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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

bacteremia cefazolin ceftaroline ceftobiprole daptomycin salvage therapy vancomycin

Introduction

Staphylococcus aureus remains a leading cause of bloodstream infections, with an annual incidence exceeding 50 cases per 100,000 people in developed nations.^1,2 Despite advancements in antibacterial therapy and source control measures, mortality rates associated with S. aureus bacteremia (SAB) remain substantial, reaching up to 30% at 90 days.^1,3,4

SAB is characterized by considerable clinical heterogeneity, ranging from mild to severe illness with life-threatening complications.^1,3–6 However, the clinical presentation of SAB has evolved significantly over the past few decades.⁵ Recent longitudinal studies demonstrated a notable increase in the proportion of patients with implantable foreign bodies, comorbid conditions, and community-acquired infections.^5,6 Concurrently, the incidence of metastatic complications has risen, contributing to increased disease severity at the time of presentation. For instance, the SABATO trial, a randomized, controlled, non-inferiority study published in 2024 that compared intravenous therapy to early oral switch therapy for uncomplicated SAB, enrolled only 4.2% (213 out of 5,063) of screened participants and was terminated early due to slow recruitment.⁷ These trends highlight the complexity of and the challenges in managing SAB.

The prevalence of methicillin-resistant S. aureus (MRSA) varies geographically. In the United States, while MRSA rates have been declining, it still accounts for 40%–50% of S. aureus clinical isolates, necessitating empiric MRSA coverage in many cases of SAB.^8,9 Rates of MRSA in the United States remain higher compared to Canada and Europe.¹⁰ Notably, the prevalence of MRSA in Europe exhibits a latitudinal gradient, with lower rates observed in Northern European countries.¹¹

Despite the changing prevalence of MRSA, most patients with SAB receive empiric anti-MRSA therapy (commonly vancomycin) until MRSA is excluded, as delayed antibacterial therapy with in vitro activity can increase mortality.^8,9,12 Once susceptibility is confirmed or rapid diagnostic results indicate the presence of MRSA (e.g., positive identification of the mecA gene), current evidence supports the use of cefazolin or an antistaphylococcal β-lactam (nafcillin or oxacillin) for methicillin-susceptible S. aureus (MSSA) bacteremia, while vancomycin or daptomycin are generally recommended for MRSA. Additionally, effective management requires early source control and infectious diseases service consultation with prolonged durations of therapy for patients with complicated SAB who are at high risk for poor outcomes.¹³ Historically, risk stratification has been based on factors such as sterile follow-up blood cultures within 48–96 h, defervescence within 72 h, absence of infective endocarditis, lack of major prosthetic or implanted devices, and no evidence of metastatic sites of infection.^14,15 While the optimal criteria for identifying high-risk patients remain a subject of ongoing debate, persistent bacteremia strongly predicts complicated SAB.^16,17

Despite these efforts, mortality rates associated with SAB largely remain static and continue to be unacceptably high.^4,5 Poor outcomes in complicated SAB likely stem from a complex interplay between the pathogen, host immune response, and antimicrobial therapy, compounded by the absence of an established optimal treatment approach. This narrative review evaluates the evidence supporting the use of β-lactams as adjunctive therapy for SAB.

What is the mechanism of synergy with adjunct β-lactam therapy for S. aureus?

β-lactam antibacterial agents irreversibly inhibit penicillin binding proteins (PBPs) by forming stable acyl-enzyme complexes, leading to cell wall disruption and bacterial death (Figure 1).^18,19 S. aureus possesses four intrinsic PBPs (PBP 1, PBP 2, PBP 3, PBP 4) and one acquired PBP (PBP 2a).²⁰ Combination β-lactam therapy has been proposed to enhance bacterial killing by targeting multiple PBPs, resulting in PBP saturation and impaired cell wall synthesis.^21,22 Inhibition of PBPs 1, 2, and 3, which are essential for the survival of MSSA, is lethal.²² However, β-lactams inhibit PBP function with different affinities, and some PBPs may remain functionally active in the presence of select β-lactams due to their low affinity.²⁰ Additionally, differences in affinity for the transpeptidase and transglycosylase domains of PBPs may influence the efficacy of specific β-lactam combinations, providing a mechanistic rationale for why certain regimens may be more effective than others.

Figure 1.

Interaction of S. aureus PBPs with β-lactam antibacterial agents.

Nafcillin demonstrated the highest affinity for PBP 1 (half-maximal inhibitory concentration (IC₅₀) 0.045 mg/L).²³ Ceftaroline, while primarily targeting PBP 2a in MRSA, also exhibits high affinity for PBP 2 and PBP 3 in MSSA (IC₅₀ 0.034 and 0.049 mg/L, respectively).²³ This distinct PBP binding profile of ceftaroline, when combined with the potent PBP 1 inhibition by nafcillin, suggests a potential synergistic interaction against MSSA infections, while both agents maintain robust activity against PBPs 1–3.

Like nafcillin, oxacillin is hypothesized to exhibit a preferential affinity for PBP 1 in MSSA.²³ However, increased PBP 2 and PBP 3 expression in response to subinhibitory concentrations suggests possible non-selective PBP inhibition. Ertapenem also primarily targets PBP 1 and in vitro synergy data support complementary PBP binding when oxacillin is combined with ertapenem or meropenem.^24,25

Among various β-lactam combinations, ertapenem plus cefazolin demonstrated the greatest potentiation of inhibition in disk diffusion assays, likely due to ertapenem targeting PBP 1 and cefazolin targeting PBP 2.²⁴ However, other agents targeting PBP 3 and PBP 4 did not enhance the zone of inhibition for cefazolin. Checkerboard testing of ertapenem and cefazolin revealed only modest synergy against S. aureus isolates from patients with persistent SAB.²¹ These findings suggest additional factors contribute to the observed clinical efficacy of this combination.

