Tuberculosis trends in a hot-spot region in Paris, France.

SETTING: Tuberculosis (TB) incidence is declining overall in France, but not in Paris where some areas remain relative hot spots for TB.OBJECTIVES: To obtain a better knowledge of local TB epidemiology in order to facilitate control measures.DESIGN: Analysis of demographic data of TB patients diagnosed at the Bichat-Claude Bernard Hospital from 2007 to 2016, with spoligotyping of Mycobacterium tuberculosis complex isolates.RESULTS: During the study period, 1096 TB patients were analysed. The incidence of TB diagnosis was stable, averaging 115 patients per year, predominantly males (71%), foreign-born (81%), with pulmonary TB (77%) and negative HIV serology (88%). The mean age of foreign-born TB patients decreased over the study period, most significantly in recent arrivals in France, whose average age decreased by two years (P = 0.001). The time period between arrival in France and being diagnosed with active TB decreased annually significantly by 0.75 years (P = 0.02). The proportion of L4.6.2/Cameroon and L2/Beijing sub-lineages increased annually by 0.7% (P < 0.05). Multi-drug resistant strains, representing 4% of all strains, increased annually by 0.75% (P = 0.03)CONCLUSION: The number of TB patients remained high in northern Paris and the surrounding suburbs, suggesting the need for increased control measures.

Investigation of the effect of the adsorbent DAV131A on the propensity of moxifloxacin to induce simulated Clostridioides (Clostridium) difficile infection (CDI) in an in vitro human gut model.

BACKGROUND: Clostridioides difficile infection (CDI) remains a high burden worldwide. DAV131A, a novel adsorbent, reduces residual gut antimicrobial levels, reducing CDI risk in animal models. OBJECTIVES: We used a validated human gut model to investigate the efficacy of DAV131A in preventing moxifloxacin-induced CDI. METHODS: C. difficile (CD) spores were inoculated into two models populated with pooled human faeces. Moxifloxacin was instilled (43 mg/L, once daily, 7 days) alongside DAV131A (5 g in 18 mL PBS, three times daily, 14 days, Model A), or PBS (18 mL, three times daily, 14 days, Model B). Selected gut microbiota populations, CD total counts, spore counts, cytotoxin titre and antimicrobial concentrations (HPLC) were monitored daily. We monitored for reduced susceptibility of CD to moxifloxacin. Growth of CD in faecal filtrate and medium in the presence/absence of DAV131A, or in medium pre-treated with DAV131A, was also investigated. RESULTS: DAV131A instillation reduced active moxifloxacin levels to below the limit of detection (50 ng/mL), and prevented microbiota disruption, excepting Bacteroides fragilis group populations, which declined by ∼3 log10 cfu/mL. DAV131A delayed onset of simulated CDI by ∼2 weeks, but did not prevent CD germination and toxin production. DAV131A prevented emergence of reduced susceptibility of CD to moxifloxacin. In batch culture, DAV131A had minor effects on CD vegetative growth, but significantly reduced toxin/spores (P < 0.005). CONCLUSIONS: DAV131A reduced moxifloxacin-induced microbiota disruption and emergence of antibiotic-resistant CD. Delayed onset of CD germination and toxin production indicates further investigations are warranted to understand the clinical benefits of DAV131A in CDI prevention.

High acquisition rate of extended-spectrum ß-lactamase-producing Enterobacteriaceae among French military personnel on mission abroad, without evidence of inter-individual transmission.

OBJECTIVES: Acquisition of extended-spectrum ß-lactamase-producing Enterobacteriaceae (ESBL-E) by Europeans travelling individually in high-endemicity countries is common. However, how the different ESBL-E strains circulate in groups of travellers has not been studied. We investigated ESBL-E transmission within several groups of French military personnel serving overseas for 4-6 months. METHODS: We conducted a prospective study among French military personnel assigned to Afghanistan, French Guiana or Côte d'Ivoire for 4-6 months. Faecal samples provided by volunteers before leaving and after returning were screened for ESBL-E isolates. ESBL Escherichia coli from each military group was characterized by repetitive element palindromic polymerase chain reaction (rep-PCR) fingerprinting followed, in the Afghanistan group, by whole-genome sequencing (WGS) if similarity was ≥97%. RESULTS: Among the 189 volunteers whose samples were negative before departure, 72 (38%) were positive after return. The highest acquisition rates were observed in the Afghanistan (29/33, 88%) and Côte d'Ivoire (39/80, 49%) groups. Acquisition rates on return from French Guiana were much lower (4/76, 5%). WGS of the 20 strains from the Afghanistan group that clustered by rep-PCR identified differences in sequence type, serotype, resistance genes and plasmid replicons. Moreover, single-nucleotide polymorphism (SNP) differences across acquired strains from a given cluster ranged from 30 to 3641, suggesting absence of direct transmission. CONCLUSIONS: ESBL-E. coli acquisition was common among military personnel posted overseas. Many strains clustered by rep-PCR but differed by WGS and SNP analysis, suggesting acquisition from common external sources rather than direct person-to-person transmission.

