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

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Essais de compatibilité seringue/équipements biomédicaux : une affaire de débit

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Do Ophthalmic Solutions of Amphotericin B Solubilised in 2-Hydroxypropyl-γ-Cyclodextrins Possess an Extended Physicochemical Stability?

International audienceFungal keratitis is a sight-threatening disease for which amphotericin B eye drops is one of the front-line treatments. Unfortunately, there are currently no commercial forms available, and there is little data concerning the long-term stability of compounded formulations based on intravenous dosages forms. New formulations of amphotericin B ophthalmic solutions solubilised with γ-cyclodextrins have shown promising in-vitro results, but stability data is also lacking. The objective of this study was therefore to investigate the stability of a formulation of ready-to-use amphotericin B solubilised in 2-hydroxypropyl-γ-cyclodextrins (AB-HP-γ-CD), for 350 days. An amphotericin B deoxycholate (ABDC) formulation was used as a comparator. Analyses used were the following: visual inspection, turbidity, osmolality and pH measurements, amphotericin B quantification by a stability-indicating liquid chromatography method, breakdown product research, and sterility assay. AB-HP-γ-CD formulation showed signs of chemical instability (loss of amphotericin B) after 28 and 56 days at 25 °C and 5 °C. Adding an antioxidant (ascorbic acid) to the formulation did not improve stability. ABDC formulation showed signs of physical instability (increased turbidy and amphotericin B precipitation) after 28 days and 168 days at 25 °C and 5 °C. As such, AB-HP-γ-CD formulation does not provide long-term stability for ophthalmic amphotericin B solutions

The association of ARRB1 polymorphisms with response to antidepressant treatment in depressed patients

International audienceIntroduction: β-arrestin 1, a protein encoded by ARRB1 involved in receptor signaling, is a potential biomarker for the response to antidepressant drug (ATD) treatment in depression. We examined ARRB1 genetic variants for their association with response following ATD treatment in METADAP, a cohort of 6-month ATD-treated depressed patients. Methods: Patients ( n = 388) were assessed at baseline (M0) and after 1 (M1), 3 (M3), and 6 months (M6) of treatment for Hamilton Depression Rating Scale (HDRS) changes, response, and remission. Whole-gene ARRB1 variants identified from high-throughput sequencing were separated by a minor allele frequency (MAF)≥5%. Frequent variants (i.e., MAF≥5%) annotated by RegulomeDB as likely affecting transcription factor binding were analyzed using mixed-effects models. Rare variants (i.e., MAF&lt;5%) were analyzed using a variant set analysis. Results: The variant set analysis of rare variants was significant in explaining HDRS score changes ( T = 878.9; p = 0.0033) and remission ( T = -1974.1; p = 0.034). Rare variant counts were significant in explaining response ( p = 0.016), remission ( p = 0.022), and HDRS scores at M1 ( p = 0.0021) and M3 ( p =&lt;0.001). rs553664 and rs536852 were significantly associated with the HDRS score (rs553664: p = 0.0055 | rs536852: p = 0.046) and remission (rs553664: p = 0.026 | rs536852: p = 0.012) through their interactions with time. At M6, significantly higher HDRS scores were observed in rs553664 AA homozygotes (13.98 ± 1.06) compared to AG heterozygotes (10.59 ± 0.86; p = 0.014) and in rs536852 GG homozygotes (14.88 ± 1.10) compared to AG heterozygotes (11.26 ± 0.95; p = 0.0061). Significantly lower remitter rates were observed in rs536852 GG homozygotes (8%, n = 56) compared to AG heterozygotes (42%, n = 105) at M6 ( p = 0.0018). Conclusion: Our results suggest ARRB1 variants may influence the response to ATD treatment in depressed patients. Further analysis of functional ARRB1 variants and rare variant burden in other populations would help corroborate our exploratory analysis. β-arrestin 1 and genetic variants of ARRB1 may be useful clinical biomarkers for clinical improvement following ATD treatment in depressed individuals. Clinical Trial Registration: clinicaltrials.gov ; identifier NCT0052638

The GG genotype of the serotonin 4 receptor genetic polymorphism, rs1345697, is associated with lower remission rates after antidepressant treatment: Findings from the METADAP cohort

International audienceBackground: Pharmacological studies have yielded valuable insights into the role of the serotonin 4 receptor (HTR4) in major depressive episodes (MDE) and response to antidepressant drugs (AD). A genetic association has been shown between HTR4 and susceptibility to mood disorders. Our study aims at assessing the association between the HTR4 genetic polymorphism, rs1345697, and improvement in depressive symptoms and remission after antidepressant treatment in MDE patients.Methods: 492 depressed patients from the METADAP cohort were treated prospectively for 6 months with ADs. The clinical outcomes according to HTR4 rs1345697 were compared after 1 (M1), 3 (M3), and 6 (M6) months of treatment. Mixed-effects logistic regression and adjusted linear models assessed the association between rs1345697 and 17-item Hamilton Depression Rating Scale (HDRS) score improvement and response/remission.Results: Over the 6 months of treatment, mixed-effects regressions showed lower improvements in HDRS scores (Coefficient=1.52; Confident Interval (CI) 95% [0.37-2.67]; p = 0.009) and lower remission rates (Odds Ratio=2.0; CI95% [1.0-4.1]; p = 0.05) in GG homozygous patients as compared to allele A carriers.Limitations: The major limitations of our study are the uncertainty of the rs1345697 effect on HTR4 function, the substantial drop-out rate, and the fact that analysis is not based on randomization between polymorphism groups.Conclusions: In our study, patients who were homozygous carriers of the variant G of the HTR4 rs1345697 had lower depressive symptoms improvement and 2-fold lower remission rates after antidepressant treatment as compared to allele A carriers. Randomization study should be done to confirm these results

The olfactory deficits of depressed patients are restored after remission with venlafaxine treatment

International audienceBackgroundIt is unclear whether olfactory deficits improve after remission in depressed patients. Therefore, we aimed to assess in drug-free patients the olfactory performance of patients with major depressive episodes (MDE) and its change after antidepressant treatment.MethodsIn the DEP-ARREST-CLIN study, 69 drug-free patients with a current MDE in the context of major depressive disorder (MDD) were assessed for their olfactory performances and depression severity, before and after 1 (M1) and 3 (M3) months of venlafaxine antidepressant treatment. They were compared to 32 age- and sex-matched healthy controls (HCs). Olfaction was assessed with a psychophysical test, the Sniffin’ Sticks test ( Threshold : T score; Discrimination: D score; Identification : I score; total score: T + D + I = TDI score) and Pleasantness (pleasantness score: p score; neutral score: N score; unpleasantness score: U score).ResultsAs compared to HCs, depressed patients had lower TDI olfactory scores [mean ( s.d. ) 30.0(4.5) v. 33.3(4.2), p < 0.001], T scores [5.6(2.6) v. 7.4(2.6), p < 0.01], p scores [7.5(3.0) v. 9.8(2.8), p < 0.001)] and higher N scores [3.5(2.6) v. 2.1(1.8), p < 0.01]. T , p and N scores at baseline were independent from depression and anhedonia severity. After venlafaxine treatment, significant increases of T scores [M1: 7.0(2.6) and M3: 6.8(3.1), p < 0.01] and p scores [M1: 8.1(3.0) and M3: 8.4(3.3), p < 0.05] were evidenced, in remitters only ( T : p < 0.01; P : p < 0.01). Olfaction improvement was mediated by depression improvement.ConclusionsThe olfactory signature of MDE is restored after venlafaxine treatment. This olfaction improvement is mediated by depression improvement