One potential mechanism involves the stimulation of interleukin-1β (IL-1β) by ertapenem as β-lactams have been observed to induce a stronger IL-1β response compared to vancomycin.^26,27 IL-1β is a critical cytokine in host defense, promoting neutrophil recruitment, antimicrobial peptide production, and adaptive immune responses. In vivo IL-1β deficiency or blockade with anakinra, an IL-1R antagonist, increases susceptibility to infection and impairs ex vivo S. aureus killing.^26,28 Notably, a deficient IL-1β response was linked to prolonged bacteremia (>4 days) in patients with SAB.²⁹ Conversely, a robust IL-1β response was associated with rapid blood culture sterilization (⩽4 days).²⁹ In vitro studies demonstrate that combining cefazolin and ertapenem significantly augments IL-1β release from peripheral blood monocytes in the presence of S. aureus, with ertapenem being the primary driver of this effect.²⁷

MRSA overcomes the activity of traditional β-lactams against intrinsic PBPs by acquiring and expressing PBP 2a, a modified PBP encoded by the mecA gene.³⁰ While PBP 2a exhibits reduced acylation rates compared to native PBPs, it remains susceptible to irreversible inhibition.^31,32 This suggests a potential role for β-lactams in combination therapies against MRSA despite intrinsic resistance. Indeed, synergistic interactions between vancomycin and β-lactams have been observed in vitro.³³

The exact mechanisms underlying the synergistic interaction between β-lactams and vancomycin against MRSA bacteremia are not yet fully understood, but several potential explanations have been proposed. β-lactams, as cell wall inhibitors, induce cell wall thinning in S. aureus, enhancing vancomycin penetration into the division septum and improving efficacy in inhibiting cell wall synthesis.^34,35 This process often reduces vancomycin minimum inhibitory concentrations (MICs), an effect known as the “see-saw effect,” which may contribute to improved therapeutic outcomes and potentially mitigate the emergence of resistance.³⁶ However, clinical validation of this in vitro finding remains to be established.³⁷

Additionally, β-lactams induce morphological changes in S. aureus that enhance vancomycin and daptomycin binding.^38,39 These antibacterial agents also augment the host’s innate immune response.⁴⁰ Although the precise mechanisms remain elusive, it is proposed that β-lactams stimulate increased cell wall autolysis, making bacteria more susceptible to cationic host defense peptides and facilitating bacterial clearance.

In vitro studies consistently demonstrate synergistic interactions between vancomycin or daptomycin and β-lactams against MRSA, characterized by accelerated bacterial killing.^37,41 Moreover, combining daptomycin with a β-lactam prevents the emergence of daptomycin-resistant variants.⁴² β-lactams also potentiate host antimicrobial peptide-mediated killing of MRSA.⁴⁰

Combination therapy with daptomycin and antistaphylococcal β-lactams, nafcillin or oxacillin, reduces bacterial surface charge and enhances daptomycin binding to the staphylococcal envelope.⁴³ Daptomycin, a cyclic lipopeptide, requires calcium for activation, acquiring a positive charge that enables targeting of bacterial membranes, similar to cationic host defense peptides (e.g., cathelicidins, defensins).⁴⁴ β-lactams, particularly nafcillin, significantly increase the killing of S. aureus by host defense peptides derived from keratinocytes, neutrophils, and platelets.⁴⁰ Notably, pretreatment with nafcillin reduces MRSA virulence in a murine infection model, despite its lack of direct anti-MRSA activity, by sensitizing MRSA to killing by components of the innate immune system, such as human cathelicidin LL-37. Other β-lactams variably induce this sensitization effect, which is absent in non-β-lactam agents like vancomycin.

Although the mechanism underlying this sensitizing effect remains unclear, β-lactams may induce the release of lipoteichoic acid (LTA) from the cell envelope, potentially increasing cell wall autolysin activity or reducing substrate availability for LTA D-alanylation, leading to an increase in the net negative charge of the bacterial cell envelope.⁴⁵ This, in turn, enhances susceptibility to cationic antimicrobials like daptomycin and host defense peptides. Additionally, β-lactams and host defense peptides may interact within the divisome complex, potentially allowing more targeted binding to regions of the cell membrane where daptomycin is most effective.^46–48

β-lactams exhibit dual anti-staphylococcal activity by directly killing susceptible strains and indirectly enhancing the efficacy of host defense peptides against both susceptible and resistant strains.⁴⁰ This dual activity may contribute to the clinical superiority of β-lactams over vancomycin against MSSA, emphasizing the importance of prioritizing β-lactam therapy for complicated MSSA bacteremia.

Evidence from in vitro studies supports synergistic interactions between daptomycin and ceftaroline.^49,50 Ceftaroline binding to PBP 2a disrupts cell wall cross-linking and thickness, enhancing daptomycin penetration. Furthermore, ceftaroline-induced alterations in cell membrane charge enhance the bactericidal activity of human cathelicidin LL-37, an endogenous cationic antimicrobial peptide, against S. aureus.^51,52

Vancomycin and ceftaroline also exhibit potent in vitro synergy against MRSA.⁵³ While the precise mechanism underlying this interaction remains unclear, one hypothesis suggests that ceftaroline may reduce MRSA cell wall thickness, facilitating vancomycin penetration.

In vitro assays demonstrated synergistic activity between ceftaroline and either ertapenem or meropenem against MRSA clinical isolates from patients with persistent bacteremia, particularly under high inoculum conditions.⁵⁴ This synergy was further confirmed in human whole blood. In a murine bacteremia model, the addition of a carbapenem to ceftaroline significantly reduced bacterial burden in the kidneys compared to ceftaroline alone. Exposure of MRSA to subtherapeutic concentrations of ceftaroline with either ertapenem or meropenem led to the downregulation of genes associated with antimicrobial resistance, virulence, and immune evasion. These transcriptional changes suggest a potential disruption of key mechanisms involved in MRSA pathogenesis, particularly in endovascular infections. By downregulating factors crucial for bacterial survival and host immune evasion, adjunctive carbapenem therapy may enhance ceftaroline efficacy, potentially reducing MRSA persistence and its capacity to cause complicated infections.

Ceftobiprole, another β-lactam targeting PBP 2a, was evaluated for potential synergistic combinations against MRSA.^55,56 Checkerboard assays revealed significant synergy between cloxacillin and ceftobiprole, as well as between cloxacillin and ceftaroline. Further analysis revealed a range of synergistic interactions between ceftobiprole and other β-lactams, including imipenem, meropenem, piperacillin, tazobactam, and cefoxitin. Among these, imipenem, which selectively targets PBP 1, exhibited significant synergy with ceftobiprole, while cefoxitin, selective for PBP 4, showed modest synergy. Cloxacillin displayed less synergy against MSSA, indicating interactions with PBPs beyond PBP 2a. Notably, while most ceftobiprole-β-lactam combinations were synergistic, no synergy was observed between ceftaroline and ceftobiprole.

Interestingly, several non-β-lactam agents, including vancomycin and daptomycin, showed only modest or no synergy with ceftobiprole against MRSA.⁵⁵ However, previous studies have reported synergy between ceftobiprole and vancomycin or daptomycin, characterized by reduced MICs and enhanced bactericidal activity against MRSA.^57,58

Should β-lactam therapy be empirically added to anti-MRSA therapy?

