2186. Treatment-emergent resistance to ceftazidime-avibactam (CZA) is more common than ceftolozane-tazobactam (CT) among patients infected with multidrug-resistant (MDR) Pseudomonas aeruginosa
Authors: Shah Sunish , Haidar Ghady , Squires Kevin M , Kline Ellen G , Pogue Jason M , McCreary Erin K , Stellfox Madison , Van Tyne Daria , Shields Ryan K 
Published: November 2023

Background

CZA and CT are front-line agents for treatment (tx) of MDR Pseudomonas aeruginosa; however, comparative data are lacking. The purpose of this study was to compare rates of tx-emergent resistance among patients (pts) with bacteremia or pneumonia at a single center.

Methods

Adult pts treated for &gt;48 hours with CZA or CT were included. Pts with cystic fibrosis or colonization were excluded. Isolates were tested by broth microdilution (BMD) in triplicate and underwent whole-genome sequencing.

Results

113 pts were included. Demographics, severity of illness, and durations of tx were similar for pts tx’d with CZA or CT (Table 1). CT-treated pts were less likely to receive prolonged infusions and monotherapy, but more likely to have empyema/endovascular infections. Baseline median (range) MICs were 4 (2–8mg/L) and 2 (0.25–8mg/L) for CZA and CT, respectively. Within 90-days from tx onset, rates of resistance defined as either ≥4-fold MIC increase or MIC &gt;8mg/L were higher among CZA-treated pts (Table 1). Corresponding median MICs of resistant isolates were 16 (16–128mg/L) and 64 (32–512mg/L), respectively. Across 107 baseline isolates, 59 different sequence types (ST) were represented. The most common P. aeruginosa cephalosporinase (PDC) variants were PDC-3, PDC-5, and PDC-8, present in 10%, 21%, and 10% of isolates, respectively. Resistance evolved across varying STs. A subgroup of contemporary pts was well-balanced and supported overall findings (Table 2). From this subgroup, rates of tx-emergent resistance among pts receiving CZA or CT monotherapy were 50% (6/12) and 6% (1/17), respectively (P=0.01). Rates of CT-resistance were lower among pts who received prolonged (5%, 1/19) versus standard (20%, 5/25) infusions. Paired baseline and resistant isolates showing ≥4-fold MIC increase were compared (Table 3). CZA resistance was associated with sequence changes in ampD and/or efflux genes in 5 pts; 2 additional pairs showed mutations in ftsI (PBP3). CT resistance was associated with new ampC mutations in 83% of pairs.

Conclusion

In this non-matched, descriptive analysis, tx-emergent resistance occurred more commonly among pts treated with CZA compared to CT for MDR P. aeruginosa infections. Future multicenter studies evaluating comparative clinical outcomes are warranted.

Disclosures

Ghady Haidar, MD, Allovir: Grant/Research Support|AstraZeneca: Advisor/Consultant|AstraZeneca: Grant/Research Support|Karius: Advisor/Consultant|Karius: Grant/Research Support|NIH: Grant/Research Support jason M. Pogue, PharmD, AbbVie: Advisor/Consultant|Entasis: Advisor/Consultant|Ferring: Advisor/Consultant|GSK: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Qpex: Advisor/Consultant|Shionogi: Advisor/Consultant Erin K. McCreary, PharmD, Abbvie: Advisor/Consultant|Ferring: Advisor/Consultant|GSK: Honoraria|La Jolla (Entasis): Advisor/Consultant|LabSimply: Advisor/Consultant|Merck: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Honoraria Ryan K. Shields, PharmD, MS, Allergan: Advisor/Consultant|Cidara: Advisor/Consultant|Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Menarini: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Utility: Advisor/Consultant|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support