Differentiating influenza from COVID-19 in patients presenting with suspected sepsis.

There is a need for a quick assessment of severely ill patients presenting to the hospital. The objectives of this study were to identify clinical, laboratory and imaging parameters that could differentiate between influenza and COVID-19 and to assess the frequency and impact of early bacterial co-infection. A prospective observational cohort study was performed between February 2019 and April 2020. A retrospective cohort was studied early in the COVID-19 pandemic. Patients suspected of sepsis with PCR-confirmed influenza or SARS-CoV-2 were included. A multivariable logistic regression model was built to differentiate COVID-19 from influenza. In total, 103 patients tested positive for influenza and 110 patients for SARS-CoV-2, respectively. Hypertension (OR 6.550), both unilateral (OR 4.764) and bilateral (OR 7.916), chest X-ray abnormalities, lower temperature (OR 0.535), lower absolute leukocyte count (OR 0.857), lower AST levels (OR 0.946), higher LDH (OR 1.008), higher ALT (OR 1.044) and higher ferritin (OR 1.001) were predictive of COVID-19. Early bacterial co-infection was more frequent in patients with influenza (10.7% vs. 2.7%). Empiric antibiotic usage was high (76.7% vs. 84.5%). Several factors determined at presentation to the hospital can differentiate between influenza and COVID-19. In the future, this could help in triage, diagnosis and early management. Clinicaltrial.gov Identifier: NCT03841162.

Lesion size is associated with genetic polymorphisms in TLR1, TLR6, and TIRAP genes in patients with major abscesses and diabetic foot infections.

Genetic variation in Toll-like receptors (TLRs) has previously been associated with susceptibility to complicated skin and skin structure infections (cSSSIs). The aim of this study was to investigate associations between the severity of cSSSIs, i.e., major abscesses and diabetic foot infections (DFIs), and a set of genetic polymorphisms in the Toll-like receptor pathway. A total of 121 patients with major abscesses and 132 with DFIs participating in a randomized clinical trial were genotyped for 13 nonsynonymous single-nucleotide polymorphisms (SNPs) in genes coding for TLRs and the signaling adaptor molecule TIRAP. Infection severity was defined by lesion size at clinical presentation for both types of infections. The PEDIS infection score was also used to define severity of DFIs. Linear regression models were used to study factors independently associated with severity. In patients with large abscesses, hetero- or homozygosity for the allelic variant TLR6 (P249S) was associated with significantly smaller lesions while homozygosity for the allelic variant TLR1 (R80T) was associated with significantly larger lesions. PRRs genes were not significantly associated with PEDIS. However, patients with DFI hetero- or homozygous for the allelic variant TLR1 (S248N) had significantly larger lesions. Polymorphisms in TLR1 and TLR6 influence the severity of cSSSIs as assessed by the lesion size of major abscesses and DFIs. ClinicalTrial.gov Identifier: NCT00402727.

Ensuring Antibiotic Development, Equitable Availability, and Responsible Use of Effective Antibiotics: Recommendations for Multisectoral Action.

Antibiotic resistance is a growing threat to global public health. The World Health Organization's Global Action Plan on Antimicrobial Resistance recommends engaging multisectoral stakeholders to tackle the issue. However, so far, few studies have addressed barriers to antibiotic development, equitable availability, and responsible antibiotic use from the perspective of stakeholders outside healthcare facilities or patient communities: the so-called third-party stakeholders. Third-party stakeholders include, inter alia, governments, regulatory agencies, and professionals working in antibiotic research and development and medical ethics. This viewpoint provides an overview of barriers to antibiotic development, equitable availability of effective antibiotics, and the responsible use of antibiotics. The barriers were identified in an exploratory, qualitative interview study with an illustrative sample of 12 third-party stakeholders. Recommendations to lift these barriers are presented, together with examples of recently-made progress. The recommendations should guide future antibiotic policies and multisectoral policy action.

Towards a global definition of responsible antibiotic use: results of an international multidisciplinary consensus procedure.

