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International audience; Background and objective: Daptomycin has been recommended in the treatment of bone and joint infection. Previous work showed that the approved dosage of daptomycin may be insufficient to achieve optimal exposure in patients with bone and joint infection. However, those studies assumed that bone exposure was similar to steady-state daptomycin-free plasma concentrations. We sought to establish a physiologically based pharmacokinetic (PBPK) model of daptomycin to describe the dynamics of daptomycin disposition in bone and skin tissue.Methods: a PBPK model of daptomycin was built using PK-Sim®. Daptomycin concentrations in plasma and bone were obtained from three previously published studies. Physicochemical drug characteristics, mass balance, anthropometrics, and experimental data were used to build and refine the PBPK model. Internal validation of the PBPK model was performed using the usual diagnostic plots. The final PBPK model was then used to run simulations with doses of 6, 8, 10, and 12 mg/kg/24 h. Pharmacokinetic profiles were simulated in 1.000 subjects and the probabilities of target attainment for the area under the concentration-time curve over the bacterial minimum inhibitory concentration were computed in blood, skin, and bone compartments.Results: the final model showed a good fit of all datasets with an absolute average fold error between 0.5 and 2 for all pharmacokinetic quantities in blood, skin and bone tissues. Results of dosing simulations showed that doses ≥10 mg/kg should be used in the case of bacteremia caused by Staphylococcus aureus with a minimum inhibitory concentration >0.5 mg/L or Enterococcus faecalis with a minimum inhibitory concentration >1 mg/L, while doses ≥12 mg/kg should be used in the case of bone and joint infection or complicated skin infection. When considering a lower minimum inhibitory concentration, doses of 6-8 mg/kg would likely achieve a sufficient success rate. However, in the case of infections caused by E. faecalis with a minimum inhibitory concentration >2 mg/L, a higher dosage and combination therapy would be necessary to maximize efficacy.Conclusions: we developed the first daptomycin PBPK/pharmacodynamic model for bone and joint infection, which confirmed that a higher daptomycin dosage is needed to optimize exposure in bone tissue. However, such higher dosages raise safety concerns. In this setting, therapeutic drug monitoring and model-informed precision dosing appear necessary to ensure the right exposure on an individual basis.

Aims To determine the prognosis of patients treated for infective endocarditis (IE) according to their healthcare pathway. To assess how the ESC guidelines are implemented concerning the performance of transoesophageal echocardiography, the use of antibiotic therapy, and the performance of valve surgery; and to compare the epidemiological profile of IE according to the type of centres in which the patients are hospitalized. Methods and results In a prospective multicentric study including 22 hospitals in the South-East of France, 342 patients were classified into three groups according to their healthcare pathway: 119 patients diagnosed and taken care entirely in a reference centre or hospital with cardiac surgery [Referral Center (RC) group], 111 patients diagnosed and initially taken care in a non-RC (NRC), then referred in a centre including cardiac surgery [transferred to the Referral Center (TRC) group] and 112 patients totally taken care in the NRC (NRC group). One-year mortality was 26% (88 deaths) and was not significantly different between Groups 1 and 2 (20 vs. 21%, P = 0.83). Patients in the NRC group had a higher mortality (37%) compared with patients in the RC and TRC groups (P Conclusion Prognosis of patients with IE is influenced by their healthcare pathway. Patients treated exclusively in NRC have a worse prognosis than patients treated in referral or surgical centres.

International audience; Purpose: Duration of antibiotic therapy for ventilator-associated pneumonia (VAP) due to non-fermenting Gram-negative bacilli (NF-GNB), including Pseudomonas aeruginosa (PA) remains uncertain. We aimed to assess the non-inferiority of a short duration of antibiotics (8 days) vs. prolonged antibiotic therapy (15 days) in VAP due to PA (PA-VAP).Methods: We conducted a nationwide, randomized, open-labeled, multicenter, non-inferiority trial to evaluate optimal duration of antibiotic treatment in PA-VAP. Eligible patients were adults with diagnosis of PA-VAP and randomly assigned in 1:1 ratio to receive a short-duration treatment (8 days) or a long-duration treatment (15 days). A pre-specified analysis was used to assess a composite endpoint combining mortality and PA-VAP recurrence rate during hospitalization in the intensive care unit (ICU) within 90 days.Results: The study was stopped after 24 months due to slow inclusion rate. In intention-to-treat population (n = 186), the percentage of patients who reached the composite endpoint was 25.5% (N = 25/98) in the 15-day group versus 35.2% (N = 31/88) in the 8-day group (difference 9.7%, 90% confidence interval (CI) -1.9%-21.2%). The percentage of recurrence of PA-VAP during the ICU stay was 9.2% in the 15-day group versus 17% in the 8-day group. The two groups had similar median days of mechanical ventilation, of ICU stay, number of extra pulmonary infections and acquisition of multidrug-resistant (MDR) pathogens during ICU stay.Conclusions: Our study failed to show the non-inferiority of a short duration of antibiotics in the treatment of PA-VAP, compared to a long duration. The short duration strategy may be associated to an increase of PA-VAP recurrence. However, the lack of power limits the interpretation of this study.

Epidemiological projections point to acquisition of ever-expanding multidrug resistance (MDR) byiEscherichia coli/i, a commensal of the digestive tract and a source of urinary tract pathogens. Bioinformatics analyses of a large collection ofiE. coli/igenomes from EnteroBase, enriched in clinical isolates of worldwide origins, suggest the Cytotoxic Necrotizing Factor 1 (CNF1)-toxin encoding gene,icnf1/i, is preferentially distributed in four common sequence types (ST) encompassing the pandemiciE. coli/iMDR lineage ST131. This lineage is responsible for a majority of extraintestinal infections that escape first-line antibiotic treatment, with known enhanced capacities to colonize the gastrointestinal tract. Statistical projections based on this dataset point to a global expansion oficnf1/i-positive multidrug-resistant ST131 strains from subcladeiH/i30Rx/C2, accounting for a rising prevalence oficnf1/i-positive strains in ST131. Despite the absence of phylogeographical signals,icnf1/i-positive isolates segregated into clusters in the ST131-iH/i30Rx/C2 phylogeny, sharing a similar profile of virulence factors and the sameicnf1/iallele. The suggested dominant expansion oficnf1/i-positive strains in ST131-iH/i30Rx/C2 led us to uncover the competitive advantage conferred byicnf1/ifor gut colonization to the clinical strain EC131GY ST131-iH/i30Rx/C2 versusicnf1/i-deleted isogenic strain. Complementation experiments showed that colon tissue invasion was compromised in the absence of deamidase activity on Rho GTPases by CNF1. Hence, gut colonization factor function oficnf1/iwas confirmed for another clinical strain ST131-iH/i30Rx/C2. In addition, functional analysis of theicnf1/i-positive clinical strain EC131GY ST131-iH/i30Rx/C2 and aicnf1/i-deleted isogenic strain showed no detectable impact of the CNF1 gene on bacterial fitness and inflammation during the acute phase of bladder monoinfection. Together these data argue for an absence of role of CNF1 in virulence during UTI, while enhancing gut colonization capacities of ST131-iH/i30Rx/C2 and suggested expansion oficnf1/i-positive MDR isolates in subclade ST131-iH/i30Rx/C2.

Background Therapeutic failure is a frequent issue in the management of post-operative peritonitis. Objectives A post hoc analysis of the prospective, multicentre DURAPOP trial analysed the risk factors for failures in post-operative peritonitis following adequate source control and empirical antibiotic therapy in critically ill patients. Patients and methods Overall failures assessed post-operatively between Day 8 and Day 45 were defined as a composite of death and/or surgical and/or microbiological failures. Risk factors for failures were assessed using logistic regression analyses. Results Among the 236 analysed patients, overall failures were reported in 141 (59.7%) patients, including 30 (12.7%) deaths, 81 (34.3%) surgical and 95 (40.2%) microbiological failures. In the multivariate analysis, the risk factors associated with overall failures were documented piperacillin/tazobactam therapy [adjusted OR (aOR) 2.10; 95% CI 1.17–3.75] and renal replacement therapy on the day of reoperation (aOR 2.96; 95% CI 1.05–8.34). The risk factors for death were age (aOR 1.08 per year; 95% CI 1.03–1.12), renal replacement therapy on reoperation (aOR 3.95; 95% CI 1.36–11.49) and diabetes (OR 6.95; 95% CI 1.34–36.03). The risk factors associated with surgical failure were documented piperacillin/tazobactam therapy (aOR 1.99; 95% CI 1.13–3.51), peritoneal cultures containing Klebsiella spp. (aOR 2.45; 95% CI 1.02–5.88) and pancreatic source of infection (aOR 2.91; 95% CI 1.21–7.01). No specific risk factors were identified for microbiological failure. Conclusions Our data suggest a predominant role of comorbidities, the severity of post-operative peritonitis and possibly of documented piperacillin/tazobactam treatment on the occurrence of therapeutic failures, regardless of their type.

