Abstract
Background:
The preferred antibiotic salvage regimen for persistent methicillin-susceptible Staphylococcus aureus bacteremia (MSSAB) is unclear. Ertapenem with cefazolin or an antistaphylococcal penicillin has been primarily described, but identifying alternative carbapenem-sparing options may support antibiotic stewardship efforts and decrease the risk of antibiotic-associated Clostridioides difficile infection.
Objective:
We sought to evaluate the effectiveness and safety of daptomycin plus oxacillin (D/O) for persistent MSSAB.
Methods:
This was a single-center, retrospective cohort of patients with persistent MSSAB who received D/O between January 1, 2014, and January 1, 2023. Adult patients were included if they had blood cultures positive for MSSA ≥72 hours and received D/O combination for ≥48 hours. Patients were excluded if they were pregnant, incarcerated, or received another antibiotic considered to have excellent activity against MSSA. The primary outcome was time to MSSA bacteremia clearance post-daptomycin initiation. Secondary outcomes included microbiological cure, hospital length of stay, 90-day all-cause mortality, MSSA bacteremia-related mortality, 90-day readmission for MSSAB, and incidence of antibiotic-associated adverse effects. Time to MSSAB clearance post-D/O initiation was plotted using Kaplan-Meier estimation.
Results:
Seven unique patient encounters were identified including 4 with endocarditis. Despite a median MSSA bacteremia duration of 7.8 days, median clearance was 2 days post-daptomycin initiation. All achieved microbiological cure, and no adverse effects were reported. Ninety-day all-cause mortality, MSSAB-related mortality, and 90-day readmission for MSSAB occurred in 28.6%, 14.3%, and 14.3% of patients, respectively.
Conclusions and Relevance:
D/O was an effective, well-tolerated salvage regimen in this cohort and may represent a carbapenem-sparing option for persistent MSSAB.
Background
Methicillin-susceptible Staphylococcus aureus bacteremia (MSSAB) is associated with considerable morbidity and mortality. 1 In addition to effective source control, an antistaphylococcal penicillin (ASP) or cefazolin remains the preferred antibiotic treatment; however, many patients may not be candidates for various surgical interventions and may progress to persistent MSSAB.2,3 Combination antibiotic salvage regimens for persistent MSSAB may help achieve bloodstream clearance faster, limit complications, and improve outcomes.4,5
Few antibiotic salvage regimens exist for persistent MSSAB, and data are limited to case reports and case series to describe their effectiveness and safety.5-13 Ertapenem plus cefazolin or an ASP has been predominately described, but identifying alternative carbapenem-sparing options is consistent with antibiotic stewardship efforts and may decrease the risk of antibiotic-associated Clostridioides difficile infection (CDI).14-16 Daptomycin is a lipopeptide antibiotic with activity against only gram-positive bacteria and has been shown to be effective in combination with a beta-lactam (e.g. ceftaroline) for persistent methicillin-resistant S. aureus bacteremia. 17 Synergy has previously been observed with daptomycin and beta-lactams through the following proposed mechanisms: (1) beta-lactams reduce the net positive charge on the bacterial cell membrane to increase daptomycin binding; (2) daptomycin may inhibit bacterial peptidoglycan synthesis preventing penicillin-binding protein cross-linking and increasing beta-lactams’ activity; and (3) daptomycin may have some benefit against MSSA isolates that express low amounts of the mecA gene. 18 Daptomycin also has an approved indication for infective endocarditis (IE), which the supporting study included patients predominately with MSSA. 19 As such, daptomycin plus an ASP is a plausible salvage regimen for persistent MSSAB. Despite this, daptomycin in combination with a beta-lactam previously failed to demonstrate a reduction in bacteremia duration or mortality compared with beta-lactam monotherapy for MSSAB.20,21 However, these studies did not evaluate daptomycin plus oxacillin (D/O) as a salvage regimen specifically for persistent MSSAB. Herein, we report our experience evaluating the effectiveness and safety of D/O for persistent MSSAB.
Methods
Study Design
This was a single-center, retrospective cohort of patients with persistent MSSAB treated with D/O between January 1, 2015, and January 1, 2023, at the State University of New York Upstate University Hospital, a 748-bed tertiary care, academic medical center in Syracuse, NY. Patients 18 years of age and older were included if they had blood cultures positive for MSSA ≥72 hours21-23 and received D/O combination for ≥48 hours for MSSAB. Selection of and when to add daptomycin to oxacillin was based on the clinical judgment of the infectious disease (ID) physician and pharmacist during consultation. All patients who were started on D/O had persistent MSSA bacteremia. Patients were excluded if they were pregnant, incarcerated, or received another antibiotic considered to have excellent activity against MSSA (i.e., cefazolin, linezolid, and/or ceftaroline) to minimize potential confounding effects of these therapies on D/O for persistent MSSAB. All data collection was performed by a single investigator specifically trained in data collection using the electronic medical record. Study data were collected and managed using a Research Electronic Data Capture platform. Institutional review board exemption was obtained from the State University of New York Upstate Medical University.