Travel and acquisition of multidrug-resistant Enterobacteriaceae.

Bacterial resistance to antibiotics is considered a major threat to health. Enterobacteriaceae have increasingly become resistant to antibiotics through the acquisition and dissemination of extended-spectrum beta-lactamases (ESBL) that confer resistance to most beta-lactams. While ESBL-producing Enterobacteriaceae were formerly restricted to hospitals, they have now spread to community settings, especially in developing countries. The tremendous expansion of international travels contributed to the importation of multidrug-resistant Enterobacteriaceae (MRE) to low prevalence countries. Several studies reported that 21 to 51% of healthy travelers acquire a MRE when travelling abroad, depending on the visited region (Asia, and especially South Asia being associated with the highest risk - up to 85%). Traveling to Africa or the Middle East is associated with lower but still disturbing rates (13-44%). In addition, the occurrence of digestive disorders and/or diarrhea and antibiotic intake increase the risk of MRE acquisition by 2-3 folds. After traveling though, the length of MRE carriage seems to be short (<1 month) and the risk of transmission within the household appears to be low. Nonetheless and beyond the intestinal carriage of MRE, traveling to endemic areas has also been pointed as a risk factor for infections involving MRE, mainly urinary tract infections.

Cefazolin versus anti-staphylococcal penicillins for treatment of methicillin-susceptible Staphylococcus aureus bacteraemia: a narrative review.

BACKGROUND: Anti-staphylococcal penicillins (ASPs) are recommended as first-line agents in methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia. Concerns about their safety profile have contributed to the increased use of cefazolin. The comparative clinical effectiveness and safety profile of cefazolin versus ASPs for such infections remain unclear. Furthermore, uncertainty persists concerning the use of cefazolin due to controversies over its efficacy in deep MSSA infections and its possible negative ecological impact. AIMS: The aim of this narrative review was to gather and balance available data on the efficacy and safety of cefazolin versus ASPs in the treatment of MSSA bacteraemia and to discuss the potential negative ecological impact of cefazolin. SOURCES: PubMed and EMBASE electronic databases were searched up to May 2017 to retrieve available studies on the topic. CONTENTS: Although described in vitro and in experimental studies, the clinical relevance of the inoculum effect during cefazolin treatment of deep MSSA infections remains unclear. It appears that there is no significant difference in rate of relapse or mortality between ASPs and cefazolin for the treatment of MSSA bacteraemia but these results should be cautiously interpreted because of the several limitations of the available studies. Compared with cefazolin, there is more frequent discontinuation for adverse effects with ASP use, especially because of cutaneous and renal events. No study has evidenced any change in the gut microbiota after the use of cefazolin. IMPLICATIONS: Based on currently available studies, there are no data that enable a choice to be made of one antibiotic over the other except in patients with allergy or renal impairment. This review points out the need for future prospective studies and randomized controlled trials to better address these questions.

Prevalence of extended-spectrum beta-lactamase phenotypes in enterobacteria isolated from blood cultures of patients at admission to the University Hospital of Bamako.