The genus Bordetella includes bacteria that are found in the environment and/or associated with humans and other animals. A few closely related species, including Bordetella pertussis, are human pathogens that cause diseases such as whooping cough. Here, we present a large database of Bordetella isolates and genomes and develop genotyping systems for the genus and for the B. pertussis clade. To generate the database, we merge previously existing databases from Oxford University and Institut Pasteur, import genomes from public repositories, and add 83 newly sequenced B. bronchiseptica genomes. The public database currently includes 2582 Bordetella isolates and their provenance data, and 2085 genomes (https://bigsdb.pasteur.fr/bordetella/). We use core-genome multilocus sequence typing (cgMLST) to develop genotyping systems for the whole genus and for B. pertussis, as well as specific schemes to define antigenic, virulence and macrolide resistance profiles. Phylogenetic analyses allow us to redefine evolutionary relationships among known Bordetella species, and to propose potential new species. Our database provides an expandable resource for genotyping of environmental and clinical Bordetella isolates, thus facilitating evolutionary and epidemiological research on whooping cough and other Bordetella infections.

Objectives: To identifyHaemophilus species and characterise the antimicrobial susceptibility of isolates from patients with respiratory tract infections (RTIs) in Cameroon. Methods: Isolates (n = 95) were from patients with RTIs obtained from two hospitals in Yaoundé, Cameroon. Isolates were identified by biochemical assay, a polymerase chain reaction (PCR)-based method, matrix-assisted laser desorption ionization-time of flight (MALDI-TOF), and whole genome sequencing. Antibiotic minimum inhibitory concentrations were determined by E-test. Results: Haemophilus influenzae (H. influenzae) was the most prevalent species, varying from 76.8 to 84.2% according to the different methods. The isolates were mainly non-typeable (n = 70, 96%). Three H. influenzae isolates were capsulated (b, e and f). The isolates were genetically diverse and 40 unique sequence types were identified, including 11 new ones. Resistance to ampicillin was observed among 52 of 94 (55.3%), and 14 of the 52 (26.9%) produced TEM-1 β-lactamase. PBP3 mutations occurred in 40 of 52 (76.9%) ampicillin-resistant isolates. Eleven isolates were chloramphenicol-resistant, with eight of 10 (80%) producing chloramphenicol acetyltransferase. Four Haemophilus isolates were rifampicin-resistant, with two mutations in rpoB gene. Five isolates were ciprofloxacin-resistant and harboured mutations in the quinolone-resistance-determining regions of gyrA and parC genes. Conclusion: TheH. influenzae isolates were highly diverse and showed high levels of antibiotic resistance. H. influenzae serotype b is still circulating in the post-vaccination era.

International audience; A local outbreak caused by Neisseria meningitidis occurred in the migration camp in the Greek island of Lesbos during January-February 2020 (4 of 5 cases). In total, 5 samples positive for N. meningitidis were further investigated for sero-/genogroup, PorA, and WGS analysis. MenB was found among 3 cases, while in two cases, MenY was identified. WGS analysis and antibiotic susceptibility testing on the 2 culture positive MenB samples showed the new ST-3129, ciprofloxacin-resistant clone was circulating among the immigrants in the aforementioned camp. This is the first report of ciprofloxacin resistance in Greece.

Background There is a level-1 evidence indicating that postoperative antibiotics are unnecessary following cholecystectomy for grade I or II acute calculous cholecystitis (ACC). We wanted to evaluate the applications of this recommendation in clinical practice four years after the original publication in ABCAL-participating centers. Methods A retrospective analysis of patients operated for grade I or II ACC from January to December 2016 in ABCAL-participating centers was performed. Inclusion criteria were the same as for the ABCAL-study. The primary endpoint was the postoperative antibiotic administration rate. The secondary endpoints were postoperative outcomes. Results Of the 283 patients included, 64% received postoperative antibiotics. Only 19% received antibiotics after POD1. The perioperative outcomes were similar between those that did or did not receive antibiotics after POD1. The median [range] length of stay was significantly shorter in patients who did not receive postoperative antibiotics (4 days [1–20]) compared to the others (6 days [1–50], p > 0.001). Conclusion Despite strong recommendations included in the Tokyo 2018 guidelines, the results of the ABCAL-study are poorly applied even if the absence of postoperative antibiotics has no impact on morbidity. It is important to stress that postoperative antibiotics are not necessary after cholecystectomy for grade I or II ACC.

Background The optimal dosing of antibiotics in critically ill patients receiving renal replacement therapy (RRT) remains unclear. In this study, we describe the variability in RRT techniques and antibiotic dosing in critically ill patients receiving RRT and relate observed trough antibiotic concentrations to optimal targets. Methods We performed a prospective, observational, multinational, pharmacokinetic study in 29 intensive care units from 14 countries. We collected demographic, clinical, and RRT data. We measured trough antibiotic concentrations of meropenem, piperacillin-tazobactam, and vancomycin and related them to high- and low-target trough concentrations. Results We studied 381 patients and obtained 508 trough antibiotic concentrations. There was wide variability (4–8-fold) in antibiotic dosing regimens, RRT prescription, and estimated endogenous renal function. The overall median estimated total renal clearance (eTRCL) was 50 mL/minute (interquartile range [IQR], 35–65) and higher eTRCL was associated with lower trough concentrations for all antibiotics (P < .05). The median (IQR) trough concentration for meropenem was 12.1 mg/L (7.9–18.8), piperacillin was 78.6 mg/L (49.5–127.3), tazobactam was 9.5 mg/L (6.3–14.2), and vancomycin was 14.3 mg/L (11.6–21.8). Trough concentrations failed to meet optimal higher limits in 26%, 36%, and 72% and optimal lower limits in 4%, 4%, and 55% of patients for meropenem, piperacillin, and vancomycin, respectively. Conclusions In critically ill patients treated with RRT, antibiotic dosing regimens, RRT prescription, and eTRCL varied markedly and resulted in highly variable antibiotic concentrations that failed to meet therapeutic targets in many patients.

Improvements in cost and speed of next generation sequencing (NGS) have provided a new pathway for delivering disease diagnosis, molecular typing, and detection of antimicrobial resistance (AMR). Numerous published methods and protocols exist, but a lack of harmonisation has hampered meaningful comparisons between results produced by different methods/protocols vital for global genomic diagnostics and surveillance. As an exemplar, this study evaluated the sensitivity and specificity of five well-established in-silico AMR detection software where the genotype results produced from running a panel of 436 Escherichia coli were compared to their AMR phenotypes, with the latter used as gold-standard. The pipelines exploited previously known genotype–phenotype associations. No significant differences in software performance were observed. As a consequence, efforts to harmonise AMR predictions from sequence data should focus on: (1) establishing universal minimum to assess performance thresholds (e.g. a control isolate panel, minimum sensitivity/specificity thresholds); (2) standardising AMR gene identifiers in reference databases and gene nomenclature; (3) producing consistent genotype/phenotype correlations. The study also revealed limitations of in-silico technology on detecting resistance to certain antimicrobials due to lack of specific fine-tuning options in bioinformatics tool or a lack of representation of resistance mechanisms in reference databases. Lastly, we noted user friendliness of tools was also an important consideration. Therefore, our recommendations are timely for widespread standardisation of bioinformatics for genomic diagnostics and surveillance globally.

International audience; Metallo-β-lactamases (MBLs) contribute to the resistance of Gram-negative bacteria to carbapenems, last-resort antibiotics at hospital, and MBL inhibitors are urgently needed to preserve these important antibacterial drugs. Here, we describe a series of 1,2,4-triazole-3-thione-based inhibitors displaying an α-amino acid substituent, which amine was mono- or disubstituted by (hetero)aryl groups. Compounds disubstituted by certain nitrogen-containing heterocycles showed submicromolar activities against VIM-type enzymes and strong NDM-1 inhibition (Ki = 10-30 nM). Equilibrium dialysis, native mass spectrometry, isothermal calorimetry (ITC), and X-ray crystallography showed that the compounds inhibited both VIM-2 and NDM-1 at least partially by stripping the catalytic zinc ions. These inhibitors also displayed a very potent synergistic activity with meropenem (16- to 1000-fold minimum inhibitory concentration (MIC) reduction) against VIM-type- and NDM-1-producing ultraresistant clinical isolates, including Enterobacterales and Pseudomonas aeruginosa. Furthermore, selected compounds exhibited no or moderate toxicity toward HeLa cells, favorable absorption, distribution, metabolism, excretion (ADME) properties, and no or modest inhibition of several mammalian metalloenzymes.

