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Aim Antimicrobials are among the most widely prescribed therapeutic agents among paediatric population. Irrational use of these agents increases the risk of antimicrobial resistance. We described the prevalence and pattern of antimicrobial use among paediatric inpatients from 2017 to 2019. Subject and Method The study was a repeated point prevalence survey over a 3-year period using the global point prevalence standardized tools among all paediatric inpatients. The prevalence of antimicrobial use, the prescription indicators and patterns of antimicrobial use were estimated. Result Among 191 paediatric inpatients assessed, the 3-year period prevalence antimicrobial use was 85.9% (164/191) with prevalence of 80.6% in 2017, 94.6% in 2018, and 83.6% in 2019. Antimicrobial agents used ranged from one agent (20.1%) to five different agents (5.5%). Parenteral route (66.6%) was the preferred route of administration. The reason for the use of antimicrobial agents (92.6%) and the stop/review date (99.5%) were mostly well documented. Only 4.5% of the antimicrobial use were targeted. There were no antimicrobial guidelines or policy guiding the use of antimicrobial agents, except the national guideline on the treatment of malaria and tuberculosis. Ceftriaxone, a third generation cephalosporin was the most commonly used agent across the period under review. Community-acquired infection was the commonest indication for antimicrobial use. Conclusion Our findings of high antimicrobial prevalence has raised the attention for the need to develop hospital-based antimicrobial guideline and antimicrobial stewardship program to protect the vulnerable children, their contacts and the environment from the impact of antimicrobial resistance.

Colistin heteroresistance has been identified in several bacterial species, including Escherichia coli and Klebsiella pneumoniae, and may underlie antibiotic therapy failures since it most often goes undetected by conventional antimicrobial susceptibility tests. This study utilizes population analysis profiling (PAP) and time–kill assay for the detection of heteroresistance in K. pneumoniae and for evaluating the association between in vitro regrowth and heteroresistance. The mechanisms of colistin resistance and the ability of combination therapies to suppress resistance selection were also analysed. In total, 3 (18%) of the 16 colistin-susceptible strains (MIC ≤ 2 mg/L) were confirmed to be heteroresistant to colistin by PAP assay. In contrast to the colistin-susceptible control strains, all three heteroresistant strains showed regrowth when exposed to colistin after 24 h following a rapid bactericidal action. Colistin resistance in all the resistant subpopulations was due to the disruption of the mgrB gene by various insertion elements such as ISKpn14 of the IS1 family and IS903B of the IS5 family. Colistin combined with carbapenems (imipenem, meropenem), aminoglycosides (amikacin, gentamicin) or tigecycline was found to elicit in vitro synergistic effects against these colistin heteroresistant strains. Our experimental results showcase the potential of combination therapies for treatment of K. pneumoniae infections associated with colistin heteroresistance.

Background Streptococcus pneumoniae is a global cause of community-acquired pneumonia (CAP) and invasive disease in children that requires antibiotic treatment. As part of the CAP-IT trial (grant No. 13/88/11; https://www.capitstudy.org.uk/), we analyzed nasopharyngeal swabs from children with clinically diagnosed CAP, and found no differences in pneumococcal susceptibility between patients receiving oral amoxicillin treatment for shorter or longer durations and at higher or lower antibiotic doses. Here, we perform high-resolution genomics to understand pneumococcal diversity and to unravel potential mechanisms underlying persistence of pneumococcal (vaccine) serotypes.Methods Three-hundred and ninety pneumococci cultured from 1132 nasopharyngeal swabs from 718 children were whole-genome sequenced (Illumina) and tested for susceptibility to penicillin and amoxicillin. Recombination analysis was performed using long-read sequenced isolates (PacBio) and publicly available sequences.Results In 390 unique pneumococcal isolates, non-susceptibility to penicillin (n = 61, 15.6%) and amoxicillin (n = 10, 2.6%) was low and independent of the amoxicillin treatment dosage and duration. Serotypes 15B/C, 11A, 15A and 23B1 were most prevalent. PCV13 serotypes 3, 19A, and 19F were also identified (n = 25, 6.4%), and recombination analysis and genome-wide comparisons with historical isolates dating from 1995 identified several potential capsule switch events in these highly recombinant vaccine serotypes 19A and 19F, in contrast to serotype 3 genomes (n = 13, 3.3%) that showed high genomic stability over the last 20 years. All 23B1 isolates (n = 27, 6.9%) were penicillin non-susceptible, and one was the result of a potential capsule-switch in 19F.Conclusions Our data suggest that vaccination strategies, but not amoxicillin use, are more likely to drive pneumococcal serotype prevalence among children in the UK and prompts consideration of PCVs with additional serotype coverage that are likely to further decrease invasive disease in this target population. Emergence of 23B1, a non-vaccine genotype with penicillin non-susceptibility, might provide a persistence strategy for vaccine serotypes, highlighting the need for continued genomic surveillance.

Purpose: Women infected with human papillomavirus (HPV) with normal cytology to mild abnormalities currently have no treatment options other than watchful waiting or surgery if high-grade cervical lesions or cancer develop. A therapeutic vaccine would offer the possibility of preventing high-grade lesions in HPV-infected women. GTL001 is a therapeutic vaccine composed of recombinant HPV16 and HPV18 E7 proteins fused to catalytically inactive Bordetella pertussis CyaA. This study examined the tolerability and immunogenicity of GTL001 in women infected with HPV16 or HPV18 with normal cytology.Experimental Design: This was a phase I trial (EudraCT No. 2010-018629-21). In an open-label part, subjects received two intradermal vaccinations 6 weeks apart of 100 or 600 μg GTL001 + topical 5% imiquimod cream at the injection site. In a double-blind part, subjects were randomized 2:1:1 to two vaccinations 6 weeks apart of 600 μg GTL001 + imiquimod, 600 μg GTL001 + placebo cream, or placebo + imiquimod.Results: Forty-seven women were included. No dropouts, treatment-related serious adverse events, or dose-limiting toxicities occurred. Local reactions were transient and mostly mild or moderate. HPV16/18 viral load decreased the most in the 600 μg GTL001 + imiquimod group. In post hoc analyses, the 600 μg GTL001 + imiquimod group had the highest rates of initial and sustained HPV16/18 clearance. Imiquimod increased antigen-specific T-cell response rates but not rates of solicited reactions. All subjects seroconverted to CyaA.Conclusions: For women infected with HPV16 or HPV18 with normal cervical cytology, GTL001 was immunogenic and had acceptable safety profile. Clin Cancer Res; 22(13); 3238–48. ©2016 AACR.

Worst Cervical cytology during the study

Supplemental Methods

Most common treatment-related TEAEs

ELISpot response rates

Mean background corrected ELISpot magnitudes

Up to 80% of antibiotics are prescribed in the community. An assessment of prescribing by indication will help to identify areas where improvement can be made. A point prevalence audit study (PPAS) of consecutive respiratory tract infection (RTI) consultations in general practices in 13 European countries was conducted in January–February 2020 (PPAS-1) and again in 2022 (PPAS-4). The European Surveillance of Antibiotic Consumption quality indicators (ESAC-QI) were calculated to identify where improvements can be made. A total of 3618 consultations were recorded for PPAS-1 and 2655 in PPAS-4. Bacterial aetiology was suspected in 26% (PPAS-1) and 12% (PPAS-4), and an antibiotic was prescribed in 30% (PPAS-1) and 16% (PPAS-4) of consultations. The percentage of adult patients with bronchitis who receive an antibiotic should, according to the ESAC-QI, not exceed 30%, which was not met by participating practices in any country except Denmark and Spain. For patients (≥1) with acute upper RTI, less than 20% should be prescribed an antibiotic, which was achieved by general practices in most countries, except Ireland (both PPAS), Croatia (PPAS-1), and Greece (PPAS-4) where prescribing for acute or chronic sinusitis (0–20%) was also exceeded. For pneumonia in adults, prescribing is acceptable for 90–100%, and this is lower in most countries. Prescribing for tonsillitis (≥1) exceeded the ESAC-QI (0–20%) in all countries and was 69% (PPAS-1) and 75% (PPAS-4). In conclusion, ESAC-QI applied to PPAS outcomes allows us to evaluate appropriate antibiotic prescribing by indication and benchmark general practices and countries. Up to 80% of antibiotics are prescribed in the community. An assessment of prescribing by indication will help to identify areas where improvement can be made. A point prevalence audit study (PPAS) of consecutive respiratory tract infection (RTI) consultations in general practices in 13 European countries was conducted in January–February 2020 (PPAS-1) and again in 2022 (PPAS-4). The European Surveillance of Antibiotic Consumption quality indicators (ESAC-QI) were calculated to identify where improvements can be made. A total of 3618 consultations were recorded for PPAS-1 and 2655 in PPAS-4. Bacterial aetiology was suspected in 26% (PPAS-1) and 12% (PPAS-4), and an antibiotic was prescribed in 30% (PPAS-1) and 16% (PPAS-4) of consultations. The percentage of adult patients with bronchitis who receive an antibiotic should, according to the ESAC-QI, not exceed 30%, which was not met by participating practices in any country except Denmark and Spain. For patients (≥1) with acute upper RTI, less than 20% should be prescribed an antibiotic, which was achieved by general practices in most countries, except Ireland (both PPAS), Croatia (PPAS-1), and Greece (PPAS-4) where prescribing for acute or chronic sinusitis (0–20%) was also exceeded. For pneumonia in adults, prescribing is acceptable for 90–100%, and this is lower in most countries. Prescribing for tonsillitis (≥1) exceeded the ESAC-QI (0–20%) in all countries and was 69% (PPAS-1) and 75% (PPAS-4). In conclusion, ESAC-QI applied to PPAS outcomes allows us to evaluate appropriate antibiotic prescribing by indication and benchmark general practices and countries.