The aim of our study was to determine the frequency of extended-spectrum beta-lactamase (ESBL) phenotypes among the enterobacteria present in blood cultures of patients at admission to two university hospitals of Bamako (Mali). During a period of three months, we isolated enterobacteria from blood cultures from patients upon admission to the Point G and Gabriel Toure University Hospitals. The ESBL-positive enterobacteria were initially identified by API 20E strips and VITEK®2 and then confirmed in France by MALDI-TOF mass spectrometry at the Bichat Hospital bacteriology laboratory. Antibiotic susceptibility was determined by the diffusion method as recommended by EUCAST. The species isolated were K. pneumoniae (14/40, 35.0 %), E. coli (11/40, 27.5 %), and E. cloacae (9/40, 22.5 %); 21/34 (61.8 %) had an ESBL phenotype, including 10/14 (71.4 %) K. pneumoniae, 8/11 (72.7 %) E. coli, and 3/9 (33 3 %), E. cloacae. The ESBL strains of K. pneumoniae, E. coli, and E. cloacae were associated, respectively, with resistance to the following antibiotics: gentamicin (10/10, 100 %; 6/8, 75%; 2/3, 67%), amikacin (2/10, 20 %; 0/8, 0%; 0/3, 0%), ofloxacin (8/10, 80. %; 7/8, 87%; 3/3, 100%), cotrimoxazole (10/10, 100 %; 6/8, 75%; 3/3, 100%). Almost two thirds (61.8%) of the enterobacteria isolated from blood cultures produced extended-spectrum beta-lactamases. They retained regular sensitivity only to carbapenems and amikacin.

Unexpected persistence of extended-spectrum ß-lactamase-producing Enterobacteriaceae in the faecal microbiota of hospitalised patients treated with imipenem.

Imipenem is active against extended-spectrum ß-lactamase-producing Enterobacteriaceae (ESBL-E) but favours the intestinal emergence of resistance. The effects of imipenem on intestinal microbiota have been studied using culture-based techniques. In this study, the effects were investigated in patients using culture and metagenomic techniques. Seventeen hospitalised adults receiving imipenem were included in a multicentre study (NCT01703299, http://www.clinicaltrials.gov). Most patients had a history of antibiotic use and/or hospitalisation. Stools were collected before, during and after imipenem treatment. Bacterial and fungal colonisation was assessed by culture, and microbiota changes were assessed using metagenomics. Unexpectedly, high colonisation rates by imipenem-susceptible ESBL-E before treatment (70.6%) remained stable over time, suggesting that imipenem intestinal concentrations were very low. Carriage rates of carbapenem-resistant Gram-negative bacilli (0-25.0%) were also stable over time, whereas those of yeasts (64.7% before treatment) peaked at 76.5% during treatment and decreased thereafter. However, these trends were not statistically significant. Yeasts included highly diverse colonising Candida spp. Metagenomics showed no global effect of imipenem on the bacterial taxonomic profiles at the sequencing depth used but demonstrated specific changes in the microbiota not detected with culture, attributed to factors other than imipenem, including sampling site or treatment with other antibiotics. In conclusion, culture and metagenomics were highly complementary in characterising the faecal microbiota of patients. The changes observed during imipenem treatment were unexpectedly limited, possibly because the microbiota was already disturbed by previous antibiotic exposure or hospitalisation.

First report of human infection due to Streptococcus devriesei.

So far, Streptococcus devriesei, which belongs to the mutans streptococci group, has been incriminated in the formation of caries in Equidae. We report the first human infection due to this species in a 54-year-old man with gangrenous cholecystitis. The patient was treated successfully by cholecystectomy and ceftriaxone.

Prevention of urinary tract infections by antibiotic cycling in spinal cord injury patients and low emergence of multidrug resistant bacteria.

BACKGROUND: Urinary tract infections (UTIs) are a major recurrent problem for spinal cord injury (SCI) patients. Repeated antibiotic treatments contribute to the emergence of multidrug-resistant bacteria (MDRB). We evaluated the use of weekly oral cycling antibiotics (WOCA) in the prevention of UTIs over a mean follow-up period of 53 months (median follow-up period: 57 months) and analyzed the risk of MDRB emergence. METHODS: We conducted a cross-sectional study of adult SCI patients with neurogenic bladder who were receiving the WOCA regimen. RESULTS: We included 50 patients, mainly men (60%), with a mean age of 51±13.5 years. Overall, 66% of patients had been paraplegic or tetraplegic for 19.4±14.3 years; 92% underwent intermittent catheterization; and 36% had no postvoid residual. The number of febrile and non-febrile UTIs significantly reduced after WOCA initiation (9.45 non-febrile UTIs before WOCA initiation vs. 1.57 after; 2.25 febrile UTIs before WOCA initiation vs. 0.18 after; P=0.0001). Only one adverse event was reported during the follow-up period. The number of MDRB-colonized patients decreased from 9/50 to 4/50 during the follow-up period. CONCLUSION: WOCA is an effective and safe strategy to prevent UTIs in SCI patients with neurogenic bladder. WOCA does not lead to the emergence of MDRB resistance and even seems to reduce MDRB carriage.

