Focusing the Lens on the CAMERA Concepts: Early Combination β-Lactam and Vancomycin Therapy in Methicillin-Resistant Staphylococcus aureus Bacteremia

Methicillin-resistant Staphylococcus aureus (MRSA) has grown to become a major burden on health care systems. The cumulation of limited therapeutic options and worsened patient outcomes with persistent MRSA bacteremia has driven research in optimizing its initial management. The guidelines published by the Infectious Diseases Society of America currently recommend combination therapy for refractory MRSA bacteremia, but the utility of combining antibiotics from the start of therapy is under investigation.

ABSTRACT

Methicillin-resistant Staphylococcus aureus (MRSA) has grown to become a major burden on health care systems. The cumulation of limited therapeutic options and worsened patient outcomes with persistent MRSA bacteremia has driven research in optimizing its initial management. The guidelines published by the Infectious Diseases Society of America currently recommend combination therapy for refractory MRSA bacteremia, but the utility of combining antibiotics from the start of therapy is under investigation. The alternative strategy of early use of β-lactam antibiotics in combination with vancomycin upon initial MRSA bacteremia detection has shown promise. While this concept has gained international attention, providers should give this strategy serious consideration prior to implementation. The objective of this review is to examine retrospective and prospective evidence for early combination with vancomycin and β-lactam antibiotics, as well as explore potential consequences of combination therapy.

INTRODUCTION

The current standard management of invasive methicillin-resistant Staphylococcus aureus (MRSA) infections, as directed by the Infectious Diseases Society of America (IDSA), is vancomycin or daptomycin (1). Due to factors such as drug cost, provider familiarity, empirical coverage needs, and adverse drug events, certain hospitals may consider vancomycin as their initial therapy. This is supported by a recent, multicenter, international study where, at provider discretion, approximately 99% of patients received vancomycin for the treatment of MRSA bacteremia (2). Despite the widespread use of vancomycin, it is slowly bactericidal and has poor tissue penetration, prompting interest into alternative treatment strategies (3). Researchers have sought to optimize our workhorse therapy of vancomycin through the addition of a second agent, taking advantage of the antibiotics’ different mechanisms of action. The strategy of early β-lactam antibiotics in combination with vancomycin from the index blood culture has received recent attention for the management of MRSA bacteremia. As a majority of institutions favor the use of vancomycin as their initial therapy for methicillin-resistant Staphylococcus aureus bacteremia, vancomycin in combination with β-lactam antibiotics will be discussed in the remainder of this review.

BACKGROUND

Methicillin-resistant Staphylococcus aureus epidemiology.

While commonly a commensal organism of the human microbiota, Staphylococcus aureus remains one of the most clinically significant pathogens (4). S. aureus is frequently the causative organism of a variety of clinical infections, including bacteremia, infective endocarditis, and osteoarticular and device-related infections. The introduction of penicillin G in the mid-20th century vastly improved patient outcomes but was quickly followed by the development of resistance (5). Methicillin, a semisynthetic penicillinase-resistant β-lactam, was released to combat penicillin resistance, but within a year of its introduction, methicillin-resistant isolates were reported (6). MRSA has since grown to become a major burden on health care systems and is listed as a severe threat by the Centers for Disease Control and Prevention (CDC) (7). Nationally, the CDC reports over 80,000 MRSA infections per year and 11,285 annual deaths. Health care-associated risk factors include recent or prolonged hospitalization, hemodialysis, invasive device or lines, and recent antibiotic use. The CDC has implemented a nationwide plan to prevent the spread of MRSA, improve antibiotic use, and better track the number and type of MRSA infections. While some evidence suggests the positive impact of these interventions, there is a growing prevalence of community-associated MRSA infections with the rising opioid epidemic (8). The CDC reported that the those who inject drugs are approximately 16 times more likely to develop MRSA infections, with an increased incidence of invasive MRSA infections within this patient population (9). Limiting the spread of infection in health care settings and expanding our opioid education and abuse prevention programs are important steps for reducing MRSA infections.

Methicillin-resistant Staphylococcus aureus bacteremia treatment.

