Initial Low-Dose Aminoglycosides in Staphylococcus aureus Bacteremia: Good Science, Urban Legend, or Just Plain Toxic?

Combining antibiotics to amplify their individual efficacies has been a long-standing paradigm in infectious diseases to accomplish 1 or more of the following goals: (1) to increase the extent or rapidity of microbial killing, (2) to exert synergistic interactions based on distinct mechanisms of action, and/or (3) to prevent the emergence of resistance to the component agents in a drug combination. In this context, the use of an initial low-dose aminoglycoside (ILA) in Staphylococcus aureus bacteremia for clinical synergy has a rich and colorful history. This approach was initially promoted by the impressive in vitro data showing more rapid killing of the organism, as well as in experimental infective endocarditis (IE) in vivo data showing more rapid and complete eradication of vegetation staphylococci, by combinations of cell wall–active agents plus aminoglycosides [1]. Clinical trials in both right- and left-sided IE were performed in the 1980s in which patients with methicillin-susceptible S. aureus IE were given cell wall–active agents (usually an antistaphylococcal penicillin) for 4–6 weeks plus aminoglycosides (usually for the first 2 weeks). In right-sided S. aureus IE, addition of 2 weeks of aminoglycoside therapy did not substantially affect outcome metrics, although subsequent studies supported a short-course regimen of 2 weeks of an antistaphylococcal penicillin plus aminoglycosides as being highly effective [2, 3]. However, more recent comparative investigations have not confirmed the additive benefit of supplementary amino-glycosides for 2 weeks in the treatment of right-sided methicillin-susceptible S. aureus IE [4].

In left-sided methicillin-susceptible S. aureus IE, the addition of 2 weeks of aminoglycoside therapy to standard 4- to 6-week courses of antistaphylococcal penicillins reduced the duration of S. aureus bacteremia by 1–2 days [2], although a drawback of this approach in terms of enhanced renal impairment was noted. This effect on reducing the duration of early S. aureus bacteremia in such cases led to the recommendation of experts in the field and the American Heart Association's Infective Endocarditis Writing Group to use a short (5-day) course of aminoglycosides to accompany cell wall–active agents for the treatment of S. aureus IE [5]. The philosophy of this recommendation was not only the perceived salutary influence on S. aureus bacteremia, but also the notion that such ILA use could do no harm. More recently, the lack of evidence on measurable benefits of the ILA regimens for native valve IE led the American Heart Association's Infective Endocarditis Writing Group to recommend such strategies as “optional” in the latest iteration of their recommendations for IE treatment [6]. In addition, until recently, the downside of the ILA approach had not been systematically analyzed.

In 2006, Fowler et al. [7] published their seminal study on the comparative efficacies of daptomycin versus either antistaphylococcal penicillin or vancomycin therapy, plus ILA, in 236 patients with S. aureus bacteremia. These patients had cases of either complicated or uncomplicated S. aureus bacteremia or right-sided S. aureus IE. Most cases were caused by methicillin-susceptible S. aureus bacteremia. In methicillin-susceptible S. aureus bacteremia, daptomycin was noninferior to the antistaphylococcal penicillin or vancomycin regimens, whereas a noteworthy trend was seen of better outcomes in methicillin-resistant S. aureus bacteremia in favor of daptomycin. One of the striking outcomes of this study was the high rate of nephrotoxicity in the ILA groups. The patients from this daptomycin versus standard-of-care clinical trial of S. aureus bacteremia have now been further analyzed and form the basis of the article by Cosgrove et al. [8] in the current issue of Clinical Infectious Diseases. A number of important findings emerged from this retrospective, observational investigation. First, renal adverse events were relatively common; ∼25% of patients who received antistaphylococcal penicillin or vancomycin plus ILA (mean of ∼4 days at ∼2 mg/kg daily) experienced clinically significant decreases in creatinine clearance (compared with ∼ 8% among those receiving daptomycin alone). Second, renal impairment occurred early, especially in the antistaphylococcal penicillin arm (peaking at study days 4 and 7) and later in the vancomycin arm (peaking at study days 14, 21, and 28). Third, no significant difference was found in the frequencies of nephrotoxicity in the antistaphylococcal penicillin versus vancomycin arms. This finding was somewhat unexpected, given the common mantra that vancomycin-aminoglycoside combinations are particularly important in fostering nephrotoxicity [9]. Fourth, ILA-associated renal impairment was durable. For example, 6% and 21% of patients receiving ILA experienced a 50% or 25% sustained decrease of creatinine clearances, respectively, during the 6-week observation period. Fifth, the greatest risk factors for ILA-associated renal impairment were predictable and included the following: age ⩾65 years, underlying diabetes mellitus, and reduced baseline creatinine clearances (50–80 mL/min).