Study Outcomes
The primary outcome was time to MSSAB clearance post-D/O initiation. Secondary outcomes included microbiological cure, hospital length of stay (LOS), 90-day all-cause mortality, MSSAB-related mortality, 90-day readmission for MSSAB, and incidence of antibiotic-associated adverse effects.
Definitions
Bacteremia duration was calculated as the number of days between the first positive and first negative blood cultures. Persistent bacteremia was defined as blood cultures positive for ≥72 hours.21-23 Bacteremia source was determined based on ID consultation notes. Source control was defined as catheter removal, drainage and/or debridement, valve replacement, or chest tube depending on the applicable source. Acute kidney injury was defined as an increase in serum creatinine of ≥0.5 mg/dL or a 50% increase from baseline in consecutive daily readings. 24 Neutropenia was defined as an absolute neutrophil count of <1500 cells/mm3. Alanine aminotransferase and creatinine phosphokinase elevation were defined as ≥3 times the upper limit of the reference range. 20 Myalgias and hypersensitivity/rash were determined by a provider’s documentation. Microbiological cure was defined as a negative blood culture without skip phenomenon, which was defined as a positive blood following a previously negative blood culture. 25 Ninety-day all-cause mortality was measured from the date of the first positive blood culture. MSSAB-related mortality was defined as death prior to blood culture clearance or within 2 weeks following blood culture clearance using the date of first positive blood cultures as day 1. 23 Hospital LOS was calculated from the date of the first positive blood culture to the date of discharge and/or death.
Statistical Analysis
All data analyses were performed using R (R Foundation for Statistical Computing, Vienna, Austria). Continuous data were presented using median and IQR. Categorical data were presented using number and percentage (%). Time to MSSAB clearance post-D/O initiation was plotted using Kaplan-Meier estimation.
Results
Between January 1, 2015, and January 1, 2023, 7 unique patients received D/O for persistent MSSAB. Table 1 displays patient demographics, treatment characteristics, and clinical outcomes. Most patients were male with a median age of 66 years. Diabetes mellitus and immunocompromised state were the most common comorbidities. Patients were medically complex with a median Pitt bacteremia score of 7.5, and most (71.4%) were admitted to the ICU.
Demographics, Treatment Characteristics, and Clinical Outcomes (n = 7).
Abbreviations: ID, infectious diseases; IQR, interquartile range; MIC, minimum inhibitory concentration; MSSAB, methicillin-susceptible Staphylococcus aureus bacteremia.
Serum creatinine was recorded within 24 hours of the first positive blood culture for methicillin-susceptible Staphylococcus aureus.
Three patients were on continuous venovenous hemofiltration.
Percentages based on the number of patients with infective endocarditis.
Two patients achieved blood culture clearance with daptomycin plus oxacillin prior to a source control procedure.
Limited to only 1 patient.
The median total MSSAB duration was 7.8 days, and multiple patients (57.1%) had IE. Sources varied, but bone/joint was the most common. Nearly all (85.7%) had a source control procedure performed including 2 patients with valve replacement surgeries for IE. One patient (14.3%) did not have any source control procedures performed; however, this patient had IE and was not deemed a candidate for valve replacement based on cardiac surgery’s evaluation. The median time to blood culture clearance following source control was still 4.9 days. Two patients (28.5%) achieved blood culture clearance with D/O prior to source control achievement. Empiric antibiotic therapy prior to oxacillin (and subsequently the addition of daptomycin) consisted primarily of vancomycin (57.1%) and/or piperacillin-tazobactam (57.1%). Optimized daptomycin dosing strategies varied with 57.1% and 42.9% of patients administered 8 and 10 mg/kg, respectively, and all patients were dosed based on total body weight regardless of body mass index or total weight. The median time to oxacillin and daptomycin following the first positive blood culture for MSSA was 1.8 and 6.0 days, respectively. Median daptomycin and oxacillin duration from MSSAB clearance was 7.9 and 41.3 days, respectively. No patients experienced daptomycin- and/or oxacillin-associated adverse effects.
For the primary outcome, the median time to MSSAB clearance post-D/O initiation was 2 days with specific times to clearance plotted in Figure 1. All patients demonstrated microbiological cure without skip phenomenon. Median hospital LOS was 23 days. Ninety-day all-cause mortality, MSSAB-related mortality, and 90-day readmission for MSSAB occurred in 28.6% (transitioned to comfort care measures), 14.3%, and 14.3% of patients, respectively. The 1 patient with 90-day readmission for MSSAB was in the setting of ongoing injection drug use.
Kaplan-Meier curve for the time to methicillin-susceptible Staphylococcus aureus bacteremia clearance post-daptomycin/oxacillin initiation.
Discussion
To the best of our knowledge, this is the first detailed report describing D/O specifically for persistent MSSAB. This regimen was evaluated in a medically complex cohort with most patients requiring ICU admission, having elevated Pitt bacteremia scores, and evidence of IE. Despite a median initiation of oxacillin after 1.8 days of bacteremia, the median MSSAB duration was still prolonged at 7.8 days, further representing the complexity of these patients. However, the median time to clearance post-D/O initiation was 2 days. Nearly all patients (85.7%) received at least 1 source control procedure. This combination was also well-tolerated overall. The 90-day all-cause mortality was 28.6%; however, MSSAB-related mortality was lower at 14.3% with all patients achieving microbiologic cure prior to death.
