Persistent Methicillin-resistant Staphylococcus Aureus Bacteremia Research Articles

Short versus long duration of ceftaroline combination therapy and outcomes in persistent or high-grade MRSA bacteremia: A retrospective single-center study.

Methicillin-resistant Staphylococcus aureus (MRSA) is associated with high mortality rates. Despite antibiotic therapy, persistent bacteremia is challenging to treat. Combination therapy with ceftaroline has emerged as a potential treatment option; however, the optimal duration and clinical implications after bacteremia clearance are unknown. This retrospective cohort study examined patients with high-grade or persistent MRSA bacteremia who were treated with ceftaroline combination therapy at the University of New Mexico Hospital between January 2014 and June 2021. Patients were categorized into short- (<7 days) or long-duration (≥7 days) groups based on the duration of combination therapy after bacteremia clearance. Outcomes included 30-day all-cause mortality, bacteremia recurrence, post-bacteremia clearance length of stay, and adverse events. A total of 32 patients were included in this study. The most common sources of bacteremia were bone/joint and endovascular (28.1%, 9/32 each). The median duration of combination therapy after clearance was seven days (IQR 2.8, 11). Patients in the long-duration group had a lower Charlson comorbidity index (1.0 vs 5.5, p = 0.017) than those in the short-duration group. After adjusting for confounders, there was no significant difference in the 30-day all-cause mortality between the groups (AOR 0.17, 95% CI 0.007-1.85, p = 0.18). No association was found between combination therapy duration and recurrence (OR 2.53, 95% CI 0.19-inf, p = 0.24) or adverse drug events (OR 3.46, 95% CI 0.39-74.86, p = 0.31). After controlling for total hospital length of stay, there was no significant difference in the post-bacteremia clearance length of stay between the two groups (p = 0.37). Prolonging ceftaroline combination therapy after bacteremia clearance did not significantly improve outcomes in patients with persistent or high-grade MRSA bacteremia. The limitations of this study warrant cautious interpretation of its results. Larger studies are needed to determine the optimal duration and role of combination therapy for this difficult-to-treat infection.

Tensor modeling of MRSA bacteremia cytokine and transcriptional patterns reveals coordinated, outcome-associated immunological programs

Abstract Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is a common and life-threatening infection that imposes up to 30% mortality even when appropriate therapy is used. Despite in vitro efficacy determined by minimum inhibitory concentration (MIC) breakpoints, antibiotics often fail to resolve these infections in vivo, resulting in persistent MRSA bacteremia. Recently, several genetic, epigenetic, and proteomic correlates of persistent outcomes have been identified. However, the extent to which single variables or their composite patterns operate as independent predictors of outcome or reflect shared underlying mechanisms of persistence is unknown. To explore this question, we employed a tensor-based integration of host transcriptional and cytokine datasets across a well-characterized cohort of patients with persistent or resolving MRSA bacteremia outcomes. This method yielded high correlative accuracy with outcomes and immunologic signatures united by transcriptomic and cytokine datasets. Results reveal that patients with persistent MRSA bacteremia exhibit signals of granulocyte dysfunction, suppressed antigen presentation, and deviated lymphocyte polarization. In contrast, patients with resolving bacteremia heterogeneously exhibit correlates of robust antigen-presenting cell trafficking and enhanced neutrophil maturation corresponding to appropriate T lymphocyte polarization and B lymphocyte response. These results suggest that transcriptional and cytokine correlates of persistent versus resolving bacteremia outcomes are complex and may not be disclosed by conventional modeling. In this respect, a tensor-based integration approach may help to reveal consensus molecular and cellular mechanisms and their biological interpretation.

Daptomycin and Ceftaroline Combination Therapy in Complicated Endovascular Infections Caused by Methicillin-Resistant Staphylococcus epidermidis.

