Human carriage of ESBL/pAmpC-producing Escherichia coli and Klebsiella pneumoniae in relation to the consumption of raw or undercooked vegetables, fruits, and fresh herbs.

We investigated to what extent the consumption of raw or undercooked vegetables, fruits, and fresh herbs influences carriage rates of ESBL/pAmpC-producing Escherichia coli and Klebsiella pneumoniae (ESBL-E/K) in the general population. We assessed long-term carriage and changes in ESBL-E/K prevalence over time, by comparing the results to findings in the same population 5 years earlier. Between July and December 2021, participants sent in two fecal samples and questionnaires, 3 months apart. Food frequency questionnaires were sent on a monthly basis. Fecal samples were cultured and screened for ESBL-E/K, and phenotypically positive isolates were sequenced. Multivariable logistic regression models were established to assess the association between the consumption of fresh produce and ESBL-E/K carriage. The ESBL-E/K prevalence was 7.6% [41/537; 95% confidence interval (CI): 5.7-10.2] in the first sampling round and 7.0% (34/489; 95% CI: 5.0-9.6) in the second. Multivariable models did not result in statistical significance for any of the selected fruit and vegetable types. Trends for increased carriage rates were observed for the consumption of raspberry and blueberry in the summer period. ESBL-E/K prevalence was comparable with the prevalence in the same cohort 5 years earlier (7.5%; 95% CI: 5.6-10.1%). In six persons (1.2%) a genetically highly homologous ESBL-E/K was found. In conclusion, the contribution of the consumption of raw fruits, vegetables, and herbs to ESBL-E/K carriage in humans in the Netherlands is probably low. Despite COVID-19 containment measures (e.g., travel restrictions, social distancing, and hygiene) the ESBL-E/K prevalence was similar to 5 years earlier. Furthermore, indications for long-term carriage were found.IMPORTANCEESBL-producing bacteria are resistant against important classes of antibiotics, including penicillins and cephalosporines, which complicates treatment of infections. Food is one of the main routes of transmission for carriage of these bacteria in the general population. Although fruits, vegetables, and herbs are generally less frequently contaminated with ESBL-producing bacteria compared to meat, exposure might be higher since these products are often eaten raw or undercooked. This research showed that the contribution of the consumption of raw or undercooked fresh produce to ESBL-E/K carriage in the general Dutch population was low. No specific types of fruit or vegetables could be identified that gave a higher risk of carriage. In addition, we demonstrated the presence of genetically highly homologous ESBL-E/K in six persons after a period of 5 years, indicative for long-term carriage.

Severe acute respiratory infections surveillance for early signals in the community.

BACKGROUND: Surveillance of acute respiratory infections (ARI) in the Netherlands and other European countries is based mostly on primary care data, with little insight into the severe spectrum of the disease. We compared time-trends for ARI in secondary care with influenza-like illness (ILI), ARI and pneumonia in primary care, and crude mortality, in order to assess the value of routinely collected data on respiratory infections in hospitals and the added value of severe acute respiratory infections (SARI) surveillance. METHODS: We calculated incidence of ARI in secondary care, ILI, ARI, and pneumonia in primary care, and crude mortality using five historical databases (2008-2016). RESULTS: Over eight years, seasonal incidence peaks of ARI in secondary care occurred earlier than ILI and ARI incidence peaks in primary care, except during the 2009 influenza A(H1N1) pandemic and post-pandemic season. The median time-lag between ARI in secondary care and ILI, ARI and pneumonia in primary care was 6.5 weeks, 7 weeks, and 1 week, respectively. Crude mortality lagged a median 5 weeks behind ARI in secondary care. CONCLUSION: This observational study demonstrates that routinely collected data can be used for describing trends of ARI in secondary care and may be suitable for near real-time SARI surveillance. In most seasons, the incidence peaks for ARI in secondary care preceded the peaks in primary care and crude mortality with a considerable time-lag. It would be of great value to add microbiological test results to the incidence data to better explain the difference in time-lag between these surveillance systems.

[No scientific lower threshold for compulsory vaccination]. / Geen wetenschappelijke ondergrens voor verplicht vaccineren.

The national vaccination rate in young children in the Netherlands has decreased in recent years. This has led to social and political discussions, for instance about compulsory vaccination for children in child-care. The national commission on child-care and vaccination has advised that vaccination should be made compulsory when the rate of vaccination has declined to a pre-determined lower threshold, to be determined by the government. A frequently quoted lower threshold is 95%. The idea behind this is the concept of a critical vaccination rate, a threshold needed for elimination of an infection in a large, well-mixed population. In this article we argue why the critical vaccination rate does not offer a scientific basis for a lower threshold to the national vaccination rate.

