Targeting mrsa in cystic fibrosis: ceftaroline-meropenem combination therapy and the predictive role of prsa

The National Institute of Allergy and Infectious Diseases awarded Mainehealth a $489,848 Project Grant on September 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate combination therapy targeting methicillin-resistant Staphylococcus aureus (MRSA) infection in cystic fibrosis patients.

The research optimizes dosing and evaluates efficacy of ceftaroline-meropenem combination therapy in chronic MRSA infections, with and without CFTR modulators. The work defines the role of penicillin-binding protein 2A (PrSA) dysfunction in the synergistic mechanism of the combination and assesses its potential predictive value. Prior laboratory findings demonstrated that combining ceftaroline with meropenem restores efficacy against high-level ceftaroline-resistant MRSA and may prevent Pseudomonas emergence during MRSA suppression by exploiting genetic vulnerabilities and disrupting PBP2A membrane localization. The research addresses a significant clinical need: chronic MRSA infection in people with cystic fibrosis is linked to faster lung function decline and increased early mortality, yet no effective suppressive treatments currently exist.

Performance occurs in Portland, Maine. The award period runs through August 31, 2028. Mainehealth operates the Maine Medical Center Research Institute and conducts NIH-funded investigations in immunology and infectious disease.

Abstract

Cystic fibrosis (CF) is an autosomal recessive disorder caused by cftr gene mutations affecting a camp-activated chloride channel. While cftr modulators have improved outcomes, airway infections remain a major challenge. Methicillin-resistant staphylococcus aureus (mrsa) is a common infection in people with CF (pwcf) and difficult to treat due to rapid antibiotic resistance. The CF patient registry 2023 reports that chronic suppressive therapy for pseudomonas aeruginosa infections has significantly improved outcomes, including better lung function and fewer exacerbations. However, this progress has led to a rise in mrsa infections. Chronic mrsa infection is linked to faster declines in lung function and increased early mortality in pwcf. Given these challenges, continued investigation of chronic mrsa suppression is essential. Currently, no effective suppressive treatments exist. Recent trials of inhaled dry powder vancomycin were ineffective and caused bronchospasm in some study subjects. Ceftaroline a potent fifth-generation cephalosporin, is often a drug of last resort. Our team and others found ceftaroline resistance in mrsa isolates without prior ceftaroline exposure. This resistance is prevalent in pwcf, where prior carbapenem use for pseudomonas aeruginosa infections compromises ceftaroline efficacy. Our lab has discovered that combining ceftaroline with meropenem restores efficacy against high-level ceftaroline-resistant mrsa. This combination therapy may also prevent pseudomonas emergence during mrsa suppression. This synergy exploits genetic vulnerabilities and disrupts PBP2A membrane localization via prsa dysfunction. Our specific aims are: aim 1: to optimize CPT/MER dosing via PK/PD and evaluate combination efficacy in chronic mrsa with/without cftr modulators. Aim 2: to define prsa's role in CPT/MER synergy and assess its potential as a predictive biomarker in CF-mrsa. The proposed studies address a critical unmet need by innovatively repurposing existing antibiotics to treat chronic mrsa infections in people with cystic fibrosis (pwcf), while also uncovering resistance mechanisms that will enable biomarker-guided precision therapy.