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

Commun Biol. 2020 Oct 22;3(1):599. doi: 10.1038/s42003-020-01313-5.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use
  • Bacterial Proteins / genetics
  • Carbapenems / pharmacology*
  • Carbapenems / therapeutic use
  • Ceftaroline
  • Cephalosporins / pharmacology*
  • Cephalosporins / therapeutic use
  • Cystic Fibrosis / complications*
  • Drug Resistance, Multiple, Bacterial*
  • Drug Therapy, Combination
  • Genome, Bacterial
  • Humans
  • Methicillin-Resistant Staphylococcus aureus / classification
  • Methicillin-Resistant Staphylococcus aureus / drug effects*
  • Methicillin-Resistant Staphylococcus aureus / genetics
  • Microbial Sensitivity Tests
  • Mutation
  • Staphylococcal Infections / drug therapy
  • Staphylococcal Infections / etiology*


  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Carbapenems
  • Cephalosporins