Background In complicated endovascular infections by methicillin-resistant Staphylococcus aureus (MRSA) or Staphylococcus epidermidis (MRSE), when first-line therapy with vancomycin (VAN) or daptomycin (DAP) fails, combination therapy with ceftaroline (CFT) and DAP has been shown to be a useful approach as salvage therapy for persistent MRSA bacteremia. Objectives This study aimed to describe experience with daptomycin and ceftaroline combination therapy in MRSE-complicated endovascular infections. Methods A single-center retrospective review of consecutive patients with MRSE-complicated endovascular infections treated with ≥72 hours of DAP+CFT at any time during the course of treatment, from January 1, 2016 to December 31, 2020, at Centro Hospitalar Universitário São João (CHUSJ), Porto, Portugal, was conducted. The exclusion criteria were known resistance to daptomycin or ceftaroline, total time of combination therapy <72 hours and loss to follow-up. Results We identified seven cases that matched our criteria: five endocarditis and two central venous catheter infections. Six patients switched to combination therapy due to treatment failure with first-line agents - three due to persistent bacteremiaand three due to progression of infection despite negative blood cultures. Effective surgical source control took one to four weeks to occur. Three patients died during the treatment, one from progression of the disease and two due to another infection. Conclusions We consider the DAP+CFT combination therapy to be a valid and safe therapeutic choice in complicated patients, such as those with severe infection, poor functional status, and impossibility or delay of surgical source control. However, conclusions on the role of combination therapy should be careful due to the low number of patients and the several confounding factors.

A Retrospective Cohort Study Comparing Dual Therapy With Ceftaroline With Vancomycin or Daptomycin Monotherapy for High-Grade or Persistent MRSA Bacteremia.

Background: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is a serious clinical infection associated with a high risk of mortality. Dual therapy is often used in patients with persistent bacteremia. Objective: This study aimed to compare the outcomes of vancomycin or daptomycin monotherapy with those of dual therapy with ceftaroline in high-grade or persistent MRSA bacteremia. Methods: We conducted a retrospective cohort study at a university teaching hospital between January 2014 and June 2021, involving adults initially treated with vancomycin or daptomycin. Patients were categorized into monotherapy and dual therapy groups. The primary outcome was 30-day mortality. Secondary outcomes included microbiological relapse and antibiotic-related adverse events. Results: In a group of 155 patients, 30-day mortality rates were similar between the monotherapy (23.4%) and dual therapy (22.6%) groups, with comparable microbiological relapse rates (6.5%). In inverse probability of treatment weighting analysis, we found no significant association between dual therapy and mortality (adjusted risk ratio [ARR] 1.38, 95% CI 0.64-2.41, P = 0.38) or microbiological relapse (ARR 0.95, 95% CI 0.31-2.73, P = 0.93). Dual therapy was associated with a lower risk of antibiotic-related adverse events (ARR 0.45, 95% CI 0.21-0.89, P = 0.02). Infectious diseases (ID) consultation was associated with a reduced mortality risk (ARR 0.27, 95% CI 0.07-0.95, P = 0.04). Conclusions: Dual therapy with ceftaroline did not reduce mortality risk compared with monotherapy in patients with MRSA bacteremia. However, patients with ID consultations showed a 73% reduction in mortality rates. Large-scale, prospective, and randomized controlled trials are needed to provide conclusive evidence regarding the potential benefits of dual therapy with ceftaroline for MRSA bacteremia.

174. Impact of Ceftaroline Duration after Bacteremia Clearance When Used in Combination Therapy for Persistent or High-grade MRSA Bacteremia

Abstract Background Methicillin resistant Staphylococcus aureus (MRSA) bacteremia is a clinically relevant syndrome with high mortality. Combination therapy with beta-lactam antibiotics has been employed in persistent MRSA bacteremia with reported clinical success. Ceftaroline is a beta-lactam antibiotic with activity against MRSA, which has been commonly used in combination therapy for this indication. However, adequate ceftaroline duration after bacteremia clearance continues to be elucidated. Thus, we aimed to evaluate clinical outcomes of patients receiving short vs. long duration of ceftaroline after persistent or high-grade bacteremia clearance. Methods This was a single-center, retrospective cohort study conducted from January 1, 2014, to June 30, 2021. Patients were included if ≥18 years of age, with high grade or persistent MRSA bacteremia, who received combination therapy with ceftaroline. The primary outcome was 30-day mortality. Secondary outcomes included hospital length of stay, time to bacteremia clearance, antibiotic-related adverse events and microbiological relapse. Results A total of 32 patients were included (mean age: 51.5 years; 71.9% white; 61.3% male). 96.9% had high-grade MRSA bacteremia and 68.8% had persistent bacteremia. The most common bacteremia source was bone and joint infections (28.1%). 56.3% of patients received ceftaroline in combination with vancomycin; mean duration was 8 days. Multivariable analysis showed increasing the duration of combination therapy after bacteremia clearance was not associated with a lower risk of 30-day mortality after controlling for Charlson comorbidity index and Pitt bacteremia scores (OR 0.75, 95% CI 0.94-2.45; p=0.07). Similarly, no association was observed with microbiological relapse (OR 1.03, 95% CI 0.92-1.16; p=0.73), antibiotic-related adverse event (OR 0.97, 95% CI 0.78-1.10; p=0.75), time to bacteremia clearance (p=0.88) or hospital length of stay (p=0.06). Conclusion Longer durations of ceftaroline in combination therapy after bacteremia clearance was not associated with lower rates of 30-day mortality, microbiological relapse, or higher rates of antibiotic-related adverse events. Larger studies are needed to determine the appropriate duration of combination therapy. Disclosures Cecilia Thompson, PhD, D(ABMM), MLS (ASCP), Roche Diagnostics: Honoraria

In Vivo-Acquired Resistance to Daptomycin during Methicillin-Resistant Staphylococcus aureus Bacteremia.