Impact of a short exposure to levofloxacin on faecal densities and relative abundance of total and quinolone-resistant Enterobacteriaceae.

Emergence of resistant Enterobacteriaceae in the intestinal microbiota during antibiotic treatment is well documented but its early dynamic is not. Here, we compared the densities of total Enterobacteriaceae and relative abundance (RA) of quinolone-resistant Enterobacteriaceae (QRE) in the first stool passed by patients who had a short exposure to levofloxacin (levofloxacin, n=12) or not (control, n=8). Mean densities (SD) (log CFU/g stool) of total Enterobacteriaceae were lower in the levofloxacin group than in the control group-3.4 (1.6) versus 6.7 (1.7), respectively, p <0.001. Conversely, mean RA (SD) of QRE was significantly higher in the levofloxacin group than in the control group-49.7% (23.4) versus 0.1% (3.2), respectively, p <0.05). In conclusion, even a short exposure to levofloxacin has a profound impact on the densities of total Enterobacteriaceae and the QRE-RA.

Prevalence of extended-spectrum beta-lactamase-producing Enterobacteriaceae isolated from blood cultures in Africa.

Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae have been isolated from many regions of the world. Epidemiological studies are being conducted in Europe, North America, and Asia. No study has however been conducted in Africa to determine the prevalence and distribution of ESBLs on the continent. This literature review aimed at describing the prevalence of ESBL-producing Enterobacteriaceae isolated from blood cultures, as well as the ESBL genes involved at the international level. Our focus was mainly on Africa. We conducted a literature review on PubMed. Articles related to our study field and published between 1996 and 2014 were reviewed and entirely read for most of them, while we only focused on the abstracts of some other articles. Relevant articles to our study were then carefully reviewed and included in the review. The prevalence of ESBL-producing Enterobacteriaceae differs from one country to another. The results of our literature review however indicate that class A ESBLs prevail over the other types. We took into consideration articles focusing on various types of samples to assess the prevalence of ESBL-producing Enterobacteriaceae, but information on isolates from blood cultures is limited. The worldwide prevalence of ESBL-producing Enterobacteriaceae has increased over time. Evidence of ESBL-producing Enterobacteriaceae can be found in all regions of the world. Studies conducted in Africa mainly focused on the Northern and Eastern parts of the continent, while only rare studies were carried out in the rest of the continent.

Performance and impact of a rapid method combining mass spectrometry and direct antimicrobial susceptibility testing on treatment adequacy of patients with ventilator-associated pneumonia.

Inappropriate antibiotic therapy in ventilator-associated pneumonia (VAP) is associated with increased mortality. Using broad-spectrum antibiotics for 48 h until the results of conventional cultures and antimicrobial susceptibility testing (AST) are available, may promote the emergence of drug-resistant bacteria. Performing AST directly on clinical respiratory samples would hasten the process by at least 24 h. Here, we analysed the diagnostic performance of a rapid method combining mass spectrometry and direct AST (DAST), and compared it with the conventional method (mass spectrometry with conventional AST (CAST)). Additionally, we assessed its potential impact on antimicrobial use in patients. Over a period of 18 months, the two methods were performed on 85 bronchoalveolar lavages obtained from intensive care unit patients with suspected VAP, and in which Gram-negative bacilli were observed on direct examination. Only the CAST results were reported to the clinicians. DAST produced useable results in 85.9% of the patients. The sensitivity and negative predictive values of DAST were 100% for all antibiotics tested, except gentamicin (97.1%, (95% CI 93.3-101) and 97.4% (93.7-101), respectively) and amikacin (88.9% (81.7-96.1) and 96.4% (92.1-100.7), respectively), compared with CAST. Specificity and positive predictive values ranged from 82.9 (74.2-91.5) to 100%, and from 86.4 (78.5-94.2) to 100%, respectively. If the DAST results had been reported to the clinicians, treatment could have been optimized 24 h earlier in 35/85 (41.2%) patients, with 17 carbapenem patient-days saved. Overall, routine use of the DAST method could help optimize earlier antibiotic treatment in patients with suspected VAP.

