PDF(Pubmed)
Abstract：
Extended-spectrum-beta-lactamase (ESBL)-producing Enterobacterales continue to pose a major threat to human health worldwide. Given the limited therapeutic options available to treat infections caused by these pathogens, identifying additional effective antimicrobials or revisiting existing drugs is important. Ceftriaxone-resistant Escherichia coli and Klebsiella pneumoniae containing CTX-M-type ESBLs or AmpC, in addition to narrow-spectrum OXA and SHV enzymes, were selected from blood culture isolates obtained from the MERINO trial. Isolates had previously undergone whole-genome sequencing (WGS) to identify antimicrobial resistance genes. Cefotetan MICs were determined by broth microdilution (BMD) testing with a concentration range of 0.125 to 64 mg/liter; CLSI breakpoints were used for susceptibility interpretation. BMD was performed using an automated digital antibiotic dispensing platform (Tecan D300e). One hundred ten E. coli and 40 K. pneumoniae isolates were used. CTX-M-15 and CTX-M-27 were the most common beta-lactamases present; only 7 isolates had coexistent ampC genes. Overall, 98.7% of isolates were susceptible, with MIC50s and MIC90s of 0.25 mg/liter and 2 mg/liter (range, ≤0.125 to 64 mg/liter), respectively. MICs appeared higher among isolates with ampC genes present, with an MIC50 of 16 mg/liter, than among those containing CTX-M-15, which had an MIC50 of only 0.5 mg/liter. Isolates with an ampC gene exhibited an overall susceptibility of 85%. Presence of a narrow-spectrum OXA beta-lactamase did not appear to alter the cefotetan MIC distribution. Cefotetan demonstrated favorable in vitro efficacy against ESBL-producing E. coli and K. pneumoniae bloodstream isolates. IMPORTANCE Carbapenem antibiotics remain the treatment of choice for severe infection due to ESBL- and AmpC-producing Enterobacterales. The use of carbapenems is a major driver of the emergence of carbapenem-resistant Gram-negative bacilli, which are often resistant to most available antimicrobials. Cefotetan is a cephamycin antibiotic developed in the 1980s that demonstrates enhanced resistance to beta-lactamases and has a broad spectrum of activity against Gram-negative bacteria. Cefotetan holds potential to be a carbapenem-sparing treatment option. Data on the in vitro activity of cefotetan against ESBL-producing Enterobacterales remain scarce. Our study assessed the in vitro activity of cefotetan against ceftriaxone-nonsusceptible blood culture isolates obtained from patients enrolled in the MERINO trial.
摘要：
产超广谱β-内酰胺酶(ESBL)的肠杆菌继续对全球人类健康构成重大威胁。鉴于可用于治疗由这些病原体引起的感染的治疗选择有限，确定其他有效的抗菌药物或重新审视现有药物非常重要.含CTX-M型ESBLs或AmpC的耐头孢曲松大肠埃希菌和肺炎克雷伯菌,除了窄谱OXA和SHV酶，从MERINO试验获得的血液培养分离物中选择。分离株先前已经进行了全基因组测序(WGS)以鉴定抗微生物抗性基因。头孢替坦MIC是通过浓度范围为0.125至64mg/L的肉汤微量稀释（BMD）测试确定的；CLSI断点用于敏感性解释。使用自动数字抗生素分配平台(TecanD300e)进行BMD。使用一百一十种大肠杆菌和40种肺炎克雷伯菌分离物。CTX-M-15和CTX-M-27是存在的最常见的β-内酰胺酶;只有7个分离株具有共存的ampC基因。总的来说,98.7%的分离株是易感的,MIC50s和MIC90s分别为0.25毫克/升和2毫克/升(范围，≤0.125至64毫克/升)，分别。在存在ampC基因的分离株中，MIC似乎更高，MIC50为16毫克/升，比那些含有CTX-M-15，其MIC50仅为0.5毫克/升。具有ampC基因的分离株表现出85％的总体易感性。窄谱OXAβ-内酰胺酶的存在似乎没有改变头孢替坦MIC分布。头孢替坦证明了对产生ESBL的大肠杆菌和肺炎克雷伯菌血流分离株的良好体外功效。重要性碳青霉烯类抗生素仍然是由于产ESBL和AmpC肠杆菌引起的严重感染的首选治疗方法。碳青霉烯类抗生素的使用是碳青霉烯类耐药革兰氏阴性杆菌出现的主要驱动因素,通常对大多数可用的抗菌剂具有抗性。头孢替坦是1980年代开发的头孢霉素抗生素，对β-内酰胺酶具有增强的抗性，并且具有针对革兰氏阴性细菌的广谱活性。头孢替坦具有成为碳青霉烯保留治疗选择的潜力。关于头孢替坦对产生ESBL的肠杆菌的体外活性的数据仍然很少。我们的研究评估了头孢替坦对来自MERINO试验患者的头孢曲松非易感血液培养分离株的体外活性。
