Background. The comparative efficacy of ceftazidime/avibactam and meropenem/vaborbactam for treatment of carbapenem-resistant Enterobacteriaceae (CRE) infections remains unknown.Methods. This was a multicenter, retrospective cohort study of adults with CRE infections who received ceftazidime/avibactam or meropenem/vaborbactam for ≥72 hours from February 2015 to October 2018. Patients with a localized urinary tract infection and repeat study drug exposures after the first episode were excluded. The primary endpoint was clinical success compared between treatment groups. Secondary endpoints included 30- and 90-day mortality, adverse events (AE), 90-day CRE infection recurrence, and development of resistance in patients with recurrent infection. A post-hoc subgroup analysis was completed comparing patients who received ceftazidime/avibactam monotherapy, ceftazidime/avibactam combination therapy, and meropenem/vaborbactam monotherapy.Results. 131 patients were included (ceftazidime/avibactam, n = 105; meropenem/vaborbactam, n = 26), 40% of whom had bacteremia. No significant difference in clinical success was observed between groups (62% vs 69%; p = 0.49). Patients in the ceftazidime/avibactam arm received combination therapy more often than patients in the meropenem/vaborbactam arm (61% vs 15%; p less then 0.01). No difference in 30- and 90-day mortality resulted, and rates of AE were similar between groups.  https://www.selleckchem.com/products/Gefitinib.html  In patients with recurrent infection, development of resistance occurred in three patients that received ceftazidime/avibactam monotherapy and no patients in the meropenem/vaborbactam arm.Conclusions. Clinical success was similar between patients receiving ceftazidime/avibactam and meropenem/vaborbactam for treatment of CRE infections, despite ceftazidime/avibactam being used more often as combination therapy. Development of resistance was more common with ceftazidime/avibactam monotherapy. Copyright © 2020 American Society for Microbiology.Background The RESTORE-IMI 1 phase 3 trial (NCT02452047) demonstrated efficacy and safety of imipenem/cilastatin (IMI) combined with relebactam (REL) for treating imipenem-nonsusceptible infections. The objective of this analysis was to compare outcomes among patients meeting eligibility requirements based on central laboratory susceptibility versus local laboratory susceptibility.Methods Patients with serious infections caused by imipenem-nonsusceptible, colistin-susceptible, and imipenem/REL-susceptible pathogens were randomized 21 to IMI/REL plus placebo or colistin plus IMI for 5-21 days. The primary endpoint was favorable overall response. Key endpoints included clinical response and all-cause mortality. We compared outcomes between the primary microbiological modified intent-to-treat population (mMITT), where eligibility was based on central laboratory susceptibility testing, and the supplemental mMITT population (SmMITT), where eligibility was based on local, site-level testing.Results SmMITT (N=41) and MITT (N=31) had similar baseline characteristics, including sex, age, illness severity, and renal function. In both analysis populations, favorable overall response rates in the IMI/REL treatment group were >70%. Favorable clinical response rates at day 28 were 71.4% for IMI/REL and 40.0% for colistin plus IMI in mMITT compared with 75.0% for IMI/REL and 53.8% for colistin plus IMI in SmMITT. Day 28 all-cause mortality rates were 9.5% for IMI/REL and 30.0% for colistin plus IMI in mMITT compared with 10.7% for IMI/REL and 23.1% for colistin plus IMI in SmMITT.Conclusions Outcomes in SmMITT were generally consistent with those in mMITT, suggesting that outcomes may be applicable to real-world use of IMI/REL for treating imipenem-nonsusceptible gram-negative pathogens. Copyright © 2020 American Society for Microbiology.Current treatments for Acanthamoeba keratitis rely on a combination of chlorhexidine gluconate, propamidine isethionate, and polyhexamethylene biguanide. These disinfectants are nonspecific and inherently toxic, which limits their effectiveness. Furthermore, in 10% of cases, recurrent infection ensues due to the difficulty in killing both trophozoites and double-walled cysts. Therefore, development of efficient, safe, target-specific drugs which are capable of preventing recurrent Acanthamoeba infection is a critical unmet need for averting blindness. Since both trophozoites and cysts contain specific sets of membrane sterols, we hypothesized that antifungal drugs targeting sterol 14-demethylase (CYP51), known as conazoles, would have deleterious effects on A. castellanii trophozoites and cysts. To test this hypothesis, we first performed a systematic screen of the FDA-approved conazoles against A. castellanii trophozoites using a bioluminescence-based viability assay adapted and optimized for Acanthamoeba The most potent drugs were then evaluated against cysts. Isavuconazole and posaconazole demonstrated low nanomolar potency against trophozoites of three clinical strains of A. castellanii Furthermore, isavuconazole killed trophozoites within 24 hours and suppressed excystment of pre-formed Acanthamoeba cysts into trophozoites. The rapid action of isavuconazole was also evident from the morphological changes at nanomolar drug concentrations causing rounding of trophozoites within 24 hours of exposure. Given that isavuconazole has an excellent safety profile, is well tolerated in humans, and blocks A. castellanii excystation, this opens an opportunity for the cost-effective repurposing of isavuconazole for the treatment of primary and recurring Acanthamoeba keratitis. Copyright © 2020 American Society for Microbiology.The most significant feature of meiosis is the recombination process during prophase I. CXXC finger protein 1 (CXXC1) binds to CpG islands and mediates the deposition of H3K4me3 by the SETD1 complex. CXXC1 is also predicted to recruit H3K4me3-marked regions to the chromosome axis for the generation of double-strand breaks (DSBs) in the prophase of meiosis. Therefore, we deleted Cxxc1 before the onset of meiosis with Stra8-Cre The conditional knockout mice were completely sterile with spermatogenesis arrested at MII. Knockout of Cxxc1 led to a decrease in the H3K4me3 level from the pachytene to the MII stage and caused transcriptional disorder. Many spermatogenesis pathway genes were expressed early leading to abnormal acrosome formation in arrested MII cells. In meiotic prophase, deletion of Cxxc1 caused delayed DSB repair and improper crossover formation in cells at the pachytene stage, and more than half of the diplotene cells exhibited precocious homologous chromosome segregation in both male and female meiosis.