Background: Conducted as part of the Driving Reinvestment in Research and Development and Responsible Antibiotic Use (DRIVE-AB) project, this study aimed to identify key elements for a global definition of responsible antibiotic use based on diverse stakeholder input. Methods: A three-step RAND-modified Delphi method was applied. First, a systematic review of antibiotic stewardship literature and relevant organization web sites identified definitions and synonyms of responsible use. Identified elements of definitions were presented by questionnaire to a multidisciplinary international stakeholder panel for appraisal of their relevance. Finally, questionnaire results were discussed in a consensus meeting. Results: The systematic review and the web site search identified 17 synonyms (e.g. appropriate, correct) and 22 potential elements to include in a definition of responsible use. Elements were grouped into patient-level (e.g. Indication, Documentation) or societal-level elements (e.g. Education, Future Effectiveness). Forty-eight stakeholders with diverse backgrounds [medical community, public health, patients, antibiotic research and development (R&D), regulators, governments] from 18 countries across all continents participated in the questionnaire. Based on relevance scores, 21 elements were retained, 9 were rephrased and 1 was added. Together, the 22 elements and associated best-practice descriptions comprise an exhaustive list of elements to be considered when defining responsible use. Conclusions: Combination of concepts from the literature and stakeholder opinion led to an international multidisciplinary consensus on a global definition of responsible antibiotic use. The widely diverging perspectives of stakeholders providing input should ensure the comprehensiveness and relevance of the definition for both individual patients and society. An aspirational goal would be to address all elements.

Do medical students feel prepared to prescribe antibiotics responsibly? Results from a cross-sectional survey in 29 European countries.

Background: In an era of antibiotic resistance, medical students must be prepared to prescribe antibiotics responsibly. Objectives: To assess self-reported preparedness among final-year medical students at European universities, using a comprehensive set of topics related to prudent antibiotic use. Methods: We conducted a cross-sectional, multicentre, web-based survey. All medical-degree students in their final year of studies at European universities were eligible to participate. A preparedness score was calculated for each student and mean scores were compared at medical school and country levels. Comparisons were made with national-level data on resistance among four common bacterial pathogens. Results: In total, 7328 responses were included from 179/296 eligible medical schools in 29/29 countries. Students felt at least sufficiently prepared on a mean of 71.2% of topics assessed, ranging from 54.8% (Portugal) to 84.8% (Latvia). The proportion of students wanting more education on prudent antibiotic use or general antibiotic use ranged from 20.3% (Sweden) to 94.3% (Slovakia), with a mean of 66.1%, and was strongly inversely correlated with preparedness scores (Spearman's ρ = -0.72, n = 29, P < 0.001). Higher prevalence rates of antibiotic-non-susceptible bacteria were associated with lower preparedness scores and higher self-reported needs for further education (P < 0.01). Conclusions: Most final-year European medical students feel they still need more education on antibiotic use for their future practice as junior doctors. Patterns of preparedness on specific topics were identified, were highly consistent across countries, and correlated with both perceived need for further education and levels of antibiotic resistance among common bacteria.

Quality indicators assessing antibiotic use in the outpatient setting: a systematic review followed by an international multidisciplinary consensus procedure.

Objectives: Quality indicators (QIs) assessing the appropriateness of antibiotic use are essential to identify targets for improvement and guide antibiotic stewardship interventions. The aim of this study was to develop a set of QIs for the outpatient setting from a global perspective. Methods: A systematic literature review was performed by searching MEDLINE and relevant web sites in order to retrieve a list of QIs. These indicators were extracted from published trials, guidelines, literature reviews or consensus procedures. This evidence-based set of QIs was evaluated by a multidisciplinary, international group of stakeholders using a RAND-modified Delphi procedure, using two online questionnaires and a face-to-face meeting between them. Stakeholders appraised the QIs' relevance using a nine-point Likert scale. This work is part of the DRIVE-AB project. Results: The systematic literature review identified 43 unique QIs, from 54 studies and seven web sites. Twenty-five stakeholders from 14 countries participated in the consensus procedure. Ultimately, 32 QIs were retained, with a high level of agreement. The set of QIs included structure, process and outcome indicators, targeting both high- and middle- to low-income settings. Most indicators focused on general practice, addressing the common indications for antibiotic use in the community (particularly urinary and respiratory tract infections), and the organization of healthcare facilities. Twelve indicators specifically addressed outpatient parenteral antimicrobial therapy (OPAT). Conclusions: We identified a set of 32 outpatient QIs to measure the appropriateness of antibiotic use. These QIs can be used to identify targets for improvement and to evaluate the effects of antibiotic stewardship interventions.

