Ceftaroline Fosamil for the Treatment of Methicillin-Resistant Staphylococcus Aureus Bacteremia: A Real-World Comparative Clinical Outcomes Study

Methicillin-resistant Staphylococcus aureus (MRSA) continues to represent a significant public health challenge, estimated to result in more than 80,000 invasive infections and 11,000 deaths every year in the USA alone [1]. MRSA bacteremia is associated with substantial morbidity and mortality, and compared with methicillin-susceptible S. aureus (MSSA) bacteremia, MRSA bacteremia is associated with an increased risk of 30-day readmission for bacteremia recurrence, in-hospital mortality, and longer hospitalization [2].

Vancomycin and daptomycin are currently recommended as first-line therapies for treating MRSA bacteremia [3]. However, limitations have been reported for both agents. Increasing reports of vancomycin failures, attributed to elevated vancomycin minimum inhibitory concentrations (MICs), and the emergence of reduced-vancomycin-susceptibility phenotypes have led to increased utilization of newer agents for the treatment of MRSA bacteremia [4, 5]. Daptomycin is often the preferred therapy choice for MRSA bacteremia caused by strains with elevated MICs to vancomycin (> 2 mg/L). However, rising daptomycin MICs have also been observed on treatment [6, 7].

The Infectious Diseases Society of America (IDSA) is currently developing new guidelines for S. aureus bacteremia [8]. Based on the existing IDSA guidelines, if MRSA bacteremia persists for approximately 7 days, it is recommended that patients be assessed to determine whether a change in therapy is appropriate [3]. However, no clear alternative or salvage regimen is proposed. Therefore, there is a clear need for evidence guiding alternative therapy options.

Several studies have demonstrated improved outcomes in the treatment of MSSA bacteremia with beta(β)-lactams versus vancomycin [9‐13]. Clinical superiority of β-lactams compared with vancomycin in MSSA bacteremia may be partially explained by the observed pharmacodynamic synergy of β-lactams with the innate immune system—a synergy that seems to be absent among the non-β-lactam agents typically used for the treatment of MRSA [12, 14, 15].

Ceftaroline fosamil is the pro-drug of ceftaroline, a fifth-generation cephalosporin (β-lactam), which has potent in vitro activity against MRSA [16]. Ceftaroline fosamil was the first widely approved β-lactam agent with activity against MRSA. It is approved in Europe and several other countries for the treatment of adults and children with complicated skin and soft tissue infections (cSSTI), including those caused by MRSA, and for community-acquired pneumonia (CAP; MSSA only) [17]; with similar approved indications in the USA [18].

Studies evaluating clinical outcomes with ceftaroline fosamil in patients with MRSA bacteremia, either as monotherapy [19] or combination therapy [15, 20, 21], suggest that it may be a useful treatment option for MRSA bacteremia, including refractory cases and those who have failed prior antimicrobial therapy, but most investigations have been limited by small sample sizes. Owing to the frequently severe disease status and poor outcomes of MRSA bacteremia, there is also interest in combinations of anti-MRSA treatments in this setting. A recent retrospective matched cohort study of 171 patients with MRSA bacteremia reported a lower 30-day mortality rate in patients receiving ceftaroline fosamil plus daptomycin within 72 h of index culture (8.3%), versus those receiving standard care (vancomycin or daptomycin; 14.2%) [22].

Geriak et al. (2019) prospectively investigated outcomes in MRSA bacteremic patients treated with ceftaroline fosamil plus daptomycin versus standard of care vancomycin or daptomycin monotherapy [15]. Results for the small numbers of patients studied showed that initial therapy with ceftaroline fosamil plus daptomycin was associated with reduced in-hospital mortality compared with vancomycin or daptomycin monotherapy in patients with MRSA bacteremia. However, the unexpected higher mortality incidence in the monotherapy treatment groups resulted in early termination of the study.

The objective of this large retrospective, observational study was to explore the outcomes of patients treated for MRSA bacteremia with ceftaroline fosamil, vancomycin, or daptomycin, according to whether they were administered separately or in combination.

