Abstract
Background
Observational data suggest ceftaroline may be effective for methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI), but comparative data with standard of care are limited. This analysis compares the outcomes of MRSA BSI treated with ceftaroline or daptomycin.
Methods
Multicenter, retrospective, observational cohort study of adult patients with MRSA BSI from 2010 to 2017. Patients treated with ≥72 hours of ceftaroline or daptomycin were included. Those clearing BSI before study drug and those with a pneumonia source were excluded. The primary outcome was composite treatment failure, defined as 30-day mortality, BSI duration ≥7 days on study drug, and 60-day MRSA BSI recurrence. Inverse probability of treatment weighted risk difference in composite failure between daptomycin and ceftaroline groups was computed and 15% noninferiority margin applied.
Results
Two hundred seventy patients were included; 83 ceftaroline and 187 daptomycin. Ceftaroline was noninferior to daptomycin with respect to composite failure (39% daptomycin, 32.5% ceftaroline; weighted risk difference, 7.0% [95% confidence interval, –5.0% to 19.0%]). No differences between treatment groups was observed for 30-day mortality or other secondary efficacy outcomes. Creatine phosphokinase elevation was significantly more common among daptomycin patients (5.3% vs 0%, P = .034). Rash was significantly more common among ceftaroline patients (10.8 vs 1.1%, P = .001).
Conclusions
No difference in treatment failure or mortality was observed between MRSA BSI treated with ceftaroline or daptomycin. These data support future study of ceftaroline as a primary MRSA BSI treatment and current use of ceftaroline when an alternative to vancomycin and daptomycin is required.
Keywords: bacteremia, β-lactam, infective endocarditis, lipoglycopeptide, MRSA
No difference in treatment failure or mortality was observed between methicillin-resistant Staphylococcus aureus(MRSA) bloodstream infection (BSI) treated with ceftaroline or daptomycin. These data support future study of ceftaroline as a primary MRSA BSI treatment and use when a vancomycin and daptomycin alternative is required.
Methicillin-resistant Staphylococcus aureus (MRSA) is a serious public health threat resulting in thousands of infections and deaths annually [1]. A major contributor to the associated morbidity and mortality is MRSA bloodstream infection (BSI) [2, 3]. Vancomycin has been the treatment of choice for MRSA BSI for decades, but treatment failure rates are in excess of 30% [4–6]. This, along with emergence of reduced-vancomycin-susceptibility phenotypes and vancomycin-associated adverse drug reactions, necessitates alternative treatment options. Despite availability of newer alternative anti-MRSA antibiotics, none have been shown to be conclusively more effective than vancomycin [6–11]. Daptomycin is currently the vancomycin alternative with the most available clinical evidence and the only US Food and Drug Administration (FDA) alternative for S aureus BSI and right-sided infective endocarditis [12, 13]. However, the use of daptomycin for MRSA BSI is not without limitation. Similar to vancomycin, daptomycin failure is common and nonsusceptibility, although rare, has emerged [14–17]. Data suggest that as S aureus becomes less susceptible to vancomycin, susceptibility to daptomycin may also decrease [18]. Interactions with pulmonary surfactant also render daptomycin ineffective for BSI secondary to pneumonia source, which is an important subpopulation of MRSA BSI [19].
Ceftaroline fosamil, the prodrug of ceftaroline, is an advanced-generation cephalosporin with potent bactericidal gram-positive activity including against MRSA and many strains exhibiting reduced vancomycin susceptibility and daptomycin nonsusceptibility [20]. Observational data suggest that ceftaroline may be effective for MRSA BSI, but data comparing ceftaroline to standard of care are limited, and ceftaroline is not FDA approved for this indication. Without additional comparative data, clinicians may be hesitant to use ceftaroline, even when alternatives to vancomycin are required. Considering that vancomycin and/or daptomycin alternatives are frequently necessary for MRSA BSI management, these data are urgently needed. Because daptomycin is the primary vancomycin alternative, the objective of this study was to compare clinical outcomes between patients treated with ceftaroline or daptomycin for MRSA BSI.
METHODS
Study Design and Population
This was a multicenter, retrospective, observational cohort study of adult patients with MRSA BSI from 2010 to 2017 in 10 acute-care hospitals: Detroit Medical Center and Henry Ford Hospital in Detroit, Michigan; University of Florida Health, Shands Hospital in Gainesville, Florida; Lee Memorial Hospital in Fort Myers, Florida; University of Tennessee Medical Center in Knoxville, Tennessee; University of Maryland Medical Center in Baltimore, Maryland; San Diego Veterans Affairs Medical Center in San Diego, California; Huntsville Hospital in Huntsville, Alabama; HonorHealth John C. Lincoln Medical Center in Phoenix, Arizona; and Our Lady of the Lake Regional Medical Center in Baton Rouge, Louisiana. Patients aged ≥18 years with ≥1 positive blood culture for MRSA who received ≥72 hours of ceftaroline or daptomycin for MRSA BSI treatment were eligible for inclusion [21]. Patients who received ≥96 hours of MRSA BSI therapy prior to first dose of study therapy, cleared BSI prior to first dose of study therapy, had a suspected pneumonia BSI source, or had a polymicrobial BSI were excluded. Patients receiving ≥24 hours of concomitant MRSA-active therapy during the initial 96 hours of study drug were also excluded.
Patient Consent Statement
This study was approved by the institutional review board at each study site and at Wayne State University (WSU). Waiver of patient informed consent was granted.
