Investigational agents for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia: progress in clinical trials

ABSTRACT

Introduction

Bacteremia caused by Staphylococcus aureus is common. Cases caused by methicillin-resistant S. aureus (MRSA) are particularly formidable and often lethal. The mortality associated with MRSA bacteremia has not significantly decreased over the past couple of decades and concerns regarding efficacy and toxicity of standard therapy highlight the need for novel agents and new therapeutic approaches.

Areas covered

This paper explores clinical trials investigating novel therapeutic approaches to S. aureus bacteremia. There is a special focus on MRSA bacteremia. Monotherapy and combination therapies and novel antimicrobials and adjunctive therapies that are only recently being established for therapeutic use are discussed.

Expert opinion

The unfavorable safety profile of combination antimicrobial therapy in clinical trials has outweighed its benefits. Therefore, future investigation should focus on optimizing duration and de-escalation protocols. Antibody and bacteriophage lysin-based candidates have mostly been limited to safety trials, but progress with these agents is demonstrated through a lysin-based agent receiving a phase III trial. Antibiotics indicated for use in treating MRSA skin infections see continued investigation as treatments for MRSA bacteremia despite the difficulty of completing trials in this patient population. Promising agents include dalbavancin, ceftobiprole, ceftaroline, and exebacase.

KEYWORDS:

• Bacteremia
• clinical trials
• investigational agent
• MRSA
• staphylococcus aureus

Article highlights

• The mortality associated with MRSA bacteremia has remained high and steady for decades, and there are concerns about the toxicity of standard therapy and the potential for antibiotic resistance to affect treatment efficacy.

• In large trials investigating the efficacy of combination therapy, no benefit has been shown for vancomycin plus rifampicin or β-lactam antibiotics. Moreover, safety profiles favor monotherapy over combination therapy.

• Ceftobiprole and ceftaroline are unusual in that they are β-lactam antibiotics that are used to treat MRSA infections. Both are currently under investigation as treatments for MRSA bacteremia and show acceptable safety profiles.

• Trials that are focused on investigating novel antimicrobials and adjunctive therapies, including antibody and bacteriophage lysin-based agents, have mostly been limited to small studies that seek to establish their safety and pharmacokinetics.

• Exebacase, a bacteriophage lysin-based candidate, is a standout among its class with efficacy as an adjunctive therapy to vancomycin for MRSA bacteremia shown in a phase II trial. Exebacase is undergoing further investigation in an upcoming phase III trial.

• There are no clear alternatives to vancomycin or daptomycin for treating MRSA bacteremia, but several agents currently under investigation demonstrate a continued effort to improving patient outcomes.

Abbreviations

ABSSSI, acute bacterial skin and skin structure infections; β-GlcNAc, β-N-acetylglucosamine; BSI, bloodstream infection; CABP, community-acquired bacterial pneumonia; CoNS, coagulase-negative staphylococci; CPS, capsular polysaccharide; cSSTIs, complicated skin and soft tissue infections; FDA, U.S. Food and Drug Administration; HABP, hospital-acquired bacterial pneumonia; HR, hazard ratio; hVISA, heterogeneous vancomycin-intermediate Staphylococcus aureus; IV, intravenous; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; MSCRAMM, microbial surface components recognizing adhesive matrix molecules; MSSA, methicillin-sensitive Staphylococcus aureus; NAG, N-acetylglucosamine; NAM, N-acetylmuramic acid; PBP, penicillin-binding protein; PG, phosphatidylglycerol; SAB, Staphylococcus aureus bacteremia; SAE, serious adverse event; SOC, standard of care; SSTIs, skin and soft tissue infections; TEAE, treatment-emergent adverse event; TMP/SMX, trimethoprim-sulfamethoxazole; TOC, test-of-cure; VC, valine-citrulline; VABP, ventilator-associated bacterial pneumonia; VISA, vancomycin-intermediate Staphylococcus aureus; VRSA, vancomycin-resistant Staphylococcus aureus; WTA, wall teichoic acid.

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.

Disclosure statement

One reviewer is currently the site PI for a clinical study on exebacase. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Additional information

Funding

Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), U.S. National Institutes of Health (NIH) under project number ZIA AI000904