Adjunctive β-lactams for Staphylococcus aureus bacteremia: a narrative review

Abstract

Staphylococcus aureus bacteremia (SAB) remains a major clinical challenge, with persistently high mortality despite advancements in antimicrobial therapy. The evolving epidemiology of SAB, characterized by a rise in community-acquired infections, increased use of indwelling medical devices, and a growing burden of metastatic complications, adds to its complexity. Given these challenges, adjunctive β-lactam therapy has been proposed as a strategy to enhance bactericidal activity and improve patient outcomes. β-lactams may exert synergistic effects when combined with other antistaphylococcal agents by saturating multiple penicillin-binding proteins and modifying bacterial cell wall structure, thereby increasing susceptibility to host immune responses. Early evidence for adjunctive β-lactam therapy emerged from retrospective studies and incidental observations of "unplanned synergy," which suggested improved bacterial clearance. Subsequent randomized controlled trials have explored this approach, with some demonstrating reductions in bacteremia duration. However, survival benefits have been inconsistent, and concerns regarding acute kidney injury (AKI) have tempered enthusiasm. Recent investigations, however, suggest that judicious β-lactam selection and targeted patient selection can mitigate AKI risk. A limitation of many randomized controlled trials evaluating combination therapy for SAB is the adoption of uniform treatment protocols that fail to account for patient heterogeneity. This approach may limit the generalizability of findings and obscure potential benefits in specific patient subgroups. Conversely, retrospective analyses suggest that high-risk patients, including those with rapid blood culture positivity, inadequate source control, significant comorbidities, and metastatic disease, may derive the greatest benefit from early combination therapy. Optimizing SAB management necessitates a multifaceted strategy that incorporates patient-specific clinical factors, refined risk stratification, and innovative assessment frameworks. Approaches such as the Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR) enable holistic evaluations of treatment efficacy and safety, accounting for the overall patient experience. Future research should prioritize individualized treatment strategies, leveraging biomarkers and refined risk stratification to identify patients most likely to benefit from adjunct β-lactam therapy while minimizing adverse events.

Keywords: Staphylococcus aureus; bacteremia; cefazolin; ceftaroline; ceftobiprole; daptomycin; salvage therapy; vancomycin.

Figure 1.

Interaction of S. aureus PBPs with β-lactam antibacterial agents. Green shading indicates interaction with the respective PBP, while red shading indicates no interaction. PBP, penicillin binding protein.

Figure 2.

Comparison of sources among patients with MRSA bacteremia in prospective and retrospective comparative studies. This figure illustrates the distribution of sources among patients with MRSA bacteremia treated with monotherapy or combination therapy included in the prospective (CAMERA-1, CAMERA-2, Geriak et al.) and comparative retrospective (Jorgensen et al. and McCreary et al.) studies. The proportions of patients with MRSA bacteremia who had endovascular (including infective endocarditis) (dark blue) or osteoarticular involvement (including native and device-related) (light blue), and MRSA bacteremia from all other sources (such as primary, skin and soft tissue infections, vascular catheters, unknown, etc.) (gray) are presented based on the results reported in the individual studies. MRSA, methicillin-resistant Staphylococcus aureus.