Metrics to assess the quantity of antibiotic use in the outpatient setting: a systematic review followed by an international multidisciplinary consensus procedure.

Background: The international Innovative Medicines Initiative (IMI) project DRIVE-AB (Driving Reinvestment in Research and Development and Responsible Antibiotic Use) aims to develop a global definition of 'responsible' antibiotic use. Objectives: To identify consensually validated quantity metrics for antibiotic use in the outpatient setting. Methods: First, outpatient quantity metrics (OQMs) were identified by a systematic search of literature and web sites published until 12 December 2014. Identified OQMs were evaluated by a multidisciplinary, international stakeholder panel using a RAND-modified Delphi procedure. Two online questionnaires and a face-to-face meeting between them were conducted to assess OQM relevance for measuring the quantity of antibiotic use on a nine-point Likert scale, to add comments or to propose new metrics. Results: A total of 597 articles were screened, 177 studies met criteria for full-text screening and 138 were finally included. Twenty different OQMs were identified and appraised by 23 stakeholders. During the first survey, 14 OQMs were excluded and 6 qualified for discussion. During the face-to-face meeting, 10 stakeholders retained five OQMs and suggestions were made considering context and combination of metrics. The final set of metrics included defined daily doses, treatments/courses and prescriptions per defined population, treatments/courses and prescriptions per defined number of physician contacts and seasonal variation of total antibiotic use. Conclusions: A small set of consensually validated metrics to assess the quantity of antibiotic use in the outpatient setting was obtained, enabling (inter)national comparisons. The OQMs will help build a global conceptual framework for responsible antibiotic use.

Quality indicators for responsible antibiotic use in the inpatient setting: a systematic review followed by an international multidisciplinary consensus procedure.

Background: This study was conducted as part of the Driving Reinvestment in Research and Development and Responsible Antibiotic Use (DRIVE-AB) project and aimed to develop generic quality indicators (QIs) for responsible antibiotic use in the inpatient setting. Methods: A RAND-modified Delphi method was applied. First, QIs were identified by a systematic review. A complementary search was performed on web sites of relevant organizations. Duplicates were removed and disease and patient-specific QIs were combined into generic indicators. The relevance of these QIs was appraised by a multidisciplinary international stakeholder panel through two questionnaires and an in-between consensus meeting. Results: The systematic review retrieved 70 potential generic QIs. The QIs were appraised by 25 international stakeholders with diverse backgrounds (medical community, public health, patients, antibiotic research and development, regulators, governments). Ultimately, 51 QIs were selected in consensus. QIs with the highest relevance score included: (i) an antibiotic plan should be documented in the medical record at the start of the antibiotic treatment; (ii) the results of bacteriological susceptibility testing should be documented in the medical record; (iii) the local guidelines should correspond to the national guidelines but should be adapted based on local resistance patterns; (iv) an antibiotic stewardship programme should be in place at the healthcare facility; and (v) allergy status should be taken into account when antibiotics are prescribed. Conclusions: This systematic and stepwise method combining evidence from literature and stakeholder opinion led to multidisciplinary international consensus on generic inpatient QIs that can be used globally to assess the quality of antibiotic use.

Variation in antibiotic use among and within different settings: a systematic review.

