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

ROS-responsive copolymer micelles for inflammation triggered delivery of ibuprofen

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used for the treatment of pain, inflammation and fever. However, most NSAIDs are poorly water soluble, making it difficult to be administered thus high doses are required to reach the intended therapeutic effect, resulting in associated side effects. In this study, ROS-responsive micellar systems based on a block copolymer consisting of methylpropyl thioether (MTPA) and N'N-dimethylacrylamide was developed and loaded with ibuprofen (IBU). Using lipopolysaccharide activated RAW 264.7 macrophage like cells, we demonstrated that IBU was released from the copolymer, specifically in the presence of ROS. Interestingly, IBU encapsulated in ROS-responsive nanoparticles exhibited greater anti-inflammatory potency compared to its free form. The work highlights the potential of the ROS-responsive micellar system developed in this work to be used as carrier of NSAIDs for the treatment of relevant inflammatory conditions

Self-Assembly of Stimulus-Responsive Water Soluble RAFT (Co)Polymers

In this thesis, homopolymers and well-defined AB diblock copolymers that are stimulus responsive were prepared via a combination of reversible-addition fragmentation chain transfer (RAFT) polymerization and post-polymerization modification. For the first part of the thesis, CO2-responsive (co)polymers containing an amidine and/or guanidine moiety were synthesized through the post-polymerization modification of pentafluorophenyl acrylate (PFPA) containing precursors. The use of CO2 as a gas trigger to tune the self-assembly of an amidine containing AB diblock copolymer was also successfully demonstrated. In the second and third part of the thesis, the ring opening reaction of 2-vinyl-4,4-dimethylazlactone (VDA) was highlighted. A range of novel pH and/or thermo-responsive (co)polymers were derived using RAFT synthesized (co)polymers containing the reactive 2-vinyl-4,4-dimethylazlactone (VDA) scaffold in the second part of the thesis and their aqueous solution behaviour were studied through the application of various temperature and/or pH stimuli. Finally, for the third part of the thesis, VDA homopolymers with different hydrophobic α end groups were post-modified using a range of different amines and their behaviour in aqueous media was studied. A comparison of their aqueous solution behaviour was made to determine the effects that different hydrophobic α end groups may have on the solution properties of the various homopolymers

Block copolymer micelles with pendant bifunctional chelator for platinum drugs : effect of spacer length on the viability of tumor cells

Three monomers with 1,3-dicarboxylate functional groups but varying spacer lengths were synthesized via carbon Michael addition using malonate esters and ethylene- (MAETC), butylene- (MABTC), and hexylene (MAHTC) glycol dimethacrylate, respectively. Poly[oligo-(ethylene glycol) methylether methacrylate] (POEGMEMA) was prepared in the presence of a RAFT (reversible addition-fragmentation chain transfer) agent, followed by chain extension with the prepared monomers to generate three different block copolymers (BP-E80, BP-B82, and BP-H79) with similar numbers of repeating units, but various spacer lengths as distinguishing features. Conjugation with platinum drugs created macromolecular platinum drugs resembling carboplatin. The amphiphilic natures of these Pt-containing block copolymers led to the formation micelles in solution. The rate of drug release of all micelles was similar, but a noticeable difference was the increasing stability of the micelle against dissociation with increasing spacer length. The platinum conjugated polymer showed high activity against A549, OVCAR3, and SKOV3 cancer cell lines exceeding the activity of carboplatin, but only the micelle based on the longest spacer had IC50 values as low as cisplatin. Cellular uptake studies identified a better micelle uptake with increasing micelle stability as a possible reason for lower IC50 values. The clonogenic assay revealed that micelles loaded with platinum drugs, in contrast to low molecular weight carboplatin, have not only better activity within the frame of a 72 h cell viability study, but also display a longer lasting effect by preventing the colony formation A549 for more than 10 days

