Aminoglycosides are very potent bactericidal antibiotic agents that are active against susceptible aerobic microorganisms. They kill by inhibiting protein synthesis and to some extent by lysing the cell envelope. All the aminoglycosides (streptomycin, kanamycin, neomycin, gentamicin, amikacin, tobramycin, sisomicin, and netilmicin) share common structural features. Streptomycin is used once a day in combination with other antibiotics to treat mycobacterial infections.
Neomycin is used topically to treat superficial infections (a use to be discouraged) and is also given orally preoperatively for chemoprophylaxis before large-bowel surgery. The other agents are used parenterally to treat systemic bacterial septicemia (e.g., bacterial endocarditis, or urinary tract infections) or topically to treat local infection (e.g., bacterial conjunctivitis).
The physical environment where the aminoglycosides act considerably influences their antibacterial efficacy. Under conditions of low oxygen tension and low pH, and in the midst of extensive proteinaceous debris, aminoglycosides cannot exert antibacterial effects. Such an environment exists in many situations (e.g., pneumonia, abscesses, skin, and skin structure infections), and aminoglycosides should not be used as monotherapy in these settings. Likewise, aminoglycosides should not be used as monotherapy to treat osteomyelitis or central nervous system infections because they do not penetrate well into these tissues.
The major indication for aminoglycosides is in combination with other antibiotics (e.g., β-lactams) to treat serious aerobic bacterial infections. When combined with β-lactams, they are particularly useful for treating aerobic gram-negative septicemia (notably that caused by Enterobacteriaceae) and enterococcal endocarditis. The combination therapy also decreases the rate of development of bacterial resistance to the aminoglycoside by ribosomal mutation and acquisition of aminoglycoside-modifying enzymes. Because gentamicin is less costly than and as efficacious as tobramycin and amikacin, for most indications gentamicin is the preferred aminoglycoside.
Amikacin should be reserved to treat bacterial infections that are known to be resistant to gentamicin and tobramycin, since it is the most stable aminoglycoside known against bacterial R-plasmid-mediated enzymes. For this reason, amikacin is active against most gentamicin- and tobramycin-resistant gram-negative bacilli. There is concern that extensive usage of amikacin will eventually select for resistant organisms and nullify its current effectiveness. Tobramycin has been recommended by some authorities because its activity against P. aeruginosa is greater than that of gentamicin in most hospitals, and because it may be less nephrotoxic than other aminoglycosides given parenterally. Despite these recommendations, it is still prudent to use gentamicin if the bacterial isolate is sensitive to this agent.
A number of points should be kept in mind regarding nephrotoxicity when deciding when and which aminoglycoside to use. All the aminoglycosides are concentrated in the renal cortex. The proximal tubules are most susceptible to their toxic effects, but glomerular lesions also are part of the nephrotoxicity caused by aminoglycosides. In general, when patients receive these drugs for less than 5 days, nephrotoxic effects are minimal. The nephrotoxicity is more severe in patients with previous renal insufficiency and coexisting prolonged hypovolemia, sodium depletion, and acidosis, and in those who simultaneously are given other nephrotoxic agents, including radiocontrast dye, furosemide, or indomethacin.
Since aminoglycoside nephrotoxicity is related to the dose of the drugs and their concentrations in plasma, monitoring plasma concentrations in clinically unstable patients, or in those who receive prolonged therapy, is mandatory. Based on these drug concentrations, the dose and frequency of administration of aminoglycosides should be modified (see part 1, Introduction, chapter 23, Clinical Pharmacokinetics and Pharmacodynamics). Once daily dosing of gentamicin and tobramycin (6 mg/kg per day) and amikacin (15 mg/kg per day) is recommended for patients with normal renal function. This regimen is less nephrotoxic and may be more effective since peak levels are higher (and thereby takes advantage of concentration-dependent killing — a property shared by aminoglycosides). Once-daily aminoglycoside dosing should not be used for patients with endocarditis or those with ascites. The trough level should be measured 6 hours before the next dose and it should be ≤6µg/mL (for gentamicin, tobramycin).
For amikacin the trough level is 4 to 5 µg/mL. Aminoglycosides are also toxic to both the cochlear and vestibular components of the VIIIth cranial nerve, especially when plasmas concentrations are above the therapeutic range.