Determinants of between-country differences in ambulatory antibiotic use and antibiotic resistance in Europe: a longitudinal observational study.

OBJECTIVES: To identify key determinants explaining country-year variations in antibiotic use and resistance. METHODS: Ambulatory antibiotic use data [in defined daily doses per 1000 inhabitants per day (DIDs)] for 19 European countries from 1999 to 2007 were collected, along with 181 variables describing countries in terms of their agriculture, culture, demography, disease burden, education, healthcare organization and socioeconomics. After assessing data availability, overlap and relevance, multiple imputation generalized estimating equations were applied with a stepwise selection procedure to select significant determinants of global antibiotic use (expressed in DIDs), relative use of subgroups (amoxicillin and co-amoxiclav) and resistance of Escherichia coli and Streptococcus pneumoniae. RESULTS: Relative humidity, healthcare expenditure proportional to gross domestic product, feelings of distrust, proportion of population aged >65 years and availability of treatment guidelines were associated with higher total antibiotic use expressed in DIDs. Restrictions on marketing activities towards prescribers, population density, number of antibiotics, educational attainment and degree of atheism were associated with a lower number of total DIDs used. Relative prescribing of amoxicillin and co-amoxiclav was mainly determined by healthcare system choices [e.g. general practitioner (GP) registration and restricted marketing]. Specific antibiotic use was found to be a significant determinant of resistance for some but not all drug/organism combinations. Incentives to stimulate GP gatekeeping were associated with lower levels of resistance, and life expectancy at age 65+ and atheism were associated with more resistance. CONCLUSIONS: Myriad factors influence antibiotic use and resistance at the country level and an important part of these can be modified by policy choices.

Long-term effects of ciprofloxacin treatment on the gastrointestinal and oropharyngeal microbiome are more pronounced after longer antibiotic courses.

BACKGROUND: Urinary tract infections (UTIs) are one of the main reasons for antibiotic prescriptions in primary care. Recent studies demonstrate similar clinical outcomes with shorter antibiotics courses. Here, we investigated the differential collateral effect of ciprofloxacin treatment duration on the gastrointestinal and oropharyngeal microbiome in patients presenting with uncomplicated UTI to primary care practices in Switzerland, Belgium and Poland. METHODS: Stool and oropharyngeal samples were obtained from 36 treated patients and 14 controls at the beginning of antibiotic therapy, end of therapy and one month after end of therapy. Samples underwent shotgun metagenomics. RESULTS: At the end of therapy, patients treated with both shorter (≤7 days) and longer (>7 days) ciprofloxacin courses showed similar changes in the gastrointestinal microbiome compared to non-treated controls. After one month, most changes in patients receiving shorter courses were reversed; however, longer courses led to increased abundance of the genera Roseburia, Faecalicatena and Escherichia. Changes in the oropharynx were minor and reversed to baseline levels within one month. Ciprofloxacin resistance encoding mutations in gyrA/B and parC/E reads were observed in both treatment groups, which decreased to baseline levels after one month. An increased abundance of resistance genes was observed in the gastrointestinal microbiome after longer treatment, and correlated to increased prevalence of aminoglycoside, beta-lactam, sulphonamide, and tetracycline resistance genes. CONCLUSION: Collateral effects on the gastrointestinal community, including an increased prevalence of antimicrobial resistance genes, persists at least up to one month following longer ciprofloxacin therapy. Our data, therefore, support the use of shorter treatment duration.

Predicting benign course and prolonged illness in lower respiratory tract infections: a 13 European country study.

BACKGROUND: Clinicians and patients are often uncertain about the likely clinical course of community-acquired lower respiratory tract infection (LRTI) in individual patients. We therefore set out to develop a prediction rule to identify patients at risk of prolonged illness and those with a benign course. METHODS: We determined which signs and symptoms predicted prolonged illness (moderately bad symptoms lasting >3 weeks after consultation) in 2690 adults presenting in primary care with LRTI in 13 European countries by using multilevel modelling. RESULTS: 212 (8.1%) patients experienced prolonged illness. Illness that had lasted >5 days at the time of presentation, >1 episode of cough in the preceding year, chronic use of inhaled pulmonary medication and diarrhoea independently predicted prolonged illness. Applying a rule based on these four variables, 3% of the patients with ≤ 1 variable present (n = 955, 37%) had prolonged illness. Patients with all four variables present had a 30% chance of prolonged illness (n = 71, 3%). CONCLUSIONS: Most patients with acute cough (>90%) recover within 3 weeks. A prediction rule containing four clinical items had predictive value for the risk of prolonged illness, but given its imprecision, appeared to have little clinical utility. Patients should be reassured that they are most likely to recover within three weeks and advised to re-consult if their symptoms persist beyond that period.

