Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Protecting the gut against Clostridium difficile: A role for Keratinocyte growth factor

Clostridium difficle (Cdiff) infection (CDI) causes severe colitis via its toxins: toxin A and toxin B (TcdAB), inducing barrier disruption, inflammation and cell death. Current treatments are failing and the need to search for new targets is urgent. Several host factors have shown to modulate CDI in animals and patients. Intestinal growth factors are a major part of the mucosal host response in the gut. Among them, keratinocyte growth factor (KGF) has been shown to be protective in many colitis models. In this thesis, the protective role of KGF was demonstrated against Cdiff toxin injury. In vitro, KGF protected Caco-2 cells from barrier disruption and cell death induced by TcdAB. Exogenous KGF administration protected mice from acute intestinal toxin damage. Interestingly, KGF deletion did not impact the acute toxin-induced colitis in mice; however, endogenous KGF was essential for normal recovery from TcdAB-induced colitis as KGF−/− mice demonstrated impaired recovery after 24-48 hours post TcdAB exposure. Findings from this study may lead to identifying a cause for the variability in clinical response among patients with CDI as well as new therapeutic targets for this devastating disease.2 year

The P2Y6 receptor mediates Clostridium difficile toxin-induced CXCL8/IL-8 production and intestinal epithelial barrier dysfunction.

C. difficile is a Gram-positive spore-forming anaerobic bacterium that is the leading cause of nosocomial diarrhea in the developed world. The pathogenesis of C. difficile infections (CDI) is driven by toxin A (TcdA) and toxin B (TcdB), secreted factors that trigger the release of inflammatory mediators and contribute to disruption of the intestinal epithelial barrier. Neutrophils play a key role in the inflammatory response and the induction of pseudomembranous colitis in CDI. TcdA and TcdB alter cytoskeletal signaling and trigger the release of CXCL8/IL-8, a potent neutrophil chemoattractant, from intestinal epithelial cells; however, little is known about the surface receptor(s) that mediate these events. In the current study, we sought to assess whether toxin-induced CXCL8/IL-8 release and barrier dysfunction are driven by the activation of the P2Y6 receptor following the release of UDP, a danger signal, from intoxicated Caco-2 cells. Caco-2 cells express a functional P2Y6 receptor and release measurable amounts of UDP upon exposure to TcdA/B. Toxin-induced CXCL8/IL-8 production and release were attenuated in the presence of a selective P2Y6 inhibitor (MRS2578). This was associated with inhibition of TcdA/B-induced activation of NFκB. Blockade of the P2Y6 receptor also attenuated toxin-induced barrier dysfunction in polarized Caco-2 cells. Lastly, pretreating mice with the P2Y6 receptor antagonists (MSR2578) attenuated TcdA/B-induced inflammation and intestinal permeability in an intrarectal toxin exposure model. Taken together these data outline a novel role for the P2Y6 receptor in the induction of CXCL8/IL-8 production and barrier dysfunction in response to C. difficile toxin exposure and may provide a new therapeutic target for the treatment of CDI

The Effect of the Digital Manufacturing Technique, Preparation Taper, and Cement Type on the Retention of Aged Anterior Provisional Crowns: An In Vitro Study

A well-made provisional fixed prosthesis must present as a preview of the future prosthesis and may also augment the health of the abutments and periodontium. Provisional restorations have been prepared chairside with polymethyl methacrylate (PMMA) since time immemorial. CAD/CAM additive and subtractive technologies have revolutionized the fabrication of interim restorations in dental clinics. The current literature lacks substantial data about retention of provisional crowns manufactured using Computer-Aided Design/Computer-Aided Manufacturing (CAD/CAM) additive and subtractive techniques with various temporary cements. This in vitro study aims to assess and compare the retention of temporary/provisional anterior crowns based on the combined effect of different digital manufacturing techniques, preparation tapers, and the temporary cements used for cementation. Two maxillary right central incisor typodont teeth were prepared to receive all-ceramic crowns, one with a 10-degree taper and the other with a 20-degree taper. Forty 3D-printed working models with the 10&deg; taper and forty working models with the 20&deg; taper were prepared to receive the temporary crowns. Forty temporary crowns were 3D-printed and forty crowns were milled (20 from each taper group). Kerr Temp-Bond NE conventional cement and Kerr Temp-Bond clear cement were used for cementation in the two groups. The number of samples per test group was 10. All samples were thermocycled and subjected to a universal testing machine to measure the pull-off force until retention loss (N) under tension with a crosshead speed of 5 mm/min. The pull-off force was highest for group 8, i.e., 3D-printed crowns with a 20&deg; taper and cemented with Kerr Temp-Bond clear cement, followed by groups 6, 7, 4, 5, 3, and 2. Group 1, i.e., milled crowns with 10&deg; taper cemented with Kerr Temp-Bond NE conventional cement, exhibited the lowest pull-off retentive force. The clinical selection of long-term provisional crowns fabricated using 3D-printing technology, prepared with 10&deg; or 20&deg; tapers, and cemented with clear cement, is the most favorable in terms of the retention of provisional crowns. 3D-printed provisional crowns can be used as an alternative to conventional and CAD/CAM-milled crowns for long-term provisionalization

The Effect of the Digital Manufacturing Technique, Preparation Taper, and Cement Type on the Retention of Aged Anterior Provisional Crowns: An In Vitro Study