In total, 24,479 patients with MRSA bacteremia were included (Group 1, n = 532; Group 2, n = 21,555; Group 3, n = 2392; Table 1). Of patients receiving combination therapy, 371 (15.5%) received ceftaroline fosamil plus vancomycin, 158 (6.6%) received ceftaroline fosamil plus daptomycin, and 1863 (77.9%) received vancomycin plus daptomycin. No patients were recorded as receiving all three treatments concurrently (Table 2). Demographic and clinical characteristics of patients with MRSA bacteremia are shown in Table 1. The majority of patients in all groups were male. Group 3 was, on average, younger, with fewer comorbidities compared with Groups 1 and 2. Endocarditis, diabetes mellitus, and chronic kidney disease were more common in patients in Group 1 than in Groups 2 and 3 (Table 1), and mean Charlson Comorbidity Index score was also higher in patients in Group 1. A larger proportion of patients in Group 1 had documented MRSA infection within the past year versus patients in Groups 2 and 3.

Treatment characteristics of patients included in the analysis are shown in Table 2. In Group 1, ceftaroline fosamil was administered as first-line therapy to 42.1% of patients and as third-line or later to 41.4% of patients, whereas in Group 2, vancomycin or daptomycin were administered as first-line to 95.4% and as third-line or later to 1.7% of patients. In Group 3, combination therapy was administered as third-line or later to most (67.8%) patients.

This retrospective study compared outcomes in patients with MRSA bacteremia treated with ceftaroline fosamil versus the non-β-lactam anti-MRSA agents, vancomycin and daptomycin; to our knowledge it is the largest real-world MRSA bacteremia study on this topic to date. Ceftaroline fosamil monotherapy was shown to result in a similar probability of favorable clinical outcomes to those of vancomycin or daptomycin monotherapy, with patients receiving ceftaroline fosamil monotherapy less likely to switch antibiotic treatment. Patients receiving ceftaroline fosamil monotherapy were shown to be more likely to require 30-day all-cause readmission, compared with those receiving vancomycin or daptomycin monotherapy. However, when sensitivity analysis criteria were applied (analysis included only patients who received 2 or more consecutive days of the same treatment regimen), there was a similar probability of 30-day all-cause readmission both in patients receiving ceftaroline fosamil monotherapy and in patients receiving any combination therapy, compared with vancomycin or daptomycin monotherapy. Of note, ceftaroline fosamil was more frequently used as third-line or later therapy than vancomycin or daptomycin (41.4% versus 1.7%, respectively); however, subgroup analysis showed that 30-day readmission outcomes in Group 1 were not significantly affected by the ceftaroline fosamil line of therapy.

Combination therapy with two of the three antibiotics assessed was generally associated with improved outcomes versus any agent as monotherapy; patients receiving any combination therapy were more likely to achieve clinical response and were less likely to switch treatment. Furthermore, subgroup analyses of the specific Group 3 combinations that patients received indicated that, compared with vancomycin or daptomycin monotherapy, each of the combination regimens had generally consistent associations with improved clinical response. Statistical significance of this result was borderline for the ceftaroline fosamil plus daptomycin combination; however, this is not unexpected given that patients receiving this regimen consisted of the smallest sample size in the study. In contrast, patients receiving ceftaroline fosamil plus vancomycin were more likely to achieve a clinical response than those receiving ceftaroline fosamil monotherapy. For those receiving vancomycin plus daptomycin or ceftaroline fosamil plus daptomycin, the likelihood of clinical response was generally similar versus ceftaroline fosamil monotherapy.

Possible reasons for the overall improved outcomes with combination versus monotherapy include synergy between the agents used in combination, potentially as a result of an increase in penicillin-binding protein inhibition. The activity of daptomycin against MRSA has been shown to be enhanced in the presence of β-lactam antibiotics [24, 25]. Additionally, synergistic mechanisms have been observed in vitro when ceftaroline fosamil is added to daptomycin [26]. Indeed, a previous retrospective, comparative cohort study found that combination therapy with daptomycin and a β-lactam, including ceftaroline fosamil, resulted in improved clinical outcomes versus daptomycin alone, in patients with MRSA bacteremia [27]. However, of note in the present study, no significant improvement in clinical response was observed with ceftaroline fosamil plus daptomycin combination therapy versus ceftaroline fosamil alone.

There has been an emergence of clinical MRSA isolates with reduced vancomycin susceptibility, considered to be due in part to increased vancomycin use [28, 29]. Combination therapy may therefore offer an alternative option for treating these infections. In vitro data have shown enhanced antibacterial activity of vancomycin and cephalosporin combinations against MRSA strains with decreased susceptibility to vancomycin versus vancomycin alone [30].

Combination therapy with vancomycin and a β-lactam has also been shown to lead to significantly fewer treatment failures than vancomycin monotherapy for MRSA bacteremia [31]. However, some studies have found no significant advantages in microbiologic or clinical efficacy as a result of using vancomycin in combination with other antibiotics [32].

