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Purpose: This study aimed at describing the use of oral cyclines (i.e., doxycycline and minocycline) as suppressive antibiotic therapy (SAT) in patients with periprosthetic joint infections (PJIs).Methods: Medical charts of all patients with surgical revisions for PJIs who were given cycline-based SAT because of a high failure of various origins were reviewed. Data regarding tolerability and effectiveness of cycline-based SAT were analysed.Results: Seventy-eight patients of mean age 64 ± 17 years received cycline-base SAT in the period from January 2006 to January 2014. PJIs involved the knee in 37 patients (47%), the hip in 35 (45%), the elbow in 4 (5%), and the shoulder in 2 (3%) and were qualified as early in 31 patients (39.7%). Staphylococcus spp. were the most common pathogens accounting for 72.1% of the total number of bacterial strains identified. All included patients had surgery which consisted in debridement and implant retention in 59 of them (75.6%). Doxycycline and minocycline were prescribed as SAT in 72 (92%) and 6 (8%) patients, respectively. Adverse events were reported in 14 patients (18%), leading to SAT discontinuation in 6 of them (8%). After a mean follow-up of 1020 ± 597 days, a total of 22 (28.2%) patients had failed including 3 cases (3.8%) with documented acquisition of tetracycline resistance in initial pathogen(s).Conclusions: Our results suggest that oral cyclines used as SAT in patients treated for PJI have an acceptable tolerability and effectiveness and appear to be a reasonable option in this setting. [ABSTRACT FROM AUTHOR]

Background: Outcome of patients with streptococcal prosthetic joint infections (PJIs) is not well known. Methods: We performed a retrospective multicenter cohort study that involved patients with total hip/knee prosthetic joint (THP/TKP) infections due to Streptococcus spp. from 2001 through 2009. Results: Ninety-five streptococcal PJI episodes (50 THP and 45 TKP) in 87 patients of mean age 69.1 ± 13.7 years met the inclusion criteria. In all, 55 out of 95 cases (57.9 %) were treated with debridement and retention of the infected implants with antibiotic therapy (DAIR). Rifampicin-combinations, including with levofloxacin, were used in 52 (54.7 %) and 28 (29.5 %) cases, respectively. After a mean follow-up period of 895 days (IQR: 395-1649), the remission rate was 70.5 % (67/95). Patients with PJIs due to S. agalactiae failed in the same proportion as in the other patients (10/37 (27.1 %) versus 19/58 (32.7 %); p = .55). In the univariate analysis, antibiotic monotherapy, DAIR, antibiotic treatments other than rifampicin-combinations, and TKP were all associated with a worse outcome. The only independent variable significantly associated with the patients' outcomes was the location of the prosthesis (i.e., hip versus knee) (OR = 0.19; 95 % CI 0.04-0.93; p value 0.04). Conclusions: The prognosis of streptococcal PJIs may not be as good as previously reported, especially for patients with an infected total knee arthroplasty. Rifampicin combinations, especially with levofloxacin, appear to be suitable antibiotic regimens for these patients. [ABSTRACT FROM AUTHOR]

As many drugs are unavailable for paediatric use, hospital pharmacies are often required to develop suitable formulations themselves. Clonidine is commonly used in paediatrics (in severe hypertension, in opiate withdrawal syndrome, in tics and Gilles de la Tourette syndrome or in anaesthetic premedication) but no appropriate formulation has been drawn up. The aims of this work were to develop an oral solution of clonidine dedicated to children and to assess its physicochemical and microbiological stability.