Patient Data Elements and Collection
Eligible patients were identified for inclusion by screening a list of patients who received either ceftaroline or daptomycin during the study period. Patient data were extracted from the medical record by trained reviewers using a structured data collection form within the REDCap (Research Electronic Data Capture, Vanderbilt University) data capture tool hosted at WSU [22]. Data elements included demographics, past medical history, comorbid conditions, antibiotic therapy and associated laboratory parameters, infectious diseases consult, and pursuit of source control. The degree of patient comorbidity was quantified using the Charlson Comorbidity Index [23]. Severity of illness was quantified using the Acute Physiology and Chronic Health Evaluation II (APACHE II) score using the worst physiological parameters within 24 hours of index MRSA blood culture [24]. Source of MRSA BSI and/or metastatic foci of infection was based on treating physicians’ notes and available clinical/diagnostic data. Microbiologic data including antibiotic susceptibilities by Microscan (Siemens Healthcare Diagnostics), Vitek-2 (bioMérieux), Phoenix (BD), and/or Etest (bioMérieux) were collected from the medical record.
Outcomes
The primary outcome was composite treatment failure, defined as any of the following: mortality within 30 days of first dose of study therapy, BSI duration ≥7 days after first dose of study therapy [12], or MRSA BSI recurrence within 60 days of the end of MRSA BSI therapy. Secondary efficacy outcomes included each single component of composite failure, 60-day readmission related to MRSA bacteremia defined as presence of positive blood cultures on readmission, BSI duration post–study drug initiation, and length of stay post–study drug initiation.
Multiple safety outcomes of interest were included. Creatine phosphokinase (CPK) elevation was defined as an increase to >600 U/L or >1000 U/L if baseline CPK was >200 U/L [25]. Neutropenia was defined as a decrease in absolute neutrophil count (ANC) to <1500 cells/mm3 or ≥50% decline from initiation of study medication if baseline ANC <1500 cells/mm3 [26]. Clostridioides difficile infection was defined as signs/symptoms along with positive laboratory test at least 48 hours after initiation of study therapy. Any adverse event apart from those defined above (eg, nausea, vomiting, rash) that was attributed to a study medication in the medical record by the treating physician was also recorded.
Data Analysis
The primary analysis focused on comparing composite treatment failure between patients receiving ceftaroline and daptomycin. We hypothesized that composite failure would be approximately equal between ceftaroline and daptomycin based on previously published data. Thus, the primary analysis was designed to test noninferiority of ceftaroline compared to daptomycin. Assuming a 25% incidence of composite treatment failure in both treatment groups, a noninferiority margin of 15%, and a 2:1 daptomycin to ceftaroline allocation ratio, a minimum of 156 and 78 patients was required in the daptomycin and ceftaroline groups, respectively, to yield a statistical power of 80% and an α = 2.5% [13, 27, 28]. Actual and weighted risk differences with 95% confidence intervals (CIs) were computed for composite failure between the daptomycin and ceftaroline groups (ie, daptomycin minus ceftaroline). Ceftaroline was considered noninferior if the lower bound of the 95% CI for this risk difference did not cross –15%.
Weighted risk differences were based on inverse probability of treatment weighting (IPTW). This was employed to address the high likelihood of confounding and treatment selection bias introduced by the fact that treatment assignment was not random. Logistic regression was used to estimate each patient’s probability of receiving ceftaroline (ie, a propensity score). The model included a priori–identified covariates known to be associated with mortality and/or microbiologic failure in patients with MRSA BSI including age, BSI source/foci of infection, Charlson Comorbidity Index, APACHE II score, infectious diseases consult, and source control [5, 29–34]. Stabilized weights for each subject were generated from the inverse of the propensity score. A pseudo-cohort was then generated using these stabilized weights, and the standardized difference between treatment groups of each a priori–identified covariate of importance was examined to ensure balance was achieved. A threshold of >25% standardized difference was used to assess the need for a respecified propensity score model, and a threshold of >10% was used to assess the need for further adjustment of a covariate in outcome analysis [35–37].
Secondary analyses were also conducted to compare secondary efficacy and safety outcomes between treatment groups and using actual and weighted risk differences in a manner consistent with the primary analysis. Secondary analyses evaluating composite failure between treatment groups in both a priori–specified and post hoc subgroups of interest were also conducted. These subgroups included infective endocarditis BSI source/foci, skin and soft tissue BSI source/foci, bone/joint BSI source/foci, patients with chronic kidney disease stage 3 or greater, patients on intermittent hemodialysis, and patients with acute kidney injury (Acute Kidney Injury Network stages 1–3).
When comparing patient characteristics and outcomes between those receiving ceftaroline or daptomycin, the χ2 or Fisher exact test was used for categorical variables and the Mann-Whitney U test was used for continuous and numeric ordinal variables. All statistical tests were 2-sided; P values ≤ .05 were considered statistically significant. Analyses were performed using SAS software version 9.4 (SAS Institute, Cary, North Carolina).
RESULTS
A total of 270 patients were included. A full description of demographics, clinical characteristics, and outcomes of the cohort is available in Supplementary Table 1. The cohort was predominantly African American (52.6%) and White (42.2%), majority male (64.8%), and had a median age of 58 (interquartile range [IQR], 46–66.5) years. Common comorbidities were diabetes (38.5%), moderate/severe renal disease (40.0%), chronic hemodialysis (20.0%), heart failure (24.1%), injection drug use (24.1%), and liver disease (21.1%). The median Charlson Comorbidity Index and APACHE II scores were 2.5 (IQR, 1.0–5.0) and 14.0 (IQR, 9.0–19.0), respectively. The most common MRSA BSI sources/foci were endovascular (34.8%), bone/joint (31.1%), skin and soft tissue (20.4%), and intravenous catheter (19.3%). Composite failure occurred in 100 (37%) patients: 32 (11.9%) with 30-day mortality, 50 (18.5%) with BSI duration ≥7 days on study therapy, and 38 with (14.1%) 60-day MRSA BSI recurrence.
