Effectiveness of Fosfomycin for the Treatment of Multidrug-Resistant Escherichia coli Bacteremic Urinary Tract Infections

IMPORTANCE The consumption of broad-spectrum drugs has increased as a consequence of the spread of multidrug-resistant (MDR) Escherichia coli. Finding alternatives for these infections is critical, for which some neglected drugs may be an option. OBJECTIVE To determine whether fosfomycin is noninferior to ceftriaxone or meropenem in the targeted treatment of bacteremic urinary tract infections (bUTIs) due to MDR E coli. DESIGN, SETTING, AND PARTICIPANTS This multicenter, randomized, pragmatic, open clinical trial was conducted at 22 Spanish hospitals from June 2014 to December 2018. Eligible participants were adult patients with bacteremic urinary tract infections due to MDR E coli; 161 of 1578 screened patients were randomized and followed up for 60 days. Data were analyzed in May 2021. INTERVENTIONS Patients were randomized 1 to 1 to receive intravenous fosfomycin disodium at 4 g every 6 hours (70 participants) or a comparator (ceftriaxone or meropenem if resistant; 73 participants) with the option to switch to oral fosfomycin trometamol for the fosfomycin group or an active oral drug or pa renteral ertapenem for the comparator group after 4 days. MAIN OUTCOMES AND MEASURES The primary outcome was clinical and microbiological cure (CMC) 5 to 7 days after finalization of treatment; a noninferiority margin of 7% was considered. RESULTS Among 143 patients in the modified intention-to-treat population (median [IQR] age, 72 [62-81] years; 73 [51.0%] women), 48 of 70 patients (68.6%) treated with fosfomycin and 57 of 73 patients (78.1%) treated with comparators reached CMC (risk difference, -9.4 percentage points; 1-sided 95% CI, -21.5 to infinity percentage points; P = .10). While clinical or microbiological failure occurred among 10 patients (14.3%) treated with fosfomycin and 14 patients (19.7%) treated with comparators (risk difference, -5.4 percentage points; 1-sided 95% CI. -infinity to 4.9; percentage points; P = .19), an increased rate of adverse event-related discontinuations occurred with fosfomycin vs comparators (6 discontinuations [8.5%] vs 0 discontinuations; P = .006). In an exploratory analysis among a subset of 38 patients who underwent rectal colonization studies, patients treated with fosfomycin acquired a new ceftriaxone-resistant or meropenem-resistant gram-negative bacteria at a decreased rate compared with patients treated with comparators (0 of 21 patients vs 4 of 17 patients [23.5%]; 1-sided P = .01). CONCLUSIONS AND RELEVANCE This study found that fosfomycin did not demonstrate noninferiority to comparators as targeted treatment of bUTI from MDR E coli; this was due to an increased rate of adverse event-related discontinuations. This finding suggests that fosfomycin may be considered for selected patients with these infections

Adelante / Endavant

Séptimo desafío por la erradicación de la violencia contra las mujeres del Institut Universitari d’Estudis Feministes i de Gènere "Purificación Escribano" de la Universitat Jaume

Chemical inactivation of Pat1: A novel approach to synchronize meiosis

This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License.Comment on: Guerra-Moreno A, et al. Cell Cycle 2012; 11:1621–5; PMID:22456336; and Cipak L, et al. Cell Cycle 2012; 11:1626–33; PMID:22487684.Peer Reviewe

Nutrients control cell size

Editorials: Cell Cycle Features.Cells must grow to reach a critical size before cell division. In 1977 Fantes and Nurse established that this critical size depends on the nutritional environment.Peer Reviewe

Regulation of meiotic progression by the meiosis-specific checkpoint kinase Mek1 in fission yeast

During the eukaryotic cell cycle, accurate transmission of genetic information to progeny is ensured by the operation of cell cycle checkpoints. Checkpoints are regulatory mechanisms that block cell cycle progression when key cellular processes are defective or chromosomes are damaged. During meiosis, genetic recombination between homologous chromosomes is essential for proper chromosome segregation at the first meiotic division. In response to incomplete recombination, the pachytene checkpoint (also known as the meiotic recombination checkpoint) arrests or delays meiotic cell cycle progression, thus preventing the formation of defective gametes. Here, we describe a role for a meiosis-specific kinase, Mek1, in the meiotic recombination checkpoint in fission yeast. Mek1 belongs to the Cds1/Rad53/Chk2 family of kinases containing forkhead-associated domains, which participate in a number of checkpoint responses from yeast to mammals. We show that defects in meiotic recombination generated by the lack of the fission yeast Meu13 protein lead to a delay in entry into meiosis I owing to inhibitory phosphorylation of the cyclin-dependent kinase Cdc2 on tyrosine 15. Mutation of mek1+ alleviates this chekpoint-induced delay, resulting in the formation of largely inviable meiotic products. Experiments involving ectopic overexpression of the mek1+ gene indicate that Mek1 inhibits the Cdc25 phosphatase, which is responsible for dephosphorylation of Cdc2 on tyrosine 15. Furthermore, the meiotic recombination checkpoint is impaired in a cdc25 phosphorylation site mutant. Thus, we provide the first evidence of a connection between an effector kinase of the meiotic recombination checkpoint and a crucial cell cycle regulator and present a model for the operation of this meiotic checkpoint in fission yeast.L.P.-H. is a recipient of a predoctoral fellowship from CSIC, Spain. P.A.S.-S. is a ‘Ramón y Cajal’ investigator of the Ministry of Science and Technology of Spain. This work was supported by grants from CICYT and the European Union to S.M.Peer Reviewe