The Infectious Diseases Society of America (IDSA) MRSA treatment guidelines were released in 2011 (1). They recommend intravenous vancomycin or daptomycin as first-line agents for the management of MRSA bacteremia. IDSA guidelines suggest the definition of “bacteremia persistence” as positive blood cultures beyond 7 days of adequate therapy. However, due to the variability of MRSA manifestations, an objective definition of bacteremia persistence may be difficult to apply (10). Blood sterility is highly dependent on source control, as well as vancomycin serum concentrations and susceptibility. A patient’s overall response and a provider’s clinical judgment should be used when declaring treatment failure. In cases of MRSA persistence and vancomycin treatment failure, IDSA guidelines recommend high-dose daptomycin (10 mg/kg/day) in combination with another agent. Suggested combination agents include gentamicin, rifampin, linezolid, trimethoprim-sulfamethoxazole, or a β-lactam antibiotic. No specific β-lactam agent is listed for this combination approach within the IDSA guidelines.

Persistently positive blood cultures have been shown to be associated with worse outcomes. The likelihood of metastatic complications increases with duration of bacteremia by approximately 45% following ≥10 days of S. aureus bacteremia (11). Even without bacterial seeding, patients with MRSA bacteremia for >7 days had significantly higher rates of mortality than those achieving sterility within ≤3 days of starting vancomycin treatment (45.2% versus 9.4%, respectively; P = 0.002) (12). It is important to recognize that extensive vancomycin exposure prior to switching to guideline-directed daptomycin for persistent MRSA bacteremia has been linked with increased rates of daptomycin nonsusceptible strains (13). Strains resistant to vancomycin have demonstrated thicker cell walls, which may conceivably impact the ability of daptomycin to access relevant binding regions on the bacterial cell membrane.

The cumulation of limited therapeutic options and worsened patient outcomes with persistent MRSA bacteremia has driven research in optimizing its initial management. Combination therapy is currently recommended for refractory MRSA bacteremia, but the utility of combining antibiotics from the start of therapy is under investigation. The early addition of a β-lactam antibiotic in combination with vancomycin upon initial MRSA bacteremia detection has garnered international attention. The goal of combining these two agents early in a patient’s treatment is to more rapidly achieve blood sterility, thereby decreasing metastatic complications. This reduction in the duration of bacteremia is theorized to improve patient morbidity and mortality.

EARLY SYNERGY

Pathophysiology.

β-Lactam antibiotics exert their bactericidal effects by irreversibly interfering with the enzymes involved in cell wall synthesis, namely, penicillin-binding proteins (PBPs) (14). A long-lived covalent acyl-enzyme complex forms between the β-lactam antibiotic and the PBP, rendering it ineffective. Inhibiting enzymatic activity results in impaired cell wall synthesis, cell wall destabilization, and subsequently cell death. The resistance of MRSA to antistaphylococcal penicillins (ASPs) is chromosomally mediated, with the expression of the mecA gene encoding a structurally modified penicillin-binding protein 2a (PBP-2a) (15). These alterations allow PBP-2a to maintain synthetic function in the presence of β-lactam antibiotics and retain cell wall integrity. It may seem counterintuitive to suggest that the addition of a β-lactam may have any benefit to standard therapy for an organism of which, by definition, is resistant to ASPs. However, in vitro studies have demonstrated synergistic interactions between vancomycin and β-lactam antibiotic agents (16). While the presence of PBP-2a results in a reduced rate of acylation that is about 2- to 3-fold times slower than the native PBP, it is essential to recognize that acylation still occurs (17). Once the PBP-2a is acylated, its cell wall synthesis capabilities are as effectively inhibited as β-lactam-susceptible PBPs (18).

Mechanism of synergy.

While not entirely fully understood, there are a variety of proposed mechanisms behind the observed synergy between β-lactam antibiotics and vancomycin for the treatment of MRSA bacteremia. As β-lactam antibiotics are cell wall agents, it has been observed that the addition of β-lactam antibiotics results in S. aureus cell wall thinning (19). Decreased cell wall thickness results in improved vancomycin penetration into the division septum, increasing the ability for vancomycin to inhibit target sites during cell wall synthesis (20). This is the theorized mechanism behind the reduction in baseline vancomycin MIC seen with the addition of β-lactam agents. This inverse relationship between glycopeptide and β-lactam susceptibilities, coined the “see-saw effect,” may allow for improved efficacy of vancomycin and potentially curb further development of resistance. A recent publication demonstrated a consistent lowering of vancomycin MIC values in MRSA strains with various susceptibilities to vancomycin (21). While this in vitro MIC data support a trend of an increasing degree of synergy with increasing vancomycin MIC, this has yet to be translated to clinical response (22). Additionally, β-lactams result in morphological changes to the surface of S. aureus, which has been shown to increase target-specific vancomycin binding (23). Sakoulas et al. demonstrated that the addition of β-lactams enhanced the activity of the innate host defense system. While the detailed mechanism remains unknown, one theory suggests that β-lactams may prompt increased cell wall autolysin activity, improving susceptibility to various cationic host defense peptides, thus augmenting MRSA clearance (24).