Eighty-three patients (30.7%) were in the ceftaroline group while 187 (69.3%) were in the daptomycin group. The majority of patients in both the ceftaroline group (71.1%) and daptomycin group (66.3%) initially received vancomycin therapy prior to study therapy. The most common ceftaroline dose was 600 mg (68.7%) and the most common dosing frequencies were every 12 hours (56.6%) and every 8 hours (42.2%). The median daptomycin dose was 600 mg (IQR, 500–700 mg), which equates to 7.7 (IQR, 6.1–9.3) mg/kg of total body weight and 8.5 (IQR, 6.9–10.1) mg/kg of adjusted body weight. Using total body weight for nonobese (body mass index [BMI] <30 kg/m2) daptomycin patients, and adjusted body weight for obese daptomycin patients (BMI ≥30 kg/m2), only 5 (2.7%) daptomycin patients had a dose <6 mg/kg, whereas 63 (33.7%) had a dose ≥10 mg/kg. The median duration of inpatient ceftaroline and daptomycin was 10 (IQR, 5–18) days and 9 (IQR, 6–15) days, respectively.
A complete bivariate comparison of patient characteristics between the ceftaroline and daptomycin groups in the unadjusted cohort is displayed in Table 1. While select comorbidities were significantly different between groups, the distribution of Charlson Comorbidity Index was similar. A similar proportion of patients had acute kidney injury at index culture and the distribution of APACHE II scores was similar between groups. A similar proportion of patients in each group had an endovascular BSI source/foci. However, skin/soft tissue source/foci was significantly more common in the ceftaroline group whereas intravenous catheter source/foci was significantly more common in the daptomycin group. Median time from index blood culture to study drug was similar in both groups (42 [IQR, 20–71] hours for ceftaroline vs 44 [IQR, 21–71] hours for daptomycin). However, daptomycin was significantly more likely to be the first MRSA BSI treatment compared to ceftaroline.
Table 1.
Bivariate Comparisons of Demographic and Clinical Characteristics Between Patients Receiving Daptomycin or Ceftaroline
| Covariate | Daptomycin (n = 187) | Ceftaroline (n = 83) | P Value |
|---|---|---|---|
| Demographics | |||
| Age, y, median (IQR) | 58 (48–68) | 56 (40–63) | .248 |
| Male sex | 117 (62.6) | 58 (69.9) | .246 |
| Race/ethnicity | |||
| African American | 120 (64.3) | 22 (26.5) | <.001 |
| White | 57 (30.5) | 57 (35.0) | <.001 |
| Asian | 3 (1.6) | 1 (1.2) | 1.000 |
| Hispanic | 1 (0.5) | 1 (1.2) | .521 |
| Other/unknown | 6 (5.5) | 2 (2.4) | 1.000 |
| Study site | |||
| Detroit Medical Center | 122 (65.2) | 12 (14.5) | <.001 |
| UF Health–Shands Hospital | 24 (12.8) | 11 (13.3) | .925 |
| Henry Ford Hospital | 23 (12.3) | 7 (8.4) | .351 |
| University of Tennessee Medical Center | 0 | 17 (20.5) | <.001 |
| Lee Memorial Hospital | 15 (8.0) | 1 (1.2) | .027 |
| University of Maryland Medical Center | 3 (1.6) | 10 (12.0) | .001 |
| VA San Diego Healthcare System | 0 | 11 (13.3) | <.001 |
| Huntsville Hospital | 0 | 9 (10.8) | <.001 |
| HonorHealth John C. Lincoln Medical Center | 0 | 3 (3.6) | .028 |
| Our Lady of the Lake Medical Center | 0 | 2 (2.4) | .094 |
| Comorbidities and past medical history | |||
| Myocardial infarction | 17 (9.1) | 11 (13.3) | .301 |
| Heart failure | 47 (25.1) | 18 (21.7) | .541 |
| Peripheral vascular disease | 37 (19.8) | 8 (9.6) | .039 |
| Cerebrovascular disease | 25 (13.4) | 10 (12.0) | .766 |
| Dementia | 8 (4.3) | 3 (3.6) | .799 |
| Chronic pulmonary disease | 42 (22.5) | 15 (18.1) | .415 |
| COPD | 29 (15.5) | 12 (14.5) | .824 |
| Asthma | 19 (10.2) | 3 (3.6) | .070 |
| Connective tissue disease | 25 (13.4) | 4 (4.8) | .036 |
| Peptic ulcer disease | 0 | 0 | |
| Liver disease | 34 (18.2) | 23 (27.7) | .077 |
| Milda | 28 (15.0) | 19 (22.9) | .113 |
| Moderate/severeb | 6 (3.2) | 4 (4.8) | .502 |
| Diabetes | 74 (39.6) | 30 (36.1) | .593 |
| Without end-organ damage | 17 (9.1) | 10 (12.0) | .455 |
| With end-organ damage | 57 (30.5) | 20 (24.1) | |
| Hemiplegia | 9 (4.8) | 0 | .061 |
| Moderate/severe renal diseasec | 82 (43.9) | 26 (31.3) | .053 |
| Chronic hemodialysis | 44 (23.5) | 10 (12.0) | .030 |
| Solid tumor without metastasis | 6 (3.2) | 2 (2.4) | 1.000 |
| Leukemia | 1 (0.5) | 3 (3.6) | .088 |
| Lymphoma | 1 (0.5) | 0 | 1.000 |
| Metastatic solid tumor | 2 (1.1) | 2 (2.4) | .589 |
