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Background: β-lactams are the main antibiotics used against wild-type AmpC-producing Enterobacterales (wtAE). However, they may fail or select AmpC-overproducing mutants. Our aim was to assess factors associated with clinical failure of β-lactams in the treatment of wtAE infection., Methods: From September 2017 to December 2020, we prospectively included all consecutive patients treated by definitive β-lactams therapy for wtAE infection in four university ICUs. Clinical failure was defined as inadequate response to antimicrobial therapy leading to death or to the switch for a broader-spectrum antibiotic., Results: 177 patients were included and 29.4% progressed to clinical failure. E. cloacae was the most prevalent species (42.4%) and ventilator-associated pneumonia (VAP) was the most frequent wtAE infection (69.5%). Cefepime and cefotaxime were used as definitive antibiotic treatment in 42.9% and 27.7% of patients, respectively. Occurrence of AmpC-overproduction was documented in 5.6% of patients and was associated with clinical failure (p = 0.004). In multivariate analysis, VAP (p < 0.001, OR 11.58 [95% CI 3.11-43.02] and K. aerogenes (p = 0.030, OR 3.76 [95% CI 1.13-12.46]) were independently associated with clinical failure. Conversely, cefotaxime as definitive treatment was found inversely associated with the risk of clinical failure (p = 0.022, OR 0.25 [95% CI 0.08-0.82]). After inverse probability weighting, cefotaxime showed a 20% risk reduction of clinical failure (95% CI  5-35%, p = 0.007) whatever the location of infection, the SOFA score on the day of wtAE infection, or the bacterial species., Conclusions: Clinical failure in the treatment of wtAE infections is associated with the infection site and the causal microorganism. Additionally, cefotaxime use is probably protective against clinical failure in wtAE infection., (© 2022. The Author(s).)

Sporadic colorectal cancer (CRC) is a result of complex interactions between the host and its environment. Environmental stressors act by causing host cell DNA alterations implicated in the onset of cancer. Here we investigate the stressor ability of CRC-associated gut dysbiosis as causal agent of host DNA alterations. The epigenetic nature of these alterations was investigated in humans and in mice. Germ-free mice receiving fecal samples from subjects with normal colonoscopy or from CRC patients were monitored for 7 or 14 wk. Aberrant crypt foci, luminal microbiota, and DNA alterations (colonic exome sequencing and methylation patterns) were monitored following human feces transfer. CRC-associated microbiota induced higher numbers of hypermethylated genes in murine colonic mucosa (vs. healthy controls' microbiota recipients). Several gene promoters including SFRP1,2,3, PENK, NPY, ALX4, SEPT9, and WIF1 promoters were found hypermethylated in CRC but not in normal tissues or effluents from fecal donors. In a pilot study ( n = 266), the blood methylation levels of 3 genes ( Wif1 , PENK , and NPY ) were shown closely associated with CRC dysbiosis. In a validation study ( n = 1,000), the cumulative methylation index (CMI) of these genes was significantly higher in CRCs than in controls. Further, CMI appeared as an independent risk factor for CRC diagnosis as shown by multivariate analysis that included fecal immunochemical blood test. Consequently, fecal bacterial species in individuals with higher CMI in blood were identified by whole metagenomic analysis. Thus, CRC-related dysbiosis induces methylation of host genes, and corresponding CMIs together with associated bacteria are potential biomarkers for CRC., Competing Interests: Competing interest statement: I.S. shares rights in 3 patents: EP B31120, EP2635705, and EP 2955232 A1 20151216 based on methods for diagnosing adenomas and/or colorectal cancer.