The clinical evidence supporting the combination of vancomycin or daptomycin with β-lactams for MRSA bacteremia primarily originated from retrospective analyses of coincidental combination therapy. These analyses included instances of broad-spectrum empirical antibacterial therapy, “unplanned synergy,” and salvage therapy for persistent or recurrent bacteremia.^43,59–61 While most studies suggest a potential reduction in bacteremia duration with combination therapy, few have rigorously investigated the clinical benefit of empirically adding β-lactam therapy to initial anti-MRSA therapy.

Vancomycin plus antistaphylococcal β-lactams

The Combination Antibiotics for Methicillin Resistant S. aureus (CAMERA-1) trial was a multicenter, randomized pilot study that enrolled 60 patients with MRSA bacteremia (Table 1).⁶² Participants received either vancomycin monotherapy (n = 29) or combination therapy with vancomycin plus intravenous flucloxacillin for 7 days (n = 31). Few patients had indwelling hardware. Notably, 65% of patients in the monotherapy group had received a β-lactam within 48 h prior to randomization. Source control data were not reported for either group.

Table 1.

Comparative studies evaluating vancomycin or daptomycin plus β-lactam for MRSA bacteremia.

Study	Design	Treatment regimen (s)	Underlying conditions and severity of illness	Location of acquisition	Source (s)	Outcome (s)
CAMERA-1 ⁶²	Open label, multicenter, RCT	VAN (n = 29) vs VAN plus FCX (n = 31)	Charlson Comorbidity index, median (IQR): 3 (1–5) vs 2 (1–6) Septic shock: 24% vs 26% SOFA score, median (IQR: 1 (1–3) vs 1 (0–2)	Community-acquired: 34% vs 35% Community-onset, healthcare-associated: 52% vs 29% Nosocomial: 14% vs 35%	Device-related osteoarticular: 3% vs 6% IE: 0% vs 3% Osteoarticular: 0% vs 13% Primary: 34% vs 23% Pulmonary: 10% vs 0% SSTI: 21% vs 23% Urinary: 7% vs 3% VC-related: 7% vs 19%	Duration of bacteremia, median (IQR): 1 (1–2) vs 1 (1–4) days Bacteremia > 3 days: 27% vs 19% Bacteremia > 7 days: 12% vs 4% AKI (1.5-fold increase in SCr): 11% vs 28% 28-day in-hospital mortality: 17% vs 16% 90-day in-hospital mortality: 21% vs 16%
CAMERA 2 ⁶³	Open label, multicenter, RCT	VAN or DAP (n = 178 (100% VAN, 3% DAP)) vs VAN or DAP plus βL (n = 174 (98% VAN, 4% DAP), (63.8% FCX or CLX, 15.5% CFZ, 20.7% FCX or CLX plus CFZ))	Charlson Comorbidity index, median (IQR): 5 (2–7) vs 5 (2–7) SOFA score, median (IQR): 1 (0–4) vs 2 (1–4) Pitt bacteremia score, median (IQR): 2 (2–3) vs 2 (2–3)	Healthcare-associated (isolates resistant to ⩾3 classes of non-β-lactams): 67% vs 60% Nosocomial: 27% vs 32%	IE: 3% vs 5% Osteoarticular: 15% vs 18% Primary: 20% vs 20% Pulmonary: 6% vs 7% SSTI: 28% vs 23% VC-related: 12% vs 14%	Bacteremia > 1 day: 35% vs 30% Bacteremia > 6 days: 20% vs 11% AKI (1.5-fold increase in SCr): 6% vs 23% 14-day mortality: 7% vs 8% 42-day mortality: 11% vs 15% 90-day mortality: 16% vs 21%
Jorgensen et al ⁶⁸	Retrospective, multicenter Analyses adjusted using inverse probability of treatment weighting	DAP (n = 157) vs DAP plus βL (n = 72 (43.1% FEP, 25% CFZ, 9.7% CPT, 9.7% CRO, 6.9% MEM, 2.8% TZP, 1.4% ERT, or 1.4% SAM))	Charlson Comorbidity index, median (IQR): 3 (1–5) vs 2 (1–5) ICU admission: 13.4% vs 11.1%	Nosocomial: 21.7% vs 25%	Endovascular: 40.8% vs 31.9% IE: 37.6% vs 30.6% Osteoarticular: 22.9% vs 37.5% SSTI: 15.3% vs 30.6% VC-related: 30.6% vs 12.5%	Duration of bacteremia, median (IQR): 4.8 (3.3–7.5) vs 4.4 (2.6–6.5) days Bacteremia ⩾ 7 days: 27.5% vs 19.4% AKI: 2.9% vs 10.8% 30-day mortality: 11.5% vs 6.9% 60-day mortality: 14.6% vs 5.6%
Geriak et al ⁶⁹	Open label, single center, RCT	VAN or DAP (n = 23 (91% VAN, 9% DAP)) vs DAP plus CPT (n = 17)	Charlson Comorbidity index, median: 6 vs 5 (IQR NR) ICU admission: 13% vs 18% Pitt bacteremia score, median: 1 vs 2 (IQR NR)	NR	Endovascular: 35% vs 47% Secondary tissue: 52% vs 53% VC-related: 13% vs 9%	Duration of bacteremia, median (IQR): 3 (1–5.3) vs 3 (1.5–5.5) days AKI: 4% vs 0% In-hospital mortality: 26% vs 0% 30-day mortality: 26% vs 0% 90-day mortality: 30% vs 0%
McCreary et al ⁸⁷	Retrospective, multicenter, matched cohort	VAN or DAP (n = 113 (96% VAN, 4% DAP)) vs DAP plus CPT (n = 58)	Charlson Comorbidity index ⩾ 3: 49% vs 57% ICU admission: 16% vs 16% Pitt bacteremia score, median (range): 1 (0–10) vs 2 (0–9)	NR	Endovascular: 53% vs 53% Osteoarticular: 21% vs 15% Pulmonary: 7% vs 12% Secondary: 42% vs 42% SSTI: 10% vs 12% VC-related: 5% vs 5%	Duration of bacteremia, mean (SD): 4.8 vs 9.3 days 30-day mortality: 14.2% vs 6.8%

AKI, acute kidney injury; CFZ, cefazolin; CLX, cloxacillin; CPT, ceftaroline; CRO, ceftriaxone; DAP, daptomycin; ERT, ertapenem; FCX, flucloxacillin; FEP, cefepime; IQR, interquartile range; MEM, meropenem; MRSA, methicillin-resistant Staphylococcus aureus; NAF, nafcillin; NR, not reported; OXA, oxacillin; RCT, randomized controlled trial; SAM, ampicillin/ sulbactam; SCr, serum creatinine; SD, standard deviation; SSTI, skin and soft tissue infection; TZP, piperacillin/ tazobactam; VAN, vancomycin; VC, vascular catheter.

