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.

Antimicrobial susceptibility testing (AST) remains the cornerstone of effective antimicrobial selection and optimization in patients. Despite recent advances in rapid pathogen identification and resistance marker detection with molecular diagnostics (e.g.,...

Vancomycin was introduced nearly 65 years ago and remains the standard antibiotic for serious methicillin-resistant Staphylococcus aureus (MRSA) infections. S. aureus remain highly susceptibility to vancomycin (>97%). Despite this, MRSA treatment failure with vancomycin is high in complicated bacteremia. Additionally, vancomycin can cause nephrotoxicity, leading to new therapeutic drug monitoring guidance. This demonstrates how difficult it is to dose vancomycin in a way that is both efficacious and safe, especially during long courses of therapy. Often underappreciated are the cost, resources, and complexity of vancomycin care at a time when alternative antibiotics are becoming cost comparable. This perspective highlights a bigger picture of how the treatment repertoires of many other diseases have changed and advanced since vancomycin’s introduction in the 1950s, yet the vancomycin MRSA treatment standard remains. While vancomycin can still have a role, 65 years may be a practical retirement age for vancomycin in highly complex endovascular infections.

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.

Antimicrobial susceptibility testing (AST) remains the cornerstone of effective antimicrobial selection and optimization in patients. Despite recent advances in rapid pathogen identification and resistance marker detection with molecular diagnostics, phenotypic AST methods remain relatively unchanged over the last few decades. Guided by the principles of microfluidics, we describe the application of a multi-liquid-phase microfluidic system, named under-oil open microfluidic systems (UOMS) to achieve a rapid phenotypic AST. UOMS provides a next-generation solution for AST (UOMS-AST) by implementing and recording a pathogen antimicrobial activity in micro-volume testing units under an oil overlay with label-free, single-cell resolution optical access. UOMS-AST can accurately and rapidly determine antimicrobial activity from nominal sample/bacterial cells in a system aligned with clinical laboratory standards. Further, we combine UOMS-AST with cloud lab data analytic techniques for real-time image analysis and report generation to provide a rapid (i.e., <4 h) sample-to-answer turnaround time, shedding light on its utility as a next-generation phenotypic AST platform for clinical application.