Amikacin is rapidly absorbed after intramuscular administration. In normal adult volunteers, average peak serum concentrations of about 12, 16 and 21 mcg/mL are obtained 1 hour after intramuscular administration of 250 mg (3.7 mg/kg), 375 mg (5 mg/kg), 500 mg (7.5 mg/kg), single doses, respectively. At 10 hours, serum levels are about 0.3 mcg/mL, 1.2 mcg/mL and 2.1 mcg/mL, respectively.
Tolerance studies in normal volunteers reveal that amikacin is well tolerated locally following repeated intramuscular dosing, and when given at maximally recommended doses, no ototoxicity or nephrotoxicity has been reported. There is no evidence of drug accumulation with repeated dosing for 10 days when administered according to recommended doses.
With normal renal function, about 91.9% of an intramuscular dose is excreted unchanged in the urine in the first 8 hours and 98.2% within 24 hours. Mean urine concentrations for 6 hours are 563 mcg/mL following a 250 mg dose, 697 mcg/mL following a 375 mg dose and 832 mcg/mL following a 500 mg dose.
Preliminary intramuscular studies in newborns of different weights (less than 1.5 kg, 1.5 to 2 kg, over 2 kg) at a dose of 7.5 mg/kg revealed that, like other aminoglycosides, serum half-life values were correlated inversely with post-natal age and renal clearances of amikacin. The volume of distribution indicates that amikacin, like other aminoglycosides, remains primarily in the extra-cellular fluid space of neonates. Repeated dosing every 12 hours in all the above groups did not demonstrate accumulation after 5 days.
Single doses of 500 mg (7.5 mg/kg) administered to normal adults as an infusion over a period of 30 minutes produced a mean peak serum concentration of 38 mcg/mL at the end of the infusion and levels of 24 mcg/mL, 18 mcg/mL and 0.75 mcg/mL at 30 minutes, 1 hour and 10 hours post-infusion, respectively. Eighty-four percent of the administered dose was excreted in the urine in 9 hours and about 94% within 24 hours.
Repeat infusions of 7.5 mg/kg every 12 hours in normal adults were well tolerated and caused no drug accumulation.
Pharmacokinetic studies in normal adult subjects reveal the mean serum half-life to be slightly over 2 hours with a mean total apparent volume of distribution of 24 liters (28% of the body weight). By the ultrafiltration technique, reports of serum protein binding range from 0 to 11%. The mean serum clearance rate is about 100 mL/min and the renal clearance rate is 94 mL/min in subjects with normal renal function.
Amikacin is excreted primarily by glomerular filtration. Patients with impaired renal function or diminished glomerular filtration pressure excrete the drug much more slowly (effectively prolonging the serum half-life). Therefore, renal function should be monitored carefully and dosage adjusted accordingly (see suggested dosage schedule under
DOSAGE AND ADMINISTRATION).
Following administration at the recommended dose, therapeutic levels are found in bone, heart, gallbladder, and lung tissue in addition to significant concentrations in urine, bile, sputum, bronchial secretions, interstitial, pleural, and synovial fluids.
Spinal fluid levels in normal infants are approximately 10 to 20% of the serum concentrations and may reach 50% when the meninges are inflamed. Amikacin has been demonstrated to cross the placental barrier and yield significant concentrations in amniotic fluid. The peak fetal serum concentration is about 16% of the peak maternal serum concentration and maternal and fetal serum half-life values are about 2 and 3.7 hours, respectively.
Amikacin is active in vitro against Pseudomonas species, Escherichia coli, Proteus species (indole-positive and indole-negative), Providencia species, Klebsiella-Enterobacter-Serratia species, Acinetobacter (formerly Mima-Herellea) species and Citrobacter freundii.
When strains of the above organisms are found to be resistant to other aminoglycosides, including gentamicin, tobramycin and kanamycin, many are susceptible to amikacin in vitro.
Amikacin is active in vitro against penicillinase and non-penicillinase-producing Staphylococcus species, including methicillin-resistant strains. However, aminoglycosides in general have a low order of activity against other Gram-positive organisms, viz., Streptococcus pyogenes, enterococci and Streptococcus pneumoniae (formerly Diplococcus pneumoniae).
Amikacin resists degradation by most aminoglycoside inactivating enzymes known to affect gentamicin, tobramycin and kanamycin.
In vitro studies have shown that amikacin sulfate combined with a beta-lactam antibiotic acts synergistically against many clinically significant Gram-negative organisms.
Disc Susceptibility Test
Quantitative methods that require measurement of zone diameters give the most precise estimates of antibiotic susceptibility. One such procedure has been recommended for use with discs to test susceptibility to amikacin. Interpretation involves correlation of the diameters obtained in the disc test with MIC values for amikacin. When the causative organism is tested by the Kirby-Bauer method of disc susceptibility, a 30 mcg amikacin disc should give a zone of 17 mm or greater to indicate susceptibility. Zone sizes of 14 mm or less indicate resistance. Zone sizes of 15 to 16 mm indicate intermediate susceptibility. With this procedure, a report from the laboratory of "susceptible" indicates that the infecting organism is likely to respond to therapy. A report of "resistant" indicates that the infecting organism is not likely to respond to therapy. A report of "intermediate susceptibility" suggests that the organism would be susceptible if the infection is confined to tissues and fluids (e.g., urine) in which high antibiotic levels are attained.