The intention-to-treat analysis revealed a significantly shorter mean (SD) duration of bacteremia in the combination therapy group (1.94 (1.79) days) compared to the monotherapy group (3.00 (3.35) days). Similar results were observed in the per-protocol analysis, with mean durations of bacteremia of 1.82 (1.59) and 2.92 (3.37) days, respectively. Combination therapy was associated with more rapid blood culture sterilization, with 90% of patients achieving sterile cultures within 4 days, compared to 9 days in the monotherapy group. However, no significant differences were observed between groups in mortality, relapse rates, nephrotoxicity, hepatotoxicity, or other clinically relevant outcomes.

The CAMERA-2 trial, a multicenter, randomized controlled trial, enrolled 352 patients with MRSA bacteremia.⁶³ Participants were randomized to receive either monotherapy (vancomycin or daptomycin) (n = 178) or combination therapy with a β-lactam (flucloxacillin, cloxacillin, or cefazolin) for 7 days (n = 174). Vancomycin was administered to nearly all patients (99%) in both groups. Notably, 64% of patients in the monotherapy group had received a β-lactam within 72 h prior to randomization. Source control was achieved in 80% of patients in the monotherapy group versus 73% in the combination therapy group. Baseline serum creatinine was similar in the monotherapy group (median 1.22 mg/dL, IQR 0.8–2.7) and combination therapy group (median 1.13 mg/dL, IQR 0.8–2.5). Concomitant medications with potential for renal impairment were administered within 48 h of randomization to 61% of patients in the monotherapy group and 56% of patients in the combination therapy group.

The primary composite outcome, comprising 90-day mortality, persistent bacteremia at day 5, microbiological relapse, and microbiological treatment failure, did not differ between the monotherapy and combination therapy groups (39% vs 35%). Interestingly, although there was a lower incidence of persistent bacteremia at day 5 in the combination group (11% vs 20%), 90-day mortality rates were higher in the combination therapy group (21%) compared to the monotherapy group (16%).

The CAMERA-2 trial was prematurely terminated due to a higher incidence of acute kidney injury (AKI) in the combination therapy group (23%) compared to the monotherapy group (6%). Although the modified RIFLE criteria were originally used in the CAMERA-2 trial (defined as a ⩾1.5-fold increase in serum creatinine or a new need for renal replacement therapy between days 1 and 90, without considering urine output), the majority of AKIs (53%) were classified as mild (stage 1) when utilizing a modified KDIGO (Kidney Disease: Improving Global Outcomes) criteria. These criteria defined AKI as a ⩾1.5-fold increase in serum creatinine within the first 7 days, an increase in serum creatinine of ⩾0.3 mg/dL within a 48-h period, or a new need for renal replacement therapy before day 90.

Although combination therapy demonstrated accelerated clearance of bacteremia, it was associated with increased rates of AKI and unexpectedly higher mortality compared to monotherapy. Notably, mortality in the vancomycin-only group was lower than observed in historical control cohorts.^1,3,4

A post-hoc analysis revealed substantial heterogeneity in AKI risk among β-lactam agents, with cefazolin associated with a lower incidence of AKI compared to flucloxacillin and cloxacillin (4% vs 27%).⁶³ However, the small number of patients receiving cefazolin precludes definitive conclusions.

A separate post-hoc analysis of 266 participants receiving vancomycin within the CAMERA-2 trial identified clinical risk factors for AKI using the modified KDIGO criteria.⁶⁴ This analysis revealed a significantly increased risk of AKI associated with concurrent flucloxacillin use compared to cefazolin or no β-lactam (OR 4.50, 95% CI 2.09–9.70).⁶⁴ Furthermore, an increase in vancomycin area under the concentration-time curve (AUC) was independently associated with an increased risk of AKI (OR 1.10 per 50 mg × h/L increase, 95% CI 1.01–1.21).

A translational rat model corroborated these findings, demonstrating increased kidney injury in animals receiving the combination of vancomycin and flucloxacillin.⁶⁵ This was evidenced by elevated urinary concentrations of kidney injury molecule-1 (KIM-1) and higher vancomycin accumulation within kidney tissue compared to vancomycin alone. In contrast, vancomycin in combination with imipenem-cilastatin demonstrated nephroprotective effects, with reduced urinary concentrations of KIM-1 and lower vancomycin accumulation. These findings suggest that vancomycin plus flucloxacillin may pose a greater risk of nephrotoxicity compared to vancomycin plus other β-lactams, especially hydrophilic agents such as cefazolin, cefepime, and meropenem.⁶⁶

An additional post-hoc analysis of extended follow-up data from the CAMERA-2 trial included 260 patients, with a follow-up period ranging from 2 days to 5.7 years, totaling 523 person-years of observation.⁶⁷ Over this period, 123 patients (47%) died. The overall mortality rate was 50% in the combination therapy group and 44% in the monotherapy group. However, neither treatment allocation (combination therapy vs monotherapy) nor the occurrence of AKI was significantly associated with an increased risk of mortality.

Beyond the 90-day observation period, no patients required kidney transplantation. However, 2.2% of participants in the combination therapy group and 3.1% in the monotherapy group developed new-onset kidney failure requiring maintenance renal replacement therapy. Furthermore, 22% of patients in the combination therapy group and 18% in the monotherapy group exhibited a ⩾40% decline in estimated glomerular filtration rate (eGFR) with a final eGFR below 60 mL/min/1.73 m².

Cox proportional hazards regression analysis identified age, country of enrollment, Charlson Comorbidity Index score, Sequential Organ Failure Assessment (SOFA) score, Pitt Bacteremia Score, and baseline serum creatinine as independent predictors of mortality. Despite prior evidence linking AKI to adverse outcomes, and the higher AKI incidence observed in the combination therapy arm of CAMERA-2, neither treatment allocation (combination therapy vs monotherapy) nor the occurrence of AKI was significantly associated with increased mortality risk.

The CAMERA-2 trial primarily assessed vancomycin monotherapy versus vancomycin in combination with an antistaphylococcal penicillin.⁶³ This limited the generalizability of these findings to other combination regimens, such as those involving daptomycin or β-lactams like cefazolin. Furthermore, the frequent use of oxacillin and nafcillin in the United States may limit the clinical relevance of these findings in this setting.⁶⁶

These results emphasize the need for further research to define optimal therapeutic strategies for MRSA bacteremia, particularly the role of adjunct β-lactams, including their dosing and infusion strategies. While combination therapy may accelerate bacteremia clearance, the associated risks, especially AKI, demand rigorous assessment prior to widespread clinical implementation. These observations prompt further inquiry into alternative antimicrobial combinations that could improve outcomes for MRSA bacteremia without increasing toxicity compared to standard monotherapy.