International audience; Several human intestinal microbiota studies suggest that bacteriophages, viruses infecting bacteria, play a role in gut homeostasis. Currently, bacteriophages are considered a tool to precisely engineer the intestinal microbiota, but they have also attracted considerable attention as a possible solution to fight against bacterial pathogens resistant to antibiotics. These two applications necessitate bacteriophages to reach and kill their bacterial target within the gut environment. Unfortunately, exploitable clinical data in this field are scarce. Here, we review the administration of bacteriophages to target intestinal bacteria in mammalian experimental models. While bacteriophage amplification in the gut was often confirmed, we found that in most studies, it had no significant impact on the load of the targeted bacteria. In particular, we observed that the outcome of bacteriophage treatments is linked to the behavior of the target bacteria toward each animal model. Treatment efficacy ranges from poor in asymptomatic intestinal carriage to high in intestinal disease. This broad range of efficacy underlines the difficulties to reach a consensus on the impact of bacteriophages in the gut and calls for deeper investigations of key parameters that influence the success of such interventions before launching clinical trials.

International audience; Non-optimal prescriptions of antibiotics have a negative impact on patients and population. Clinical practice guidelines are not always followed by doctors because the rationale of the recommendations is not always clear and can be difficult to understand. In this paper, we propose a new approach consisting in presenting the properties of antibiotics for allowing doctors to compare them and choose the most appropriate one. For that, we used and extended rainbow boxes, a new technique for overlapping set visualization. We tested our approach on 11 clinical situations related to urinary infections, and assessed the simplicity, the interest and utility with 11 doctors. 10 of them found that this approach was interesting and useful in clinical practice. Further studies are needed to confirm this preliminary work.

International audience; Objective: To report the nature, diagnosis and therapeutic strategy of infectious emergencies in urology.Material and methods: Bibliographic research from Pubmed, Embase, and Google scholar in July 2021. A synthesis of the guidelines of national infectious diseases societies.Results: Urosepsis and complicated urinary tract infection have a standardized definition. Diagnosis and therapeutic strategy are presented for upper tract urinary infection, male urinary infection, healthcare associated urinary infection, symptomatic canduria and urinary infections of the elderly. Appropriate antibiotherapy should be tailored to the degree of severity, bacterial ecosystem, patient characteristics et localization of the infection.Conclusion: Urinary infections can be critical and require immediate care. Knowledge of the guidelines and of appropriate diagnosis and therapeutics strategy improve care which should be rapidly applied, and collegial.; ObjectifRapporter la nature, les stratégies diagnostiques et thérapeutiques des urgences infectieuses en urologie.Matériel et méthodeRecherche bibliographique à partir de Pubmed, Embase et Google Scholar en juillet 2021. Synthèse des recommandations nationales du comité d’infectiologie de l’AFU (CIAFU) et de la Société de Pathologies Infectieuses de Langue Française (SPILF).RésultatsL’urosepsis et sepsis urinaire grave répondent à des critères diagnostiques stricts. La prise en charge infectieuse diagnostique et thérapeutique des pyélonéphrites graves, infections urinaires masculines graves, infections urinaires associées aux soins, candiduries symptomatiques et infections urinaires chez la personne âgée sont décrites. L’antibiothérapie doit être adaptée à la gravité, l’écologie bactérienne, aux particularités du patient et au site d’infection.ConclusionLes infections urinaires peuvent être graves et nécessitent une prise en charge en urgence. La connaissance des recommandations et des stratégies diagnostiques et thérapeutiques adaptées aux diverses présentations permet une optimisation de la prise en charge qui doit être la plus rapide possible, et collégiale.

International audience; The human microbiome can protect against colonization with pathogenic antibiotic-resistant bacteria (ARB), but its impacts on the spread of antibiotic resistance are poorly understood. We propose a mathematical modeling framework for ARB epidemiology formalizing within-host ARB-microbiome competition, and impacts of antibiotic consumption on microbiome function. Applied to the healthcare setting, we demonstrate a trade-off whereby antibiotics simultaneously clear bacterial pathogens and increase host susceptibility to their colonization, and compare this framework with a traditional strain-based approach. At the population level, microbiome interactions drive ARB incidence, but not resistance rates, reflecting distinct epidemiological relevance of different forces of competition. Simulating a range of public health interventions (contact precautions, antibiotic stewardship, microbiome recovery therapy) and pathogens ( Clostridioides difficile , methicillin-resistant Staphylococcus aureus , multidrug-resistant Enterobacteriaceae) highlights how species-specific within-host ecological interactions drive intervention efficacy. We find limited impact of contact precautions for Enterobacteriaceae prevention, and a promising role for microbiome-targeted interventions to limit ARB spread.

Background Antibiotic misuse is a serious public health problem worldwide. National health authorities release clinical practice guidelines (CPGs) to guide general practitioners (GPs) in their choice of antibiotics. However, despite the large-scale dissemination of CPGs, GPs continue to prescribe antibiotics that are not recommended as first-line treatments. This nonadherence to recommendations may be due to GPs misunderstanding the CPGs. A web interface displaying antibiotic prescription recommendations and their justifications could help to improve the comprehensibility and readability of CPGs, thereby increasing the adoption of recommendations regarding antibiotic treatment. Objective This study aims to design and evaluate a web interface for antibiotic prescription displaying both the recommended antibiotics and their justifications in the form of antibiotic properties. Methods A web interface was designed according to the same principles as e-commerce interfaces and was assessed by 117 GPs. These GPs were asked to answer 17 questions relating to the usefulness, user-friendliness, and comprehensibility and readability of the interface, and their satisfaction with it. Responses were recorded on a 4-point Likert scale (ranging from “absolutely disagree” to “absolutely agree”). At the end of the evaluation, the GPs were allowed to provide optional, additional free comments. Results The antibiotic prescription web interface consists of three main sections: a clinical summary section, a filter section, and a recommended antibiotics section. The majority of GPs appreciated the clinical summary (90/117, 76.9%) and filter (98/117, 83.8%) sections, whereas 48.7% (57/117) of them reported difficulty reading some of the icons in the recommended antibiotics section. Overall, 82.9% (97/117) of GPs found the display of drug properties useful, and 65.8% (77/117) reported that the web interface improved their understanding of CPG recommendations. Conclusions The web interface displaying antibiotic recommendations and their properties can help doctors understand the rationale underlying CPG recommendations regarding antibiotic treatment, but further improvements are required before its implementation into a clinical decision support system.

Highly Resistant Cholera Outbreak Strain in Zimbabwe Whole genomes of 11 Vibrio cholerae O1 isolates from the 2018–2019 outbreak in Zimbabwe were sequenced to investigate the determinants of antimi...

International audience; Purpose. Pertussis remains a public health concern in most countries. Our study aimed to prospectively explore the epidemiology of pertussis in the Tunis area of Tunisia between 2007 and 2016, and to characterize the virulence-associated genes of the collected Bordetella pertussis isolates.Methodology. Infants and children hospitalized at the Children’s Hospital of Tunis, Tunisia, between 2007 and 2016 for suspicion of pertussis were enrolled in the study. Culture and real-time PCR (qPCR) assays targeting IS481, IS1001, recA, H-IS1001 and ptxP were used to confirm the pertussis diagnosis. Phenotypic and genotypic characterization of recovered isolates was performed.Results/Key findings. A total of 1844 children were included in the study. Overall, 306 children (16.6 %) with Bordetella infection were confirmed by qPCR. Among them, 265 (86.6 %) were confirmed as having B. pertussis (IS481+, ptxP+, H-IS1001−), 18 (5.9 %) as having Bordetella parapertussis (IS481−, IS1001+) and 11 (3.6 %) as having Bordetella spp. (IS481+, ptxP−, H-IS1001−). No Bordetella holmesii (IS481+, IS1001−, H-IS1001+) was identified. The estimated pertussis incidence in the Tunis area was 134/100 000 in children aged less than 5 years. Two epidemic peaks were observed in 2009 and 2014. Ten B. pertussis isolates were cultured and characterized. Deficiency in pertactin expression was not observed, and genotyping of the isolates revealed a predominant allelic profile: ptxP3-ptxA1-prn2-fim2-1-fim3-2.Conclusion. This study demonstrated that pertussis is still present as a cyclical disease in Tunisia, despite high primo-vaccination coverage with a pertussis whole-cell vaccine. The predominant genotype of Tunisian B. pertussis isolates is similar to isolates circulating in countries using the acellular vaccine.