A well-made provisional fixed prosthesis must present as a preview of the future prosthesis and may also augment the health of the abutments and periodontium. Provisional restorations have been prepared chairside with polymethyl methacrylate (PMMA) since time immemorial. CAD/CAM additive and subtractive technologies have revolutionized the fabrication of interim restorations in dental clinics. The current literature lacks substantial data about retention of provisional crowns manufactured using Computer-Aided Design/Computer-Aided Manufacturing (CAD/CAM) additive and subtractive techniques with various temporary cements. This in vitro study aims to assess and compare the retention of temporary/provisional anterior crowns based on the combined effect of different digital manufacturing techniques, preparation tapers, and the temporary cements used for cementation. Two maxillary right central incisor typodont teeth were prepared to receive all-ceramic crowns, one with a 10-degree taper and the other with a 20-degree taper. Forty 3D-printed working models with the 10° taper and forty working models with the 20° taper were prepared to receive the temporary crowns. Forty temporary crowns were 3D-printed and forty crowns were milled (20 from each taper group). Kerr Temp-Bond NE conventional cement and Kerr Temp-Bond clear cement were used for cementation in the two groups. The number of samples per test group was 10. All samples were thermocycled and subjected to a universal testing machine to measure the pull-off force until retention loss (N) under tension with a crosshead speed of 5 mm/min. The pull-off force was highest for group 8, i.e., 3D-printed crowns with a 20° taper and cemented with Kerr Temp-Bond clear cement, followed by groups 6, 7, 4, 5, 3, and 2. Group 1, i.e., milled crowns with 10° taper cemented with Kerr Temp-Bond NE conventional cement, exhibited the lowest pull-off retentive force. The clinical selection of long-term provisional crowns fabricated using 3D-printing technology, prepared with 10° or 20° tapers, and cemented with clear cement, is the most favorable in terms of the retention of provisional crowns. 3D-printed provisional crowns can be used as an alternative to conventional and CAD/CAM-milled crowns for long-term provisionalization

TcdB, but not TcdA triggers CXCL8/IL-8 production and release from Caco-2 cells in a manner dependent on extracellular nucleotides and the P2Y₆ receptor.

<p>(A) CXCL8/IL-8 release from Caco-2 cells treated with purified TcdA or TcdB (16 hr). N = 5; * denotes p<0.05 compared to TcdA. (B) TcdB, but not TcdA, treatment of Caco-2 cells increases cell death as assessed by LDH release. N = 5; * denotes p<0.05 compared to TcdA. TcdB-induced CXCL8/IL-8 release is significantly reduced by (C) MRS2578 (10 μM) and (D) co-treatment with apyrase (20 u/mL). N = 5; * denotes p<0.05 compared to no treatment; # denotes p<0.05 compared to all groups. </p

<i>C. difficile</i> TcdA/B triggers the release of UDP from Caco-2 cells that express a functional P2Y₆ receptor.

<p>(A) Western blot analysis of lysates reveals the expression of the P2Y₆ receptor in differentiated Caco-2 cells and PMA-differentiated THP-1 macrophages (included as positive control). (B) Stimulation of the Caco-2 cells with the selective P2Y₆ receptor agonist 5-OMe-UDP (1 μM) increases intracellular calcium concentrations as assessed by fluorescence imaging. (B-i) Pseudocolour images of Caco-2 cells before and after 5-OMe-UDP treatment. (B-ii) Representative traces of individual cells challenged with 5-OMe-UDP. (B-iii) The mean of the 5-OMe-UDP-induced calcium responses (n=46; grey denotes the standard error of the mean). (C) P2Y₆ receptor agonist 5-OMe-UDP triggers CXCL8/IL-8 release from Caco-2 cells, an effect that blocked by the potent P2Y₆ receptor antagonist MRS2578. N = 6; * denotes p<0.05 compared to control; # denotes p<0.05 compared to vehicle; % denotes p<0.05 compared to vehicle and 1 μM MRS 2578. (D) TcdA/B triggers the release of UDP as assessed by HPLC. i – control treated culture supernatant; ii – UDP-spiked control culture supernatant (100 μM UDP); iii – TcdA/B-spiked control culture supernatant (10 μg/mL); iv – TcdA/B-treated cell culture supernatant (10 μg/mL; 16 hr). (E) Summary data from HPLC measurement of TcdA/B-induced UDP release. N=5; * denotes p<0.05.</p

TcdA/B-induced CXCL8/IL-8 production from Caco-2 IECs involves the NFκB activation, an effect that is inhibited by pharmacological blockade of the P2Y₆ receptor by MRS2578.

<p>(A) TcdA/B-induced CXCL8/IL-8 release is inhibited by pretreatment with the selective NFκB pathway inhibitor BAY 11-7085 (20 μM). N=6; ** denotes p<0.005 compared to vehicle-treated TcdA/B stimulated cells (10 μg/mL). (B) Representative western blot for phosphorylated p65 (P-p65) in lysates from TcdA/B (10 μg/mL) stimulated Caco-2 IECs over the course of 60 min in the presence of the P2Y₆ antagonist MRS2578 (10 μM) or vehicle control (DMSO). (C) The summarized western blot data for P-p65 expressed as a percentage of the total p65. N = 4, *, denotes p<0.05 compared to time 0 min; # denotes p<0.05 compared to respective vehicle control (DMSO). </p