Carbapenems drive the collateral resistance to ceftaroline in cystic fibrosis patients with MRSA

Varela, Maria Celeste; Roch, Melanie; Taglialegna, Agustina; Long, Scott W.; Saavedra, Matthew Ojeda; Rose, Warren E.; Davis, James J.; Hoffman, Lucas R.; Hernandez, Rafael E.; Rosato, Roberto R.; Rosato, Adriana E.

doi:10.1038/s42003-020-01313-5

Title: Carbapenems drive the collateral resistance to ceftaroline in cystic fibrosis patients with MRSA

Journal Article · Thu Oct 22 00:00:00 EDT 2020 · Communications Biology

DOI:https://doi.org/10.1038/s42003-020-01313-5· OSTI ID:1775136

Varela, Maria Celeste ^[1]; Roch, Melanie ^[1]; Taglialegna, Agustina ^[1]; Long, Scott W. ^[1]; Saavedra, Matthew Ojeda ^[1]; Rose, Warren E. ^[2]; Davis, James J. ^[3]; Hoffman, Lucas R. ^[4]; Hernandez, Rafael E. ^[5]; Rosato, Roberto R. ^[6]; Rosato, Adriana E.

Houston Methodist Research Institute, TX (United States). Center for Molecular and Translational Human Infectious Diseases Research, Dept. of Pathology and Genomic Medicine
Univ. of Wisconsin, Madison, WI (United States). School of Pharmacy
Argonne National Lab. (ANL), Argonne, IL (United States); Univ. of Chicago, IL (United States). Computation Institute
Univ. of Washington, Seattle, WA (United States). Dept. of Pediatrics and Dept. of Microbiology; Seattle Children's Research Institute, WA (United States). Center for Clinical and Translational Research
Houston Methodist Hospital, TX (United States). Houston Methodist Cancer Center
Houston Methodist Research Institute, TX (United States). Center for Molecular and Translational Human Infectious Diseases Research, Dept. of Pathology and Genomic Medicine; Loma Lima Univ., Loma Linda, CA (United States). Comparative Effectiveness and Clinical Outcomes Research Center (CECORC), Riverside University Health System-Medical Center

Chronic airways infection with methicillin-resistant Staphylococcus aureus(MRSA) is associated with worse respiratory disease cystic fibrosis (CF) patients. Ceftaroline is a cephalosporin that inhibits the penicillin-binding protein (PBP2a) uniquely produced by MRSA. We analyzed 335 S. aureus isolates from CF sputum samples collected at three US centers between 2015–2018. Molecular relationships demonstrated that high-level resistance of preceding isolates to carbapenems were associated with subsequent isolation of ceftaroline resistant CF MRSA. In vitro evolution experiments showed that pre-exposure of CF MRSA to meropenem with further selection with ceftaroline implied mutations in mecA and additional mutations in pbp1 and pbp2, targets of carbapenems; no effects were achieved by other β-lactams. An in vivo pneumonia mouse model showed the potential therapeutic efficacy of ceftaroline/meropenem combination against ceftaroline-resistant CF MRSA infections. Thus, the present findings highlight risk factors and potential therapeutic strategies offering an opportunity to both prevent and address antibiotic resistance in this patient population.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: Weill Cornell Medical College; National Institutes of Health (NIH). National Institute of Allergy and Infectious Diseases (NIAID); Houston Methodist Research Institute

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1775136

Journal Information:: Communications Biology, Vol. 3, Issue 1; ISSN 2399-3642

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

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Title: Carbapenems drive the collateral resistance to ceftaroline in cystic fibrosis patients with MRSA

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