Activities of Cefiderocol with Simulated Human Plasma Concentrations against Carbapenem-Resistant Gram-Negative Bacilli in an In Vitro Chemostat Model.

Activities of cefiderocol under simulated human plasma concentrations at the recommended dosing regimen of 2 g every 8 h with a 3-h infusion were evaluated using an in vitro chemostat model. Against a total of 6 meropenem-resistant Gram-negative strains with cefiderocol MICs of 0.5 to 4 µg/ml, including metallo-ß-lactamase producers and carbapenem-resistant Acinetobacter baumannii, cefiderocol treatment showed a bactericidal effect within 8 h and sustained efficacy with no marked bacterial regrowth over 24 h.

Comparison of the risk of acquiring in vitro resistance to doripenem and tazobactam/piperacillin by CTX-M-15-producing Escherichia coli.

To compare the risk of acquiring in vitro resistance between doripenem and tazobactam/piperacillin by CTX-M-15-producing Escherichia coli, the in vitro frequency of resistance was determined. Four strains carrying multiple ß-lactamases such as blaOXA-1 or blaCTX-M-27 as well as blaCTX-M-15 and blaTEM-1 were used. No resistant colonies appeared on doripenem-containing plates, whereas resistant colonies were obtained from three of four test strains against tazobactam/piperacillin using agar plate containing 8- to 16-fold MIC of each drug. These three acquired tazobactam/piperacillin-resistant strains were not cross-resistant to doripenem, and they showed 1.9- to 3.1-fold higher piperacillin-hydrolysis activity compared to those of each parent strain. The change of each ß-lactamase mRNA expression measured by real-time PCR varied among three resistant strains. One of three tazobactam/piperacillin-resistant strains with less susceptibility to ceftazidime overexpressed both blaCTX-M-15 and blaTEM-1, and the other two strains showed higher mRNA expression of either blaTEM-1 or blaOXA-1. These results demonstrate that multiple ß-lactamases carried by CTX-M-15-producing E. coli contributed to the resistance to tazobactam/piperacillin. On the other hand, these resistant strains maintained susceptibility to doripenem. The risk of acquiring in vitro resistance to doripenem by CTX-M-15-producing E. coli seems to be lower than that to tazobactam/piperacillin.

Prevalence and molecular characterization of CTX-M extended-spectrum ß-lactamase-producing Escherichia coli from 2000 to 2010 in Japan.

The prevalence of extended-spectrum ß-lactamase (ESBL) in Enterobacteriaceae has been increasing worldwide. The aims of this study were to determine the prevalence of ESBLs among clinical isolates of Escherichia coli obtained from 2000 to 2010 in Japan, and to characterize the sequence type (ST) and antimicrobial susceptibility of the bla(CTX-M)-carrying strains. The genes for ß-lactamases were determined by conventional PCR and sequencing, and the antimicrobial susceptibility test was performed by the broth microdilution method. Among the 948 strains, 35 were judged as ESBL-positive strains. The positive rates ranged from 0.6% to 3.9% until 2008, but surged to 10.3% in 2010. Thirty-three of them carried bla(CTX-M), but all were negative for ESBL-type bla(TEM) and bla(SHV). bla(CTX-M-14) was the most prevalent (18/33) among bla(CTX-M)-carrying strains, followed by bla(CTX-M-15) (7/33) of which five were isolated in 2008 and 2010. Additionally, bla(CTX-M-27) appeared in 2010 for the first time in this study and accounted for more than a third of the bla(CTX-M)-carrying strains. From the MLST analysis, ST131 known as a world pandemic clone, has been predominantly isolated since 2006. The major types of ESBLs carried by ST131 strains clearly shifted from bla(CTX-M-14) to bla(CTX-M-15) and/or bla(CTX-M-27) between 2006 and 2010. Most of these isolates were still susceptible to doripenem, latamoxef (moxalactam), flomoxef and cefmetazole. Our results suggest that a change of the dominant type of ESBL among Enterobacteriaceae is currently in progress in Japan, and therefore further periodic surveillance is needed.

Discovery of 2-Sulfinyl-Diazabicyclooctane Derivatives, Potential Oral ß-Lactamase Inhibitors for Infections Caused by Serine ß-Lactamase-Producing Enterobacterales.

Coadministration of ß-lactam and ß-lactamase inhibitor (BLI) is one of the well-established therapeutic measures for bacterial infections caused by ß-lactam-resistant Gram-negative bacteria, whereas we have only two options for orally active BLI, clavulanic acid and sulbactam. Furthermore, these BLIs are losing their clinical usefulness because of the spread of new ß-lactamases, including extended-spectrum ß-lactamases (ESBLs) belonging to class A ß-lactamases, class C and D ß-lactamases, and carbapenemases, which are hardly or not inhibited by these classical BLIs. From the viewpoints of medical cost and burden of healthcare personnel, oral therapy offers many advantages. In our search for novel diazabicyclooctane (DBO) BLIs possessing a thio-functional group at the C2 position, we discovered a 2-sulfinyl-DBO derivative (2), which restores the antibacterial activities of an orally available third-generation cephalosporin, ceftibuten (CTB), against various serine ß-lactamase-producing strains including carbapenem-resistant Enterobacteriaceae (CRE). It can be orally absorbed via the ester prodrug modification and exhibits in vivo efficacy in a combination with CTB.

Mechanism of resistance and antibacterial susceptibility in extended-spectrum ß-lactamase phenotype Klebsiella pneumoniae and Klebsiella oxytoca isolated between 2000 and 2010 in Japan.

Clinical isolates of Klebsiella pneumoniae and Klebsiella oxytoca collected from 20 Japanese medical facilities between 2000 and 2010 were analysed to evaluate the mechanisms of resistance and antibacterial susceptibilities to 14 antimicrobials. Overall, eight of 484 (1.6%) K. pneumoniae and 19 of 359 (5.3%) K. oxytoca were determined to be extended-spectrum ß-lactamase (ESBL) phenotype isolates, and the identified ESBLs amongst the K. pneumoniae isolates were CTX-M-2, -3, -14 and -15, and SHV-12. In contrast, overproduction of chromosomal ß-lactamase OXY-2, which was due to a distinct mutation at the - 10 promoter region of this gene, conferred the ESBL phenotype to all the K. oxytoca isolates except one. Based on the Clinical and Laboratory Standards Institute breakpoints, all the ESBL phenotype K. pneumoniae were susceptible to doripenem, flomoxef, moxalactam (latamoxef), cefmetazole and tazobactam/piperacillin, whereas the ESBL phenotype K. oxytoca were susceptible to ceftazidime and ceftibuten in addition to the above, with the exception of tazobactam/piperacillin. Amongst the oral antimicrobials, ceftibuten was relatively effective against both ESBL phenotype Klebsiella species compared with levofloxacin and amoxicillin/clavulanic acid.