Once-Daily Dosing of Gentamicin

abstract & commentary

Synopsis: In yet another confirmatory study, once-daily dosing of gentamicin proved as effective as traditional three-times-a-day dosing, with no increase in toxicity.

Source: Gilbert DN, et al. A randomized comparison of the safety and efficacy of once-daily gentamicin or thrice-daily gentamicin in combination with ticarcillin-clavulanate. Am J Med 1998;105:182-191.

Yet another study comparing once-daily with thrice-daily aminoglycoside has demonstrated comparable safety and possibly diminished renal toxicity. This report describes three groups of patients randomized to receive either ticarcillin-clavulanate (TC) alone; TC plus gentamicin, the latter administered every 8 hours; or TC plus gentamicin, with the total daily aminoglycoside dose delivered every 24 hours. Patients, all suspected to have serious gram-negative bacterial infection, were comparable in terms of underlying disease (approximately half had malignancies), severity of illness (approximately one-fifth were in critical care units), and frequency of immunosuppression (some 20% were neutropenic and another 20% had AIDS). Only patients with estimated creatinine clearance of 30 mL/min or greater were enrolled.

A broad cross-section of infections routinely encountered in tertiary medical centers was represented in study patients, including unspecified fever in neutropenic patients, lower respiratory tract infections, peritonitis, biliary tract and intraabdominal sepsis, pyelonephritis, and skin and soft tissue infections. Bacteremia was documented in 23% of the 175 evaluable patients.

This study was different from most others of this type in that Gilbert and colleagues endeavored into each of the gentamicin treatment groups to achieve a predefined target serum concentration of gentamicin and found it necessary to adjust the dose upward within the first 48 hours in a substantial number of patients—particularly those receiving once-daily dosing. Duration of therapy averaged seven days but extended to as many as 55 days in one patient.

The results: nearly 90% of patients were clinically cured and had the infecting microorganism eradicated at the end of therapy in each of the gentamicin-containing regimens. A lesser success rate was achieved in the TC group, but the difference was apparently not statistically significant. Seven percent nephrotoxicity and 4-6% ototoxicity was encountered equally in each of the gentamicin treatment groups, although there was a suggestion (based on the fact that post-treatment renal function was unchanged or actually improved over base line measurements more often in once-daily gentamicin recipients) that once-daily treatment might be less toxic than every-8-hour dosing.

COMMENT BY JERRY D. SMILACK, MD

According to one survey, there have now been at least 30 published comparative trials to determine the efficacy and safety of once-daily vs. thrice-daily aminoglycoside dosing, and at least eight meta-analyses have been generated. Essentially all have concluded that clinical and microbiologic efficacy is equivalent, and toxicity seems no greater (some studies have even suggested less toxicity) with once-daily dosing. The message has gotten across. Whereas some 19% of hospital pharmacies reported once-daily aminoglycoside dosing in their hospitals in 1995, a recent report from the Infectious Diseases Society of America Emerging Infections Network, largely composed of infectious diseases clinicians, indicated that 70% currently prescribe or recommend once-daily gentamicin dosing, and some 55% of patients receiving gentamicin do so as a once-daily medication. A somewhat lower estimate from the CDC indicates that 28% of all gentamicin administered in the United States is done so in a once-daily regimen.

In an editorial accompanying Gilbert et al’s paper, Gerberding highlights possible advantages of once-daily dosing:1 equivalent efficacy and toxicity, fewer intravascular line-related infections, opportunity for outpatient treatment, and diminished cost of therapy. She concludes that "extended-interval dosing is the preferred aminoglycoside treatment regimen" for serious gram-negative infection in most patients, even those with neutropenia or other types of severe immunocompromise, for whom an anti-pseudomonal b-lactam should also be used. She recommends, however, that traditional multiple-daily dosing is warranted in patients with severe renal impairment or in those where pharmacokinetics (drug distribution or clearance) may be difficult to predict, such as ascites, extensive burns, or massive fluid replacement, or where once-daily dosing has not been studied, such as pregnancy and pediatrics. Usage in endocarditis is uncertain. She also points out that it is unclear whether extended-interval dosing in patients with mild renal insufficiency should use reduction in the total daily dosage or extension of the dosing interval.

An unanticipated adverse effect associated with once-daily gentamicin dosing has recently been reported by the CDC.2 A number of patients developed shaking chills, fever, tachycardia, and/or hypotension shortly after an intravenous infusion of gentamicin. The clinical scenario strongly suggested endotoxemia, and in fact it was discovered that patients receiving gentamicin supplied by one particular manufacturer contained endotoxin at a level higher than that found with other manufacturers’ gentamicin, but still within USP-allowed limits for endotoxin in antibiotic formulations. Administration of a large dose of gentamicin in a single infusion permitted delivery of an amount of endotoxin that could result in overt symptoms, whereas administering the traditional 1.5 mg/kg dose q 8 h would deliver an amount of endotoxin below the known threshold for clinically apparent reactions.

References

1. Gerberding JL. Aminoglycoside dosing: Timing is of the essence. Am J Med 1998;105:256-258.

2. Endotoxin-like reactions associated with intravenous gentamicin. MMWR Morb Mortal Wkly Rep 1998;47: 877-880.