Background Daptomycin is increasingly used in the treatment of bone and joint infection (BJI), but its pharmacokinetics (PK) and dosage requirements have not been thoroughly investigated in this indication. Daptomycin may be co-administered with rifampicin, which raises questions about a potential drug interaction. Objectives To investigate the population PK and dosage requirements of daptomycin in patients with BJI, and examine the influence of rifampicin co-administration. Methods A population approach was used to analyse PK data from patients who received daptomycin in our regional reference for BJI. We examined the influence of available covariates, including rifampicin co-administration on daptomycin PK. Simulations performed with the final model investigated the influence of dosages and covariates on PTA for both efficacy and safety. Results A total of 1303 daptomycin concentrations from 183 patients were analysed. A two-compartment model best described the data. Significant intra-individual variability was observed. Daptomycin clearance was influenced by renal function and sex, with females having a 26% lower typical clearance than males. Central volume of distribution (V1) was influenced by body weight, age, sex and rifampicin co-administration. Typical V1 was 11% lower in patients who were co-administered rifampicin. In PK/PD simulations, sex influenced the probability of AUC24/MIC target attainment, while rifampicin had a marginal effect. Conclusions A daptomycin dosage of 8 mg/kg/24 h in women and 10 mg/kg/24 h in men should optimize efficacy but may lead to excessive trough concentrations in many patients, especially in women. Therapeutic drug monitoring appears necessary for precision dosing of daptomycin.

International audience; No abstract available

International audience; Cardiac toxicity can be induced by hydroxychloroquine, especially when used in combination with azithromycin. Interest in hydroxychloroquine and azithromycin as potential therapies for COVID-19 has renewed concerns about the possible cardiovascular risk these drugs present to patients with rheumatoid arthritis.

Objectives To characterize genomes of Klebsiella pneumoniae ST11 NDM-1 responsible for a countrywide outbreak in Poland and compare them phylogenetically with other Polish and international ST11 strains. Methods Seventy-one carbapenemase-producing K. pneumoniae ST11 isolates from Poland, including 66 representatives of the NDM-1 epidemic from 2012–18, were sequenced using Illumina MiSeq. Additionally, three outbreak isolates were also sequenced using MinION. The clonality and phylogenetic analysis was done by core-genome MLST and SNP approaches. Resistomes, virulomes, K/O antigens and plasmid replicons were screened for. The detailed plasmid analysis was based on full assemblies using Oxford Nanopore Technologies data. Results Chromosomes of the outbreak isolates formed an essentially homogeneous cluster (though accumulating SNPs gradually with time), differing remarkably from other Polish NDM-1/-5-, KPC-2- or OXA-48-producing K. pneumoniae ST11 strains. The cluster belonged to a clade with 72 additional isolates identified worldwide, including closely related NDM-1 producers from several countries, including organisms from Bulgaria and Greece. All these had KL24 and O2v1 antigens and the chromosomal yersiniabactin locus YbST230 residing in the ICEKp11 element. The specific blaNDM-1-carrying Tn125 transposon derivative, named Tn125A, was located in IncFII/pKPX-1- and/or IncR-like plasmids; however, the IncRs rearranged extensively during the outbreak, contributing to highly dynamic plasmid profiles and resistomes. Conclusions The K. pneumoniae ST11 NDM-1 genotype that has been expanding in Poland since 2012 is largely monoclonal and represents a novel international high-risk lineage that is also spreading in other countries.

Objectives To characterize and compare resistance trends in clinical Escherichia coli isolates from humans, food-producing animals (poultry, cattle and swine) and pets (dogs and cats). Methods Antibiogram results collected between January 2014 and December 2017 by MedQual [the French surveillance network for antimicrobial resistance (AMR) in bacteria isolated from the community] and RESAPATH (the French surveillance network for AMR in bacteria from diseased animals) were analysed, focusing on resistance to antibiotics of common interest to human and veterinary medicine. Resistance dynamics were investigated using generalized additive models. Results In total, 743 637 antibiograms from humans, 48 170 from food-producing animals and 7750 from pets were analysed. For each antibiotic investigated, the resistance proportions of isolates collected from humans were of the same order of magnitude as those from food-producing animals or pets. However, resistance trends in humans differed from those observed in pets and food-producing animals over the period studied. For example, resistance to third-generation cephalosporins and fluoroquinolones was almost always below 10% for both humans and animals. However, in contrast to the notable decreases in resistance observed in both food-producing animals and pets, resistance in humans decreased only slightly. Conclusions Despite several potential biases in the data, the resistance trends remain meaningful. The strength of the parallel is based on similar data collection in humans and animals and on a similar statistical methodology. Resistance dynamics seemed specific to each species, reflecting different antibiotic-use practices. These results advocate applying the efforts already being made to reduce antibiotic use to all sectors and all species, both in human and veterinary medicine.

Objectives A molecular analysis was performed of two Providencia rettgeri (P. rettgeri) strains (Pr 297 and Pr 269) collected in 2007 and 2009 from wound swabs of patients admitted to the intensive care units at Joseph Ravoangy Andrianavalona hospital and the Military Hospital in Antananarivo, Madagascar. Methods The two P. rettgeri isolates were subjected to susceptibility testing. Whole genome sequencing was performed to characterise the antibiotic resistance genes, genomic islands and mobilomes (integrons, plasmids and insertion sequences). Results All isolates were found to be multidrug-resistant. Antibiotic-resistant genes described were amongst eight different classes of antimicrobial agents. Thirty insertion sequences and twelve genomic islands were predicted in each genome. Class 1 and class 2 integrons were found in both genomes, with gene cassette regions encompassing arr-2 - cmlA5 - blaOXA-10 - ant (3”)-Ia and dfrA1 - sat2 - ant (3”)-Ia – orfX, respectively. IncA/C2, ColM and ColE1-like plasmids were described harbouring blaCMY-30, qnrD and aac(6’)-Ib-cr4 genes, respectively. Phylogenetic analysis showed that Pr 297 and Pr 269 isolates were genetically identical and clustered with P. rettgeri strains described in the USA and Spain. Conclusions It is believed that this is the first molecular characterisation of wound infection pathogens from Madagascan patients and the first description of P. rettgeri co-producing CMY-30, OXA-10 and AAC(6’)-Ib-cr4 enzymes. The diversity of the resistance determinants and mobile genetic elements was probably due to extensive horizontal gene transfer events, highlighting the need to conduct further molecular monitoring studies to understand the genomic plasticity of resistant bacteria in Madagascan hospitals.

bahar tokman, hrisi/0000-0002-2205-5120 WOS:000525325200020 PubMed ID: 31634565 Objectives: Studies on the antimicrobial susceptibility profile of anaerobic bacteria are underrepresented in the literature. Within this study we aim to give an extensive overview of the differences in antimicrobial susceptibility profiles between different European and surrounding countries. Methods: Minimal inhibitory concentration (MIC) data of different antibiotics were collected from 10 participating laboratories, representing an equal number of countries. All MIC's were determined using Etest, according to the protocol used by the participating laboratory. Anaerobic genera represented by at least 10 clinical isolates were included in the study. Results: Each country tested different antibiotics, sometimes depending on the kind of infection and/or the anaerobic species isolated. All countries tested clindamycin and metronidazole. Resistance rates differed remarkably between the different countries. Especially in Kuwait, resistance was high for all tested antibiotics. Unexpected metronidazole resistance was observed for Finegoldia magna isolates, Peptoniphilus isolates and Eggerthella lenta isolates. Conclusions: Due to the extensive differences in antimicrobial susceptibility profile of anaerobic bacteria isolated within different countries, we strongly recommend to perform this kind of study on a regular basis. (C) 2019 The Authors. Published by Elsevier Ltd.

International audience; Introduction - Measures for controlling antimicrobial resistance are urgently required. We describe here AntibioGame®, a serious game for improving the training of medical students in antibiotic use in primary care. Objective - We aimed to design a serious game for antibiotics teaching and to evaluate its usability and playability by medical students. Methods - We used various gamification techniques (e.g. use of mascots, avatars, rewards, leader board) and cartoon graphics in the design of AntibioGame®. This game implements clinical case templates built from a list of learning goals defined by a medical team through an analysis of clinical practice guidelines. The game was evaluated by asking medical students to rate their satisfaction and the usability and playability of the game on an electronic form and through group discussions. The electronic form was derived from the MEEGA + scale, a five-point Likert scale including 32 items for assessing both usability and playability. Results - AntibioGame® is a case-based game in which students play the role of a doctor meeting patients in consultation and helping other health professionals to solve their problems, as in real life. The scenarios are realistic and cover situations frequently encountered in primary care. The 57 medical students enrolled found the game attractive, usable, fun, and appropriate for learning. Game quality was considered "good" (score = 60 on the MEEGA + scale). All the students said they would recommend the game, 96 % liked it and 81 % would use it for revision. Conclusion - AntibioGame® is a promising tool for improving knowledge in antibiotic prescription that could easily be included in multifaceted programs for training medical students.