Background. The global point prevalence survey (Global-PPS) is the standard for the surveillance of prescribed antimicrobials among inpatients and provides data for the development of hospital antimicrobial stewardship programs. Aim. To evaluate the prevalence and quality of antimicrobial prescriptions using the universally standardized Global-PPS protocol in a non-acute care hospital in Saitama Prefecture, Japan. Methods. Antimicrobial prescriptions for inpatients, staying at the hospital overnight, were surveyed on three separate week days in November 2018, January 2019, and May 2019. Information on the prescribed antimicrobials on the survey target day was obtained from the in-hospital pharmacy. Survey data were collected by physicians, based on the extracted information. Patient information was anonymized and entered in the Global-PPS Web application by physicians. We report the antimicrobial use prevalence, the indication for prescription, diagnosis, the most prescribed antimicrobials, and a set of quality indicators related to antimicrobial prescribing. Results. In total, 6.7% of the surveyed inpatients (120/1796) were prescribed antimicrobials on the survey day. Sulfamethoxazole/trimethoprim was the most commonly prescribed, with 20.0% of systemic antibiotic prescriptions (ATC J01). Of all antibiotics for systemic use, up to 58.4% were Watch antibiotics, as defined by the World Health Organization AWaRe classification. The most prescribed group of systemic antibiotics was non-penicillin beta-lactam antibiotics (34.4%), followed by penicillin antibiotics in combination with beta-lactamase inhibitors (25.6%), and sulfonamides with trimethoprim (20.8%). Healthcare-associated infections and medical prophylaxis were the most common indications reported in 69.3% and 26.3% of prescriptions, respectively. The most common diagnosis for systemic antibiotic prescriptions was pneumonia (49.6%). Reasons for antimicrobial prescriptions were indicated in the medical records for 67.1% of prescriptions, and the stop/review date was documented to be 50.3%. Compliance with local guidelines reached 66.7%. Conclusions. This study highlights important challenges related to antimicrobial prescription in a highly specific, non-acute care patient population.

Objectives To evaluate a testing algorithm for the rapid identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that includes the use of PCR-based targeted single nucleotide polymorphism (SNP) detection assays preceded by a multiplex PCR sensitive to S-Gene Target Failure (SGTF). Methods PCR SNP assays targeting SARS-CoV-2 S-gene mutations ΔH69–V70, L452R, E484K, N501Y, H655Y and P681R using melting curve analysis were performed on 567 samples in which SARS-CoV-2 viral RNA was detected by a multiplex PCR. Viral whole-genome sequencing (WGS) was performed to confirm the presence of SNPs and to identify the Pangolin lineage. Additionally, 1133 SARS-CoV-2 positive samples with SGTF were further assessed by WGS to determine the presence of ΔH69–V70. Results The N501Y-specific assay (n = 567) had an overall percentage agreement (OPA) of 98.5%. The ΔH69-V70-specific (n = 178) and E484K-specific (n = 401) assays had OPA of 96.6% and 99.7%, respectively. Assessment of H655Y (n = 139) yielded a 100.0% concordance when applied in the proposed algorithm. The L452R-specific (n = 67) and P681R-specific (n = 62) assays had an OPA of 98.2% and 98.1%, respectively. The proposed algorithm identified six variants of concern/interest (VOC/VOI)—Alpha (n = 149), Beta (n = 65), Gamma (n = 86), Delta (n = 49), Eta (n = 6), Kappa (n = 6)—and 205 non-VOC/VOI strains—including the variants under monitoring B.1.214.2 (n = 43) and B.1.1.318 (n = 18) and Epsilon (n = 1). An excellent concordance was observed for the identification of all SARS-CoV-2 lineages evaluated. Conclusions We present a flexible testing algorithm for the rapid detection of current and emerging SARS-CoV-2 VOC/VOIs, which can be easily adapted based on the local endemicity of specific variants.

ObjectivesTo estimate the prevalence, incidence and longevity of antibodies against SARS-CoV-2 among primary healthcare providers (PHCPs).DesignProspective cohort study with 12 months of follow-up.SettingPrimary care in Belgium.ParticipantsAny general practitioner (GP) working in primary care in Belgium and any other PHCP from the same GP practice who physically manages (examines, tests, treats) patients were eligible. A convenience sample of 3648 eligible PHCPs from 2001 GP practices registered for this study (3044 and 604 to start in December 2020 and January 2021, respectively). 3390 PHCPs (92,9%) participated in their first testing time point (2820 and 565, respectively) and 2557 PHCPs (70,1%) in the last testing time point (December 2021).InterventionsParticipants were asked to perform a rapid serological test targeting IgM and IgG against the receptor binding domain of SARS-CoV-2 and to complete an online questionnaire at each of maximum eight testing time points.Primary and secondary outcome measuresThe prevalence, incidence and longevity of antibodies against SARS-CoV-2 both after natural infection and after vaccination.ResultsAmong all participants, 67% were women and 77% GPs. Median age was 43 years. The seroprevalence in December 2020 (before vaccination availability) was 15.1% (95% CI 13.5% to 16.6%), increased to 84.2% (95% CI 82.9% to 85.5%) in March 2021 (after vaccination availability) and reached 93.9% (95% CI 92.9% to 94.9%) in December 2021 (during booster vaccination availability and fourth (delta variant dominant) COVID-19 wave). Among not (yet) vaccinated participants the first monthly incidence of antibodies against SARS-CoV-2 was estimated to be 2.91% (95% CI 1.80% to 4.01%). The longevity of antibodies is higher in PHCPs with self-reported COVID-19 infection.ConclusionsThis study confirms that occupational health measures provided sufficient protection when managing patients. High uptake of vaccination resulted in high seroprevalence of SARS-CoV-2 antibodies in PHCPs in Belgium. Longevity of antibodies was supported by booster vaccination and virus circulation.Trial registration numberNCT04779424.

Assess the incidence, risk factors, clinical and microbiological features, and outcome of both probable invasive and invasive group A Streptococcus (GAS) infections in children and adults in the BrusselsCapital Region between 2005 and 2020. A retrospective, multicentric study was performed in three university hospitals in Brussels. Patients were identified through the centralized laboratory information system. Epidemiological and clinical data were collected from patients' hospital records. A total of 467 cases were identified. Incidence has increased from 2.1 to 10.9/100,000 inhabitants between 2009 and 2019 in non-homeless adults while it was above 100/100,000 on homeless in years with available denominators. Most of GAS were isolated from blood (43.6%), and the most common clinical presentation was skin and soft tissue infections (42.8%). A third of all the patients needed surgery, a quarter was admitted to the intensive care unit, and 10% of the adult patients died. Wounds and chickenpox disease were the main risk factors for children. Tobacco, alcohol abuse, wounds or chronic skin lesion, being homeless, and diabetes were identified as major predisposing factors for adults. The most common emm clusters were D4, E4, and AC3; 64% of the isolates were theoretically covered by the 30-valent M-protein vaccine. The burden of invasive and probable invasive GAS infections is on the rise in the studied adult population. We identified potential interventions that could contribute to decrease this burden: appropriate care of wounds, specifically among homeless and patients with risk factors such as diabetes and systematic chickenpox vaccination for children.

Background: Patient-level surveillance of antimicrobial use (AMU) in Canadian hospitals empowers the reduction of inappropriate AMU and was piloted in 2017 among 14 hospitals in Canada. We aimed to describe AMU on the basis of patient-level data in Canadian hospitals in 2018 in terms of antimicrobial prescribing prevalence and proportions, antimicrobial indications, and agent selection in medical, surgical and intensive care wards. Methods: Canadian adult, pediatric and neonatal hospitals were invited to participate in the standardized web-based cross-sectional Global Point Prevalence Survey of Antimicrobial Consumption and Resistance (Global-PPS) conducted in 2018. An identified site administrator assigned all wards admitting inpatients to specific surveyors. A physician, pharmacist or nurse with infectious disease training performed the survey. The primary outcomes were point prevalence rates for AMU over the study period regarding prescriptions, indications and agent selection in medical, surgical and intensive care wards. The secondary outcomes were AMU for resistant organisms and practice appropriateness evaluated on the basis of quality indicators. Antimicrobial consumption is presented in terms of prevalence and proportions. Results: Forty-seven of 118 (39.8%) hospitals participated in the survey; 9 hospitals were primary care centres, 15 were secondary care centres and 23 were tertiary or specialized care centres. Of 13 272 patients included, 33.5% (n = 4447) received a total of 6525 antimicrobials. Overall, 74.1% (4832/6525) of antimicrobials were for therapeutic use, 12.6% (n = 825) were for medical prophylaxis, 8.9% (n = 578) were for surgical prophylaxis, 2.2% (n = 143) were for other use and 2.3% (n = 147) were for unidentified reasons. A diagnosis or indication was documented in the patient’s file at the initiation for 87.3% (n = 5699) of antimicrobials; 62.9% (n = 4106) of antimicrobials had a stop or review date; and 72.0% (n = 4697) of prescriptions were guided by local guidelines. Interpretation: Overall, three-quarters of AMU was for therapeutic use across participating hospitals. Canadian hospitals should be further incentivized to create and adapt local guidelines on the basis of recent antimicrobial resistance data.

