The Pharmacokinetics/Pharmacodynamic Relationship of Durlobactam in Combination With Sulbactam in In Vitro and In Vivo Infection Model Systems Versus Acinetobacter baumannii-calcoaceticus Complex

Abstract

Sulbactam-durlobactam is a β-lactam/β-lactamase inhibitor combination currently in development for the treatment of infections caused by Acinetobacter, including multidrug-resistant (MDR) isolates. Although sulbactam is a β-lactamase inhibitor of a subset of Ambler class A enzymes, it also demonstrates intrinsic antibacterial activity against a limited number of bacterial species, including Acinetobacter, and has been used effectively in the treatment of susceptible Acinetobacter-associated infections. Increasing prevalence of β-lactamase–mediated resistance, however, has eroded the effectiveness of sulbactam in the treatment of this pathogen. Durlobactam is a rationally designed β-lactamase inhibitor within the diazabicyclooctane (DBO) class. The compound demonstrates a broad spectrum of inhibition of serine β-lactamase activity with particularly potent activity against class D enzymes, an attribute which differentiates it from other DBO inhibitors. When combined with sulbactam, durlobactam effectively restores the susceptibility of resistant isolates through β-lactamase inhibition. The present review describes the pharmacokinetic/pharmacodynamic (PK/PD) relationship associated with the activity of sulbactam and durlobactam established in nonclinical infection models with MDR Acinetobacter baumannii isolates. This information aids in the determination of PK/PD targets for efficacy, which can be used to forecast efficacious dose regimens of the combination in humans.

Sulbactam-durlobactam susceptibility test method development and quality control ranges for MIC and disk diffusion tests

“…Because there was no benefit of increasing durlobactam to 8 µg/mL, the susceptibility testing paradigm deemed optimal was to hold the concentration of durlobactam constant at 4 µg/mL while varying the sulbactam concentration in twofold increments. This testing paradigm for susceptibility was in good agreement with the pharmacokinetic/pharmacodynamic (PK/PD) targets determined within in vitro and in vivo infection model systems where both sulbactam and durlobactam exposure targets are normalized by the potentiated sulbactam-durlobactam MIC (MIC of sulbactam in the presence of 4 µg/mL of durlobactam) ( 34 ). In these studies, % f T > MIC and f AUC 0–24 /MIC were determined to be the PK/PD drivers for sulbactam and durlobactam, respectively.…”

“…Within a sulbactam-durlobactam MIC ≤4/4 µg/mL, the sulbactam bactericidal activity was restored when durlobactam f AUC 0–24 /MIC = 10 and sulbactam concentrations exceeded the MIC for 50% of the dosing interval. This relationship was the same for isolates that were evaluated across an MIC range from 0.5/4 to 4/4 µg/mL ( 34 ).…”

Unveiling the Secrets of Acinetobacter baumannii: Resistance, Current Treatments, and Future Innovations

“…Furthermore, the combination has shown favorable results in clinical settings, significantly reducing mortality compared to other treatments, such as colistin, which is often reserved as a last-line choice owing to its nephrotoxicity and limited efficacy against resistant organisms. In vivo studies in mouse models have revealed that the proportion of the dosing interval during which the sulbactam concentration exceeds the minimum inhibitory concentration (% fT > MIC) is critical for its efficacy [78,79]. Moreover, in murine thigh and lung infection models, significant reductions in bacterial counts were observed, with durlobactam ensuring the sustained activity of sulbactam by inhibiting key β-lactamases produced by CRAB.…”

Cefiderocol and Sulbactam-Durlobactam against Carbapenem-Resistant Acinetobacter baumannii

“…In most studies, all showing excellent activity of SUL/DUR against representative collections of ABC, MICs for SUL-DUR were determined by the CLSI standard BMD using a cation-adjusted Mueller-Hinton broth, with SUL-DUR tested in 2-fold dilutions of SUL in combination with a fixed concentration of 4 mg/mL of DUR [11,12,78]. In keeping with the in vitro data, treatment with SUL/DUR resulted in a dose-dependent reduction in XDR A. baumannii in both the neutropenic mice thigh abscess and pneumonia infection models [14].…”

“…Recently, cefiderocol (FDC; S-649266), a novel siderophore cephalosporin, which possesses a broad activity against CRAB in vitro and in vivo [6][7][8], has been approved by the Food and Drug Administration for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CR-GNB) [9]. Also, sulbactam-durlobactam (SUL/DUR), a bactericidal β-lactam-β-lactamase inhibitor combination [10], has been demonstrated to be active against CRAB in vitro [11][12][13] and in vivo [14,15]. SUL/DUR, XACDURO, was approved in the USA for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) caused by susceptible isolates of A. baumannii [16].…”