Previous case reports/series have primarily used various ertapenem-based regimens for persistent MSSAB.6-9,12,13 Ulloa and colleagues described 11 patients who received cefazolin plus ertapenem. 6 Of these 11 patients, 36.3% were admitted to ICU, Pitt bacteremia scores were not reported, and 54.5% had endocarditis representing a potentially less critically ill population than ours. Median MSSAB duration was 6 days, and time to MSSAB clearance post-cefazolin/ertapenem was ≤24 hours in 8 of 11 patients; however, this was rounded to the nearest day including 0 days after combination initiation, so a true median time to bacteremia clearance post-cefazolin/ertapenem cannot be calculated in a similar manner as described in our report. The number of patients who received source control was not fully described. All patients demonstrated microbiological cure and survived to hospital discharge, but no safety assessments or other outcomes were evaluated. El-Dalati and colleagues described 10 patients with persistent MSSAB; however, only 7 received oxacillin plus ertapenem. 7 Cefazolin/ertapenem, nafcillin/ertapenem, and oxacillin/meropenem were used in the other 3 cases. Of these 10 patients, 70% were admitted to ICU, the median Pitt bacteremia score was 0.5, and 70% had endocarditis representing a potentially similar critically ill population to ours. The median MSSAB duration was 5 days, which is shorter than we reported; however, the median time to MSSAB clearance post-cefazolin/ertapenem initiation was 1 day, which is slightly earlier than reported in our cohort. Source control was performed in 70% of patients, which is slightly less than in our cohort. With regard to adverse effects, 1 patient experienced elevated liver function tests that were attributed to oxacillin. All patients demonstrated microbiological cure, survived to hospital discharge, and 90 days post-discharge. However, 20% of patients demonstrated MSSAB recurrence within 90 days post-discharge.
However, carbapenem-sparing options may be advantageous to support antibiotic stewardship efforts and potentially decrease CDI. To the best of our knowledge, only 1 report described a carbapenem-sparing option with ceftaroline plus nafcillin for persistent MSSAB and IE (n = 2) with an approximate median time to MSSAB clearance post-combination of 3 days, which was longer than compared with our study. 10 Both patients had source control performed, demonstrated microbiological cure, and survived to hospital discharge.
As mentioned previously, daptomycin plus a beta-lactam (i.e., cefazolin or cloxacillin) previously failed to demonstrate a reduction in bacteremia duration or mortality compared with beta-lactam monotherapy among patients with MSSAB (n = 104). 20 However, this study also included many patients without persistent MSSAB. Furthermore, considerably fewer patients received daptomycin plus cloxacillin (22.6%) compared with daptomycin plus cefazolin (77.4%). Daptomycin 6 mg/kg was used as the standard dosing regimen, which is also not considered an optimized dosing regimen for bacteremia. 26 In our cohort, all patients received an optimized dosing regimen with 8 or 10 mg/kg and were dosed based on total body weight regardless of body mass index or weight. Finally, our cohort appears to have included more medically complex patients with a larger percentage having IE (57.1% versus 22.6%) and a higher median Pitt bacteremia score (7.5 versus 0). Grillo and colleagues performed a retrospective cohort study to evaluate beta-lactam monotherapy (n = 214) compared with beta-lactam plus daptomycin 10 mg/kg combination therapy (n = 136) for MSSAB. 21 While no significant differences in all-cause mortality were identified, most patients included did not have persistent MSSAB (84%), and further analyses evaluating daptomycin plus beta-lactam combination therapy were not performed making it challenging to extrapolate these findings specifically in the treatment of persistent MSSAB. Therefore, D/O still warrants further evaluation for persistent MSSAB, which is supported by our findings.
Our experience may provide clinicians with a carbapenem-sparing option for persistent MSSAB, which may align with antibiotic stewardship efforts and potentially minimize antibiotic-associated CDI risk.14-16 However, this study is not without limitations. First, this was retrospective in design and performed at a single center with a small sample size. Second, we did not include a comparator group to compare D/O to another salvage regimen. However, our study is consistent with the design and structure of previous studies that evaluated salvage regimens for persistent MSSAB.6,7
Conclusions and Relevance
Prompt blood culture clearance occurred in 2 days following D/O in a critically ill and medically complex patient cohort, yet all achieved microbiological cure and no antibiotic-associated adverse effects were reported. D/O may represent an effective and well-tolerated carbapenem-sparing salvage regimen for persistent MSSAB. Additional research is necessary to further evaluate and identify the preferred salvage regimen for persistent MSSAB.
Footnotes
Declaration of Conflicting Interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Wesley D. Kufel has received research grants from Merck and Melinta and has served on the advisory board for Theratechnologies, Inc. Jeffrey M. Steele has served on the advisory board for Paratek Pharmaceuticals. All other authors have nothing to disclose.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
