iVertigo.net Aminoglycoside Cochlear Toxicity, B.Todd Troost

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The aminoglycoside antibiotics streptomycin, kanamycin, neomycin, gentamicin, tobramycin, amikacin, and netilmicin all contain an amino acid sugar linked to an aminocylitol ring by glycoside bonds.² In ordinary use, such antibiotics have been used for treating infections produced by aerobic gram-negative bacteria. The drugs are poorly absorbed with oral administration and are not transported into the cerebrospinal fluid readily. Ordinarily, they are excreted rapidly by the kidneys with enhancement of toxicity in patients with decreased renal function. The majority of the toxicity comes from parenteral administration, however, toxicity from oral absorption has been reported, especially with neomycin, the toxicity being magnified in patients with gastrointestinal disease.

Aminoglycoside antibiotics interact with polyphosphoinositides in the 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. Studies on aminoglycoside toxicity in animals showed that giving a loop diuretic followed by an aminoglycoside does not affect cochlear toxicity any more than any drug singly. However, if the order is reversed with an aminoglycoside antibiotic first and then a loop diuretic, the drugs act synergistically to produce toxicity and the organ of Corti is severely damaged.³

Different definitions of cochlear toxicity have been employed while monitoring a large number of patients. The usual definition is a hearing loss of 10 db bilaterally, or in some patients a 20 db hearing loss. Matz and Lerner⁴ have shown in a number of studies that the rates of toxicity were similar for gentamicin, tobramycin, and amikacin, with netilmicin resulting in the lower incidence of cochlear toxicity.

Neomycin and kanamycin are exquisitely toxic to the cochlea and, therefore, the parenteral use of such drugs should be limited. On a personal note, my first experience with iatrogeny with aminoglycosides came in a patient who was entirely paralyzed with Guillian Barré syndrome and went on ventilatory support for a year. At that point, the patient was the longest survivor on total ventilatory support. She eventually returned to an ambulatory status, but was totally and bilaterally deaf because of the use of kanamycin to treat a gram-negative infection. Gentamicin effects the vestibular system twice as frequently as the cochlear system. At particular risk are patients with chronic osteomyelitis who are treated with gentamicin because of the long duration of therapy and the high doses required for treatment.⁵ It should be emphasized that due to the extremely long half-life of gentamicin in the endolymph, vestibulotoxicity is probably equally dependent on dose as well as the length of therapy and can occur even with normal peak and trough levels. There is some evidence that there is an inherited mitochondrial DNA susceptibility for aminoglycoside toxicity. It is believed that the cochlear toxicity of gentamicin may be reversible in about 50% of the patients affected with a recovery time ranging from one week to six months following discontinuation of therapy. As pointed out by Matz^6,7 investigators have attempted to determine whether once-daily versus continuous aminoglycoside dosage results in reduced ototoxicity. Some believe that intermittent dosage with an aminogylcoside antibiotic causes infrequent high maximum serum concentrations. This may be less toxic and yet as efficacious as frequent dosage. Kahlmeter and Dahlager⁷ reviewed reports of aminoglycoside toxicity in more than 10,000 patients focusing particularly on prospective trials. The authors found the incidence of ototoxicity to be 8.6% for gentamicin, 6.1% for tobramycin, 13.9% for amikacin, and 2.4% for netilmicin. Of interest is the fact that cochlear toxicity from aminoglycoside antibiotics is less common in neonates and children.

Monitoring of Aminoglycosides

Patients treated with aminoglycosides are monitored for two reasons: 1) to insure that levels are adequate for therapy, and 2) to detect elevated levels that may be associated with a greater risk of ototoxicity and nephrotoxicity with the belief that the dose can be altered appropriately. Matz⁶ states that there are no data showing that occasionally elevated peak and trough levels result in cochlear toxicity. Toxicity can occur even in patients whose serum levels remain within an acceptable range. Table 14-1 gives the suggested dosage of aminoglycosides in adults with normal, as well as, impaired renal function. These peak levels may be modified according to the nature of the infection and the pathogen according to Matz.⁶

Table 14-1: Dosage Of Aminoglycosides In Adults With Normal And Impaired Renal Function

DRUG		Desirable Serum Level (&uumlg/ml)			Maintenance Dose*
Aminoglycoside		Peak*	Trough	Initial Dose*	Normal Renal Function	Impaired Renal Function>	After Each Hemodialysis
Gentamycin Tobramycin	} }	4-8	<2.5	2.0-3.0 mg/kg	1.7-2.0 mg/kg every 8 hr	0.8-1.0 mg/kg at intervals (hr) approximately 4 X serum creatinine (level mg/100 ml)	50% of the initial dose
Kanamycin Amikacin	} }	15-30	<7.5	6.0-9.0 mg/kg	5.0-6.0 mg/kg every 8 hr; or 7.5 mg/kg every 12 hr	2.5-3.0 mg/kg at intervals (hr) approximately 4 X serum creatinine level (mg/100 ml)	50% of the initial dose

*Some infections may require higher dosage and serum levels.
FAC

HPatients with impaired renal function may have higher trough levels.

IAn initial loading dose higher than the maintenance dose is given to patients with impaired renal function or for whom rapid onset of maximum therapy is essential (e.g., septic shock). Most patients with normal renal function receive the lower maintenance dose for the initiation of therapy.

'For obese patients, the appropriate dosage may be less than that indicated on a body weight basis.

2For example, if the serum creatinine level is 3.0 mg/100 ml, the maintenance dose would be given every 12 hours. (Table modified with permission.⁶)

Relatively resistant organisms may require peak aminoglycoside levels above the recommended range for cure to be achieved. This is particularly true with severe infections such as endocarditis caused by pseudomonas. If renal function is normal, the trough level generally falls below the indicated ranges. A rising trough level usually indicates a decline in renal function, although errors in timing of the sampling relative to administration of the dose must first be ruled out. As Matz⁶ again points out, peak and trough levels are obtained because of the convenience in relating them to the dose. However, it is not clear whether the risk of ototoxicity is related to either the peak level or the trough level; it is probably related to more complex pharmacokinetic function, such as the area under the curve, which is approximated by determining the peak and trough levels. The following is quoted from Matz as a suggested schedule for determination of serum levels:

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 thereafter 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.

When monitoring renal function and serum levels, the incidence and severity of aminoglycoside ototoxicity is reduced. Unfortunately, once ototoxicity occurs, it may be irreversible and can even progress after the cessation of therapy. Once ototoxicity is detected, unless there is a compelling reason to continue aminoglycoside therapy, it should be stopped. In patients for whom even subtle additional inner ear damage would be catastrophic or who are at high risk for ototoxicity, such as those patients with impaired renal function, one should consider testing vestibular and auditory function.⁶ Since this is rarely done, the benefits of such early detection is not completely known.