BackgroundPatients with cancer, especially hematological cancer, are at increased risk for breakthrough COVID-19 infection. So far, a predictive biomarker that can assess compromised vaccine-induced anti-SARS-CoV-2 immunity in cancer patients has not been proposed. MethodsWe employed machine learning approaches to identify a biomarker signature based on blood cytokines, chemokines, and immune- and non-immune-related growth factors linked to vaccine immunogenicity in 199 cancer patients receiving the BNT162b2 vaccine. ResultsC-reactive protein (general marker of inflammation), interleukin (IL)-15 (a pro-inflammatory cytokine), IL-18 (interferon-gamma inducing factor), and placental growth factor (an angiogenic cytokine) correctly classified patients with a diminished vaccine response assessed at day 49 with >80% accuracy. Amongst these, CRP showed the highest predictive value for poor response to vaccine administration. Importantly, this unique signature of vaccine response was present at different studied timepoints both before and after vaccination and was not majorly affected by different anti-cancer treatments. ConclusionWe propose a blood-based signature of cytokines and growth factors that can be employed in identifying cancer patients at persistent high risk of COVID-19 despite vaccination with BNT162b2. Our data also suggest that such a signature may reflect the inherent immunological constitution of some cancer patients who are refractive to immunotherapy. This work was supported by the Belgian Government through Sciensano [grant numbers COVID-19_SC004, COVID19_SC059, COVID-19_SC061], ORCHESTRA project, which has received funding from the European Union’s Horizon 2020 research and innovation program [grant agreement number 101016167] and University of Antwerp-GOA grant [s30729].

Background Invasive extraintestinal pathogenic Escherichia coli disease (IED) occurs more frequently with increasing age, and antimicrobial resistance (AMR) can complicate treatment. Yet IED is under-monitored by major disease surveillance systems. In addition, the diagnosis of IED can be challenging due to the diversity of clinical presentations. More research is warranted to better characterize IED. Here we report EXPECT-2 (NCT04117113) results describing the clinical profile of IED and AMR patterns of causative E. coli isolates. Methods EXPECT-2 was a prospective observational study conducted in patients aged ≥60 years with an IED and hospitalized at 8 sites in Europe, North America, and Asia. Data were collected from October 24, 2019 to January 28, 2021. IED was determined by clinical criteria of either systemic inflammatory response syndrome (SIRS) or Sequential Organ Failure Assessment (SOFA), and a positive E. coli culture either from blood (bacteremic IED), or other normally sterile body site samples and/or urine (non-bacteremic IED). Results Overall, 240 IED patients were enrolled (median age, 75 years; females: 51%); 80.4% of IED cases were bacteremic and 19.6% were non-bacteremic. IED was community-acquired in 50.4%, hospital-acquired in 20.0%, and health care–associated in 29.6% of patients. The most common source of IED was urinary tract (62.9%). Fever occurred in 51.5%, tachycardia in 58.6%, tachypnea in 24.3%, and altered mentation in 15.7% of patients. Laboratory markers of a systemic infection were observed in 86.3% of patients, including leukocytosis in 42.7% and leukopenia in 10.9% of patients. SIRS criteria (≥ 2) were met in 65.8% and SOFA criteria (≥ 2) in 60.4% of patients. According to the investigator, 76.5% of patients met criteria for sepsis and 10.6% for septic shock. At 28 days post diagnosis, 14.6% of patients were unrecovered; 12.9% had a complication of kidney dysfunction, and 4.6% had died. Of 238 patients whose E. coli isolates were tested, the AMR rates for ≥ 1 antibiotic were 62.6% in ≥ 1 drug class, 45.9% in ≥ 2 drug classes, and 35.0% in ≥ 3 drug classes. Conclusion In patients aged ≥ 60 years, IED manifested as a severe infection. AMR was frequently observed. The data suggest a need of preventive interventions for IED. Disclosures Joachim Doua, MD, MPH, Janssen: Employee|Janssen: Stocks/Bonds Jeroen Geurtsen, PhD, Janssen: Employee of Janssen Vaccines & Prevention BV Oscar Go, PhD, Janssen: Employee of Janssen Research & Development LLC. Michal Sarnecki, MD, Janssen: Employee|Janssen: Stocks/Bonds Bart Spiessens, PhD, Janssen: Employee Marc Bonten, MD, PhD, Astra-Zeneca: Advisor/Consultant|Janssen: Advisor/Consultant|Merck: Advisor/Consultant|Novartis: Advisor/Consultant Jan Poolman, PhD, Janssen: Janssen Vaccines & Prevention B.V.|Janssen: Stocks/Bonds.

Peer reviewed: True, INTRODUCTION: International travel has been a major determinant for the introduction of pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) into naïve geographic areas. MRSA clonal complex 239 (CC239) is a highly virulent clone that is predominant in Asia. The objective of this study was to determine the geographic origin of MRSA CC239 isolates recovered from Danish cases with or without a history of international travel during 2004-2016. MATERIALS AND METHODS: Human MRSA isolates with spa types t030 and t037 (n = 60) were obtained from the National Reference Laboratory for Antimicrobial Resistance. For each case, the following data were collected from notification forms: sex, age, isolation year, specimen source (screening swab or clinical sample), infection type, and international travel history. All isolates were whole-genome sequenced, and a comparative genome and phylogenetic analysis was performed. RESULTS: The majority of isolates originated from skin and soft tissue (SST) infections and screening swabs. In 31 out of 60 cases reported international travel to different parts of the world. Fifty-four isolates belonged to CC239, including sequence type 239 (ST239) (n = 43), ST241 (n = 5), ST4377 (n = 2), ST4378 (n = 1), ST1465 (n = 1), ST343 (n = 1), and ST592 (n = 1). The majority of the CC239 MRSA isolates (40/54) belonged to well-known geographic clades, including the Asian (n = 12), Serbian (n = 11), South American (n = 2), and Turkish (n = 15). Most MRSA ST239 isolates belonging to the highly virulent Asian clade carried sasX and were recovered from individuals who had travelled to Asia, Africa and the Middle East. CONCLUSION: Our data reveal multiple introductions of MRSA CC239 into Denmark through international travel, which highlights the importance of continued genomic surveillance of MRSA in persons returning from international travel to areas where MRSA is endemic.

The COVID-19 pandemic saw a massive investment into collaborative research projects with a focus on producing data to support public health decisions. We relay our direct experience of four projects funded under the Hori-zon2020 programme, namely ReCoDID, ORCHESTRA, unCoVer and SYNCHROS. The projects provide insight into the complexities of sharing patient level data from observational cohorts. We focus on compliance with the Gen-eral Data Protection Regulation (GDPR) and ethics approvals when sharing data across national borders. We discuss procedures for data mapping; submission of new international codes to standards organisation; federated approach; and centralised data curation. Finally, we put forward recommendations for the development of guidelines for the application of GDPR in case of major public health threats; mandatory standards for data collection in funding frameworks; training and capacity building for data owners; cataloguing of international use of metadata standards; and dedicated funding for identified critical areas.

BackgroundPatients with cancer, especially haematological cancer, are at increased risk for breakthrough COVID-19 infection. However, so far, a predictive biomarker that can assess compromised vaccine-induced anti-SARS-CoV-2 immunity in cancer patients has not been proposed.MethodsHere, we employed machine learning approaches to identify a biomarker signature based on blood cytokine and growth factors linked to vaccine response from 199 cancer patients receiving BNT162b2 vaccine.ResultsWe show that C-reactive protein (CRP; general marker of inflammation), interleukin (IL)-15 (a pro-inflammatory cytokine), IL-18 (interferon-gamma inducing factor), and placental growth factor (an angiogenic cytokine) can correctly classify patients with a diminished vaccine response assessed at day 49 with >80% accuracy. Amongst these, CRP showed the highest predictive value for poor response to vaccine administration. Importantly, this unique signature of vaccine response was present at different studied timepoints both before and after vaccination and was not majorly affected by different anti-cancer treatments.ConclusionWhile we propose a blood-based signature of cytokines and growth factors that can be employed in identifying cancer patients at continued risk of COVID-19, our data also importantly suggest that such a signature could reflect the inherent make-up of some cancer patients who are also refractive to immunotherapy.

