Abstract
Background
The genus Burkholderia contains several pathogenic species with distinct etiologies, including Burkholderia pseudomallei the biothreat pathogen responsible for melioidosis and Burkholderia mallei which causes glanders. β-Lactams, such as ceftazidime and meropenem, are important therapeutic options for these infections. However, clinical resistance to β-lactams, which is primarily mediated by multiple types of β-lactamases in these species, is a growing concern. Durlobactam (ETX2514, DUR) is a novel β-lactamase inhibitor with broad-spectrum activity against Ambler class A, C, and D β-lactamases. Sulbactam (SUL) is an Ambler Class A β-lactamase inhibitor with intrinsic antibacterial activity against a limited number of species, including Acinetobacter spp. SUL-DUR is currently in Phase 3 clinical testing for the treatment of carbapenem-resistant infections caused by Acinetobacter spp. In this study, SUL-DUR was tested for in vitro antibacterial activity against B. pseudomallei and B. mallei as well as for in vivo efficacy in a preclinical model of melioidosis.
Methods
The antibacterial activity of SUL alone or in combination with DUR (fixed at 4 mg/L) against B. pseudomallei (n = 30) and B. mallei (N = 28) was determined following CLSI guidelines. In vivo efficacy was tested in an acute murine model of melioidosis in which 4 × 104 cfu Bp K96423 (SUL-DUR MIC = 1 mg/L) was administered intranasally to BalbC mice. SUL-DUR (100/200 or 400/200 mg/kg) was administered q4h subcutaneously 4 hours post-challenge for 6 days and murine survival was monitored for 45 days. Doxycycline (DOX) and ciprofloxacin (CIP) were dosed as positive controls at 40 mg/kg q12 h for 6 days.
Results
The addition of DUR effectively lowered the SUL MIC50/90 from 8/16 to 0.25/0.5 mg/L vs. B. pseudomallei and from 8/8 to 1/2 mg/L for B. mallei. All untreated mice in the melioidosis model succumbed to infection within 3 days of challenge. 60% survival was observed for both dose arms of SUL-DUR as compared with 40% survival observed for both CIP and DOX.
Conclusion
Preliminary preclinical data demonstrating robust in vitro and in vivo antibacterial activity of SUL-DUR against Burkholderia spp. suggests this combination may be an effective new therapy for the treatment of these challenging pathogens.
Disclosures
All authors: No reported disclosures.
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