[Rise and threat of infectious diseases]. / Opkomst en dreiging van infectieziekten.

In 2019, 1 in 4 deaths was caused by infectious diseases. In addition to the big 3 - HIV, malaria and tuberculosis - these diseases are mainly respiratory infections, infectious diarrhoea and sepsis. The burden of disease caused by infections also remains high in the Netherlands. This could still get worse because of several factors: ageing, 'vaccination doubts', increased use of immunosuppressive drugs, increased mobility of people and globalisation of food chains. Global warming also affects the spread of pathogens and disease vectors. Pathogens have an impressive ability to adapt and, for example, to develop resistance to antimicrobial agents. In order to cope with these threats, we would do well to consider the emergence of new infectious diseases as well as the threat of old ones. What can we learn from decades past? Why do new infections keep emerging? What does the future look like?

Experience of establishing severe acute respiratory surveillance in the Netherlands: Evaluation and challenges.

The 2009 influenza A (H1N1) pandemic prompted the World Health Organization (WHO) to recommend countries to establish a national severe acute respiratory infections (SARI) surveillance system for preparedness and emergency response. However, setting up or maintaining a robust SARI surveillance system has been challenging. Similar to other countries, surveillance data on hospitalisations for SARI in the Netherlands are still limited, in contrast to the robust surveillance data in primary care. The objective of this narrative review is to provide an overview, evaluation, and challenges of already available surveillance systems or datasets in the Netherlands, which might be used for near real-time surveillance of severe respiratory infections. Seven available surveillance systems or datasets in the Netherlands were reviewed. The evaluation criteria, including data quality, timeliness, representativeness, simplicity, flexibility, acceptability and stability were based on United States Centers for Disease Control and Prevention (CDC) and European Centre for Disease Prevention and Control (ECDC) guidelines for public health surveillance. We added sustainability as additional evaluation criterion. The best evaluated surveillance system or dataset currently available for SARI surveillance is crude mortality monitoring, although it lacks specificity. In contrast to influenza-like illness (ILI) in primary care, there is currently no gold standard for SARI surveillance in the Netherlands. Based on our experience with sentinel SARI surveillance, a fully or semi-automated, passive surveillance system seems most suited for a sustainable SARI surveillance system. An important future challenge remains integrating SARI surveillance into existing hospital programs in order to make surveillance data valuable for public health, as well as hospital quality of care management and individual patient care.

Prediction model for pneumonia in primary care patients with an acute respiratory tract infection: role of symptoms, signs, and biomarkers.

BACKGROUND: Diagnosing pneumonia can be challenging in general practice but is essential to distinguish from other respiratory tract infections because of treatment choice and outcome prediction. We determined predictive signs, symptoms and biomarkers for the presence of pneumonia in patients with acute respiratory tract infection in primary care. METHODS: From March 2012 until May 2016 we did a prospective observational cohort study in three radiology departments in the Leiden-The Hague area, The Netherlands. From adult patients we collected clinical characteristics and biomarkers, chest X ray results and outcome. To assess the predictive value of C-reactive protein (CRP), procalcitonin and midregional pro-adrenomedullin for pneumonia, univariate and multivariate binary logistic regression were used to determine risk factors and to develop a prediction model. RESULTS: Two hundred forty-nine patients were included of whom 30 (12%) displayed a consolidation on chest X ray. Absence of runny nose and whether or not a patient felt ill were independent predictors for pneumonia. CRP predicts pneumonia better than the other biomarkers but adding CRP to the clinical model did not improve classification (- 4%); however, CRP helped guidance of the decision which patients should be given antibiotics. CONCLUSIONS: Adding CRP measurements to a clinical model in selected patients with an acute respiratory infection does not improve prediction of pneumonia, but does help in giving guidance on which patients to treat with antibiotics. Our findings put the use of biomarkers and chest X ray in diagnosing pneumonia and for treatment decisions into some perspective for general practitioners.

The simplified oral flucloxacillin absorption test: an accurate method to identify patients with inadequate oral flucloxacillin absorption.