Daptomycin (DAP) represents an interesting alternative to treat methicillin-resistant Staphylococcus aureus (MRSA) infections. Different mechanisms of DAP resistance have been described; however, in vivo-acquired resistance is uncharacterized. This study described the phenotypic and genotypic evolution of MRSA strains that became resistant to DAP in two unrelated patients with bacteremia under DAP treatment, in two hospitals in the South of France. DAP MICs were determined using broth microdilution method on the pairs of isogenic (DAP-S/DAP-R) S. aureus isolated from bloodstream cultures. Whole genome sequencing was carried out using Illumina MiSeq Sequencing system. The two cases revealed DAP-R acquisition by MRSA strains within three weeks in patients treated by DAP. The isolates belonged to the widespread ST5 (patient A) and ST8 (patient B) lineages and were of spa-type t777 and t622, respectively. SNP analysis comparing each DAP-S/DAP-R pair confirmed that the isolates were isogenic. The causative mutations were identified in MprF (Multiple peptide resistance Factor) protein: L826F (Patient A) and S295L (Patient B), and in Cls protein: R228H (Patient B). These proteins encoded both proteins of the lipid biosynthetic enzymes. The resistance to DAP is particularly poorly described whereas DAP is highly prescribed to treat MRSA. Our study highlights the non-systematic cross-resistance between DAP and glycopeptides and the importance of monitoring DAP MIC in persistent MRSA bacteremia.

Clinical Outcomes of Ceftaroline Fosamil in the Treatment of Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia

Abstract Background Limited evidence exists in the management of persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia with ceftaroline as salvage therapy. This retrospective study aims to evaluate the use of ceftaroline as salvage therapy in the treatment of persistent MRSA bacteremia (MRSAB). Methods Electronic medical charts of patients who received ceftaroline for the treatment of persistent MRSAB at an academic, quaternary care medical center from January 1, 2015, to December 31, 2021, were reviewed for clinical cure, reinfection, prior antibiotic use, source of infection, microbiological culture clearance, patient mortality, and adverse effects. Primary endpoints included clinical and microbiological success, and secondary endpoints were recurrence of infection and 60-day all-cause mortality. Results Nineteen patient charts were identified, and 9 patients met the inclusion criteria for this analysis. Vancomycin or daptomycin was given for a median of 7 ± 2.3 days, respectively, before the initiation of ceftaroline. The total daily dose of ceftaroline ranged from 400 to 1800 mg depending on the patients' kidney function. Five patients achieved clinical cure and 4 patients died. No patients experienced a recurrence. Three patients (33%) experienced adverse effects while on ceftaroline therapy. Conclusions The use of ceftaroline in persistent MRSAB demonstrated microbiological cure, clinical cure, and minimal reinfection in the reviewed patient population. Ceftaroline may be a potential treatment option for patients with persistent MRSAB as salvage therapy.

Effectiveness and Safety of Linezolid Versus Vancomycin, Teicoplanin, or Daptomycin against Methicillin-Resistant Staphylococcus aureus Bacteremia: A Systematic Review and Meta-Analysis.

Vancomycin (VCM) and daptomycin (DAP) are standard therapies for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia, despite concerns regarding clinical utility and growing resistance. Linezolid (LZD) affords superior tissue penetration to VCM or DAP and has been successfully used as salvage therapy for persistent MRSA bacteremia, indicating its utility as a first-choice drug against MRSA bacteremia. In a systematic review and meta-analysis, we compared the effectiveness and safety of LZD with VCM, teicoplanin (TEIC), or DAP in patients with MRSA bacteremia. We evaluated all-cause mortality as the primary effectiveness outcome, clinical and microbiological cure, hospital length of stay, recurrence, and 90-day readmission rates as secondary effectiveness outcomes, and drug-related adverse effects as primary safety outcomes. We identified 5328 patients across 2 randomized controlled trials (RCTs), 1 pooled analysis of 5 RCTs, 1 subgroup analysis (1 RCT), and 5 case-control and cohort studies (CSs). Primary and secondary effectiveness outcomes were comparable between patients treated with LZD versus VCM, TEIC, or DAP in RCT-based studies and CSs. There was no difference in adverse event incidence between LZD and comparators. These findings suggest that LZD could be a potential first-line drug against MRSA bacteremia as well as VCM or DAP.

Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia: Host, Pathogen, and Treatment.

Methicillin-resistant Staphylococcus aureus (MRSA) is a devastating pathogen responsible for a variety of life-threatening infections. A distinctive characteristic of this pathogen is its ability to persist in the bloodstream for several days despite seemingly appropriate antibiotics. Persistent MRSA bacteremia is common and is associated with poor clinical outcomes. The etiology of persistent MRSA bacteremia is a result of the complex interplay between the host, the pathogen, and the antibiotic used to treat the infection. In this review, we explore the factors related to each component of the host-pathogen interaction and discuss the clinical relevance of each element. Next, we discuss the treatment options and diagnostic approaches for the management of persistent MRSA bacteremia.

1834. Evaluation of De-Escalation Options after Combination Daptomycin and Ceftaroline Therapy for Persistent MRSA Bacteremia

Abstract Background Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia carries high mortality with limited treatment options. Studies over the last decade support glycolipopeptide and beta-lactam combination therapy with daptomycin (DAP) and ceftaroline (CFT) combination gaining prominence. While data supports de-escalation to monotherapy after bacteremia clearance it does not guide the choice of agent. With barriers including accessibility, cost, and tolerability of these agents, data is needed to optimize treatment. This study aims to evaluate de-escalation options after combination DAP/CFT therapy for persistent MRSA bacteremia. Methods A single-center, retrospective review of cases of persistent MRSA bacteremia (defined as greater than 72 hours on appropriate therapy) requiring escalation to DAP/CFT between 2014 and 2021 was performed. Details of bacteremia, source of infection, and comorbidities were assessed, and outcomes including recurrence of infection, infection-associated mortality, and tolerability were compared using exact Chi-square testing and univariant analysis. Results Sixty-six cases were identified of which 7 were de-escalated to vancomycin (VAN), 48 to DAP, 4 to CFT, and 7 continued DAP/CFT combination. Demographics and details of bacteremia such as prior anti-MRSA therapy, duration prior to DAP/CFT therapy, and source identification were similar between groups. Differences included higher rates of hemodialysis patients in the VAN group, higher rates of immunocompromised hosts in the DAP group, higher average Pitt bacteremia score in the DAP/CFT group, and lower rates of source control in the VAN group. Recurrence of infection (29% VAN, 13% DAP, 25% CFT) and infection-related mortality (14% VAN, 8% DAP) were higher in the VAN group (p=0.0452). In the DAP group 23% required change in therapy during their course. Univariant analysis assessing for confounding from comorbidities and source control yielded no significant associations. Conclusion This study is limited by small, uneven sample sizes but the results identify a trend of increased recurrence rates and mortality with de-escalation to VAN but tolerability concerns with DAP. More study is needed to guide clinical care and this data provides framework for future research. Disclosures All Authors: No reported disclosures.

Vancomycin plus ceftaroline for persistent methicillin-resistant Staphylococcus aureus bacteremia.

The preferred antibiotic salvage regimen for persistent methicillin-resistant Staphylococcus aureus bacteremia (MRSAB) is unclear. We sought to evaluate the effectiveness and safety of vancomycin plus ceftaroline for persistent MRSAB. The primary outcome was time to MRSAB clearance post-ceftaroline initiation. Secondary outcomes included microbiological cure, hospital length of stay, 90-day readmission for MRSAB, 90-day all-cause mortality, MRSAB-related mortality, and incidence of antibiotic-associated adverse effects. Single-center, retrospective cohort study between January 1, 2016, and December 31, 2021. State University of New York Upstate University Hospital, a 748-bed tertiary care, academic medical center in Syracuse, NY. Adult patients were included if they had blood cultures positive for MRSA ≥72 h, received vancomycin monotherapy initially, and received vancomycin plus ceftaroline for ≥24 h. Patients were excluded if they received other anti-MRSA antibiotics, were pregnant, or were incarcerated. Of the 178 patients identified, 30 unique patients were evaluated. Patients were medically complex with a median Pitt bacteremia score of 3, 63.3% (19/30) were admitted to the intensive care unit, and 66.7% (20/30) had infective endocarditis. Vancomycin-associated acute kidney injury was observed in 10% (3/30) of patients, which resulted in dose adjustments. No patients experienced ceftaroline-associated neutropenia or Clostridioides difficile infection, but 6.7% (2/30) developed a rash attributed to ceftaroline. Median time to MRSAB clearance post-ceftaroline initiation was 2.6 days. Microbiologic cure occurred in nearly all patients 96.7% (29/30). Median hospital length of stay was 19.5 days, and 6.7% (2/30) of patients had 90-day readmission for MRSAB. 90-day all-cause mortality and MRSAB-related mortality occurred in 26.7% (8/30) and 13.3% (4/30) of patients, respectively. Vancomycin plus ceftaroline may represent an effective and well-tolerated salvage regimen option for persistent MRSAB.