Introduction of highly resistant bacteria into a hospital via patients repatriated or recently hospitalized in a foreign country.

We describe the prevalence of carriage and variables associated with introduction of highly drug-resistant microorganisms (HDRMO) into a French hospital via patients repatriated or recently hospitalized in a foreign country. The prevalence of HDRMO was 11% (15/132), with nine carbapenamase-producing Enterobacteriaceae, nine carbapenem-resistant Acinetobacter baumannii and six glycopeptide-resistant enterococci. Half of the admitted patients (63/132, 48%) were colonized with extended spectrum beta-lactamase-producing Enterobacteriaceae (ESBLPE). Among the four episodes with secondary cases, three involved A. baumannii.

Acquisition of carbapenemase-producing Enterobacteriaceae by healthy travellers to India, France, February 2012 to March 2013.

Healthy travellers to countries where carbapenemases-producing Enterobacteriaceae (CPE) are endemic might be at risk for their acquisition, even without contact with the local healthcare system. Here, we report the acquisition of CPE (two OXA-181, one New Delhi metallo-beta-lactamase 1 (NDM-1)) in three healthy travellers returning from India. The duration of CPE intestinal carriage was less than one month. The results indicate that healthy travellers recently returning from India might be considered as at risk for CPE carriage.

The emergence of linezolid resistance among Enterococci in intestinal microbiota of treated patients is unrelated to individual pharmacokinetic characteristics.

Linezolid is an antimicrobial agent for the treatment of multiresistant Gram-positive infections. We assessed the impact of linezolid on the microbiota and the emergence of resistance and investigated its relationship with plasma pharmacokinetics of the antibiotic. Twenty-eight patients were treated for the first time with linezolid administered orally (n = 17) or parenterally (n = 11) at 600 mg twice a day. Linezolid plasma pharmacokinetic analysis was performed on day 7. Colonization by fecal enterococci, pharyngeal streptococci, and nasal staphylococci were assessed using selective media with or without supplemental linezolid. The resistance to linezolid was characterized. The treatment led to a decrease of enterococci, staphylococci, and streptococci in the fecal (P = 0.03), nasal, and pharyngeal (P < 0.01) microbiotas. The appearance of resistant strains was observed only in enterococci from the fecal microbiota between the 7th and 21st days of treatment in four patients (14.3%). The resistance was mainly due for the first time to the mutation G2447T in the 23S rRNA gene. No pharmacokinetic parameters were significantly different between the patients, regardless of the appearance of resistance. The emergence of linezolid resistance during treatment was observed only in the intestinal microbiota and unrelated to pharmacokinetic parameters. However, colonization by Gram-positive bacteria was reduced as a result of treatment in all microbiotas.

Enterobacteriaceae bacteremia: risk factors for ESBLPE.

OBJECTIVES: The increasing prevalence of extended spectrum beta-lactamase producing enterobacteriaceae (ESBLPE) requires defining the use of carbapenems in first intention. We analyzed the associations between enterobacteriaceae bacteremia (EbBact) and ESBLPE carriage during 10 years in a 950-bed teaching hospital. METHODS: We analyzed a 10-year (July 2001 to June 2011) prospective collection of bacteremia cases including 2 databases: (1) EbBact and (2) a computerized database of patients carrying EBLSE. Only one episode of EbBact was analyzed per patient and hospital stay. Factors associated with ESBLPE bacteremia were assessed by univariate and multivariate logistic regression analysis. RESULTS: Overall, 2355 cases of EbBact were identified, among which 135 (5.7%) were ESBLPE (2001-05: 1.4%, 2006-09: 7.6%, 2010-11: 14.2%). ESBLPE bacteremia was observed in 52 of the 88 (59%) patients carrying ESBLPE and in 83/2267 (3.7%) patients not known to be colonized with ESBLPE. Factors associated with ESBLPE bacteremia in patients not known to be colonized were: female gender (ORa=0.56, CI95% [0.34-0.91]), hospitalization in the ICU (ORa=2.51 [1.27-5.05]) or medical/surgical wards (ORa=1.83 [1.04-3.38]), the period (2006-09, ORa=4.08 [2.21-8.16]; 2010-11, ORa=8.17 [4.14-17.06] compared to 2001-05), and history of EbBact (ORa=2.29 [0.97-4.79]). CONCLUSION: In case of EbBact, patients known to be colonized with ESBLPE present with ESBLPE bacteremia in more than half of the cases, requiring carbapenems as empirical antibiotic treatment. The global prevalence of ESBLPE among patients presenting with EbBact not known to be colonized with ESBLPE was 3.7%.

