Background Patient interleukin (IL)-1β and IL-10 responses early in Staphylococcus aureus bacteremia (SaB) are associated with bacteremia duration and mortality. We hypothesized that these responses vary depending on antimicrobial therapy, with particular interest in whether the superiority of β-lactams links to key cytokine pathways. Methods Three medical centers included 59 patients with SaB (47 methicillin-resistant S. aureus [MRSA], 12 methicillin-sensitive S. aureus [MSSA]) from 2015–2017. In the first 48 hours, patients were treated with either a β-lactam (n = 24), including oxacillin, cefazolin, or ceftaroline, or a glyco-/lipopeptide (n = 35), that is, vancomycin or daptomycin. Patient sera from days 1, 3, and 7 were assayed for IL-1β and IL-10 by enzyme-linked immunosorbent assay and compared using the Mann-Whitney U test. Results On presentation, IL-10 was elevated in mortality (P = .008) and persistent bacteremia (P = .034), while no difference occurred in IL-1β. Regarding treatment groups, IL-1β and IL-10 were similar prior to receiving antibiotic. Patients treated with β-lactam had higher IL-1β on days 3 (median +5.6 pg/mL; P = .007) and 7 (+10.9 pg/mL; P = .016). Ex vivo, addition of the IL-1 receptor antagonist anakinra to whole blood reduced staphylococcal killing, supporting an IL-1β functional significance in SaB clearance. β-lactam–treated patients had sharper declines in IL-10 than vancomycin or daptomycin –treated patients over 7 days. Conclusions These data underscore the importance of β-lactams for SaB, including consideration that the adjunctive role of β-lactams for MRSA in select patients helps elicit favorable host cytokine responses.

BackgroundBL therapy has been associated with reduced SaB duration compared with non-BL therapy. It has been shown that patients with SaB who fail to generate increased serum IL-1β are at risk for prolonged SaB (> 4 days duration), a predictor of mortality. This suggests a major role for the IL-1β host response in prompt clearance of SaB. Furthermore, BL result in reduced peptidoglycan cross-linking, reduced peptidoglycan O-acetylation, and increased alpha-toxin expression, all of which have independently been shown to enhance IL-1β release. This study aims to show that BL therapy results in a more robust IL-1β host response compared with non-BL therapy to explain, in part, more rapid SaB clearance.MethodsFifty-nine patients (47 MRSA and 12 MSSA) with diverse SaB sources, including endovascular, extravascular (e.g., pneumonia), and catheter-related infections were included. In the first 48 hours, patients were treated with either BL, including oxacillin, ceftaroline, or cefazolin (n = 24), vs. non-BL vancomycin or daptomycin (n = 35). IL-1β concentrations were determined by ELISA on serum samples obtained on Days 1, 3 and Day 7 after bacteremia onset and compared between groups by Mann–Whitney U test.ResultsPatients in BL and non-BL groups had similar IL-1β concentrations on Day 1 of bacteremia (median BL 6.1 pg/mL vs. non-BL 2.8 pg/mL, P = 0.090). BL-treated patients had significantly higher IL-1β serum concentrations on Day 3 (median 7.54 mg/mL vs. 1.9 pg/mL; P = 0.007) and Day 7 (12.52 pg/mL vs. 1.56 pg/mL, P = 0.016) when compared with non-BL-treated patients. BL therapy resulted in 23% and 105% increase in IL-1β at Days 3 and 7, respectively, while non-BL treatment resulted in 32% and 44% reduction in IL-1β. The median duration of SaB was similar between BL and non-BL-treated patients (2.5 vs. 2.0 days, respectively, P = 0.590).ConclusionGiven that a lack of inflammasome-mediated IL-1β production is associated with prolonged SaB, the significant increases in IL-1β levels in patients treated with BL has important therapeutic implications. Previously observed reduced duration of MRSA bacteremia with the addition of BL to vancomycin may have its basis on enhancing IL-1β release. A therapeutic regimen of vancomycin or daptomycin in combination with BL to treat MRSA bacteremia and use of BL therapy in MSSA bacteremia is strongly advised to improve outcomes based on these results.Disclosures G. Sakoulas, Allergan: Consultant and Speaker, Consulting fee and Speaker honorarium. Sunovion: Speaker, Speaker honorarium. The Medicines Company: Speaker, Consulting fee. Paratek Pharmaceuticals: Consultant, Consulting fee. Cidara Therapeutics: Scientific Advisor, None. Arsanis Pharmaceuticals: Scientific Advisor, None. W. Rose, Merck: Grant Investigator, Research grant.

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BackgroundPatients with complicated S. aureus bacteremia (SaB) require a transesophageal echocardiogram (TEE) to rule out endocarditis. Risks of TEE may exceed benefits in patients with a low pretest probability of endocarditis. Given our prior findings that endovascular bacterial burden drives elevated serum IL-10 concentrations, we hypothesize that time to positive blood culture and IL-10 serum concentrations may be used to risk stratify patients for selection of TEE. We compared time to positive blood culture and serum IL-10 in patients with negative and positive TEE.MethodsPatients with SaB were included if they had a diagnosis of primary, endovascular infection source of bacteremia identified by an infectious diseases consult team and a TEE performed. A retrospective chart review was done to identify the time to positivity (hours) of patient blood cultures grown aerobically or anaerobically and TEE results. Sera collected at clinical presentation of these patients were tested for biomarkers IL-10 and IL-1β. Mann–Whitney U test compared the data between the two groups.ResultsThis study included 66 patients with SaB: 17 with negative TEE and 49 with positive TEE. Patients with a positive TEE confirming endocarditis had a faster time to positive blood cultures compared with patients with negative TEE (P = 0.031; figure). IL-10 serum concentrations were significantly higher in patients with positive TEE (26.2 pg/mL) vs. negative TEE (14.39 pg/mL). Time-to-positivity in blood culture was linearly associated serum IL-10 concentrations (P = 0.044; figure). Serum IL-1β concentrations were also higher in TEE positive vs. TEE negative patients (32.1 vs. 14.7 pg/mL, P = 0.067)ConclusionThese data lend further evidence to link high endovascular bacterial burden (measured by shorter time to positive blood culture) and serum IL-10 concentrations. As anticipated, patients with positive TEE had significantly shorter time to blood culture positivity and higher IL-10 serum concentrations than those with negative TEE. With further study on a larger number of patients, time to positive blood cultures and serum biomarkers like IL-10 may be used to risk stratify patients for performance of TEE, as well as to select antimicrobial therapy and to adjust treatment duration.Disclosures All authors: No reported disclosures.