Background: CRE BSIs have high mortality and limited treatment options. PLZ is a next-generation aminoglycoside with activity against multidrug-resistant Enterobacteriaceae. CARE was a phase 3, open-label study that evaluated the efficacy and safety of PLZ in pts with infections due to CRE. The aim of this exploratory analysis was to evaluate outcomes in the subgroup with CRE BSI.
Methods: CARE enrolled 2 cohorts: Cohort 1 (C1), a randomized comparison of PLZ vs CST and Cohort 2 (C2), a single-arm study of PLZ in pts ineligible for C1. Pts in C1 received PLZ (15 mg/kg q24h) or CST (300-mg load [colistin base activity] then 5 mg/kg/d) plus tigecycline or meropenem. Pts in C2 received PLZ plus investigators choice of adjunctive agent. Treatment was 7-14 days. The primary endpoint was all-cause mortality (ACM) at Day 28 or significant disease-related complications (SDRCs) in pts with confirmed CRE who received ≥1 dose of study drug (mMITT population). Clearance of bacteremia by Day 5 required 2 negative cultures ≥24 h apart with sustained clearance through the study period. Serum creatinine levels were assessed by a central lab.
Results: Of 39 pts enrolled in C1, 30 had BSI (29 mMITT). PLZ pts had lower ACM at Day 28 or SDRCs and ACM at Day 28 compared with CST pts and higher rates of bacteremia clearance by Day 5 (Table). Lack of clearance in PLZ pts was due to recurrence beyond Day 5 (1 pt) and insufficient follow-up to demonstrate clearance (1 pt); 6 CST pts failed to clear by Day 5 and 2 had recurrence beyond Day 5. 10%(1/10) of PLZ and 25% (3/12) of CST pts experienced a ≥0.5 mg/dL increase in serum creatinine from baseline through the end of therapy. Of 30 pts enrolled in C2, 15 had BSI (14 mMITT). ACM at Day 28 or SDRCs and ACM at Day 28 were 35.7% (5/14) and 14.3% (2/14), respectively. Clearance of bacteremia at Day 5 was observed in 64.3% (9/14); of the 5 whose bacteremia did not clear, 1 failed to clear by Day 5 and 4 had recurrence beyond Day 5. A ≥0.5 mg/dL increase in serum creatinine through the end of therapy was reported in 33.3% (4/12).
Conclusion: PLZ was associated with improved survival and microbiological clearance compared with CST in C1 pts with BSI; outcomes in C2 were supportive of these findings. PLZ may be an important potential new treatment option for pts with CRE BSI.
J. A. McKinnell,
R. Pushkin, Achaogen, Inc.: Employee , Salary
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