Antimicrobial agent exposure and the emergence and spread of resistant microorganisms: issues associated with study design.

Antibiotics are essential agents that have greatly reduced human mortality due to infectious diseases. Their use, and sometimes overuse, have increased over the past several decades in humans, veterinary medicine and agriculture. However, the emergence of resistant pathogens is becoming an increasing problem that could result in the re-emergence of infectious diseases. Antibiotic prescription in human medicine plays a key role in this phenomenon. Under selection pressure, resistance can emerge in the commensal flora of treated individuals and disseminate to others. However, even if the effects of antimicrobial use on resistance is intuitively accepted, scientific rationales are required to convince physicians, legislators and public opinion to adopt appropriate behaviours and policies. With this review, we aim to provide an overview of different epidemiological study designs that are used to study the relationship between antibiotic use and the emergence and spread of resistance, as well as highlight their main strengths and weaknesses.

Clinical predictive values of extended-spectrum beta-lactamase carriage in patients admitted to medical wards.

We aimed to reassess, through clinical items, populations at risk for extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) carriage at admission to hospital and to assess the risk of further positive clinical culture of ESBL-E among carriers. We performed a 5-month cohort study in a medicine ward of a 500-bed university teaching hospital in the Parisian area of France. All admitted patients were prospectively enrolled for rectal swabbing and clinical data collection, including bacterial infection at admission and during stay. Variables associated with ESBL-E carriage were identified by univariate and multivariate analysis. Five hundred patients were included. The prevalence of ESBL-E was 6.6% (33/500) upon admission. Only previous carriage of multidrug-resistant bacteria (MDRB) was associated with carriage (odds ratio [OR]: 17.7, 95% confidence interval (CI) 5.8-54.2, p < 0.001), yet, the positive predictive value (PPV) was not higher than 50%. When prior MDRB carriage was not considered in the multivariate analysis, only prior antibiotic consumption was found to be associated with carriage at admission (OR: 2.2 [1.1-4.5], p = 0.02). Two patients had ESBL-E infection at admission, yet, no patient became infected with ESBL-E during their stay. The clinical prediction of ESBL carriage at admission in our wards was found to be poorly efficient for assessing the at-risk population.

Suitability of initial antibiotic therapy for the treatment of bloodstream infections and the potential role of antibiotic management teams in improving it.

Hospital antibiotic management teams (AMTs) have been recommended, but, in France, their concrete implementation remains scarce and their effectiveness largely unevaluated. The objective of this investigation was to evaluate the appropriateness of antibiotic therapy (AT) for bloodstream infections (BSIs) at a 950-bed university teaching hospital, and assess the role of an AMT in improving it. A prospective analysis of all significant BSIs occurring outside of the intensive care unit (ICU) during an 18-month period was carried out. AT was deemed effective if at least one prescribed antibiotic was effective in vitro, and appropriate if it was consistent with local recommendations. Out of 574 BSIs, 512 were evaluated: 231 community-acquired, 206 nosocomial, and 75 healthcare-associated. For 219 (42.8%) BSIs, the AT initiated prior to AMT intervention proved to be effective and appropriate, inappropriate but effective in 136 (26.5%), and ineffective or absent in 157 (30.7%). In the multivariate analysis, hospital-acquired and other healthcare-associated BSIs, as well as catheter-borne (CB) infections, were associated with inappropriate or absent AT. A recommendation from the AMT was given and followed in 233 (94%) out of 249 BSIs requiring intervention. Initially, two-thirds of BSIs outside the ICU did not receive appropriate AT. Healthcare-associated BSIs should, therefore, be the priority target of AMTs.