In this issue of American Family Physician, Gonzalez and Spencer1 update us on the current status of aminoglycosides, presenting new insight into their mechanism of action, and revisiting their clinical roles and the pharmacologic and therapeutic basis for single daily dosing vis-à-vis multiple daily dosing. As the authors explain,1 50 years after the introduction of aminoglycosides and despite the long-held association of these agents with nephrotoxicity and ototoxicity, they remain important in the treatment of serious infections with gram-negative and selected gram-positive microorganisms.
Strategies to minimize these toxicities are a topic that Gonzalez and Spencer1 briefly explore and have been the subject of numerous studies and published papers. As described, two basic strategies currently exist to safely and effectively administer aminoglycosides to patients. Optimal multiple daily dosing of aminoglycosides uses pharmacokinetic principles to guide patient-specific dosing, with the goal of achieving appropriate “peak” serum drug levels to ensure antimicrobial response and sufficiently low “trough” levels to minimize the risks for toxicity. Because this has been the standard approach for aminoglycoside dosing for decades, it is ironic that there continues to be conflicting data on the effectiveness of pharmacokinetic-based multiple daily dosing for reducing the risks for toxicity.2,3
The literature regarding single daily dosing is no less frustrating. The scores of papers found in the literature evaluating the safety and efficacy of single large doses of several different aminoglycosides given at extended intervals have generally lacked sufficient statistical power to reach clinically definitive conclusions. Consequently, studies on single daily dosing have been the subject of meta-analysis; nine meta-analyses have been published to date.4–12 Given the variability that exists in how a meta-analysis may be conducted, the lack of uniform conclusions from meta-analyses on single daily dosing of aminoglycosides is perhaps not surprising (see Table 4 in the Gonzalez and Spencer article1 ).
But what do these studies tell us? In many of these meta-analyses, an association was found between the use of single daily dosing regimens of aminoglycosides and a reduced risk of clinical or microbiologic failure and a relative decrease in the risk of mortality, compared with multiple daily dosing of the same aminoglycoside using the same total daily dosages. A reduction in the relative risk of aminoglycoside toxicity was observed in several meta-analyses as well. Also, several of the remaining meta-analyses describe so-called trends that suggest benefit from single daily doses but lack sufficient power to achieve statistical significance. Importantly, in no meta-analysis was there a finding or a trend indicating a greater risk for therapeutic failure or toxicity associated with single daily dosing.
By design, these meta-analyses do not incorporate relevant data from nonrandomized trials. Perhaps the largest study evaluating any method of aminoglycoside dosing is the experience of Nicolau and colleagues13 at Hartford Hospital. These investigators first pharmacokinetically validated a single daily dosing gentamicin protocol using a dose of 7 mg per kg (with the dosage interval extended to 36 or 48 hours based on diminishing creatinine clearance) in study patients and subsequently followed the protocol to treat 2,184 patients for an average of 4.5 days. They documented a 1.2 percent incidence of nephrotoxicity that compared favorably with their historical rate of 3 to 5 percent. Since their original report, more than 2,000 additional patients have been treated according to this protocol, with no significant deviation from the original findings (personal communication, Nicolau). While this was not a controlled clinical trial, the magnitude of the Hartford experience gives additional support to the safety of single daily dosing. Further, the decrease in the cost of antimicrobial therapy associated with the reduction in the number of intravenous administrations of aminoglycosides, the reduced need for serum drug level monitoring and lower rates of toxicity provide evidence for the cost-effectiveness of single daily dosing with aminoglycosides.14
So what may be considered the current standard of practice with regard to aminoglycoside dosing? Recent information indicates that approximately 28 percent of all intravenous gentamicin administered in the United States is given using regimens of single daily dosing.15 In Europe, an aminoglycoside (isepamicin) undergoing clinical trials will have a formally approved once-daily dosing regimen. The U.S. Food and Drug Administration has indicated support for approving labeling of aminoglycosides for once-daily dosage, but no pharmaceutical manufacturer has responded, presumably in part because of the lack of an economic incentive given the number of generic aminoglycoside products available.16
Despite the lack of regulatory and industry guidance in the United States, the clinical use of single-daily-dose regimens of aminoglycosides has steadily grown, and now may be routinely recommended for many patient populations (see table) based on numerous published clinical studies and the meta-analyses that have shown them to be clinically safe and effective.
|Creatinine clearance of < 20 mL per minute|
|Severe liver disease with ascites|