NEODOSE

INDICATIONS

Amikacin was effective for infections caused by gram-negative bacilli that are resistant to other aminoglycosides. Usually used in combination with a β-lactam antibiotic for neonatal sepsis and other severe infections because of the possibility of infections due to grampositive organisms such as streptococci or pneumococci.

• 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%)

FDA APPROVED INDICATION

Short-term treatment of serious infections caused by susceptible strains of Gram-negative bacteria, including Pseudomonas species, E. coli, species of indole-positive and indolenegative Proteus, Providencia species, Klebsiella-Enterobacter-Serratia species, and Acinetobacter (Mima-Herellea) species.

Contraindications / Precautions :

PRECAUTIONS

• Administration:
  • In vitro mixing of aminoglycosides with beta-lactam antibiotics (penicillin or cephalosporins) may result in a significant mutual inactivation. A reduction in serum halflife or serum level may occur when an aminoglycoside or penicillin-type drug is administered by separate routes. Inactivation of the aminoglycoside is clinically significant only in patients with severely impaired renal function. Inactivation may continue in specimens of body fluids collected for assay, resulting in inaccurate aminoglycoside readings. Such specimens should be properly handled (assayed promptly, frozen or treated with betalactamase).
• Gastrointestinal:
  • Clostridium difficile associated diarrhea has been reported and ranged from mild diarrhea to fatal colitis; discontinue use if suspected.
• Immunologic:
  • Allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic reactions, may occur in patients with sulfite sensitivity as preparation contains sodium metabisulfite.
• Neurologic:
  • Use caution in patients with myasthenia gravis or parkinsonism; muscle weakness may be aggravated.
• Topical irrigation:
  • Irreversible deafness, renal failure, and death due to neuromuscular blockade have been reported following irrigation of both small and large surgical fields with aminoglycoside preparations

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 (eg, furosemide, vancomycin) may increase these adverse effects. Increased neuromuscular blockade (ie, neuromuscular weakness and respiratory failure) may occur when used with pancuronium or other neuromuscular blocking agents and in patients with hypermagnesemia.

BLACK BOX WARNING

• Patients treated with parenteral aminoglycosides should be under close clinical observation because of the potential ototoxicity and nephrotoxicity associated with their use. Safety for treatment periods which are longer than 14 days has not been established.
• Neurotoxicity, manifested as vestibular and permanent bilateral auditory ototoxicity, can occur in patients with preexisting renal damage and in patients with normal renal function treated at higher doses and/or for periods longer than those recommended. The risk of aminoglycoside-induced ototoxicity is greater in patients with renal damage. High frequency deafness usually occurs first and can be detected only by audio1metric testing. Vertigo may occur and may be evidence of vestibular injury. Other manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching and convulsions . The risk of hearing loss due to aminoglycosides increases with the degree of exposure to either high peak or high trough serum concentrations . Patients developing cochlear damage may not have symptoms during therapy to warn them of developing eighth-nerve toxicity, and total or partial irreversible bilateral deafness may occur after the drug has been discontinued. Aminoglycoside-induced ototoxicity is usually irreversible.
• Aminoglycosides are potentially nephrotoxic. The risk of nephrotoxicity is greater in patients with impaired renal function and in those who receive high doses or prolonged therapy.
• Neuromuscular blockade and respiratory paralysis have been reported following parenteral injection, topical instillation (as in orthopedic and abdominal irrigation or in local treatment of empyema), and following oral use of aminoglycosides. The possibility of these phenomena should be considered if aminoglycosides are administered by any route, especially in patients receiving anesthetics; neuromuscular blocking agents such as tubocurarine, succinylcholine, decamethonium; or in patients receiving massive transfusions of citrate-anticoagulated blood. If blockage occurs, calcium salts may reverse these phenomena, but mechanical respiratory assistance may be necessary.
• Renal and eighth-nerve function should be closely monitored especially in patients with known or suspected renal impairment at the onset of therapy and also in those whose renal function is initially normal but who develop signs of renal dysfunction during therapy. Serum concentrations of amikacin should be monitored when feasible to assure adequate levels and to avoid potentially toxic levels and prolonged peak concentrations above 35 micrograms per mL. Urine should be examined for decreased specific gravity, increased excretion of proteins and the presence of cells or casts . Blood urea nitrogen, serum creatinine or creatinine clearance should be measured periodically. Serial audio1grams should be obtained where feasible in patients old enough to be tested, particularly high risk patients . Evidence of ototoxicity (dizziness, vertigo, tinnitus , roaring in the ears and hearing loss) or nephrotoxicity requires discontinuation of the drug or dosage adjustment.
• Concurrent and/or sequential systemic, oral or topical use of other neurotoxic or nephrotoxic products, particularly bacitracin, cisplatin, amphotericin B, cephaloridine, paromomycin, viomycin, polymyxin B, colistin, vancomycin, or other aminoglycosides should be avoided. Other factors that may increase risk of toxicity are advanced age and dehydration.
• The concurrent use of amikacin with potent diuretics (ethacrynic acid or furosemide) should be avoided since diuretics by themselves may cause ototoxicity. In addition, when administered intravenously, diuretics may enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue.

ADMINISTRATION

Dilute to a final concentration of 2.5 to 10 mg/mL and administer as IV infusion by syringe pump over 60 to 120 minutes; in neonatal studies amikacin was infused over 20 minutes and in neonatal pharmacokinetic modeling studies infusion rates of 20 to 30 minutes were applied. Administer as a separate infusion from penicillin-containing compounds. IM injection is associated with variable absorption, especially in the very small infant.

MONITORING

Measure serum concentrations when treating for more than 48 hours. Obtain peak concentration 30 minutes after end of infusion, 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: 20 to 30 mcg/mL (or C_max/MIC ratio greater than 8:1) (Draw 30 minutes after end of infusion, 1 hour after IM injection.)
• Trough: 2 to 5 mcg/mL