State of the art in cystic fibrosis pharmacology—Optimization of antimicrobials in the treatment of cystic fibrosis pulmonary exacerbations: I. Anti‐methicillin‐resistant <i>Staphylococcus aureus</i> (MRSA) antibiotics

Epps, Quovadis J; Epps, Kevin; Young, David C.; Zobell, Jeffery T.

doi:10.1002/ppul.24537

Cited by 17 publications

(26 citation statements)

References 61 publications

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“…The changing epidemiology of CF infections and varying resistance to commonly used antibiotics, and in particular the involvement of MRSA are influencing the choice and the efficacy of anti-infective treatments. In this contex, ceftaroline (CPT), a fifth-generation cephalosporin with potent bactericidal activity against MRSA, is considered as a clinically relevant therapeutic option 10 . Among the β-lactam antibiotics, CPT has the particular ability to inhibit both the native PBPs and the acquired PBP2a, the principal determinant of high-level β-lactam resistance in MRSA by allosteric opening of its active site 11 .…”

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confidence: 99%

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

et al. 2020

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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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confidence: 99%

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

et al. 2020

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“…In order to limit toxicity and reduce side effects while directly targeting the lungs, many studies took an interest in using aerosols as a method of administration. In this frame of mind, Levofloxacin was developed for CF patients to target P. aeruginosa infections (Chirgwin et al, 2019;Epps et al, 2019). This drug, derived from the fluoroquinolone family, inhibits topoisomerases, which is essential for the synthesis of bacterial DNA.…”

Section: New Development In Antibiotic Approachesmentioning

confidence: 99%

Novel Anti-Inflammatory Approaches for Cystic Fibrosis Lung Disease: Identification of Molecular Targets and Design of Innovative Therapies

Mitri

Bardin

et al. 2020

Front. Pharmacol.

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Cystic fibrosis (CF) is the most common genetic disorder among Caucasians, estimated to affect more than 70,000 people in the world. Severe and persistent bronchial inflammation and chronic bacterial infection, along with airway mucus obstruction, are hallmarks of CF lung disease and participate in its progression. Anti-inflammatory therapies are, therefore, of particular interest for CF lung disease. Furthermore, a better understanding of the molecular mechanisms involved in airway infection and inflammation in CF has led to the development of new therapeutic approaches that are currently under evaluation by clinical trials. These new strategies dedicated to CF inflammation are designed to treat different dysregulated aspects such as oxidative stress, cytokine secretion, and the targeting of dysregulated pathways. In this review, we summarize the current understanding of the cellular and molecular mechanisms that contribute to abnormal lung inflammation in CF, as well as the new anti-inflammatory strategies proposed to CF patients by exploring novel molecular targets and novel drug approaches.

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“…Prevention and therapy of chronic bacterial and fungal inflammation are therefore key in the treatment regimen of CF (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Allergic Reactions to Serine Protease-Like Proteins of Staphylococcus aureus

et al. 2021

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In cystic fibrosis (CF) infectious and allergic airway inflammation cause pulmonary exacerbations that destroy the lungs. Staphylococcus aureus is a common long-term colonizer and cause of recurrent airway infections in CF. The pathogen is also associated with respiratory allergy; especially the staphylococcal serine protease-like proteins (Spls) can induce type 2 immune responses in humans and mice. We measured the serum IgE levels specific to 7 proteases of S. aureus by ELISA, targeting 5 Spls (76 CF patients and 46 controls) and the staphopains A and B (16 CF patients and 46 controls). Then we compared cytokine release and phenotype of T cells that had been stimulated with Spls between 5 CF patients and 5 controls. CF patients had strongly increased serum IgE binding to all Spls but not to the staphopains. Compared to healthy controls, their Spl-stimulated T cells released more type 2 cytokines (IL-4, IL-5, IL-13) and more IL-6 with no difference in the secretion of type 1- or type 3 cytokines (IFNγ, IL-17A, IL-17F). IL-10 production was low in CF T cells. The phenotype of the Spl-exposed T cells shifted towards a Th2 or Th17 profile in CF but to a Th1 profile in controls. Sensitization to S. aureus Spls is common in CF. This discovery could explain episodes of allergic inflammation of hitherto unknown causation in CF and extend the diagnostic and therapeutic portfolio.

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State of the art in cystic fibrosis pharmacology—Optimization of antimicrobials in the treatment of cystic fibrosis pulmonary exacerbations: I. Anti‐methicillin‐resistant Staphylococcus aureus (MRSA) antibiotics

Cited by 17 publications

References 61 publications

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

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

Novel Anti-Inflammatory Approaches for Cystic Fibrosis Lung Disease: Identification of Molecular Targets and Design of Innovative Therapies

Allergic Reactions to Serine Protease-Like Proteins of Staphylococcus aureus

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