| Title: |
Genomic investigation and clinical correlates of the in vitro β-lactam: NaHCO3 responsiveness phenotype among methicillin-resistant Staphylococcus aureus isolates from a randomized clinical trial |
| Authors: |
Petersiel, Neta; Giulieri, Stefano; Daniel, Diane S; Fan, Sook-Ha; Ersoy, Selvi C; Davis, Joshua S; Bayer, Arnold S; Howden, Benjamin P; Tong, Steven YC; Lye, David C; Yahav, Dafna; Sud, Archana; Robinson, J Owen; Nelson, Jane; Archuleta, Sophia; Roberts, Matthew A; Cass, Alan; Paterson, David L; Foo, Hong; Paul, Mical; Guy, Stephen D; Tramontana, Adrian R; Walls, Genevieve B; McBride, Stephen; Bak, Narin; Ghosh, Niladri; Rogers, Benjamin A; Ralph, Anna P; Davies, Jane; Ferguson, Patricia E; Dotel, Ravindra; McKew, Genevieve L; Gray, Timothy J; Holmes, Natasha E; Smith, Simon; Warner, Morgyn S; Kalimuddin, Shirin; Young, Barnaby E; Runnegar, Naomi; Andresen, David N; Anagnostou, Nicholas A; Johnson, Sandra A; Chatfield, Mark D; Cheng, Allen C; Fowler, Vance G; Meagher, Niamh; Price, David J; van Hal, Sebastiaan J; O'Sullivan, Matthew VN |
| Contributors: |
Boucher, Helen |
| Source: |
Antimicrobial Agents and Chemotherapy, vol 68, iss 7 |
| Publisher Information: |
eScholarship, University of California |
| Publication Year: |
2024 |
| Collection: |
University of California: eScholarship |
| Subject Terms: |
31 Biological Sciences (for-2020); 32 Biomedical and Clinical Sciences (for-2020); 3107 Microbiology (for-2020); 3202 Clinical Sciences (for-2020); 3211 Oncology and Carcinogenesis (for-2020); Clinical Research (rcdc); Sepsis (rcdc); Clinical Trials and Supportive Activities (rcdc); Hematology (rcdc); Genetics (rcdc); Biodefense (rcdc); Infectious Diseases (rcdc); Emerging Infectious Diseases (rcdc); Antimicrobial Resistance (rcdc); 6.1 Pharmaceuticals (hrcs-rac); Infection (hrcs-hc); Methicillin-Resistant Staphylococcus aureus (mesh); Microbial Sensitivity Tests (mesh); Humans (mesh); Anti-Bacterial Agents (mesh); Cefazolin (mesh); Staphylococcal Infections (mesh); Oxacillin (mesh); Bacteremia (mesh); Phenotype (mesh); beta-Lactams (mesh); Male (mesh); Sodium Bicarbonate (mesh); Female (mesh); Middle Aged (mesh) |
| Subject Geographic: |
e00218 - e00224 |
| Description: |
NaHCO3 responsiveness is a novel phenotype where some methicillin-resistant Staphylococcus aureus (MRSA) isolates exhibit significantly lower minimal inhibitory concentrations (MIC) to oxacillin and/or cefazolin in the presence of NaHCO3. NaHCO3 responsiveness correlated with treatment response to β-lactams in an endocarditis animal model. We investigated whether treatment of NaHCO3-responsive strains with β-lactams was associated with faster clearance of bacteremia. The CAMERA2 trial (Combination Antibiotics for Methicillin-Resistant Staphylococcus aureus) randomly assigned participants with MRSA bloodstream infections to standard therapy, or to standard therapy plus an anti-staphylococcal β-lactam (combination therapy). For 117 CAMERA2 MRSA isolates, we determined by broth microdilution the MIC of cefazolin and oxacillin, with and without 44 mM of NaHCO3. Isolates exhibiting ≥4-fold decrease in the MIC to cefazolin or oxacillin in the presence of NaHCO3 were considered "NaHCO3-responsive" to that agent. We compared the rate of persistent bacteremia among participants who had infections caused by NaHCO3-responsive and non-responsive strains, and that were assigned to combination treatment with a β-lactam. Thirty-one percent (36/117) and 25% (21/85) of MRSA isolates were NaHCO3-responsive to cefazolin and oxacillin, respectively. The NaHCO3-responsive phenotype was significantly associated with sequence type 93, SCCmec type IVa, and mecA alleles with substitutions in positions -7 and -38 in the regulatory region. Among participants treated with a β-lactam, there was no association between the NaHCO3-responsive phenotype and persistent bacteremia (cefazolin, P = 0.82; oxacillin, P = 0.81). In patients from a randomized clinical trial with MRSA bloodstream infection, isolates with an in vitro β-lactam-NaHCO3-responsive phenotype were associated with distinctive genetic signatures, but not with a shorter duration of bacteremia among those treated with a β-lactam. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
qt7bb7z3ts; https://escholarship.org/uc/item/7bb7z3ts; https://escholarship.org/content/qt7bb7z3ts/qt7bb7z3ts.pdf |
| DOI: |
10.1128/aac.00218-24 |
| Availability: |
https://escholarship.org/uc/item/7bb7z3ts; https://escholarship.org/content/qt7bb7z3ts/qt7bb7z3ts.pdf; https://doi.org/10.1128/aac.00218-24 |
| Rights: |
public |
| Accession Number: |
edsbas.471A2CC9 |
| Database: |
BASE |