Antibiotic prescribing for adults with acute cough/lower respiratory tract infection: congruence with guidelines.

European guidelines for treating acute cough/lower respiratory tract infection (LRTI) aim to reduce nonevidence-based variation in prescribing, and better target and increase the use of first-line antibiotics. However, their application in primary care is unknown. We explored congruence of both antibiotic prescribing and antibiotic choice with European Respiratory Society (ERS)/European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines for managing LRTI. The present study was an analysis of prospective observational data from patients presenting to primary care with acute cough/LRTI. Clinicians recorded symptoms on presentation, and their examination and management. Patients were followed up with self-complete diaries. 1,776 (52.7%) patients were prescribed antibiotics. Given patients' clinical presentation, clinicians could have justified an antibiotic prescription for 1,915 (71.2%) patients according to the ERS/ESCMID guidelines. 761 (42.8%) of those who were prescribed antibiotics received a first-choice antibiotic (i.e. tetracycline or amoxicillin). Ciprofloxacin was prescribed for 37 (2.1%) and cephalosporins for 117 (6.6%). A lack of specificity in definitions in the ERS/ESCMID guidelines could have enabled clinicians to justify a higher rate of antibiotic prescription. More studies are needed to produce specific clinical definitions and indications for treatment. First-choice antibiotics were prescribed to the minority of patients who received an antibiotic prescription.

Antibiotic prescribing for discoloured sputum in acute cough/lower respiratory tract infection.

We investigated whether discoloured sputum and feeling unwell were associated with antibiotic prescription and benefit from antibiotic treatment for acute cough/lower respiratory tract infection (LTRI) in a prospective study of 3,402 adults in 13 countries. A two-level model investigated the association between producing discoloured sputum or feeling generally unwell and an antibiotic prescription. A three-level model investigated the association between an antibiotic prescription and symptom resolution. Patients producing discoloured sputum were prescribed antibiotics more frequently than those not producing sputum (OR 3.2, 95% CI 2.1-5.0), unlike those producing clear/white sputum (OR 0.95, 95% CI 0.61-1.48). Antibiotic prescription was not associated with a greater rate or magnitude of symptom score resolution (as measured by a 13-item questionnaire completed by patients each day) among those who: produced yellow (coefficient 0.00; p = 0.68) or green (coefficient -0.01; p = 0.11) sputum; reported any of three categories of feeling unwell; or produced discoloured sputum and felt generally unwell (coefficient -0.01; p = 0.19). Adults with acute cough/LRTI presenting in primary care settings with discoloured sputum were prescribed antibiotics more often compared to those not producing sputum. Sputum colour, alone or together with feeling generally unwell, was not associated with recovery or benefit from antibiotic treatment.

Antibiotic use and resistance in Belgium: the impact of two decades of multi-faceted campaigning.

