Charles Burdet

Trends in Human Fecal Carriage of Extended-Spectrum β-Lactamases in the Community: Toward the Globalization of CTX-M

SUMMARY In the last 10 years, extended-spectrum β-lactamase-producing enterobacteria (ESBL-E) have become one of the main challenges for antibiotic treatment of enterobacterial infections, largely because of the current CTX-M enzyme pandemic. However, most studies have focused on hospitalized patients, though today it appears that the community is strongly affected as well. We therefore decided to devote our investigation to trends in ESBL-E fecal carriage rates and comprehensively reviewed data from studies conducted on healthy populations in various parts of the world. We show that (i) community ESBL-E fecal carriage, which was unknown before the turn of the millennium, has since increased significantly everywhere, with developing countries being the most affected; (ii) intercontinental travel may have emphasized and globalized the issue; and (iii) CTX-M enzymes, especially CTX-M-15, are the dominant type of ESBL. Altogether, these results suggest that CTX-M carriage is evolving toward a global pandemic but is still insufficiently described. Only a better knowledge of its dynamics and biology will lead to further development of appropriate control measures.

Escherichia coli bacteremia in children: age and portal of entry are the main predictors of severity.

Background: Escherichia coli bacteremia is a major cause of severe sepsis in children. Little is known about predictors of severity. Methods: We analyzed 84 children ⩽18 years of age with E. coli bacteremia from the prospective COLIBAFI study performed during 2005–2007. The severity of bacteremia was defined as occurrence of death or transfer to intensive care unit. Studied characteristics included age, gender, birth weight, history of prematurity, immunodepression, nosocomial infection, portal of entry, phylogenetic group and subgroup belonging, O-type, virulence gene content and antimicrobial susceptibility. We compared bacterial characteristics in urinary- versus digestive-source bacteremia, in children ⩽3 versus >3 month of age, and in children versus adults. We also searched for risk factors of severity. Results: Median age was 2.4 months, 57% males. Most frequent portals of entry were urinary (66.2%) and digestive (19.5%) tracts. Most isolates (63.1%) belonged to B2 phylogroup. Strains in children ⩽3 months of age exhibited more virulence genes, especially neuC and fyuA/irp2, and were less resistant to antibiotics than in children >3 months of age. Comparing community-acquired urinary-source bacteremia between children and adults, we found that bacteremia were less severe in children, whose strains exhibited a specific virulence gene repertoire and had a higher resistance score than in adults. Seventeen children (20.2%) had a severe bacteremia and 8 died. Non-urinary portal of entry and age ⩽3 months of age were the only risk factors associated with severity. Conclusions: E. coli strains responsible for bacteremia exhibit specific characteristics according to age of children. However, host characteristics and portal of entry are the main determinants of severity of E. coli bacteremia in children, as observed in adults.

Complexity of Escherichia coli bacteremia pathophysiology evidenced by comparison of isolates from blood and portal of entry within single patients

The portal of entry of Escherichia coli bacteremia, a frequent and severe disease, is most commonly the urinary tract followed by the digestive tract. Recent reports have evidenced the presence of several distinct E. coli clones within a single patient suffering of extra-intestinal infection. To explore the relationships between the blood and portal of entry strains, we thoroughly studied 98 bacteremic patients from the French prospective COLIBAFI cohort. In these patients, we compared genotypically and phenotypically E. coli strains isolated from the blood and the suspected portal of entry [non-urinary pus (n=52) and urine (n=52)]. We found genetically distinct strains exhibiting distinct antibiotypes in the blood and pus samples (8 patients; 15%) and the blood and urine samples (2 patients; 3.8%) (p=0.09). These data highlight the complexity of pathophysiology of E. coli bacteremia and should be taken into consideration when strain antibiotic susceptibility is tested, especially in bacteremia of pus origin.

