With traditional dosing, adjustments must be made to prevent accumulation of drug and toxicity in patients with renal insufficiency. Either the dose of drug is kept constant and the interval between doses is increased, or the interval is kept constant and the dose is reduced. Nomograms and formulas have been constructed relating serum creatinine levels to adjustments in traditional treatment regimens. Because aminoglycoside clearance is directly proportional to the creatinine clearance, a method for determining the aminoglycoside dose is to estimate creatinine clearance using the Cockcroft-Gault formula described in Chapter 60. For a traditional twiceor thrice-daily dosing regimen, peak serum concentrations should be determined from a blood sample obtained 30–60 minutes after a dose, and trough concentrations from a sample obtained just before the next dose. Doses of gentamicin and tobramycin should be adjusted to maintain peak levels between 5 and 10 mcg/mL (typically between 8 and 10 mcg/mL in more serious infections) and trough levels <2 mcg/mL (<1 mcg/mL is optimal).
E. Adverse Effects
All aminoglycosides are ototoxic and nephrotoxic. Ototoxicity and nephrotoxicity are more likely to be encountered when therapy is continued for more than 5 days, at higher doses, in the elderly, and in the setting of renal insufficiency. Concurrent use with loop diuretics (eg, furosemide, ethacrynic acid) or other nephrotoxic antimicrobial agents (eg, vancomycin or amphotericin) can potentiate nephrotoxicity and should be avoided if possible. Ototoxicity can manifest either as auditory damage, resulting in tinnitus and high-frequency hearing loss initially, or as vestibular damage with vertigo, ataxia, and loss of balance. Nephrotoxicity results in rising serum creatinine levels or reduced creatinine clearance, although the earliest indication often is an increase in trough serum aminoglycoside concentrations. Neomycin, kanamycin, and amikacin are the agents most likely to cause auditory damage. Streptomycin and gentamicin are the most vestibulotoxic. Neomycin, tobramycin, and gentamicin are the most nephrotoxic.
In very high doses, aminoglycosides can produce a curare-like effect with neuromuscular blockade that results in respiratory paralysis. This paralysis is usually reversible by calcium gluconate, when given promptly, or neostigmine. Hypersensitivity occurs infrequently.
F. Clinical Uses
Aminoglycosides are mostly used against aerobic Gram-negative bacteria, especially when there is concern for drug-resistant pathogens or in critically ill patients. They are almost always used in combination with a β-lactam antibiotic to extend empiric coverage and to take advantage of the potential synergism between these two classes of drugs. Penicillin-aminoglycoside combinations have also been used to achieve bactericidal activity in treatment of enterococcal endocarditis and to shorten duration of therapy for viridans streptococcal endocarditis. Due to toxicity, these combinations are used less frequently when alternate regimens are available. For example, in the case of enterococcal endocarditis, studies suggest that the combination of ampicillin and ceftriaxone is an effective regimen with less risk for nephrotoxicity. When aminoglycosides are used, the selection of agent and dose depends on the infection being treated and the susceptibility of the isolate.
Streptomycin (Figure 45–1) was isolated from a strain of Streptomyces griseus. The antimicrobial activity of streptomycin is typical of that of other aminoglycosides, as are the mechanisms of resistance. Resistance has emerged in most species, restricting the current usefulness of streptomycin, with the exceptions listed below.