Probiotics for the Prevention of Antibiotic-Associated Diarrhea in Outpatients:A Systematic Review and Meta-Analysis

A common adverse effect of antibiotic use is diarrhea. Probiotics are living microorganisms, which, upon oral ingestion, may prevent antibiotic-associated diarrhea (AAD) by the normalization of an unbalanced gastrointestinal flora. The objective of this systematic review was to assess the benefits and harms of probiotics used for the prevention of AAD in an outpatient setting. A search of the PubMed database was conducted and yielded a total of 17 RCTs with 3631 participants to be included in the review. A meta-analysis was conducted for the primary outcome: the incidence of AAD. The pooled results found that AAD was present in 8.0% of the probiotic group compared to 17.7% in the control group (RR 0.49, 95% CI 0.36 to 0.66; I2 = 58%), and the species-specific results were similar regarding the probiotic strains L. rhamnosus GG and S. boulardii. However, the overall quality of the included studies was moderate. A meta-analysis of the ten trials reporting adverse events demonstrated no statistically significant differences in the incidence of adverse events between the intervention and control group (RD 0.00, 95% CI −0.02 to 0.02, 2.363 participants). The results suggests that probiotic use may be beneficial in the prevention of AAD among outpatients. Furthermore, the use of probiotics appears safe

Prescribing style and variation in antibiotic prescriptions for sore throat: cross-sectional study across six countries

BACKGROUND: Variation in prescription of antibiotics in primary care can indicate poor clinical practice that contributes to the increase of resistant strains. General Practitioners (GPs), as a professional group, are expected to have a fairly homogeneous prescribing style. In this paper, we describe variation in prescribing style within and across groups of GPs from six countries. METHODS: Cross-sectional study with the inclusion of 457 GPs and 6394 sore throat patients. We describe variation in prescribing antibiotics for sore throat patients across six countries and assess whether variation in “prescribing style” – understood as a subjective tendency to prescribe – has an important effect on variation in prescription of antibiotics by using the concept of prescribing style as a latent variable in a multivariable model. We report variation as a Median Odds Ratio (MOR) which is the transformation of the random effect variance onto an odds ratio; Thus, MOR = 1 means similar odds or strict homogeneity between GPs’ prescribing style, while a MOR higher than 1 denotes heterogeneity in prescribing style. RESULTS: In all countries some GPs always prescribed antibiotics to all their patients, while other GPs never did. After adjusting for patient and GP characteristics, prescribing style in the group of GPs from Russia was about three times more heterogeneous than the prescribing style in the group of GPs from Denmark – Median Odds Ratio (6.8, 95% CI 3.1;8.8) and (2.6, 95% CI 2.2;4.4) respectively. CONCLUSION: Prescribing style is an important source of variation in prescription of antibiotics within and across countries, even after adjusting for patient and GP characteristics. Interventions aimed at influencing the prescribing style of GPs must encompass context-specific actions at the policy-making level alongside GP-targeted interventions to enable GPs to react more objectively to the external demands that are in place when making the decision of prescribing antibiotics or not

Changes in HbA_1cduring the first six years after the diagnosis of Type 2 diabetes mellitus predict long-term microvascular outcomes

To analyze the association between change in HbA1c during the first 6 years after diagnosis of Type 2 diabetes mellitus (Type 2 DM) and incident micro- and macrovascular morbidity and mortality during 13 years thereafter. This is an observational study of the participants in the intervention arm of the randomized controlled trial Diabetes Care in General Practice (DCGP) in Denmark. 494 newly diagnosed persons with Type 2 DM aged 40 years and over with three or more measurements of HbA1c during six years of intervention were included in the analyses. Based on a regression line, fitted through the HbA1c-measurements from 1 to 6 years after diabetes diagnosis, glycaemic control was characterized by the one-year level of HbA1c after diagnosis, and the slope of the regression line. Outcomes were incident diabetes-related morbidity and mortality from 6 to 19 years after diabetes diagnosis. The association between change in HbA1c (the slope of the regression line) and clinical outcomes were assessed in adjusted Cox regression models. The median HbA1c level at year one was 60 (IQR: 52-71) mmol/mol or (7.65 (IQR: 6.91-8.62) %). Higher HbA1c levels one year after diagnosis were associated with a higher risk of later diabetes-related morbidity and mortality. An increase in HbA1c during the first 6 years after diabetes diagnosis was associated with later microvascular complications (HR per 1.1 mmol/mol or 0.1% point increase in HbA1c per year; 95% CI) = 1.14; 1.05-1.24). Change in HbA1c did not predict the aggregate outcome 'any diabetes-related endpoint, all-cause mortality, diabetes-related mortality, myocardial infarction, stroke, or peripheral vascular diseases. We conclude that suboptimal development of glycaemic control during the first 6 years after diabetes diagnosis was an independent risk factor for microvascular complications during the succeeding 13-year follow-up, but not for mortality or macrovascular complications

