Adverse effects from aminoglycosides are both timeand concentration-dependent. Toxicity is unlikely to occur until a certain threshold concentration is reached, but, once that concentration is achieved, the time beyond this threshold becomes critical.
This threshold is not precisely defined, but a trough concentration above 2 mcg/mL is predictive of toxicity. At clinically relevant doses, the total time above this threshold is greater with multiple smaller doses of drug than with a single large dose.
Numerous clinical studies demonstrate that a single daily dose of aminoglycoside is just as effective—and probably less toxic— than multiple smaller doses. Therefore, many authorities recommend that aminoglycosides be administered as a single daily dose in most clinical situations. However, the efficacy of once-daily aminoglycoside dosing in combination therapy of enterococcal and staphylococcal endocarditis in patients with a prosthetic valve remains to be defined, and administration of lower doses two or three times daily is still recommended. In contrast, limited data do support once-daily dosing in streptococcal endocarditis. The role of once-daily dosing in pregnancy, obesity, and in neonates also is not well defined.
Once-daily dosing has potential practical advantages. For example, repeated determinations of serum concentrations are unnecessary unless an aminoglycoside is given for more than 3 days. A drug administered once a day rather than three times a day is less labor intensive. And once-a-day dosing is more feasible for outpatient therapy.
Aminoglycosides are cleared by the kidney, and excretion is directly proportional to creatinine clearance. To avoid accumulation and toxic levels, once-daily dosing of aminoglycosides is generally avoided if renal function is impaired. Rapidly changing renal function, which may occur with acute kidney injury, must also be monitored to avoid overdosing or underdosing. Provided these pitfalls are avoided, once-daily aminoglycoside dosing is safe and effective. If the creatinine clearance is >60 mL/min, then a single daily dose of 5–7 mg/kg of gentamicin or tobramycin is recommended (15 mg/kg for amikacin). For patients with creatinine clearance <60 mL/min, traditional dosing as described below is recommended. With once-daily dosing, serum concentrations need not be routinely checked until the second or third day of therapy, depending on the stability of renal function and the anticipated duration of therapy. In most circumstances, it is unnecessary to check peak concentrations; an exception may be when ensuring adequately high peak concentrations for treating infections caused by drug-resistant pathogens. The goal is to administer drug so that concentrations of <1 mcg/mL are present between 18 and 24 hours after dosing. This provides sufficient time for washout of drug to occur before the next dose is given. Several nomograms have been developed and validated to assist clinicians with once-daily dosing (eg, Freeman reference).