| HIV | 7 (3.7) | 2 (2.4) | .726 |
| AIDS | 0 | 2 (2.4) | .094 |
| Charlson Comorbidity Index, median (IQR) | 3 (1–5) | 2 (1–5) | .275 |
| Intravenous drug use | 37 (19.8) | 28 (33.7) | .013 |
| Prior hospitalization (90 d) | 76 (40.6) | 25 (30.1) | .099 |
| Prior MRSA infection (1 y) | 51 (27.3) | 20 (24.1) | .584 |
| Prior IV vancomycin (90 d) | 33 (17.6) | 14 (16.9) | .876 |
| Prior daptomycin (90 d) | 22 (11.8) | 5 (6.0) | .189 |
| Prior ceftaroline (90 d) | 0 | 3 (3.6) | .028 |
| Clinical data | |||
| Admitted from: | .471 | ||
| Home | 137 (73.7) | 66 (62.6) | |
| Transferred from another hospital | 24 (12.9) | 10 (12.0) | |
| Nursing facility | 25 (13.4) | 7 (9.9) | |
| Weight, kg, median (IQR) | 79.8 (68.0–96.0) | 83.6 (72.6–99.5) | .235 |
| BMI, kg/m2, median (IQR) | 26.6 (23.4–32.6) | 27.2 (23.7–32.4) | .614 |
| Obesityd | 60 (32.1) | 29 (34.9) | .645 |
| Creatinine clearancee,f, mL/min, median (IQR) | 61.7 (35.7–95.4) | 62.6 (35.8–104.9) | .861 |
| >50 mL/min | 89 (47.6) | 47 (56.6) | .350 |
| 30.01–50 mL/min | 30 (16.0) | 14 (16.9) | |
| 15–30 mL/min | 21 (11.2) | 9 (10.8) | |
| <15 mL/min or ESRD | 47 (25.1) | 13 (15.7) | |
| Acute kidney injuryf | 61 (32.6) | 29 (34.9) | .709 |
| APACHE II scoref, median (IQR) | 14 (9–20) | 14 (9–19) | .527 |
| Neutropeniaf | 3 (1.6) | 1 (1.2) | 1.000 |
| Infection data | |||
| Endovascular | 65 (34.8) | 29 (34.9) | .977 |
| Infective endocarditis | 55 (29.4) | 27 (32.5) | .607 |
| Other endovascular | 11 (5.9) | 2 (2.4) | .356 |
| Intra-abdominal | 4 (2.1) | 2 (2.4) | 1.000 |
| Lower respiratory tract | 0 | 0 | |
| Bone/joint | 56 (29.9) | 28 (33.7) | .535 |
| Invasive prosthetic device | 20 (10.7) | 4 (4.8) | .117 |
| Skin/soft tissue | 32 (17.1) | 23 (27.7) | .046 |
| Deep tissue abscess | 13 (7.0) | 9 (10.8) | .281 |
| Intravenous catheter | 42 (22.5) | 10 (12.0) | .045 |
| Urinary | 5 (2.7) | 1 (1.2) | .670 |
| Unknown | 8 (4.3) | 5 (6.0) | .546 |
| Treatment data | |||
| Infectious diseases consult | 173 (93.0) | 82 (98.8) | .071 |
| Source control pursued | 97 (52.4) | 36 (43.9) | .198 |
| Study drug line of therapyg | .014 | ||
| First-line | 62 (33.2) | 16 (19.3) | |
| Second-line | 124 (66.3) | 64 (77.1) | |
| Third-line | 1 (0.5) | 3 (3.6) | |
| Preceding MRSA BSI therapy | |||
| Vancomycin | 122 (65.2) | 59 (71.1) | .346 |
| Daptomycin | 0 | 6 (7.2) | .001 |
| Ceftaroline | 1 (0.5) | 0 | 1.000 |
| Linezolid | 3 (1.6) | 6 (7.2) | .026 |
| Time to study drug, h, median (IQR) | 44 (21–71) | 42 (20–71) | .964 |
| Ceftaroline dose (n = 83) | … | ||
| 600 mg | 57 (68.7) | ||
| 400 mg | 12 (14.5) | ||
| 300 mg | 11 (13.3) | ||
| 200 mg | 3 (3.6) | ||
| Ceftaroline dose interval (n = 83) | … | ||
| Every 8 h | 35 (42.2) | ||
| Every 12 h | 47 (56.6) | ||
| Every 24 h | 1 (1.2) | ||
| Daptomycin dose, mg, median (IQR) | 600 (500–770) | … | |
| Daptomycin dose, mg/kg (actual body weight), median (IQR) | 7.7 (6.1–9.3) | … | |
| Daptomycin dose, mg/kg (adjusted body weight), median (IQR) | 8.5 (6.9–10.1) | … | |
| Daptomycin dose interval | |||
| Every 24 h | 120 (64.2) | … | |
| Every 48 h/posthemodialysis | 67 (35.8) | … | |
| Inpatient study drug duration, d, median (IQR) | 9 (6–15) | 10 (5–18) | .545 |
Data are presented as No. (%) unless otherwise indicated.
Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; BMI, body mass index; BSI, bloodstream infection; COPD chronic obstructive pulmonary disease; ESRD, end-stage renal disease; HIV, human immunodeficiency virus; IQR, interquartile range; IV, intravenous; MRSA, methicillin-resistant Staphylococcus aureus; UF, University of Florida; VA, Veterans Affairs.
Mild liver disease defined as chronic hepatitis without cirrhosis.
Severe liver disease defined as portal hypertension or cirrhosis.
Moderate/severe renal disease defined as chronic kidney disease stage 3 or greater or receiving chronic dialysis.
Defined as BMI ≥30 kg/m2.
Calculated using Cockcroft-Gault formula using actual body weight for BMI <30 kg/m2 and adjusted body weight for BMI ≥30 kg/m2.
At time of index MRSA blood culture.
Reasons for switch to daptomycin or ceftaroline, when documented, included elevated vancomycin minimum inhibitory concentration, concern for failure or previous therapy, concern for adverse reaction on previous therapy, and perceived improved target site penetration.