Background Klebsiella pneumoniae is a leading cause of intractable hospital-acquired multidrug-resistant infections and carbapenemase-producing K. pneumoniae (CPKp) are particularly feared. Most of the clinical isolates produce capsule as a major virulence factor. Recombination events at the capsule locus are frequent and responsible for capsule diversity within Klebsiella spp. Capsule diversity may also occur within clonal bacterial populations generating differences in colony aspect. However, little is known about this phenomenon of phenotypic variation in CPKp and its consequences. Results Here, we explored the genetic causes of in vitro switching from capsulated, mucoid to non-mucoid, non-capsulated phenotype in eight clinical CPKp isolates. We compared capsulated, mucoid colony variants with one of their non-capsulated, non-mucoid isogenic variant. The two colony variants were distinguished by their appearance on solid medium. Whole genome comparison was used to infer mutations causing phenotypic differences. The frequency of phenotypic switch was strain-dependent and increased along with colony development on plate. We observed, for 72 non-capsulated variants that the loss of the mucoid phenotype correlates with capsule deficiency and diverse genetic events, including transposition of insertion sequences or point mutations, affecting genes belonging to the capsule operon. Reduced or loss of capsular production was associated with various in vitro phenotypic changes, affecting susceptibility to carbapenem but not to colistin, in vitro biofilm formation and autoaggregation. Conclusions The different impact of the phenotypic variation among the eight isolates in terms of capsule content, biofilm production and carbapenem susceptibility suggested heterogeneous selective advantage for capsular loss according to the strain and the mutation. Based on our results, we believe that attention should be paid in the phenotypic characterization of CPKp clinical isolates, particularly of traits related to virulence and carbapenem resistance.

International audience; Background. Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-Kp) has emerged globally over the last decade as a major nosocomial pathogen that threatens patient care. These highly resistant bacteria are mostly associated with a single Kp clonal group, CG258, but the reasons for its host and hospital adaptation remain largely unknown. Methods. We analyzed the in vivo evolution of a colistin-resistant KPC-Kp CG258 strain that contaminated a patient following an endoscopy and was responsible for a fatal bacteremia 4.5 years later. Whole-genome sequencing was performed on 17 KPC-Kp isolates from this patient; single-nucleotide polymorphisms were analyzed and their implication in antimicrobial resistance and bacterial host adaptation investigated. Results. The patient KPC-Kp strain diversified over 4.5 years at a rate of 7.5 substitutions per genome per year, resulting in broad phenotypic modifications. After 2 years of carriage, all isolates restored susceptibility to colistin. Higher expression of the fimbriae conferred the ability to produce more biofilm, and the isolate responsible for a bacteremia grew in human serum. The convergent mutations occurring in specific pathways, such as the respiratory chain and the cell envelope, revealed a complex long-term adaptation of KPC-Kp. Conclusions. Broad genomic and phenotypic diversification and the parallel selection of pathoadaptive mutations might contribute to long-term carriage and virulence of KPC-Kp CG258 strains and to the dissemination of this clone.

International audience; Objectives: Patient-and procedure-related changes in modern medicine have turned CoNS into one of the major nosocomial pathogens. Treatments of CoNS infections are challenging owing to the large proportion of MDR strains and oxazolidinones often remain the last active antimicrobial molecules. Here, we have investigated a long-lasting outbreak (2010-13) due to methicillin-and linezolid-resistant (LR) CoNS (n " 168), involving 72 carriers and 49 infected patients. Methods: Antimicrobial susceptibilities were tested by the disc diffusion method and MICs were determined by broth microdilution or Etest. The clonal relationship of LR Staphylococcus epidermidis (LRSE) was first determined using a semi-automated repetitive element palindromic PCR (rep-PCR) method. Then, WGS was performed on all cfr-positive LRSE (n " 30) and LRSE isolates representative of each rep-PCR-defined clone (n " 17). Self-transferability of cfr-carrying plasmids was analysed by filter-mating experiments. Results: This outbreak was caused by the dissemination of three clones (ST2, ST5 and ST22) of LRSE. In these clones, linezolid resistance was caused by (i) mutations in the chromosome-located genes encoding the 23S RNA and L3 and L4 ribosomal proteins, but also by (ii) the dissemination of two different self-conjugative plasmids carrying the cfr gene encoding a 23S RNA methylase. By monitoring linezolid prescriptions in two neighbouring hospitals, we highlighted that the spread of LR-CoNS was strongly associated with linezolid use. Conclusions: Physicians should be aware that plasmid-encoded linezolid resistance has started to disseminate among CoNS and that rational use of oxazolidinones is critical to preserve these molecules as efficient treatment options for MDR Gram-positive pathogens.

International audience; In this study, we aimed to decipher the natural resistance mechanisms of mycobacteria against novel compounds isolated by whole-cell-based high-throughput screening (HTS). We identified active compounds using Mycobacterium aurum. Further analyses were performed to determine the resistance mechanism of M. smegmatis against one hit, 3-bromo-N-(5-nitrothiazol-2-yl)-4-propoxybenzamide (3), which turned out to be an analog of the drug nitazoxanide (1). We found that the repression of the gene nfnB coding for the nitroreductase NfnB was responsible for the natural resistance of M. smegmatis against 3. The overexpression of nfnB resulted in sensitivity of M. smegmatis to 3. This compound must be metabolized into hydroxylamine intermediate for exhibiting antibacterial activity. Thus, we describe, for the first time, the activity of a mycobacterial nitroreductase against 1 analogs, highlighting the differences in the metabolism of nitro compounds among mycobacterial species and emphasizing the potential of nitro drugs as antibacterials in various bacterial species.

International audience; Background: Postoperative pneumonia (POP) is a severe complication of major lung resection. The objective of this study was to describe the current epidemiology and appropriateness of antibiotic prescriptions in severe POP, 4 years after implementation of an antimicrobial stewardship program that was based on weekly multidisciplinary review of all antibiotic therapies.Methods: This study was a retrospective analysis of a prospectively collected database. It included all cases of severe POP occurring within 30 days after major lung resection of in a 1,500-bed hospital between 2013 and 2015. Criteria for severe POP were acute respiratory failure, severe sepsis, or a rapidly extensive pulmonary infiltrate. The study collected data on incidence, clinical outcomes, and microbiological analyses. Appropriateness of antibiotic prescribing was assessed by quality indicators previously validated in the literature.Results: Over the study period, 1,555 patients underwent major lung surgery. Severe POP occurred in 91 patients (5.8%; confidence interval, 4.7%; 7.0%), with a mortality rate of 9.0% (8 of 91; confidence interval, 3.0%; 14.6%). In POP with positive microbiological results, the proportion of gram-negative bacteria other than Haemophilus was 76% (50 of 66 cases). All patients (91 of 91) had respiratory samples taken within 24 hours after the start of antibiotics; empiric therapy was concordant with the guideline in 80% (69 of 86), and it was switched to pathogen-directed therapy in 74% (46 of 62). In 71 of 91 patients (78%), the antibiotic duration was up to 7 days.Conclusions: This study reported a high proportion of gram-negative bacteria in severe POP. Four years after implementation of the program, quality indicators of antibiotic prescribing were all >70%. The rate of de-escalation to pathogen-directed therapy could be improved, however.

