Aminoglycosides are a group of bactericidal medications sharing chemical, antimicrobial, pharmacologic, and toxic characteristics. At present, the group includes streptomycin, neomycin, kanamycin, amikacin, gentamicin, tobramycin, sisomicin, netilmicin, paromomycin, spectinomycin, and plazomicin. All these agents inhibit protein synthesis in bacteria by inhibiting the function of the 30S subunit of the bacterial ribosome. Resistance is based on (1) a deficiency of the ribosomal receptor (chromosomal mutant); (2) the enzymatic destruction of the medication (plasmid-mediated transmissible resistance of clinical importance) by acetylation, phosphorylation, or adenylylation; or (3) a lack of permeability to the medication molecule or failure of active transport across cell membranes. Resistance can be chromosomal (eg, streptococci are relatively impermeable to aminoglycosides) or plasmid-mediated (eg, in gram-negative enteric bacteria). Anaerobic bacteria are resistant to aminoglycosides because transport across the cell membrane is an oxygen-dependent energy-requiring process.
All aminoglycosides are potentially ototoxic (cochlear and vestibular) and nephrotoxic, although to different degrees. All can accumulate in kidney disease; therefore, dosage adjustments must be made in patients with kidney dysfunction.
Because of their considerable toxicity and the availability of less toxic agents (eg, cephalosporins, quinolones, carbapenems, beta-lactamase inhibitor combinations), aminoglycosides are used less often than in the past. They are most commonly used in combination with other agents to treat resistant gram-negative organisms or in low doses with beta-lactam medications or vancomycin for their synergistic effect against gram-positive bacterial infection (eg, enterococci, penicillin-resistant viridans streptococci, S aureus and S epidermidis prosthetic heart valve infections). Although aminoglycosides demonstrate in vitro activity against many gram-positive bacteria, they should never be used alone to treat infections caused by these organisms—both because there is minimal clinical experience with such infections and because less toxic alternatives are available. Aminoglycosides are inferior to beta-lactams as monotherapy in the treatment of Pseudomonas infections, particularly in febrile neutropenic patients.
GENERAL PROPERTIES OF AMINOGLYCOSIDES
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 GI 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 ...