Background: Antibiotic-impregnated external ventricular drains (AI-EVDs) have a debated efficacy in clinical studies., Objectives: Our aim was to assess the durability of antimicrobial activity of AI-EVDs used in clinical settings., Methods: From April 2017 to January 2018, all consecutive AI-EVDs (Bactiseal™) inserted in adult patients were prospectively included. After removal, each AI-EVD was cultured and assessed for antimicrobial activity on both internal and external sides of AI-EVDs. Catheters were each challenged with a single Staphylococcus strain [MSSA, MRSA or methicillin-resistant Staphylococcus epidermidis (MRSE)]. MS was used to measure residual concentrations of rifampicin and clindamycin., Results: Sixty-five AI-EVDs were included (56 patients). Among these, 21 were challenged with MSSA, 23 with MRSA and 21 with MRSE. Five ventriculostomy-related colonizations (9%) and two ventriculostomy-related infections (4%) occurred. Staphylococcus was the main bacterium responsible for colonization (4/5). AI-EVD inhibition decreased significantly against MRSA and MRSE according to duration of catheterization (for external and internal sides, P < 0.02) and overall volume of CSF drained (P < 0.005 for both sides against MRSE, P < 0.005 for external side against MRSA), but not against MSSA. Clindamycin concentration was not correlated with duration of catheterization or CSF volume drained, but <20% of initial concentration was recovered even after 5 days of AI-EVD dwelling. Conversely, rifampicin concentration showed a rapid and significant decline correlated to duration and CSF volume (P < 0.001 and P = 0.03, respectively)., Conclusions: Antimicrobial activity of AI-EVDs dropped quickly in vivo. Antimicrobial impregnation did not prevent AI-EVD colonization by susceptible strains in 9% of the cases., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: This study aimed to assess the reliability of clinical features, noninvasive transcranial Doppler-related pulsatility index (PI) calculation, and optic nerve sheath diameter (ONSD) measured by ultrasound (US) and initial computed tomography (CT) scan (Marshall CT scan classification) in predicting the occurrence of early (<24 hours) high intracranial pressure (EHICP) (>20 mm Hg) after severe traumatic brain injury (TBI)., Methods: We conducted an observational prospective study in a level 1 trauma center. Patients were measured simultaneously for PI and US ONSD in the triage zone. Patients were categorized into 2 groups: those who had EHICP after TBI (EHICP+) and those who did not (EHICP-)., Results: Fifty-four patients were included; 32 were categorized as EHICP+ and 22 as EHICP-. PI >1.4 did not correlate with EHICP+ patients (69% vs. 46%, P = 0.09). US ONSD measurement was higher in the EHICP+ group (6.25; range, 6-6.95 vs. 5.7; range, 5.2-6.4; P = 0.005). The area under the receiver operating characteristic curve for US ONSD as a predictor of developing EHICP was 0.73 (95% confidence interval [CI], 0.59-0.86). CT ONSD measurement was higher in the EHICP+ group (6.71; range, 6.35-7.87 vs. 6.25; range, 5.8-6.93; P = 0.04). The area under the receiver operating characteristic curve for CT ONSD measurement as a predictor for EHICP+ was 0.67 (95% CI, 0.53-0.81). The diffuse injury III and IV categories in the Marshall CT scan classification were associated with the occurrence of EHICP (P = 0.004)., Conclusions: None of the clinical features or noninvasive tools assessed in this study enabled clinicians to strictly ascertain EHICP. Further studies are needed to establish their potential role before intracranial pressure probe insertion., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Acinetobacter baumannii meningitis and ventriculitis are difficult issues, because of the low diffusion of antibiotics in the cerebrospinal fluid and bacterial multidrug resistance. The presence of an infected intraventricular hematoma, constituting an equivalent of undrained abscess, may promote biofilm formation and failure of medical treatment., Case Description: In this case of ventriculostomy-related infection after ventricular hemorrhage, Acinetobacter baumannii was sensitive only to colistin and tigecycline. Despite a combination therapy involving intraventricular injections of colistin, we observed clinical and bacteriologic failure. Therefore, at day 4 of antibiotic therapy, we performed intraventricular fibrinolysis, which dissolved the clot, enabling sterilization of the cerebrospinal fluid after 48 hours., Conclusion: This clinical case suggests the usefulness of intraventricular fibrinolysis to lyse the clot and optimize the action of antibiotics., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: The authors aimed to describe the natural history of ventriculostomy-related infections (VRIs) under appropriate treatment and to assess risk factors for poor outcome., Methods: All patients older than 18 years in whom an external ventricular drain (EVD) had been implanted and who had developed a VRI requiring treatment were included in this retrospective study. D0 was defined as the first day of antibiotic administration. Clinical and biological parameters were compared each day beginning with D1 and ending with D10 to those of D0. The authors defined D0 in a control group as the day a CSF culture came back positive, without any sign of infection. The authors then searched for poor prognostic factors in the VRI group., Results: Among 567 patients requiring an EVD between January 2007 and October 2017, 39 developed a VRI. Most were monomicrobial infections, and 47 microbes were responsible (45% were gram-positive cocci). Clinical parameters differed significantly from the control group during the first 2 days and then returned to baseline. The CSF parameters differed significantly from the control group for a longer period, returning to baseline after 5 days. CSF sterilization occurred in a median time of 2 days. An intrathecal route or EVD exchange was not associated with a poor outcome. No clinical or biological parameter between D3 and D5 was linked to outcome., Conclusions: Clinical status improved faster than CSF parameters (before and after D5, respectively). Some CSF parameters remained abnormal until D10. Body temperature and microbiological cultures normalized faster than other parameters.