LAB-Net, the laboratory network of COMBACTE, has established itself as an indispensable network for clinical trials in infectious diseases that plays a crucial part across 30 clinical studies not only within, but also outside the COMBACTE consortium. Since its official launch in January 2013, LAB-Net has expanded more than threefold and in Q4 2020 it encompasses 841 labs across 41 countries in Europe. In addition, LAB-Net has crossed the European borders and collaborates with more than 300 laboratories spread across the globe. The tight collaboration with partners within COMBACTE and beyond contributed tremendously to the growth of LAB-Net over the years. A sustainable infrastructure beyond COMBACTE-NET is needed to ensure the smooth handover and continuity of the achievements made by the project.

Objective The aim of this study was to determine the prevalence and antibiotic resistance patterns of bacterial isolates from inpatients and outpatients in Mbale and Soroti regional referral hospitals in Eastern Uganda. Methods A retrospective analysis of culture and antibiotic sensitivity test results from the microbiology laboratories of the two tertiary hospitals was conducted for a 3-year period (January 2016–December 2018). Results Microbiology records of 3092 patients were reviewed and analysed, with 1305 (42.1%) samples yielding clinical isolates. The most prevalent isolates were Escherichia coli (n = 442; 33.9%), Staphylococcus aureus (n = 376; 28.8%), Klebsiella pneumoniae (n = 237; 18.2%), and Streptococcus pneumoniae (n = 76; 5.8%). High rates of antimicrobial resistance were detected across both Gram-negative and Gram-positive bacteria. Escherichia coli and K. pneumoniae were resistant to several agents such as amoxicillin/clavulanate (83.5%; 64.6%), cefotaxime (74.2%; 52.7%), ciprofloxacin (92.1%; 27.8%), gentamicin (51.8%; 76%), imipenem (3.2%; 10.5%), tetracycline (98%; 74.5%), and trimethoprim-sulfamethoxazole (74.1%; 74.3%), respectively. Staphylococcus aureus and S. pneumoniae exhibited the following resistance profile: cefoxitin (44.4%; 40.9%), chloramphenicol (69.1%; 27.6%) clindamycin (21.5%; 24.4%), gentamicin (83.2%; 66.9%), penicillin (46.5%; -) tetracycline (85.6%; 97.6%), trimethoprim-sulfamethoxazole (88%; 91.3%), and vancomycin (41.2%; -). Conclusion We observed high resistance rates to antibiotics among the majority of microorganisms that were isolated from the samples collected from patients in Eastern Uganda. Furthermore, measures should be undertaken locally to improve microbiology diagnostics and to prevent the spread of antibiotic-resistant strains as this impedes the optimal treatment of bacterial infections and narrows the choice of effective therapeutic options.

The use of saliva for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sparks debate due to presumed lower sensitivity and lack of standardization. Our aim was to evaluate the performance characteristics of (i) saliva collected by the ORAcollect (TM) device as a matrix for SARS-CoV-2 reverse-transcriptase polymerase chain reaction (RT-PCR), and (ii) 2 saliva rapid antigen tests (AgRDT). From 342 ambulatory individuals, both a nasopharyngeal swab and saliva sample via ORAcollect (TM) were obtained for a SARS-CoV-2 RT-PCR test. Furthermore, 54 and 123 additionally performed the V-Chek (TM) or Whistling (TM) saliva AgRDT. In total, 35% of individuals screened positive for SARS-CoV-2 via nasopharyngeal swab. Saliva, as a matrix for the RT-PCR, had a specificity of 96.5% and a negative predictive value (NPV) of 91.3%. Interestingly, 6 out of 8 patients thought to be false positive in saliva re-tested positive by nasopharyngeal sampling after 2 to 9 days. Both V-Chek (TM) and Whistling (TM) AgRDT had a lack of sensitivity, resulting in an NPV of 66.9 and 67.3%, respectively. Saliva proved to be a sensitive and specific matrix for SARS-CoV-2 detection by the RT-PCR. In this setting, saliva might have an earlier window of detection than the nasopharyngeal swab. By contrast, both AgRDT showed an unacceptably low sensitivity and NPV.

OBJECTIVEUsing data from European prospective household studies, we systematically compared the symptom burden of the wild-type and Alpha variant infected individuals versus the Omicron BA.1 and BA.2 infected individuals across paediatric and adult age-groups. In addition, we measured the impact of COVID-19 vaccination on the Omicron symptom burden.METHODSThe household transmission studies were conducted during the wild-type and Alpha period (April 2020 to April 2021) and the early Omicron BA.1 and BA.2 dominant period (January to March 2022). All three studies used similar protocols. Households were prospectively followed from detection of the first SARS-CoV-2 index case until at least day 21 including (repeated) PCR testing, paired serology and daily symptom reporting for all household members. To avoid possible index-case ascertainment bias, we restricted analyses to secondary household cases. Age-stratified SARS-CoV-2 symptom burden was compared for wild-type/Alpha versus Omicron infections and for primary versus primary plus booster series vaccinated adult cases.FINDINGSIn total 216 secondary cases from wild-type/Alpha, and 130 from the Omicron period were included. Unvaccinated children INTERPRETATIONIn children, the Omicron variant causes higher symptom burden compared to the wild-type/Alpha. Adults experienced a lower symptom burden possibly due to prior vaccination. A shift in most frequently reported symptoms occurred with a marked reduction in loss of smell or taste during the Omicron period. An additional effect of booster vaccination on symptom severity in infected adults compared to primary series only, could not be demonstrated.

Human noroviruses are a major cause of gastroenteritis outbreaks worldwide. The majority of outbreaks and sporadic cases are caused by norovirus genotype GII.4 but 48 capsid genotypes and 60 polymerase genotypes (P-types) have been described, some of which are frequently reported while others are rarely detected. Little is known about the circulation and reservoirs of the less common genotypes. In this study, we have investigated whether children could pose a possible reservoir for undetected circulation of norovirus diversity. We, therefore, tested IgG and IgA responses of sera obtained from 287 children aged While we found no evidence to suggest that rarely detected genotypes widely circulate in children, this is the first study to investigate seroprevalence against such a wide variety of human norovirus capsid and polymerase genotypes.ImportanceNorovirus is a leading cause of epidemic acute gastroenteritis, causing severe disease in children, the elderly, and immunocompromised individuals. Although norovirus is a diverse genus of viruses, the majority of reported cases are caused by viruses of the GII.4 genotype. Many of the genotypes are rarely detected and it is unknown where they circulate between outbreaks. Here we investigated the possibility of children posing a reservoir for undetected circulation. While previous serological studies have tested antibodies against a limited set of capsid genotypes, we profiled the antibody repertoire of children against the capsid and the non-structural proteins, representing the known diversity of human noroviruses. While we detected high seroprevalence in children older than one year, we found no evidence to suggest a wide circulation of rare genotypes in children in Europe.

International travel has been a major determinant for the introduction of pathogens such as methicillin-resistantHuman MRSA isolates withThe majority of isolates originated from skin and soft tissue (SST) infections and screening swabs. In 31 out of 60 cases reported international travel to different parts of the world. Fifty-four isolates belonged to CC239, including sequence type 239 (ST239) (Our data reveal multiple introductions of MRSA CC239 into Denmark through international travel, which highlights the importance of continued genomic surveillance of MRSA in persons returning from international travel to areas where MRSA is endemic.

BackgroundMethicillin-resistantStaphylococcus aureus(MRSA), a leading cause of chronic infections, forms prolific biofilms which afford an escape route from antibiotic treatment and host immunity. However, MRSA clones are genetically diverse, and mechanisms underlying biofilm formation remain under-studied. Such studies form the basis for developing targeted therapeutics. Here, we studied the temporal changes in the biofilm transcriptome of three pandemic MRSA clones: USA300, HEMRSA-15, and ST239.MethodsBiofilm formation was assessed using a static model with one representative strain per clone. Total RNA was extracted from biofilm and planktonic cultures after 24, 48, and 72 h of growth, followed by rRNA depletion and sequencing (Illumina Inc., San Diego, CA, United States, NextSeq500, v2, 1 × 75 bp). Differentially expressed gene (DEG) analysis between phenotypes and among early (24 h), intermediate (48 h), and late (72 h) stages of biofilms was performed together within silicoco-expression network construction and compared between clones. To understand the influence of SCCmecand ACME on biofilm formation, isogenic mutants containing deletions of the entire elements or of single genes therein were constructed in USA300.ResultsGenes involved in primarily core genome-encoded KEGG pathways (transporters and others) were upregulated in 24-h biofilm culture compared to 24-h planktonic culture. However, the number of affected pathways in the ST239 24 h biofilm (n= 11) was remarkably lower than that in USA300/EMRSA-15 biofilms (USA300:n= 27, HEMRSA-15:n= 58). TheclfAgene, which encodes clumping factor A, was the single common DEG identified across the three clones in 24-h biofilm culture (2.2- to 2.66-fold). In intermediate (48 h) and late (72 h) stages of biofilms, decreased expression of central metabolic and fermentative pathways (glycolysis/gluconeogenesis, fatty acid biosynthesis), indicating a shift to anaerobic conditions, was already evident in USA300 and HEMRSA-15 in 48-h biofilm cultures; ST239 showed a similar profile at 72 h. Last, SCCmec+ACME deletion andopp3Ddisruption negatively affected USA300 biofilm formation.ConclusionOur data show striking differences in gene expression during biofilm formation by three of the most important pandemic MRSA clones, USA300, HEMRSA-15, and ST239. TheclfAgene was the only significantly upregulated gene across all three strains in 24-h biofilm cultures and exemplifies an important target to disrupt early biofilms. Furthermore, our data indicate a critical role for arginine catabolism pathways in early biofilm formation.