Objectives: Variation in antibiotic use may reflect inappropriate use. We aimed to systematically describe the variation in measures for antibiotic use among settings or providers. This study was conducted as part of the innovative medicines initiative (IMI)-funded international project DRIVE-AB. Methods: We searched for studies published in MEDLINE from January 2004 to January 2015 reporting variation in measures for systemic antibiotic use (e.g. DDDs) in inpatient and outpatient settings. The ratio between a study's reported maximum and minimum values of a given measure [maximum:minimum ratio (MMR)] was calculated as a measure of variation. Similar measures were grouped into categories and when possible the overall median ratio and IQR were calculated. Results: One hundred and forty-three studies were included, of which 85 (59.4%) were conducted in Europe and 12 (8.4%) in low- to middle-income countries. Most studies described the variation in the quantity of antibiotic use in the inpatient setting (81/143, 56.6%), especially among hospitals (41/81, 50.6%). The most frequent measure was DDDs with different denominators, reported in 23/81 (28.4%) inpatient studies and in 28/62 (45.2%) outpatient studies. For this measure, we found a median MMR of 3.7 (IQR 2.6-5.0) in 4 studies reporting antibiotic use in ICUs in DDDs/1000 patient-days and a median MMR of 2.3 (IQR 1.5-3.2) in 18 studies reporting outpatient antibiotic use in DDDs/1000 inhabitant-days. Substantial variation was also identified in other measures. Conclusions: Our review confirms the large variation in antibiotic use even across similar settings and providers. Data from low- and middle-income countries are under-represented. Further studies should try to better elucidate reasons for the observed variation to facilitate interventions that reduce unwarranted practice variation. In addition, the heterogeneity of reported measures clearly shows that there is need for standardization.

Metrics for quantifying antibiotic use in the hospital setting: results from a systematic review and international multidisciplinary consensus procedure.

Background: Quantifying antibiotic use is an essential element of antibiotic stewardship since it allows comparison between different settings and time windows, and measurement of the impact of interventions. However, quantity metrics (QMs) and methods have not been standardized. Objectives: To propose a set of QMs for antibiotic use in inpatients (IQMs) that are accepted globally by professionals in a range of disciplines. The study was conducted within the Driving Reinvestment in Research and Development and Responsible Antibiotic Use (DRIVE-AB) project. Methods: A systematic literature review using MEDLINE identified articles on measuring inpatient antibiotic use, published up to 29 January 2015. A consensually selected list of national and international web sites was screened for additional IQMs. IQMs were classified according to the type of numerator used and presented to a multidisciplinary panel of stakeholders. A RAND-modified Delphi consensus procedure, which consisted of two online questionnaires and a face-to-face meeting, was performed. Results: The systematic literature review and web site search identified 168 eligible articles from which an initial list of 20 IQMs, composed of 20 different numerators and associated denominators was developed. The consensus procedure resulted in a final set of 12 IQMs. Among this final set, DDDs per 100(0) patient-days and days of therapy per patient-days were most frequently found in the review. The panel recommended that antibiotic use should be expressed in at least two metrics simultaneously. Conclusions: Our consensus procedure identified a set of IQMs that we propose as an evidence-based global standard.

Outbreak of trichinellosis related to eating imported wild boar meat, Belgium, 2014.

Trichinellosis is a rare parasitic zoonosis caused by Trichinella following ingestion of raw or undercooked meat containing Trichinella larvae. In the past five years, there has been a sharp decrease in human trichinellosis incidence rates in the European Union due to better practices in rearing domestic animals and control measures in slaughterhouses. In November 2014, a large outbreak of trichinellosis occurred in Belgium, related to the consumption of imported wild boar meat. After a swift local public health response, 16 cases were identified and diagnosed with trichinellosis. Of the 16 cases, six were female. The diagnosis was confirmed by serology or the presence of larvae in the patients' muscle biopsies by histology and/or PCR. The ensuing investigation traced the wild boar meat back to Spain. Several batches of imported wild boar meat were recalled but tested negative. The public health investigation allowed us to identify clustered undiagnosed cases. Early warning alerts and a coordinated response remain indispensable at a European level.

