NEODOSE

INDICATIONS

• Treatment of infections caused by aerobic gram-negative bacilli (eg, Pseudomonas, Klebsiella, E coli). Usually used in combination with a β-lactam antibiotic.
• Infective endocarditis: The following recommendations are based on a consensus of experts. The full pediatric guidelines can be found here:
• Sepsis: Optimal treatment for suspected, early-onset sepsis is broad-spectrum antimicrobial coverage using a combination of ampicillin and an aminoglycoside (usually gentamicin); once a pathogen is identified, therapy should be narrowed unless synergism is required. Therapy should be discontinued at 48 hours if the probability of sepsis is low. Duration of treatment is usually 10 days for bacteremia without an identifiable focus. There was no difference in failure rate between a 7-day vs 10-day duration of empiric treatment with IV cefTRIAXone and amikacin for culture-proven sepsis in 132 neonates, 1.5 kg or more and gestational age 32 weeks or more, who remitted clinically by day 5 in a randomized study. The follow-up period was 28 days. The median age at presentation was 3 days (2 to 4 days) and 56.8% had early-onset sepsis. The majority of organisms in blood cultures were Klebsiella spp. (40.9%), Staphylococcus aureus (22.7%), Enterobacter spp. (16.7%), and MRSA (7.6%) .

PRECAUTIONS

• Concomitant Use:
  • Avoid concomitant or sequential use of the inhalation formulation with drugs that have neurotoxic, ototoxic, or nephrotoxic potential.
• Dermatologic:
  • Serious and sometimes fatal allergic reactions, including anaphylaxis and dermatologic reactions (eg, exfoliative dermatitis, toxic epidermal necrolysis, erythema multiforme, and Stevens-Johnson syndrome) have been reported; discontinue use if occurs.
  • Significant absorption leading to neurotoxicity or nephrotoxicity may occur following local irrigation or application.
• Immunologic:
  • Cross-sensitivity to other aminoglycoside antibiotics may occur.
  • Topical sensitivity reaction may occur.
  • Overgrowth of nonsusceptible organisms may occur.
  • Clostridium difficile-associated diarrhea has been reported; discontinuation may be needed.
  • Contains sodium metabisulfite, a sulfite that may cause allergic-type reactions (eg, anaphylactic symptoms or asthmatic episodes) in susceptible patients.
• Neuromuscular:
  • Neuromuscular disorders (eg, myasthenia gravis); aminoglycosides may aggravate muscle weakness.
• Neurologic:
  • Neuromuscular blockade and respiratory paralysis may occur in anesthetized patients who also received neuromuscular blocking drugs (eg, succinylcholine, tubocurarine, or decamethonium), or large transfusions with citrate-anticoagulated blood; calcium salts may reverse blockade.
• Ophthalmic:
  • Not approved for intraocular or subconjunctival use as macular necrosis has been reported.
• Otic:
  • Auditory or vestibular dysfunction; particularly with high doses or prolonged therapy, previous courses of ototoxic therapy, and dehydration; monitoring recommended
• Renal:
  • Use with caution in patients with renal impairment, due to an increased risk of ototoxicity and nephrotoxicity; monitoring recommended
  • Nephrotoxicity may occur and discontinuation may be necessary; monitoring recommended.
• Reproductive:
  • Pregnancy; may cause fetal harm.
• Respiratory:
  • Bronchospasm may occur with inhalation tobramycin.
• Special Population:
  • Reduced serum concentrations may occur in patients with extensive burns; monitoring recommended
  • Reduced serum concentrations may occur in patients with cystic fibrosis; monitoring recommended.

ADVERSE EFFECTS

Transient and reversible renal tubular dysfunction may occur, resulting in increased urinary losses of sodium, calcium, and magnesium. Vestibular and auditory ototoxicity may occur. The addition of other nephrotoxic and/or ototoxic medications (e.g. furosemide, vancomycin) may increase these adverse effects. Increased neuromuscular blockade (i.e. neuromuscular weakness and respiratory failure) may occur when used with pancuronium or other neuromuscular blocking agents and in patients with hypermagnesemia.

