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Treating MRSA bacteremia and endocarditis: What are the options?
There has been a dramatic increase in the number of staphylococcal bacteremias and cases of infective endocarditis involving strains of Staphylococcus aureus resistant to methicillin. Related either to delays in adequate antimicrobial therapy and/or a greater inherent virulence of MRSA compared with methicillin-sensitive strains, most, if not all, evidence and meta-analyses support an overall poorer outcome and increased risk for mortality associated with MRSA as compared with methicillin-sensitive S. aureus bacteremia.
For decades, vancomycin has been the only viable alternative and standard-of-care antimicrobial agent for the treatment of serious MRSA infections. However, many infectious disease experts would agree that, historically, this glycopeptide’s performance has been suboptimal compared with antistaphylococcal beta-lactam agents (ASBLs), exhibiting slower bacterial clearance and poorer response rates in the treatment of methicillin-sensitive S. aureus (MSSA) bacteremia and endocarditis. That, coupled with the fact that we have witnessed elevations in the minimal inhibitory concentration (MIC) of vancomycin for MRSA brings into question the future utility of vancomycin in treating serious MRSA infections. Whether defined as persistence of bacteremia, recurrence of infection or increased overall mortality, many published investigations have looked at the consequence of elevated vancomycin MICs ( 1.5 g/mL), most times demonstrating a link between high vancomycin-MIC MRSA infections and poorer outcomes. What’s more, the emergence of heterogeneous (or hetero-resistant) vancomycin-intermediate S. aureus (hVISA) containing subpopulations of vancomycin-intermediate S. aureus (VISA) further jeopardizes the future utility of this antibiotic when treating serious MRSA infections. With the selective pressure of vancomycin administration, the VISA phenotypes are favored, eventually becoming the uniform population in that specific clinical setting. The detection of hVISA is problematic for most clinical microbiology laboratories, and this phenomenon often goes unnoticed. Furthermore, current automated susceptibility testing methods, relied upon by most clinical microbiology laboratories, do not accurately reflect the higher MICs produced when methods that are considered the reference standards, such as broth microdilution and Etest (bioMérieux), are applied to the same specimen. The yet-to-be-answered question is which antimicrobial agent(s) has the greatest potential to be superior to vancomycin for treating these MRSA infections?
Of the newer agents that have entered into clinical practice over the past decade or more, most — Cubicin (daptomycin, Cubist), Vibativ (telavancin, Theravance), Dalvance (dalbavancin, Durata Therapeutics), Orbactiv (oritavancin, The Medicines Company), Tygacil (tigecycline, Pfizer), Zyvox (linezolid, Pfizer), Sivextro (tedizolid, Cubist) and Teflaro (ceftaroline-fosamil, Forest Laboratories) — possess anti-MRSA activity. While all of these agents have been compared with vancomycin in randomized controlled trials, it is not surprising that none has been found superior to vancomycin. The ability to demonstrate superiority in either arm may have been hampered by protocol design and the inherent flaws and pitfalls associated with noninferiority trials. Moreover, none of these trials compared one new agent with another. Unfortunately, only daptomycin has sufficient trial data to warrant approval for the treatment of staphylococcal bacteremia (including MRSA) and right-sided infective endocarditis (IE).
