TY - JOUR
T1 - Carbapenems drive the collateral resistance to ceftaroline in cystic fibrosis patients with MRSA
AU - Varela, Maria Celeste
AU - Roch, Melanie
AU - Taglialegna, Agustina
AU - Long, Scott W.
AU - Saavedra, Matthew Ojeda
AU - Rose, Warren E.
AU - Davis, James J.
AU - Hoffman, Lucas R.
AU - Hernandez, Rafael E.
AU - Rosato, Roberto R.
AU - Rosato, Adriana E.
N1 - Funding Information:
We would like to thank the Epigenomics Core Facility at Weill Cornell Medical College (New York, NY) for its resources and assistance with whole-genome sequencing experiments and the Academic Office and Development, Dr. Sasha Pejerrey and Adrienne Winston for manuscript editing services. This work was supported by NIH/NIAID NIH-R56 AI118756 to A.E.R., and Allergan (now Abbvie); TEF-IT-54 award in the form of an investigator-initiated grant to Houston Methodist Research Institute (A.E.R., PI). The CF center repository at Seattle, WA, is funded through P30 NIH DK089507 (L.R.H. and R.E.H.).
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/10/22
Y1 - 2020/10/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85093870027&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85093870027&partnerID=8YFLogxK
U2 - 10.1038/s42003-020-01313-5
DO - 10.1038/s42003-020-01313-5
M3 - Article
C2 - 33093601
AN - SCOPUS:85093870027
SN - 2399-3642
VL - 3
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 599
ER -