Salmonella enterica serotype Kentucky can be a common causative agent of salmonellosis, usually associated with consumption of contaminated poultry. Antimicrobial resistance (AMR) to multiple drugs, including ciprofloxacin, is an emerging problem within this serotype. We used whole-genome sequencing (WGS) to investigate the phylogenetic structure and AMR content of 121 S. e nterica serotype Kentucky sequence type 198 isolates from five continents. Population structure was inferred using phylogenomic analysis and whole genomes were compared to investigate changes in gene content, with a focus on acquired AMR genes. Our analysis showed that multidrug-resistant (MDR) S. enterica serotype Kentucky isolates belonged to a single lineage, which we estimate emerged circa 1989 following the acquisition of the AMR-associated Salmonella genomic island (SGI) 1 (variant SGI1-K) conferring resistance to ampicillin, streptomycin, gentamicin, sulfamethoxazole and tetracycline. Phylogeographical analysis indicates this clone emerged in Egypt before disseminating into Northern, Southern and Western Africa, then to the Middle East, Asia and the European Union. The MDR clone has since accumulated various substitution mutations in the quinolone-resistance-determining regions (QRDRs) of DNA gyrase (gyrA) and DNA topoisomerase IV (parC), such that most strains carry three QRDR mutations which together confer resistance to ciprofloxacin. The majority of AMR genes in the S. e nterica serotype Kentucky genomes were carried either on plasmids or SGI structures. Remarkably, each genome of the MDR clone carried a different SGI1-K derivative structure; this variation could be attributed to IS26-mediated insertions and deletions, which appear to have hampered previous attempts to trace the clone’s evolution using sub-WGS resolution approaches. Several different AMR plasmids were also identified, encoding resistance to chloramphenicol, third-generation cephalosporins, carbapenems and/or azithromycin. These results indicate that most MDR S. e nterica serotype Kentucky circulating globally result from the clonal expansion of a single lineage that acquired chromosomal AMR genes 30 years ago, and has continued to diversify and accumulate additional resistances to last-line oral antimicrobials. This article contains data hosted by Microreact.

Background Limited epidemiological and antimicrobial resistance data are available on Salmonella enterica from sub-Saharan Africa. We determine the prevalence of resistance to antibiotics in isolates in the Central African Republic (CAR) between 2004 and 2013 and the genetic basis for resistance to third-generation cephalosporin (C3G). Methodology/Principal findings A total of 582 non-duplicate human clinical isolates were collected. The most common serotype was Typhimurium (n = 180, 31% of the isolates). A randomly selected subset of S. Typhimurium isolates were subtyped by clustered regularly interspaced short palindromic repeat polymorphism (CRISPOL) typing. All but one invasive isolate tested (66/68, 96%) were associated with sequence type 313. Overall, the rates of resistance were high to traditional first-line drugs (18–40%) but low to many other antimicrobials, including fluoroquinolones (one resistant isolate) and C3G (only one ESBL-producing isolate). The extended-spectrum beta-lactamase (ESBL)-producing isolate and three additional ESBL isolates from West Africa were studied by whole genome sequencing. The blaCTX-M-15 gene and the majority of antimicrobial resistance genes found in the ESBL isolate were present in a large conjugative IncHI2 plasmid highly similar (> 99% nucleotide identity) to ESBL-carrying plasmids found in Kenya (S. Typhimurium ST313) and also in West Africa (serotypes Grumpensis, Havana, Telelkebir and Typhimurium). Conclusions/Significance Although the prevalence of ESBL-producing Salmonella isolates was low in CAR, we found that a single IncHI2 plasmid-carrying blaCTX-M-15 was widespread among Salmonella serotypes from sub-Saharan Africa, which is of concern., Author summary Salmonella enterica infections are common causes of bloodstream infection in sub-Saharan Africa and associated with a high mortality rate. Levels of multidrug resistance have become alarmingly high. Then, third-generation cephalosporin (C3G) and fluoroquinolones have become standard for first-line empirical treatment. Recently, C3G-resistant Salmonella populations have emerged and spread over all continents. This resistance is mainly mediated by acquired extended-spectrum beta-lactamase (ESBL) genes carried by mobile genetic elements such as plasmids. We report here the prevalence of resistance to antibiotics in isolates in the Central African Republic (CAR) between 2004 and 2013 and the genetic basis for resistance to C3G. Overall, resistance rates to antimicrobials were low during the study period, for all classes other than conventional antimicrobials, confirming recommendations for first-line treatment based on C3G and fluoroquinolones. Only one ESBL-producing isolate was recovered. The ESBL gene and the majority of antimicrobial resistance genes found were present in a large plasmid highly similar to ESBL-carrying plasmids found in East and West Africa, highlighting its significant role in the spread of ESBL genes in Salmonella isolates in sub-Saharan Africa. These finding have implications for treatment of salmonellosis and support the growing necessity for increased microbiological surveillance based on networks of clinical laboratories in order to control dissemination of antibiotic resistance among Salmonella isolates.

International audience; A limitation of antibiotic treatments for P. aeruginosa (PA) chronic pulmonary infections is the reduced efficacy due to sub-therapeutic concentrations at the infection site and the development of biofilm. A novel approach to sustain ciprofloxacin (CIP) in the lungs after inhalation is to reduce its pulmonary absorption rate by its complexation with copper (CIP-Cu). This study aimed to evaluate the antimicrobial action of cationic CIP-Cu complex in PA biofilms in terms of drug concentration and time. Two PA strains, PA01 and PA14, were grown to form biofilm layers in equilibrium with planktonic cells. Static parameters such as pyoverdine production by planktonic cells, enzymatic activity within biofilms, and biofilm biomass 24 h after the addition of CIP or CIP-Cu were evaluated. Also, the kinetic effects of CIP and CIP-Cu on biofilms were evaluated by bioluminescence kinetics using transgenic strains. No differences were observed between CIP and CIP-Cu in terms of efficacy against biofilms, validating the potential of using this complex to treat PA biofilms. Interestingly, CIP concentrations slightly below the MIC value against planktonic bacteria stimulated both virulence and biofilm PA01 production. These results support the need to accurately achieve high CIP concentration in the lungs, which can be more easily achieved by pulmonary delivery of advanced CIP formulations (CIP-metal complexes or liposomal CIP) instead of the oral administration of free CIP.

International audience; In France, the frequency of premature rupture of the membranes (PROM) is 2%-3% before 37 weeks' gestation (level of evidence [LE] 2) and less than 1% before 34 weeks (LE2). Preterm delivery and intrauterine infection are the major complications of preterm PROM (PPROM) (LE2). Prolongation of the latency period is beneficial (LE2). Compared with other causes of preterm delivery, PPROM is associated with a clear excess risk of neonatal morbidity and mortality only in cases of intrauterine infection, which is linked to higher rates of in utero fetal death (LE3), early neonatal infection (LE2), and necrotizing enterocolitis (LE2). The diagnosis of PPROM is principally clinical (professional consensus). Tests to detect IGFBP-1 or PAMG-1 are recommended in cases of uncertainty (professional consensus). Hospitalization is recommended for women diagnosed with PPROM (professional consensus). Adequate evidence does not exist to support recommendations for or against initial tocolysis (Grade C). If tocolysis is prescribed, it should not continue longer than 48 h (Grade C). The administration of antenatal corticosteroids is recommended for fetuses with a gestational age less than 34 weeks (Grade A) and magnesium sulfate if delivery is imminent before 32 weeks (Grade A). The prescription of antibiotic prophylaxis at admission is recommended (Grade A) to reduce neonatal and maternal morbidity (LE1). Amoxicillin, third-generation cephalosporins, and erythromycin (professional consensus) can each be used individually or eythromycin and amoxicillin can be combined (professional consensus) for a period of 7 days (Grade C). Nonetheless, it is acceptable to stop antibiotic prophylaxis when the initial vaginal sample is negative (professional consensus). The following are not recommended for antibiotic prophylaxis: amoxicillin-clavulanic acid (professional consensus), aminoglycosides, glycopeptides, first- or second-generation cephalosporins, clindamycin, or metronidazole (professional consensus). Women who are clinically stable after at least 48 h of hospital monitoring can be managed at home (professional consensus). Monitoring should include checking for clinical and laboratory factors suggestive of intrauterine infection (professional consensus). No guidelines can be issued about the frequency of this monitoring (professional consensus). Adequate evidence does not exist to support a recommendation for or against the routine initiation of antibiotic therapy when the monitoring of an asymptomatic woman produces a single isolated positive result (e.g., elevated CRP, or hyperleukocytosis, or a positive vaginal sample) (professional consensus). In cases of intrauterine infection, the immediate intravenous administration (Grade B) of antibiotic therapy combining a beta-lactam with an aminoglycoside (Grade B) and early delivery of the child are both recommended (Grade A). Cesarean delivery of women with intrauterine infections is reserved for the standard obstetric indications (professional consensus). Expectant management is recommended for uncomplicated PROM before 37 weeks (Grade A), even when a sample is positive for Streptococcus B, as long as antibiotic prophylaxis begins at admission (professional consensus). Oxytocin and prostaglandins are two possible options for the induction of labor in women with PPROM (professional consensus).

