Antibiotics

Several kinds of antibiotics are known to be ototoxic. The most famous one is aminoglycoside. These ototoxic antibiotics will be discussed below.

 

Aminoglycoside

Introduction:

This group of antibiotic includes streptomycin, kanamycin, neomycin gentamicin, tobramycin, amikacin and netilmicin, all of which containing an amino acid sugar linked to an aminocylitol ring by glycoside bonds. It is famous for its ototoxicity and nephrotoxicity. It is commonly used in treating against gram-negative enteric bacteria, especially when there is bacteremia and sepsis. It is poorly absorbed through gastrointestinal tract and thus, it is commonly given through parental route or sometimes as topical agent, e.g. as ear drop for chronic otitis media. It is cleared through kidney.

Ototoxicity:

Prospective study demonstrates an incidence ranging from 4% to 24%. Generally, almost all patients with aminoglycoside ototoxicity receive it through parental route (intramuscular, intrathecal or intravenous). Ototoxicity can be divided into cochlear toxicity (loss of interpretation of high frequency sound first) and vestibular toxicity. Neomycin and kanamycin are more likely to cause cochlear toxicity while gentamicin and streptomycin are more likely to cause vestibular toxicity. Ototoxicity can also be classified into acute and chronic type. It should also be mentioned that the use of some aminoglycoside (e.g. streptomycin) in pregnant women, especially within the first trimester, may cause ototoxicity and other congenital abnormalities in the fetus.

1. Mechanism:

  1. Postulated mechanism for acute ototoxicity:
  2. It appears that there is an antagonist relationship between aminoglycoside and calcium. Based on this finding, it is suggested that it may block the postsynaptic actions of the excitatory amino acids on primary afferents in the vestibular and cochlear system.

  3. Postulated mechanism for chronic ototoxicity:

Chronic ototoxicity relates to irreversible damage to the cochlear and vestibular hair cell. An important feature is the delayed onset (few weeks to months after cease of treatment) of cochlear and vestibular damage in almost all patients probably because it takes a relatively longer time for the drug accumulated in perilymph to be cleared. Aminoglycoside antibiotics interact with polyphosphoinositides in hair cell membranes. The aminoglycosides increase the permeability of the membranes, causing the cells to lose magnesium, which are normally present in high concentration in the mitochondria. It is believed that the loss of magnesium ions blocks enzymatic reactions, especially oxidative phosphorylation, in which magnesium is utilized as a cofactor and leads to cell death.

2. Risky group:

  1. Therapy for more than 7 days
  2. High doses (e.g. for bacterial endocarditis)
  3. In the elderly and neonate
  4. In renal failure
  5. Noise exposure

3. Monitoring:

Ways of monitoring: a) serum aminoglycoside level (main) and b) cochlear and vestibular function test (not usually done).

Serum aminoglycoside level:

Although there is no evidence that ototoxicity is directly related to either the peak or the trough serum aminoglycoside level, it is safer to keep the serum level within the therapeutic dosage.

Desirable therapeutic margin for some aminoglycosides

Drug

Desirable serum level (&uumlg/ml)

Aminoglycoside

Peak (taken 30-60 mins after a dose)

Trough (taken just before a dose)

Gentamycin and tobramycin

4-8

< 2.5

Kanamycin and amikacin

15-30

<7.5

Guidelines for the timing and frequency of taking serum sample are as follows:

1. For patients with normal renal function, the peak level is determined within the first 1 to 2 days of therapy, the trough level within 1 week, and both peak and trough levels approximately weekly thereafter.

2. For patients with impaired but stable renal function, the peak level is determined within the first 1 to 2 days of therapy, the trough level and another peak level within 1 week, and peak and trough levels approximately twice a week from then on.

3. In the case of impaired and unstable renal function, peak and trough levels are determined within the first 1 to 2 days of therapy. Determination of serum levels may have to be made as often as daily hereafter while the renal function remains unstable.

4. After any adjustments of dosage, the peak and trough levels should be determined within 1 to 2 days.

Other antibiotics that cause ototoxicity

 

A. Vancomycin

Vancomycin is commonly used for methicillin resistance Stapylcoccus aureus infection (MRSA), given intravenously. There are reported cases of vancomycin induced toxicity at a high serum level, and the hearing loss is apparently permanent (irreversible). There are evidences of synergic effect (augmentation) for the ototoxicity, especially when used together with erythromycin or aminoglycosides

(e.g. gentamycin).

  1. Erythromycin
  2. Erythromycin belongs to the macrolides group. Erythromycin itself and its salts can cause temporary ototoxicity, especially for those with renal insufficiency. There have been published, documented reports of ototoxicity caused by these drugs, whether given orally (the most common way to give them) or intravenously. Most of these cases have occurred when very high doses (e.g. 2-4 gm per 24 hrs) have been given for a couple of weeks, with either intravenous or oral administration. On usual dosage (i.e. 1 gm per 24 hrs), however, is not ototoxic.

    Hearing loss due to erythromycin toxicity occurs in high frequencies (as in aminoglycosides toxicity) and in speech frequencies. So it is noticeable hearing change in these patients at the very beginning of the disease.

    This problem seems not to occur in other macrolides (e.g. clarithromycin) since they require lower dosage.

    Drug

    Vestibulotoxicity

    Hearing Toxicity

    Toxic Level

    Vancomycin

    Nontoxic

    None to moderate

    Synergistic with gentamicin

    Erythromycin

    Nontoxic

    Yes

    High IV doses only

  3. Tetracyclines
  4. Minocycline is the only member in this class that can cause ototoxicity, used mainly for sexually transmitted diseases such as syphilis and gonorrhea. The ototoxic effect is transient. Signs & symptoms occur early, after one or two doses, and are gone one or two days after stopping the medication.

  5. Capreomycin

Capreomycin is used to treat tuberculosis, about 10% of patients taking this drug develop subclinical hearing loss (that can merely detected by audiometry). Another 5% patients develop noticeable hearing loss. The ototoxicity tends to be transient and does not progress after stopping the offending drug.