Purpose: F14512 is a new topoisomerase II inhibitor containing a spermine moiety that facilitates selective uptake by tumor cells and increases topoisomerase II poisoning. F14512 is currently in a phase I/II clinical trial in patients with acute myeloid leukemia. The aim of this study was to investigate F14512 potential in a new clinical indication. Because of the many similarities between human and dog lymphomas, we sought to determine the tolerance, efficacy, pharmacokinetic/pharmacodynamic (PK/PD) relationship of F14512 in this indication, and potential biomarkers that could be translated into human trials., Experimental Design: Twenty-three dogs with stage III-IV naturally occurring lymphomas were enrolled in the phase I dose-escalation trial, which consisted of three cycles of F14512 i.v. injections. Endpoints included safety and therapeutic efficacy. Serial blood samples and tumor biopsies were obtained for PK/PD and biomarker studies., Results: Five dose levels were evaluated to determine the recommended dose. F14512 was well tolerated, with the expected dose-dependent hematologic toxicity. F14512 induced an early decrease of tumoral lymph node cells, and a high response rate of 91% (21/23) with 10 complete responses, 11 partial responses, 1 stable disease, and 1 progressive disease. Phosphorylation of histone H2AX was studied as a potential PD biomarker of F14512., Conclusions: This trial demonstrated that F14512 can be safely administered to dogs with lymphoma resulting in strong therapeutic efficacy. Additional evaluation of F14512 is needed to compare its efficacy with standards of care in dogs, and to translate biomarker and efficacy findings into clinical trials in humans., (©2015 American Association for Cancer Research.)

Objective: There are no available criteria for determining the optimal flow rate and mean arterial pressure level in patients undergoing cardiopulmonary bypass (CPB). Transcutaneous carbon dioxide tension (PtCO2) has been proposed for microcirculation monitoring and it could be useful for guiding hemodynamic optimization under CPB. The goal of this exploratory study was to determine the factors that influence PtCO2 variations during CPB., Design: Cutaneous ear lobe CO2 tension was monitored along with hemodynamic parameters every 10 minutes during CPB, until aortic unclamping., Setting: French university teaching hospital., Participants: Patients scheduled for cardiac surgery requiring CPB were prospectively included., Intervention: None., Measurements and Main Results: A total of 41 patients were included (520 observations). There was a statistically significant association between PaCO2 and PtCO2 (beta = 0.493 [0.154-0.832], p = 0.043), mostly when PaCO2 was outside the normal range. When PaCO2 was normal, PtCO2 was inversely correlated with mean arterial pressure (after adjustment for PaCO2 and body temperature: Beta -0.245, SE = 0.037, p<0.001) but not with CPB flow rate (p = 0.11)., Conclusion: The factors that influence PtCO2 during CPB cardiac surgery are PaCO2, body temperature, and mean arterial pressure. When PaCO2 is normal, a PtCO2 elevation might be explained by insufficient mean arterial pressure. Whether low PtCO2 values during CPB should trigger the administration of vasoconstrictors remains to be evaluated., (Copyright © 2015 Elsevier Inc. All rights reserved.)