Retrospective evidence for early synergy.

The evidence for the combination of vancomycin and β-lactam antibiotics has begun to expand beyond in vitro studies. Initial clinical evidence has been derived from retrospective reviews of coincidental combination therapy as a result of broad-spectrum empirical antibiotic therapy, or “unplanned synergy.” In 2014, Dilworth and colleagues described the outcomes of patients with MRSA bacteremia who received combination therapy with vancomycin and at least 24 h of β-lactam antibiotics to vancomycin alone (25). Piperacillin-tazobactam was the β-lactam recorded in the combination arm for 68% of patients, with a median duration of 6 days of β-lactam administration. They found a higher rate of microbiological eradication, defined as negative cultures and no relapse for 30 days, with the combination therapy group (96.0% versus 80%, P = 0.02). After adjusting for potential confounders, this effect persisted in a multivariate model (odds ratio [OR], 11.24; 95% confidence interval [CI], 1.7 to 144.3; P = 0.01). These results were later demonstrated in similar studies. Casapao et al. reported improvements in the time to bacterial clearance (median time 3 days versus 4 days, P = 0.047) and combination therapy with vancomycin and a β-lactam to be inversely associated with clinical failure (adjusted odds ratio [aOR], 0.24; 95% CI, 0.06 to 0.98; P = 0.047) (26). These two studies highlight the varied primary sources of MRSA bacteremia, which must be considered when determining the appropriate role of combination therapy. The combination arms of both trials had approximately 50% of patients included with a primary source of bacteremia listed as pulmonary, urinary, soft tissue, or catheter related (25, 26). While bacteremia of less-invasive origins are included in most trials evaluating combination therapy, it is important to recognize these patients likely dilute key outcomes.

Trihn and colleagues saw significantly fewer composite treatment failures with vancomycin plus cefazolin versus vancomycin alone for MRSA bacteremia (aOR, 0.33: 95% CI, 0.13 to 0.83) (27). Most recently, Truong et al. published a similarly designed retrospective cohort study evaluating treatment failure in those patients receiving vancomycin plus a β-lactam versus vancomycin only for MRSA bacteremia in 2018 (28). Piperacillin-tazobactam was administered to 54% of those in the combination arm, which was frequently deescalated to an alternative β-lactam for a median duration of 6 days of treatment. Treatment failure was a composite outcome, comprised of both clinical and microbiologic failure. After multivariate analysis, the combination therapy decreased treatment failure (OR, 0.38; 95% CI, 0.24 to 0.99; P = 0.049). This outcome appears to be driven by clinical failure only, namely, the initiation of a new MRSA agent, due to ongoing symptoms or persistent bacteremia (9.8% versus 20.0%, P = 0.165). Unique from the above studies, they report no difference in the rates of bacterial clearance, duration of bacteremia, or microbiologic failure. The potential benefit of combination therapy may have been limited by significantly higher acute physiology and chronic health evaluation II (APACHE II) scores (21 versus 16, P = 0.003) and rates of septic shock (31.8% versus 14.9%, P = 0.047) in the β-lactam cohort. Furthermore, 36% of those patients in the “vancomycin only” cohort received a β-lactam within 48 h of the index blood culture, with the longest duration of β-lactam therapy being 43 h. The above studies suggest that combination therapy may affect the duration of bacteremia; however, this conclusion has yet to translate to patient-centered outcomes.

Prospective evidence for early synergy.

Prospective, controlled trials of “planned synergy,” or the purposeful addition of β-lactam to vancomycin in initial MRSA bacteremia management, remains limited. In 2016, Davis and colleagues were the first to investigate the outcomes of β-lactam use in a small, multicenter, randomized controlled pilot trial (CAMERA) (29). Sixty patients were randomized in a 1:1 fashion to either vancomycin or vancomycin plus 2 g of intravenous (i.v.) flucloxacillin 4 times daily for the first 7 days after randomization. In the intention-to-treat (ITT) population, the mean duration of bacteremia was 3.00 days in the vancomycin therapy group and 1.94 days in the combination group (ratio of means, 0.65; 95% CI, 0.41 to 1.02; P = 0.06). They also reported numerically higher rates of renal impairment in the combination therapy group (28% versus 11%, P = 0.18). The small scale of this study limits the ability to draw strong conclusions but served its role as a pilot trial and led the groundwork for a larger scale investigation, namely, CAMERA2.

