Anti-Polymyxin E monoclonal antibody

The aim of this study is to investigate the combination of cefepime and sulbactam. Sulbactam, when administered , will effectively inhibit all Extended-spectrum beta lactamases (ESBLs) of the microorganism, while cefepime will inhibit the growth of the resistant microorganisms since it will not be hydrolyzed by OXA-48. Forty OXA-48-producingK. pneumoniaestrains were investigated for their Minimum inhibitory concentrations (MICs) for carbapenems, cefepime, and cefepime + sulbactam by broth microdilution method. Also, the mutant prevention concentration (MPC)s of cefepime alone or in combination with sulbactam was determined. Additionally, the bactericidal activities of cefepime and cefepime + sulbactam were evaluated by the time-kill curve (TKC) assay against selected strains. Also, the in vitro synergistic activity of cefepime + sulbactam combination was determined by TKC. Based on MIC results, up to 35/40 and 34/40 of the strains were resistant to carbapenems and cefepime, respectively. Cefepime + sulbactam MIC range was lower than those for cefepime alone against all the studied isolates. Moreover, cefepime + sulbactam combination presented lower MPC values than cefepime alone. The synergistic interactions of cefepime + sulbactam were also achieved against studied strains at 24 h. No antagonism was observed against studiedK. pneumoniaestrains. The findings of this study displayed that cefepime + sulbactam combination had synergistic or additive effect against OXA-48-producingK. pneumoniaestrains. Additionally, it was first observed that this combination could display a lower MPC than cefepime alone. Further investigations may be helpful for understanding the effectiveness of cefepime + sulbactam combinations for OXA-48-positive carbapenem-resistantK. pneumoniaeisolates.

Background. Polymyxins are antimicrobials of last resort for the treatment of carbapenem-resistant Enterobacteriaceae, but resistance in 5% to >40% isolates has been reported. We conducted a genomic survey of clinical polymyxin-resistant (PR) Klebsiella pneumoniae to determine the molecular mechanisms of PR and the role of polymyxin exposure versus transmission in PR emergence. Methods. We included 88 patients with PR K. pneumoniae from 2011-2018 and collected demographic, antimicrobial exposure, and infection data. Whole-genome sequencing was performed on 388 isolates, including 164 PR isolates. Variant calling and insertion sequence detection were performed, focusing on key genes associated with PR (mgrB, crrAB, phoPQ, and pmrAB). We conducted phylogenetic analyses of key K. pneumoniae multi-locus sequence types (ST258, ST17, ST307, and ST392). Results. Polymyxin exposure was documented in 53/88 (60%) patients prior to PR detection. Through an analysis of key PR genes, we detected 129 individual variants and 72 unique variant combinations in PR isolates. This included multiple, distinct changes in 36% of patients with serial PR isolates. Insertion sequence disruption was limited to mgrB (P<.001). Polymyxin minimum inhibitory concentrations showed stepwise increases with the number of PR genes affected (P<.001). When clusters containing PR isolates in >= 2 patients were analyzed, 10/14 had multiple genetic events leading to PR. Conclusions. Molecular mechanisms leading to PR in clinical K. pneumoniae isolates are remarkably heterogenous, even within clusters or individual patients. Polymyxin exposure with de novo PR emergence led to PR in the majority of patients, rather than transmission. Optimizing polymyxin use should be a key strategy in stopping the spread of PR.