This workshop presents the recommendations of the Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC) for simulation-based training on bone marrow harvesting from healthy donors. Due to the decline in bone marrow harvests in favor of peripheral stem cells, a loss of expertise has been observed among younger hematologists. The training consists of an online theoretical component and a hands-on workshop using a mannequin at the PRESAGE simulation center at the Lille University School of Medicine. The goal is to acquire the necessary skills to safely perform bone marrow harvesting according to best practices, avoiding technical errors. Both theoretical and practical evaluations are conducted, and participants receive a training certificate upon completion., (Copyright © 2024 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

The ability of bacteria to interact with their environment is crucial to form aggregates and biofilms, and develop a collective stress resistance behavior. Despite its environmental and medical importance, bacterial aggregation is poorly understood and mediated by few known adhesion structures. Here, we identified a new role for a surface-exposed Escherichia coli protein, YfaL, which can self-recognize and induce bacterial autoaggregation. This process occurs only under acidic conditions generated during E. coli growth in the presence of fermentable sugars. These findings were supported by electrokinetic and atomic force spectroscopy measurements, which revealed changes in the electrostatic, hydrophobic, and structural properties of YfaL-decorated cell surface upon sugar consumption. Furthermore, YfaL-mediated autoaggregation promotes biofilm formation and enhances E. coli resistance to acid stress. The prevalence and conservation of YfaL in environmental and clinical E. coli suggest strong evolutionary selection for its function inside or outside the host. Overall, our results emphasize the importance of environmental parameters such as low pH as physicochemical cues influencing bacterial adhesion and aggregation, affecting E. coli and potentially other bacteria's resistance to environmental stress.

Background: Inflammatory Bowel Diseases (IBD) are a major public health issue with unclear aetiology. Changes in the composition and functionality of the intestinal microbiota are associated with these pathologies, including the depletion of strict anaerobes such as Feacalibacterium prausnitzii. Less evidence is observed for depletion in other anaerobes, among which bifidobacteria. This study characterized the taxonomic and functional diversity of bifidobacteria isolated from the human intestinal microbiota in active and non-active IBD patients by a culturomics approach and evaluated if these bifidobacteria might be used as probiotics for gut health., Results: A total of 341 bifidobacteria were isolated from the intestinal microbiota of IBD patients (52 Crohn's disease and 26 ulcerative colitis patients), with a high proportion of Bifidobacterium dentium strains (28% of isolated bifidobacteria). In ulcerative colitis, the major species identified was B. dentium (39% of isolated bifidobacteria), in active and non-active ulcerative colitis. In Crohn's disease, B. adolescentis was the major species isolated from non-active patients (40%), while similar amounts of B. dentium and B. adolescentis were found in active Crohn's disease patients. The relative abundance of B. dentium was increased with age, both in Crohn's disease and ulcerative colitis and active and non-active IBD patients. Antibacterial capacities of bifidobacteria isolated from non-active ulcerative colitis against Escherichia coli LF82 and Salmonella enterica ATCC 14028 were observed more often compared to strains isolated from active ulcerative colitis. Finally, B. longum were retained as strains with the highest probiotic potential as they were the major strains presenting exopolysaccharide synthesis, antibacterial activity, and anti-inflammatory capacities. Antimicrobial activity and EPS synthesis were further correlated to the presence of antimicrobial and EPS gene clusters by in silico analysis., Conclusions: Different bifidobacterial taxonomic profiles were identified in the microbiota of IBD patients. The most abundant species were B. dentium, mainly associated to the microbiota of ulcerative colitis patients and B. adolescentis, in the intestinal microbiota of Crohn's disease patients. Additionally, the relative abundance of B. dentium significantly increased with age. Furthermore, this study evidenced that bifidobacteria with probiotic potential (antipathogenic activity, exopolysaccharide production and anti-inflammatory activity), especially B. longum strains, can be isolated from the intestinal microbiota of both active and non-active Crohn's disease and ulcerative colitis patients., (© 2024. The Author(s).)