Prevalence of respiratory viruses among adults, by season, age, respiratory tract region and type of medical unit in Paris, France, from 2011 to 2016

Background Multiplex PCR tests have improved our understanding of respiratory viruses’ epidemiology by allowing their wide range detection. We describe here the burden of these viruses in hospital settings over a five-year period. Methods All respiratory samples from adult patients (>20 years old) tested by multiplex-PCR at the request of physicians, from May 1 2011 to April 30 2016, were included retrospectively. Viral findings are reported by season, patient age group, respiratory tract region (upper or lower) and type of clinical unit (intensive care unit, pneumology unit, lung transplantation unit and other medical units). Results In total, 7196 samples (4958 patients) were included; 29.2% tested positive, with viral co-infections detected in 1.6% of samples. Overall, two viral groups accounted for 60.2% of all viruses identified: picornaviruses (rhinovirus or enterovirus, 34.3%) and influenza (26.6%). Influenza viruses constituted the group most frequently identified in winter (34.4%), in the upper respiratory tract (32%) and in patients over the age of 70 years (36.4%). Picornavirus was the second most frequently identified viral group in these populations and in all other groups, including lower respiratory tract infections (41.3%) or patients in intensive care units (37.6%). Conclusion This study, the largest to date in Europe, provides a broad picture of the distribution of viruses over seasons, age groups, types of clinical unit and respiratory tract regions in the hospital setting. It highlights the burden associated with the neglected picornavirus group. These data have important implications for the future development of vaccines and antiviral drugs.

Protection of Hamsters from Mortality by Reducing Fecal Moxifloxacin Concentration with DAV131A in a Model of Moxifloxacin-Induced Clostridium difficile Colitis

ABSTRACT Lowering the gut exposure to antibiotics during treatments can prevent microbiota disruption. We evaluated the effects of an activated charcoal-based adsorbent, DAV131A, on the fecal free moxifloxacin concentration and mortality in a hamster model of moxifloxacin-induced Clostridium difficile infection. A total of 215 hamsters receiving moxifloxacin subcutaneously (day 1 [D1] to D5) were orally infected at D3 with C. difficile spores. They received various doses (0 to 1,800 mg/kg of body weight/day) and schedules (twice a day [BID] or three times a day [TID]) of DAV131A (D1 to D8). Moxifloxacin concentrations and C. difficile counts were determined at D3, and mortality was determined at D12. We compared mortality rates, moxifloxacin concentrations, and C. difficile counts according to DAV131A regimen and modeled the links between DAV131A regimen, moxifloxacin concentration, and mortality. All hamsters that received no DAV131A died, but none of those that received 1,800 mg/kg/day died. Significant dose-dependent relationships between DAV131A dose and (i) mortality, (ii) moxifloxacin concentration, and (iii) C. difficile count were evidenced. Mathematical modeling suggested that (i) lowering the moxifloxacin concentration at D3, which was 58 μg/g (95% confidence interval [CI] = 50 to 66 μg/g) without DAV131A, to 17 μg/g (14 to 21 μg/g) would reduce mortality by 90%; and (ii) this would be achieved with a daily DAV131A dose of 703 mg/kg (596 to 809 mg/kg). In this model of C. difficile infection, DAV131A reduced mortality in a dose-dependent manner by decreasing the fecal free moxifloxacin concentration.

Predictors of return rate for an HIV-positive result in a French Voluntary Counseling and Testing centre

Bichat Hospitals free and anonymous Voluntary Counseling and Testing centre in Paris is widely visited, with a high rate of HIV-positive diagnosis. This study proposed, in this centre, to describe the HIV newly-diagnosed patients over an 8-year period and to determinate risk factors for failure to return for a positive result. Higher risk for failure to return was found among the heterosexual subjects regardless of their socio-economic background.

Intestinal carriage of Extended Spectrum Beta-Lactamase producing E. coli in women with urinary tract infections, Cameroon

INTRODUCTION During the last decade, the prevalence of the intestinal carriage of extended spectrum beta-lactamases - producing Escherichia coli (ESBL-E. coli) has continued to increase worldwide in the community, especially in developing countries. Hence, we undertook a study to determine the ESBL-E. coli fecal carriage rate and the associated risk factors in Cameroonian women. METHODOLOGY A total of 86 women suspected of community-acquired urinary tract infections (UTI) were included in 10 health structures from May 2011 to April 2012. After filling a questionnaire, they provided a stool sample that was plated on selective media for ESBL producing bacteria. The identification of strains was obtained with mass spectrometry and the antibiotic susceptibility by disk diffusion in agar media. The ESBL type was determined by PCR. The relative abundance of ESBL-E. coli was measured for positive samples. Eventually, the presence of antibiotics in stool was assessed. RESULTS The carriage rate of ESBL-E. coli was 57/86 (66.3%). Phenotypic and molecular characterization showed that all ESBL-E. coli strains contained group 1 CTX-M enzymes. Multivariate analysis showed that ESBL-E. coli fecal carriage was associated with the presence of antibiotics in stools (p < 0.05). Although not significant, mean ESBL relative abundance tended to be higher in patients with antibiotic exposure. CONCLUSIONS Our results show that the carriage of ESBL-E. coli fecal carriage in women with UTI suspicion from the Cameroonian community is extremely high and associated with recent antibiotic intake.