International audience; Objectives: Urinary tract infections (UTIs) have rarely been studied in the Amazon region. We aimed to describe the epidemiology of bacteria causing UTIs in French Guiana.Patients and methods: We performed a monocenter retrospective study of adults consulting at the emergency department of Cayenne Hospital in 2014 with a diagnosis of UTI. The bacterial species and resistance profile were described.Results: Two-hundred-and-eighty-nine patients presenting with UTI were included: 82 (28.4%) presented with cystitis, 166 (57.4%) with pyelonephritis, and 41 (14.2%) with male UTI. E. coli was predominant (74.1%), and had decreased susceptibility to ampicillin, amoxicillin-clavulanic acid, fluoroquinolones, co-trimoxazole, and furans compared with data from metropolitan France. Extended-spectrum beta-lactamases (ESBL) was isolated in 3.1% of E. coli and 31.6% of K. pneumoniae.Conclusions: Antibiotic susceptibility in UTI is lower than reported in metropolitan France without evidence for an excessive consumption of antibiotics.

Introduction Clinical decision support systems (CDSS) implementing clinical practice guidelines (CPGs) have 2 main limitations: they target only patients for whom CPGs provide explicit recommendations, and their rationale may be difficult to understand. These 2 limitations result in poor CDSS adoption. We designed AntibioHelp® as a CDSS for antibiotic treatment. It displays the recommended and nonrecommended antibiotics, together with their properties, weighted by degree of importance as outlined in the CPGs. The aim of this study was to determine whether AntibioHelp® could increase the confidence of general practitioners (GPs) in CPG recommendations and help them to extrapolate guidelines to patients for whom CPGs provide no explicit recommendations. Materials and Methods We carried out a 2-stage crossover study in which GPs responded to clinical cases using CPG recommendations either alone or with explanations displayed through AntibioHelp®. We compared error rates, confidence levels, and response times. Results We included 64 GPs. When no explicit recommendation existed for a particular situation, AntibioHelp® significantly decreased the error rate (−41%, P value = 6x10−13), and significantly increased GP confidence (+8%, P value = .02). This CDSS was considered to be usable by GPs (SUS score = 64), despite a longer interaction time (+9–22 seconds). By contrast, AntibioHelp® had no significant effect if there was an explicit recommendation. Discussion/Conclusion The visualization of weighted antibiotic properties helps GPs to extrapolate recommendations to patients for whom CPGs provide no explicit recommendations. It also increases GP confidence in their prescriptions for these patients. Further evaluations are required to determine the impact of AntibioHelp® on antibiotic prescriptions in real clinical practice.

Background Bone and joint infections (BJIs) due to Streptococcus agalactiae are rare but has been described to increase in the past few years. The objective of this study was to describe clinical features and outcomes of cases of S. BJIs. Methods We conducted a retrospective analysis of adult cases of S. agalactiae BJIs that occurred between January 2009 and June 2015 in a French university hospital. The treatment success was assessed until 24 months after the end of antibiotic treatment. Results Among the 26 patients included, 20 (77%) were male, mean age was 62 years ± 13 and mean Charlson comorbidity index score was 4.9 ± 3.2. Diabetes mellitus was the most common comorbidity (n = 14, 54%). Six had PJI (Prosthetic Joint Infections), five osteosynthesis-associated infections, 11 osteomyelitis and four native septic arthritis. Eleven patients had a delayed or late infection: six with a prosthetic joint infection and five with an internal fixation device infection. Sixteen patients (62%) had a polymicrobial BJI, most commonly with Gram-positive cocci (75%) notably Staphylococcus aureus (44%). Polymicrobial infections were more frequently found in foot infections (90% vs 44%, p = 0.0184). During the two-year follow-up, three patients died (3/25, 12%) and seven (7/25, 28%) had treatment failure. Conclusion Diabetes mellitus was the most common comorbidity. We observed an heterogenous management and a high rate of relapse.

International audience; The design and synthesis of efficient ligands for DC-SIGN is a topic of high interest, because this C-type lectin has been implicated in the early stages of many infection processes. DC-SIGN membrane-protein presents four carbohydrate-binding domains (CRD) that specifically recognize mannose and fucose. Therefore, antagonists of minimal disaccharide epitope Manα(1,2)Man, represent potentially interesting antibacterial and antiviral agents. In the recent past, we were able to develop efficient antagonists, mimics of the natural moiety, characterized by the presence of a real d-carbamannose unit which confers greater stability to enzymatic breakdown than the corresponding natural disaccharide ligand. Herein, we present the challenging stereoselective synthesis of four new amino or azide glycomimetic DC-SIGN antagonists with attractive orthogonal lipophilic substituents in C(3), C(4) or C(6) positions of the real carba unit, which were expected to establish crucial interactions with lipophilic areas of DC-SIGN CRD. The activity of the new ligands was evaluated by SPR binding inhibition assays. The interesting results obtained, allow to acquire important information about the influence of the lipophilic substituents present in specific positions of the carba scaffold. Furthermore, C(6) benzyl C(4) tosylamide pseudodisaccharide displayed a good affinity for DC-SIGN with a more favorable IC50 value than those of the previously described real carba-analogues. This study provides valuable knowledge for the implementation of further structural modifications towards improved inhibitors.

International audience

International audience; OBJECTIVE:We aimed to assess medical practices of French infectious disease specialists or any other relevant physicians related to the management of non-necrotizing cellulitis (NNC).METHODS:We sent an online questionnaire to members of the French Infectious Diseases Society (SPILF) mailing list in September 2015.RESULTS:A total of 108 specialists took part in the survey and 10% (11/107) declared to always admit NNC patients to hospital. As for the others, 18% declared to admit patients in more than 80% of cases, 49% in 50-80% of cases, 26% in 20-50% of cases, and 7% in less than 20% of cases. The most frequent criteria for hospital admission were severe sepsis/septic shock (99%), poor social conditions (99%), rapid extension of skin lesions (93%), high level of pain (86%), and failure of first-line antibiotic therapy (84%). Participants mentioned similar criteria for reasons to initiate the intravenous (IV) antibiotic therapy. Fifty-three percent of respondents declared initiating antibiotic therapy using the IV route in more than 80% of cases. Physicians declared that the usual antibiotic therapy duration were 15 days (3%).CONCLUSION:Criteria for hospital admission and use of the IV route for antibiotic therapy as well as optimal treatment duration in patients presenting with NNC need to be detailed in guidelines and evaluated in prospective studies.

The objective of this study was to characterize the pharmacokinetics of unbound and total concentrations of daptomycin in infected ICU patients with various degrees of renal impairment. From these results, the probability of attaining antimicrobial efficacy and the risks of toxicity were assessed.Twenty-four ICU patients with various renal functions and requiring treatment of complicated skin and soft-tissue infections, bacteraemia, or endocarditis with daptomycin were recruited. Daptomycin (Cubicin®) at 10 mg/kg was administered every 24 h for patients with creatinine clearance (CLCR) ≥30 mL/min and every 48 h for patients with CLCR30 mL/min. Total and unbound plasma concentrations and urine concentrations of daptomycin were analysed simultaneously following a population pharmacokinetic approach. Simulations were conducted to estimate the probability of attaining efficacy (unbound AUCu/MIC40 or80) or toxicity (Cmin24.3 mg/L) targets.Exposure to unbound daptomycin increased when the renal function decreased, thus increasing the probability of reaching the efficacy targets, but also the risk of toxicity. Modifications of the unbound fraction (fu) of daptomycin did not affect the pharmacokinetics of unbound daptomycin, but did affect the pharmacokinetics of total daptomycin.Daptomycin at 10 mg/kg q24h allowed efficacy pharmacokinetic/pharmacodynamic targets for ICU patients with CLCR ≥30 mL/min to be reached. For patients with CLCR30 mL/min, halving the rate of drug administration, i.e. 10 mg/kg q48h, was sufficient to reach these targets. No adverse events were observed, but the toxicity of the 10 mg/kg q24h dosing regimen should be further assessed, particularly for patients with altered renal function.

International audience; Clinical practice guidelines provide evidence-based recommendations. However, many problems are reported, such as contradictions and inconsistencies. For example, guidelines recommend sulfamethoxazole/trimethoprim in child sinusitis, but they also state that there is a high bacteria resistance in this context. In this paper, we propose a method for the semi-automatic detection of inconsistencies in guidelines using preference learning, and we apply this method to antibiotherapy in primary care. The preference model was learned from the recommendations and from a knowledge base describing the domain. We successfully built a generic model suitable for all infectious diseases and patient profiles. This model includes both preferences and necessary features. It allowed the detection of 106 candidate inconsistencies which were analyzed by a medical expert. 55 inconsistencies were validated. We showed that therapeutic strategies of guidelines in antibiotherapy can be formalized by a preference model. In conclusion, we proposed an original approach, based on preferences, for modeling clinical guidelines. This model could be used in future clinical decision support systems for helping physicians to prescribe antibiotics.