Introduction: The relationship between the occurrence of a periprosthetic hip or knee joint infection, a post-surgical hematoma and the time to surgical revision, along with the need to take samples for microbiology analysis has not been clearly defined. This led us to perform a retrospective study to: 1) define the rate of infected hematoma and subsequent infection after surgical revision for hematoma and 2) analyze in which time frame the hematoma was likely to be infected., Hypothesis: The more time elapsed before the postoperative hematoma is drained surgically after hip or knee replacement, the higher the hematoma infection rate and the late infection rate., Patients and Methods: Between 2013 and 2021, 78 patients (48 hip and 30 knee replacements) who had a postoperative hematoma without signs of infection upon draining were included in the study. Surgeons decided whether samples for microbiology were collected (33/78 patients (42%)). The data compiled consisted of the patient's demographics, the risk factors for infection, number of infected hematomas, number of subsequent infections at a minimum follow-up of 2 years, and the time to revision surgery (lavage)., Results: Of the 27 samples collected from the hematoma during the first lavage, 12/27 (44%) were infected. Of the 51 that did not have samples collected initially, 6/51 (12%) had them collected during the second lavage; 5 were infected and 1 was sterile. Overall, 17/78 (22%) of the hematomas were infected. Conversely, there were no late infections at a mean follow-up of 3.8 years (min 2, max 8) after the hematoma was drained in any of the 78 patients. The median time to revision was 4 days (Q1=2, Q3=14) for non-infected hematomas that were drained surgically versus 15 days (Q1=9, Q3=20) for hematomas that were found to be infected (p=0.005). No hematoma was infected when it was drained surgically within 72hours post-arthroplasty (0/19 (0%)). The infection rate went up to 2/16 (12.5%) when it was drained 3 to 5 days later and 15/43 (35%) when it was drained after more than 5 days (p=0.005). We believe this justifies collecting microbiology samples immediately when the hematoma is drained more than 72hours after the joint replacement procedure. Diabetes was more prevalent in patients who had an infected hematoma (8/17 [47%] versus 7/61 [11.5%], p=0.005). The infection was due to a single bacterium in 65% of cases (11/17); S. epidermidis was found in 59% (10/17) of infections., Conclusion: The occurrence of a hematoma after hip or knee replacement that requires surgical revision is associated with increased risk of infection, since the hematoma infection rate was 22%. Since hematomas drained within 72hours are less likely to be infected, samples do not need to be collected for microbiology at that time. Conversely, any hematomas being drained surgically beyond this time point should be considered as infected, thus microbiology samples should be collected, and empirical postoperative antibiotic therapy initiated. Early revision may prevent the occurrence of late infections. The standard treatment of infected hematomas appears to resolve the infection at a minimum follow-up of 2 years., Level of Evidence: Level IV Retrospective study., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: Bacteria and their viruses, bacteriophages, are the most abundant entities of the gut microbiota, a complex community of microorganisms associated with human health and disease. In this ecosystem, the interactions between these two key components are still largely unknown. In particular, the impact of the gut environment on bacteria and their associated prophages is yet to be deciphered., Results: To gain insight into the activity of lysogenic bacteriophages within the context of their host genomes, we performed proximity ligation-based sequencing (Hi-C) in both in vitro and in vivo conditions on the 12 bacterial strains of the OMM 12 synthetic bacterial community stably associated within mice gut (gnotobiotic mouse line OMM 12 ). High-resolution contact maps of the chromosome 3D organization of the bacterial genomes revealed a wide diversity of architectures, differences between environments, and an overall stability over time in the gut of mice. The DNA contacts pointed at 3D signatures of prophages leading to 16 of them being predicted as functional. We also identified circularization signals and observed different 3D patterns between in vitro and in vivo conditions. Concurrent virome analysis showed that 11 of these prophages produced viral particles and that OMM 12 mice do not carry other intestinal viruses., Conclusions: The precise identification by Hi-C of functional and active prophages within bacterial communities will unlock the study of interactions between bacteriophages and bacteria across conditions (healthy vs disease). Video Abstract., (© 2023. The Author(s).)