Prescribing antibiotics:the use of diagnostic tests in general practice. A register-based study

OBJECTIVE: To assess (i) the pattern of antibiotic prescribing in Danish general practice, (ii) the use of diagnostic tests [point-of-care (POC) and tests analysed at the hospital laboratory (laboratory tests)], and (iii) the frequency of diagnostic testing in relation to antibiotic prescriptions. DESIGN: Retrospective cross-sectional register-based study. SETTING: General practice in a geographical area of Denmark covering 455,956 inhabitants. SUBJECTS: We studied redeemed antibiotic prescriptions and performed diagnostic tests in general practice from 2013 to 2017 among inhabitants in nine selected municipalities. MAIN OUTCOME MEASURES: Frequency of antibiotic courses. Frequency and type of diagnostic testing performed in relation to types of antibiotics. RESULTS: A total of 783,252 antibiotic courses were redeemed from general practice with an overall decrease of 19% during 2013–2017. Diagnostic testing increased by 6% during this period. POC tests comprised the majority of performed diagnostic tests (83%) with C-reactive protein (CRP) as the most frequently used test. A 27% increase in the use of laboratory tests was observed. Tests were performed in relation to 43% of all antibiotic courses; most in relation to prescriptions for sulphonamide and trimethoprim (57%) and rarely when prescribing tetracyclines (10%). Conflicting with national guidelines, Danish GPs prescribed fluoroquinolones without performing any kind of diagnostic testing in 48% of the cases. CONCLUSIONS: This study provides an overview of the use of diagnostic tests in relation to antibiotics and creates basis for further research into the variability between types of antibiotics. The study indicates that there is room for improvement to use diagnostic tests as an aid to promote prudent antibiotic use. KEY POINTS: Diagnostic tests (point-of-care or tests analysed at the hospital laboratory), can increase diagnostic certainty and lead to a reduction in antibiotic use in general practice. A decrease in antibiotic courses in general practice in Denmark was observed during 2013–2017, while the use of diagnostic tests increased. A diagnostic test was performed in relation to 43% of antibiotic courses. Only 52% of prescribed fluoroquinolones was related to a diagnostic test, conflicting with national guidelines

Factors associated with C-reactive protein testing when prescribing antibiotics in general practice:a register-based study

BACKGROUND: The use of C-reactive protein (CRP) tests has been shown to safely reduce antibiotic prescribing for acute respiratory tract infections (RTIs). The aim of this study was to explore patient and clinical factors associated with the use of CRP testing when prescribing antibiotics recommended for RTIs. METHODS: A nation-wide retrospective cross-sectional register-based study based on first redeemed antibiotic prescriptions issued to adults in Danish general practice between July 2015 and June 2017. Only antibiotics recommended for treatment of RTIs were included in the analysis (penicillin-V, amoxicillin, co-amoxicillin or roxithromycin/clarithromycin). Logistic regression models were used to estimate odds ratios for patient-related and clinical factors on performing a CRP test in relation to antibiotic prescribing. RESULTS: A total of 984,149 patients redeemed at least one antibiotic prescription during the two-year period. About half of these prescriptions (49.6%) had an RTI stated as the indication, and a CRP test was performed in relation to 45.2% of these scripts. Lower odds of having a CRP test performed in relation to an antibiotic prescription was found for patients aged 75 years and above (OR 0.82, 95CI 0.79–0.86), with a Charlson Comorbidity Index of more than one (OR 0.93, 95CI 0.91–0.95), unemployed or on disability pension (OR 0.84, 95CI 0.83–0.85) and immigrants (OR 0.91, 95CI 0.88–0.95) or descendants of immigrants (OR 0.90, 95CI 0.84–0.96). Living with a partner (OR 1.08, 95CI 1.07–1.10), being followed in practice for a chronic condition (OR 1.22, 95CI 1.18–1.26) and having CRP tests performed in the previous year (OR 1.78, 95CI 1.73–1.84) were associated with higher odds of CRP testing in relation to antibiotic prescribing. CONCLUSIONS: Differences were observed in the use of CRP tests among subgroups of patients indicating that both sociodemographic factors and comorbidity influence the decision to use a CRP test in relation to antibiotic prescriptions in general practice. Potentially, this means that the use of CRP tests could be optimised to increase diagnostic certainty and further promote rational prescribing of antibiotics. The rationale behind the observed differences could be further explored in future qualitative studies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12875-021-01614-6