Objective: To present an overview of almost two decades of multi-faceted campaigning by the Belgian Antibiotic Policy Coordination Committee (BAPCOC) and partners, and its impact on public and prescribers' awareness, outpatient antibiotic use, its cost and antimicrobial resistance in Belgium.Methods: Awareness of both public and prescribers was assessed through pre- and post-campaign interviews and surveys. Outpatient antibiotic use was evaluated using national reimbursement data expressed in number of defined daily doses and packages (a good proxy for treatments) per 1000 inhabitants per day (DID and PID, respectively) from July 1997 to June 2018. Its cost was studied using the same data expressed in number of euros per 1000 inhabitants per day. Antimicrobial resistance was evaluated between 1986 and 2017 using national data on the proportion of Streptococcus pneumoniae isolates not susceptible to penicillins, macrolides and tetracyclines.Results: Antibiotic awareness improved significantly, with general practitioners preferred by 87.5% of respondents as source of information. The Belgian outpatient antibiotic use has decreased by 12.8% in DID and by 42.8% in PID in the 2017-2018 winter compared to the winter before the start of its public awareness campaigns (1999-2000). This evolution coincided with decreasing costs for antibiotics and decreasing antimicrobial resistance. Despite multi-faceted campaigning, outpatient antibiotic use and use of broad-spectrum antibiotics, especially fluoroquinolones and amoxicillin with clavulanic acid, are still high in Belgium.Conclusion: Almost two decades of multi-faceted campaigning coincide with improvements in antibiotic awareness among the public and prescribers, outpatient antibiotic use and resistance. Nevertheless, additional efforts are needed to reach the targets set in BAPCOC's national action plan 2014-2019. Therefore, a new national action plan was developed for 2020-2024 using a One Health approach.

Quality of care in an inflammatory bowel disease clinical trial center : a prospective study evaluating patients' satisfaction.

BACKGROUND AND STUDY AIMS: Quality of care is a very timely topic in medicine. We designed a questionnaire to measure perceived quality of care and to explore areas of improvement. PATIENTS AND METHODS: In this prospective study a questionnaire was developed and administered to all patients with inflammatory bowel disease participating in a randomized clinical trial. The questionnaire was based on validated surveys and supplemented with novel, relevant questions. Factors associated with (poor) quality of care were identified. RESULTS: Between October 2016 and January 2017, all 107 patients participating in a randomized controlled trial completed the questionnaire (63% male, 76% ulcerative colitis, median age of 47 years). The median satisfaction score was 9 out of 10. Areas of improvement were that too little attention was paid to the disease impact on family and work, dietary and exercise pattern, daily activities and quality of life. Multivariate analysis showed that clinical remission [5.77 (2.03-16.39), p=0.001] was a predictor of good quality of care. CONCLUSIONS: In this large IBD trial bureau, inflammatory bowel disease patients were very satisfied with the quality of care. Domains for quality improvement, such as attention to the impact of IBD on family and work, were identified.

Prevention of hepatic encephalopathy by administration of rifaximin and lactulose in patients with liver cirrhosis undergoing placement of a transjugular intrahepatic portosystemic shunt (TIPS): a multicentre randomised, double blind, placebo controlled trial (PEARL trial).

INTRODUCTION: Cirrhotic patients with portal hypertension can suffer from variceal bleeding or refractory ascites and can benefit from a transjugular intrahepatic portosystemic shunt (TIPS). Post-TIPS hepatic encephalopathy (HE) is a common (20%-54%) and often severe complication. A prophylactic strategy is lacking. METHODS AND ANALYSIS: The Prevention of hepatic Encephalopathy by Administration of Rifaximin and Lactulose in patients with liver cirrhosis undergoing placement of a TIPS (PEARL) trial, is a multicentre randomised, double blind, placebo controlled trial. Patients undergoing covered TIPS placement are prescribed either rifaximin 550 mg two times per day and lactulose 25 mL two times per day (starting dose) or placebo 550 mg two times per day and lactulose 25 mL two times per day from 72 hours before and until 3 months after TIPS placement. Primary endpoint is the development of overt HE (OHE) within 3 months (according to West Haven criteria). Secondary endpoints include 90-day mortality; development of a second episode of OHE; time to development of episode(s) of OHE; development of minimal HE; molecular changes in peripheral and portal blood samples; quality of life and cost-effectiveness. The total sample size is 238 patients and recruitment period is 3 years in six hospitals in the Netherlands and one in Belgium. ETHICS AND DISSEMINATION: This study protocol was approved in the Netherlands by the Medical Research Ethics Committee of the Academic Medical Centre, Amsterdam (2018-332), in Belgium by the Ethics Committee Research UZ/KU Leuven (S62577) and competent authorities. This study will be conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. Study results will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov (NCT04073290) and EudraCT database (2018-004323-37).

Transcriptional and epigenetic profiling of nutrient-deprived cells to identify novel regulators of autophagy.

