Pharmacokinetic and pharmacodynamic evaluation of sulbactam-durlobactam in a critically ill patient on continuous venovenous hemofiltration infected with carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex.

Abstract

Background: Drug databases currently do not provide dosing guidance for sulbactam-durlobactam in continuous renal replacement therapy. Herein, we present the first in vivo pharmacokinetic (PK) evaluation of sulbactam-durlobactam during continuous venovenous hemofiltration (CVVH) in a patient with carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRAB) bacteremia and ventilator-associated bacterial pneumonia (VABP).

Methods: A 59-year-old critically ill patient (body mass index 60 kg/m²) required CVVH and developed CRAB bacteremia secondary to VABP. Sulbactam-durlobactam 2 g every 4 h infused over 3 h was initiated based on previous ex vivo data and the effluent rate of 6 L/h. The sulbactam-durlobactam minimum inhibitory concentration (MIC) was determined by reference broth microdilution, and whole genome sequencing (WGS) was performed. Steady-state pre-filter blood, post-filter blood, and effluent samples were collected on three different dosing intervals to characterize plasma exposure and estimate the sieving coefficient (SC).

Results: The sulbactam-durlobactam MIC was 4/4 mcg/mL (susceptible). WGS revealed penicillin-binding protein (PBP)-1b and PBP-3 mutations. The selected dose exceeded sulbactam and durlobactam PK/pharmacodynamic (PD) targets with 100% free time above MIC (fT > MIC) and the ratio of area under the unbound concentration-time curve to MIC (fAUC/MIC) = 139, respectively. The SC for sulbactam and durlobactam was 0.68 and 0.67, respectively, and protein binding was 54% and 51%, respectively. Sulbactam-durlobactam monotherapy resulted in initial microbiological clearance for CRAB bacteremia but recurred later in hospitalization 11 days after sulbactam-durlobactam treatment. The patient was ultimately transitioned to comfort care.

Conclusion: Sulbactam-durlobactam monotherapy dosed at 2 g every 4 h (3-h infusion) in CVVH achieved PD targets for this CRAB isolate with a MIC of 4/4 mcg/ml. Although sulbactam-durlobactam monotherapy resulted in initial microbiological clearance for the CRAB bacteremia, recurrence occurred, and the patient ultimately died.