Tobramycin is a parenterally administered, broad spectrum aminoglycoside antibiotic that is widely used in the treatment of moderate to severe bacterial infections due to sensitive organisms. Despite its wide use, tobramycin has rarely been linked to instances of clinically apparent liver injury.
Tobramycin (toe" bra mye' sin) is a semisynthetic aminoglycoside, similar in spectrum of activity to gentamicin, that is widely used for severe bacterial infections caused by sensitive agents, primarily aerobic gram negative bacteria. Like other aminoglycosides, tobramycin is thought to act by binding to bacterial ribosomes and inhibiting protein synthesis. Nevertheless, tobramycin is considered bacteriocidal as well as bacteriostatic. Tobramycin and other aminoglycosides are typically used in combination with a penicillin or cephalosporin for treatment of severe infections with E. coli, Staphylococcus aureus, Enterobacter, Klebsiella, Serratia, Pseudomonas aeruginosa, and other gram negative bacteria resistant to less toxic antibiotics. Tobramycin is most commonly used for septicemia, bacterial endocarditis, peritonitis, meningitis, pelvic inflammatory disease and pneumonia. Tobramycin was approved for use in the United States in 1980 and is available in multiple generic forms in parenteral formulations; typical adult doses are 3 mg/kg per day im or iv, usually in three divided doses, often after an initial loading dose. The dose of tobramycin must be modified based upon renal function and monitoring of drug levels is advisable. Pediatric formulations, nebulizer solutions for inhalation, and topical formulations for ophthalmologic use are also available. Common side effects include dizziness, headache, confusion, nausea and skin rash. Important, dose related adverse effects include oto- and nephrotoxicity, which are shared by all aminoglycosides.
Intravenous and intramuscular therapy with tobramycin is usually associated with no increase in rates of serum aminotransferase or bilirubin elevations. Only isolated case reports of acute liver injury with jaundice have been associated with aminoglycoside therapy including tobramycin, not all of which are very convincing. The hepatic injury is typically mixed but can evolve into a cholestatic hepatitis. The latency to onset is rapid, occurring within 1 to 3 weeks and is typically associated with skin rash, fever and sometimes eosinophilia. Recovery typically occurs within 1 to 2 months and chronic injury has not been described. Aminoglycosides are not mentioned in large case series of drug induced liver disease and acute liver failure; thus, hepatic injury due to tobramycin is rare if it occurs at all.
Mechanism of Injury
The cause of symptomatic, icteric hepatic injury from tobramycin is not known, but is likely to be immunoallergic. Uptake of the aminoglycosides into hepatocytes is limited and they are rapidly excreted in the urine; high concentrations are found mainly in renal tubular cells and hair cells of the inner ear, perhaps explaining why they are more likely to cause nephro- or oto- rather than hepatotoxicity.
Outcome and Management
The outcome of hepatic injury due to aminoglycosides is usually benign. Acute liver failure has not been associated with tobramycin use and no convincing cases of chronic bile duct vanishing syndrome have been described after its use. Patients with tobramycin hepatotoxicity should probably avoid all systemic aminoglycoside use.
References to the safety and potential hepatotoxicity of tobramycin are provided in the Overview section on the Aminoglycosides.
Drug Class: Aminoglycosides
Other Drugs in the Class: Amikacin, Gentamicin, Neomycin, Streptomycin
Case 1. Acute hepatitis arising during tobramycin therapy.
|Medication:||Tobramycin, 70-100 mg every 8 hours for 9 days|
|Severity:||3+ (jaundice, hospitalization)|
|Latency:||3-4 days to ALT elevations, 8 days to jaundice|
|Other medications:||Paroxetine, alprazolam, hydrocodone/acetaminophen, oxycodone, hydromorphone, promethazine, docusate, metoclopramide, piperacillin/tazobactam, ciprofloxacin, aztreonam, and ceftazidime|
|Time After Starting||Time After Stopping||ALT (U/L)||Alk P (U/L)||Bilirubin (mg/dL)||Other|
|Pre||48||220||3.2||Admission with fever|
|1 day||40||200||Started tobramycin/ceftazidime|
|6 days||139||432||1.8||Piperacillin/tazobactam started|
|8 days||315||330||4.9||Aztreonam started|
|10 days||330||320||All antibiotics stopped|
|13 days||1 days||180||210|
|14 days||2 days||160||200||Aztreonam/ciprofloxacin started|
|15 days||3 days||110||180|
|17 days||5 days||65||158||1.5|
|DRUG||CAS REGISTRY NO.||MOLECULAR FORMULA||STRUCTURE|