Our study, investigating outcomes of ceftaroline fosamil, daptomycin, or vancomycin, alone or in combination, is conducted on a far larger scale than other real-world studies, analyzing data for just under 25,000 patients. Furthermore, unlike some other retrospective studies, the present study compares a number of clinical outcomes (including response, treatment switch, and 30-day readmission rates) for more than two treatment groups, thus further adding to published data.

In the CAMERA-1 pilot randomized controlled trial (RCT), a trend toward a reduction in the duration of MRSA bacteremia infection was observed in patients who received combination therapy of vancomycin plus flucloxacillin versus patients receiving vancomycin monotherapy, although the study was not powered for superiority [33]. In the larger, adequately powered, CAMERA-2 RCT, the addition of an anti-staphylococcal β-lactam (flucloxacillin, cloxacillin, or cefazolin) to vancomycin or daptomycin did not significantly reduce the primary composite end point of mortality, bacteremia, relapse, or treatment failure (35% versus 39%, respectively) [34]. Of note, this study was terminated early because of an increased risk of acute kidney injury in the combination therapy group. A subsequent analysis from the study found that increasing vancomycin exposure, even within the therapeutic range and regardless of concomitant anti-staphylococcal β-lactam use, was associated with an increasing probability of acute kidney injury [35]. As a result of the early termination of the main study, the study may not have been sufficiently powered to detect any improvement in the composite primary end point; however, the authors note that it is probable that any potential gains in efficacy with combination therapy would be offset by an increase in toxicity [34]. It is therefore important to consider that, while combination therapies may be beneficial, certain therapeutic combinations may lead to unexpected adverse events. The fact that these studies did not lead to conclusions on the value of combining a β-lactam with vancomycin also reiterates the need to supplement the available RCT data with evidence from real-world clinical settings.

Planned and currently ongoing studies, including the Staphylococcus aureus bacteremia Network Adaptive Platform (SNAP) RCT [36], which is evaluating a range of interventions in patients with S. aureus bacteremia, should also provide additional insights into the benefits of various treatment options in this patient population.

The high probability of a clinical response observed with ceftaroline fosamil in this study is consistent with previous observational studies of ceftaroline fosamil for the treatment of MRSA bacteremia, which have reported generally favorable outcomes, and highlighted that ceftaroline fosamil may be useful in the setting of salvage therapy after other antibiotic treatments have failed [19‐21, 37‐43].

A strength of this large database study is that the data obtained may be more representative of real-world use of these antibiotics in patients, compared with patients enrolled in controlled trials with restrictive study eligibility criteria. The retrospective design, intended for hypothesis generation, represents a limitation of this study; as this is a secondary database study, patients were not followed up for safety outcomes (including mortality) subsequent to hospital discharge, potentially resulting in underestimation of mortality and other adverse events. Underlying differences between the groups also limit outcomes comparisons in this observational study, as unlike in randomized clinical trials or case-control studies, matching the treatment groups for all baseline characteristics is not possible. Furthermore, it is an inherent limitation of observational data that there is no control over unmeasured potentially confounding factors, such as prior therapies received. Additionally, while Premier is one of the most comprehensive hospital discharge and services databases available, the database is nonetheless a convenience sample, which could result in estimates with unknown biases. The patient inclusion criteria also have implications for bias. The requirement of patients to have certain characteristics to qualify for study inclusion may have resulted in potential selection bias, specifically immortal time bias (survivor bias), as patients must have survived or not have been transferred to another healthcare facility and received treatment to be included. Finally, no adjustments were made for multiplicity in this analysis, which could have implications for increased rate of Type I and type II errors.

An additional limitation is that the evaluated outcome of clinical improvement was based on patient outcomes and discharge status only, as patient clinical assessment information is not available in the Premier Healthcare Database. A further limitation is that the reason(s) for treatment regimen switch was not recorded and is therefore unknown; potential reasons may have included cost considerations, patient response, treatment , and/or other clinical factors, such as co-infections in addition to MRSA bacteremia.

The scope of this study focuses on three specific anti-MRSA agents for the treatment of MRSA bacteremia among hospitalized patients. Considerations outside of the scope of the current study include combination therapies consisting of agents other than ceftaroline fosamil, vancomycin, and daptomycin; polymicrobial infections; and patients treated in a hospice setting. Accordingly, any interpretations of these results are limited to the type of infection, treatments, and patient population covered in this study. While the findings are hypothesis-generating, in the absence of large-scale RCTs, these real-world observational data provide insights into the potential role of ceftaroline fosamil as a treatment option for MRSA bacteremia.