Clinical Pharmacology of amikacin in infants and children
Amikacin spectrum of activity is the broadest of all aminoglycosides. Amikacin is active against most strains of Serratia, Proteus, and Pseudomonas aeruginosa as well as most strains of Klebsiella, Enterobacter, and Escherichia coli that are resistant to gentamicin and tobramycin and is rapidly bactericidal. Amikacin doses are 15 mg/kg once-daily, and 7.5 mg/kg twice-daily in infants, and 20 to 40 mg/kg once-daily in children.
Amikacin is preferentially administered once daily, because yields lower though and higher peak concentrations, thus reducing the risks of toxicity, and increases peak concentration, thus improving therapeutic efficacy. Amikacin is absorbed rapidly after intramuscular injection; peak plasma concentration is 20 µg/ml after an injection of 7.5 mg/kg. Amikacin mean half-lives are 6.0 hours in infants in the first weeks of life, and 1.9 hours in children aged up to 6 years. This antibiotic causes limited ototoxicity and nephrotoxicity in infants and children. After a single intramuscular amikacin dose of 7.5 mg/kg, concentrations (µg/ml) are 14.9 in serum, 2.2 in skeletal muscle, and 1.9 in fat tissue. Because of its polar nature, amikacin penetrates poorly into the cerebrospinal fluid, and the ratio of amniotic fluid to serum concentration is 0.03. Amikacin pharmacokinetics have been extensively studied in infants and children and pharmacokinetic parameters vary remarkably. Half-life and clearance decrease and increases, respectively, during infant maturation. Burn, cancer and renal impairment have an important impact on pharmacokinetics. Some bacteria may become resistant to amikacin. The aim of this study is to review the published data on amikacin effects, metabolism, pharmacokinetics, and bacteria-resistance in infants and children.
Amikacin is particularly useful in the treatment of gram-negative bacteria resistant to gentamicin and tobramycin such as certain Enterobacter species. Significant placental transfer occurs but the drug does not cause foetal damage. It would seem wise to monitor blood levels when amikacin is used in pregnancy to minimise the risk of foetal ototoxicity because drug accumulation has been documented in the foetal lung, kidney and placenta. Only small amounts appear in human milk, and as absorption from the gut is minimal, the breastfed infant is unlikely to suffer from adverse effects. Amikacin is largely excreted unchanged through the renal glomerulus. Elimination half-lives are 7 to 14 hours in infants, with a post-menstrual age of less than 30 weeks, and 4 to 7 hours at a postmenstrual age of 40 weeks. Nephrotoxicity and cochlear or vestibular damage can occur if ‘trough’ blood levels are in excess of those generally recommended. The risk is increased if amikacin is prescribed for more than 10 days, follows treatment with another aminoglycoside, or is given at the same time with a diuretic such as furosemide. Amikacin is less toxic to the neonatal kidney than gentamicin or netilmicin, and also probably less ototoxic. Absorption is said to be somewhat unpredictable after intramuscular administration in very small infants. Cerebrospinal fluid penetration is limited [1].
Measure serum concentrations when amikacin is administered for more than 48 hours. Obtain peak concentration 30 min after the end of infusion, and trough concentration just prior to the next dose. When treating infants with serious infections measure serum concentration 24 hours after a dose. The peak of serum concentration/MIC ratio should be greater than 8:1. Dosing recommendations are based on: (1) higher peak concentrations increase concentration-dependent bacterial killing. (2) There is a post-antibiotic effect on bacterial killing, especially when treating concurrently with a β-lactam antibiotic. (3) There may be less toxicity with less frequent dosing, due to less renal drug accumulation. Distribution volume is increased and clearance is decreased in infants with patent ductus arteriosus. Serum elimination half-life is prolonged in premature and asphyxiated infants. Inactivation of amikacin by penicillin-containing compounds appears to be a time-, temperature-, and concentration-depended process. This is probably clinically significant only when penicillin-containing compounds are mixed in intravenous solutions or when the blood is at room temperature for several hours before the assay is performed. Amikacin is incompatible with fat emulsion, amphotericin B, ampicillin, azithromycin, heparin (concentrations > 1 unit/ml), imipenem/cilastatin, mezlocillin, nafcillin, oxacillin, phenytoin, propofol, thiopental, and ticarcillin/clavulanate [2].
The spectrum of amikacin activity is the broadest of all aminoglycosides. Because of its resistance to many of the aminoglycoside-inactivating enzymes, amikacin has a special role for the initial treatment of serious nosocomial gram-negative bacillary infections in hospitals where resistance to gentamicin and tobramycin has become a significant problem. Amikacin is active against most strains of Serratia, Proteus, and Pseudomonas aeruginosa as well as most strains of Klebsiella, Enterobacter, and Escherichia coli that are resistant to gentamicin and tobramycin. Most resistance to amikacin is found amongst strains of Acinetobacter, Providencia, and Flavobacterium and strains of Pseudomonas and other Pseudomonas aeruginosa; these all are unusual pathogens. Amikacin is not active against the majority of gram-positive anaerobic bacteria. It is active against Mycobacterium tuberculosis, including streptomycin-resistant strains and atypical mycobacteria. The recommended dose of amikacin is 15 mg/kg once-daily as a single dose or divided into two or three equal portions, which must be reduced for patients with renal failure. Amikacin is absorbed rapidly after intramuscular injection, and peak concentrations in plasma approximate 20 µg/ml after injection of 7.5 mg/kg. The concentration, 12 hours after a 7.5 mg/kg dose, is 5 to 10 µg/ml. A 15-mg/kg once-daily dose produces peak serum concentrations of 50 to 60 µg/ml and a trough < 1 µg/ml. Aminoglycosides are frequently used in combination with a cell wall-active agents (β-lactam or glycopeptides) for the therapy of serious proven or suspected bacterial infections. The three rationales for this approach are: (1) to expand the empiric spectrum of activity of the antimicrobial regimen, (2) to provide synergistic bacterial killing, and (3) to prevent the emergence of resistance to the individual antimicrobial agents. As with the other aminoglycosides, amikacin causes ototoxicity, hearing loss, and nephrotoxicity [3]. For treatment of mycobacterial infections, thrice-weekly dosing schedules are used, with doses up to 25 mg/kg [4].
Because of their polar nature, aminoglycosides do not penetrate well into most cells, the central nervous system, or the eye. The apparent distribution volume of aminoglycosides is 25% of lean body-weight and approximates the volume of extracellular fluid. The aminoglycosides distribute poorly into adipose tissue, which must be considered when weight-based doses are administered to obese patients. Concentrations of aminoglycosides in secretions and tissue are low [5]. High concentrations are found only in the renal cortex and the endolymph and perilymph of the inner ear; high concentrations in these sites likely contribute to the nephrotoxicity and ototoxicity caused by these drugs. As a result of active hepatic secretion, concentrations in the bile approach 30% of those found in plasma, but this represents a very minor excretory route for the aminoglycosides. Inflammation increases the penetration of aminoglycosides into peritoneal and pericardial cavities. Concentrations of aminoglycosides achieved in the central nervous fluid with parenteral administration are usually subtherapeutic [6]. Treatment of meningitis with intravenous administration is generally suboptimal. Intrathecal or intraventricular administration of aminoglycosides has been used to achieve therapeutic level in this central nervous system but the availability of expanded-spectrum cephalosporins has generally made this unnecessary [3].
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