Background: Primary immunodeficiencies (PIDs) in adults are mainly revealed by recurrent and/or severe bacterial infections. The objective of this study was to evaluate a systematic research strategy of PIDs in adults with unexplained bacterial infections, with a special focus on specific polysaccharide antibody deficiency (SPAD)., Methods: In this prospective multicenter study, inclusion criteria were recurrent benign upper and lower respiratory tract infections (RTIs) for at least two years (group 1), at least one upper or lower RTI requiring hospitalization (group 2), and/or at least one invasive infection documented with encapsulated bacteria (group 3). Main exclusion criteria were all local and general conditions that could explain infections. If no PID diagnosis was made, response to polysaccharide antigens was assessed using a pneumococcal polysaccharide vaccine., Results: From March 2015 to March 2020, 118 patients were included (37 males, median age of 41 years): 73, 17, and 28 in groups 1, 2, and 3, respectively. Forty-seven PIDs were diagnosed, giving an estimated frequency of 39.8% (95% confidence interval [CI] [30.4, 48.8]). SPAD was the most frequent diagnosis by far (n = 37/47, 78.7%), and was made in 23, 5, and 9 patients from groups 1 to 3, respectively. All SPAD patients received conjugate vaccines and, according to their infectious history, were on surveillance or treated with preventive antibiotics (n = 6) and/or with immunoglobulins replacement therapy (n = 10), the latter being dramatically efficient in all cases., Conclusions: Considering its high prevalence among adults with unexplained recurrent and/or severe bacterial infections, SPAD should be screened in those patients., Clinical Trials Registration: NCT02972281., Competing Interests: Potential conflicts of interest. S. S. reports travel grants from Shire, Sanofi-Genzyme, SOBI and Novartis; consulting fees from Novartis, Biocryst, and Takeda; outside the submitted work. O. L. R. reports interventions, expertise, or non-financial support unrelated to the submitted work from AstraZeneca, Boehringer Ingelheim, Chiesi, Correvio, GlaxoSmithKline, Lilly, Mayoli, MSD, Mylan, Novartis, Pfizer, Vertex, Vitalaire, and Zambon. G. L. reports interventions, expertise, or travel grants from LFB, Octapharma, Sanofi-Genzyme, GSK, AstraZeneca, Biotest, Takeda, CSL Behring, grants unrelated to this work and paid to Lille University Hospital from LFB, Octapharma, CSL Behring, Vitalaire, and The Binding Site; payment or honoraria from Octabpharma, Shire/Takeda, and Biotest; support for attending meetings and/or travel from CSL Behring and Bitoest. A. L. reports payment or honoraria of less than $<500 for education events from GSK; and support for meetings and travel, $<1000, from GSK. L. T. reports consulting fees paid to author from GRIFOLS. D. L. reports grants or contracts from CSL Behring and Servier, unrelated to this work; consulting fees paid to author from Takeda, CSL Behring, and Octapharma; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Biocryst and Takeda; support for attending meetings and/or travel from Biocryst; participation on a Data Safety Monitoring Board or Advisory Board from Takeda and Biocryst; and receipt of equipment, materials, drugs, medical writing, gifts or other services from Mallinckrodt. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Postoperative recurrence (POR) after ileocecal resection (ICR) affects most Crohn's disease patients within 3-5 years after surgery. Adherent-invasive Escherichia coli (AIEC) typified by the LF82 strain are pathobionts that are frequently detected in POR of Crohn's disease and have a potential role in the early stages of the disease pathogenesis. Saccharomyces cerevisiae CNCM I-3856 is a probiotic yeast reported to inhibit AIEC adhesion to intestinal epithelial cells and to favor their elimination from the gut., Aim: To evaluate the efficacy of CNCM I-3856 in preventing POR induced by LF82 in an HLA-B27 transgenic (TgB27) rat model., Methods: Sixty-four rats [strain F344, 38 TgB27, 26 control non-Tg (nTg)] underwent an ICR at the 12 th wk (W12) of life and were sacrificed at the 18 th wk (W18) of life. TgB27 rats were challenged daily with oral administration of LF82 (10 9 colony forming units (CFUs)/day (d), n = 8), PBS ( n = 5), CNCM I-3856 (10 9 CFUs/d, n = 7) or a combination of LF82 and CNCM I-3856 ( n = 18). nTg rats receiving LF82 ( n = 5), PBS ( n = 5), CNCM I-3856 ( n = 7) or CNCM I-3856 and LF82 ( n = 9) under the same conditions were used as controls. POR was analyzed using macroscopic (from 0 to 4) and histologic (from 0 to 6) scores. Luminal LF82 quantifications were performed weekly for each animal. Adherent LF82 and inflammatory/regulatory cytokines were quantified in biopsies at W12 and W18. Data are expressed as the median with the interquartile range., Results: nTg animals did not develop POR. A total of 7/8 (87%) of the TgB27 rats receiving LF82 alone had POR (macroscopic score ≥ 2), which was significantly prevented by CNCM I-3856 administration [6/18 (33%) TgB27 rats, P = 0.01]. Macroscopic lesions were located 2 cm above the anastomosis in the TgB27 rats receiving LF82 alone and consisted of ulcerations with a score of 3.5 (2 - 4). Seven out of 18 TgB27 rats (39%) receiving CNCM I-3856 and LF82 had no macroscopic lesions. Compared to untreated TgB27 animals receiving LF82 alone, coadministration of CNCM I-3856 and LF82 significantly reduced the macroscopic [3.5 (2 - 4) vs 1 (0 - 3), P = 0.002] and histological lesions by more than 50% [4.5 (3.3 - 5.8) vs 2 (1.3 - 3), P = 0.003]. The levels of adherent LF82 were correlated with anastomotic macroscopic scores in TgB27 rats ( r = 0.49, P = 0.006), with a