International audience; Whole-genome sequencing (WGS) has been vital for revealing the rapid temporal and spatial evolution of antimicrobial resistance (AMR) in bacterial pathogens. Some antimicrobial-resistant pathogens have outpaced us, with untreatable infections appearing in hospitals and the community. However, WGS has additionally provided us with enough knowledge to initiate countermeasures. Although we cannot stop bacterial adaptation, the predictability of many evolutionary processes in AMR bacteria offers us an opportunity to channel them using new control strategies. Furthermore, by using WGS for coordinating surveillance and to create a more fundamental understanding of the outcome of antimicrobial treatment and AMR mechanisms, we can use current and future antimicrobials more effectively and aim to extend their longevity.

Background Defined by an infection of the ventricular system of the brain, ventriculitis is usually known as a health-care associated infection. In contrast, primary pyogenic ventriculitis complicating community-acquired meningitis is uncommon, and mainly described in infants. Only seven cases that have occured in adults have been found in the international literature. Case presentation We report here a new case due to Neisseria meningitidis occurring in an 85 year-old-man. The comparison with previous reports allows to drawn several conclusions: (i) cases occurred in relatively old adults (median age: 65 years); (ii) Streptococcus pneumoniae, N. meningitiditis and Staphylococcus aureus are the leading responsible pathogens; (iii) atypical clinical presentation seems the rule in which meningism often lacks; (iv) in absence of clinical or biological specific parameters, modern brain imaging such as magnetic resonance imaging with gadolinium enhancement is of utmost importance for the diagnosis, leading to anticipate an increase of the diagnosis in the near future, thanks to easier access to such exploration; (v) death or serious sequelae commonly occurred; (vi) prolonged antibiotic courses (6 weeks to 3 months) have been used, without strong rational. In the given case, the patient presented with a lack of meningeal irritation signs. The diagnosis was made by MRI considering a lasting confused state. A four-week antibiotic regimen was successful, combining two weeks of intravenous cefotaxime followed by two weeks of oral levofloxacin much easier to administrate and allowing early rehabilitation. Conclusion Primary bacterial ventriculitis is a real diagnosis challenge. Larger indications of MRI for bacterial meningitis, particularly in cases with an atypical presentation or poor evolution would certainly increase the number of diagnosis.

International audience; The treatment duration of acute uncomplicated pyelonephritis (AUP) is still under debate. As shortening treatment duration could be a means to reduce antimicrobial resistance, we aimed to establish whether 5 days of antibiotic treatment is non-inferior to 10 days in patients with AUP. We performed an open-label prospective randomized trial comparing 5 days to 10 days of fluoroquinolone treatment for AUP. The inclusion criteria were: female patients aged ≥18 years with clinical signs of urinary tract infection, fever >38 °C, and positive urinalysis. Patients were randomized to either 5 or 10 days of fluoroquinolone treatment. Outcome was cure at day 10 and day 30 after the end of treatment. One hundred patients were randomized and 12 were excluded after randomization. The mean ± standard deviation (SD) age was 31.8 ± 11 years old and the mean ± SD temperature was 38.6 ± 0.7 °C. The main bacterium involved was Escherichia coli (n = 86; 97.7%) and 3 (3.4%) patients had a positive blood culture. In the post-hoc analysis, clinical cure 10 days after the end of the treatment was 28/30 (93.3%) in the 5-day arm and 36/38 (94.7%) in the 10-day arm (p = 1.00). At day 30, the clinical cure rate was 23/23 (100%) in the 5-day arm and 20/20 (100%) in the 10-day arm (p = 1.00). The microbiological cure rate was 20/23 (87.0%) in the 5-day arm and 16/20 (80.0%) in the 10-day arm (p = 1.00). The efficacy of 5 days of fluoroquinolone treatment does not seem different from 10 days of treatment for AUP.

Summary Background Ampicillin, the first semi-synthetic penicillin active against Enterobacteriaceae, was released onto the market in 1961. The first outbreaks of disease caused by ampicillin-resistant strains of Salmonella enterica serotype Typhimurium were identified in the UK in 1962 and 1964. We aimed to date the emergence of this resistance in historical isolates of S enterica serotype Typhimurium. Methods In this retrospective, whole-genome sequencing study, we analysed 288 S enterica serotype Typhimurium isolates collected between 1911 and 1969 from 31 countries on four continents and from various sources including human beings, animals, feed, and food. All isolates were tested for antimicrobial drug susceptibility with the disc diffusion method, and isolates shown to be resistant to ampicillin underwent resistance-transfer experiments. To provide insights into population structure and mechanisms of ampicillin resistance, we did whole-genome sequencing on a subset of 225 isolates, selected to maximise source, spatiotemporal, and genetic diversity. Findings 11 (4%) of 288 isolates were resistant to ampicillin because of acquisition of various β lactamase genes, including bla TEM-1 , carried by various plasmids, including the virulence plasmid of S enterica serotype Typhimurium. These 11 isolates were from three phylogenomic groups. One isolate producing TEM-1 β lactamase was isolated in France in 1959 and two isolates producing TEM-1 β lactamase were isolated in Tunisia in 1960, before ampicillin went on sale. The vectors for ampicillin resistance were different from those reported in the strains responsible for the outbreaks in the UK in the 1960s. Interpretation The association between antibiotic use and selection of resistance determinants is not as direct as often presumed. Our results suggest that the non-clinical use of narrow-spectrum penicillins (eg, benzylpenicillin) might have favoured the diffusion of plasmids carrying the bla TEM-1 gene in S enterica serotype Typhimurium in the late 1950s. Funding Institut Pasteur, Sante publique France, the French Government's Investissement d'Avenir programme, the Fondation Le Roch-Les Mousquetaires.

International audience; BACKGROUND:Childhood community-acquired pneumonia is a leading cause of childhood morbidity in low-income countries. The etiologic agents are usually Staphylococcus aureus, Streptococcus pneumoniae and Mycoplasma pneumoniae. M. pneumoniae was recognized as a cofactor in asthmatic disease. High asthma prevalence was reported in Madagascar. Our aim was to clarify the prevalence of M. pneumoniae infection in this country and its relationship with asthma.METHODS:A prospective study was conducted in 351 children (from 2 to 16 years of age) from January 2012 to December 2014. According to the clinical symptoms, children were enrolled in 3 groups: "control group" (CG, n = 106), "asthma group" (n = 129) and "pneumonia group" (n = 116). The IgG and IgM M. pneumoniae status was evaluated by an enzyme-linked immunosorbent assay. Clinical signs of infection, socioeconomic data and antimicrobial treatment were recorded.RESULTS:The overall prevalence of M. pneumoniae infection was 18.2%. The multivariate analysis demonstrated that M. pneumoniae infection was significantly more frequent in the CG [pneumonia group vs. CG: odds ratio = 0.45 (0.21-0.91), P = 0.037 and asthma group vs. CG: odds ratio = 0.39 (0.18-0.87), P = 0.021]. The C-reactive protein value was significantly higher in children with M. pneumonia-positive serology (85 vs. 61 mg/L, P = 0.03). Of note, 99 (41%) children received antibiotics before attending.CONCLUSIONS:We report a prevalence of 18.2% for M. pneumoniae infection in children in Madagascar. The prevalence of M. pneumoniae infection was higher in the control patients than in asthmatic ones.

International audience; The use of central venous catheters (CVC) is associated with a risk of microbial colonization and subsequent potentially severe infection. Microbial contamination of the catheter leads to the development of a microbial consortia associated with the CVC surface and embedded in an extracellular matrix, named biofilm. This biofilm provides bacterial cells the ability to survive antimicrobial agents and the host immune system and to disseminate to other sites of the body. The best preventive strategy is to avoid any unnecessary catheterization or to reduce indwelling duration when a CVC is required. Beside aseptic care and antibiotic-impregnated catheters (like minocycline/rifampin), preventive locks can be proposed in some cases, whereas non-biocidal approaches are under active research like anti-adhesive or competitive interactions strategies. When the diagnosis of catheter-related bloodstream infection (CRBSI) is suspected on clinical symptoms, it requires a microbiological confirmation by paired blood cultures in order to avoid unnecessary catheter removal. The treatment of CRBSI relies on catheter removal and systemic antimicrobials. However, antibiotic lock technique (ALT) can be used as an attempt to eradicate biofilm formed on the inside lumen of the catheter in case of uncomplicated long-term catheter-related BSI caused by coagulase-negative staphylococci (CoNS) or Enterobacteriaceae. Recently, promising strategies have been developed to improve biofilm eradication; they rely on matrix degradation or destabilization or the development of anti-persister compounds, targeting the most tolerant bacterial cells inside the biofilm. Understanding biofilm formation at the molecular level may help us to develop new approaches to prevent or treat these frequent infections.