BackgroundThe Global Point Prevalence Study (PPS) provides a platform for institutions to register and add clinical information on antimicrobial usage and determine variables related to proper antimicrobial stewardship.ObjectiveTo assess the trends in antimicrobial usage and quality indicators in antimicrobial prescriptions at our hospital.MethodWe retrospectively compared data collected at Komfo Anokye Teaching Hospital (KATH) during the Global PPS in 2015 and 2019. Both surveys took place on a day in September of the respective year. Medical records of all in-patients on admission at 0800 hours on a specific day were reviewed for antimicrobial use in the survey. Data on antibiotic use, including indications for use and the presence of quality indicators, were recorded.ResultsThe total number of patients on admission in 2015 and 2019 were 386 and 630, respectively. The proportion of patients on at least one antimicrobial was 64% (247/386) and 58.4% (368/630) in 2015 and 2019, respectively. Pneumonia was the most common medical condition for which antimicrobial was prescribed for 2015, 30(16.9%) and 2019, 44(23.0%), respectively. There was a decrease in Hospital-acquired infections from 2015, 6.2% (24/386) to 4.8% (30/630) in 2019. The use of biomarkers increased from 4.9% (12/247) to 7.6% (28/368).ConclusionOver 50% of hospitalised patients were on antimicrobials for both years. The inauguration of the antimicrobial stewardship committee at KATH will improve these quality indicators.

BackgroundSepsis severity scores are used in clinical practice and trials to define risk groups. There are limited data to derive hospital-based sepsis severity scores for neonates and young infants in high-burden low- and middle-income country (LMIC) settings where trials are urgently required. We aimed to create linked sepsis severity and recovery scores applicable to hospitalized neonates and young infants in LMIC which could be used to inform antibiotic trials.Methods & FindingsA prospective observational cohort study was conducted across 19 hospitals in 11 countries in sub-Saharan Africa, Asia, Latin America and Europe. Infants aged 3204 infants were enrolled between 2018-2020. Median age was 5 days (IQR 2-15), 90.4% (n=2,895) were A related NeoSep Recovery Score based on evolving post-baseline clinical signs and supportive care discriminated well between infants who died or survived the following day or subsequent few days. The area under the ROC curve for score on day 2 and death in the following 5 days was 0.82 (95%CI 0.78-0.85) and 0.85 (95%CI 0.78-0.93) in the derivation and validation data, respectively.ConclusionThe baseline NeoSep Severity Score predicted 28-day mortality and could identify infants with high risk of mortality for inclusion in hospital-based sepsis trials. The NeoSep Recovery Score predicts day-by-day inpatient mortality and could, with further validation, help to identify poor response to antibiotics.Author SummaryWhy was this study done?➣Evidence to guide hospital-based antibiotic treatment of sepsis in neonates and young infants is scarce, and clinical trials are particularly urgent in low- and middle-income (LMIC) settings where antimicrobial resistance threatens to undermine existing guidelines➣There is limited data to inform the design of antibiotic trials in LMIC settings, particularly to define risk stratification and inclusion and escalation criteria in hospitalised neonates and young infantsWhat did the researchers do and find?➣To our knowledge this is the first global, prospective, hospital-based observational study of clinically diagnosed neonatal sepsis across 4 continents including LMIC settings, with extensive daily data collection on clinical status, antibiotic use and outcomes.➣There was a high mortality among infants with sepsis in LMIC hospital settings. 4 non-modifiable and 6 modifiable factors predicted mortality and were included in a NeoSep Severity score which defines patterns of mortality risk at baseline➣A NeoSep Recovery Score including the same modifiable factors (with the addition of cyanosis) predicted mortality on the following day during the course of treatment.What do these findings mean?➣The NeoSep Severity Score and NeoSep Recovery score are now informing inclusion and escalation criteria in the NeoSep1 antibiotic trial (ISRCTN48721236) which aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis➣The NeoSep Severity Score could be used to predict mortality at baseline in future studies of targeting resources in routine care. With further validation, the NeoSep Recovery Score could potentially be used to identify poor response to empiric antibiotic treatment

BackgroundNeonatal sepsis is a leading cause of child mortality, and increasing antimicrobial resistance threatens progress towards the Sustainable Development Goals. Evidence to guide antibiotic treatment for sepsis in neonates and young infants from randomized controlled trials or observational studies in low- and middle-income countries (LMICs) is scarce. We aimed to describe patterns of antibiotic use, pathogens and outcomes in LMIC hospital settings globally to inform future clinical trials on the management of neonatal sepsis.Methods & FindingsHospitalised infants aged 206 different empiric antibiotic combinations were used, which were structured into 5 groups that were developed from the World Health Organisation (WHO) AWaRe classification. 25.9% (n=814) of infants started a WHO first line regimen (Group 1 -Access, penicillin-based regimen) and 13.8% (n=432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2- ‘Low’ Watch). The largest group (34.0%, n=1068) started a regimen providing partial extended-spectrum beta-lactamase (ESBL)/pseudomonal coverage (piperacillin-tazobactam, ceftazidime, or fluoroquinolone-based) (Group 3 – ‘Medium’ Watch), 18.0% (n=566) started a carbapenem (Group 4 – ‘High’ Watch), and 1.8% (n=57) started a Reserve antibiotic (Group 5, largely colistin-based). Predictors of starting non-WHO recommended regimens included lower birth weight, longer in-hospital stay, central vascular catheter use, previous culture positive sepsis or antibiotic exposure, previous surgery and greater sepsis severity. 728/2880 (25.3%) of initial regimens in Group 1-4 were escalated, mainly to carbapenems, and usually for clinical indications (n=480; 65.9%).564 infants (17.6%) isolated a pathogen from their baseline blood culture, of which 62.9% (n=355) had a Gram-negative organism, predominantlyKlebsiella pneumoniae(n=132) andAcinetobacterspp. (n=72). These leading Gram-negatives were both mostly resistant to WHO-recommended regimens, and also resistant to carbapenems in 32.6% and 71.4% of cases respectively. MRSA accounted for 61.1% ofStaphylococcus aureus(n=54) isolates.Overall, 350/3204 infants died (11.3%; 95%CI 10.2-12.5%), with 17.7% case fatality rate among infants with a pathogen in baseline culture (95%CI 14.7-20.1%, n=99/564). Gram-negative infections accounted for 75/99 (75.8%) of pathogen-positive deaths, especiallyKlebsiella pneumoniae(n=28; 28.3%), andAcinetobacterspp. (n=24; 24.2%).ConclusionA very wide range of antibiotic regimens are now used to treat neonatal sepsis globally. There is common use of higher-level Watch antibiotics, frequent early switching and very infrequent de-escalation of therapy. Future hospital based neonatal sepsis trials will ideally need to account for the multiple regimens used as standard of care globally and include both empiric first line regimens and subsequent switching in the trial design.Author SummaryWhy was this study done?➢Increasing trends in antimicrobial resistance (AMR) disproportionately affect neonates and young infants with sepsis in LMIC settings and undermine the effectiveness of WHO-recommended antibiotics.➢Despite this, longitudinal data on antibiotic management strategies and outcomes of affected hospitalised neonates and young infants in LMIC settings are extremely limited, impeding the design of robust antibiotic trials.What did the researchers do and find?➢To our knowledge this is the first global, prospective, hospital-based observational study of clinically diagnosed neonatal sepsis across 4 continents including LMIC settings, with daily data on clinical status, antibiotic use and outcomes.➢There was a high mortality among infants with culture positive sepsis (almost 1 in 5), and a significant burden of antibiotic resistance.➢This study highlights wide variations in standard of care for sepsis in neonates and young infants with more than 200 different antibiotic combinations, significant divergence from WHO-recommended regimens, and frequent switching of antibiotics.What do these findings mean?➢These data demonstrate that patterns of routine antibiotic use are now markedly divergent from global guidance➢There is an urgent need for randomised controlled trials to address optimal empiric first and second line antibiotic treatment strategies in LMIC hospital settings with a significant AMR burden.➢Data from this study can inform the design of multicentre hospital-based neonatal antibiotic trials in LMIC settings.➢The wide range of multiple antibiotic regimens routinely used as Standard of Care (SOC) suggests the need for novel trial designs.