Physical Texturing for Superhydrophobic Polymeric Surfaces: A Design Perspective

Surface wetting on the textured surface is classically explained by the theories of Cassie–Baxter or Wenzel. However, in recent years, an increasing number of complex surface topographies with superhydrophobic properties have been achieved without prediction or simulation using these theories. One example is biomimetic surfaces. In many instances, theories were used to explain surface properties found in nature but have not led to or predicted the complex topographies. Although new wetting theories continue to emerge, there is not yet a set of design rules to guide the selection of surface topographies to achieve superhydrophobicity. By grouping known surface topographies into common geometrical descriptions and length scale, this paper suggests a set of surface topography classifications to provide selection guidelines for engineering superhydrophobic surfaces. Two key outcomes emerged from the design analysis: first, categorization of frequently reported surface patterns shows that there exists a set of commonly used descriptions among diverse designs; second, the degree of hydrophobicity improvement within a class of topography design can be used to predict the limit of improvement in superhydrophobicity for a given material. The presentation of topography descriptors by categories of design and performance may serve as a prologue to an eventually complete set of design guidelines for superhydrophobic performance

Thermoresponsive (Co)polymers through Postpolymerization Modification of Poly(2-vinyl-4,4-dimethylazlactone)

Poly­(2-vinyl-4,4-dimethylazlactone), pVDMA, is emerging as a versatile reactive platform in polymer chemistry. Herein, postpolymerization modification of pVDMA leading to thermoresponsive homo- and copolymers is investigated. VDMA was polymerized by reversible addition–fragmentation chain transfer (RAFT) polymerization. The resulting reactive scaffolds with molecular weights ranging from 3.0 to 12.5 kg/mol were converted with a selection of alcohols and amines of varying polarity into functional poly­(2-acrylamido isobutyrate)­s and poly­(2-acrylamido isobutyramide)­s with molecular weights ranging from <i>M</i>_n = 4.2–65.1 kg/mol and low polydispersity indices <i>M</i>_w/<i>M</i>_n < 1.37. Spectra obtained by ¹H NMR and infrared spectroscopic measurements conformed to the expected structures. While alcohols and amines producing water-soluble or water insoluble VDMA-derived homopolymers were identified, seven homopolymers were found to show a lower critical solution temperature in aqueous solution; those formed by reacting pVDMA with <i>N</i>-ethylamine, <i>N</i>-isopropylamine, <i>N</i>,<i>N</i>-dimethylamine, <i>N</i>,<i>N</i>-diethylamine, <i>N</i>,<i>N</i>-diethylaminoethylamine, Jeffamine M-600, and tetrahydrofurfurylamine (THF amine). Cloud points increased with decreasing molecular weight. With a cloud point of 31 °C, the phase separation of poly­(tetrahydrofurfuryl 2-acrylamido isobutyramide) (pTAI) occurred close to body temperature, was highly reproducible, and, above a concentration of 0.5 wt %, was largely concentration independent. The transition temperature of pTAI-based copolymers could easily be tuned by reacting pVDMA with a mixture of THF amine and varying amounts of pentylamine or di­(ethylene glycol) methyl ether amine

Biocompatible Polycationic Silver Nanocluster-Impregnated PLGA Nanocomposites with Potent Antimicrobial Activity

Ultrasmall cationic silver nanoparticles (AgNPs) have recently emerged as highly potent antimicrobial agents for the treatment of multidrug-resistant bacteria and their biofilms. However, the clinical application of these cationic AgNPs is hampered by their poor stability and high reactivity in solution, leading to uncontrolled release of toxic silver ions. An ideal platform featuring broad-spectrum antibacterial activity and high biocompatibility that prevents overexposure to silver ions, is therefore highly desirable. Herein, we explored a biocompatible and biodegradable polymer, poly(lactic-co-glycolic) acid (PLGA) as an effective carrier for the recently discovered polycationic silver nanoclusters (pAgNCs). These pAgNCs impregnated PLGA nanocomposites (pAgNCs@PLGA) were developed by water-in-oil-in-water (W1/O/W2) emulsion method and characterized by various analytical techniques. Our experimental results reveal that pAgNCs@PLGA had spherical morphology with an average diameter of ∼188 nm and consists of multiple ultrasmall (∼2 nm) pAgNCs at the polymeric core. The minimum inhibitory concentration of pAgNCs for Staphylococcus aureus and Pseudomonas aeruginosa were found to be 6.9 μg/mL. After impregnation within PLGA, the antimicrobial efficacy of our pAgNCs against Staphylococcus aureus and Pseudomonas aeruginosa remained consistent, while the nanocomposites were biocompatible at the minimum inhibitory concentration (MIC) against both bacteria. The pAgNCs@PLGA nanocomposite developed in this work may present a path forward to bring these highly potent pAgNCs into medical practice

