Once-daily dosing regimen for aminoglycoside plus beta-lactam combination therapy of serious bacterial infections: comparative trial with netilmicin plus ceftriaxone.

Once-daily dosing of aminoglycosides has been suggested to improve their efficacy and reduce their toxicity. To test the clinical validity of this suggestion, we conducted a prospective, randomized trial comparing a conventional multiple-daily-dosing regimen of netilmicin with once-daily administration of the same total daily dose of this aminoglycoside. We enrolled 141 predominantly elderly patients with severe bacterial infections. All patients received once-daily doses of 2 g ceftriaxone, in addition to netilmicin. Patients randomized to either of the two dosing strategies were comparable regarding age, APACHE II score, concomitant diseases, infection site, and rate of culture-proven bacteremia. Netilmicin treatment did not differ significantly in mean daily dose per kg body weight and days of therapy between the two treatment arms. Compared to patients receiving conventional doses, patients treated with a once-daily dose had higher serum peak netilmicin levels and lower trough levels. Outcome of infection and mortality were not influenced by dosing strategy. Although the overall incidence of nephrotoxicity was similar in both groups (16%), the occurrence of nephrotoxicity in patients treated with once-daily doses of netilmicin was significantly shifted to those given prolonged treatment, i.e., beyond 9 days. Auditory toxicity was documented in one patient treated with conventional doses and two patients treated with once-daily doses. Once-daily dosing of an aminoglycoside plus a long-acting cephalosporin in these patients constituted cost-effective and safe treatment for severe bacterial infections. Netilmicin-induced toxicity may be reduced by using once-daily dosing regimens and limiting the duration of treatment.