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DESCRIPTION
Aminoglycosides are antimicrobial agents commonly used in the treatment of infections by gram-negative organisms.
FORMS AND USES
Aminoglycoside antimicrobials include amikacin (Amikin), gentamicin (Garamycin), kanamycin (Kanasig), netilmicin (Netromycin), neomycin (Neo-Myxin, Neocin), and tobramycin (Nebcin) and are used for the treatment of local or systemic infection, particularly infection with gram-negative bacterial organisms.
TOXIC DOSE
- A single overdose of any aminoglycoside rarely produces toxic effects.
- Gentamicin or tobramycin peak serum levels persistently above 12 µg/ml or trough levels greater than 2 µg/ml are associated with renal injury.
- Amikacin peak levels persistently above 20 µg/ml or trough levels greater than 8 µg/ml are associated with renal injury.
PATHOPHYSIOLOGY
An overdose of an aminoglycoside may result in nephrotoxicity and ototoxicity.
- Nephrotoxicity is the result of proximal tubular injury leading to acute tubular necrosis and subsequent oliguric renal failure.
- Ototoxicity manifests by cochlear and vestibular nerve dysfunction.
- Damage is dependent on dose, duration of therapy, preexisting renal disease or dysfunction, and concomitant use of other nephrotoxic or ototoxic drugs.
EPIDEMIOLOGY
- Intravenous overdose is usually the result of iatrogenic error.
- Oral overdoses are rare.
- Child neglect or abuse should be considered if patient is less than 1 year of age, suicide attempt if patient is over 6 years of age.
RISK FACTORS
- Nephrotoxicity is seen most frequently in the context of prolonged elevation of trough levels in elderly, dehydrated patients with underlying renal dysfunction or during treatment with other nephrotoxic drugs.
- Allergic sensitivity to antimicrobials is common. Patients with a history of sensitivity to other antimicrobial agents or sulfites are at increased risk.
- In the elderly, underlying renal disease may enhance the potential for toxicity.
DRUG AND DISEASE INTERACTIONS
- Aminoglycosides, when used with vancomycin, increase the incidence of nephrotoxicity and ototoxicity.
- When used with lincomycin, interstitial nephritis has occurred.
- Acute renal failure has resulted from the use of aminoglycosides with clindamycin.
- Ticarcillin may complex with either gentamicin or tobramycin, shortening its half-life. Therefore, the combination should not be used therapeutically.
- Aminoglycosides potentiate the effects of neuromuscular blockade (e.g., botulism).
PREGNANCY AND LACTATION
- Amikacin, gentamicin, and neomycin. US FDA Category C. The drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women.
- Kanamycin and tobramycin. US FDA Category D. Positive evidence of human fetal risk exists, but benefits in certain situations (e.g., life-threatening situations or serious diseases) may make use of the drug acceptable despite its risks.
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DIFFERENTIAL DIAGNOSIS
- Toxicologic causes of renal injury include acetaminophen, chlorinated hydrocarbons, certain mushrooms, ethylene glycol, mercury, methemoglobinemia and rhabdomyolysis, among others.
- Other causes include hypotension, rhabdomyolysis, infection, and anatomical obstruction.
SIGNS AND SYMPTOMS
- The main toxicologic effects of aminoglycosides are nephrotoxicity and ototoxicity.
- Repeated inappropriately high doses are usually required to produce toxicity.
HEENT
- Partial or complete hearing loss may occur. Loss of high-frequency hearing may precede clinically apparent hearing loss.
- Vertigo occurs rarely.
Pulmonary
Apnea secondary to neuromuscular blockade may occur.
Renal
Especially if repeated, a high dosage may result in nephrotoxicity leading to renal failure.
Immunologic
Aminoglycosides have been reported to produce hypersensitivity reactions, including anaphylaxis.
PROCEDURES AND LABORATORY TESTS
Essential Tests
- Periodic trough and peak levels during therapy to maintain appropriate levels, serial levels following overdose.
- BUN, serum creatinine, and creatinine clearance to evaluate potential renal injury.