Epidemiological Profile of Newly Diagnosed HIV-Infected Patients in Northern Paris: A Retrospective Study.

Abstract In attempt to identify the factors associated with delayed diagnosis during HIV infection, we studied retrospectively the epidemiological profile of HIV-infected patients diagnosed between January 1, 2012 and December 31, 2013 and followed in our clinical center in Paris. Data were compared to those obtained at the same site during the year 2003. One hundred eighty-six patients fulfilled the inclusion criteria: 49 (26%) had a CD4 count <200/mm3 at diagnosis. Compared to subjects with CD4 count ≥200/mm3, advanced patients were older, had a higher plasma viral load, had more often an AIDS-defining event at the time of HIV diagnosis (45% vs. 3%), had been infected more often through heterosexual contact (69% vs. 44%), had less frequently past HIV testing (23% vs. 63%), and tended to live in less favorable conditions. A higher proportion of these patients initiated antiretroviral therapy in the 3 months following diagnosis (93.9% vs. 48.1%). Compared to data obtained in 161 patients in 2003, the prop...In attempt to identify the factors associated with delayed diagnosis during HIV infection, we studied retrospectively the epidemiological profile of HIV-infected patients diagnosed between January 1, 2012 and December 31, 2013 and followed in our clinical center in Paris. Data were compared to those obtained at the same site during the year 2003. One hundred eighty-six patients fulfilled the inclusion criteria: 49 (26%) had a CD4 count <200/mm3 at diagnosis. Compared to subjects with CD4 count ≥200/mm3, advanced patients were older, had a higher plasma viral load, had more often an AIDS-defining event at the time of HIV diagnosis (45% vs. 3%), had been infected more often through heterosexual contact (69% vs. 44%), had less frequently past HIV testing (23% vs. 63%), and tended to live in less favorable conditions. A higher proportion of these patients initiated antiretroviral therapy in the 3 months following diagnosis (93.9% vs. 48.1%). Compared to data obtained in 161 patients in 2003, the proportions of advanced patients were similar between the two periods (26% vs. 22%). There was a significant increase from year 2003 to the 2012-2013 period in the proportion of men who have sex with men (MSM) (50% vs. 27%) and in the percentage of patients infected with HIV-1 subtype B (48% vs. 27%) and with positive syphilis serology (22% vs. 8%). Our data show that (1) HIV screening should be extended to populations with the following characteristics: older age, heterosexuality, and low socioeconomic level, and (2) HIV transmission continues to progress in MSM, arguing for the value of preexposure prophylaxis.

Efficacy of cloxacillin versus cefazolin for methicillin-susceptible Staphylococcus aureus bacteraemia (CloCeBa): study protocol for a randomised, controlled, non-inferiority trial