Table 2 shows the actual and weighted risk differences between the daptomycin and ceftaroline groups for treatment outcomes. No significant difference in composite treatment failure was observed between daptomycin and ceftaroline patients (39% daptomycin, 32.5% ceftaroline; weighted risk difference, 7.0% [95% CI, –5.0% to 19.0%]). This met the definition of noninferiority of ceftaroline compared to daptomycin for composite treatment failure. No statistically significant difference in any of the secondary efficacy outcomes was observed between daptomycin and ceftaroline patients, including 30-day mortality. No significant difference in BSI duration post–study drug initiation was observed between treatment groups (daptomycin, 3 [IQR, 2–5] days vs ceftaroline, 4 [IQR, 2–6] days; P = .134). Similarly, length of stay post–study drug initiation was not different between groups (daptomycin, 11 [IQR, 7–18] days vs ceftaroline, 13 [IQR, 7–24] days; P = .095). With respect to safety outcomes, creatine phosphokinase elevation was significantly more common among daptomycin patients whereas rash was significantly more common among ceftaroline patients (Table 2). No significant difference was noted in any other safety outcome. Clostridioides difficile infection occurred numerically more frequently in the ceftaroline group. There were no cases of study drug–associated neutropenia in either group. There were 2 cases of eosinophilic pneumonia in the daptomycin group.
Table 2.
Actual and Inverse Probability of Treatment Weighted Risk Differences Between Daptomycin and Ceftaroline for the Primary and Secondary Outcomes
| Outcome | Daptomycin (n = 187) | Ceftaroline (n = 83) | Risk Difference (95% CI) | P Valuea | Weighted Risk Difference (95% CI) | P Valueb |
|---|---|---|---|---|---|---|
| Composite failure | 73 (39.0) | 27 (32.5) | 6.5 (–5.8 to 18.8) | .307 | 7.0 (–5.0 to 19.0) | .264 |
| 30-d mortality | 20 (10.7) | 12 (14.5) | –3.8 (–12.5 to 5.0) | .377 | –5.2 (–13.8 to 3.5) | .215 |
| BSI duration ≥7 d | 36 (19.3) | 14 (16.9) | 2.4 (–7.5 to 12.2) | .642 | 5.4 (–3.8 to 14.5) | .273 |
| 60-d MRSA BSI recurrence | 31 (16.6) | 7 (8.4) | 8.1 (.001–16.2) | .076 | 7.8 (–.002 to 15.9) | .085 |
| 60-d MRSA BSI-related readmission | 17 (9.1) | 6 (7.2) | 1.9 (–5.1 to 8.8) | .613 | 1.3 (–5.8 to 8.4) | .718 |
| Adverse drug reactionc | 24 (12.8) | 17 (20.5) | –7.7 (–17.6 to 2.3) | .106 | –6.3 (–15.7 to 3.1) | .164 |
| CPK elevationd | 10 (5.4) | 0 | 5.4 (2.1–8.6) | .034 | 5.0 (1.9 to 8.1) | .034 |
| Rash | 2 (1.1) | 9 (10.8) | –9.8 (–16.6 to –2.9) | .001 | –8.0 (–14.3 to –1.8) | .001 |
| Neutropeniae | 0 | 0 | … | … | ||
| Clostridioides difficile infectionf | 2 (1.1) | 4 (4.8) | –3.8 (–8.6 to 1.1) | .074 | –3.3 (–7.8 to 1.2) | .076 |
Data are presented as No. (%) unless otherwise indicated.
Abbreviations: BSI, bloodstream infection; CI, confidence interval; CPK, creatine phosphokinase; MRSA, methicillin-resistant Staphylococcus aureus.
P value for χ2 or Fisher exact test of actual risk differences.
P value for χ2 test of weighted risk differences.
Includes CPK elevation, neutropenia, rash, Clostridioides difficile infection (data presented in table), and additional adverse reactions occurring while on study drug or attributed to study drug by treating clinicians, such as acute kidney injury, thrombocytopenia, fever, hypotension and bradycardia, and eosinophilic pneumonia.
Increase to >600 U/L or >1000 U/L if baseline CPK >200 U/L.
Decrease in absolute neutrophil count (ANC) to <1500 cells/mm3 or ≥50% decline from initiation of study medication if baseline ANC <1500 cells/mm3.
Clostridioides difficile infection defined as signs/symptoms along with positive laboratory test at least 48 hours after initiation of study drug.
The results of the a priori secondary subgroup analyses are displayed in Table 3. The results were consistent with primary analyses. No statistically significant association was observed between treatment group and composite failure in any of the subgroups of interest. The results of the post hoc subgroup analyses evaluating composite failure by study drug line of therapy are displayed in Supplementary Table 2. No statistically significant association was observed between treatment group and composite failure when study therapy was used as first-line or second-line therapy.
Table 3.
Actual and Inverse Probability of Treatment Weighted Risk Differences Between Daptomycin and Ceftaroline for the Composite Treatment Failure in A Priori–Specified Subgroups of Interest
| Subgroup | Daptomycin | Ceftaroline | Risk Difference (95% CI) | P Valuea | Weighted Risk Difference (95% CI) | P Valueb |
|---|---|---|---|---|---|---|
| Infective endocarditis source/foci (n = 82) | 25/55 (45.5) | 9/27 (33.3) | 12.1 (–10.0 to 34.2) | .295 | 12.2 (–10.2 to 34.7) | .299 |
| Skin/soft tissue source/foci (n = 55) | 11/32 (34.4) | 7/23 (30.4) | 3.9 (–21.1 to 28.9) | .759 | –2.8 (–30 to 24.5) | .840 |
| Bone/joint source/foci (n = 84) | 25/56 (44.6) | 8/28 (28.6) | 16.1 (–5.1 to 37.3) | .155 | 19.8 (–1.9 to 41.4) | .095 |
| Moderate/severe renal disease (n = 108) | 37/82 (45.1) | 11/26 (42.3) | 2.8 (–19 to 24.7) | .801 | –0.6 (–21.3 to 20) | .951 |
| Chronic hemodialysis (n = 54) | 18/44 (40.9) | 3/10 (30) | 10.9 (–21 to 42.8) | .723 | 2.5 (–27.1 to 32.1) | .870 |
| Acute kidney injury (n = 90) | 29/61 (47.5) | 10/29 (34.5) | 13.1 (–8.3 to 34.4) | .243 | 13.2 (–9.1 to 35.5) | .260 |
Data are presented as no./No. (%) unless otherwise indicated.
