Combatting resistant enterococcal infections: a pharmacotherapy review

ABSTRACT

Introduction: The role of enterococci in infectious diseases has evolved from a gut and urinary commensal to a major pathogen of concern. Few options exist for resistant enterococci, and appropriate use of the available agents is crucial.

Areas covered: Herein, the authors discuss antibiotics with clinically useful activity against Enterococcus faecalis and E. faecium. The article specifically discusses: antibiotics active against enterococci and their mechanism of resistance, pharmacokinetic and pharmacodynamic principles, in vitro combinations, and clinical studies which focus on urinary tract, intra-abdominal, central nervous system, and bloodstream infections due to enterococci.

Expert opinion: Aminopenicillins are preferred over all other agents when enterococci are susceptible and patients can tolerate them. Daptomycin and linezolid have demonstrated clinical efficacy against vancomycin-resistant enterococci (VRE). Synergistic combinations are often warranted in complex infections of high inoculum and biofilms while monotherapies are generally appropriate for uncomplicated infections. Although active against resistant enterococci, the pharmacokinetics, efficacy and safety of tigecycline and quinupristin/dalfopristin can problematical for severe infections. For cystitis, amoxicillin, nitrofurantoin, or fosfomycin are ideal. Recently, approved agents such as tedizolid and oritavancin have good in vitro activity against VRE but clinical studies against other resistant enterococci are lacking.

KEYWORDS:

• Antibiotic resistance
• Enterococcus
• Gram-positive antibiotics
• antimicrobial stewardship

Article highlights

• Antimicrobial resistance in enterococci is caused by multiple mechanisms and contributes to increased morbidity and mortality. Resistant enterococci are underrepresented in clinical trials of new antimicrobials.

• Vancomycin resistance is mediated mostly by the VanA/VanB plasmids. Management typically involves linezolid or higher doses of daptomycin, often in combination with beta-lactams, aminoglycosides, or intravenous fosfomycin for severe disease. Aminopenicillins are preferred when susceptible.

• Intrinsic beta-lactam resistance exists in enterococci through greater expression of penicillin-binding-protein-5 (PBP5), and higher-level acquired resistance occurs through PBP5 mutations less commonly penicillinase production. Addition of cephalosporins or aminoglycosides to aminopenicillins offers bactericidal action in susceptible enterococci.

• Daptomycin is bactericidal against enterococci. Non-susceptibility is rare but most often occurs in immunocompromised patients and those with prior daptomycin exposure. Resistance can be overcome by combining high doses of daptomycin with beta-lactams such as ceftaroline or ampicillin.

• Mutations in the genes encoding for 23S ribosomal RNA are responsible for most oxazolinidone resistance. Linezolid is a useful agent for VRE associated with pyelonephritis, intra-abdominal infections, meningitis, and uncomplicated bloodstream infections.

• Preferred antimicrobials for the lower urinary tract include oral fosfomycin, amoxicillin, and nitrofurantoin due to narrow spectrum of activity and well tolerability. Tigecycline’s role in VRE should be reserved to intra-abdominal infections and/or salvage regimens. The lipoglycopeptide oritavancin may have a place in VRE management, however, clinical data remain limited.

• Uncomplicated bloodstream infections may be managed with shorter courses and monotherapy, while complicated bloodstream infections may require long durations and combinations of antimicrobials for synergy.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.