During its intraerythrocytic development, Plasmodium falciparum synthesizes several proteins that are exported beyond its membrane. Some of these secreted antigens are involved in the formation of protuberances or knobs, a major virulence factor, at the erythrocyte membrane. Various secreted malarial polypeptides, the transport of which is sensitive to brefeldin A, are translocated in vitro into dog pancreatic microsomes. We present evidence that the histidine-rich protein I (PfHRPI) is secreted by the parasite via a novel pathway, independent of the ER/Golgi apparatus. The secretion of PfHRPI was not blocked by incubation of parasite cultures at 15 degrees C and 20 degrees C or 37 degrees C in the presence of brefeldin A. PfHRPI was not translocated into microsomes in an in vitro translation-translocation cell-free system. Unlike other polypeptides from eukaryotic cells that bypass the ER/Golgi pathway and do not have a signal peptide, PfHRPI has an atypical signal sequence consisting of 21 amino acids, including eight positively charged residues followed by 11 hydrophobic residues. We also found that the unusually charged PfHRPI signal sequence diverts Exp-1, which is usually exported, away from the translocation machinery of microsomal membranes.

Plasmodium falciparum secretes several proteins that cause changes in the erythrocyte membrane enabling it to survive within red blood cells. Little is known of the mechanisms involved in the secretion and targeting of parasite polypeptides to the various cell compartments. The P. falciparum gene homologous to the mammalian Sec61alpha, gene, which encodes a component of the translocation pore in the endoplasmic reticulum of eukaryotic cells, was characterised to investigate the translocation process in the parasite. PfSec61 is present as a unique copy in the parasite genome and was mapped to chromosome 13. It encodes a 40 kDa polypeptide, as shown by immunoblotting and immunoprecipitation of [35S]methionine metabolically-labelled parasite extracts. The deduced amino acid sequence of PfSec61 is 87% similar to the mammalian polypeptide, and the two proteins give similar hydropathy plots. These results strongly suggest that PfSec61 has the same topological orientation and functional role as Sec61alpha. Anti-PfSec61 antibodies were used to investigate the cellular location and kinetics of expression of the polypeptide in the parasite. Immunofluorescence confocal microscopy showed that PfSec61 was located in the parasite cytoplasm, close to the nucleus, in a position consistent with its being in the endoplasmic reticulum.

A highly sensitive and specific assay was developed for routine analysis of zacopride at the femtomole level in human plasma and urine. Zacopride and the deuterated internal standard [(2H3)zacopride] were measured by gas chromatography/negative ion chemical ionization mass spectrometry with methane as the reagent gas. A multiple-step liquid-liquid extraction procedure was used to isolate the two compounds of interest from complex biological matrices. Zacopride was converted to the fluorinated derivative with pentafluoropropionic anhydride. The mass spectrometer was tuned to monitor the very intense [M-HF]- ion at m/z 435 which was generated into the ion source by a dissociative capture process. This assay was performed with 1 ml of plasma or 0.2 ml of urine, and the quantification limit of the method was calculated as 10 pg ml-1 using a suitable statistical test. The very low relative standard deviation and mean percentage error values calculated during the within-day or between-day repeatability assays have clearly demonstrated the ruggedness of the technique for the routine quantitative measurement of zacopride in plasma and urine. Some preliminary results on the pharmacokinetics of this potent drug are presented to illustrate the applicability of this new powerful gas chromatographic/mass spectrometric method.