Abbreviation: CI, confidence interval.
P value for χ2 or Fisher exact test of actual risk differences.
P value for χ2 test of weighted risk differences.
DISCUSSION
This study sought to compare the effectiveness and safety of ceftaroline and daptomycin for the treatment of MRSA BSI. Patients receiving ceftaroline and daptomycin had similar treatment outcomes in both unadjusted and IPTW-adjusted analysis designed to mitigate the influence of treatment selection bias and confounding. This was also true in the prespecified subgroup analysis, most notably patients with an infective endocarditis source/foci and those with moderate/severe renal impairment. The only notable differences in outcome observed between the 2 treatment groups was with respect to safety outcomes. Not surprisingly, patients treated with ceftaroline were more likely to develop a rash whereas patients treated with daptomycin were more likely to experience a CPK elevation.
The results of this study contribute to a growing body of clinical evidence suggesting that ceftaroline may be a viable treatment option for MRSA BSI. Numerous noncomparative observational studies have demonstrated the potential utility of ceftaroline for MRSA BSI. These data are the first clinical data comparing ceftaroline to daptomycin, a standard-of-care therapy for MRSA BSI. Although observational in nature, and thus unable to firmly establish ceftaroline as noninferior to daptomycin, these data do represent an increase in the level and quality of the evidence to support the use of ceftaroline for MRSA BSI. Ceftaroline should be a priority for inclusion into future randomized clinical trials evaluating novel treatments for MRSA BSI in order to fully delineate its place in therapy.
There are a number of considerations to bear in mind when interpreting these findings. First and foremost, although we conducted noninferiority testing on the primary outcome of composite treatment failure, the observational nature of this study precludes the ability to conclude that ceftaroline is truly noninferior to daptomycin for MRSA BSI. That would require one or more robustly designed randomized controlled trials. The noninferiority testing was conducted due to the fact that we wanted to power the study under the hypothesis that there would be no difference in failure between ceftaroline and daptomycin. A noninferiority margin of 15% was selected a priori due to the anticipated difficulty in obtaining a large enough sample of ceftaroline monotherapy–treated patients to use a stricter margin and the fact that a less-strict noninferiority margin of 20% was used to conclude daptomycin was noninferior to vancomycin for MRSA BSI [6]. Readers should note that a noninferiority margin of 10% would have been ideal considering that a 10% difference in treatment failure is clinically meaningful. Although the primary analysis suggests that it is statistically unlikely the incidence of failure is more than 5% greater in the ceftaroline group, noninferiority at any threshold <15% cannot be concluded because the study was not powered to do so.
It is also important to note that the study therapy was not the initial MRSA BSI therapy for the majority of the patients in this study, particularly those in the ceftaroline group. It is unclear whether the results would be similar if more patients had been given ceftaroline or daptomycin as first-line therapy. It is encouraging that the majority of patients in both treatment groups received study therapy within 48 hours of index culture. This is similar to currently published randomized clinical trials where the transition from standard of care to experimental therapy often takes up to 48 hours [6]. However, this similarity with published clinical trials does not nullify the potential impact that studying sequential therapy could have. Data suggest that the initial 24–48 hours of MRSA BSI therapy is most strongly associated with outcome [34, 38]. Ideally, the comparison of 2 MRSA BSI treatments would occur during this early timeframe to best capture treatment effect and minimize the potential bias and confounding imparted by prior treatment.
Due to the observational nature of the study and in the absence of pharmacokinetic sampling, we were unable confirm pharmacodynamically optimized dosing in either treatment group. The majority of patients received daptomycin at doses that exceed the FDA-approved dosage for bloodstream infections including right-sided endocarditis of 6 mg/kg. However, only one-third of daptomycin patients received daptomycin doses of at least 10 mg/kg. Although in vitro data suggest that 10 mg/kg is the optimal dose for serious staphylococcal infections, data derived from patients with MRSA BSI suggest that fixed doses of 500–750 mg provide similar probability of effective exposures as 10 mg/kg [39]. At least 75% of the patients in this study received a daptomycin dose of at least 500 mg. Moreover, clinical data suggest success with daptomycin doses ≥7 mg/kg daily [40]. Evaluating adequacy of ceftaroline exposure is more complicated as the optimal dosing for serious infection is unknown. Less than half of the ceftaroline patients were given ceftaroline every 8 hours, a frequency often used for serious infections [10]. However, no clinical data indicate increased effectiveness of this more aggressive dosing, and pharmacokinetic simulation studies suggest it would be most beneficial for infections caused by isolates with a ceftaroline minimum inhibitory concentration ≥1 mg/L, accounting for only 4 (4.8%) of the ceftaroline group in the present study [41].
It is also important to note that the generalizability of the study may be limited. Patients with a pneumonia BSI source/foci were excluded given the lack of daptomycin efficacy for pulmonary infections. As such, these data are unable to demonstrate the comparative effectiveness of ceftaroline for BSI with a pneumonia source. It should also be noted that although adverse drug reactions were evaluated, the study was not specifically designed for this purpose. Many of the adverse reactions did not have an objective definition (eg, rash) and relied upon the diagnosis and documentation in the electronic medical record by treating clinicians. As such, the results should be interpreted with caution. Last, it is possible that some misclassification of BSI recurrence could have occurred. Although the 60-day threshold for an infection to be considered recurrence rather than reinfection is commonly used, data indicate that it is not a perfect threshold.