higher risk of POR in animals having high levels of luminal LF82 (71.4% vs 25%, P = 0.02). Administration of CNCM I-3856 significantly reduced the levels of luminal and adherent LF82, increased the production of interleukin (IL)-10 and decreased the production of IL-23 and IL-17 in TgB27 rats., Conclusion: In a reliable model of POR induced by LF82 in TgB27 rats, CNCM I-3856 prevents macroscopic POR by decreasing LF82 infection and gut inflammation., Competing Interests: Conflict-of-interest statement: Mourey F is an employee of Lesaffre. Desreumaux P reports personal fees from Abbvie, personal fees from Abbott, personal fees from Amgen, personal fees from Biocodex, personal fees from Biofortis, personal fees from Biogen, personal fees from Biokuris, personal fees from Ferring, personal fees from Fresenius, personal fees from Janssen, personal fees from Kitozyme, personal fees from Lesaffre, personal fees from MSD, personal fees from Norgine, personal fees from Pfizer, personal fees from Sandoz, personal fees from Shire, personal fees from Takeda, personal fees from Tillotts, and personal fees from UCB, outside of the submitted work. In addition, Dr. Desreumaux has a patent (WO2009103884) issued. All other authors have nothing to disclose., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Introduction: Osteoarticular infections (OAIs) of native joints lead to cartilage damage which may require subsequent arthroplasty. There is no consensus on systematic intraoperative microbiological sampling when performing an arthroplasty on a native joint with a history of OAI. We carried out a retrospective study to: (1) identify the frequency of the persistence of the microorganism(s) involved during the initial, presumed cured OAI, when performing an arthroplasty for sequelae of osteoarthritis, (2) to find an association between the length of time between the OAI and arthroplasty, and the recurrence of bacterial infection, (3) to assess the influence of the presence of hardware on the risk of infectious recurrence., Hypothesis: Systematic sampling is justified during a subsequent arthroplasty after an OAI, even after a prolonged period., Material and Method: This single-center, retrospective descriptive study included all patients whose indication for arthroplasty resulted from osteoarthritis, osteitis or bacterial osteomyelitis of a native joint, or in the aftermath of an infection post osteosynthesis. All patients were considered to have recovered from the initial infection at the time of the arthroplasty. Between 2008 and 2019, 92 patients were included in the study, with an average age of 56.5years (range: 21-97years). OAI occurred at a mean age of 35years (range: 1-84years). The average time from OAI to implantation was 15years (range: 1-65years). The bacteria most frequently found in the initial OAI was Staphylococcus aureus, involved in 35.8% of cases (n=33/92)., Results: The intraoperative samples came back positive in 17% of cases (n=16/92), including 9 positive for the same bacteria as the OAI (56%, n=9/16). For these 16 cases, the time between the OAI and the arthroplasty was 1year for 5 patients, between 1 and 15years for 5 patients and greater than 15years for 6 patients. For 3 positive patients, the information on the initial microorganism was not known and 4 patients were positive for a bacterium different from the initial one. The time from the initial OAI to the arthroplasty was not associated with positive results (p=0.38). There was no significant difference between a positive culture at the time of arthroplasty and the initial type of OAI [native joint versus presence of hardware and/or open fracture (p=0.41)]., Conclusion: The results of this work suggest there is value in microbiological sampling when performing an arthroplasty on a previously infected joint, regardless of the duration of the infection., Level of Evidence: IV; retrospective study., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: The optimal length of the intravenous antibiotic treatment of periprosthetic joint infections (PJIs) generally ranges from one to six weeks and is a matter of debate. Most antibiotics active against Gram-positive cocci (GPC) exhibit both high oral bioavailability and bone diffusion. Thus, early oral therapy may be a reasonable option in GPC-related PJIs., Methods: A 2 year before and after monocentric study that aimed to compare two antibiotic strategies. Empirical intravenous postoperative antibiotic treatment was followed by 7 to 10 days of intravenous targeted therapy ('before' group) or by full orally targeted antibiotic treatment ('after' group). The primary outcome was a treatment failure during follow-up., Results: A total of 93 patients were analysed, 43 and 50 in the before and the after groups, respectively. Both groups were comparable in terms of surgical procedures, comorbidities, microbiological documentation and infection site. Antibiotics prescribed to our patients had high oral bioavailability and bone diffusion with rifampicin/fluoroquinolone combinations being the most frequent antibiotic regimens. Both hospital stay and intravenous antibiotic treatment mean durations were shorter in the before group than in the after group [15.0 versus 11.0 days; (P < 0.01) and 13.0 versus 7.0 days; P < 0.001, respectively]. The remission rate assessed after at least a year of follow-up was comparable in the before and the after groups (hazard ratio = 0.70; 95% CI 0.30-1.58)., Conclusions: Full oral targeted antibiotic therapy using a drug regimen with high oral bioavailability and good bone diffusion is an option for the treatment of patients with GPC-related PJIs., (© The Author(s) 2021. 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.)