ObjectivesTo estimate the prevalence, incidence, and longevity of antibodies against SARS-CoV-2 among primary healthcare providers (PHCPs).DesignProspective cohort study with 12 months of follow-up.SettingPrimary care in BelgiumParticipantsAny general practitioner (GP) working in primary care in Belgium and any other PHCP from the same GP practice who physically manages (examines, tests, treats) patients were eligible. A convenience sample of 3,648 eligible PHCPs from 2,001 GP practices registered for this study (3,044 and 604 to start in December 2020 and January 2021, respectively). 3,390 PHCPs (92,9%) participated in their first testing timepoint (2,820 and 565, respectively) and 2,557 PHCPs (70,1%) in the last testing timepoint (December 2021).InterventionsParticipants were asked to perform a rapid serological test (RST) targeting IgM and IgG against the receptor binding domain (RBD) of SARS-CoV-2 and to complete an online questionnaire at each of maximum 8 testing timepoints.Primary and secondary outcome measuresThe prevalence, incidence, and longevity of antibodies against SARS-CoV-2 both after natural infection and after vaccination.ResultsAmong all participants, 67% were women and 77% GPs. Median age was 43 years. The seroprevalence in December 2020 (before vaccination availability) was 15.1% (95% CI: 13.5% to 16.6%), increased to 84.2% (95% CI: 82.9% to 85.5%) in March 2021 (after vaccination availability) and reached 93.9% (95% CI: 92.9% to 94.9%) in December 2021 (during booster vaccination availability and fourth (delta variant dominant) covid wave). Among not (yet) vaccinated participants the first monthly incidence of antibodies against SARS-CoV-2 was estimated to be 2.91% (95% CI: 1.80% to 4.01%). The longevity of antibodies is higher in PHCPs with self-reported COVID-19 infection.ConclusionsThis study confirms that occupational health measures provided sufficient protection when managing patients. High uptake of vaccination resulted in high seroprevalence of SARS-CoV-2 antibodies in PHCPs in Belgium. Longevity of antibodies was supported by booster vaccination and virus circulation.RegistrationTrial registration number: NCT04779424Strengths and limitations of this studyThis large cohort study with 12 months follow-up could provide precise estimates of the prevalence and incidence of antibodies against SARS-CoV-2 among primary health care providers (PHCPs) at national and regional level in Belgium.The rapid serological test (RST) used targets IgM and IgG against the receptor binding domain of SARS-CoV-2 and could therefore also assess the antibody response after vaccination, and longevity of antibodies against SARS-CoV-2 both after natural infection and after vaccination, but cannot distinguish between both.The results in PHCPs could be compared to that of the general population and other population groups, e.g. health care workers in hospitals and nursing homes.The use of a convenience sample, missing data points and reduced RST accuracy when performed and interpreted by many different participants could limit the validity of the study results.

Background: Nigeria joined the global community in monitoring antimicrobial prescribing practices since 2015. Results of individual hospital Global Point Prevalence Survey (Global-PPS) have stimulated efforts at instituting hospital-based antimicrobial stewardship (AMS) programmes. We report the trends of antimicrobial prescribing rates and quality indicators for 3 surveillance periods; 2015, 2017 and 2018.Methodology: The web-based Global-PPS for surveillance of antimicrobial use in hospitals (www.globalpps.com) was completed by each participating hospital site for all inpatients receiving antimicrobials on a selected day in 2015, 2017 and 2018. Data included details on antimicrobial agents, reasons and indications for treatment and a set of quality prescribing indicators. Data were validated by the web-based data management system of University of Antwerp, exported into Microsoft Excel and analyzed with EPI INFO version 7.2.Results: Thirteen hospitals participated in the survey involving a total of 5,174 inpatients. Mean weighted overall antimicrobial prescribing prevalence was 70.7% which declined over the years from 71.7% in 2015 to 59.1% in 2018 (p

Background: Antimicrobial stewardship (AMS) provides a means of tackling antimicrobial resistance (AMR). Unfortunately, in Nigeria, like in some other low-and-middle-income countries (LMICs), AMS practice has been lacklustre due to poor institutional support amongst other factors. Efforts were made to address this situation by engaging with the management of National Hospital Abuja, Nigeria, using antibiotic prescription information obtained through repeated point prevalence survey.Methodology: Two rounds of antibiotic PPS were conducted in 2015 and 2017 using the Global Point Prevalence Survey (G-PPS) format. Data were collected from all inpatients receiving antibiotics on the selected day of study, including patient characteristics, antimicrobial prescription details, laboratory results and information on a set of quality indicators. The data were uploaded to an online G-PPS application hosted at the University of Antwerp in Belgium for validation, analysis and reporting.Results: The PPS data showed that hospital-wide antibiotic use prevalence increased from 58% in 2015 to 61% in 2017. Surgical prophylaxis beyond 24 hours also increased from 88-90% in 2015 to 100% in 2017, and only minority of therapies were supported by laboratory input for diagnosis and monitoring; 22% in 2015 and 5% in 2017.Conclusion: These results were used for evidence-based engagement with the management to formally support AMS activities in the hospital. Positive outcomes were the formal reconstitution and inauguration of AMS committee in 2018 as well as the issuance of a formal policy statement by the hospital in 2020. The ease and free availability of Global PPS methodology makes it ideal in driving antimicrobial stewardship programme (ASP) in LMICs like Nigeria. Keywords: Antibiotic stewardship checklist, institutional support, point French Title: Utilisation d'une enquête longitudinale sur la prévalence ponctuelle des antibiotiques (PPS) pour conduire des programmes de gestion des antimicrobiens dans un hôpital tertiaire nigérian Contexte: La gestion des antimicrobiens (AMS) offre un moyen de lutter contre la résistance aux antimicrobiens (RAM). Malheureusement, au Nigéria, comme dans certains autres pays à revenu faible ou intermédiaire (PRFI), la pratique de la MGS a été médiocre en raison d'un soutien institutionnel insuffisant, entre autres facteurs. Des Longitudinal PPS for AMS programmes efforts ont été faits pour remédier à cette situation en collaborant avec la direction de l'hôpital national d'Abuja, au Nigéria, en utilisant les informations sur les prescriptions d'antibiotiques obtenues grâce à une enquête ponctuelle répétée de prévalence.Méthodologie: Deux séries d'antibiotiques PPS ont été menées en 2015 et 2017 en utilisant le format Global Point Prevalence Survey (G-PPS). Des données ont été recueillies auprès de tous les patients hospitalisés recevant des antibiotiques le jour sélectionné de l'étude, y compris les caractéristiques des patients, les détails de la prescription d'antimicrobiens, les résultats de laboratoire et les informations sur un ensemble d'indicateurs de qualité. Les données ont été téléchargées sur une application en ligne G-PPS hébergée à l'Université d'Anvers en Belgique à des fins de validation, d'analyse et rapports.Résultats: Les données PPS ont montré que la prévalence de l'utilisation d'antibiotiques à l'échelle de l'hôpital est passée de 58% en 2015 à 61% en 2017. La prophylaxie chirurgicale au-delà de 24 heures est également passée de 88 à 90% en 2015 à 100% en 2017, et seule une minorité de thérapies a été soutenue par entrée de laboratoire pour le diagnostic et la surveillance; 22% en 2015 et 5% en 2017.Conclusion: Ces résultats ont été utilisés pour un engagement fondé sur des données probantes avec la direction afin de soutenir officiellement les activités AMS à l'hôpital. Les résultats positifs ont été la reconstitution formelle et l'inauguration du comité AMS en 2018 ainsi que la publication d'une déclaration de politique formelle par l'hôpital en 2020. La facilité et la disponibilité gratuite de la méthodologie Global PPS la rend idéale pour conduire le programme de gestion des antimicrobiens (ASP) en PRFI comme le Nigéria. Mots clés: liste de contrôle pour la gestion des antibiotiques, soutien institutionnel, enquête ponctuelle de prévalence, déclaration de politique prevalence survey, policy statement

ObjectivesTo validate a rapid serological test (RST) for SARS-CoV-2 antibodies used in seroprevalence studies in healthcare providers, including primary healthcare providers (PHCPs) in Belgium.DesignA phase III validation study of the RST (OrientGene) within a prospective cohort study.SettingPrimary care in Belgium.ParticipantsAny general practitioner (GP) working in primary care in Belgium and any other PHCP from the same GP practice who physically manages patients were eligible in the seroprevalence study. For the validation study, all participants who tested positive (376) on the RST at the first testing timepoint (T1) and a random sample of those who tested negative (790) and unclear (24) were included.InterventionAt T2, 4 weeks later, PHCPs performed the RST with fingerprick blood (index test) immediately after providing a serum sample to be analysed for the presence of SARS-CoV-2 immunoglobulin G antibodies using a two-out-of-three assay (reference test).Primary and secondary outcome measuresThe RST accuracy was estimated using inverse probability weighting to correct for missing reference test data, and considering unclear RST results as negative for the sensitivity and positive for the specificity. Using these conservative estimates, the true seroprevalence was estimated both for T2 and RST-based prevalence values found in a cohort study with PHCPs in Belgium.Results1073 paired tests (403 positive on the reference test) were included. A sensitivity of 73% (a specificity of 92%) was found considering unclear RST results as negative (positive). For an RST-based prevalence at T1 (13.9), T2 (24.9) and T7 (70.21), the true prevalence was estimated to be 9.1%, 25.9% and 95.7%, respectively.ConclusionThe RST sensitivity (73%) and specificity (92%) make an RST-based seroprevalence below (above) 23% overestimate (underestimate) the true seroprevalence.Trial registration numberNCT04779424.

