Hear loss and tinnitus as side effects of amikacin

Fråga: Hear loss and tinnitus as side effects of amikacin? What is the prognosis of amikacin induced hearing loss? Is it reversible?

Sammanfattning: Aminoglycoside-induced ototoxicity is irreversible. No therapy is currently available to reverse ototoxic damage apart from amplification and cochlear implantation. Studies are continually seeking to find new methods to minimize ototoxic injury while retaining the therapeutic efficacy of aminogycosides. N-acetylcysteine can be considered among high risk patients receiving an aminoglycoside.

Svar: Amikacin is an aminoglycoside antibiotic, active against a broad spectrum of Gram-negative organisms, and some Gram-positive organisms. It is bactericidal in action; appear to inhibit protein synthesis in susceptible bacteria by irreversibly binding to 30S ribosomal subunits (1).

As with other aminoglycosides, ototoxicity is a well documented adverse effect (1). The exact mechanisms of aminoglycoside ototoxicity remain unknown. Formation of free oxygen radicals within the inner ear is thought to induce sensory hair cell apoptosis in both the cochlea and vestibular apparatus, resulting in permanent hearing loss or balance dysfunction, respectively. Aminoglycosides can be detected in the inner ear a short time after the dose is administered systemically up to eleven months after treatment in animal experiments (10).

Aminoglycosides have variable cochleotoxicity and vestibulotoxicity. Amikacin is primarily cochleotoxic. The cochleotoxic effect is reported as permanent because the hair cells in the cochlea do not regenerate (2,3,4).

Symptoms of cochleotoxicity include bilateral hearing loss and/or tinnitus. The high speech frequency (>4000 Hz) is initially affected and then with progression, extends towards the lower frequencies. These symptoms may not be detected and the patient may become profoundly deaf if the drug is continued (1). Aminoglycoside-induced ototoxicity is dose related but it may develop after a single dose or even if serum concentrations within the reference range (10). Genetic predisposing factor has been discussed in various articles (10).

However, the risk increases with the cumulative dose as in patients with impaired renal function, in those who receive high doses or prolonged courses (10). Other high-risk patients include elderly patients, those with a family history of ototoxicity, those with preexisting hearing problems, and those receiving loop diuretics or other ototoxic medications(5). Decreasing daily dose, careful monitoring of serum drug levels and renal function as well as hearing evaluations before, during, and after therapy should be considered whenever possible in high-risk patients.

At present there are no treatments that can reverse the damage. Currently available treatments focus on possible mechanisms to prevent ototoxicity during aminoglycoside treatment. Several agents, including anti-free radical agents, iron chelators, and inhibitors of cell death pathways, have been found to be otoprotective in animal studies. (4).

Effectiveness of aspirin and N-acetylcysteine as an otoprotectant against gentamicin ototoxity was evaluated in small studies.

In a randomized, double-blind placebo-controlled study, 195 patients receiving gentamicin were randomly assigned to receive 14 days of either 3 g of aspirin daily (n= 89) or placebo (n=106). The incidence of hearing loss in the aspirin group was significantly lower (3%) compared to placebo group (13%). However, three patients from the aspirin group are removed from the study because of gastric bleeding (6). Another smaller study of 60 patients using a lower dose of aspirin (1.5 g/d) revealed similar outcome (7). High dose aspirin may provide some protection against ototoxicity of gentamicin at the cost of gastrointestinal toxicity. Both study reports are brief and lack some important information, e.g. renal function of the subject.

The efficacy of N-acetylcysteine (NAC) was evaluated in hemodialysis patients receiving gentamicin. In this study, 53 hemodialysis patients with catheter-induced bacteremia were randomly assigned to gentamicin plus NAC (600 mg twice daily) or gentamicin alone. NAC was given till one week after completion of antibiotic therapy. NAC therapy significantly lowered the incidence of ototoxicity (25 %versus 60 %) and was not associated with any adverse effects (8). Another study that included 60 patients on continuous ambulatory peritoneal dialysis (CAPD) found that oral administration of NAC prevented ototoxicity related to intraperitoneal amikacin and vancomycin, and may have improved high-frequency function at four weeks (9).

We recommend that the case is reported as an adverse event to the Swedish medical products agency. Biklin. Summary of Product Characteristics (last updated 2013-10-17) Greenwood GJ. Neomycin ototoxicity; report of a case. AMA Arch Otolaryngol 1959;69(4):390-7 (abstract) Meyers RM. Ototoxic effects of gentamicin. Arch Otolaryngol 1970;92(2):160-2 (abstract) Huth ME, Ricci AJ, Cheng AG. Mechanisms of aminoglycoside ototoxicity and targets of hair cell protection. Int J Otolaryngol 2011;2011:937861 Roland PS. New developments in our understanding of ototoxicity. Ear Nose Throat J 2004;83(9 Suppl 4):15-6 (abstract) Behnoud F, Davoudpur K, Goodarzi MT. Can aspirin protect or at least attenuate gentamicin ototoxicity in humans? Saudi Med J 2009;30(9):1165-9 Sha SH, Qiu JH, Schacht J. Aspirin to prevent gentamicin-induced hearing loss. N Engl J Med 2006;354(17):1856-7 Feldman L, Efrati S, Eviatar E, Abramsohn R, Yarovoy I, Gersch E, Averbukh Z, Weissgarten J. Gentamicin-induced ototoxicity in hemodialysis patients is ameliorated by N-acetylcysteine. Kidney Int 2007;72(3):359-63 Tokgoz B, Ucar C, Kocyigit I, Somdas M, Unal A, Vural A, Sipahioglu M, Oymak O, Utas C. Protective effect of N-acetylcysteine from drug-induced ototoxicity in uraemic patients with CAPD peritonitis. Nephrol Dial Transplant 2011;26(12):4073-8 Aminoglykosider RAFs rationaldokument. Remissversion 2012-06-27