Objectives: Antibiotics for febrile neutropenia (FN) in acute myeloid leukaemia (AML) patients undergoing intensive chemotherapy are usually maintained until neutropenia resolution, because of the risk of uncontrolled sepsis in this vulnerable population. This leads to unnecessarily prolonged antimicrobial therapy., Methods: Based on ECIL-4 recommendations, we modified our management strategy and discontinued antibiotics after a pre-established duration in patients treated for a first episode of FN between August 2014 and October 2017., Results: Antibiotics were stopped during 62 FN episodes, and maintained in the control group (n = 13). Median age of patients was 54 years. A total of 39 (63%) patients received induction and 23 (37%) consolidation chemotherapy; 36 (58%) patients had fever of unknown origin. Median neutropenia length was 26 days (IQR 24-30). Antibiotics were started at day 9 (IQR 5-13). Most patients received piperacillin-tazobactam (56%) or cefepime (32%). Antimicrobial therapy was longer in the control group than in the policy compliant group, 10 (IQR 7-16) vs. 19 days (IQR 15-23), P = 0.0001. After antibiotics discontinuation, 20% patients experienced fever recurrence, within 5.5 days (IQR 3-7.5). None of these febrile episodes were severe and 80% patients remained afebrile, with neutrophil recovery occurring within 5 days (IQR 2-8.5). Overall, 287 antibiotics days were spared; this represents 49% of all days with antibiotics. No patient had died at day 30 from intervention; six died during late follow-up, two from graft-versus-host disease and four from relapsed or refractory leukaemia., Conclusions: Discontinuing antibiotics in neutropenic AML patients treated for a first episode of FN is safe, and results in significant antibiotic sparing., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A mass spectrometry (MS) method that detects a serum disaccharide (DS) (MS-DS) was recently described for the diagnosis of invasive fungal infections (IFI). We carried out a European collaborative study to evaluate this assay. Patients with the following IFI were selected according to the availability of sera obtained at about the time that IFI was documented: invasive candidiasis (IC; n  = 26 patients), invasive aspergillosis (IA; n  = 19), and mucormycosis (MM; n  = 23). Control sera originated from 20 neutropenic patients and 20 patients with bacteremia. MS-DS was carried out in blind manner for the diagnosis of IFI. A diagnosis of IC or IA was confirmed by detection of mannan (Man) or galactomannan (GM), respectively, associated with detection of (1,3)-β-d-glucan (BDG) in both infections. MM was detected by quantitative real-time PCR (qPCR). All tests discriminated sera from patients with IC from sera from control subjects with bacteremia ( P  ≤ 0.0009). For IC, the MS-DS sensitivity and specificity were 51% and 87%, respectively. MS-DS complemented the high specificity of Man monitoring. All tests discriminated sera from IA patients from sera from neutropenic controls ( P  ≤ 0.0009). For IA, MS-DS sensitivity and specificity were 64% and 95%, respectively. Only 13/36 serum samples from patients with MM were concordant by MS-DS and qPCR (6 were positive, and 7 were negative); 14 were positive by MS-DS alone. qPCR and MS-DS made a similar contribution to the diagnosis of MM. In patients undergoing long-term monitoring, the persistent circulation of serum disaccharide was observed, whereas DNA was detected only for a short period after initiation of treatment. MS-DS has an important role to play in the early diagnosis of IFI. Its panfungal nature and complementarity with other tests may justify its use in the management of IFI., (Copyright © 2019 Cornu et al.)