Transcriptome Analyses of Prophage in Mediating Persistent Methicillin-Resistant Staphylococcus aureus Endovascular Infection.

Persistent methicillin-resistant Staphylococcus aureus (MRSA) endovascular infections represent a significant subset of S. aureus infections and correlate with exceptionally high mortality. We have recently demonstrated that the lysogenization of prophage ϕSA169 from a clinical persistent MRSA bacteremia isolate (300-169) into a clinical resolving bacteremia MRSA isolate (301-188) resulted in the acquisition of well-defined in vitro and in vivo phenotypic and genotypic profiles related to persistent outcome. However, the underlying mechanism(s) of this impact is unknown. In the current study, we explored the genetic mechanism that may contribute to the ϕSA169-correlated persistence using RNA sequencing. Transcriptomic analyses revealed that the most significant impacts of ϕSA169 were: (i) the enhancement of fatty acid biosynthesis and purine and pyrimidine metabolic pathways; (ii) the repression of galactose metabolism and phosphotransferase system (PTS); and (iii) the down-regulation of the mutual prophage genes in both 300-169 and 301-188 strains. In addition, the influence of different genetic backgrounds between 300-169 and 301-188 might also be involved in the persistent outcome. These findings may provide targets for future studies on the persistence of MRSA.

Persistent Methicilin-Resistant Staphylococcus aureus Bacteremia: Resetting the Clock for Optimal Management.

A positive follow-up blood culture for methicillin-resistant Staphylococcus aureus (MRSA) while on seemingly appropriate therapy is a common and ominous development. However, the definition and management of persistent MRSA bacteremia is unstandardized. In this Opinion Paper, we identify the presence of bacteremia for > 1 calendar day as a "worry point" that should trigger an intensive diagnostic evaluation to identify metastatic infection sites. Next, we define the duration of MRSA bacteremia that likely constitutes antibiotic failure and outline a potential management algorithm for such patients. Finally, we propose pragmatic clinical trial designs to test treatment strategies for persistent MRSA bacteremia.

128. Mutations that Inactivate the Tricarboxylic Acid Cycle in Staphylococcus aureus Arise During Persistent MRSA Bacteremia

