FormalPara Key Summary Points

Combination therapy was independently associated with reduced odds of clinical failure in methicillin-resistant Staphylococcus aureus bloodstream infections.

The composite endpoint of clinical failure was driven by 60-day recurrence and persistent bacteremia but not 30-day mortality.

Time to bacterial clearance was shorter in patients managed with combination therapy compared to monotherapy.

Background

Methicillin-resistant Staphylococcus aureus (MRSA) is a major public health concern causing serious community and health-care-associated infections annually [1,2,3]. Mortality rates associated with MRSA bloodstream infections (BSI) can be as high as 57% [3]. For decades, vancomycin (VAN) has been the mainstay for the management of MRSA BSI despite complex dosing strategies, nephrotoxicity risk, and slower bactericidal rate [4]. Daptomycin (DAP) is an alternative agent that offers solutions to VAN pitfalls; however; clinical outcomes for DAP treated patients, especially with Food and Drug Administration (FDA)-approved doses, are not superior to VAN plus gentamicin [5]. Furthermore, some S. aureus mutations encode DAP resistance and permit enhanced survival characteristics while on DAP treatment [6]. Interestingly, none of the novel agents for MRSA have been shown to be superior to VAN for MRSA BSI [5, 7].

Combination therapy (CT) with an active β-lactam (BL) early in the course of MRSA BSI has been suggested as a possible treatment strategy due to observed synergy between glycopeptides and BLs [8,9,10,11,12,13,14,15,16,17]. This phenomenon has been termed the “see-saw” effect; where, in the presence of glycopeptide or lipoglycopeptide, the susceptibility to BLs improves [18,19,20,21]. Additionally, this strategy achieves higher bactericidal activity, enables use of lower VAN or DAP doses in vitro and may even allow de-escalation to one agent [13, 17, 22, 23]. This approach had been utilized for the clinical management of MRSA BSI, particularly if adopted early in therapy [8,9,10,11, 16, 17, 22, 24,25,26]. While it had been quite promising with regards to faster microbiological eradication, the impact on other clinical outcomes, particularly mortality, had been underwhelming due to the scarcity of quality clinical evidence [8,9,10,11, 15, 16, 25, 27]. On a more sobering note, VAN CT with some BL agents, specifically flucloxacillin and piperacillin-tazobactam, had been associated with an increased risk of acute kidney injury (AKI) [9, 15, 28, 29]. We sought to determine whether CT improves clinical outcomes and safety compared to VAN or DAP monotherapy (MT) in patients with MRSA BSI.

Methods

Study Design and Population

This was a retrospective cohort study at the Detroit Medical Center (DMC) between 2006 and 2019. The DMC is a single large health-system of eight hospitals including six centered in midtown Detroit. Patients were screened and eligible for inclusion upon meeting the following criteria: (1) age ≥ 18 years; (2) MRSA-positive blood culture meeting Centers for Disease Control and Prevention criteria for BSI [30], and (3) treated with VAN or DAP within 72 h of index culture for ≥ 72 h. Patients were classified in the MT group if they did not receive any BL for ≥ 24 h up to 7 days following VAN/DAP initiation. Patients were in the CT group if they received BL for ≥ 24 h within 72 h after VAN/DAP initiation. Patients were excluded if they (1) experienced polymicrobial BSI, (2) did not have follow-up blood cultures, (3) a second MRSA BSI episode < 90 days of first episode, (4) cleared their bacteremia prior to MT or CT initiation, or (5) switched to ceftaroline ≥ 72 h following MT or CT (Fig. 1). The study was reviewed and approved by the Wayne State University Human Investigational Review Board and the DMC Research Review Committee.

Fig. 1
figure 1

Patient enrollment and selection. Exclusion criteria: (1) experienced polymicrobial BSI, (2) did not have follow-up blood cultures, (3) a second MRSA BSI episode. BSI blood stream infections, DAP daptomycin, VAN Vancomycin, MRSA methicillin-resistant Staphylococcal aureus

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Data Collection and Study Definitions

Demographics, comorbid conditions, laboratory, clinical and treatment data, infectious disease consult, and the pursuit of source control were extracted from the electronic medical record and entered into REDCap (Research Electronic Data Capture, Vanderbilt Univeristy), an electronic data capture tool hosted at Wayne State University [31]. Blood cultures were processed at the DMC microbiology laboratories according to standard procedures. MicroScan (Siemans Healthcare Diagnostics), Phoenix (BD), or Vitek2 (bioMerieux) were used for bacterial identification and antimicrobial susceptibility testing. The source of BSI was determined based on clinical notes and microbiological/diagnostic reports. Infective endocarditis was defined according to the modified Duke criteria [32]. BSI was classified as hospital-acquired if the index blood culture was obtained ≥ 48 h after hospital admission. The Charlson Comorbidity Index (CCI) was used to measure the degree of patient comorbidity [33]. The severity of illness was quantified using the Acute Physiology and Chronic Health evaluation II (APACHE II) score at BSI onset [34].

