In vitro identification of underutilized β-lactam combinations against methicillin-resistant Staphylococcus aureus bacteremia isolates.

Autor: Davis KP; Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA.; The Stuart B. Levy Center for Integrated Management of Antimicrobial Resistance, Tufts University School of Medicine, Boston, Massachusetts, USA., McDermott LA; Division of Geographic Medicine and Infectious Diseases, Department of Medicine, Tufts Medical Center, Boston, Massachusetts, USA., Snydman DR; The Stuart B. Levy Center for Integrated Management of Antimicrobial Resistance, Tufts University School of Medicine, Boston, Massachusetts, USA.; Division of Geographic Medicine and Infectious Diseases, Department of Medicine, Tufts Medical Center, Boston, Massachusetts, USA., Aldridge BB; Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, USA.; The Stuart B. Levy Center for Integrated Management of Antimicrobial Resistance, Tufts University School of Medicine, Boston, Massachusetts, USA.; Department of Biomedical Engineering, Tufts University School of Engineering, Medford, Massachusetts, USA.
Jazyk: angličtina
Zdroj: Microbiology spectrum [Microbiol Spectr] 2024 Aug 06; Vol. 12 (8), pp. e0097624. Date of Electronic Publication: 2024 Jun 25.
DOI: 10.1128/spectrum.00976-24
Abstrakt: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is a serious clinical challenge with high mortality rates. Antibiotic combination therapy is currently used in cases of persistent infection; however, the limited development of new antibiotics will likely increase the need for combination therapy, and better methods are needed for identifying effective combinations for treating persistent bacteremia. To identify pairwise combinations with the most consistent potential for benefit compared to monotherapy with a primary anti-MRSA agent, we conducted a systematic study with an in vitro high-throughput methodology. We tested daptomycin and vancomycin each in combination with gentamicin, rifampicin, cefazolin, and oxacillin, and ceftaroline with daptomycin, gentamicin, and rifampicin. Combining cefazolin with daptomycin lowered the daptomycin concentration required to reach 95% growth inhibition (IC 95 ) for all isolates tested and lowered daptomycin IC 95 below the sensitivity breakpoint for five out of six isolates that had daptomycin minimum inhibitory concentrations at or above the sensitivity breakpoint. Similarly, vancomycin IC 95 s were decreased when vancomycin was combined with cefazolin for 86.7% of the isolates tested. This was a higher percentage than was achieved by adding any other secondary antibiotic to vancomycin. Adding rifampicin to daptomycin or vancomycin did not always reduce IC 95 s and failed to produce synergistic interaction in any of the isolates tested; the addition of rifampicin to ceftaroline was frequently synergistic and always lowered the amount of ceftaroline required to reach the IC 95 . These analyses rationalize further in vivo evaluation of three drug pairs for MRSA bacteremia: daptomycin+cefazolin, vancomycin+cefazolin, and ceftaroline+rifampicin.IMPORTANCEBloodstream infections caused by methicillin-resistant Staphylococcus aureus (MRSA) have a high mortality rate despite the availability of vancomycin, daptomycin, and newer antibiotics including ceftaroline. With the slow output of the antibiotic pipeline and the serious clinical challenge posed by persistent MRSA infections, better strategies for utilizing combination therapy are becoming increasingly necessary. We demonstrated the value of a systematic high-throughput approach, adapted from prior work testing antibiotic combinations against tuberculosis and other mycobacteria, by using this approach to test antibiotic pairs against a panel of MRSA isolates with diverse patterns of antibiotic susceptibility. We identified three antibiotic pairs-daptomycin+cefazolin, vancomycin+cefazolin, and ceftaroline+rifampicin-where the addition of the second antibiotic improved the potency of the first antibiotic across all or most isolates tested. Our results indicate that these pairs warrant further evaluation in the clinical setting.
Competing Interests: D.R.S. has research contracts with Tufts Medical Center from Prolacta, Summit Therapeutics, Seres Health, and Merck. He is a consultant to Merck, Prolacta, and Seres Health. K.P.D., B.B.A., and L.A.M. have no conflicts of interest to disclose.
Databáze: MEDLINE
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