Oral and Fecal Campylobacter concisus Strains Perturb Barrier Function by Apoptosis Induction in HT-29/B6 Intestinal Epithelial Cells

Campylobacter concisus infections of the gastrointestinal tract can be accompanied by diarrhea and inflammation, whereas colonization of the human oral cavity might have a commensal nature. We focus on the pathophysiology of C. concisus and the effects of different clinical oral and fecal C. concisus strains on human HT-29/B6 colon cells. Six oral and eight fecal strains of C. concisus were isolated. Mucus-producing HT-29/B6 epithelial monolayers were infected with the C. concisus strains. Transepithelial electrical resistance (Rt) and tracer fluxes of different molecule size were measured in Ussing chambers. Tight junction (TJ) protein expression was determined by Western blotting, and subcellular TJ distribution was analyzed by confocal laser-scanning microscopy. Apoptosis induction was examined by TUNEL-staining and Western blot of caspase-3 activation. All strains invaded confluent HT-29/B6 cells and impaired epithelial barrier function, characterized by a time- and dose-dependent decrease in Rt either after infection from the apical side but even more from the basolateral compartment. TJ protein expression changes were sparse, only in apoptotic areas of infected monolayers TJ proteins were redistributed. Solely the barrier-forming TJ protein claudin-5 showed a reduced expression level to 66±8% (P<0.05), by expression regulation from the gene. Concomitantly, Lactate dehydrogenase release was elevated to 3.1±0.3% versus 0.7±0.1% in control (P<0.001), suggesting cytotoxic effects. Furthermore, oral and fecal C. concisus strains elevated apoptotic events to 5-fold. C. concisus-infected monolayers revealed an increased permeability for 332 Da fluorescein (1.74±0.13 vs. 0.56±0.17 10−6 cm/s in control, P<0.05) but showed no difference in permeability for 4 kDa FITC-dextran (FD-4). The same was true in camptothecin-exposed monolayers, where camptothecin was used for apoptosis induction

Adverse events in people taking macrolide antibiotics versus placebo for any indication