Coupling TOR to the cell cycle by the greatwall-endosulfine-PP2A-B55 pathway

Cell growth and division are two processes tightly coupled in proliferating cells. While Target of Rapamycin (TOR) is the master regulator of growth, the cell cycle is dictated by the activity of the cyclin-dependent kinases (CDKs). A long-standing question in cell biology is how these processes may be connected. Recent work has highlighted that regulating the phosphatases that revert CDK phosphorylations is as important as regulating the CDKs for cell cycle progression. At mitosis, maintaining a low level of protein phosphatase 2A (PP2A)-B55 activity is essential for CDK substrates to achieve the correct level of phosphorylation. The conserved Greatwall–Endosulfine pathway has been shown to be required for PP2A-B55 inhibition at mitosis in yeasts and multicellular organisms. Interestingly, in yeasts, the Greatwall–Endosulfine pathway is negatively regulated by TOR Complex 1 (TORC1). Moreover, Greatwall–Endosulfine activation upon TORC1 inhibition has been shown to regulate the progression of the cell cycle at different points: the G1 phase in budding yeast, the G2/M transition and the differentiation response in fission yeast, and the entry into quiescence in both budding and fission yeasts. In this review, we discuss the recent findings on how the Greatwall–Endosulfine pathway may provide a connection between cell growth and the cell cycle machineryThis work was supported by grants from the Spanish Ministry of Economy and Competitiveness MINECO (BFU2014-55439) and Junta de Castilla y León (CSI084U16).Peer reviewe

Fission yeast cell cycle synchronization methods

Fission yeast cells can be synchronized by cell cycle arrest and release or by size selection. Cell cycle arrest synchronization is based on the block and release of temperature-sensitive cell cycle mutants or treatment with drugs. The most widely used approaches are cdc10-129 for G1; hydroxyurea (HU) for early S-phase; cdc25-22 for G2, and nda3-KM311 for mitosis. Cells can also be synchronized by size selection using centrifugal elutriation or a lactose gradient. Here we describe the methods most commonly used to synchronize fission yeast cells.This work was funded by grants BFU2011-28274 from the Spanish Ministry of Economy and Competitiveness MINECO and CSI151U13 from la Junta de Castilla y León. M.T.-P. is a recipient of a CSIC JAE-predoctoral fellowship.Peer Reviewe

Slk1 is a meiosis-specific Sid2-related kinase that coordinates meiotic nuclear division with growth of the forespore membrane

Septation and spore formation in fission yeast are compartmentalization processes that occur during the mitotic and meiotic cycles, and that are regulated by the septation. initiation network (SIN). In mitosis, activation of Sid2 protein kinase transduces the signal from the spindle pole body (SPB) to the middle of the cell in order to promote the constriction of the actomyosin ring. Concomitant with ring contraction, membrane vesicles are added at the cleavage site to enable the necessary expansion of the cell membrane. In meiosis, the forespore membrane is synthesized from the outer layers of the SPB by vesicle fusion. This membrane grows and eventually engulfs each of the four haploid nuclei. The molecular mechanism that connects the SIN pathway with synthesis of the forespore membrane is poorly understood. Here, we describe a meiosis-specific Sid2-like kinase (Slk1), which is important for the coordination of the growth of the forespore membrane with the meiotic nuclear divisions. Slk1 and Sid2 are required for forespore membrane biosynthesis and seem to be the final output of the SIN pathway in meiosis.This work was supported by grants from the Spanish Ministry of Science and Education to S.M. (BFU2005-03195, GEN2003-20243-C08-05 and CDS2007-00015).Peer Reviewe

Modified cell cycle regulation in meiosis

The study of meiosis regulation has always been carried out in parallel with mitotic cell cycle discoveries. The basic cell cycle machinery that regulates mitosis, based on fluctuations in the activity of cyclin-dependent kinases (CDKs), is responsible for the main transitions that occur during meiosis. However, the special characteristics of meiosis (e.g., the absence of an S-phase between meiosis I and meiosi II, a long prophase in which homologous recombination events occur, etc.) require specific regulation, and cells respond to this challenging situation in different ways. In some cases, mitotic regulators carry out the new functions or change their relative importance in a particular process, while in other cases novel meiosis-specific regulators emerge. In this chapter, we shall analyze these special modifications, beginning with the specific signals that cells receive to exit the mitotic cell cycle and enter meiosis. We shall review how mitotic regulators adapt to the necessities of the meiotic program, paying particular attention to meiosis-specific factors whose functions are essential for meiosis to be completed successfully.C.M.-C. is supported by the Spanish Ministry of Science and Education-FEDER (Ramón y Cajal Program). The work in our laboratory is supported by grants from the Spanish Ministry of Health to C.M.-C. (FIS-FEDER 03/1193) and the Spanish Ministry of Science and Education to S.M. (BMC2005-03195 and GEN2003-20243-C08-05).Peer Reviewe