Macroautophagy (hereafter autophagy) is a lysosomal degradation pathway critical for maintaining cellular homeostasis and viability, and is predominantly regarded as a rapid and dynamic cytoplasmic process. To increase our understanding of the transcriptional and epigenetic events associated with autophagy, we performed extensive genome-wide transcriptomic and epigenomic profiling after nutrient deprivation in human autophagy-proficient and autophagy-deficient cells. We observed that nutrient deprivation leads to the transcriptional induction of numerous autophagy-associated genes. These transcriptional changes are reflected at the epigenetic level (H3K4me3, H3K27ac, and H3K56ac) and are independent of autophagic flux. As a proof of principle that this resource can be used to identify novel autophagy regulators, we followed up on one identified target: EGR1 (early growth response 1), which indeed appears to be a central transcriptional regulator of autophagy by affecting autophagy-associated gene expression and autophagic flux. Taken together, these data stress the relevance of transcriptional and epigenetic regulation of autophagy and can be used as a resource to identify (novel) factors involved in autophagy regulation.

Achievements of the Belgian Antibiotic Policy Coordination Committee (BAPCOC).

A Belgian Antibiotic Policy Coordination Committee (BAPCOC) was officially established in 1999 by Royal Decree. The overall objective of BAPCOC is to promote judicious use of antibiotics in humans and animals and to promote infection control and hospital hygiene, with the overall aim to reduce antibiotic resistance. BAPCOC fostered strong and interdisciplinary public health, scientific and political leadership, which led to many evidence-based interventions such as multimedia campaigns to promote the prudent use of antibiotics in the community, national campaigns to promote hand hygiene in hospitals, publication of clinical practice guidelines, staffing and technical support for establishment of antibiotic management teams in all Belgian hospitals, surveillance programmes on antibiotic use and resistance in humans and animals and the promotion of research. These activities and interventions resulted in a measurable decrease in antibiotic use and resistance in the community and hospitals.

Amoxicillin for acute lower respiratory tract infection in primary care: subgroup analysis by bacterial and viral aetiology.

OBJECTIVE: We aimed to assess the effects of amoxicillin treatment in adult patients presenting to primary care with a lower respiratory tract infection (LRTI) who were infected with a potential bacterial, viral, or mixed bacterial/viral infection. METHODS: This multicentre randomized controlled trial focused on adults with LRTI not suspected for pneumonia. Patients were randomized to receive either antibiotic (amoxicillin 1 g) or placebo three times daily for 7 consecutive days using computer-generated random numbers (follow-up 28 days). In this secondary analysis of the trial, symptom duration (primary outcome), symptom severity (scored 0-6), and illness deterioration (reconsultation with new or worsening symptoms, or hospital admission) were analysed in pre-specified subgroups using regression models. Subgroups of interest were patients with a (strictly) bacterial, (strictly) viral, or combined infection, and patients with elevated values of procalcitonin, C-reactive protein, or blood urea nitrogen. RESULTS: 2058 patients (amoxicillin n = 1036; placebo n = 1022) were randomized. Treatment did not affect symptom duration (n = 1793). Patients from whom a bacterial pathogen only was isolated (n = 207) benefited from amoxicillin in that symptom severity (n = 804) was reduced by 0.26 points (95% CI -0.48 to -0.03). The odds of illness deterioration (n = 2024) was 0.24 (95% CI 0.11 to 0.53) times lower from treatment with amoxicillin when both a bacterial and a viral pathogen were isolated (combined infection; n = 198). CONCLUSIONS: Amoxicillin may reduce the risk of illness deterioration in patients with a combined bacterial and viral infection. We found no clinically meaningful benefit from amoxicillin treatment in other subgroups.

Effect of outpatient antibiotics for urinary tract infections on antimicrobial resistance among commensal Enterobacteriaceae: a multinational prospective cohort study.