Objectives: This study determined associations between respiratory viruses and subsequent illness course in primary care adult patients presenting with acute cough and/or suspected lower respiratory tract infection. Methods: A prospective European primary care study recruited adults with symptoms of lower respiratory tract infection between November 2007 and April 2010. Real-time in-house polymerase chain reaction (PCR) was performed to test for six common respiratory viruses. In this secondary analysis, symptom severity (scored 1 = no problem, 2 = mild, 3 = moderate, 4 = severe) and symptom duration were compared between groups with different viral aetiologies using regression and Cox proportional hazard models, respectively. Additionally, associations between baseline viral load (cycle threshold (Ct) value) and illness course were assessed. Results: The PCR tested positive for a common respiratory virus in 1354 of the 2957 (45.8%) included patients. The overall mean symptom score at presentation was 2.09 (95% confidence interval (CI) 2.07-2.11) and the median duration until resolution of moderately bad or severe symptoms was 8.70 days (interquartile range 4.50-11.00). Patients with influenza virus, human metapneumovirus (hMPV), respiratory syncytial virus (RSV), coronavirus (CoV) or rhinovirus had a significantly higher symptom score than patients with no virus isolated (0.07-0.25 points or 2.3-8.3% higher symptom score). Time to symptom resolution was longer in RSV infections (adjusted hazard ratio (AHR) 0.80, 95% CI 0.65-0.96) and hMPV infections (AHR 0.77, 95% CI 0.62-0.94) than in infections with no virus isolated. Overall, baseline viral load was associated with symptom severity (difference 0.11, 95% CI 0.06-0.16 per 10 cycles decrease in Ct value), but not with symptom duration. Conclusions: In healthy, working adults from the general community presenting at the general practitioner with acute cough and/or suspected lower respiratory tract infection other than influenza impose an illness burden comparable to influenza. Hence, the public health focus for viral respiratory tract infections should be broadened. (C) 2020 Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.

Purpose To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19). Methods Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable. Results We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (– 1 to 15), 0 (– 1 to 9) and—1 (– 1 to 7), respectively, compared to 6 (– 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively). Conclusion Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06448-5.

Background The outpatient setting is a key scenario for the implementation of antimicrobial stewardship (AMS) activities, considering that overconsumption of antibiotics occurs mainly outside hospitals. This publication is the result of a joint initiative by the JPIAMR ARCH and COMBACTE-MAGNET EPI-Net networks, which is aimed at formulating a set of target actions for linking surveillance data with AMS activities in the outpatient setting. Methods A scoping review of the literature was carried out in three research areas: AMS leadership and accountability; antimicrobial usage and AMS; antimicrobial resistance and AMS. Consensus on the actions was reached through a RAND-modified Delphi process involving over 40 experts in infectious diseases, clinical microbiology, AMS, veterinary medicine or public health, from 18 low-, middle- and high-income countries. Results Evidence was retrieved from 38 documents, and an initial 25 target actions were proposed, differentiating between essential or desirable targets according to clinical relevance, feasibility and applicability to settings and resources. In the first consultation round, preliminary agreement was reached for all targets. Further to a second review, 6 statements were re-considered and 3 were deleted, leading to a final list of 22 target actions in the form of a practical checklist. Conclusions This White Paper is a pragmatic and flexible tool to guide the development of calibrated surveillance-based AMS interventions specific to the outpatient setting, which is characterized by substantial inter- and intra-country variability in the organization of healthcare structures, maintaining a global perspective and taking into account the feasibility of the target actions in low-resource settings.

Presence of SARS-CoV-2 was monitored in nasopharyngeal samples from young children aged 6-30 months attending day-care centres (DCCs) in Belgium from May 2020-February 2022. SARS-CoV-2 carriage among DCC children was only detected from November 2021, after emergence of Delta and Omicron variants, in 9 of the 42 DCCs screened. In only one DCC, two children tested positive for SARS-CoV-2 at the same sampling time point, suggesting limited transmission of SARS-CoV-2 in Belgian DCCs among young children during the studied period. ispartof: EUROSURVEILLANCE vol:27 issue:21 ispartof: location:Sweden status: published

Human coronavirus HKU1 (HCoV-HKU1) is one of the four endemic coronaviruses. It has been suggested that there is a difference in incidence, with PCR-confirmed HCoV-NL63 and HCoV-OC43 infections occurring more commonly, whereas HCoV-HKU1 is the least seen. Lower incidence of HCoV-HKU1 infection has also been observed in serological studies. The current study aimed to investigate antibody dynamics during PCR-confirmed HCoV-HKU1 infections using serum collected during infection and 1 month later. We expressed a new HCoV-HKU1 antigen consisting of both the linker and carboxy-terminal domain of the viral nucleocapsid protein and implemented it in ELISA. We also applied a spike-based Luminex assay on serum samples from PCR-confirmed infections by the four endemic HCoVs. At least half of HCoV-HKU1-infected subjects consistently showed no antibody rise via either assay, and some subjects even exhibited substantial antibody decline. Investigation of self-reported symptoms revealed that HCoV-HKU1-infected subjects rated their illness milder than subjects infected by other HCoVs. In conclusion, HCoV-HKU1 infections reported in this study displayed atypical antibody dynamics and milder symptoms when compared to the other endemic HCoVs.

Staphylococcusaureus bacteremia (SAB) is a relevant finding which prompts a thorough diagnostic work-up. Follow-up blood cultures (BC) are essential in this work-up. We investigate the probability of detecting an ongoing bacteremia after initiation of active therapy according to the number of BC taken at key time points. A retrospective analysis of all patients with SAB in a 6-year period was performed. Total number of BCs taken and the positivity was registered for each day after start of therapy. A positivity-rate was corrected using a logistic mixed effects model. Observed detection frequencies were applied to calculate detection probabilities using binomial distributions. Three hundred and seventeen cases were withheld for analysis. A BC bottle positivity rate of 66.7% was found 1 day after initiation of active therapy, which decreased to 48.5% on day 4. When using 1 set of FU-BC, 73.4% of persisting SABs are detected. To maintain a probability of detection of >= 90%, 2 BC sets should be taken on day 2 and day 4 after start of therapy. In 10 of 109 patients with positive FU-BC, skip phenomena were registered, with a significant higher proportion in patients with < 4 BC bottles taken (14%) than when >= 4 BC bottles were taken (4.1%). We recommend taking 2 BC sets on days 2 and 4 after start of therapy in order to detect >= 90% of persisting SABs, limiting skip phenomena and blood volume required. We strongly advice against taking a single BC set as follow-up for SAB.

Objectives Development and implementation of SARS-CoV-2 serologic assays gained momentum. Laboratories keep on investigating the performance of these assays. In this study, we compared three fully automated SARS-CoV-2 antibody assays. Methods A total of 186 samples from 84 PCR-positive COVID-19 patients and 120 control samples taken before the SARS-CoV-2 pandemic were analyzed using commercial serologic assays from Roche, Siemens and DiaSorin. Time after the positive COVID-19 PCR result and onset of symptoms was retrieved from the medical record. An extended golden standard, using the result of all three assays was defined, judging if antibodies are present or absent in a sample. Diagnostic and screening sensitivity/specificity and positive/negative predictive value were calculated. Results Diagnostic sensitivity (ability to detect a COVID-19 positive patient) ≥14 days after positive PCR testing was 96.7% (95% CI 88.5–99.6%) for DiaSorin, 93.3% (95% CI 83.8–98.2%) for Roche and 100% (95% CI 94.0–100%) for Siemens. Lower diagnostic sensitivities were observed Conclusions This study revealed acceptable performance for all three assays. An orthogonal testing algorithm using the Siemens and Roche assay achieved the highest positive predictive values for antibody detection in low seroprevalence settings.

Cellular models of induced pluripotent stem cell (iPSC)-derived microglia and macrophages are an emerging toolbox to investigate neuroinflammation in vitro. We previously demonstrated that murine iPSC-microglia and iPSC-macrophages display phenotypical activation properties highly comparable to microglia and macrophages in vivo.Here we extended the characterization of iPSC-microglia and iPSC-macrophages with the analysis of their transcriptome profile. Next, these cellular models were employed to evaluate neuroimmune toxicity in vitro and to investigate the immune-modulatory properties of interleukin 13 (IL13), a cytokine known for its ability to protect against neuroinflammation-induced pathology by modulating microglia and macrophage activation. iPSC-microglia and iPSC-macrophages, in co-culture with astrocyte-committed neural stem cells (NSC), were (pre)treated with IL13 and stimulated with lipopolysaccharide (LPS) and interferon gamma (IFN gamma), to assess how IL13 modulates their inflammatory response. Additionally, the use of luciferase-expressing NSC (Luc-NSC) allowed real-time monitoring of immune-mediated neurotoxicity. Despite the known anti-inflammatory properties of IL13, iPSC-microglia primed with IL13 before LPS + IFN gamma stimulation significantly increased NO secretion. This was associated with a marked reduction of the luminescence signal produced by Luc-NSC. Interestingly, we observed that IL13 signaling has a divergent functional outcome in microglia as compared to macrophages, as for the latter no major alterations in NO release and Luc-NSC viability were observed upon IL13 (pre)treatment. Finally, the striking IL13-induced upregulation of NO secretion by microglia under pro-inflammatory conditions was confirmed in vivo, where intracerebral delivery of IL13 increased inducible nitric oxide synthase mRNA expression. Concluding, we applied iPSC-derived neuroimmune cell culture models to identify distinct neuroimmune (toxicity) responses of microglia and macrophages to IL13-based immune modulation.