CAMERA2 is the largest MRSA bacteremia randomized controlled trial to date, investigating 90-day complication-free survival in patients treated with monotherapy vancomycin or daptomycin compared with either agent plus 7 days of i.v. flucloxacillin, cloxacillin, or cefazolin (2). While the study design allowed for vancomycin or daptomycin, it is important to note that approximately 99% of patients were treated with vancomycin. In cases of a penicillin allergy, patients were to receive 2 g of i.v. cefazolin every 8 h. A total of 356 patients were enrolled over a 3-year period, with a majority of patients receiving vancomycin compared with daptomycin. The primary outcome was complication-free 90-day survival, which was a composite outcome measure with the following four components: (i) all-cause mortality; (ii) persistent bacteremia at day 5 or beyond; (iii) microbiological relapse, defined as positive blood cultures for MRSA at least 72 h after a preceding negative culture; and (iv) microbiologic treatment failure, defined as positive sterile site culture for MRSA at least 14 days after randomization. Unfortunately, this trial was halted early due to an excess of renal injury in the combination therapy arm. In the primary analysis population, there was no significant difference in composite endpoint between combination and standard treatment cohorts (ITT; 35% versus 39%; 95% CI, −14.3 to −6.0). Acute kidney injury (AKI) rates were significantly more common with combination therapy than with standard therapy (23% versus 6%; 95% CI, 9.3% to 25.2%). The 90-day mortality rates (21% versus 16%; 95% CI, −3.7 to 12.7) were also higher in the combination. In exploratory post hoc analyses, AKI was associated with a need for renal replacement therapy and death. Furthermore, renal impairment varied significantly between β-lactam agents, with 27% of patients developing AKI receiving only flucloxacillin compared with 4% receiving only cefazolin. It is important to note that only a small fraction of patients received cefazolin only, and thus, these results should only be hypothesis generating. Consistent with prior evidence, the combination arm did result in faster clearance of bacteremia than standard therapy (day 5 positive blood cultures; 11% versus 20%; 95% CI, −16.6 to −1.2]). However, the potential benefit of more rapid clearance may have been confounded by AKI. In contrast to prior literature citing a typical mortality of 20% to 25% for MRSA bacteremia, CAMERA2 reported 11% and 16% mortality in the vancomycin alone cohort at 42 and 90 days, respectively. Any potential signal of benefit with combination therapy may have been further diminished given this low rate of mortality. The early termination of CAMERA2 limits the exploration of cefazolin-specific outcomes, but the trial suggests that cefazolin may be a safer alternative. Overall, these results highlight the need for additional research into different β-lactam agents and support their effects on the speed of bacteremia clearance but have yet to translate to improved patient outcomes.

SYNERGY SELECTION

β-Lactam agent.

Ceftaroline is a new cephalosporin β-lactam that has a significantly higher affinity for PBP-2a than others within the class, exhibiting anti-MRSA activity (47, 48). The successful addition of ceftaroline to vancomycin for persistent MRSA bacteremia has been reported, but no evidence exists for using ceftaroline in combination for the early management of MRSA bacteremia (30). Additionally, ceftaroline is associated with a high cost ($210.54 per 600-mg vial, average wholesale price) and not with risk, including hematologic and neurologic adverse events (31). Based on the mechanism of synergy and the literature discussed above, agents without inherent anti-MRSA activity may be considered. Tran et al. published in vitro evidence that suggests synergy as a class effect (21). They compared vancomycin alone with vancomycin in combination with either cefazolin, cefepime, ceftaroline, or nafcillin at various concentrations against 50 strains of MRSA. Based on combination susceptibility and time-kill curve analysis, a similar effect was observed for all tested β-lactam agents. While concentrations used in this study do not reflect clinical application, this study suggests a β-lactam benefit, regardless of MRSA activity. In 2018, Dilworth and colleagues attempted to assess the impact of β-lactam class on persistent MRSA bacteremia in a retrospective pooled analysis of 2 observational studies with 156 patients (32). Their findings support that early β-lactam combination therapy compared with vancomycin alone resulted in less rates of persistent bacteremia, defined as ≥5 days (26.7% versus 43.9%; P = 0.027). However, they were unable to find significant differences in rates of persistence stratified by β-lactam class. With no strong evidence to support tiered efficacy of β-lactam options, our decision may be guided by alternative factors.