BACKGROUND: Macrolide antibiotics (macrolides) are among the most commonly prescribed antibiotics worldwide and are used for a wide range of infections. However, macrolides also expose people to the risk of adverse events. The current understanding of adverse events is mostly derived from observational studies, which are subject to bias because it is hard to distinguish events caused by antibiotics from events caused by the diseases being treated. Because adverse events are treatment-specific, rather than disease-specific, it is possible to increase the number of adverse events available for analysis by combining randomised controlled trials (RCTs) of the same treatment across different diseases. OBJECTIVES:To quantify the incidences of reported adverse events in people taking macrolide antibiotics compared to placebo for any indication. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which includes the Cochrane Acute Respiratory Infections Group Specialised Register (2018, Issue 4); MEDLINE (Ovid, from 1946 to 8 May 2018); Embase (from 2010 to 8 May 2018); CINAHL (from 1981 to 8 May 2018); LILACS (from 1982 to 8 May 2018); and Web of Science (from 1955 to 8 May 2018). We searched clinical trial registries for current and completed trials (9 May 2018) and checked the reference lists of included studies and of previous Cochrane Reviews on macrolides. SELECTION CRITERIA: We included RCTs that compared a macrolide antibiotic to placebo for any indication. We included trials using any of the four most commonly used macrolide antibiotics: azithromycin, clarithromycin, erythromycin, or roxithromycin. Macrolides could be administered by any route. Concomitant medications were permitted provided they were equally available to both treatment and comparison groups. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted and collected data. We assessed the risk of bias of all included studies and the quality of evidence for each outcome of interest. We analysed specific adverse events, deaths, and subsequent carriage of macrolide-resistant bacteria separately. The study participant was the unit of analysis for each adverse event. Any specific adverse events that occurred in 5% or more of any group were reported. We undertook a meta-analysis when three or more included studies reported a specific adverse event. MAIN RESULTS: We included 183 studies with a total of 252,886 participants (range 40 to 190,238). The indications for macrolide antibiotics varied greatly, with most studies using macrolides for the treatment or prevention of either acute respiratory tract infections, cardiovascular diseases, chronic respiratory diseases, gastrointestinal conditions, or urogynaecological problems. Most trials were conducted in secondary care settings. Azithromycin and erythromycin were more commonly studied than clarithromycin and roxithromycin.Most studies (89%) reported some adverse events or at least stated that no adverse events were observed.Gastrointestinal adverse events were the most commonly reported type of adverse event. Compared to placebo, macrolides caused more diarrhoea (odds ratio (OR) 1.70, 95% confidence interval (CI) 1.34 to 2.16; low-quality evidence); more abdominal pain (OR 1.66, 95% CI 1.22 to 2.26; low-quality evidence); and more nausea (OR 1.61, 95% CI 1.37 to 1.90; moderate-quality evidence). Vomiting (OR 1.27, 95% CI 1.04 to 1.56; moderate-quality evidence) and gastrointestinal disorders not otherwise specified (NOS) (OR 2.16, 95% CI 1.56 to 3.00; moderate-quality evidence) were also reported more often in participants taking macrolides compared to placebo.The number of additional people (absolute difference in risk) who experienced adverse events from macrolides was: gastrointestinal disorders NOS 85/1000; diarrhoea 72/1000; abdominal pain 62/1000; nausea 47/1000; and vomiting 23/1000.The number needed to treat for an additional harmful outcome (NNTH) ranged from 12 (95% CI 8 to 23) for gastrointestinal disorders NOS to 17 (9 to 47) for abdominal pain; 19 (12 to 33) for diarrhoea; 19 (13 to 30) for nausea; and 45 (22 to 295) for vomiting.There was no clear consistent difference in gastrointestinal adverse events between different types of macrolides or route of administration.Taste disturbances were reported more often by participants taking macrolide antibiotics, although there were wide confidence intervals and moderate heterogeneity (OR 4.95, 95% CI 1.64 to 14.93; Iand#178; = 46%; low-quality evidence).Compared with participants taking placebo, those taking macrolides experienced hearing loss more often, however only four studies reported this outcome (OR 1.30, 95% CI 1.00 to 1.70; Iand#178; = 0%; low-quality evidence).We did not find any evidence that macrolides caused more cardiac disorders (OR 0.87, 95% CI 0.54 to 1.40; very low-quality evidence); hepatobiliary disorders (OR 1.04, 95% CI 0.27 to 4.09; very low-quality evidence); or changes in liver enzymes (OR 1.56, 95% CI 0.73 to 3.37; very low-quality evidence) compared to placebo.We did not find any evidence that appetite loss, dizziness, headache, respiratory symptoms, blood infections, skin and soft tissue infections, itching, or rashes were reported more often by participants treated with macrolides compared to placebo.Macrolides caused less cough (OR 0.57, 95% CI 0.40 to 0.80; moderate-quality evidence) and fewer respiratory tract infections (OR 0.70, 95% CI 0.62 to 0.80; moderate-quality evidence) compared to placebo, probably because these are not adverse events, but rather characteristics of the indications for the antibiotics. Less fever (OR 0.73, 95% 0.54 to 1.00; moderate-quality evidence) was also reported by participants taking macrolides compared to placebo, although these findings were non-significant.There was no increase in mortality in participants taking macrolides compared with placebo (OR 0.96, 95% 0.87 to 1.06; Iand#178; = 11%; low-quality evidence).Only 24 studies (13%) provided useful data on macrolide-resistant bacteria. Macrolide-resistant bacteria were more commonly identified among participants immediately after exposure to the antibiotic. However, differences in resistance thereafter were inconsistent.Pharmaceutical companies supplied the trial medication or funding, or both, for 91 trials. AUTHORS' CONCLUSIONS: The macrolides as a group clearly increased rates of gastrointestinal adverse events. Most trials made at least some statement about adverse events, such as "none were observed". However, few trials clearly listed adverse events as outcomes, reported on the methods used for eliciting adverse events, or even detailed the numbers of people who experienced adverse events in both the intervention and placebo group. This was especially true for the adverse event of bacterial resistance.</p

Antivirals for influenza-Like Illness? A randomised Controlled trial of Clinical and Cost effectiveness in primary CarE (ALIC4 E): the ALIC4 E protocol