Was there any definable benefit to the ILA approach? As pointed out by Fowler et al. [7] in the original publication of this work, no mortality benefit was found with the use of combination therapy. Data on duration of bacteremia confirmed older publications that found that the addition of aminoglycosides to conventional therapy could shorten the duration of bacteremia by 1 day, compared with standard therapy alone.

Why was there such a high rate of nephrotoxicity in this study with short-course ILA regimens? As noted herein, there was a distinct association between the development of renal impairment and age, underlying disease, and baseline renal function. Moreover, a high proportion of patients in the ILA group were also receiving concomitant potentially nephrotoxic agents (∼50%), including antihypertensives and nonsteroidal anti-inflammatory drugs. In addition, it is possible that renal perfusion was differentially impaired in ILA recipients by either dehydration or heart failure (although we were not provided this information). Furthermore, we know from experimental data that S. aureus bacteremia, with or without IE, commonly seeds the kidney, causing microabscess formation. Finally, immune complex glomerulonephritis occurs in S. aureus IE by activation of either the alternate or classic complement pathways [10]. Either of these events could lay a solid foundation for renal insufficiency in ILA-exposed patients.

The current study has several limitations and leaves unanswered questions. Do these data have any relevance to pediatric patients? Are the findings relevant only to patients with S. aureus bacteremia, or are patients with coagulase-negative staphylococcal bacteremia (especially those with prosthetic valve IE for whom aminoglycoside-containing regimens are currently recommended [5, 6]) also at increased risk of aminoglycoside-induced renal toxic effects? Are ILA regimens advisable for patients with left-sided S. aureus IE or S. aureus prosthetic valve IE, few if any of whom were considered in this study? Is daptomycin protective against aminoglycoside-associated renal dysfunction? Such protection was suggested in experimental studies in the 1990s [11] but could not be evaluated in the current study because of the shorter duration (2 days) of aminoglycoside use with daptomycin in a small subset of patients. Did the vancomycin trough levels in the vancomycin-ILA group influence onset of renal toxicity?

Also unanswered is whether there are patients with S. aureus bacteremia who might still be appropriate candidates for ILA strategies, such as those with methicillin-resistant S. aureus strains exhibiting higher MICs of vancomycin that are still within the susceptible range (i.e., 1.5–2 µg/mL) [12]. Should ILA regimens be considered for patients for whom empirical single-drug vancomycin or antistaphylococcal penicillin regimens fail?

Although these data on ILA-associated renal impairment, when combined with antistaphylococcal penicillin or vancomycin, are impressive, it is important to underscore that the degree of renal insufficiency was modest at best, and no patients developed hemodialysis-dependent renal failure. However, as cogently pointed out by the authors, even modest decreases in creatinine clearances can evoke “additional laboratory and imaging studies, nephrology consultation, changes in medications and doses, prolonged hospitalization and increased mortality” [8]

In summary, to paraphrase a common theme among infectious disease experts, we have been “tapping on the nail in the coffin” of aminoglycoside use with antistaphylococcal penicillin and vancomycin in S. aureus bacteremia and S. aureus IE for many years. The current study by Cosgrove and colleagues in this issue of Clinical Infectious Diseases should help us “drive the final nail in the coffin” against this approach on a routine basis, at least for the patient populations and drugs used herein.

• Received November 24, 2008.
• Accepted November 24, 2008.

• © 2009 by the Infectious Diseases Society of America