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The Concern for Vancomycin Failure in the Treatment of PediatricStaphylococcus aureusDisease

Year: 2018
Type: editorial
Abstract: (See the Major Article by Randolph et al on pages 365–72.) Few agents in our antimicrobial armamentarium have as complex a history as vancomycin. Many US medical centers prescribe more vancomycin each month than any other antimicrobial agent [1]. Yet, despite its inordinate frequency in empiric antimicrobial regimens and its continuous use for more than 60 years [2], vancomycin resistance among clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) remains rare in the United States, though the rate of intermediate resistance is increasing [3]. Without question, vancomycin has saved countless lives as the first-line agent for invasive MRSA infections in children and adults for decades. However, it is foreseeable that we may encounter the unusual situation where a mainstay anti-staphylococcal drug falls out of favor for reasons beyond the development of antimicrobial resistance. Vancomycin has long been beset by toxicity concerns. The therapeutic window for the drug is narrow, with complex dosing nomograms and therapeutic drug monitoring occupying a substantial amount of time and cost for prescribing providers and pharmacists. Therapeutic drug monitoring is particularly challenging in the pediatric population where drug metabolism can vary widely, particularly in adolescents. Further, it has recently become clear that the risk of nephrotoxicity is unacceptably high when vancomycin is used concomitantly with piperacillin-tazobactam [4], another commonly used antimicrobial for empiric therapy in the setting of invasive and life-threatening infections. While these concerns are important, a separate and even more incriminating concern is arising: vancomycin simply may not be sufficiently effective as a first-line agent targeting life-threatening MRSA disease. In this issue of Clinical Infectious Diseases, Randolph and coauthors provide evidence to support a concern that many infectious diseases physicians have anecdotally observed for years—the inadequacy of vancomycin monotherapy to control secondary MRSA disease following influenza infection in children. The authors conducted a multicenter study that prospectively captured outcomes across 34 pediatric intensive care units and found that risk of death was increased more than 5-fold if vancomycin monotherapy was used compared to vancomycin plus a second MRSA-active agent (usually clindamycin). The results of this study are compelling, and a potential mortality signal of this magnitude should give providers pause before treating severe disease with vancomycin alone. One hypothesis for the inferiority of vancomycin monotherapy observed in this study is that target drug levels may be insufficient to maintain adequate time of drug concentration above the minimum inhibitory concentration (MIC), particularly in specific tissue compartments such as the lungs. However, median trough levels of vancomycin did not differ significantly between groups in this study. Another potential explanation is that vancomycin lacks the ability to interfere with toxin production by S. aureus, unlike protein synthesis inhibitors such as clindamycin or linezolid (which was shown to be superior to vancomycin for the treatment of MRSA pneumonia in at least 1 study) [5]. Staphylococcus aureus produces numerous toxins that play clear roles in pathogenesis in a variety of models, including alpha hemolysin, which is critical for virulence in animal models of pneumonia [6]; Panton-Valentine leukocidin, which is epidemiologically associated with community-associated MRSA strains, though with a less clear role in virulence [7]; and the more recently described leukocidin LukAB (also known as LukGH), which is a key mediator of staphylococcal escape from innate host defenses [8, 9] that is known to be produced in the setting of invasive human infection [10]. Given the breadth of functions of these and other toxins secreted by S. aureus in the setting of tissue invasion, it is certainly plausible that direct protein synthesis inhibition is an advantageous component of antimicrobial therapy. Some aspects of the study design temper the strength of the conclusions we might draw from these data. The sample size was relatively small for a condition that varies substantially in its clinical spectrum and severity, although the authors can hardly be faulted for the sample size given that the study includes data from 34 sites over 8 years. In addition, vancomycin MIC data were not available for 30% of the patients in the study, and 13% of patients were infected with isolates with an MIC of 1–2 µg/mL. It is conceivable, given the relatively small number of deaths in the study, that intermediate vancomycin resistance could have disproportionately occurred in the group that received vancomycin alone, biasing the outcome in this way. Moreover, the potential presence of heteroresistant subpopulations of vancomycin-intermediate S. aureus strains not detected by typical susceptibility testing further complicates our ability to truly assess vancomycin susceptibility [11]. One additional limitation is that the complexity of the patients enrolled in the study precludes the discernment of potential adverse effects of combination antimicrobial therapy. This is important given that increased adverse effects, along with increased costs and a desire for antimicrobial stewardship, are the primary arguments against “double coverage” of invasive MRSA disease. While adverse event data are lacking from this study, one could argue that this is of lower importance given the observed mortality signal. Despite these mostly unavoidable limitations, the findings from the study are notable and are in line with outcomes that we observe in a variety of settings where vancomycin monotherapy is used for invasive MRSA disease [12]. Compared to the previous several decades, the past 8–10 years have seen a relatively large number of antibiotics brought to market with MRSA activity. In 2011, the Infectious Diseases Society of America published guidelines for the treatment of MRSA that recommended either daptomycin or vancomycin as first-line therapy for MRSA bacteremia or endocarditis, with daptomycin receiving a superior level-of-evidence grade of A-1 [13]. (For cases of pneumonia, however, daptomycin is not recommended for use due to its inactivation by surfactant [14], though its role in hematogenous pulmonary infection is less clear [15].) In the several years since these guidelines were compiled, new agents, including ceftaroline, telavancin, tedizolid, dalbavancin, oritavancin, and ceftobiprole, have been introduced. These agents differ in their specific indications, dosing strategies, capacity for toxin inhibition, and potential adverse effect profiles [16, 17], and phase 4 clinical data are forthcoming. It remains to be seen whether any of these agents will replace vancomycin as the standard first-line agent against suspected invasive MRSA disease or if monotherapy remains appropriate at all. Providers who care for children with suspected life-threatening MRSA infection, whether following influenza or not, are encouraged to consider the findings of Randolph et al before prescribing vancomycin alone in this setting. It may be that combination therapy, or an alternative agent altogether, represents a superior option for management of these high-risk patients. As S. aureus continues to evolve in its virulence factor repertoire and antimicrobial resistance spectrum, we must continue to assess whether we are providing optimal antimicrobial therapy for this major bacterial pathogen. Financial support. The author is supported by the National Institute of Allergy and Infectious Diseases (grant 1K23AI113150 K23). Potential conflicts of interest. The author serves as an investigator on studies funded by GlaxoSmithKline and Horizon Pharma. None of these studies conflict with the contents of this manuscript. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
DOI: 10.1093/cid/ciy497
Language: English
Field: Medicine
Open Access status: bronze
OpenAlex ID: W2806189833
Cites: 19
Cited by: 5
Related to: 10