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Combination Therapy of Cefiderocol and Polymyxin B Against Pseudomonas aeruginosa Keratitis Isolates In Vitro
Eric G Romanowski1, Emily K Young1, Sonya M Mumper1
1Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA, USA.
Purpose:
Antibiotic combination therapy is commonly used for empiric treatment of microbial keratitis, a potentially blinding infection of the cornea. Pseudomonas aeruginosa (P. aeruginosa) is a major cause of severe keratitis, and the 2023 outbreak linked to artificial tears involved a strain resistant to aminoglycosides and fluoroquinolones, resulting in widespread vision loss. Despite various proposed treatments, no consensus exists for management of keratitis caused by the outbreak strain. The purpose of this study was to evaluate the efficacy of cefiderocol (FDC) combined with polymyxin B (PB) against ocular P. aeruginosa keratitis isolates, including extensively drug-resistant (XDR) strains from the 2023 artificial tear-associated outbreak.
Methods:
Time-kill assays and epsilometer (E-test) synergy testing were performed on a panel of keratitis isolates. Genetic analysis was conducted on mutants with reduced FDC susceptibility.
Results:
Time-kill assays demonstrated synergy for two XDR outbreak isolates (P < 0.05), whereas the E-test used across diverse keratitis isolates showed additive to indifferent interactions. Quorum-sensing-deficient, sheen-positive strains showed reduced responsiveness (P < 0.01). Non-antagonistic interactions were observed for Serratia marcescens (S. marcescens) and Staphylococcus aureus (S. aureus) keratitis isolates, with synergy for some S. marcescens strains. Mutants with reduced FDC susceptibility harbored mutations in baeS and fepA, yet remained responsive to the antibiotic combination.
Conclusions:
FDC combined with PB demonstrates promising activity against drug-resistant Gram-negative keratitis pathogens, including XDR P. aeruginosa.
Translational Relevance:
These findings support the further development of FDC with PB as a candidate therapy for drug-resistant ocular infections.
Insights
Cefiderocol (FDC) combined with polymyxin B (PB) shows promise against drug-resistant Pseudomonas aeruginosa keratitis. This antibiotic combination may offer a new treatment option for severe ocular infections caused by resistant bacterial strains.
Area of Science:
- Ophthalmology
- Infectious Diseases
- Microbiology
Background:
- Microbial keratitis is a serious eye infection that can lead to blindness.
- Pseudomonas aeruginosa (P. aeruginosa) is a common cause of severe keratitis.
- A 2023 outbreak involved P. aeruginosa strains resistant to common antibiotics, highlighting the need for new treatments.
Purpose of the Study:
- To evaluate the efficacy of cefiderocol (FDC) combined with polymyxin B (PB) against P. aeruginosa keratitis isolates.
- To assess this combination therapy against extensively drug-resistant (XDR) strains from the 2023 outbreak.
Main Methods:
- Time-kill assays and E-test synergy testing were performed on clinical isolates.
- Genetic analysis was conducted on bacterial mutants with decreased susceptibility to FDC.
Main Results:
- Time-kill assays showed synergistic activity of FDC with PB against two XDR outbreak isolates.
- E-tests indicated additive to indifferent interactions across a broader range of isolates.
- Mutations in baeS and fepA were identified in FDC-resistant mutants, which remained responsive to the combination therapy.
Conclusions:
- The combination of cefiderocol and polymyxin B demonstrates potential efficacy against drug-resistant Gram-negative bacteria causing keratitis.
- This combination therapy warrants further investigation as a treatment for drug-resistant ocular infections.