BACKGROUND: The preferred treatment for severe methicillin-sensitive Staphylococcus aureus infections is flucloxacillin, a small-spectrum antibiotic administered intravenously (IV) and orally. However, clinicians switch to the less preferred broad-spectrum antibiotics because of the variable absorption after oral administration of flucloxacillin. A classical oral absorption test (OAT) requires overnight fasting and interruption of IV therapy, and is laborious. In the current study, we investigated whether a simplified OAT can be utilized in a clinical setting to guide antibiotic treatment in patients with severe S. aureus infections. For this, OAT IV therapy is continued and oral dosing is performed after a one-hour fast and implemented after a small study. METHODS: In 196 patients receiving IV flucloxacillin by continuous infusion, a classical OAT (test A) or simplified version of the OAT (test B) was performed. In both tests, 1 g oral flucloxacillin was given and serum samples were taken prior to intake and at one and two hours after administration. Flucloxacillin concentrations were determined by high-performance liquid chromatography. Adequate absorption was defined as an increase of flucloxacillin concentration of at least 10 mg/l after one or two hours compared to baseline. RESULTS: In a sample of 196 patients (85 F/111 M), test A was performed in 28 patients, and test B in 168 patients. Age, gender, and baseline values of creatinine and albumin were similar in both groups. The maximal increase of flucloxacillin absorption was highly variable between patients. In 26 (13%) of the 196 patients, the flucloxacillin increase did not reach the value of 10 mg/l. The median (interquartile range, IQR) maximal increase of flucloxacillin absorption was 22.0 (15-31.25) mg/l for test A and 21.5 (13-32.25) mg/l for test B. There was no significant difference in maximal increase of flucloxacillin absorption between test A and B (p = 0.74), nor between males and females (p = 0.95). Age, creatinine, and albumin were not correlated with flucloxacillin levels. CONCLUSIONS: The simplified version of the OAT is useful to identify patients with adequate oral flucloxacillin absorption, and to ensure the effective continuation of an oral small-spectrum treatment.

Marburg haemorrhagic fever in returning travellers: an overview aimed at clinicians.

Marburg virus haemorrhagic fever (MARV HF) is a dramatic disease that can occur in a traveller returning from an area where the virus is endemic. In this article, we provide an overview of MARV HF as an imported infection with an emphasis on clinical aspects. Although late features such as rash, signs of haemorrhagic diathesis and liver necrosis may point to the diagnosis, the initial clinical picture is non-specific. If in this early phase the patient's epidemiological exposure history is compatible with MARV HF, the patient should be isolated and managed according to viral haemorrhagic fever protocol and RT-PCR should be performed on the patient's blood as soon as possible to rule out MARV HF (or other possible viral haemorrhagic fevers). In severe cases, direct electron microscopy of blood in specialized centres (e.g. Bernhard-Nocht Institute in Hamburg, Germany) may be considered if the result of the RT-PCR is not readily available. Adequate diagnostics and empirical treatment for other acute life-threatening illnesses should not be withheld while test results are awaited, but all management and diagnostics should be weighed against the risks of nosocomial transmission.

[Enterovirus type D68 and acute flaccid paralysis: a new duo?] / Enterovirus type D68 en acute slappe verlamming: een nieuw duo?

Following a case of acute flaccid paralysis after infection with enterovirus type D68, we highlight current understanding of the causal role of enterovirus infection in this neurological syndrome. Acute flaccid paralysis is a rare complication of enterovirus infections. Such viruses have become a more common cause of severe respiratory-tract infections, especially in children with underlying lung disease such as asthma.

The licorice pentacyclic triterpenoid component 18ß-glycyrrhetinic acid enhances the activity of antibiotics against strains of methicillin-resistant Staphylococcus aureus.

This study aimed to identify compounds that enhance the activity of current antibiotics against multidrug-resistant bacteria. Screening of a 350+ compound proprietary small molecules library revealed that the Glycyrrhiza glabra (licorice)-derived triterpenoid 18ß-glycyrrhetinic acid (18ß-GA) potentiated the antibacterial activity of certain antibiotics against Staphylococcus aureus. Here, we evaluated the ability of pentacyclic triterpenoids to potentiate the activity of antibiotics against strains of methicillin-resistant S. aureus (MRSA). Checkerboard assays were used to assess the minimum inhibitory concentration (MIC) of tobramycin and ten pentacyclic triterpenoids against S. aureus. The effect of 18ß-GA on the MIC of different antibiotics against MRSA was also determined in an in vitro airway MRSA infection model. 18ß-GA enhanced the bactericidal activity of the aminoglycosides tobramycin, gentamicin and amikacin, and of polymyxin B against two MRSA strains, reducing the MIC of these antibiotics 32-64-fold [fractional inhibitory concentration index (FICI) of 0.12-0.13]. Other ß-amyrin triterpenoids and α-amyrin triterpenoids did not exert such synergistic effects. 18ß-GA did not enhance the activity of antibiotics from other structural classes against the MRSA strains. In an air-exposed airway epithelial cell culture, 18ß-GA enhanced the bactericidal activity of tobramycin and polymyxin B against the MRSA strain. These data demonstrate the potential of 18ß-GA to synergise with certain types of antibiotics to eliminate strains of MRSA.

