1-10%

Ototoxicity

Nephrotoxicity

Neurotoxicity (neuromuscular blockade)

<1%

Hypotension

Drug fever

Drowsiness

Headache

Paresthesia

Tremor

Rash

Nausea

Vomiting

Anemia

Eosinophilia

Arthralgia

Weakness

Eyelid edema

Itching eyes

Keratitis

Lacrimation

Dyspnea

Contraindications

Documented hypersensitivity to any aminoglycoside or history of hypersensitivity or serious toxic reactions to aminoglycosides

Cautions

Serious allergic sometimes fatal reactions including anaphylaxis and dermatologic reactions including exfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme, and Stevens-Johnson Syndrome reported rarely; discontinue therapy If allergic reaction occurs, drug should be discontinued and appropriate therapy instituted

Serum and urine specimens for examination should be collected during therapy; serum calcium, magnesium, and sodium should be monitored

Cross-allergenicity among aminoglycosides has been demonstrated

In patients with extensive burns or cystic fibrosis, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides; in such patients treated with tobramycin, measurement of serum concentration is especially important as a basis for determination of appropriate dosage

Elderly patients may have reduced renal function that may not be evident in results of routine screening tests, such as BUN or serum creatinine; a creatinine clearance determination may be more useful; monitoring of renal function during treatment with aminoglycosides is particularly important in such patients

An increased incidence of nephrotoxicity reported following concomitant administration of aminoglycoside antibiotics and cephalosporins

Aminoglycosides should be used with caution in patients with muscular disorders, such as myasthenia gravis or parkinsonism, since these drugs may aggravate muscle weakness because of potential curare-like effect on neuromuscular function

Aminoglycosides may be absorbed in significant quantities from body surfaces after local irrigation or application and may cause neurotoxicity and nephrotoxicity

Aminoglycosides have not been approved for intraocular and/or subconjunctival use; physicians are advised that macular necrosis has been reported following administration of aminoglycosides, including tobramycin, by these routes

The inactivation of tobramycin and other aminoglycosides by ß-lactam-type antibiotics (penicillins or cephalosporins) has been demonstrated in vitro and in

patients with severe renal impairment; such inactivation has not been found in patients with normal renal function who have been given the drugs by separate routes of administration

Therapy with tobramycin may result in overgrowth of nonsusceptible organisms; if overgrowth of nonsusceptible organisms occurs, appropriate therapy should be initiated

Clostridium difficile

• Clostridium difficile associated diarrhea (CDAD) reported; may range
• in severity from mild diarrhea to fatal colitis; treatment with antibacterial agents alters normal flora of colon leading to overgrowth of C. difficile
• C. difficile produces toxins A and B which contribute to development of CDAD; hypertoxin producing strains of C. difficile cause increased morbidity and mortality
• As these infections can be refractory to antimicrobial therapy and may require colectomy; CDAD must be considered in all patients who present with diarrhea following antibiotic use
• Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents
• If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued
• Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated

Peak and trough levels

• Peak and trough serum levels should be measured periodically during therapy; prolonged concentrations above 12 mcg/mL should be avoided
• Rising trough levels (above 2 mcg/mL) may indicate tissue accumulation; such accumulation, advanced age, and cumulative dosage may contribute to ototoxicity and nephrotoxicity; it is particularly important to monitor serum levels closely in patients with known renal impairment.
• A useful guideline would be to perform serum level assays after 2 or 3 doses, so that dosage could be adjusted if necessary, and at 3- to 4-day intervals during therapy
• In the event of changing renal function, more frequent serum levels should be obtained and the dosage or dosage interval adjusted according to guidelines
• In order to measure the peak level, a serum sample should be drawn about 30 minutes following intravenous infusion or 1 hour after an intramuscular injection
• Trough levels are measured by obtaining serum samples at 8 hours or just prior to next dose; these suggested time intervals are intended only as guidelines and may vary according to institutional practices
• It is important, that there be consistency within individual patient program unless computerized pharmacokinetic dosing programs are available in the institution
• Serum-level assays may be especially useful for monitoring treatment of severely ill patients with changing renal function or of those infected with less susceptible organisms or those receiving maximum dosage

Ototoxicity

• Ototoxicity may occur in some patients even when their aminoglycoside serum levels are within recommended range
• Postmarketing experience, patients receiving therapy have reported hearing loss; vestibular toxicity may be manifested by vertigo, ataxia or dizziness; patients with known or suspected auditory or vestibular dysfunction should be closely monitored when receiving therapy; monitoring might include obtaining audiometric evaluations and serum tobramycin levels;
• Mitochondrial DNA variants are present in <1% of the general US population, and the proportion of the variant carriers who may develop ototoxicity as well as severity of ototoxicity is unknown
• In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless increased risk of permanent hearing loss is outweighed by severity of infection and lack of safe and effective alternative therapies

Neuromuscular blockade

• Neuromuscular blockade and respiratory paralysis have been reported in cats receiving very high doses of tobramycin (40 mg/kg)
• Possibility of prolonged or secondary apnea should be considered if tobramycin is administered to anesthetized patients who are also receiving neuromuscular blocking agents, such as succinylcholine, tubocurarine, or decamethonium, or to patients receiving massive transfusions of citrated blood
• If neuromuscular blockade occurs, may be reversed by administration of calcium salts

Pregnancy & Lactation