1642. A Novel β-lactamase Inhibitor (Durlobactam, DUR) and β-Lactams Enhance Susceptibility Against Multidrug-Resistant (MDR) Mycobacterium abscessus (Mab)
In: Open Forum Infect Dis, 2020
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Zugriff:
BACKGROUND: Mab is a MDR nontuberculous mycobacterium that causes lung infections in patients with structural lung disease. Mab harbors a chromosomally encoded class A β-lactamase, Bla(Mab), able to hydrolyze penicillins, cephalosporins and carbapenems. L,D- and D,D-transpeptidases (L,D TP and D,D TP) shape peptidoglycan (PG) synthesis and contribute to cell wall structure. Select combinations of β-lactams that inhibit L,D TP and D,D TPs and Bla(Mab) are desirable as they can potentially improve treatment outcomes. DUR is a novel DBO β-lactamase inhibitor (BLI) with broad-spectrum activity against Ambler class A, C, and D β-lactamases (Fig.). Here, we investigated the mechanism of action and efficacy of DUR alone and combined with select β-lactams in restoring susceptibility of Mab to β-lactam antibiotics METHODS: Minimum inhibitory concentrations (MICs) of cefuroxime (CEF), imipenem (IMI) and amoxicillin (Amox) with or without DUR were determined using microdilution. Approximately 5 x 10(5) colony-forming units per milliliter were inoculated into Middlebrook 7H9 Broth supplemented with 10% (vol/vol) oleic albumin dextrose catalase and 0.05% (vol/vol) Tween 80. When more than 2 drugs were combined, Amox was added at fixed concentration of 8 µg/ml to serial dilutions of CEF-DUR or IMI-DUR. Mab isolates were incubated with test agents at 30°C for 48 h, and MIC was defined as lowest antibiotic concentration that prevented visible bacterial growth. Reaction intermediates in the inactivation pathway of Bla(Mab,) L,D-TP and D,D-TPs with DUR RESULTS: One hundred clinically derived and previously characterized isolates were tested in these assays. MIC(50) and MIC(90) of DUR alone was 4 and 8 µg/ml, demonstrating intrinsic activity. Combinations of DUR-IMI or DUR-CEF plus 8 µg/mL Amox lowered MIC(50) to < 0.06 µg/ml in all 100 clinical isolates (Table). Mass spectrometry analyses of Bla(Mab), L,D-TP and D,D-TPs (Mab (2,4)) inactivated by DUR showed formation of stable adducts of DUR to Bla(Mab), L,D-TP and D,D-TPs ...
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1642. A Novel β-lactamase Inhibitor (Durlobactam, DUR) and β-Lactams Enhance Susceptibility Against Multidrug-Resistant (MDR) Mycobacterium abscessus (Mab)
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Autor/in / Beteiligte Person: | Dousa, Khalid M ; Kurz, Sebastian G ; Bethel, Christopher ; Miller, Alita ; Bonomo, Robert A |
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Zeitschrift: | Open Forum Infect Dis, 2020 |
Veröffentlichung: | Oxford University Press, 2020 |
Medientyp: | academicJournal |
DOI: | 10.1093/ofid/ofaa439.1822 |
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