LB2306. Population Pharmacokinetic (PPK), Pharmacokinetic/Pharmacodynamic attainment (PTA), and Clinical Pharmacokinetic/Pharmacodynamic (PK/PD) Analyses for Sulbactam-Durlobactam (SUL-DUR) to Support Dose Selection for the Treatment of <i>Acinetobacter baumannii-calcoaceticus</i> Complex (ABC) Infections

Bhavnani, Sujata M.; Rubino, Christopher M.; Hammel, Jeffrey; Cammarata, Anthony; Larson, Kajal; Liolios, Kathryn; McLeod, Sarah M.; Miller, Alita A.; Ambrose, Paul G.; Tommasi, Rubén; O’Donnell, John P.

doi:10.1093/ofid/ofac492.1896

Cited by 3 publications

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“…An unbound AUC:MIC ratio of approximately 10 for durlobactam and 50% f T > MIC for sulbactam for a 1-log 10 CFU reduction from baseline were supported by in vivo and in vitro studies and are likely to correlate with clinical efficacy. The results of analyses assessing the probability of attaining these PK/PD targets based on human exposures in the epithelial lining fluid support the proposed clinical dose of 1 g/1 g sulbactam/durlobactam administered via a 3-hour infusion q6h to treat patients with A. baumannii isolates with MIC values of 4 µg/mL or less [ 37 ]. Moreover, the most recent in vitro surveillance data demonstrate an SUL-DUR MIC 90 of 2 µg/mL for 5032 ABC isolates, thereby supporting the goal for covering a potentiated MIC of 4 µg/mL [ 38 ].…”

Section: Discussionmentioning

confidence: 85%

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

O’Donnell

Bhavnani

2023

Clinical Infectious Diseases

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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.

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Section: Discussionmentioning

confidence: 85%

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

O’Donnell

Bhavnani

2023

Clinical Infectious Diseases

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“…These in vitro data are supported by preclinical PK-PD and safety studies [ 123 ] that have led to clinical development of sulbactam-durlobactam dosed at 1 g of sulbactam and 1 g of durlobactam administered every 6 hours as a 3-hour infusion. The dosing regimen that includes 4 g/day of sulbactam was validated through robust population PK studies of both infected patients (n = 162) and healthy subjects (n = 211) using free-drug plasma targets associated with 1-log killing in murine infection models of 50% f T > MIC for sulbactam and an AUC:MIC target of 10 for durlobactam [ 124 ]. Target attainment rates across all targets investigated were greater than 90% for isolates with sulbactam-durlobactam MICs of ≤4 mg/L.…”

Section: Are We Close To Entering a New Era In The Treatment Of Crab ...mentioning

confidence: 99%

Navigating Available Treatment Options for Carbapenem-ResistantAcinetobacter baumannii-calcoaceticusComplex Infections

Shields

Paterson

2023

Clinical Infectious Diseases

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Carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRAB) is one of the top-priority pathogens for new antibiotic development. Unlike other antibiotic-resistant threats, none of the available therapies have been shown to consistently reduce mortality or improve patient outcomes in clinical trials. Antibiotic combination therapy is routinely used in clinical practice; however, the preferred combination has not been defined. This narrative review focuses on evidence-based solutions for the treatment of invasive CRAB infections. We dissect the promise and perils of traditional agents used in combination, such as colistin, sulbactam, and the tetracyclines, and offer clinical pearls based on our interpretation of the available data. Next, we investigate the merits of newly developed β-lactam agents like cefiderocol and sulbactam-durlobactam, which have demonstrated contrasting results in recent randomized clinical trials. The review concludes with the authors’ perspective on the evolving treatment landscape for CRAB infections, which is complicated by limited clinical data, imperfect treatment options, and a need for future clinical trials. We propose that effective treatment for CRAB infections requires a personalized approach that incorporates host factors, the site of infection, pharmacokinetic-pharmacodynamic principles, local molecular epidemiology of CRAB isolates, and careful interpretation of antibiotic susceptibility testing results. In most clinical scenarios, a dose-optimized, sulbactam-based regimen is recommended with the addition of at least one other in vitro active agent. Should sulbactam-durlobactam receive regulatory approval, recommendations will need to be re-evaluated with the most recent evidence.

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In vitro synergy of the combination of sulbactam-durlobactam and cefepime at clinically relevant concentrations against A. baumannii, P. aeruginosa and Enterobacterales

Fouad,

Nicolau,

Gill

2023

Journal of Antimicrobial Chemotherapy

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Background Sulbactam-durlobactam is a potent combination active against Acinetobacter baumannii; however, it lacks activity against other nosocomial pathogens. Cefepime is a common first-line therapy for hospital/ventilator-associated pneumonia caused by Gram-negative pathogens including Pseudomonas aeruginosa and Enterobacterales. With increasing resistance to cefepime, and the significant proportion of polymicrobial nosocomial infections, effective therapy for infections caused by Acinetobacter baumannii, P. aeruginosa and Enterobacterales is needed. This study investigated the in vitro synergy of sulbactam-durlobactam plus cefepime against relevant pathogens. Methods Static time–kills assays were performed in duplicate against 14 cefepime-resistant isolates (A. baumannii, n = 4; P. aeruginosa, n = 4; Escherichia coli, n = 3; Klebsiella pneumoniae, n = 3). One WT K. pneumoniae isolate was included. Antibiotic concentrations simulated the free-steady state average concentration of clinically administered doses in patients. Results Sulbactam-durlobactam alone showed significant activity against A. baumannii consistent with the MIC values. Sulbactam-durlobactam plus cefepime showed synergy against one A. baumannii isolate with an elevated MIC to sulbactam-durlobactam (32 mg/L). Against all P. aeruginosa isolates, synergy was observed with sulbactam-durlobactam plus cefepime. For the Enterobacterales, one E. coli isolate demonstrated synergy while the others were indifferent due to significant kill from sulbactam-durlobactam alone. The combination of sulbactam-durlobactam plus cefepime showed synergy against one of the K. pneumoniae and additive effects against the other two K. pneumoniae tested. No antagonism was observed in any isolates including the WT strain. Conclusions Synergy and no antagonism was observed with a combination of sulbactam-durlobactam and cefepime; further in vivo pharmacokinetic/pharmacodynamics data and clinical correlation are necessary to support our findings.

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LB2306. Population Pharmacokinetic (PPK), Pharmacokinetic/Pharmacodynamic attainment (PTA), and Clinical Pharmacokinetic/Pharmacodynamic (PK/PD) Analyses for Sulbactam-Durlobactam (SUL-DUR) to Support Dose Selection for the Treatment of Acinetobacter baumannii-calcoaceticus Complex (ABC) Infections

Cited by 3 publications

References 0 publications

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

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

Navigating Available Treatment Options for Carbapenem-ResistantAcinetobacter baumannii-calcoaceticusComplex Infections

In vitro synergy of the combination of sulbactam-durlobactam and cefepime at clinically relevant concentrations against A. baumannii, P. aeruginosa and Enterobacterales

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