In vitro efficacy of humanized regimen of flomoxef against extended-spectrum ß-lactamase-producing Escherichia coli and Klebsiella pneumoniae.

This study compared the efficacy of flomoxef with other ß-lactam antibiotics against extended-spectrum ß-lactamases (ESBL)-producing bacteria of clinical relevance. First, the prevalence and ß-lactamase genotypes of ESBL-producing strains among Escherichia coli and Klebsiella pneumoniae isolates collected in Japan from 2004 to 2018 were investigated. High MIC90 values (>64 µg/mL) of ceftriaxone, cefepime, and ceftazidime and low MIC90 values (≤0.06-2 µg/mL) of flomoxef, cefmetazole, and meropenem against both species were observed. Second, a chemostat model was used to analyze the efficacy of humanized regimens of three oxacephem/cephamycin antibiotics (flomoxef, cefmetazole, cefoxitin) and two other antibiotics (meropenem and piperacillin/tazobactam) in suppressing the growth of five ESBL-producing E. coli and two K. pneumoniae strains. Flomoxef, piperacillin/tazobactam, and meropenem showed good bactericidal effects with >4 log10 CFU/mL reduction without bacterial regrowth at 24 h even when the MIC of test isolates was >MIC90. Cefmetazole and cefoxitin resulted in regrowth of test isolates with MIC ≥MIC90 at 24 h. Cefmetazole, cefoxitin, flomoxef, and meropenem showed increased MICs for regrown samples. A clear relationship between the proportion of time that the free drug concentration exceeded the MIC (%fT>MIC) and antibiotic efficacy was found for flomoxef, cefoxitin, and cefmetazole, and flomoxef had the highest %fT>MIC, whereas discrepancies between Clinical and Laboratory Standards Institute breakpoint and bactericidal activity were observed for cefmetazole. Flomoxef was effective in preventing the growth of all ESBL-producing strains, even those with an MIC eight times the MIC90. Thus, flomoxef may be a good alternative to meropenem in context of carbapenems sparing stewardship.

Efficacy of ensitrelvir against SARS-CoV-2 in a delayed-treatment mouse model.

OBJECTIVES: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiological agent of coronavirus disease 2019 (COVID-19) and a devastating worldwide health concern. Development of safe and effective treatments is not only important for interventions during the current pandemic, but also for providing general treatment options moving forward. We have developed ensitrelvir, an antiviral compound that targets the 3C-like protease of SARS-CoV-2. In this study, a delayed-treatment mouse model was used to clarify the potential in vivo efficacy of ensitrelvir. METHODS: Female BALB/cAJcl mice of different ages were infected with the SARS-CoV-2 gamma strain (hCoV-19/Japan/TY7-501/2021) or mouse-adapted SARS-CoV-2 MA-P10 and then 24 h post-infection orally administered various doses of ensitrelvir or vehicle. Viral titres and RNA levels in the lungs were quantified using VeroE6/TMPRSS2 cells and RT-qPCR, respectively. Body weight loss, survival, lung weight, cytokine/chemokine production, nucleocapsid protein expression and lung pathology were evaluated to investigate the in vivo efficacy of ensitrelvir. RESULTS: Based on infectious viral titres and viral RNA levels in the lungs of infected mice, ensitrelvir reduced viral loads in a dose-dependent manner. The antiviral efficacy correlated with increased survival, reduced body weight loss, reduced pulmonary lesions and suppression of inflammatory cytokine/chemokine levels. CONCLUSIONS: This was the first evaluation of the in vivo anti-SARS-CoV-2 efficacy of ensitrelvir in a delayed-treatment mouse model. In this model, ensitrelvir demonstrated high antiviral potential and suppressed lung inflammation and lethality caused by SARS-CoV-2 infection. The findings support the continued clinical development of ensitrelvir as an antiviral agent to treat patients with COVID-19.

[In vitro combination effects of doripenem with aminoglycoside or ciprofloxacin against Pseudomonas aeruginosa].

This study evaluated the in vitro activity of combinations of doripenem (DRPM) with aminoglycosides (tobramycin or amikacin) or fluoroquinolone (ciprofloxacin) against 92 isolates of Pseudomonas aeruginosa from 16 clinical facilities in 2004 in Japan. We also tested combination effect of other carbapenems (imipenem (IPM), meropenem, biapenem) with aminoglycosides or fluoroquinolone by checkerboard dilution methods. DRPM showed synergistic or additive effects with the aminoglycosides or the fluoroquinolone against 90% of the isolates. The combination of DRPM and aminoglycosides showed the strongest synergistic effects against IPM-intermediate resistant and IPM resistant strains among the tested combinations. These results suggested that combination of DRPM with aminoglycosides would be useful for the treatment of infections caused by P aeruginosa including IPM-resistant strains.

Susceptibility of Pseudomonas aeruginosa clinical isolates in Japan to doripenem and other antipseudomonal agents.

We investigated the susceptibility of 694 Pseudomonas aeruginosa clinical isolates to nine antipseudomonal agents including doripenem. Test strains were collected from 23 Japanese medical facilities from 1992 to 2004. Doripenem showed a minimum inhibitory concentration for 90% of the organisms (MIC(90)) of 8 microg/mL, which was the lowest among the tested antipseudomonal agents. The MIC(90) of doripenem was 2-fold lower than that of meropenem, imipenem and amikacin and was > or =4-fold lower than that of piperacillin/tazobactam, ceftazidime, cefepime, ciprofloxacin and tobramycin. Amikacin showed the lowest rate of resistance against all clinical isolates (5.8%) followed by doripenem (7.1%). No remarkable changes were observed from 1992 to 2004 in the frequency of P. aeruginosa strains resistant to the tested agents, except for imipenem. Of 116 ceftazidime-resistant strains, from 44.0% to 50.8% were susceptible to the three carbapenems, but only 2.6% to cefepime. Of 138 imipenem-resistant strains, from 44.2% to 51.4% were susceptible to doripenem and both cephems, but 25.4% to meropenem. Doripenem was more active against imipenem- or ceftazidime-resistant strains than meropenem, although the activity of doripenem correlated well with that of meropenem. In conclusion, doripenem had the most potent in vitro activity against P. aeruginosa clinical isolates among the tested antibiotics. Considering the trend of antimicrobial resistance of the clinical isolates in well-focused surveillance, pseudomonal infections should be treated with appropriate chemotherapy using antimicrobial agents with potent antipseudomonal activity and low resistance rates, such as doripenem, in order to prevent the outbreak of resistant strains.