Introduction Methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia is a common and severe disease responsible for approximately 65 000 deaths every year in Europe. Intravenous antistaphylococcal penicillins (ASP) such as cloxacillin are the current recommended antibiotics. However, increasing reports of toxicity and recurrent stock-outs of ASP prompted healthcare providers to seek for alternative antibiotic treatment. Based on retrospective studies, cefazolin, a first-generation cephalosporin, is recommended in patients at risk of severe ASP-associated toxicity. We hypothesised that cefazolin has a non-inferior efficacy in comparison to cloxacillin, with a better safety profile for the treatment of MSSA bacteraemia. Methods and analysis The CloCeBa trial is an open-label, randomised, controlled, non-inferiority trial conducted in academic centres throughout France. Eligible patients are adults with MSSA bacteraemia without intravascular device or suspicion of central nervous system infection. Patients will be randomised (1:1) to receive either cloxacillin or cefazolin by the intravenous route, for the first 14 days of therapy. The evaluation criteria is a composite criteria of negative blood cultures at day 5, survival, absence of relapse and clinical success at day 90 after randomisation. Secondary evaluation criteria include both efficacy and safety assessments. Three ancillary studies are planned to describe the epidemiology of β-lactamase encoding genes, the ecological impact and pharmacokinetic/pharmacodynamic parameters of cefazolin and cloxacillin. Including 300 patients will provide 80% power to demonstrate the non-inferiority of cefazolin over cloxacillin, assuming 85% success rate with cloxacillin and taking into account loss-to-follow-up, with a 0.12 non-inferiority margin and a one-sided type I error of 0.025. Ethics and dissemination This protocol received authorisation from the ethics committee Sud-Est I on 13 November 2017 (2017-87-PP)and French National Agency for Medicines and Health Products (170661A-43). Results will be disseminated to the scientific community through congresses and publication in peer-reviewed journals. Trial registration number NCT03248063 and 2017-003967-36.

Change in bacterial diversity of fecal microbiota drives mortality in a hamster model of antibiotic-induced Clostridium difficile colitis

Abstract Background C. difficile (C diff) infection results from antibiotic-induced changes in colonic microbiota. DAV131A, an oral adsorbent-based product, can sequester antibiotic (AB) residues in the gut and reduce mortality in a hamster model of moxifloxacin (MXF) or clindamycin (CM) induced C diffcolitis. We studied the link between changes of the bacterial diversity within the fecal microbiota and mortality in this model. Methods Male Syrian hamsters were administered 30 mg/kg MXF or 5 mg/kg CM subcutaneously once a day for 5 days (D1 to D5) and orally infected at D3 with 104C diffspores. They were orally administered various doses of DAV131A (0, and 200 to 900 mg/kg twice a day), from D1 to D8. Survival was monitored up to D16 and feces were collected (D1 and D3) to characterize the microbiota by 16S rRNA gene profiling. Changes of various α- (Shannon, Observed OTUs and Chao1) and β- (Bray-Curtis dissimilarity and [un]weighted UniFrac) diversity indices between D1 and D3 were obtained for each animal. We analyzed links between (i) DAV131A dose and changes of bacterial diversity and (ii) changes of bacterial diversity and mortality using non parametric tests and logistic regression. Results Data from 70 and 60 animals were available in the MXF and CM studies, among which 10 and 28 died, respectively. Increasing doses of DAV131A reduced mortality from 100% to 0% and reduced changes in bacterial diversity of the fecal microbiota. Very strong predictors of mortality were changes in Shannon and unweighted UniFrac indices, which were markedly less affected in hamsters who survived (see table below median (min; max) according to vital status and area under the ROC curve, AUROC). Died Survived p AUROC [95% CI] MXF n 10 60 Shannon -1.7 (-3.0; -1.0) -1.0 (-1.9; 0.1) <10-4 0.91 [0.80; 0.99] Unweighted UniFrac 0.61 (0.56; 0.76) 0.51 (0.37; 0.65) <10-6 0.95 [0.89; 0.99] CM n 28 32 Shannon -2.2 (-4.3; -0.4) -1.1 (-2.6; 0.0) <10-7 0.88 [0.78; 0.96] Unweighted UniFrac 0.71 (0.59; 0.84) 0.60 (0.49; 0.68) <10-10 0.94 [0.87; 0.98] Conclusion The extent of AB-induced changes in gut bacterial diversity correlated with increased mortality in a hamster model of C diff colitis. Higher doses of DAV131A protected fecal microbiota disruption and hence mortality. Disclosures C. Burdet, Da Volterra: Consultant and Research Contractor, Consulting fee; N. Saint-Lu, Da Volterra: Employee, Salary; S. Sayah-Jeanne, Da Volterra: Employee, Salary; P. Hugon, Da Volterra: Employee, Salary; F. Sablier-Gallis, Da Volterra: Employee, Salary; S. Ferreira, Genoscreen: Employee, Salary; A. Andremont, Da Volterra: Consultant, Consulting fee; F. Mentré, Da Volterra: Consultant and Research Contractor, Consulting fee; J. De Gunzburg, Da Volterra: Consultant and Shareholder, Consulting fee