T helper 2 response in allergic bronchopulmonary aspergillosis is not driven by specific Aspergillus antigens.

Allergic bronchopulmonary aspergillosis (ABPA) is characterized by an allergic immunological response to Aspergillus fumigatus. In this study, we investigated whether certain Aspergillus antigens are more allergenic than others, as was postulated previously. We stimulated peripheral blood mononuclear cells from patients with ABPA with the classically described A. fumigatus allergens Aspf1, Aspf2, Aspf3, and Aspf4, as well as two other Aspergillus antigens, Crf1 and Catalase1. Activated CD4+ T cells displayed a T helper 2 phenotype with the production of IL-4 in response to stimulation with several of these different antigens. Immune responses were not limited to the classically described A. fumigatus allergens. In healthy individuals, we demonstrated a similar recognition profile to the different antigens, but in contrast the activated CD4+ T cells exerted a T helper 1 phenotype and mainly produced IFN-γ after stimulation with A. fumigatus antigens. In conclusion, irrespective of the A. fumigatus antigen, the T-cell immune response in patients with ABPA is skewed to a T helper 2 cytokine secretion profile.

Primary immunodeficiencies in the Netherlands: national patient data demonstrate the increased risk of malignancy.

PURPOSE: To analyze the data of the national registry of all Dutch primary immune deficiency (PID) patients, according to the European Society for Immunodeficiencies (ESID) definitions. RESULTS: In the Netherlands, 745 patients had been registered between 2009 and 2012. An overall prevalence of 4.0 per 100,000 inhabitants was calculated. The most prevalent PID was 'predominantly antibody disorder (PAD)' (60.4%). In total, 118 transplantations were reported, mostly hematopoietic stem cell transplantations (HSCT). Almost 10% of the PID patients suffered from a malignancy, in particular 'lymphoma' and 'skin cancer'. Compared to the general Dutch population, the relative risk of developing any malignancy was 2.3-fold increased, with a >10-fold increase for some solid tumors (thymus, endocrine organs) and hematological disease (lymphoma, leukemia), varying per disease category. CONCLUSIONS: The incidence rate and characteristics of PID in the Netherlands are similar to those in other European countries. Compared to the general population, PID patients carry an increased risk to develop a malignancy.

Humoral immune response as predictor of recurrence in Clostridium difficile infection.

Low serum concentrations of antibodies directed against the toxins TcdA and TcdB have been associated with a higher risk of recurrence of Clostridium difficile infection (CDI) after successful antibiotic treatment. However, there are conflicting reports. Herein, we compared serum levels of antibodies of patients with a single episode of CDI with those of patients who subsequently suffered a recurrence. We used a serum bank from patients who received an experimental whey protein product following successful antibiotic treatment for CDI. We determined levels of IgA and IgG directed against TcdA, TcdB and non-toxin cell surface antigens in serum collected directly and 3 weeks after completing a 10-day course of antibiotic treatment for CDI. We also developed an objective flow cytometry-based assay to determine the proportion of cells exhibiting cytopathic effect after exposure to TcdB. Using this method, we measured the TcdB-neutralizing capacity of sera. We compared the results for patients without a subsequent recurrence with those of patients who suffered a recurrence within 60 days after completing the antibiotic treatment. Advanced age, comorbidity other than immunocompromised state and low serum levels of anti-TcdA and anti-TcdB antibodies were associated with recurrence, whereas serum levels of antibodies directed against cell surface antigens were not. Serum TcdB-neutralizing capacity, which correlated only weakly with serum IgG anti-TcdB, was not significantly associated with recurrence.

Prognostic value of pro-adrenomedullin, procalcitonin and C-reactive protein in predicting outcome of febrile urinary tract infection.