The infectious diseases caused by multidrug-resistant bacteria pose serious threats to humankind. It has been suggested that an antibiotic targeting LpxC of the lipid A biosynthetic pathway in Gram-negative bacteria is a promising strategy for curing Gram-negative bacterial infections. However, experimental proof of this concept is lacking. Here, we describe our discovery and characterization of a biphenylacetylene-based inhibitor of LpxC, an essential enzyme in the biosynthesis of the lipid A component of the outer membrane of Gram-negative bacteria. The compound LPC-069 has no known adverse effects in mice and is effective in vitro against a broad panel of Gram-negative clinical isolates, including several multiresistant and extremely drug-resistant strains involved in nosocomial infections. Furthermore, LPC-069 is curative in a murine model of one of the most severe human diseases, bubonic plague, which is caused by the Gram-negative bacterium Yersinia pestis Our results demonstrate the safety and efficacy of LpxC inhibitors as a new class of antibiotic against fatal infections caused by extremely virulent pathogens. The present findings also highlight the potential of LpxC inhibitors for clinical development as therapeutics for infections caused by multidrug-resistant bacteria. IMPORTANCE The rapid spread of antimicrobial resistance among Gram-negative bacilli highlights the urgent need for new antibiotics. Here, we describe a new class of antibiotics lacking cross-resistance with conventional antibiotics. The compounds inhibit LpxC, a key enzyme in the lipid A biosynthetic pathway in Gram-negative bacteria, and are active in vitro against a broad panel of clinical isolates of Gram-negative bacilli involved in nosocomial and community infections. The present study also constitutes the first demonstration of the curative treatment of bubonic plague by a novel, broad-spectrum antibiotic targeting LpxC. Hence, the data highlight the therapeutic potential of LpxC inhibitors against a wide variety of Gram-negative bacterial infections, including the most severe ones caused by Y. pestis and by multidrug-resistant and extensively drug-resistant carbapenemase-producing strains., (Copyright © 2017 Lemaître et al.)

Background: Pseudotuberculosis is an infection caused by the bacterial enteropathogen Yersinia pseudotuberculosis and is considered to be a significant problem in veterinary medicine. We previously found that intranasal administration of a recombinant Lactococcus lactis strain that secretes the low-calcium response V (LcrV) antigen from Y. pseudotuberculosis (Ll-LcrV) confers protection against a lethal Y. pseudotuberculosis infection. Here, we aimed at characterizing the immunological basis of this LcrV-elicited protective response and at determining the duration of vaccine-induced immunity., Methods: Splenocytes from BALB/c mice intranasally immunized with Ll-LcrV or Ll as control were immunostained then analyzed by flow cytometry. Protection against a lethal intravenous injection of Y. pseudotuberculosis was also determined (i) in immunized BALB/c mice depleted or not of CD4 + , CD8 + or CD25 + cells and (ii) in naïve BALB/c mice receiving serum from immunized mice by counting the number of bacteria in liver and spleen. Lastly, survival rate of immunized BALB/c mice following a lethal intravenous injection of Y. pseudotuberculosis was followed up to 9-months., Results: We found that T and B lymphocytes but not non-conventional lymphoid cells were affected by Ll-LcrV immunization. We also observed that depletion of CD4 + and CD25 + but not CD8 + cells in immunized mice eradicated protection against a lethal systemic Y. pseudotuberculosis infection, suggesting that activated CD4 + T lymphocytes are required for vaccine-induced protection. Adoptive transfer of LcrV-specific antibodies from Ll-LcrV-immunized animals significantly reduced the bacterial counts in the liver compared to non-vaccinated mice. Lastly, the protective immunity conferred by Ll-LcrV decreased slightly over time; nevertheless almost 60% of the mice survived a lethal bacterial challenge at 9months post-vaccination., Conclusion: Mucosal vaccination of mice with Ll-LcrV induced cell- and antibody-mediated protective immunity against Y. pseudotuberculosis infection in the mouse and the protection is long-lasting., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives: Inhibitors of uridine diphosphate-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC, which catalyses the first, irreversible step in lipid A biosynthesis) are a promising new class of antibiotics against Gram-negative bacteria. The objectives of the present