Abstract Background Persistent MRSA bacteremia is common with high morbidity and mortality despite appropriate antibiotics. Persistent infections are associated with antibiotic tolerance and can arise from perturbations in cellular pathways. We performed whole genome sequencing of clinical isolates to identify the genetic bases of antibiotic tolerance. Methods Whole genomes of MRSA from patients with persistent bacteremia were sequenced, which identified 8 isolates harboring different citZ mutations. To assess the effect of the mutations directly on citrate synthase activity, purified recombinant enzymes were assayed using a commercially available kit. The same kit was used to measure activity in whole cell lysates of MRSA isolates harboring wild-type and mutant citZ alleles. Enzyme kinetic parameters were determined by fitting initial rate data to the Michaelis-Menten equation using nonlinear regression. Figure 1. Whole Genome Sequencing of Persistent MRSA Bacteremia Whole genome sequencing of 206 blood cultures from 20 patients with persistent MRSA bacteremia (defined as &amp;gt;7 days) under the hypothesis that continuous antibiotic exposure will give rise to - and enrich for - mutations that convey antibiotic tolerance through in-host evolution. Results Analysis of whole genomes from 206 blood cultures from 20 patients with persistent MRSA bacteremia identified citZ, which encodes for citrate synthase, the first step of the tricarboxylic acid cycle, as the most repeatedly mutated gene. The data revealed parallelism in its evolution, as citZ was mutated 8 independent times, a rate far greater than from chance alone. To characterize the impact of the mutations on enzyme activity, recombinant proteins were expressed in E. coli and purified for enzymatic assays. As compared to wildtype enzyme, two mutants had reduced activity, and four mutants had near-absent activity; two mutants were unable to be expressed due to destabilizing mutations. Michaelis-Menten analysis of the two mutants with residual activity show that, as compared to wildtype, both had lower affinity for its substrates, and lower maximum activity. Furthermore, we found the cell was unable to compensate for the loss of citrate synthase activity, as lysates harboring these mutations also displayed analogous reductions in activity. Figure 2. Purified citrate synthase mutant proteins have reduced enzyme activity Citrate synthase catalyzes the reaction between acetyl-CoA and oxaloacetic acid to form citric acid with CoA-SH as a byproduct. CoA-SH can interact with DTNB to form TNB, which can be measured spectrophotometrically at A412nm to indirectly measure the activity of citrate synthase. Wildtype citrate synthase and the D141N mutant have comparable activity whereas the remaining study mutants have either reduced (mutants A313P and A313V) or near-absent (mutants G7D, G7D + D141N, S201P, P354S) activity. The three active site mutants (H248G, D309G, H219G) also have near-absent activity and serve as negative controls. Positive control is citrate synthase provided in the Sigma Citrate Synthase Assay Kit. No enzyme control replaces enzyme with assay buffer. All error bars are ± 1 SD, calculated from at least three replicate experiments. Figure 3. A313P and A313V mutants have decreased substrate affinity and decreased maximal activity Panels A and B show plots of the initial rate of citrate synthase activity (Y-axis, in units of µmole/mL/sec) versus OAA/AcCoA substrate concentration (X-axis, in millimolar units), for wildtype citrate synthase and the A313P and A313V mutants. Panel (A) shows enzymatic parameters for wildtype, A313P mutant, and A313V mutant with variable OAA (0-0.625 mM) and fixed AcCoA (0.3 mM). Panel (B) shows enzymatic parameters for wildtype, A313P mutant, and A313V mutant with fixed OAA (0.5 mM) and variable AcCoA (0-2.5 mM). Three replicates were performed for each condition, with error bars showing ± 1 SD. Figure 4. Citrate synthase mutants disrupt functional dimerization and destabilize alpha-helix packing Identified citrate synthase mutants mapped onto the crystal structure of T. thermophilus citrate synthase (PDB 1IOM) show that the mutations are located either at dimerization interfaces or within the interior of hydrophobic packing interfaces. Conclusion Cellular metabolism and virulence regulation are interconnected in S. aureus, as alterations in TCA cycle activity lead to increased persister formation and host macrophage inactivation. Our findings that inactivating citZ mutations are enriched can provide a potential explanation for the mechanism of persistent bacteremia. Disclosures All Authors: No reported disclosures

190. Outcomes of Early Ceftaroline-based Combination Therapy for Methicillin-resistant Staphylococcus aureus Bacteremia

BackgroundMonotherapy with vancomycin (VAN) or daptomycin (DAP) remains the guideline-driven standard of care for methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B) despite concerns regarding efficacy. While combination therapy is often utilized as salvage treatment for persistent MRSA-B, growing data suggest a potential benefit of combination therapy with ceftaroline as initial therapy for MRSA-B. In light of these data, we updated practice guidance at our institution for management of MRSA-B in March 2020 to favor initial combination therapy with ceftaroline. Herein, we present an assessment of outcomes of patients with MRSA-B initiated on early combination therapy.MethodsThis was a single-center, retrospective, cohort study of adult patients admitted to the University of Virginia with MRSA-B between July 1, 2018 and February 28, 2021. Patients were considered to have received combination therapy if they received VAN or DAP plus ceftaroline (CPT) within 5 days of index blood culture, and monotherapy if during that period they received VAN and/or DAP alone. The primary outcome was a composite of persistent bacteremia, 30-day all-cause mortality, and 30-day bacteremia recurrence. Time to microbiological cure and safety outcomes were also assessed. A propensity score-weighted logistic regression was conducted. A post-hoc analysis of the primary composite outcome was performed in which patients were only deemed to have received combination therapy if it was started within 72 hours.ResultsOf 94 patients included, 57 received monotherapy (55 VAN, 2 DAP) and 37 received combination therapy with CPT (30 VAN, 7 DAP). There was no difference between groups for the primary composite outcome in the primary analysis (OR 2.7, 95% CI 0.95-7.72) or the post-hoc analysis (OR 2.37, 95% CI 0.68-8.22). Time to microbiological cure was not different between groups (mean difference 1.47, 95% CI 0.20-2.74). Safety outcomes were similar.ConclusionIn this retrospective study, there was no clear benefit or harm of early initiation of combination therapy for MRSA-B. Additional study of initial combination therapy with ceftaroline is warranted given the small number of subjects in the study presented.Disclosures All Authors: No reported disclosures