Genetic Variation in TLR10, an Inhibitory Toll-Like Receptor, Influences Susceptibility to Complicated Skin and Skin Structure Infections.

BACKGROUND: Toll-like receptors (TLRs) play a central role in the innate immune response to complicated skin and skin structure infections (cSSSIs), with TLR10 being the first family member known to have an inhibitory function. This study assessed the role of TLR10 in recognition of cSSSI-related pathogens and whether genetic variation in TLR10 influences susceptibility to cSSSIs. METHODS: Human peripheral blood mononuclear cells (PBMCs) preincubated with anti-TLR10 antibody and HEK-293 cells overexpressing TLRs were exposed to cSSSI pathogens, and cytokine secretion was determined by enzyme-linked immunosorbent assay. A total of 318 patients with cSSSI and 328 healthy controls were genotyped for 4 nonsynonymous single-nucleotide polymorphisms in TLR10, and functional consequences of the TLR10 SNPs were assessed via in vitro stimulation assays. RESULTS: PBMC stimulation with cSSSI pathogens in the presence of TLR10 neutralizing antibody significantly increased interleukin 6 secretion. Overexpression of TLR10 completely abrogated TLR2-induced interleukin 8 secretion by HEK-293 cells in response to cSSSI pathogens. Three polymorphisms in TLR10, I775L, I369L, and N241H, were associated with reduced susceptibility to cSSSIs. The presence of the TLR10 alleles 775L, 369L, or 241H increased interleukin 6 secretion by PBMCs in response to cSSSI pathogens. CONCLUSIONS: TLR10 is a modulatory receptor of innate immune responses to cSSSI-related pathogens, and genetic variants in TLR10 are associated with protection against cSSSIs.

TLR1, TLR2, and TLR6 gene polymorphisms are associated with increased susceptibility to complicated skin and skin structure infections.

BACKGROUND: Complicated skin and skin structure infections (cSSSIs) are characterized by infections with gram-positive or gram-negative aerobic or anaerobic bacteria, as well as by a polymicrobial etiology. These invading microorganisms are recognized by pattern-recognition receptors (PRRs) of the innate immune system. This study assessed whether genetic variation in genes encoding PRRs influences the susceptibility to cSSSIs. METHODS: A total of 318 patients with cSSSI and 328 healthy controls were genotyped for 9 nonsynonymous single-nucleotide polymorphisms (SNPs) in PRR genes coding for Toll-like receptors (TLRs) 1, 2, 4, and 6; NOD-like receptor 2; and the signaling adaptor molecule TIRAP. Associations between susceptibility to cSSSIs and a SNP were investigated by means of logistic regression models. In an additional cohort of 74 healthy individuals in whom the same SNPs were genotyped, peripheral blood mononuclear cells (PBMCs) were obtained and stimulated with Staphylococcus aureus. Interleukin 6 concentrations were determined in supernatants by enzyme-linked immunosorbent assay to determine the correlation between genotypes and levels of IL-6 secretion. RESULTS: In the genetic association analysis, polymorphisms in TLR1 (S248N and R80T), TLR2 (P631H), and TLR6 (P249S) were associated with an increased susceptibility to cSSSIs. No association with susceptibility to cSSSIs was observed for polymorphisms TLR2 (R753Q), TLR4 (D299G and T399I), NOD2 (P268S), and TIRAP (S180L). In the functional analysis, individuals bearing the TLR1 248N or 80T allele showed lower IL-6 secretion upon stimulation with S. aureus. CONCLUSIONS: Polymorphisms in TLR1, TLR2, and TLR6 are associated with increased susceptibility to cSSSIs. For TLR1, impaired proinflammatory cytokine production due to the polymorphism is most likely the mechanism mediating this effect.

Development of quality indicators for antimicrobial treatment in adults with sepsis.

