Biology subjects

Yates, K. A.

Publications and source records attributed to Yates, K. A..

3 recordsLinked to original sources

bioRxiv2023

Cefiderocol: A new and effective topical monotherapy treatment for experimental extensively-drug resistant Pseudomonas aeruginosa keratitis

PurposeTo test cefiderocol, a siderophore-cephalosporin antibiotic for topical monotherapy treatment of experimental extensively drug resistant (XDR) Pseudomonas aeruginosa keratitis. DesignPreclinical study. Subjects and ControlsDeidentified P. aeruginosa keratitis isolates, XDR P. aeruginosa from eye drop outbreak, rabbits, saline, cefiderocol 50 mg/ml, ciprofloxacin 0.3%, and tobramycin 14 mg/ml. Methods, Intervention, or TestingCefiderocol antibacterial activity against P. aeruginosa keratitis isolates (n=135) was evaluated by minimum inhibitory concentration (MIC) testing. Ocular toxicity/tolerability and antibacterial efficacy were tested in vivo with experimental rabbit models. Corneal concentrations and stability were assessed using a bioassay. Main Outcome MeasuresMIC analysis for susceptibility, graded tests for ocular toxicity/tolerability, CFU analysis for bacterial burden, corneal cefiderocol concentrations. Results100% of P. aeruginosa keratitis isolates were susceptible to cefiderocol (n=135), the MIC90 was 0.125 {micro}g/ml including the XDR isolate (MIC = 0.125 {micro}g/ml). Topical cefiderocol 50 mg/ml was minimally toxic to the ocular surface and was well tolerated. For the XDR P. aeruginosa isolate, topical cefiderocol 50 mg/ml, significantly decreased corneal CFU compared to ciprofloxacin 0.3%, tobramycin 14 mg/ml, and saline. In addition, tobramycin 14 mg/ml was more effective than the saline control. Mean cefiderocol corneal concentrations were 191x greater than the MIC90 of the P. aeruginosa keratitis isolates. Refrigerated cefiderocol maintained antimicrobial activity over a one-month period. ConclusionsThese results demonstrate that cefiderocol is well tolerated on rabbit corneas and is effective against P. aeruginosa keratitis isolates in vitro and was effective in vivo against an XDR isolate in a rabbit keratitis model. Given the recent outbreak of keratitis caused by this XDR P. aeruginosa, cefiderocol is a promising additional antibiotic that should be further evaluated for topical treatment of keratitis caused by antibiotic resistant P. aeruginosa.

microbiology↗

bioRxiv2021

Bacterial keratitis: similar bacterial and clinical outcomes in female versus male New Zealand White rabbits infected with Serratia marcescens

Females and males respond differently to a number of systemic viral infections. Differences between females and males with respect to the severity of keratitis caused by Gram-negative bacteria such as Serratia marcescens are less well established. In this study we injected female and male New Zealand White rabbit corneas with a keratitis isolate of S. marcescens and evaluated the eyes after 48 hours for a number of clinical and microbiological parameters. No statistical differences in bacterial burden and corneal scores were recorded between female and male rabbits although there was a non-significant trend toward a higher frequency of female rabbits demonstrating hypopyons. This data suggests that for experimental bacterial keratitis studies involving Gram-negative rods, a single sex or mixed group of rabbit is sufficient for evaluating pathology and bacterial burdens. This will reduce the number of animals used for subsequent studies.

microbiology↗

bioRxiv2020

The Rcs stress response system modulates Serratia marcescens induced inflammation and bacterial proliferation in a rabbit keratitis model

In this study, we tested the hypothesis that the conserved bacterial Rcs stress response system mediates corneal pathogenesis associated with Serratia marcescens ocular infections. This was accomplished by modifying Rcs activity using mutant strains. These include a mutant that has a hyper-active Rcs system due to deletion of the IgaA family gene, gumB, and a gumB rcsC double mutant that is defective for Rcs signaling. The role of the Rcs system and bacterial stress response systems for microbial keratitis is not known. Here we observed that the Rcs-activated gumB mutant had a >50-fold reduction in proliferation compared to the wild type within rabbit corneas at 48 h, and demonstrated a notable reduction in inflammation based on inflammatory signs and proinflammatory markers measured at the RNA and protein levels. The gumB mutant phenotypes could be complemented by wild-type gumB on a plasmid and partially complemented by restoration of shlA cytolysin expression and elimination of capsular polysaccharide production. We observed that inactivation of the Rcs stress response system completely restored corneal virulence to the gumB mutant. NanoString transcriptional analysis of bacterial genes expressed during microbial keratitis demonstrated expression of gumB, rcsB, shlA, and three metalloprotease genes. Data suggest that the bacterial capsular polysaccharide is not necessary for infection, but capsule overexpression reduces inflammation. Together, these data indicate that GumB regulates virulence factor production through the Rcs system and this overall stress response system is a key mediator of a bacteriums ability to induce vision-threatening keratitis.

microbiology↗