β-Lactam combination duration.

As early β-lactam combination with vancomycin for the initial management of MRSA bacteremia is an emerging practice, there are few data to guide the duration of adjunctive β-lactam use. In studies evaluating combination therapies as salvage treatments for patients with persistent bacteremia, most continued both agents for the entire duration (10). Although there is a growing body of evidence suggesting a potential benefit of adding β-lactam to standard MRSA bacteremia therapy, optimal synergy duration remains unknown. The retrospective evidence described above reports a median β-lactam duration of 5 to 6 days (25, 26, 28). The CAMERA trials were designed for a total of 7 days of combination therapy from randomization (2, 29). While these data did not impact patient-centered outcomes, treatment combination with daptomycin did indicate that a survival benefit may be achieved with a duration of less than 2 weeks (33). This suggests that with up-front adjunctive β-lactam use, combination regimens do not need to be administered for the entire length of treatment. Further research is needed to find the appropriate duration that balances risks versus benefits for the use of early adjunctive β-lactams in the treatment of MRSA bacteremia.

UNINTENDED CONSEQUENCES

Impact on resistance.

The introduction of antibiotics to our patient population invariably leads to resistance. While ASPs and cefazolin have no intrinsic anti-MRSA activity to lose, increasing their use in the MRSA bacteremia population may impact their effectiveness in the treatment of other susceptible pathogens. Increased β-lactam exposure for the early management of MRSA bacteremia may also result in further S. aureus mutations that could dampen any benefit of the combination. This theory has not been demonstrated in MRSA, but the emergence of resistance to the effects of antimicrobial combination has been documented in Enterococcus faecium (35). During the assessment of the synergistic effects between β-lactams and glycopeptides, it was found that when a high inoculum were used, stable mutants could be selected that expressed resistance to β-lactam presence. Within these mutant strains, researchers reported quantitative differences in the expression of the PBPs involved with β-lactam activity. It is important, however, to consider the so-called see-saw effect between glycopeptide and β-lactam susceptibilities, improved time-kill analyses, and the positive impact on resistance that combination therapy exerts (13, 36). Implementing vancomycin monotherapy as a method of antibiotic stewardship may serve as a greater catalyst to resistance than the upfront use of two agents. As noted above, prior treatment with vancomycin is associated with more rapid development of daptomycin nonsusceptible strains (13). Simply stated, MRSA persistence within the bloodstream has been shown to contribute to the development of antibiotic resistance, mediated via host defense cationic peptides (37). Further investigation is warranted to determine the impacts of early adjunctive β-lactam therapy on resistance.

Acute kidney injury.

The use of vancomycin alone has been frequently associated with nephrotoxicity and, more recently, refined to risk factors, such as total daily dose, duration of therapy, area under the concentration-time curve (AUC), severity of illness, and receipt of concurrent nephrotoxins (38). The latter has been proposed as a major safety concern with the implementation of early adjunctive β-lactam therapy for MRSA bacteremia. CAMERA1 highlighted that those in the combination arm had more frequent rates of a >50% rise in serum creatinine (29). CAMERA2 confirmed this risk with ASPs, which was ultimately the reason for the early termination of the trial (2). However, it is important to recognize that β-lactam agent selection appears to greatly impact the development of AKI.

Within the CAMERA2 population, 27% of patients receiving only flucloxacillin developed AKI, compared with 4% receiving cefazolin. The concept that the degree of renal injury is drug specific has been supported in previous research. Cefepime or meropenem versus piperacillin-tazobactam (PTZ) in combination with vancomycin was reviewed in a prospective, multicenter observational study (39). The incidence of AKI with vancomycin and PTZ was significantly higher than those treated with vancomycin and cefepime or meropenem (29.8% versus 8.8%, respectively; P < 0.001). Agents used in CAMERA2, namely, ASPs and cefazolin, have been compared head to head in the treatment of methicillin-sensitive Staphylococcus aureus (MSSA). Youngster et al. retrospectively reviewed adverse drug reactions in 509 patients treated with nafcillin or cefazolin (40). The overall rate of drug-emergent events per 1,000 patient-days was higher for nafcillin than for cefazolin (16.9 versus 4.8, P < 0.001), with a significantly higher rate of renal impairment (11% versus 3%, P = 0.006). These conclusions were supported by a larger retrospective study evaluating 3,951 patients, finding AKI to occur in 29.2% of nafcillin patients compared with 14.8% of those receiving cefazolin (P < 0.0001) (41). No difference was found in mortality between agents in patients with endocarditis, osteomyelitis, or bacteremia, suggesting cefazolin is a safe and reasonable alternative. In combination with vancomycin for the early management of MRSA bacteremia, cefazolin may represent an adjunctive β-lactam that is less likely to result in AKI, as suggested by the CAMERA2 results.

