times per week for patients receiving ototoxic antibiotics [17
]. Other approaches to audiologic monitoring for ototoxicity are high frequency audiometry and otoacoustic emissions [30
In the present study, pure tone audiometry was performed every other month for each patient until the completion of therapy. Because aminoglycoside ototoxicity can progress after discontinuation of the drug [13
], we also performed audiometric follow-up in all patients for an average of over one year after drug discontinuation. This long term follow-up confirmed that all aminoglycoside-induced hearing loss in this patient population was permanent and not reversible. Persistence of toxicity of sera has been reported up to one year in patients using aminoglycosides even after stopping the ototoxic drug [31
]. Twice weekly audiograms as recommended were not performed in the present study because of cost involved and the inability of the patients from far distant places to report twice weekly at our center where facilities for conventional assessment of hearing are available. It is not common to find equipment for audiometry as well as trained staff at peripheral centers in developing country like ours. Conventional frequency range (250–8000 Hz) was used in the present study as only conventional audiometers with frequency range between 125 and 8000 Hz are available with us owing to low cost compared to high frequency equipment.
Different studies have reported hearing loss as an adverse drug reaction in patients of MDR-TB ranging from 6–18% [21
]. The finding that higher frequencies are involved before the lower frequencies may be used as a monitoring procedure for the detection of ototoxicity and has the potential for minimizing irreversible communication deficits in patients receiving aminoglycoside therapy [32
]. In all the patients showing hearing loss, the aminoglycoside was stopped and changed to another second line drug done. Incidence of hearing loss may have been reduced because the aminoglycoside was stopped immediately at the outset of ototoxicity and substituted with another second line drug. All the patients included in the present study completed the remaining part of the therapy. Other authors have also reported changing to other second line drugs and completion of full therapy [21
A number of otoprotective agents are being investigated for protection against hearing loss induced by cisplatin, carboplatin, aminoglycosides or noise exposure. These agents delivered either before or in combination with ototoxic drugs may help to prevent ototoxicity. D-methionine as an otoprotective agent has shown protection against amikacin induced ototoxicity [33
There is evidence that aminoglycoside accumulation in the kidney may be related to the dosing schedule i.e. administration of larger doses less frequently may reduce the level of drug accumulation in the kidney and has been prospectively shown to reduce the nephrotoxic potentials of aminoglycosides [25
]. Conventional multiple daily dosing is being gradually abandoned in favor of once daily dosing and results from meta-analysis of randomized clinical trials show diminished [34
] or comparable [35
] nephrotoxicity, better [35
] or comparable [34
] efficacy and comparable [34
] ototoxicity with once daily dosing among adults. Once daily dosing has been used in all the patients in the present study but individualized dosing based on monitoring of serum levels of aminoglycosides has not been used in present study.
Individualized aminoglycoside dosing guided by targeted peak and trough concentrations in serum on the basis of the patient's individual pharmacokinetics parameters and standard equations has been related to decreased toxicity [40
]. An association of ototoxicity with nephrotoxicity and with an elevated mean trough aminoglycoside serum level has been observed in patients treated with aminoglycosides [41
]. Because of economic constraints and the non-affordability by the patients, serum levels of aminoglycosides during the therapy were not measured in the present study. But with individualized dosing based on patient's individual pharmacokinetic monitoring guided by targeted peak and trough concentrations, side effects could probably be avoided in some cases.
First row outer hair cells (OHCs) in the basal turn tend to be affected earlier than inner apical cells and type I cells are affected before type II cells. The progression of hair cell loss in cochlea tends to be from basal to apical and from OHCs to inner hair cells (IHCs) to supporting cells to more central neural structures like spiral ganglion cells [42
]. This stepwise progression of damage explains the clinical findings of high frequency hearing loss occurring first with ototoxic drugs.