204. Clinical Outcomes with Ceftaroline Monotherapy versus Daptomycin-Ceftaroline Combination Therapy in the Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia

BackgroundMethicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with poor outcomes and increased mortality. Daptomycin (DAP) and ceftaroline (CPT) in combination has been explored as a potential treatment option and showed improved outcomes compared to vancomycin/standard therapy. CPT monotherapy has been evaluated as salvage therapy for MRSA bacteremia but, to our knowledge, not as a comparator to DAP-CPT combination therapy. The purpose of this study is to compare the clinical outcomes of DAP and CPT combination therapy to CPT monotherapy in the setting of MRSA bacteremia. MethodsA retrospective chart review of adult patients (≥ 18 years of age) admitted to University Health from January 2017 to December 2020 with a diagnosis of MRSA bacteremia was performed. Patients received either CPT monotherapy or DAP-CPT combination therapy for a minimum of 48 hours during their course of therapy. ResultsThirty-two patients met inclusion criteria and were evaluated. Primary source of infection was pulmonary in the CPT monotherapy group (n=7/24; 29.2%) and osteomyelitis in the DAP-CPT combination group (n= 4/8; 50.0%). Median duration of bacteremia was 8 days and 9 days in the CPT monotherapy and DAP-CPT combination group, respectively. Microbiological cure was achieved in 95.8% (n=23/24) of patients in the CPT monotherapy and 100% (n=8/8) of patients in the DAP-CPT combination group. Bacteremia relapse (30 day, p=0.62; 60 day, p=0.63), readmission rates (30 day, p=0.62; 60 day, p=0.63), and mortality rates (30 day, p=0.70; 90 day, p=0.85) were similar in both groups. There was no statistically significant difference in safety parameters, including incidence of acute kidney injury (p=1.00) and creatine kinase elevations (p=1.00). Bone marrow suppression after at least 72 hours of therapy, including anemia, leukopenia, and thrombocytopenia, was also not statistically significant between groups. ConclusionThis study was unable to find a statistically significant difference in clinical outcomes between patients receiving CPT monotherapy or DAP-CPT combination therapy. A large prospective, randomized controlled trial to assess CPT monotherapy and DAP-CPT combination therapy for the treatment of persistent MRSA bacteremia is warranted. Disclosures All Authors: No reported disclosures

Impact of initial vancomycin pharmacokinetic/pharmacodynamic parameters on the clinical and microbiological outcomes of methicillin-resistant Staphylococcus aureus bacteremia in children.

Optimal vancomycin exposure is important to minimize treatment failure of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. We aimed to analyze the impact of initial vancomycin pharmacokinetic/pharmacodynamic (PK/PD) parameters, including the initial vancomycin C trough and the area under the curve (AUC)/minimal inhibitory concentration (MIC) on the outcomes of pediatric MRSA bacteremia. The study population consisted of hospitalized children aged between 2 months and 18 years with MRSA bacteremia, in whom C trough was measured at least one time within the time period of January 2010 to March 2018. Demographic profiles, underlying diseases, and clinical/microbiological outcomes were abstracted retrospectively. During the study period, 73 cases of MRSA bacteremia occurred in children with a median age of 12.4 months. Severe clinical outcomes leading to intensive care unit stay and/or use of mechanical ventilation occurred in 47.5% (35/73); all-cause 30-day mortality was 9.7% (7/72). The median dosage of vancomycin was 40.0 mg/kg/day. There was a weak linear relationship between C trough and the corresponding AUC/MIC (r = 0.235). ROC curves for achieving an AUC/MIC of 300 suggested that the initial C trough at 10 μg/mL could be used as a cut-off value with a sensitivity of 90.5% and a specificity of 44%. Although persistent bacteremia at 48-72 hours after vancomycin administration was observed more frequently when the initial C trough was < 10 μg/mL and initial AUC/MIC was < 300, initial AUC/MIC < 300 was the only risk factor associated with persistent bacteremia at 48-72 hours (adjusted OR 3.05; 95% CI, 1.07-8.68). Initial C trough and AUC/MIC were not associated with 30-day mortality. Although there was a weak relationship between C trough and AUC/MIC, initial AUC/MIC < 300 could be used as a predictor of persistent MRSA bacteremia at 48-72 hours. Further prospective data on optimal vancomycin dosing are necessary to improve clinical and microbiological outcomes in pediatric MRSA bacteremia.