Outcome

The primary outcome was composite failure defined as (1) 30-day mortality, (2) 60-day recurrence, or (3) persistent BSI. Recurrence was defined as the development of recurrent positive culture after apparent clinical cure within 90 days of discharge. Persistent BSI was defined as BSI ≥ 5 days [35]. All time points were measured from the index MRSA blood culture. Secondary outcomes of interest included the individual component of the composite outcome, nephrotoxicity, hospital readmission, length of stay and other safety outcomes. Nephrotoxicity was defined as an increase in serum creatinine (0.5 mg/dl or ≥ 50% increase from baseline, whichever was greater). Other safety outcomes included thrombocytopenia, rhabdomyolysis and Clostridioides difficile-associated diarrhea.

Statstical Analysis

Demographics were evaluated using descriptive statistics where nominal data were reported as percentages and frequencies, and continuous data were reported as medians and interquartile ranges (IQR). Categorical variables between the success and failure group were compared by the Chi squared or Fisher’s exact tests, and continuous variables were compared by the Student’s t test or Mann–Whitney U test, as appropriate. Multivariable logistic regression was performed to examine the independent association between CT and clinical failure while adjusting for confounding variables. CT and monotherapy, alone with all baseline variables associated with clinical failure in the bivariate analysis at P < 0.2 were included in the logistic regression models simultaneously and removed using a backward stepwise approach. Variables that were not deemed to be independent were not included. The variance inflation factor was used to assess the multicollinearity of candidate regression. Values in the range of 1–5 were deemed to be appropriate. Covariates were retained in the model if the P value for the likelihood ratio test for their removal was < 0.1. Model fit was assessed with the Hosmer–Lemeshow goodness of fit test. All tests were two tailed with P values ≤ 0.5 to be considered significant. IBM SPSS software, ve.6.0 (SPSS, Chicago, IL, USA) was used for all calculations.

Results

Study Population

Our database identified 1942 patients in whom MRSA BSI and VAN/DAP had been completed for ≥ 72 h. Of these patients, 1345 cases were excluded (Fig. 1). Overall, the median age of this sample was 59 years (IQR, 50, 68), the median Charlson Comorbidity and APACHE II scores were 3 (1, 5) and 17 (11, 23), respectively. The majority were male sex (64.8%), African American (78.9%) and were admitted from home (72.5%). The most common comorbidities were diabetes (38.9%), chronic kidney disease (35.0%), and chronic dialysis (25.3%). More than one-third were hospitalized for at least 48 h within the past 90 days (38.2%). Most common sources of BSI were skin and soft tissue infections (21.7%), followed by infective endocarditis (19.4%) and bone and joint infections (17.9%).

The majority of patients were on CT therapy [n = 444 (74.4%)] and a quarter of the patients received MT [n = 153 (25.6%)]. A comparison of baseline characteristics between these two groups is provided in Table 1. No MRSA BSI patients with pneumonia as a source were treated with DAP in either cohort arms. The two groups were similar in general with a few notable differences. The CT group had a greater proportion of patients > 60 years old, admitted from a nursing home, with pneumonia, endocarditis or primary bacteremia as a source, and had higher APACHE II scores. The MT group had a greater proportion of patients with a MRSA infection history, recent antibiotic usage, and bone/joint or skin and soft tissue as a bacteremia source. Various BL agents were utilized in the CT group with the most common being cefepime 204 (45.9%), followed by cefazolin 149 (33.6%) and ceftaroline 54 (12.2%). Most patients received an infectious diseases (ID) service consult; 88.1% and 85.0% in the MT and CT groups, respectively. Source control was more commonly pursued in the MT (52.9%) group compared to CT (40.5%). Median (IQR) BSI duration was significantly longer in the MT compared to CT group; 4.2 and 3.3 days, respectively (P < 0.003). Median (IQR) length of stay was also longer but not statistically significant in the MT group compared to CT; 12 (8, 19) and 10 (7, 16) days, respectively (P = 0.087).

