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Initial low-dose aminoglycosides in Staphylococcus aureus bacteremia: good science, urban legend, or just plain toxic?

Received 24 November 2008; accepted 24 November 2008; electronically published 10 February 2009. Reprints or correspondence: Dr. Arnold S. Bayer, LA Biomedical Research Institute, 1124 W. Carson St., Bldg. RB2, Rm. 225, Torrance CA 90502 (abayer@labiomed.org). Clinical Infectious Diseases 2009; 48:722–4 2009 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2009/4806-0005$15.00 DOI: 10.1086/597032 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 rightand 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 aminoglycosides 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 4to 6week 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 strik-