Daptomycin plus β-lactams

A retrospective cohort study evaluated the outcomes of 229 adults with MRSA bacteremia who received treatment with either daptomycin monotherapy (n = 157) or combination therapy with daptomycin and a β-lactam (n = 72).⁶⁸ Daptomycin was started within 5 days of the index blood culture collection and continued for at least 72 h. Patients receiving any β-lactam for at least 24 h within 24 h of initiating daptomycin were included in the combination therapy group. A minority of patients in either group received daptomycin as their initial anti-MRSA therapy (15.9% vs 27.8%). The median time from blood culture collection to daptomycin initiation was similar in both groups (72 h vs 66 h). Cefepime, cefazolin, ceftriaxone, and ceftaroline were the most common β-lactams used, with a median duration of β-lactam therapy of 6 days. Source control was achieved in a similar proportion of patients in both groups (53.5% monotherapy, 59.7% combination). A substantial proportion of patients in both the monotherapy (43.3%) and combination therapy (34.7%) groups were classified as high risk (>20% associated mortality) according to the source of infection.

Combination therapy was associated with significantly lower odds of clinical failure compared to monotherapy (OR 0.362, 95% CI 0.164–0.801). Clinical failure, defined as 60-day all-cause mortality or recurrent infection, occurred in 22.7% of patients overall, with a higher incidence observed in the monotherapy group (27.4%) compared to the combination therapy group (12.5%).

Time to blood culture sterilization was shorter in the combination therapy group (median, 56 h) compared to monotherapy (median, 66 h). Additionally, a lower proportion of patients in the combination therapy had positive blood cultures at day 5 (19.4% vs 31.7%). Notably, these primary findings remained unchanged after excluding patients treated with ceftaroline, further supporting the synergistic activity of various β-lactams in combination with daptomycin against MRSA.

However, combination therapy was associated with increased rates of AKI (10.8% vs 2.9%) and Clostridioides difficile-associated diarrhea (5.6% vs. 1.3%) compared to monotherapy.

Vancomycin or daptomycin plus ceftaroline

An open-label, pilot trial randomized 40 adults with MRSA bacteremia to either daptomycin or vancomycin as monotherapy (n = 23) or combination therapy with daptomycin and ceftaroline (n = 17) within 72 h of the initial blood culture.⁶⁹ The trial was prematurely terminated due to a significant difference in treatment outcomes observed prior to reaching the planned enrollment of 50 patients. Despite comparable durations of bacteremia between groups, in-hospital mortality was significantly higher in the monotherapy therapy group (26%) compared to the combination therapy group (0%). Notably, mortality occurred entirely within the subgroup of patients with endovascular infections, primarily left-sided infective endocarditis. Although the groups did not significantly differ in comorbidities, inflammatory markers, and infection sources, the small sample size and unadjusted analysis limit definitive conclusions. Nevertheless, these findings suggest that certain subgroups with SAB might derive the greatest benefit from combination therapy.

A limitation of prior studies using adjunctive antistaphylococcal β-lactams is their lack of direct bactericidal activity against MRSA, with synergy primarily attributed to enhanced immune responses rather than microbial killing. In contrast, ceftaroline directly targets PBP 2a, inhibiting peptidoglycan synthesis and exerting bactericidal effects. Although ceftaroline offers a unique advantage, in vitro evidence suggests a potential class effect for synergy, as studies show that vancomycin combined with various β-lactams (cefazolin, cefepime, ceftaroline, and nafcillin) demonstrates similar synergistic effects.³⁶ Further research is needed to clarify these mechanisms and optimize combination regimens for MRSA bacteremia.

Should β-lactam therapy be added to anti-MRSA therapy in patients with MRSA bacteremia who do not respond to monotherapy?

Despite the use of in vitro active antibacterial therapy, 8%–39% of patients with SAB do not respond to monotherapy and experience persistent bacteremia.⁷⁰ This persistence is often due to inadequate source control, leading to higher recurrence, treatment failure, and mortality rates. While the definition of persistent SAB has evolved since the 2011 Infectious Diseases Society of America (IDSA) guidelines for MRSA, the focus remains on optimizing combination therapies for persistent MRSA bacteremia.¹⁴ Prolonged SAB is strongly associated with increased mortality with one prospective study reporting that 90-day mortality risk doubled in patients with SAB lasting more than 1 day.^70,71 These findings support the need to redefine persistent SAB as lasting two or more days despite in vitro active antibacterial therapy that does not result in a clinical response.

Most evidence for combination therapy with vancomycin or daptomycin plus β-lactam for MRSA bacteremia in patients unresponsive to monotherapy comes from case series and retrospective cohort studies.^{50,59–61,72–79} While most of these studies have been analyzed individually elsewhere,^80,81 multiple meta-analyses consistently demonstrate that combination therapy reduces the duration of bacteremia, the risk of persistent bacteremia, relapse, and clinical failure, though without a significant effect on mortality.^82–86 However, a subgroup analysis from one meta-analysis⁸² of three studies (440 patients total)^68,69,87 suggested combining daptomycin with a β-lactam might reduce mortality (RR 0.53, 95% CI 0.28–0.98, p = 0.04, I² = 0%), particularly when using ceftaroline, though study heterogeneity (e.g., timing of administration) and clinical differences (e.g., disease severity, comorbidities) complicate interpretation.

Comparative data are limited to a retrospective, multicenter cohort study that assessed the outcomes of 171 patients with MRSA bacteremia treated with either monotherapy (vancomycin or daptomycin, n = 113) or combination therapy (daptomycin and ceftaroline, n = 58) (Table 1).⁸⁷ In the monotherapy group, 96% of patients initially received vancomycin. However, 56% of these patients transitioned to alternative therapy, most frequently daptomycin monotherapy. Ultimately, 46% of patients completed treatment with vancomycin monotherapy, 42% with daptomycin monotherapy, 3% with ceftaroline monotherapy, and 9% with other anti-MRSA agents. Combination therapy was predominantly used as salvage therapy following failed monotherapy and was initiated a mean of 6 days (range, 0–24) after bacteremia onset. Source control was attempted in similar proportions of patients in both the monotherapy and combination therapy groups (40% vs 29%, respectively).

Even though the combination therapy group included a higher proportion of patients with high-risk features, this regimen demonstrated numerically lower 30-day mortality (8.3% vs 14.2%) and a greater likelihood of clearing persistent MRSA bacteremia compared to monotherapy. This effect was most pronounced in patients with endovascular infections treated with combination therapy within 72 h of the index culture, resulting in an 80% reduction in 60-day mortality (4.3% vs 20.8%).