In the only published clinical trial comparing any new anti-MRSA agent with vancomycin or a semisynthetic penicillin for the treatment of S. aureus bacteremia and endocarditis, daptomycin was equally effective in the treatment of patients with endocarditis caused by MSSA or MRSA, but had a higher success rate than vancomycin when MRSA was the pathogen. In a subsequent evaluation, the lack of daptomycin superiority over vancomycin may have been influenced by the fact that all strains in the vancomycin arm had MICs of 1 g/mL or less. Several recent observational cohort studies have suggested that daptomycin might be preferred over vancomycin to treat MRSA bacteremia due to high vancomycin MICs, as overall statistically significant benefits have been seen with daptomycin in terms of mortality and persistent bacteremia, but not in recurrence of bacteremia. Some experts have suggested that in treating MRSA bacteremia and IE, the dose of daptomycin should be 8 mg/kg daily to 10 mg/kg daily instead of the FDA-approved dose of 6 mg/kg daily. Upward shifts in vancomycin MICs encountered when MRSA strains are exposed to the drug for prolonged periods of time or in high inoculum deep-seated infections, as well as strains associated with hVISA and VISA infection, have been observed to have concurrent shifts in MIC values for daptomycin, rendering them less susceptible or nonsusceptible to this lipopeptide. The mechanism of resistance believed secondary to changes in the permeability of the bacterial surface membrane has been successfully overcome with the addition of an ASBL in studies using oxacillin or ceftaroline. Termed the “seesaw” phenomenon, susceptibility to ASBLs increases as lipopeptide susceptibility decreases; the exposure to ASBLs effectively enhances daptomycin binding to the cell membrane, resulting in the restoration of the drug’s killing activity.
Most available studies reporting on the utility of the bacteriostatic agent linezolid for the treatment of MRSA bacteremia and IE involve either patients with strains of MRSA exhibiting elevated vancomycin MICs or those with persistent bacteremia after having received more than 1 week of this antibiotic. In these studies, linezolid was noninferior. In addition, the potential for hematologic derangements associated with the long-term administration of this oxazolidinone could become problematic. In the few published studies investigating the efficacy of the lipoglycopeptides telavancin and dalbavancin for the treatment of bacteremia, the bloodstream infection (BSI) had been related to either pneumonia or a catheter-related BSI, respectively. The data derived from the small subset of MRSA-infected patients comparing these agents with vancomycin failed to show any treatment advantage. However, dalbavancin’s once-weekly dosing schedule could make it an attractive option when treating MRSA bacteremia and IE in the outpatient antimicrobial therapy arena. To date, there are no published data on the use of oritavancin, another long-acting lipoglycopeptide, in treating MRSA infections other than acute bacterial skin and skin structure infections.
An increased affinity for multiple penicillin-binding protein (PBP) subtypes, including PBP2, which confers methicillin-resistance, provides ceftaroline-fosamil activity against MRSA, hVISA, VISA, vancomycin-resistant S. aureus and daptomycin-nonsusceptible strains of S. aureus. Several retrospective case reports and series have shown this advanced-generation cephalosporin to be successful in the treatment of MRSA bacteremia and IE. Further studies are necessary to determine if this ASBL is superior to the non-ASBL agents in the treatment of MRSA bacteremia and IE.
Trials comparing trimethoprim-sulfamethoxazole (TMP-SMX) with vancomycin for the treatment of MSSA and MRSA bacteremia have yielded variable results. In one study of IV drug users with bacteremia, vancomycin was superior to TMP-SMX when MSSA was the pathogen, but equivalent when MRSA was involved. One more recent, larger study limited to MRSA found that TMP-SMX failed to achieve noninferiority to vancomycin in the treatment of severe MRSA infections and that the difference was particularly marked for patients with bacteremia. Similarly, the use of clindamycin for the treatment of S. aureus bacteremia and IE has been met with unacceptably high rates of treatment failure and relapse. The bacteriostatic nature and very low serum concentration levels associated with tigecycline serve to essentially eliminate this glycylcycline antibiotic as a viable alternative agent.
At this point in time, vancomycin and daptomycin remain the initial therapies of choice for the treatment of MRSA bacteremia and IE.
- References:
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- For more information:
- Larry M. Bush, MD, FACP, is an affiliated professor of biomedical sciences at the Charles E. Schmidt College of Medicine, Florida Atlantic University, and affiliated associate professor of medicine at the University of Miami-Miller School of Medicine, Palm Beach County, Florida.
- Donald Kaye, MD, is a professor of medicine at Drexel University College of Medicine, associate editor of the International Society for Infectious Diseases’ ProMED-mail, section editor of news for Clinical Infectious Diseases and an Infectious Disease News Editorial Board member.
Disclosure: Bush and Kaye report no relevant financial disclosures.