Recommended Tests
Audiology testing should be performed when toxicity is suspected or toxic levels are detected.
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- Treatment is focused on assessment of toxicity and general supportive renal care.
- Patients with normal renal function, who have received a single overdose, can usually be managed with conservative and supportive measures. Exceptions include aminoglycoside overdose in the presence of renal failure or the development of neuromuscular blockade.
- Dose and time of exposure should be determined for all substances involved.
DIRECTING PATIENT COURSE
- The health-care professional should call the poison control center when:
- Decreased hearing or other severe effects are present.
- Toxic effects are not consistent with aminoglycoside poisoning.
- Coingestant, drug interaction, or underlying disease presents an unusual problem.
The patient should be referred to a health-care facility when:
- Attempted suicide or homicide is possible.
- Patient or caregiver seems unreliable.
- Any toxic effects develop.
- Coingestant, drug interaction, or underlying disease presents an unusual problem.
Admission Considerations
Inpatient management is warranted for patients requiring electrolyte management or hemodialysis due to renal injury.
DECONTAMINATION
Out of Hospital
Induced emesis is not recommended due to rapid absorption and lack of toxicity following single acute overdose.
In Hospital
Gastric lavage should be performed in pediatric (tube size 24-32 French) or adult (tube size 36-42 French) patients for large ingestion presenting within 1 hour of ingestion or if serious effects are present.
ANTIDOTES
Treatment of Neuromuscular Blockade
- Physostigmine is a cholinergic agonist that that has been proposed to reverse neuromuscular blockade enhanced by the combination of aminoglycosides and neuromuscular blocking agents.
- It should not be used, however, if there is a significant possibility of cyclic antidepressant overdose.
ADJUNCTIVE TREATMENT
- The patient's urine output should be adequately maintained.
- Hypotension should be treated with isotonic fluid infusion, the Trendelenburg position, and vasopressors if needed. Dopamine is preferred; norepinephrine may be added for refractory hypotension.
- Due to high rates of elimination, dialysis is usually not necessary when renal function is adequate; however, it should be considered when renal failure is present.
- Physostigmine has been used to reverse neuromuscular blockade.
- Mechanical ventilation may rarely be required for prolonged respiratory depression, pulmonary edema, or prolonged neuromuscular blockade.
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PATIENT MONITORING
Renal function should be followed for 24 to 48 hours or until function stabilizes.
EXPECTED COURSE AND PROGNOSIS
- Nephrotoxicity is usually reversible if detected early and the specific medication is discontinued or removed by dialysis, but residual ototoxicity occurs occasionally.
- Immunocompromise secondary to marrow suppression (neomycin) may result in opportunistic infections. Antibiotic-associated bone marrow suppression usually reverses with discontinuation of the drug. However, permanent agranulocytosis has been reported.
DISCHARGE CRITERIA/INSTRUCTIONS
- From emergency department. Patients with normal renal and otic function may be discharged after gastrointestinal decontamination and psychiatric evaluation, if needed.
- From the hospital. Patients may be discharged after toxic effects resolve or stabilize and after psychiatric evaluation, if needed.
Section Outline:
Failure to monitor renal function and adjust dose appropriately may lead to renal injury.
ICD-9-CM 960Poisoning by antibiotics.
See Also: SECTION II, Hypotension chapter; and SECTION III, Physostigmine chapter.
RECOMMENDED READING
Butkus DE, de Torrente A, Terman DS. Renal failure following gentamicin in combination with clindamycin. Nephron1976;17:307-313.
Green FJ, Lavelle KJ, Arnoff GR. Management of amikacin overdose. Am J Kidney Dis 1981;1:110-112.
Kacew S, Bergeron MG. Pathogenic factors in aminoglycoside-induced nephrotoxicity. Toxicol Lett 1990;51:237-239.
Koren G, Barzilay Z, Greenwald M. Tenfold errors in administration of drug doses: a neglected latrogenic disease in pediatrics. Pediatrics 1986;77:848-849.
Author: Steven A. Seifert
Reviewer: Richard C. Dart