BACKGROUND: Outcomes in patients with sepsis are better if initial empirical antimicrobial use is appropriate. Several studies have shown that adherence to guidelines dictating appropriate antimicrobial use positively influences clinical outcome, shortens length of hospital stay and contributes to the containment of antibiotic resistance.Quality indicators (QIs) can be systematically developed from these guidelines to define and measure appropriate antimicrobial use. We describe the development of a concise set of QIs to assess the appropriateness of antimicrobial use in adult patients with sepsis on a general medical ward or Intensive Care Unit (ICU). METHODS: A RAND-modified, five step Delphi procedure was used. A multidisciplinary panel of 14 experts appraised and prioritized 40 key recommendations from within the Dutch national guideline on antimicrobial use for adult hospitalized patients with sepsis (http://www.swab.nl/guidelines). A procedure to select QIs relevant to clinical outcome, antimicrobial resistance and costs was performed using two rounds of questionnaires with a face-to-face consensus meeting between the rounds over a period of three months. RESULTS: The procedure resulted in the selection of a final set of five QIs, namely: obtain cultures; prescribe empirical antimicrobial therapy according to the national guideline; start intravenous drug therapy; start antimicrobial treatment within one hour; and streamline antimicrobial therapy. CONCLUSION: This systematic, stepwise method, which combined evidence and expert opinion, led to a concise and therefore feasible set of QIs for optimal antimicrobial use in hospitalized adult patients with sepsis. The next step will entail subjecting these quality indicators to an applicability test for their clinimetric properties and ultimately, using these QIs in quality-improvement projects. This information is crucial for antimicrobial stewardship teams to help set priorities and to focus improvement.

European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on Infections in Leukemia.

Owing to increasing resistance and the limited arsenal of new antibiotics, especially against Gram-negative pathogens, carefully designed antibiotic regimens are obligatory for febrile neutropenic patients, along with effective infection control. The Expert Group of the 4(th) European Conference on Infections in Leukemia has developed guidelines for initial empirical therapy in febrile neutropenic patients, based on: i) the local resistance epidemiology; and ii) the patient's risk factors for resistant bacteria and for a complicated clinical course. An 'escalation' approach, avoiding empirical carbapenems and combinations, should be employed in patients without particular risk factors. A 'de-escalation' approach, with initial broad-spectrum antibiotics or combinations, should be used only in those patients with: i) known prior colonization or infection with resistant pathogens; or ii) complicated presentation; or iii) in centers where resistant pathogens are prevalent at the onset of febrile neutropenia. In the latter case, infection control and antibiotic stewardship also need urgent review. Modification of the initial regimen at 72-96 h should be based on the patient's clinical course and the microbiological results. Discontinuation of antibiotics after 72 h or later should be considered in neutropenic patients with fever of unknown origin who are hemodynamically stable since presentation and afebrile for at least 48 h, irrespective of neutrophil count and expected duration of neutropenia. This strategy aims to minimize the collateral damage associated with antibiotic overuse, and the further selection of resistance.

Targeted therapy against multi-resistant bacteria in leukemic and hematopoietic stem cell transplant recipients: guidelines of the 4th European Conference on Infections in Leukemia (ECIL-4, 2011).

The detection of multi-resistant bacterial pathogens, particularly those to carbapenemases, in leukemic and stem cell transplant patients forces the use of old or non-conventional agents as the only remaining treatment options. These include colistin/polymyxin B, tigecycline, fosfomycin and various anti-gram-positive agents. Data on the use of these agents in leukemic patients are scanty, with only linezolid subjected to formal trials. The Expert Group of the 4(th) European Conference on Infections in Leukemia has developed guidelines for their use in these patient populations. Targeted therapy should be based on (i) in vitro susceptibility data, (ii) knowledge of the best treatment option against the particular species or phenotype of bacteria, (iii) pharmacokinetic/pharmacodynamic data, and (iv) careful assessment of the risk-benefit balance. For infections due to resistant Gram-negative bacteria, these agents should be preferably used in combination with other agents that remain active in vitro, because of suboptimal efficacy (e.g., tigecycline) and the risk of emergent resistance (e.g., fosfomycin). The paucity of new antibacterial drugs in the near future should lead us to limit the use of these drugs to situations where no alternative exists.