In conclusion, ceftaroline was noninferior to daptomycin for MRSA BSI in this observational study. Notable safety differences were observed; ceftaroline patients were more likely to develop a rash and daptomycin patients were more likely to have a CPK elevation. These data lend further evidence for the use of ceftaroline in patients with MRSA BSI who have failed treatment or cannot receive vancomycin or daptomycin and suggest that evaluating ceftaroline for MRSA BSI via randomized controlled trial should be a priority.
Supplementary Data
Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Notes
Financial support. This study was funded by an investigator-initiated grant from Allergan, Plc.
Potential conflicts of interest. K. C. C. has received grants from, served as a consultant and advisory board member for, and is on the speaker’s bureau for GenMark Diagnostics, BioFire Diagnostics, and Merck & Co. K. P. K. is a current employee of Merck & Co. but was employed by the University of Florida at the time of this research; no funding or support was provided from Merck for this study. M. P. V. has been a grant recipient of and/or consultant for Melinta, Merck & Co, Paratek, and Cumberland Therapeutics. S. J. E. is a former employee of T2 Biosystems but was employed by Lee Health at the time of this research; no funding or support was provided from T2 Biosystems for this study. K. S. K. is a consultant for AbbVie (Allergan). S. L. D. is a consultant for Spero and Tetraphase. M. J. R. has received grants from, served as a consultant and advisory board member for, and is on the speaker’s bureau for AbbVie (Allergan), Bayer, Melinta, Merck & Co, Paratek, Tetraphase, Shionogi, and Spero. All other authors report no potential conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
References
- 1. Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2019. https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf. Accessed 14 November 2019.
- 2. Chesdachai S, Kline S, Helmin D, Rajasingham R.. The effect of infectious diseases consultation on mortality in hospitalized patients with methicillin-resistant Staphylococcus aureus, Candida, and Pseudomonas bloodstream infections. Open Forum Infect Dis 2020; 7:ofaa010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Kourtis AP, Hatfield K, Baggs J, et al. Vital signs: epidemiology and recent trends in methicillin-resistant and in methicillin-susceptible Staphylococcus aureus bloodstream infections—United States. MMWR Morb Mortal Wkly Rep 2019; 68:214–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011; 52:e18–55. [DOI] [PubMed] [Google Scholar]
- 5. van Hal SJ, Lodise TP, Paterson DL.. The clinical significance of vancomycin minimum inhibitory concentration in Staphylococcus aureus infections: a systematic review and meta-analysis. Clin Infect Dis 2012; 54:755–71. [DOI] [PubMed] [Google Scholar]
- 6. Fowler VG, Jr., Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006; 355:653–65. [DOI] [PubMed] [Google Scholar]
- 7. Stryjewski ME, Lentnek A, O’Riordan W, et al. A randomized phase 2 trial of telavancin versus standard therapy in patients with uncomplicated Staphylococcus aureus bacteremia: the ASSURE study. BMC Infect Dis 2014; 14:289. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Tobudic S, Forstner C, Burgmann H, et al. Dalbavancin as primary and sequential treatment for gram-positive infective endocarditis: 2-year experience at the General Hospital of Vienna. Clin Infect Dis 2018; 67:795–8. [DOI] [PubMed] [Google Scholar]
- 9. Wilcox MH, Tack KJ, Bouza E, et al. Complicated skin and skin-structure infections and catheter-related bloodstream infections: noninferiority of linezolid in a phase 3 study. Clin Infect Dis 2009; 48:203–12. [DOI] [PubMed] [Google Scholar]
- 10. Zasowski EJ, Trinh TD, Claeys KC, et al. Multicenter observational study of ceftaroline fosamil for methicillin-resistant Staphylococcus aureus bloodstream infections. Antimicrob Agents Chemother 2017; 61:e02015-16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Schweizer ML, Richardson K, Vaughan Sarrazin MS, et al. Comparative effectiveness of switching to daptomycin versus remaining on vancomycin among patients with methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections. Clin Infect Dis 2021; 72:S68–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Moore CL, Osaki-Kiyan P, Haque NZ, et al. Daptomycin versus vancomycin for bloodstream infections due to methicillin-resistant Staphylococcus aureus with a high vancomycin minimum inhibitory concentration: a case-control study. Clin Infect Dis 2012; 54:51–8. [DOI] [PubMed] [Google Scholar]
- 13. Murray KP, Zhao JJ, Davis SL, et al. Early use of daptomycin versus vancomycin for methicillin-resistant Staphylococcus aureus bacteremia with vancomycin minimum inhibitory concentration >1 mg/L: a matched cohort study. Clin Infect Dis 2013; 56:1562–9. [DOI] [PubMed] [Google Scholar]
- 14. Sakoulas G, Rose W, Rybak MJ, et al. Evaluation of endocarditis caused by methicillin-susceptible Staphylococcus aureus developing nonsusceptibility to daptomycin. J Clin Microbiol 2008; 46:220–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Sharma M, Riederer K, Chase P, Khatib R.. High rate of decreasing daptomycin susceptibility during the treatment of persistent Staphylococcus aureus bacteremia. Eur J Clin Microbiol Infect Dis 2008; 27:433–7. [DOI] [PubMed] [Google Scholar]
- 16. Kelley PG, Gao W, Ward PB, Howden BP.. Daptomycin non-susceptibility in vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous-VISA (hVISA): implications for therapy after vancomycin treatment failure. J Antimicrob Chemother 2011; 66:1057–60. [DOI] [PubMed] [Google Scholar]