Microbiota disruption.

Just a single-dose surgical antibiotic prophylaxis results in long-lasting changes to the human gut microbiota, which was shown to increase a patient’s risk of Clostridioides difficile infection (CDI) (42). Therefore, it is important to consider the risk-benefit of adding a second antimicrobial agent for the early management of MRSA bacteremia. Virtually every antibiotic has been associated with CDI, risk-stratified by certain classes. Third- and fourth-generation cephalosporins, fluoroquinolones, carbapenems, and clindamycins have all been found to be associated with a high risk of CDI (43). Neither CAMERA trial examined CDI as a secondary outcome; therefore, no data exist to examine the impact of the combination of first-generation cephalosporins or ASPs with i.v. vancomycin on rates of CDI. Comparing the agents themselves, Youngster et al. reported numerically higher rates of CDI with nafcillin versus cefazolin (2.4% versus 0.8%, P = 0.46) (40). In a 2018 meta-analysis comparing cefazolin and ASPs, no statistical difference was found between agents for the rates of diarrhea in hospitalized patients (Peto OR, 0.651; 95% CI, 0.073 to 5.83; P = 0.70) (44). Further research and outpatient monitoring are needed to better capture the risk of early β-lactam therapy on rates of CDI.

Drug shortages.

Applying the use of ASPs or cefazolin for the early management of MRSA bacteremia may result in an increased demand in an already strained and unpredictable supply. The American Society of Health-System Pharmacists (ASHP) lists cefazolin on their current drug shortage bulletin (45). Supply issues may then affect different patient populations with more established evidence, for example, our postoperative patients. Cefazolin is a recommended and widely used agent following a range of surgical procedures (46). With such a large number of patients with MRSA bacteremia annually, the adoption of cefazolin in the care of these patients would impact drug supply. Shortages would force providers to implement more broad antimicrobial agents for routine surgical prophylaxis, hindering stewardship efforts and impacting the development of future resistance.

FUTURE DIRECTIONS AND CONCLUSIONS

Future directions.

The use of vancomycin as the backbone therapy for the treatment of MRSA bacteremia is not without shortcomings. Vancomycin demonstrates slower bacterial killing, poor tissue penetration, and dose-related nephrotoxicity, as well as the emergency of intermediate and resistance strains (1, 3). This information has sparked interest in utilizing daptomycin, for which there is a clear benefit with the combination of β-lactam antibiotics. Similar mechanisms of synergy to those described above have been proposed. With the addition of β-lactam antibiotics, there is a clear increase in net cell membrane surface, subsequently enhancing the effects of both cationic daptomycin and host defense peptides (24). Furthermore, early use of this combination has shown clinical promise. An exploratory study comparing upfront daptomycin with ceftaroline versus vancomycin monotherapy from index MRSA blood culture showed that this combination may be associated with reduced in-hospital mortality (33). Importantly, the authors note this combination therapy to be at least 10-fold the cost of vancomycin monotherapy. With increasingly positive evidence and changing drug costs, the early combination of β-lactam antibiotics with daptomycin offers great potential.

Conclusions.

The early implementation of β-lactam antibiotics with vancomycin from the index blood culture for MRSA bacteremia has garnered international attention. The beneficial effects, first explored in vitro, have since been shown in retrospective studies. MRSA is notorious for the common metastatic spread of infection, which has been correlated with the duration of bacteremia. This combination has been shown to be effective in reducing the duration of bacteremia, which may reduce the development of metastatic foci. The publication of CAMERA2 represents the most robust evidence for early synergy leading to faster clearance of bacteremia and has sparked the development of the Staphylococcus aureus Network Adaptive Platform Trial (SNAP). However, it is critical to recognize that a no patient-centered benefit has been established and combination therapy risks have not been fully explored. As such, implementation of this strategy warrants serious consideration. Future research should include optimal duration of β-lactam therapy and preferred β-lactam agent, as well as consideration of unintended consequences.