1624. Real World Experience with Daptomycin (DAP) and Ceftaroline (CPT) Combination Therapy for Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia

BackgroundMethicillin-resistant Staphylococcus aureus bacteremia is associated with significant mortality rates up to 30%. Guideline-recommended first-line therapy includes monotherapy with either vancomycin or DAP. Alternative regimens are recommended for persistent MRSA bacteremia of ≥ 7 days or earlier if evident clinical deterioration. The combination of DAP plus CPT has been investigated as salvage therapy due to its synergistic mechanism potential, but real-world data with the combination therapy is limited. The aim of this study was to evaluate the efficacy of DAP plus CPT combination therapy for the treatment of MRSA bacteremia and identify independent predictors of 30-day mortality.MethodsThis was a single center retrospective study of patients receiving DAP-CPT at any point in therapy for the treatment of MRSA bacteremia. Univariable and multivariable analyses were performed to identify independent predictors of 30-day mortality.ResultsSixty-five unique patients received DAP-CPT with a median time to combination therapy of 7 days. There were no significant independent predictors of 30-day mortality. The most common reason for combination therapy was persistent bacteremia (80%, 52/65). Bacteremia was cleared in 90.8% (59/65) of patients and the 30-day mortality rate was 15.4% (10/65). Median time to bacteremia clearance after combination switch was 3 days. Eleven patients received DAP-CPT within 72 hours of index culture. Median time to bacteremia clearance for patients switched to DAP-CPT within 72 hours versus after 72 hours did not differ (2 vs 3 days; P = 0.526), however the overall median duration of bacteremia was 4 and 11 days (P = 0.018). In a sub analysis, the median time of bacteremia clearance following combination therapy was significantly longer for patients receiving renal replacement therapy (5 vs 2 days; P = 0.04).ConclusionThere were no independent predictors of 30-day mortality identified. DAP-CPT combination therapy resulted in clearance of persistent bacteremia and may serve as an effective salvage therapy.Disclosures All Authors: No reported disclosures

Impact of the Novel Prophage ϕSA169 on Persistent Methicillin-Resistant Staphylococcus aureus Endovascular Infection.

Persistent methicillin-resistant Staphylococcus aureus (MRSA) endovascular infections are life-threatening syndromes with few therapeutic options. The potential impact of bacteriophages on the persistent outcome has not been well studied. In this study, we investigated the role of a novel prophage (ϕSA169) in MRSA persistence by using a lysogen-free clinically resolving bacteremia (RB) isolate and comparing it to a derivative which was obtained by infecting the RB strain with ϕSA169, which has been lysogenized in a clinical persistent MRSA bacteremia (PB) isolate. Similar to the PB isolate, the ϕSA169-lysogenized RB strain exhibited well-defined in vitro and in vivo phenotypic and genotypic signatures related to the persistent outcome, including earlier activation of global regulators (i.e., sigB, sarA, agr RNAIII, and sae); higher expression of a critical purine biosynthesis gene, purF; and higher growth rates accompanied by lower ATP levels and vancomycin (VAN) susceptibility and stronger δ-hemolysin and biofilm formation versus its isogenic parental RB isolate. Notably, the contribution of ϕSA169 in persistent outcome with VAN treatment was confirmed in an experimental infective endocarditis model. Taken together, these results indicate the critical role of the prophage ϕSA169 in persistent MRSA endovascular infections. Further studies are needed to identify the mechanisms of ϕSA169 in mediating the persistence, as well as establishing the scope of impact, of this prophage in other PB strains.IMPORTANCE Bacteriophages are viruses that invade the bacterial host, disrupt bacterial metabolism, and cause the bacterium to lyse. Because of its remarkable antibacterial activity and unique advantages over antibiotics, for instance, bacteriophage is specific for one species of bacteria and resistance to phage is less common than resistance to antibiotics. Indeed, bacteriophage therapy for treating infections due to multidrug-resistant pathogens in humans has become a research hot spot. However, it is also worth considering that bacteriophages are transferable and could cotransfer host chromosomal genes, e.g., virulence and antimicrobial resistance genes, while lysogenizing and integrating into the bacterial chromosome (prophage), thus playing a role in bacterial evolution and virulence. In the current study, we identified a novel prophage, ϕSA169, from a clinical persistent MRSA bacteremia isolate, and we determined that ϕSA169 mediated well-defined in vitro and in vivo phenotypic and genotypic signatures related to the persistent outcome, which may represent a unique and important persistent mechanism(s).

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

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