study were to: (i) compare the antibiotic activities of three LpxC inhibitors (LPC-058, LPC-011 and LPC-087) and the reference inhibitor CHIR-090 against Gram-negative bacilli (including MDR and XDR isolates); and (ii) investigate the effect of combining these inhibitors with conventional antibiotics., Methods: MICs were determined for 369 clinical isolates (234 Enterobacteriaceae and 135 non-fermentative Gram-negative bacilli). Time-kill assays with LPC-058 were performed on four MDR/XDR strains, including Escherichia coli producing CTX-M-15 ESBL and Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii producing KPC-2, VIM-1 and OXA-23 carbapenemases, respectively., Results: LPC-058 was the most potent antibiotic and displayed the broadest spectrum of antimicrobial activity, with MIC90 values for Enterobacteriaceae, P. aeruginosa, Burkholderia cepacia and A. baumannii of 0.12, 0.5, 1 and 1 mg/L, respectively. LPC-058 was bactericidal at 1× or 2× MIC against CTX-M-15, KPC-2 and VIM-1 carbapenemase-producing strains and bacteriostatic at ≤4× MIC against OXA-23 carbapenemase-producing A. baumannii. Combinations of LPC-058 with β-lactams, amikacin and ciprofloxacin were synergistic against these strains, albeit in a species-dependent manner. LPC-058's high efficacy was attributed to the presence of the difluoromethyl-allo-threonyl head group and a linear biphenyl-diacetylene tail group., Conclusions: These in vitro data highlight the therapeutic potential of the new LpxC inhibitor LPC-058 against MDR/XDR strains and set the stage for subsequent in vivo studies., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Conformational dynamics plays an important role in enzyme catalysis, allosteric regulation of protein functions and assembly of macromolecular complexes. Despite these well-established roles, such information has yet to be exploited for drug design. Here we show by nuclear magnetic resonance spectroscopy that inhibitors of LpxC--an essential enzyme of the lipid A biosynthetic pathway in Gram-negative bacteria and a validated novel antibiotic target--access alternative, minor population states in solution in addition to the ligand conformation observed in crystal structures. These conformations collectively delineate an inhibitor envelope that is invisible to crystallography, but is dynamically accessible by small molecules in solution. Drug design exploiting such a hidden inhibitor envelope has led to the development of potent antibiotics with inhibition constants in the single-digit picomolar range. The principle of the cryptic inhibitor envelope approach may be broadly applicable to other lead optimization campaigns to yield improved therapeutics.

One year after the occurrence of the first case of infection by the Middle East Respiratory Syndrome coronavirus (MERS-CoV) there is no clear consensus on the best treatment to propose. The World Health Organization, as well as several other national agencies, are still working on different clinical approaches to implement the most relevant treatment in MERS-CoV infection. We compared innate and adaptive immune responses of two patients infected with MERS-CoV to understand the underlying mechanisms involved in the response and propose potential therapeutic approaches. Broncho-alveolar lavage (BAL) of the first week and sera of the first month from the two patients were used in this study. Quantitative polymerase chain reaction (qRTPCR) was performed after extraction of RNA from BAL cells of MERS-CoV infected patients and control patients. BAL supernatants and sera were used to assess cytokines and chemokines secretion by enzyme-linked immunosorbent assay. The first patient died rapidly after 3 weeks in the intensive care unit, the second patient still recovers from infection. The patient with a poor outcome (patient 1), compared to patient 2, did not promote type-1 Interferon (IFN), and particularly IFNα, in response to double stranded RNA (dsRNA) from MERS-CoV. The absence of IFNα, known to promote antigen presentation in response to viruses, impairs the development of a robust antiviral adaptive Th-1 immune response. This response is mediated by IL-12 and IFNγ that decreases viral clearance; levels of both of these mediators were decreased in patient 1. Finally, we confirm previous in vitro findings that MERS-CoV can drive IL-17 production in humans. Host recognition of viral dsRNA determines outcome in the early stage of MERS-CoV infection. We highlight the critical role of IFNα in this initial stage to orchestrate a robust immune response and bring substantial arguments for the indication of early IFNα treatment during MERS-CoV infection.