The mean duration of bacteremia was longer in the combination therapy group (9.3 days) compared to the monotherapy group (4.8 days). However, following the initiation of combination therapy, the mean duration of bacteremia decreased to 3.3 days. Initiating combination therapy earlier was associated with a shorter duration of bacteremia. Small retrospective studies also suggest a benefit for combining vancomycin with a β-lactam in persistent MRSA bacteremia, though data remain limited.

A single-center retrospective cohort study evaluated the time to blood culture sterilization in 30 adults with persistent MRSA bacteremia who transitioned from initial vancomycin monotherapy to combination therapy with vancomycin and ceftaroline for at least 24 h.⁸⁸ Inclusion criteria required MRSA bacteremia to persist for at least 72 h, and patients who received other anti-MRSA agents within 72 h of combination therapy were excluded. The most common sources of infection included injection drug use (53.3%), skin and soft tissue infection (13.3%), bone and joint infection (13.3%), vascular catheter-related infection (10%), and pulmonary infection (10%). Sixty-three percent of patients required ICU admission, and source control interventions were performed in 66.7% of cases. The median time from the initial positive blood culture to ceftaroline initiation was 6 days, with ceftaroline administered for a median of 16 days. Despite a prolonged median bacteremia duration of 8.7 days, sterile blood cultures were achieved a median of 2.6 days after initiating ceftaroline therapy. However, this study lacked a comparator monotherapy group.

Data on combination therapy with ceftobiprole are limited to a multicenter case series of 12 patients with infective endocarditis, including a previously reported case.^89,90 Among the eight patients with SAB, two had native valve endocarditis caused by MSSA, two had prosthetic valve endocarditis caused by MSSA, one had native valve endocarditis caused by MRSA, and three had prosthetic valve endocarditis caused by MRSA. Ceftobiprole was combined with daptomycin in seven patients. Among four patients switched to ceftobiprole due to persistent bacteremia or complications, sterile blood cultures were achieved within 1, 2, 9, and 12 days after the switch.

While some studies suggest a potential benefit of combination therapy in patients with MRSA bacteremia unresponsive to monotherapy, its definitive role remains unclear. These studies have demonstrated a reduction in time to blood culture sterilization, but a consistent impact on mortality has not been established. However, the mechanisms driving this effect are uncertain, likely due to the lack of consensus on patient stratification and the oversimplification of MRSA bacteremia as a uniform clinical entity. Given the inherent heterogeneity of MRSA bacteremia, it is possible that specific patient subgroups may exhibit differential responses to various therapeutic strategies. Additionally, the absence of direct comparisons between combination and monotherapy with consistent source control interventions hinders definitive conclusions on the optimal approach. Further research, particularly well-designed randomized controlled trials, is needed to clarify the efficacy and safety of combination therapy.

Should β-lactam therapy be added to anti-MSSA therapy in patients with MSSA bacteremia who do not respond to monotherapy?

Although antistaphylococcal β-lactams have historically been effective against MSSA bacteremia, they have encountered difficulties in managing persistent bacteremia when used as monotherapy.⁹¹ The association between persistent MSSA bacteremia and increased morbidity and mortality is well-established, yet optimal treatment strategies remain unclear. This challenge is further compounded by the lack of a standardized definition for persistent MSSA bacteremia, often extrapolated from studies on MRSA bacteremia.⁷⁰ However, recent studies have explored the potential benefits of augmenting anti-MSSA therapy with β-lactams in patients with persistent MSSA bacteremia who do not respond to monotherapy.

Antistaphylococcal β-lactams plus carbapenems

The combination of antistaphylococcal β-lactams with carbapenems in treating persistent MSSA bacteremia was first described in a case report involving an elderly patient with persistent MSSA bacteremia, despite treatment with ceftaroline followed by cefazolin for 5 days.²⁴ The addition of ertapenem to cefazolin resulted in rapid blood culture sterilization within 24 h. Subsequent case series corroborated the efficacy of this combination, particularly in patients with complicated infections such as infective endocarditis and those with left-ventricular assist devices (LVADs).^{21,25,92–94} Notably, one report demonstrated that the addition of ertapenem to cefazolin enhances eradication of MSSA biofilms, potentially contributing to improved clinical outcomes.⁹²

While the initial case reports and subsequent case series demonstrated promising results for this combination therapy, a recent retrospective multicenter study evaluated this approach in a larger patient population.⁹⁵ The study compared monotherapy with cefazolin, oxacillin, or nafcillin (n = 157) to combination therapy with a carbapenem (98% ertapenem, 2% meropenem) added to an antistaphylococcal β-lactam (n = 81) in adults with MSSA bacteremia lasting for at least 48 h. Combination therapy was initiated after a median of 4.7 days (IQR 3.6–6.5 days) and continued for a median of 7 days (IQR 5.0–8.9 days).

Although patients receiving combination therapy had a higher prevalence of infective endocarditis (51% vs 36%) and longer median duration of bacteremia (6.6 vs 5.1 days), source control was less frequently achieved in this group (45% vs 56% for spinal infections; 36% vs 54% for non-spinal infections). Despite these differences, no significant differences in in-hospital mortality (13% vs 21%) or 90-day mortality (19% vs 27%) were observed between groups.

Risk-set matching revealed that combination therapy significantly shortened the time to blood culture clearance but did not improve 90-day mortality. Among patients with infective endocarditis, combination therapy did not significantly impact time to blood culture clearance (6.5 vs 5.8 days) or 90-day mortality (22.5% vs 17.5%). Similarly, patients who received combination therapy within 96 h of the initial blood culture did not experience faster blood culture sterilization (1.6 vs 1.8 days) or reduced 90-day mortality (33% vs 24%) compared to those who received combination therapy after 96 h.

Antistaphylococcal β-lactams plus ceftaroline

Another strategy involves combining ceftaroline with an antistaphylococcal β-lactam, as demonstrated in a report of two patients with persistent MSSA bacteremia complicated by infective endocarditis.⁹⁶ Despite ongoing bacteremia with monotherapy, adding ceftaroline to nafcillin on days 7 and 25, respectively, led to blood culture sterilization 3 days later in both cases, after which therapy was completed with cefazolin monotherapy.

Overall, these findings suggest that combination therapy accelerates time to blood culture sterilization in persistent MSSA bacteremia. However, additional data are needed to determine the impact on patient outcomes.

Which patient with S. aureus bacteremia is most likely to benefit from adjunct β-lactam therapy?

Identifying patients with SAB who may benefit from combination therapy is challenging. Traditional risk factors often inadequately predict the severity of SAB due to the complex interplay of multiple factors rather than a single predictor.¹⁶ The cumulative burden of these risk factors increases the likelihood of complicated SAB, with persistent bacteremia being a strong indicator.^16,17 Over recent decades, SAB presentations have become more complex, with increased prevalence of metastatic infections often missed on initial evaluations, leading to greater disease severity.^5,6,97–99 The absence of a standardized diagnostic workup further complicates management by hindering the identification of complicated bacteremia, leading to inadequate treatment and poorer outcomes.