Bacterial infections such as febrile urinary tract infection (fUTI) may run a complicated course that is difficult to foretell on clinical evaluation only. Because the conventional biomarkers erythrocyte sedimentation rate (ESR), leucocyte count, C-reactive protein (CRP) and procalcitonin (PCT) have a limited role in the prediction of a complicated course of disease, a new biomarker-plasma midregional pro-adrenomedullin (MR-proADM)-was evaluated in patients with f UTI. We conducted a prospective multicentre cohort study including consecutive patients with f UTI at 35 primary-care centres and eight emergency departments. Clinical and microbiological data were collected and plasma biomarker levels were measured at presentation to the physician. Survival was assessed after 30 days. Of 494 fUTI patients, median age was 67 (interquartile range 49-78) years, 40% were male; two-thirds of them had significant co-existing medical conditions. Median MR-proADM level was 1.42 (interquartile range 0.67-1.57) nM; significantly elevated MR-proADM levels were measured in patients with bacteraemia, those admitted to the intensive care unit, and in 30-day and 90-day non-survivors, compared with patients without these characteristics. The diagnostic accuracy for predicting 30-day mortality in fUTI, reflected by the area-under-the-curve of receiver operating characteristics were: MR-proADM 0.83 (95% CI 0.71-0.94), PCT 0.71 (95% CI 0.56-0.85); whereas CRP, ESR and leucocyte count lacked diagnostic value in this respect. This study shows that MR-proADM assessed on first contact predicts a complicated course of disease and 30-day mortality in patients with fUTI and in this respect has a higher discriminating accuracy than the currently available biomarkers ESR, CRP, PCT and leucocyte count.

An integrated approach to control a prolonged outbreak of multidrug-resistant Pseudomonas aeruginosa in an intensive care unit.

In this paper we aim to provide insight into the complexity of outbreak management in an intensive care unit (ICU) setting. In October 2010 four patients on the ICU of our tertiary care centre were colonized or infected with a multidrug-resistant strain of Pseudomonas aeruginosa (MDR-PA). An outbreak investigation was carried out and infection control measures were taken in an attempt to identify a potential source and stop transmission. The outbreak investigation included descriptive epidemiology, comprising retrospective case finding by reviewing the laboratory information system back to 2004 and prospective case finding by patient screening for MDR-PA. Furthermore, microbiological analysis, environmental screening and a case-control study were carried out. Infection control measures consisted of re-education of healthcare personnel on basic hygiene measures, auditing of hygiene procedures used in daily practice by infection control practitioners, and stepwise up-regulation of isolation measures. From February 2009 to January 2012, 44 patients on our ICU were found to be MDR-PA positive. MDR-PA isolates of the 44 patients showed two distinct AFLP patterns, with homology within each of the AFLP clusters of more than 93%. The VIM metallo-ß-lactamase gene was detected in 20 of 21 tested isolates. A descriptive epidemiology investigation identified the rooms with the highest numbers of MDR-PA positive patients. The case-control study showed three factors to be independently associated with MDR-PA positivity: admission to ICU subunit 1 (OR, 6.1; 95% CI, 1.7, 22), surgery prior to or during admission (OR, 5.7; 95% CI, 1.6, 20) and being warmed-up with the warm-air blanket (OR, 3.6; 95% CI, 1.2, 11). After three environmental screening rounds, with sampling of sinks, furniture and devices in the ICU, without revealing a clear common source, a fourth environmental investigation included culturing of faucet aerators. Two faucets were found to be positive for MDR-PA and were replaced. The occurrence of new cases decreased with the strengthening of infection control measures and declined further with the removal of the common source. With this integrated approach a prolonged outbreak of P. aeruginosa was controlled. Contaminated faucet aerators on the ICU probably served as a persisting source, while interpatient transmission by medical staff was a likely way of spread. Seven months after the last case (January 2012) and 3 months after cessation of extended isolation measures (May 2012), single cases started to occur on the ICU, with a total of seven patients in the past year. No common source has yet been found.

Patients with cystic fibrosis have a high carriage rate of non-toxigenic Clostridium difficile.

Thirty-year-old observations report frequent asymptomatic Clostridium difficile carriage among cystic fibrosis (CF) patients. In this case-control study, we found more carriers among CF patients than controls (47% versus 11%), but most strains carried by CF patients were non-toxigenic (77% versus 17%). Among CF patients, carriers were younger, with more severe pulmonary disease than non-carriers. Strains belonged to multiple PCR-ribotypes, suggesting that these CF patients did not acquire strains from each other.

Evaluation of the antiviral response to zanamivir administered intravenously for treatment of critically ill patients with pandemic influenza A (H1N1) infection.

A retrospective nationwide study on the use of intravenous (IV) zanamivir in patients receiving intensive care who were pretreated with oseltamivir in the Netherlands was performed. In 6 of 13 patients with a sustained reduction of the viral load, the median time to start IV zanamivir was 9 days (range, 4-11 days) compared with 14 days (range, 6-21 days) in 7 patients without viral load reduction (P = .052). Viral load response did not influence mortality. We conclude that IV zanamivir as late add-on therapy has limited effectiveness. The effect of an immediate start with IV zanamivir monotherapy or in combination with other drugs need to be evaluated.