- 17. Gasch O, Camoez M, Dominguez MA, et al. Emergence of resistance to daptomycin in a cohort of patients with methicillin-resistant Staphylococcus aureus persistent bacteraemia treated with daptomycin. J Antimicrob Chemother 2014; 69:568–71. [DOI] [PubMed] [Google Scholar]
- 18. Patel N, Lubanski P, Ferro S, et al. Correlation between vancomycin MIC values and those of other agents against gram-positive bacteria among patients with bloodstream infections caused by methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2009; 53:5141–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Silverman JA, Mortin LI, Vanpraagh AD, et al. Inhibition of daptomycin by pulmonary surfactant: in vitro modeling and clinical impact. J Infect Dis 2005; 191:2149–52. [DOI] [PubMed] [Google Scholar]
- 20. Sader HS, Flamm RK, Jones RN.. Antimicrobial activity of ceftaroline tested against staphylococci with reduced susceptibility to linezolid, daptomycin, or vancomycin from U.S. hospitals, 2008 to 2011. Antimicrob Agents Chemother 2013; 57:3178–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Horan TC, Andrus M, Dudeck MA.. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control 2008; 36:309–32. [DOI] [PubMed] [Google Scholar]
- 22. Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42:377–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Charlson ME, Pompei P, Ales KL, MacKenzie CR.. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40:373–83. [DOI] [PubMed] [Google Scholar]
- 24. Knaus WA, Draper EA, Wagner DP, Zimmerman JE.. APACHE II: a severity of disease classification system. Crit Care Med 1985; 13:818–29. [PubMed] [Google Scholar]
- 25. Bhavnani SM, Rubino CM, Ambrose PG, Drusano GL.. Daptomycin exposure and the probability of elevations in the creatine phosphokinase level: data from a randomized trial of patients with bacteremia and endocarditis. Clin Infect Dis 2010; 50:1568–74. [DOI] [PubMed] [Google Scholar]
- 26. National Cancer Institute Cancer Therapy Evaluation Program. Common toxicity criteria manual. Version 2.0. 1999. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcmanual_v4_10-4-99.pdf. Accessed 14 August 2014.
- 27. Kullar R, Davis SL, Kaye KS, et al. Implementation of an antimicrobial stewardship pathway with daptomycin for optimal treatment of methicillin-resistant Staphylococcus aureus bacteremia. Pharmacotherapy 2013; 33:3–10. [DOI] [PubMed] [Google Scholar]
- 28. Casapao AM, Davis SL, Barr VO, et al. Large retrospective evaluation of the effectiveness and safety of ceftaroline fosamil therapy. Antimicrob Agents Chemother 2014; 58:2541–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Brookhart MA, Schneeweiss S, Rothman KJ, et al. Variable selection for propensity score models. Am J Epidemiol 2006; 163:1149–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Guillamet MCV, Vazquez R, Deaton B, et al. Host-pathogen-treatment triad: host factors matter most in methicillin-resistant Staphylococcus aureus bacteremia outcomes. Antimicrob Agents Chemother 2018; 62:e01902-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Chang FY, PeacockJE, Jr., Musher DM, et al. Staphylococcus aureus bacteremia: recurrence and the impact of antibiotic treatment in a prospective multicenter study. Medicine (Baltim) 2003; 82:333–9. [DOI] [PubMed] [Google Scholar]
- 32. Kreisel K, Boyd K, Langenberg P, Roghmann MC.. Risk factors for recurrence in patients with Staphylococcus aureus infections complicated by bacteremia. Diagn Microbiol Infect Dis 2006; 55:179–84. [DOI] [PubMed] [Google Scholar]
- 33. Kaasch AJ, Barlow G, Edgeworth JD, et al. Staphylococcus aureus bloodstream infection: a pooled analysis of five prospective, observational studies. J Infect 2014; 68:242–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Lodise TP, McKinnon PS, Swiderski L, Rybak MJ.. Outcomes analysis of delayed antibiotic treatment for hospital-acquired Staphylococcus aureus bacteremia. Clin Infect Dis 2003; 36:1418–23. [DOI] [PubMed] [Google Scholar]
- 35. Robins JM, Hernan MA, Brumback B.. Marginal structural models and causal inference in epidemiology. Epidemiology 2000; 11:550–60. [DOI] [PubMed] [Google Scholar]
- 36. Austin PC. Some methods of propensity-score matching had superior performance to others: results of an empirical investigation and Monte Carlo simulations. Biom J 2009; 51:171–84. [DOI] [PubMed] [Google Scholar]
- 37. Austin PC. Assessing balance in measured baseline covariates when using many-to-one matching on the propensity-score. Pharmacoepidemiol Drug Saf 2008; 17:1218–25. [DOI] [PubMed] [Google Scholar]
- 38. Lodise TP, Drusano GL, Zasowski E, et al. Vancomycin exposure in patients with methicillin-resistant Staphylococcus aureus bloodstream infections: how much is enough? Clin Infect Dis 2014; 59:666–75. [DOI] [PubMed] [Google Scholar]
- 39. Falcone M, Russo A, Venditti M, et al. Considerations for higher doses of daptomycin in critically ill patients with methicillin-resistant Staphylococcus aureus bacteremia. Clin Infect Dis 2013; 57:1568–76. [DOI] [PubMed] [Google Scholar]
- 40. Timbrook TT, Caffrey AR, Luther MK, et al. Association of higher daptomycin dose (7 mg/kg or greater) with improved survival in patients with methicillin-resistant Staphylococcus aureus bacteremia. Pharmacotherapy 2018; 38:189–96. [DOI] [PubMed] [Google Scholar]
- 41. Canut A, Isla A, Rodriguez-Gascon A.. Pharmacokinetic/pharmacodynamic analysis to evaluate ceftaroline fosamil dosing regimens for the treatment of community-acquired bacterial pneumonia and complicated skin and skin-structure infections in patients with normal and impaired renal function. Int J Antimicrob Agents 2015; 45:399–405. [DOI] [PubMed] [Google Scholar]
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