A Review of Combination Antimicrobial Therapy for Enterococcus faecalis Bloodstream Infections and Infective Endocarditis

Abstract

Enterococci, one of the most common causes of hospital-associated infections, are responsible for substantial morbidity and mortality. Enterococcus faecalis, the more common and virulent species, causes serious high-inoculum infections, namely infective endocarditis, that are associated with cardiac surgery and mortality rates that remained unchanged for the last 30 years. The best cures for these infections are observed with combination antibiotic therapy; however, optimal treatment has not been fully elucidated. It is the purpose of this review to highlight treatment options and their limitations, and provide direction for future investigative efforts to aid in the treatment of these severe infections. While ampicillin plus ceftriaxone has emerged as a preferred treatment option, mortality rates continue to be high, and from a safety standpoint, ceftriaxone, unlike other cephalosporins, promotes colonization with vancomycin resistant-enterococci due to high biliary concentrations. More research is needed to improve patient outcomes from this high-mortality disease.Keywords. Enterococcus faecalis; infective endocarditis; antimicrobials. , and ability to form biofilm at higher rates than E. faecium (87%-95% vs 16%-29%, respectively) [4,5], makes treatment of E. faecalis infections particularly challenging and may contribute to the unchanging mortality rates. Consequently, combination antimicrobial therapy is required for deep-seated E. faecalis infections, and with >50% of isolates expressing aminoglycoside resistance, treatment options are becoming limited [6]. It is the purpose of this review to highlight available treatment options and their limitations and to provide direction for investigation of future novel combination therapies, including ampicillin plus non-ceftriaxone β-lactams and daptomycin combination therapy, to further aid in the treatment of E. faecalis IE. METHODSStudies were identified by conducting PubMed and Embase searches using the following keywords in 1 or more combinations with "Enterococcus faecalis ": infective, endocarditis, bacteremia, bloodstream, infection, treatment, guideline, antibiotic, combination, synergy, resistant, biofilm, clinical, diagnosis, epidemiology, in vitro, in vivo, simulated endocardial vegetation, experimental, and β-lactamase. Manual searches of reference lists of relevant articles found from initial searches were also conducted. No limitation was placed on publication time period. Studies were selected based on authors' (M. B. and M. K. L.) judgment of relevance to topic. ORIGIN OF COMBINATION THERAPYFor serious E. faecalis infections, such as IE, bactericidal agents, often as combination therapy, are preferred [2]. β-Lactam antibiotics lack bactericidal activity against enterococci when used as monotherapy, making treatment of systemic infections

Antibiotic interactions shape short-term evolution of resistance in E. faecalis

“…to the component drugs. In addition to dual β-lactam therapies, combinations involving an aminoglycoside with a cell wall inhibiting antibiotic are commonly used for treating drug resistant E. faecalis (40). In particular, the ampicillin and streptomycin (STR) combination has been used as a first line of treatment for E. faecalis infective carditis (47,40).…”

“…In addition to dual β-lactam therapies, combinations involving an aminoglycoside with a cell wall inhibiting antibiotic are commonly used for treating drug resistant E. faecalis (40). In particular, the ampicillin and streptomycin (STR) combination has been used as a first line of treatment for E. faecalis infective carditis (47,40). Unfortunately, enterococci isolates are increasingly exhibiting high-level resistance to aminoglycosides, which has been shown to reduce the synergistic effect of the combination therapy (47).…”

“…Combination therapies are an important tool for treating enterococcal infections, which lead to significant morbidity and mortality (40,41,42,43). E. faecalis is among the most commonly isolated enterococcal species and underlies a host of human infections, including infective endocarditis, infections of the urinary tract or blood stream, and infections related to surgical devices and medical implants.…”

“…E. faecalis is among the most commonly isolated enterococcal species and underlies a host of human infections, including infective endocarditis, infections of the urinary tract or blood stream, and infections related to surgical devices and medical implants. Multiple combination therapies have been proposed or are currently in use for E. faecalis infections (44,45,40). While synergistic combinations are the standard-particularly for high inoculum infections-relatively little is known about how different combinations affect the potential for, and rate of, resistance evolution.…”

Cardiovascular implantable electronic device infections due to enterococcal species: Clinical features, management, and outcomes

“…Enterococci are a well‐recognized cause of both native and prosthetic valve infective endocarditis (IE) . Cardiac infections due to enterococci pose therapeutic challenges because of the need to utilize synergistic therapy to achieve optimal outcomes and problems with emerging resistances to traditionally employed antimicrobial agents . As compared to other forms of enterococcal cardiac infections, information about clinical features and therapeutic outcomes of patients with enterococcal infections of cardiovascular implantable electronic devices (CIED) is limited .…”