Table 1 Bivariate comparison of clinical characteristics and outcomes of patients managed with monotherapy versus combination therapy
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A total of 275 (46.1%) study patients experienced composite clinical failure; specifically 80 (52.3%) in the MT group compared to the CT 195 (43.9%) group (unadjusted P = 0.073). Bivariate analysis was conducted between cases that achieved clinical success and clinical failure, the results of the analysis are provided in Table 2. Two components of the composite endpoint were lower in the CT group: 60-day recurrence 8.7% versus 14.4% (P = 0.049) and PB 28.3% versus 41.8% (P = 0.002). On the other hand, 30-day mortality favored MT 9.2% versus 15.0%, however; that was not statistically significant (P = 0.064) (Fig. 2).

Table 2 Clinical characteristics of patients with clinical failure and no clinical failure
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Fig. 2
figure 2

Comparison of clinical outcomes between monotherapy and combination therapy patients. DAP daptomycin, Van vancomycin

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Results of the multivariable logistic regression analysis for independent predictors of the composite endpoint are illustrated in Table 3. Upon adjusting for the following variables: age > 60 years, APACHE II scores, admission from home, chronic kidney disease, MRSA risks (surgery within past 30 days and MRSA within 365 days), sources (endocarditis, skin and soft tissue infection, prosthetic device source). CT was independently associated with lower odds of clinical failure [adjusted odds ratio (aOR), 0.545; 95% confidence interval (CI), 0.364–0.817]. Because PB was the primary driver for the clinical outcome, we also performed a logistic regression analysis with PB as the dependent variable and adjusted for sources (endocarditis, pneumonia, bone and joint, invasive prosthetic device), source control, and comorbid condition of connective tissue disease. CT was independently associated with reduced odds of PB (aOR, 0.597; 95% CI, 0.393–0.907). We provide the results of the model in Table 4.

Table 3 Multivariable logistic regression model for factors independently associated with clinical failure
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Table 4 Multivariable logistic regression for factors independently associated with persistent bacteremia
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We did not observe a difference in nephrotoxicity between the CT and MT groups 14.2% and 14.4%, respectively (P = 0.954). Among subjects who were on VAN only, nephrotoxicity was comparable between CT and MT patients; 10.1% and 15.6%, respectively (P = 0.164). No differences in other secondary safety outcomes such as thrombocytopenia, rhabdomyolysis and Clostridioides difficile-associated diarrhea were observed between the two groups.

Discussion

In response to emerging evidence regarding the synergy between BL and VAN/DAP in MRSA BSI treatment, we aimed to explore the association between BL combination with VAN or DAP [8,9,10,11, 13,14,15, 19, 22, 24,25,26]. Our findings support what has been demonstrated in vitro and in vivo, suggesting that the addition of BL to VAN/DAP therapy within 72 h for at least 24 h increases the odds of clinical success. Favorable clinical outcomes occurred in the CT group even upon adjustment for all confounding variables in the multivariable regression model. Interestingly, the clinical success was primarily driven by significant reductions in 60-day recurrence and shorter BSI duration (< 5 days).

BL addition to VAN/DAP has been shown to have a significant impact on BSI duration compared with MT, with some influence on the rate of composite clinical outcomes such as mortality, relapse, and/or change in antibiotic therapy during treatment [8, 16, 26, 36,37,38]. Specifically, median duration of bacteremia had been reduced from 4 to 3 days when BL were used with VAN, and from 2.8 to 2.3 days when BL were used with DAP [8, 26]. Notably, our definition for PB at a 5-day cut-off has prevented us from comparing our results to other studies that have used other definitions such as 3 days and 7 days. In other observational studies, ceftaroline when used as salvage therapy in addition to DAP decreased the duration of bacteremia from 10 to 2 days [36]. In another study, reduction in BSI duration was more profound when ceftaroline was used with DAP than DAP MT 4.8 days versus 9.3 days, respectively [27]. However, statistically significant mortality differences were not observed between the two treatment groups. Notably, CT patients had a higher APACHE II score, intensive care unit (ICU) encounter, were more likely to be admitted from nursing facilities and had BSI sources commonly associated with high mortality (i.e., pneumonia/LRT and infective endocarditis). This further complicates the conflicting evidence in regard to survival benefits with BL combination therapy particularly with rapid bacterial eradication [8, 9, 16, 25, 37, 38].