OBJECTIVES: We quantified the impact of antibiotics prescribed in primary care for urinary tract infections (UTIs) on intestinal colonization by ciprofloxacin-resistant (CIP-RE) and extended-spectrum ß-lactamase-producing Enterobacteriaceae (ESBL-PE), while accounting for household clustering. METHODS: Prospective cohort study from January 2011 to August 2013 at primary care sites in Belgium, Poland and Switzerland. We recruited outpatients requiring antibiotics for suspected UTIs or asymptomatic bacteriuria (exposed patients), outpatients not requiring antibiotics (non-exposed patients), and one to three household contacts for each patient. Faecal samples were tested for CIP-RE, ESBL-PE, nitrofurantoin-resistant Enterobacteriaceae (NIT-RE) and any Enterobacteriaceae at baseline (S1), end of antibiotics (S2) and 28 days after S2 (S3). RESULTS: We included 300 households (205 exposed, 95 non-exposed) with 716 participants. Most exposed patients received nitrofurans (86; 42%) or fluoroquinolones (76; 37%). CIP-RE were identified in 16% (328/2033) of samples from 202 (28%) participants. Fluoroquinolone treatment caused transient suppression of Enterobacteriaceae (S2) and subsequent two-fold increase in CIP-RE prevalence at S3 (adjusted prevalence ratio (aPR) 2.0, 95% CI 1.2-3.4), with corresponding number-needed-to-harm of 12. Nitrofurans had no impact on CIP-RE (aPR 1.0, 95% CI 0.5-1.8) or NIT-RE. ESBL-PE were identified in 5% (107/2058) of samples from 71 (10%) participants, with colonization not associated with antibiotic exposure. Household exposure to CIP-RE or ESBL-PE was associated with increased individual risk of colonization: aPR 1.8 (95% CI 1.3-2.5) and 3.4 (95% CI 1.3-9.0), respectively. CONCLUSIONS: These findings support avoidance of fluoroquinolones for first-line UTI therapy in primary care, and suggest potential for interventions that interrupt household circulation of resistant Enterobacteriaceae.

Aetiology of lower respiratory tract infection in adults in primary care: a prospective study in 11 European countries.

OBJECTIVES: To describe the role of bacteria (including bacterial resistance), viruses (including those recently described) and mixed bacterial-viral infections in adults presenting to primary care with lower respiratory tract infection (LRTI). METHODS: In all, 3104 adults with LRTI were enrolled, of whom 141 (4.5%) had community-acquired pneumonia (CAP), and 2985 matched controls in a prospective study in 16 primary care networks in Europe, and followed patients up at 28-35 days. We detected Streptococcus pneumoniae and Haemophilus influenzae and assessed susceptibility, atypical bacteria and viruses. RESULTS: A potential pathogen was detected in 1844 (59%) (in 350 (11%) bacterial pathogens only, in 1190 (38%) viral pathogens only, and in 304 (10%) both bacterial and viral pathogens). The most common bacterial pathogens isolated were S. pneumoniae (5.5% overall, 9.2% in CAP patients) and H. influenzae (5.4% overall, 14.2% in CAP patients). Less than 1% of S. pneumoniae were highly resistant to penicillin and 12.6% of H. influenzae were ß-lactamase positive. The most common viral pathogens detected were human rhinovirus (20.1%), influenza viruses (9.9%), and human coronavirus (7.4%). Influenza virus, human parainfluenza viruses and human respiratory syncytial virus as well as human rhinovirus, human coronavirus and human metapneumovirus were detected significantly more frequently in LRTI patients than in controls. CONCLUSIONS: A bacterial pathogen is identified in approximately one in five adult patients with LRTI in primary care, and a viral pathogen in just under half, with mixed infections in one in ten. Penicillin-resistant pneumococci and ß-lactamase-producing H. influenzae are uncommon. These new findings support a restrictive approach to antibiotic prescribing for LRTI and the use of first-line, narrow-spectrum agents in primary care.

FOXP3 can modulate TAL1 transcriptional activity through interaction with LMO2.

