Azithromycin is often used for treating infections related to human immunodeficiency virus (HIV), including those caused by Mycobacterium avium complex (MAC). Azithromycin obtained FDA approval in November 1991. It has a similar mode of action to erythromycin, namely to bind to the bacterial 50S ribosomal subunit and inhibit protein synthesis.

Wallace and colleagues reported three cases of ototoxicity in 21 HIV patients with MAC infections receiving prolonged courses of 500 mg of azithromycin daily. (1) Symptoms occurred at 4 to 12 weeks into treatment and resolved within 2 to 4 weeks after cessation of therapy. Tseng and colleagues identified eight cases of potential azithromycin ototoxicity in a retrospective review of 46 patients from their HIV clinic who had received azithromycin (600 mg daily for a mean of 7.6 weeks). (2) Onset of ototoxicity followed 2 to 20 weeks of treatment and recovery occurred 2 to 11 weeks after discontinuing the azithromycin. Lo and colleagues reported a further case of hearing loss in a 35-year-old man with HIV and Mycobacterium infection treated with azithromycin. (3) There were many possible confounding or contributory factors in these reports, including renal disease, hepatic disease, and concurrent drug therapy, and audiograms were not performed on all patients. However, these papers suggest a potential for ototoxicity when azithromycin is used at these higher doses for prolonged periods in this population of patients.

There have also been reports of hearing loss in patients without HIV infection following azithromycin. Brown and colleagues studied adverse events in 39 elderly patients treated with 600 mg of azithromycin daily for mycobacterial lung disease. (4) Among other effects, 10 (26%) of the patients developed hearing loss that was confirmed on baseline and repeat audiology. When the daily dose was halved to 300 mg in these patients, the adverse effects were reported to resolve.

Bizjak and colleagues described a case of complete deafness in a 47-year-old woman following an 8-day course of intravenous azithromycin for community-acquired pneumonia. (5) They cautioned that intravenous dosing regimens can result in much higher serum concentrations of azithromycin and untoward toxic effects.

Ress and Gross reported a case of irreversible SNHL  in a 39-year-old woman. (6) She was prescribed a 5-day course of azithromycin (500 mg orally for 1 day followed by 250 mg orally for 4 days) for a urinary tract infection. Her medical history was otherwise unremarkable, and she was not taking other medications. She experienced bilateral tinnitus after the first dose, which worsened after the second dose and was accompanied at that stage by a subjective hearing loss. The azithromycin was subsequently stopped. Audiometry demonstrated an asymmetrical high-frequency SNHL that had not improved on retesting 12months later. No pretreatment audiogram was available. Magnetic resonance imaging (MRI) was normal. Mamikoglu and Mamikoglu replied to this paper with a letter to the editor in which they described two further cases of possible azithromycin ototoxicity occurring after short-term low-dose therapy in non–HIV-infected patients. (7) The first patient developed a 70 dB loss in one ear after 3 days of 500 mg (once daily) of azithromycin. Hearing improved to 30 dB after 5 days in conjunction with steroid and antiviral therapy. Their second patient received treatment for an acute otitismediawith a 5-day course of azithromycin (500 mg on day 1 followed by 250mg daily for 4 days) when she developed tinnitus in the affected ear. Audiometry reportedly demonstrated a
mixed (conductive and sensorineural) hearing losswith a mild tomoderate sensorineural component as well as a 10 dB air-bone gap .

Clearly it is difficult to demonstrate cause and effect in all of these cases, especiallywhen there are confounding factors including local pathology in the affected ear and no pretreatment audiometry. These cases raise concerns of azithromycin ototoxicity at lower doses and after shorter treatment durations in otherwise healthy individuals.

Referrences:

1. Wallace MR,Miller LK, Nguyen MT, et al. Ototoxicity with azithromycin. Lancet 1994;343:241.
   
2. Tseng AL, Dolovich L, Salit IE. Azithromycin-related ototoxicity in patients infected with human immunodeficiency virus. Clin Infect Dis 1997; 24:76–7.
   
3. Lo SH, Kotabe S, Mitsunaga L. Azithromycin-induced hearing loss. Am J Health Syst Pharm 1999;56:380–3.
   
4. Brown BA, Griffith DE, Girard W, et al. Relationship of adverse events to serum drug levels in patients receiving high-dose azithromycin for mycobacterial lung disease. Clin Infect Dis 1997;
   24:958–64.
   
5. Bizjak ED, Haug MT III, Schilz RJ, et al. Intravenous azithromycin-induced ototoxicity. Pharmacotherapy 1999;19:245–8.
6. Ress BD, Gross EM. Irreversible sensorineural hearing loss as a result of azithromycin ototoxicity. A case report. Ann Otol Rhinol Laryngol 2000; 109:435–7.
7. Mamikoglu B, Mamikoglu O. Irreversible sensorineural hearing loss as a result of azithromycin ototoxicity.A case report. Comment.Ann Otol Rhinol Laryngol 2001;110:102.