Laboratory preparedness with quality-assured diagnostic assays is essential for controlling the current coronavirus disease (COVID-19) outbreak. We conducted an external quality assessment study with inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) samples to support clinical laboratories with a proficiency testing option for molecular assays. To analyse SARS-CoV-2 testing performance, we used an online questionnaire developed for the European Union project RECOVER to assess molecular testing capacities in clinical diagnostic laboratories.

There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia. The trial uses a novel design, entitled “a randomized embedded multifactorial adaptive platform.” The design has five key features: 1) randomization, allowing robust causal inference; 2) embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, and generalizability; 3) a multifactorial statistical model comparing multiple interventions across multiple patient subgroups; 4) response-adaptive randomization with preferential assignment to those interventions that appear most favorable; and 5) a platform structured to permit continuous, potentially perpetual enrollment beyond the evaluation of the initial treatments. The trial randomizes patients to multiple interventions within four treatment domains: antibiotics, antiviral therapy for influenza, host immunomodulation with extended macrolide therapy, and alternative corticosteroid regimens, representing 240 treatment regimens. The trial generates estimates of superiority, inferiority, and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection. The trial will also compare ventilatory and oxygenation strategies, and has capacity to address additional questions rapidly during pandemic respiratory infections. As of January 2020, REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) was approved and enrolling patients in 52 intensive care units in 13 countries on 3 continents. In February, it transitioned into pandemic mode with several design adaptations for coronavirus disease 2019. Lessons learned from the design and conduct of this trial should aid in dissemination of similar platform initiatives in other disease areas. Clinical trial registered with www.clinicaltrials.gov (NCT02735707).

Background Patient-level surveillance (indication, appropriate choice, dosing, route, duration) of antimicrobial use in Canadian hospitals is needed to reduce antimicrobial overuse and misuse. Patient-level surveillance has not been performed on a national level in Canada. The Global Point Prevalence Survey of Antimicrobial Consumption and Resistance (Global-PPS) is an international collaborative to monitor antimicrobial use and resistance in hospitals worldwide. Global-PPS locally documents on a single day patient-level antimicrobial prescribing practices. This article presents the results of the 2017 Global-PPS in Canadian hospitals with established antimicrobial stewardship programs. Methods Hospitals part of the Canadian Nosocomial Infection Surveillance Program were invited to participate. Surveys could be performed any time in the 2017 calendar year. All in-patient wards in each hospital were surveyed by a physician, pharmacist or nurse with infectious disease training. Results Fourteen Canadian hospitals participated in the survey. Of 4118 patients, 1400 patients (34.0%) received a total of 2041 antimicrobials. Overall, 73.1% (n = 1493) of antimicrobials were for therapeutic use, 14.2% (n = 288) were for medical prophylaxis, 8.3% (n = 170) were for surgical prophylaxis, 1.8% (n = 37) were for other reasons, and 0.2% (n = 3) were used as prokinetic agents. Only 2.5% (n = 50) were for unknown reasons. For antimicrobials for therapeutic use, 29.9% of patients were treated for lower respiratory tract (343/1147), 10.5% for intra-abdominal (120/1147), 9.3% for skin and soft tissue (107/1147) and 7.5% for gastro-intestinal (86/1147) infections. Conclusions Standardized methodology amongst Global-PPSs allows the comparison of our results to the 2015 Global-PPS. The prevalence of antimicrobial use on medical, surgical, and intensive care wards are similar to those previously observed in North America. Indication of antimicrobials has not been previously reported on such a large scale in Canadian hospitals. This report serves as a comparison for further point prevalence surveys that are currently underway. It will be used for identifying opportunities and benchmarking in antibiotic stewardship.

Methicillin-resistantBiofilm formation was assessed using a static model with one representative strain per clone. Total RNA was extracted from biofilm and planktonic cultures after 24, 48, and 72 h of growth, followed by rRNA depletion and sequencing (Illumina Inc., San Diego, CA, United States, NextSeq500, v2, 1 × 75 bp). Differentially expressed gene (DEG) analysis between phenotypes and among early (24 h), intermediate (48 h), and late (72 h) stages of biofilms was performed together withGenes involved in primarily core genome-encoded KEGG pathways (transporters and others) were upregulated in 24-h biofilm culture compared to 24-h planktonic culture. However, the number of affected pathways in the ST239 24 h biofilm (Our data show striking differences in gene expression during biofilm formation by three of the most important pandemic MRSA clones, USA300, HEMRSA-15, and ST239. The

Objectives To determine the susceptibility profiles and the resistome of Pseudomonas aeruginosa isolates from European ICUs during a prospective cohort study (ASPIRE-ICU). Methods 723 isolates from respiratory samples or perianal swabs of 402 patients from 29 sites in 11 countries were studied. MICs of 12 antibiotics were determined by broth microdilution. Horizontally acquired β-lactamases were analysed through phenotypic and genetic assays. The first respiratory isolates from 105 patients providing such samples were analysed through WGS, including the analysis of the resistome and a previously defined genotypic resistance score. Spontaneous mutant frequencies and the genetic basis of hypermutation were assessed. Results All agents except colistin showed resistance rates above 20%, including ceftolozane/tazobactam and ceftazidime/avibactam. 24.9% of the isolates were XDR, with a wide intercountry variation (0%–62.5%). 13.2% of the isolates were classified as DTR (difficult-to-treat resistance). 21.4% of the isolates produced ESBLs (mostly PER-1) or carbapenemases (mostly NDM-1, VIM-1/2 and GES-5). WGS showed that these determinants were linked to high-risk clones (particularly ST235 and ST654). WGS revealed a wide repertoire of mutation-driven resistance mechanisms, with multiple lineage-specific mutations. The most frequently mutated genes were gyrA, parC, oprD, mexZ, nalD and parS, but only two of the isolates were hypermutable. Finally, a good accuracy of the genotypic score to predict susceptibility (91%–100%) and resistance (94%–100%) was documented. Conclusions An overall high prevalence of resistance is documented European ICUs, but with a wide intercountry variability determined by the dissemination of XDR high-risk clones, arguing for the need to reinforce infection control measures.

Household transmission studies are useful to quantify SARS-CoV-2 transmission dynamics. We conducted a remote prospective household study to quantify transmission, and the effects of subject characteristics, household characteristics, and implemented infection control measures on transmission. Households with a laboratory-confirmed SARS-CoV-2 index case were enrolled 85% completed sample collection. 200 secondary SARS-CoV-2 infections were detected, yielding a household SAR of 45.7% (95% CI 39.7–51.7%) and per-person SAR of 32.6% (95%CI: 28.1-37.4%). 126 (63%) secondary cases were detected at enrollment. Mild (aRR = 0.57) and asymptomatic index cases (aRR = 0.29) were less likely to transmit SARS-CoV-2, compared to index cases with an acute respiratory illness (p = 0.03 for trend), and child index cases (p = 0.03 for trend). Infection control interventions in households had no significant effect on transmission. We found high SARs with the majority of transmissions occuring early after SARS-CoV-2 introduction into the household. This may explain the futile effect of implemented household measures. Age and symptom status of the index case influence secondary transmission. Remote, digitally-supported study designs with self-sampling are feasible for studying transmission under pandemic restrictions.

The COVID-19 vaccine rollout in recent months offers a powerful preventive measure that may help control SARS-CoV-2 transmission. Nevertheless, long-standing public hesitation around vaccines has heightened public health concerns that vaccine coverage may not achieve desired public health impacts.This cross-sectional survey was conducted online in December 2020 among 7000 respondents (aged 18 to 65) in Belgium, France, Germany, Italy, Spain, Sweden, and Ukraine. The survey included open text boxes for fuller explanation of responses. Projected COVID-19 vaccine coverage varied and may not be sufficiently high among certain populations to achieve herd immunity. Overall, 56.9% would accept a COVID-19 vaccine, 19.0% would not, and 24.1% did not know or preferred not to say. By country, between 44% (France) and 66% (Italy) of respondents would accept a COVID-19 vaccine. Respondents expressed conditionality in open responses, voicing concerns about vaccine safety and mistrust of authorities. Public health campaigns must tackle these safety concerns.HighlightsMixed-method survey studied expected COVID vaccine uptake in 7 European countries.Projected COVID vaccine acceptance by country ranged from 44% to 66%.Explicit COVID vaccine acceptance or rejection was conditional.Study finds concerns about vaccine safety and authorities’ competence and honesty.Vaccine communications should address safety anxieties and target specific groups.