T-cell acute lymphoblastic leukemia (T-ALL) frequently involves aberrant expression of TAL1 (T-cell acute lymphocytic leukemia 1) and LMO2, oncogenic members of the TAL1 transcriptional complex. Transcriptional activity of the TAL1-complex is thought to have a pivotal role in the transformation of thymocytes and is associated with a differentiation block and self-renewal. The transcription factor Forkhead Box P3 (FOXP3) was recently described to be expressed in a variety of malignancies including T-ALL. Here we show that increased FOXP3 levels negatively correlate with expression of genes regulated by the oncogenic TAL1-complex in human T-ALL patient samples as well as a T-ALL cell line ectopically expressing FOXP3. In these cells, FOXP3 expression results in altered regulation of cell cycle progression and reduced cell viability. Finally, we demonstrate that FOXP3 binds LMO2 in vitro, resulting in decreased interaction between LMO2 and TAL1, providing a molecular mechanism for FOXP3-mediated transcriptional modulation in T-ALL. Collectively, our findings provide initial evidence for a novel role of FOXP3 as a tumor suppressor in T-ALL through modulation of TAL1 transcriptional activity.

Agreement on urgency assessment between secretaries and general practitioners: an observational study in out-of-hours general practice service in Belgium.

BACKGROUND: In some European countries telephone triage (TT) during out-of-hours primary care showed to be safe and effective. Other countries, such as Belgium, may not have trained auxiliary personnel while their national health services want to establish TT. OBJECTIVES: To compare urgency levels assessed by secretaries and general practitioners in one general practice cooperative in Belgium. METHODS: Percentage of correct-, under-, and over-triage were calculated in total and per reason for encounter. Inter-rater agreement was investigated. RESULTS: The secretaries correctly triaged (same urgency level) 77% of the telephone calls, under-triaged 10% and over-triaged 13%.'Shortness of breath', 'skin cuts', 'chest pain', 'feeling unwell' and 'syncope' were often under-triaged. CONCLUSION: Before introducing TT, auxiliary staff should be trained and protocols should be used.

Smoking behaviour and knowledge of the health effects of smoking in patients with inflammatory bowel disease.

BACKGROUND: The detrimental effect of smoking on development and progression of Crohn's disease (CD) is generally accepted. AIM: To evaluate the awareness of smoking risks in a Belgian inflammatory bowel disease (IBD) population. METHODS: In the out-patient clinic of a tertiary referral centre, 625 consecutive patients with CD, 238 patients with ulcerative colitis (UC) and 289 non-IBD controls, filled out a simple questionnaire. This questionnaire included data on smoking behaviour and awareness of smoking-related health effects, including effects on IBD. RESULTS: At diagnosis, more CD patients were active smokers compared to UC (40% vs. 17%, P < 0.001). Remarkably, smoking cessation rates after diagnosis were similar for CD and UC (both 56%, P = 0.997). The great majority recognised a detrimental influence of smoking on general health (98-99%), lung cancer (95-97%), myocardial infarction (89-92%) and stroke (78-87%). Although CD patients more frequently acknowledged risks of smoking on their disease, only 37% were aware of a link with CD development, 30% of increased surgical rates and 27% of increased post-operative CD recurrence. Active smokers more frequently denied an increased risk of surgery and higher post-operative CD recurrence. Intriguingly, within the active smokers with CD, those not willing to quit smoking most often denied a potential bad influence of smoking. Taking into account disease duration, previous surgery, education level, working status and nicotine dependence, we were unable to define specific subgroups of patients requiring extra education. CONCLUSION: Although patients with Crohn's disease were better informed on the detrimental effects of smoking, the awareness rate was still low.

Corrigendum to "The global threat of antimicrobial resistance: science for intervention" [New Microbes New Infect 6 (2015): 22-29].

[This corrects the article DOI: 10.1016/j.nmni.2015.02.007.].

The global threat of antimicrobial resistance: science for intervention.

In the last decade we have witnessed a dramatic increase in the proportion and absolute number of bacterial pathogens resistant to multiple antibacterial agents. Multidrug-resistant bacteria are currently considered as an emergent global disease and a major public health problem. The B-Debate meeting brought together renowned experts representing the main stakeholders (i.e. policy makers, public health authorities, regulatory agencies, pharmaceutical companies and the scientific community at large) to review the global threat of antibiotic resistance and come up with a coordinated set of strategies to fight antimicrobial resistance in a multifaceted approach. We summarize the views of the B-Debate participants regarding the current situation of antimicrobial resistance in animals and the food chain, within the community and the healthcare setting as well as the role of the environment and the development of novel diagnostic and therapeutic strategies, providing expert recommendations to tackle the global threat of antimicrobial resistance.