Because of the similarities of the aminoglycosides, a summary of properties is presented briefly.
A. Absorption, Distribution, Metabolism, and Excretion
Aminoglycosides are not absorbed from the gastrointestinal tract. They diffuse poorly into the eye, prostate, bile, central nervous system, and spinal fluid after parenteral injection.
The serum half-life is 2–3 hours in patients with normal kidney function. Excretion is almost entirely by glomerular filtration. Aminoglycosides are removed effectively by hemodialysis or continuous hemofiltration.
B. Dosage and Effect of Impaired Kidney Function
In persons with normal kidney function who have gram-negative infections, the dosage of amikacin and plazomicin is 15 mg/kg/day in a single daily dose; that for gentamicin, tobramycin, or netilmicin is 5–7 mg/kg injected once daily. A single large daily dose of gentamicin, tobramycin, netilmicin, or amikacin is as efficacious as—and no more nephrotoxic than—the originally used dosing every 8–12 hours. When a single large daily dose is given, peak levels are not required. Trough aminoglycoside levels should be undetectable in patients with normal body composition and kidney function receiving once-daily dosing. Some clinicians recommend serum level sampling 12–18 hours after the dose and extending the interval to every 48–72 hours for patients with elevated serum levels. Others have suggested maintaining the dosage interval but decreasing the dose. Patients with kidney disease, volume overload, or obesity have altered antibiotic clearance or volume of distribution. In patients with abnormal kidney function or body composition, once-daily dosing is not recommended and aminoglycoside levels are recommended to guide dosing. In such patients, peak levels greater than 6 mcg/mL are the goal in the treatment of serious gram-negative infection, including pneumonia. When using more frequent dosing (ie, not once daily), troughs of greater than 2 mcg/mL have been associated with an increased incidence of nephrotoxicity. In patients with normal body composition, once-daily dosing regimens should be followed. Reduced gentamicin doses (1 mg/kg every 8 hours) are recommended when used synergistically with beta-lactams or vancomycin in the treatment of enterococcal endocarditis. However, synergistic gentamicin dosing of 3 mg/kg every 24 hours (as opposed to 1 mg/kg every 8 hours) is preferred in the treatment of endocarditis due to viridans streptococci. Gram-negative bacterial isolates with “susceptible” MICs of 1–4 mcg/mL treated with aminoglycosides lead to unacceptably low probability of good clinical outcome. Increasing the dose of aminoglycosides to improve chances for improved outcome is likely to be associated with an increased risk of ototoxicity and nephrotoxicity.
All aminoglycosides can cause ototoxicity and nephrotoxicity. Compared with their nephrotoxicity, the ototoxicity is more likely to be irreversible and is cumulative, presenting as hearing loss (cochlear damage), noted first with high-frequency tones, or as vestibular damage, manifested by vertigo and ataxia. Amikacin is likely more cochlear-toxic than gentamicin, tobramycin, or netilmicin. Nephrotoxicity is usually reversible and occurs with similar frequency with gentamicin, tobramycin, amikacin, and netilmicin. The risk of nephrotoxicity exists even with synergistic lower doses in the treatment of serious gram-positive bacterial infection.
In very high doses, usually associated with irrigation of an inflamed peritoneum, aminoglycosides can be neurotoxic, producing a curare-like effect with reversible neuromuscular blockade that results in respiratory paralysis.