ADMINISTRATION

• Intravenous: Dilute in appropriate volume (as small as 25 mL may be used) of NS or D5W to concentrations of 2, 4, or 10 mg/mL and infuse over 20 to 60 minutes. Administer as a separate infusion from penicillin-containing compounds.
• Intramuscular: For the IM route, solution does not need to be further diluted (10 mg/mL). IM injection is associated with variable absorption, especially in the very small infant.

BLACK BOX WARNING

• Patients treated with tobramycin injection and other aminoglycosides should be under close clinical observation, because these drugs have an inherent potential for causing ototoxicity and nephrotoxicity.
• Neurotoxicity, manifested as both auditory and vestibular ototoxicity, can occur. The auditory changes are irreversible, are usually bilateral, and may be partial or total. Eighth nerve impairment and nephrotoxicity may develop, primarily in patients having preexisting renal damage and in those with normal renal function to whom aminoglycosides are administered for longer periods or in higher doses than those recommended. Other manifestations of neurotoxicity may include numbness , skin tingling, muscle twitching, and convulsions. The risk of aminoglycoside-induced hearing loss increases with the degree of exposure to either high peak or high trough serum concentrations. Patients who develop cochlear damage may not have symptoms during therapy to warn them of eighth-nerve toxicity, and partial or total irreversible bilateral deafness may continue to develop after the drug has been discontinued.
• Rarely, nephrotoxicity may not become apparent until the first few days after cessation of therapy. Aminoglycoside-induced nephrotoxicity usually is reversible.
• Renal and eighth-nerve function should be closely monitored in patients with known or suspected renal impairment and also in those whose renal function is initially normal but who develop signs of renal dysfunction during therapy. Peak and trough serum concentrations of aminoglycosides should be monitored periodically during therapy to assure adequate levels and to avoid potentially toxic levels. Prolonged serum concentrations above 12 mcg/mL should be avoided. Rising trough levels (above 2 mcg/mL) may indicate tissue accumulation. Such accumulation, excessive peak concentrations, advanced age, and cumulative dose may contribute to ototoxicity and nephrotoxicity. Urine should be examined for decreased specific gravity and increased excretion of protein, cells, and casts. Blood urea nitrogen, serum creatinine, and creatinine clearance should be measured periodically. When feasible, it is recommended that serial audio1grams be obtained in patients old enough to be tested, particularly high-risk patients. Evidence of impairment of renal, vestibular, or auditory function requires discontinuation of the drug or dosage adjustment.
• Tobramycin injection should be used with caution in premature and neonatal infants because of their renal immaturity and the resulting prolongation of serum half-life of the drug.
• Concurrent and sequential use of other neurotoxic and/or nephrotoxic antibiotics, particularly other aminoglycosides (e.g., amikacin, streptomycin, neomycin, kanamycin, gentamicin, and paromomycin), cephaloridine, viomycin, polymyxin B, colistin, cisplatin, and vancomycin, should be avoided. Other factors that may increase patient risk are advanced age and dehydration.
• Aminoglycosides should not be given concurrently with potent diuretics, such as ethacrynic acid and furosemide. Some diuretics themselves cause ototoxicity, and intravenously administered diuretics enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue.
• Aminoglycosides can cause fetal harm when administered to a pregnant woman.

MONITORING

Measure serum concentrations when treating for more than 48 hours. Obtain peak concentration 30 minutes after IV infusion or 1 hour after IM injection, and trough concentration just prior to the next dose. When treating patients with serious infections or significantly changing fluid or renal status consider measuring the serum concentration 24 hours after a dose, and use the chart below for the suggested dosing interval. Blood samples obtained to monitor serum drug concentrations should be spun and refrigerated or frozen as soon as possible.

Therapeutic serum concentrations:

Peak: 5 to 12 mcg/mL (or Cmax/MIC ratio greater than 8:1)

Trough: 0.5 to 1 mcg/mL