Once-daily dosing of aminoglycosides: how much monitoring is truly required?

Abstract

Once-daily dosing of aminoglycosides has become the standard of care in many clinical settings. More than 50 clinical trials and several metaanalyses indicate that once-daily dosing is as effective as and probably less nephrotoxic than the multiple-dose regimen (1– 4), yet there are still gaps in our knowledge. For example, once-daily dosing has been evaluated inadequately in elderly patients, patients who are obese or pregnant, or those with a creatinine clearance less than 20 mL/min. Gentamicin administered three times daily is still recommended for patients with endocarditis, as there are limited data on once-daily dosing in humans and some animal studies suggesting better clearance of Enterococcus faecalis with more frequent dosing (5). There is little information regarding the treatment of other conditions such as osteomyelitis and meningitis. Furthermore, it is not known if the current once-daily dosing regimens are optimal, or if pharmacokinetic monitoring can increase efficacy and decrease toxicity. Bartal et al. (6) in this issue of The American Journal of Medicine attempt to address the question of whether once-daily aminoglycoside dosing can be improved with pharmacokinetic monitoring. They observed that pharmacokinetically guided dosing reduced drug-related nephrotoxicity and allowed a greater dose of aminoglycoside to be given. The risk of drug-induced nephropathy is a major factor limiting the use of aminoglyclosides. Aminoglycoside uptake by lysosomes in tubular cells leads to proximal tubular cell injury (7). Prolonged exposure can result in renal tubular necrosis and interstitial fibrosis. When the aminoglycoside is discontinued early after the onset of renal injury, nephrotoxicity is usually reversible; continued exposure may cause permanent renal damage. The risk of nephrotoxicity is also greater in patients with reduced renal function and slower clearance of aminoglycosides. In once-daily dosing as compared with multiple dosing, there is sufficient time for blood aminoglycoside levels to decrease to low enough levels such that accumulation in the renal cortex is minimized. A key methodological question in studies of aminoglycoside-induced nephrotoxicity, including the one by Bartal et al., is the definition of nephrotoxicity. The authors arbitrarily defined nephrotoxicity as an increase in serum creatinine level of at least 25%, or a serum creatinine level 1.4 mg/dL if baseline values were normal. Other studies have selected higher values, such as a 50% increase in serum creatinine level. We are told that the pharmacokinetic group had significantly less increase in serum creatinine level when aminoglycoside therapy was stopped, but few other details were given. Longer-term outcomes, such as serum creatinine level at discharge or several weeks later, were also not included. Given that most aminoglycoside-related increases in serum creatinine level are transient and return to baseline after the drug is stopped, it is not clear that this intensive monitoring strategy prevented clinically important toxicity. Furthermore, ototoxicity, which may result in severe and permanent disability and which may be clinically more important than nephrotoxicity, was not evaluated; however, ototoxicity is uncommon and may be difficult to measure in seriously ill patients. In the Bartal study, the pharmacokinetic group received higher doses of aminoglycosides as a result of adjusting doses upward for below-target peak levels. Some of these adjustments may have been required because patients initially received lower-than-recommended doses for once-daily therapy; the starting dose of gentamicin was 3 mg/kg, compared with the 5to 7-mg/kg dose that is typically used (8). The authors postulated that greater cumulative doses could lead to improved outcomes, although this could not be demonstrated in this relatively small study. Indeed, the trend favored better outcomes in the comparison group. The goal of maximizing peak levels is part of the basis for once-daily dosing because aminoglycosides appear to have enhanced bactericidal activity against gram-negative organisms at higher concentrations (9). However, aminoglycosides are rarely used as single drugs for serious gram-negative infections, and it is unclear whether the addition of aminoglycosides to other potent gram-negative therapy is even required. Therefore, given the current use of aminoglycosides, it may be difficult to show that measuring drug peak concentrations has an appreciable effect on improving patient outcomes. The authors state that many physicians forgo any kind of monitoring with once-daily dosing of aminoglycosides Am J Med. 2003;114:239 –240. From the Divisions of Infectious Diseases (LW) and Clinical Pharmacology (NB), Department of Medicine, University of California, San Francisco, and San Francisco General Hospital Medical Center, San Francisco, California. Requests for reprints should be addressed to Lisa Winston, MD, Division of Infectious Diseases, Department of Medicine, University of California, San Francisco/San Francisco General Hospital, 1001 Potrero Avenue, Building 100, Room 301, San Francisco, California 94110, or lisaw@itsa.ucsf.edu. Manuscript submitted November 6, 2002.