Prognostic indicators

Traditional clinical risk assessments for SAB may be augmented by biomarkers that offer valuable prognostic insights. Dysregulation of both pro-inflammatory and anti-inflammatory cytokines has been associated with poor outcomes, including persistent bacteremia and increased mortality.^71,100 Previous research has demonstrated an association between elevated baseline IL-10 concentrations and increased mortality risk in patients with SAB, particularly in those with severe infections or high intravascular bacterial burdens.^26,29,101 This association was further supported by a study that observed significantly higher mortality rates in patients with baseline IL-10 concentrations exceeding 5 pg/mL when treated with monotherapy compared to combination therapy (26%, n = 5/19 vs 0%, n = 0/14).⁶⁹ Additionally, elevated IL-17A concentrations have been associated with persistent bacteremia, endovascular involvement, and metastatic infections.¹⁰² A combination of IL-8 and C-C motif chemokine ligand 2 (CCL2) has also been shown to predict mortality in SAB.¹⁰² However, the widespread clinical availability of these biomarkers remains limited.

Thrombocytopenia (platelet count < 150,000/mm³) at SAB onset is associated with higher bacterial burden and increased 30-day mortality compared to normal platelet counts.¹⁰³ Platelet trajectory in the early days following SAB onset serves as a key prognostic indicator.¹⁰⁴ Patients whose platelet counts normalize by day 4 have a lower mortality risk (⩽6%), whereas persistent thrombocytopenia on day 4 is associated with a higher risk (16%–21%). At one center, platelet counts below 100,000/mm³ or a decrease of more than 50,000/mm³ within the first 48 h of hospitalization were identified as markers of increased risk for complicated SAB.¹⁰⁵

Another prognostic marker, time to positivity from initial blood cultures, reflects the bacterial burden in SAB.¹⁰⁶ A shorter time to positivity, particularly within 12 h, is associated with persistent bacteremia, endovascular involvement, and increased mortality.^106–109 Recent studies suggest that sequential time to positivity and the time to positivity ratio (sequential time to positivity/initial time to positivity) may also serve as useful prognostic indicators.

In a cohort of 186 patients with SAB, 89% had complicated bacteremia, 59% had persistent bacteremia, 31% had prosthetic device infections, and 29% had infective endocarditis.¹¹⁰ The median time to positivity from initial and sequential blood cultures was 12 and 21 h, respectively. A significant association was observed between a time to positivity ratio of ⩽1.5 and native valve endocarditis. Patients with an initial time to positivity of less than 12 h had lower survival rates than those with a longer time to positivity.

These findings demonstrate the importance of stratifying patients based on clinical features and biomarkers to identify those at higher risk of complicated SAB who may benefit from combination therapy.

Clinical subtypes of SAB

A recent study analyzed three cohorts of hospitalized adults with SAB (95.5% MSSA) and identified distinct clinical subphenotypes, each characterized by unique risk profiles.¹¹¹ These subphenotypes included: (1) SAB in older patients with comorbidities; (2) younger patients with fewer comorbidities and nosocomial intravenous catheter-associated SAB; (3) community-acquired SAB with metastatic infection; (4) SAB in patients with chronic kidney disease; and (5) SAB related to injection drug use. Outcomes varied significantly among these subtypes, with higher mortality in older patients with comorbidities and lower mortality in younger individuals with nosocomial catheter-associated SAB and those with injection drug use experienced. Additionally, microbiological outcomes were worse in community-acquired metastatic SAB. These results suggest the need to tailor therapeutic interventions to the specific clinical subphenotype of SAB to improve treatment efficacy and patient outcomes.

Empirical antibacterial therapy in SAB

Prompt and effective empirical therapy for SAB is crucial, particularly for MRSA bacteremia.¹² Empirical therapy for a positive blood culture with Gram-positive cocci in clusters (e.g., Staphylococcus species) should target both MSSA and MRSA with vancomycin or daptomycin monotherapy in most cases. However, in patients identified as being at high risk for poor outcomes, including those with elevated IL-10 or IL-17, rapid blood culture positivity within 12 h, inadequate source control, older individuals with comorbidities, community-acquired metastatic SAB, or suspected endovascular involvement, combination therapy with a β-lactam and vancomycin or daptomycin may be warranted to optimize outcomes.^{15,69,102,110–116} Rapid diagnostic platforms can reduce the need for prolonged combination therapy by quickly distinguishing MSSA from MRSA (e.g., within 1 h or more of initial detected growth, depending on the platform) compared to traditional methods, which can take up to 3 days. Although clinical data supporting the use of combination therapy before distinguishing between MSSA and MRSA are lacking, prior studies suggest that initiating treatment with vancomycin and a β-lactam for SAB later identified as MSSA may be more effective than transitioning from empirical vancomycin to a β-lactam.^113–115

While previous studies of adding daptomycin to β-lactam monotherapy for MSSA bacteremia have not demonstrated significant reductions in the duration of bacteremia or mortality, it is crucial to acknowledge that these studies were primarily designed to evaluate the efficacy of daptomycin as definitive therapy rather than to assess the potential benefits of empirical combination therapy with daptomycin and a β-lactam.^117,118

Concerns about nephrotoxicity associated with vancomycin and antistaphylococcal penicillins have been raised.⁶³ However, cefazolin may mitigate this risk.^59,119 A post-hoc analysis of extended follow-up data from the CAMERA-2 trial suggests that the risk of AKI associated with combination therapy may not significantly impact mortality.⁶⁷ While AKI was not directly associated with mortality, higher baseline serum creatinine was associated with increased mortality, potentially reflecting early AKI or chronic renal impairment. Further research is needed to understand the pathophysiology of AKI, identify predictive biomarkers, and develop prevention strategies. The ongoing S. aureus Network Adaptive Platform (SNAP) trial aims to provide valuable insights into the optimal use of antistaphylococcal therapies.¹²⁰

Current clinical trials evaluating monotherapy versus combination therapy for SAB often use uniform therapeutic approaches that overlook patient heterogeneity and the potential benefits of personalized strategies.^62,63,69 The inclusion of patients with diverse sources of bacteremia, predominantly low-risk with healthcare-associated and nosocomial bacteremia in recent trials, such as CAMERA-1 and CAMERA-2, may distort results compared to real-world outcomes (Table 1 and Figure 2).^5,62,63 Future trials should consider factors such as patient risk stratification, location of acquisition, source of infection, and biomarker- or subphenotype-guided treatment selection to better assess the benefits of combination therapy.