In our study, CT subjects had higher severity of illness and more complex infections than MT subjects, and were therefore at a high risk for mortality. As demonstrated in previous studies, high-risk MRSA BSI patients benefit the most from CT when administered early in the treatment course (i.e., within 72 h) [8, 36, 39]. This underscores the importance of early BL addition to achieve timely bacterial eradication (i.e., 3–4 days) and hence avoiding the “perfect storm” [29]. The actual impact of timely bacterial eradication on mortality is well studied but not yet definitive [38].

The majority of BLs were administered as part of empiric treatment and not for targeted synergy against MRSA. Nevertheless, our CT group represents a heterogeneous group of BL agents administered within the initial 72 h of VAN/DAP initiation. Nephrotoxicity and other safety outcomes were similar between both groups, and remarkably comparable to previous studies [16, 40]. Notably, because our study includes VAN- and DAP-treated patients, it may reduce our ability to detect VAN-associated nephrotoxicity. Because our institutions avoid piperacillin-tazobactam/VAN combinations and utilize cefepime/VAN instead, due to the well-known association with nephrotoxicity, only a small proportion of CT patients in our study have received piperacillin-tazobactam, and most did in combination with DAP [28]. This may have contributed to the lower nephrotoxicity rates observed in our cohort, which is crucial, particularly in the light of the CAMERA-2 study where higher nephrotoxicity had been observed when VAN was used in combination with flucloxacillin.

To our knowledge, this is the largest real-world study to date comparing clinical outcomes in MRSA BSI patients receiving VAN/DAP MT to VAN/DAP CT with BL. Strengths of this study include a specific definition of BL exposure with regards to VAN/DAP timing, exclusion of patients who have not had a follow-up blood culture, robust sample size captured in over 12 years duration, and findings that are confirmatory of previously published data in CT for MRSA BSI [8, 25, 26].

When interpreting these findings, there are several considerations to note. First, although this was a multi-hospital site study, it was restricted to hospitals within a single health-care system in the Detroit area. Therefore, it may be challenging to generalize these findings to other patient populations with different demographics and clinical practice patterns. These hospitals, as of 2016, have mandated an infectious disease consult for all MRSA-positive blood cultures, which may have had an impact on the clinical outcomes. Second, because this was a retrospective study, results may be challenged by inherent limitations associated with this study design and unmeasured confounders. Recognizing this limitation, objective and measurable outcomes were selected (i.e., blood culture clearance and 30-day mortality). Furthermore, the MT arm was predominately treated with VAN or VAN followed by DAP and not DAP alone: 54.2%, 39.2%, and 6.5%, respectively. Despite that these two agents are similar in many aspects including spectrum of activity, these two antibiotics are not equivalent and, therefore, our results may be more generalizable to VAN or VAN/DAP rather than DAP alone. Additionally, it was not possible to account for VAN exposure in the entire cohort since the area under the curve (AUC) monitoring strategy was initiated within the last 4 years of the study period [41]. However, it is unlikely that this small proportion of patients have impacted the composite endpoint, as VAN exposure using AUC monitoring is a known factor to influence VAN safety outcomes rather than clinical outcomes [42]. Moreover, although ceftaroline was the BL of choice for only a small proportion of CT patients (12%); ceftaroline is the only BL available in the United States to date with in vitro MRSA activity providing known synergy particularly with DAP [22]. This may have had an indirect impact on PB rates within the CT group. However, it remains unclear if MT with ceftaroline alone would be superior to MT with VAN/DAP or even CT with BL. Finally, because our study evaluates a diverse group of BLs with diverse therapeutic characteristics, it is challenging to draw specific conclusions with regard to which specific BL is preferred when considering CT for MRSA BSI treatment.

Conclusion

We found that BL given ≤ 72 h of VAN/DAP therapy improves composite clinical outcomes for patients with MRSA BSI and that CT was well tolerated compared to MT alone. Time to bacterial clearance was shorter in patients managed with CT compared to MT. These data add to the evidence suggesting that CT may improve overall patient outcomes and should be further investigated to ascertain its role in MRSA BSI treatment. Additional studies, particularly prospective analysis, are warranted to explore the relationship between BL selection in CT and clinical benefit.