Virulence Factor Genes in Invasive Escherichia coli Are Associated with Clinical Outcomes and Disease Severity in Patients with Sepsis: A Prospective Observational Cohort Study.

BACKGROUND: Escherichia coli harbours virulence factors that facilitate the development of bloodstream infections. Studies determining virulence factors in clinical isolates often have limited access to clinical data and lack associations with patient outcome. The goal of this study was to correlate sepsis outcome and virulence factors of clinical E. coli isolates in a large cohort. METHODS: Patients presenting at the emergency department whose blood cultures were positive for E. coli were prospectively included. Clinical and laboratory parameters were collected at admission. SOFA-score was calculated to determine disease severity. Patient outcomes were in-hospital mortality and ICU admission. Whole genome sequencing was performed for E. coli isolates and virulence genes were detected using the VirulenceFinder database. RESULTS: In total, 103 E. coli blood isolates were sequenced. Isolates had six to 41 virulence genes present. One virulence gene, kpsMII_K23, a K1 capsule group 2 of E. coli type K23, was significantly more present in isolates of patients who died. kpsMII_K23 and cvaC (Microcin C) were significantly more frequent in isolates of patients who were admitted to the ICU. Fourteen virulence genes (mchB, mchC, papA_fsiA_F16, sat, senB, iucC, iutA, iha, sfaD, cnf1, focG, vat, cldB, and mcmA) significantly differed between patients with and without sepsis. CONCLUSIONS: Microcins, toxins, and fimbriae were associated with disease severity. Adhesins and iron uptake proteins seemed to be protective. Two genes were associated with worse clinical outcome. These findings contribute to a better understanding of host-pathogen interactions and could help identifying patients most at risk for a worse outcome.

An observational study on lifestyle and environmental risk factors in patients with acute appendicitis.

Purpose: Acute appendicitis is a common abdominal emergency worldwide. This study aimed at characterizing environmental risk factors influencing the development and severity of acute appendicitis. Methods: Patients from a Belgian acute appendicitis cohort (n = 374) and healthy controls from the 500 functional genomics (500FG) cohort (n = 513) were compared. Individuals with a history of appendectomy (n = 1067) and without a history of appendectomy (n = 8656) were available from the Nijmegen Biomedical Study (NBS). Questionnaires on demographics, lifestyle and environment were available. Binary logistic regression was used for prediction models. Results: Fifteen risk factors for developing acute appendicitis were identified. Binary logistic regression showed that 7 were independent risk factors: family history of acute appendicitis, having grown up in a rural environment, having a lower education, probiotic use as well as antibiotic use increased the risk of developing appendicitis. Fruit and fiber-rich vegetable consumption decreased the risk. Findings on vegetable consumption, smoking and level of education were replicated in the NBS population. Independent risk factors for complicated appendicitis were being male, higher age, and a delay to diagnosis of more than 48 h. Conclusions: Environmental exposures influence the risk of developing appendicitis. Further research into these factors is needed.

Forgotten antibiotics: an inventory in Europe, the United States, Canada, and Australia.

In view of the alarming spread of antimicrobial resistance in the absence of new antibiotics, this study aimed at assessing the availability of potentially useful older antibiotics. A survey was performed in 38 countries among experts including hospital pharmacists, microbiologists, and infectious disease specialists in Europe, the United States, Canada, and Australia. An international expert panel selected systemic antibacterial drugs for their potential to treat infections caused by resistant bacteria or their unique value for specific criteria. Twenty-two of the 33 selected antibiotics were available in fewer than 20 of 38 countries. Economic motives were the major cause for discontinuation of marketing of these antibiotics. Fourteen of 33 antibiotics are potentially active against either resistant Gram-positive or Gram-negative bacteria. Urgent measures are then needed to ensure better availability of these antibiotics on a global scale.