Figure 2.

Comparison of sources among patients with MRSA bacteremia in prospective and retrospective comparative studies.

The available data on empirical combination therapy primarily stems from retrospective reviews, which are inherently biased due to the common use of combination therapy in severe cases. Nonetheless, emerging evidence suggests that early combination therapy, particularly in patients at high risk for poor outcomes, may confer significant benefits.^68,69,87

Combination therapy for persistent SAB

Patients with persistent SAB (bacteremia lasting more than 1 day) require comprehensive evaluation and aggressive source control. If bacteremia persists, alternative therapies should be considered. For persistent MRSA bacteremia, switching from vancomycin to daptomycin monotherapy poses a risk of developing daptomycin resistance.¹²¹ Combining ceftaroline with vancomycin or daptomycin can mitigate this risk while reducing the duration of bacteremia, the likelihood of persistent bacteremia, and the risk of clinical failure.^68,69,87 Additionally, β-lactams may augment host innate immune responses, leading to enhanced bacterial clearance and potentially improved clinical outcomes.¹²²

In cases of persistent MSSA bacteremia, combining ertapenem with cefazolin or ceftaroline with an antistaphylococcal penicillin may achieve faster blood culture sterilization, though controlled trials with standardized dosing are needed to compare these regimens to current treatment approaches. The combination of cefazolin and ertapenem, primarily driven by ertapenem, significantly enhances IL-1β release from peripheral blood monocytes in the presence of S. aureus, which is linked to faster blood culture sterilization.²⁷

Although the impact of these combination therapies on mortality rates remains inconclusive, this may be attributed to the relatively short follow-up periods in existing studies, typically 30 or 90 days after the initial positive blood culture.⁶⁷ While a one-month follow-up is often considered adequate to capture acute mortality, longer-term observation is crucial to assess the potential long-term consequences of recurrent or persistent bacteremia.¹²³ Complications such as endothelial dysfunction and cardiovascular events, which often relapse >30 days post-treatment, may substantially influence mortality rates.¹²⁴

Balancing risks and benefits of combination therapy

The judicious use of antibacterial therapy is essential to mitigate the growing threat of antimicrobial resistance. While antistaphylococcal penicillins, cefazolin, and carbapenems lack intrinsic anti-MRSA activity, their increased use can lead to collateral damage.¹²⁵ Limiting the duration of combination therapy may reduce the risk of resistance and adverse events without compromising clinical outcomes. Multiple studies have demonstrated that the duration of combination therapy is not associated with recurrent bacteremia.^126,127 Therefore, extending combination therapy beyond blood culture sterilization may be unnecessary. To confirm blood culture sterilization in SAB, at least one blood culture set should be obtained, as single-bottle cultures may be insufficient to confirm resolution.^128,129 Serial negative blood cultures may also be warranted, as intermittent negative cultures, known as the “skip phenomenon,” occur in approximately 4% to 13% of patients with SAB.^129,130

In vitro studies demonstrate comparable efficacy in sustained bacterial suppression between samples initially treated with a combination of daptomycin and ceftaroline followed by either continued combination therapy or monotherapy with daptomycin (⩾6 mg/kg) or ceftaroline.^69,131 However, initiating monotherapy in patients at high risk of persistent SAB may prolong bacteremia, potentially necessitating subsequent combination therapy and increasing overall antimicrobial exposure.

While some studies have reported a higher incidence of C. difficile-associated diarrhea with combination therapy,^68,79 most studies have not directly evaluated this outcome. A meta-analysis found no evidence of an increased risk of C. difficile-associated diarrhea compared to monotherapy.⁸²

Traditional endpoints, such as treatment success and mortality, may not adequately capture the patient experience. In the CAMERA-1 and CAMERA-2 trials, the Desirability of Outcome Ranking (DOOR) framework revealed that combination therapy was associated with an increased risk of adverse outcomes, including AKI, even after adjusting for hospital length of stay and intravenous antibiotic duration.^132,133 This was further confirmed by the DOOR-response adjusted for the duration of antibiotic risk (RADAR) analysis. While the composite outcome in CAMERA-2 slightly favored the combination therapy group (35% vs 39%), DOOR analysis indicated worse outcomes, primarily due to AKI and other adverse events.¹³³

The increased toxicity associated with combination therapy may outweigh the benefits of faster clearance of bacteremia.^132,133 The DOOR endpoint was limited by the lack of quality-of-life measures, highlighting the need for more comprehensive assessments.^133,134 The SNAP trial, with its focus on functional capacity at 90 days, aims to address these gaps and provide a more holistic view of patient outcomes in SAB.¹²⁰

Conclusion

Optimizing the management of SAB requires a comprehensive strategy that transcends traditional risk factors and treatment endpoints. While combination therapy presents distinct advantages for patients with persistent SAB, it is crucial to carefully evaluate these benefits against the increased risk of adverse outcomes such as AKI. The development and application of biomarkers and patient stratification strategies may enable more precise identification of individuals who are likely to benefit from combination therapy, thereby minimizing unnecessary exposure to multiple antibacterial agents.

Moreover, frameworks such as the DOOR and the RADAR analysis facilitate a holistic assessment of treatment efficacy and safety, considering the overall patient experience. Future studies should focus on individualized treatment strategies, incorporating biomarkers and patient-specific factors, to better assess the benefits and risks of combination therapy. Ongoing research is essential to refine these approaches, mitigate risks, and improve outcomes for patients with SAB. The current limitations in clinically differentiating subgroups within SAB may hinder the identification of potentially beneficial therapies. Addressing these challenges will be crucial for optimizing the management of SAB and improving patient outcomes.

Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Daniel B. Chastain

Andrés F. Henao-Martínez

Christopher M. Bland

David B. Cluck

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

Abstract

Keywords

Introduction

What is the mechanism of synergy with adjunct β-lactam therapy for S. aureus?

Should β-lactam therapy be empirically added to anti-MRSA therapy?

Vancomycin plus antistaphylococcal β-lactams

Daptomycin plus β-lactams

Vancomycin or daptomycin plus ceftaroline

Should β-lactam therapy be added to anti-MRSA therapy in patients with MRSA bacteremia who do not respond to monotherapy?

Should β-lactam therapy be added to anti-MSSA therapy in patients with MSSA bacteremia who do not respond to monotherapy?

Antistaphylococcal β-lactams plus carbapenems

Antistaphylococcal β-lactams plus ceftaroline

Which patient with S. aureus bacteremia is most likely to benefit from adjunct β-lactam therapy?

Prognostic indicators

Clinical subtypes of SAB

Empirical antibacterial therapy in SAB

Combination therapy for persistent SAB

Balancing risks and benefits of combination therapy

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iDs

References