Among 177 carbapenemase-producing Gram-negative bacilli (108 KPC, 32 NDM, 11 IMP, 8 OXA-48, 4 OXA-181, 2 OXA-232, 5 IMI, 4 VIM, and 3 SME producers), aztreonam-avibactam was active against all isolates except two NDM producers with elevated MICs of 8/4 and 16/4 mg/liter; ceftazidime-avibactam was active against all KPC-, IMI-, SME-, and most OXA-48 group-producing isolates (93%) but not metallo--lactamase producers. Among older and contemporary antimicrobials, the most active were colistin, tigecycline, and fosfomycin, with overall susceptibilities of 88%, 79%, and 78%, respectively.
The recent emergence and global dissemination of carbapenemase-producing Gram-negative bacilli (CP-GNB) pose a significant therapeutic challenge. Avibactam is a diazabicyclooctane non--lactam -lactamase inhibitor with broad activity against Ambler class A and C -lactamases and certain class D -lactamases by covalent acylation of the -lactamase active site serine residue. It restores susceptibility of Enterobacteriaceae harboring extended-spectrum -lactamases (ESBLs), AmpC cephalosporinases, and class A carbapenemases to ceftazidime or ceftaroline (1). In vitro studies of avibactam in combination with aztreonam have also demonstrated activity against Enterobacteriaceae harboring NDM (a class B metallo--lactamase); however, there are scant data for the other less commonly encountered carbapenemases (2-4).The aim of this study was to examine the activities of ceftazidime and aztreonam with and without avibactam against a large, contemporary, international collection of CP-GNB with diverse resistance mechanisms, with MICs determined using agar dilution as recommended by the Clinical and Laboratory Standards Institute (CLSI) (5, 6). A secondary aim was to evaluate the activity of antimicrobials commonly used to treat CP-GNB infections, including the "legacy antibiotics" colistin, amdinocillin (mecillinam), and fosfomycin. A total of 177 CP-GNB were studied (Table 1), comprising 122 and 53 clinical isolates from the United States and Singapore, respectively, and 2 NCTC (National Collection of Type Cultures, United Kingdom) reference isolates. These consisted of 172 Enterobacteriaceae isolates (107 KPC, 32 NDM, 8 OXA-48, 4 OXA-181, 2 OXA-232, 5 IMI, 3 SME, and 11 IMP producers) and 5 Pseudomonas aeruginosa isolates (4 VIM producers and 1 KPC producer). Genotypic characterization was performed using PCR/sequencing as previously described (7-15). All CP-GNB isolates tested positive by the CarbaNP test (16), except for one isolate each of OXA-181 and OXA-232, which were CarbaNP negative, and one OXA-48-producing isolate, which was CarbaNP indeterminate. In addition, as a control/comparator group, we studied 29 Enterobacteriaceae (11 Klebsiella pneumoniae and 18 Escherichia coli isolates), including 18 ESBL producers (10 with porin loss), 6 plasmid-mediated AmpC producers (1 with porin loss and another coproducing an ESBL), and 5 derepressed AmpC mutants (2 with porin loss).(This work was presented in part at the 54th Interscience Conf...