Block Copolymer Micelles with Pendant Bifunctional Chelator for Platinum Drugs: Effect of Spacer Length on the Viability of Tumor Cells

Three monomers with 1,3-dicarboxylate functional groups but varying spacer lengths were synthesized via carbon Michael addition using malonate esters and ethylene- (MAETC), butylene- (MABTC), and hexylene (MAHTC) glycol dimethacrylate, respectively. Poly­[oligo-(ethylene glycol) methylether methacrylate] (POEGMEMA) was prepared in the presence of a RAFT (reversible addition–fragmentation chain transfer) agent, followed by chain extension with the prepared monomers to generate three different block copolymers (BP-E80, BP-B82, and BP-H79) with similar numbers of repeating units, but various spacer lengths as distinguishing features. Conjugation with platinum drugs created macromolecular platinum drugs resembling carboplatin. The amphiphilic natures of these Pt-containing block copolymers led to the formation micelles in solution. The rate of drug release of all micelles was similar, but a noticeable difference was the increasing stability of the micelle against dissociation with increasing spacer length. The platinum conjugated polymer showed high activity against A549, OVCAR3, and SKOV3 cancer cell lines exceeding the activity of carboplatin, but only the micelle based on the longest spacer had IC₅₀ values as low as cisplatin. Cellular uptake studies identified a better micelle uptake with increasing micelle stability as a possible reason for lower IC₅₀ values. The clonogenic assay revealed that micelles loaded with platinum drugs, in contrast to low molecular weight carboplatin, have not only better activity within the frame of a 72 h cell viability study, but also display a longer lasting effect by preventing the colony formation A549 for more than 10 days

RAFT Synthesis and Aqueous Solution Behavior of Novel pH- and Thermo-Responsive (Co)Polymers Derived from Reactive Poly(2-vinyl-4,4-dimethylazlactone) Scaffolds

Well-defined homopolymers of 2-vinyl-4,4-dimethylazlactone (VDA) and AB diblock copolymers of VDA with <i><i>N</i></i>,<i><i>N</i></i>-dimethylacrylamide (DMA) and <i>N</i>-isopropyl­acrylamide (NIPAM) prepared by reversible addition–fragmentation chain transfer (RAFT) radical polymerization are reported. VDA homopolymers reacted with <i><i>N</i></i>,<i><i>N</i></i>-dimethylethylenediamine (DMEDA), <i><i>N</i></i>,<i><i>N</i>-</i>diethylethylenediamine (DEEDA), and picoylamine (PA) give novel tertiary amine functional polymers that exhibit inverse temperature aqueous solution characteristics in the case of the DMEDA and DEEDA derivatives (provided they are not protonated) and a pH-dependent solubility for the PA speciesit is soluble at low solution pH but becomes hydrophobic at ca. pH 4.0. VDA-DMA/NIPAM AB diblock copolymers are also readily modified with DMEDA, DEEDA, and PA to give a novel series of stimulus responsive block copolymers including tunably amphiphilic and schizophrenic species. DMEDA-DMA and DEEDA-DMA/NIPAM block copolymer derivatives undergo reversible temperature induced self-assembly in aqueous media by virtue of the inverse temperature solubility characteristics associated with these tertiary amino species. The aggregation behavior of these species is characterized using a combination of dynamic light scattering (DLS), ¹H NMR spectroscopy and transmission electron microscopy (TEM). For the PA derivatives, schizophrenic behavior is demonstrated in AB block copolymers with NIPAM with normal and inverse micelles being readily accessible simply by controlling the solution pH or temperature. Self-assembled species derived from a DMEDA-DMA block copolymer, containing tertiary amino functionality in the core, can be readily core cross-linked, locking the self-assembled structure, using 1,10-dibromodecane as evidenced by DLS. The ability of examples of the ‘smart’ block copolymers to sequester hydrophobic Nile Red upon application of a pH or temperature stimulus from an aqueous environment is also demonstrated. Finally, we show how, if desired, the DMEDA homopolymers can be further modified via the facile reaction with 1,3-propanesultone yielding the sulfopropylbetaine analogous materials