INTRODUCTION: Effective management of seasonal and pandemic influenza is a high priority internationally. Guidelines in many countries recommend antiviral treatment for older people and individuals with comorbidity at increased risk of complications. However, antivirals are not often prescribed in primary care in Europe, partly because its clinical and cost effectiveness has been insufficiently demonstrated by non-industry funded and pragmatic studies. METHODS AND ANALYSIS: Antivirals for influenza-Like Illness? An rCt of Clinical and Cost effectiveness in primary CarE is a European multinational, multicentre, open-labelled, non-industry funded, pragmatic, adaptive-platform, randomised controlled trial. Initial trial arms will be best usual primary care and best usual primary care plus treatment with oseltamivir for 5 days. We aim to recruit at least 2500 participants ≥1 year presenting with influenza-like illness (ILI), with symptom duration ≤72 hours in primary care over three consecutive periods of confirmed high influenza incidence. Participant outcomes will be followed up to 28 days by diary and telephone. The primary objective is to determine whether adding antiviral treatment to best usual primary care is effective in reducing time to return to usual daily activity with fever, headache and muscle ache reduced to minor severity or less. Secondary objectives include estimating cost-effectiveness, benefits in subgroups according to age (64 years), severity of symptoms at presentation (low, medium and high), comorbidity (yes/no), duration of symptoms (≤48 hours/>48-72 hours), complications (hospital admission and pneumonia), use of additional prescribed medication including antibiotics, use of over-the-counter medicines and self-management of ILI symptoms. ETHICS AND DISSEMINATION: Research ethics committee (REC) approval was granted by the NRES Committee South Central (Oxford B) and Clinical Trial Authority (CTA) approval by The Medicines and Healthcare products Regulatory Agency. All participating countries gained national REC and CTA approval as required. Dissemination of results will be through peer-reviewed scientific journals and conference presentations

Should all acutely ill children in primary care be tested with point-of-care CRP: A cluster randomised trial

Background: Point-of-care blood C-reactive protein (CRP) testing has diagnostic value in helping clinicians rule out the possibility of serious infection. We investigated whether it should be offered to all acutely ill children in primary care or restricted to those identified as at risk on clinical assessment. Methods: Cluster randomised controlled trial involving acutely ill children presenting to 133 general practitioners (GPs) at 78 GP practices in Belgium. Practices were randomised to undertake point-of-care CRP testing in all children (1730 episodes) or restricted to children identified as at clinical risk (1417 episodes). Clinical risk was assessed by a validated clinical decision rule (presence of one of breathlessness, temperature ≥ 40 °C, diarrhoea and age 12-30 months, or clinician concern). The main trial outcome was hospital admission with serious infection within 5 days. No specific guidance was given to GPs on interpreting CRP levels but diagnostic performance is reported at 5, 20, 80 and 200 mg/L. Results: Restricting CRP testing to those identified as at clinical risk substantially reduced the number of children tested by 79.9 % (95 % CI, 77.8-82.0 %). There was no significant difference between arms in the number of children with serious infection who were referred to hospital immediately (0.16 % vs. 0.14 %, P = 0.88). Only one child with a CRP < 5 mg/L had an illness requiring admission (a child with viral gastroenteritis admitted for rehydration). However, of the 80 children referred to hospital to rule out serious infection, 24 (30.7 %, 95 % CI, 19.6-45.6 %) had a CRP < 5 mg/L. Conclusions: CRP testing should be restricted to children at higher risk after clinical assessment. A CRP < 5 mg/L rules out serious infection and could be used by GPs to avoid unnecessary hospital referrals

Investigation of the Enteric Pathogenic Potential of Oral Campylobacter concisus Strains Isolated from Patients with Inflammatory Bowel Disease

BACKGROUND: Campylobacter concisus, a bacterium colonizing the human oral cavity, has been shown to be associated with inflammatory bowel disease (IBD). This study investigated if patients with IBD are colonized with specific oral C. concisus strains that have potential to cause enteric diseases. METHODOLOGY: Seventy oral and enteric C. concisus isolates obtained from eight patients with IBD and six controls were examined for housekeeping genes by multilocus sequence typing (MLST), Caco2 cell invasion by gentamicin-protection-assay, protein analysis by mass spectrometry and SDS-PAGE, and morphology by scanning electron microscopy. The whole genome sequenced C. concisus strain 13826 which was isolated from an individual with bloody diarrhea was included in MLST analysis. PRINCIPAL FINDINGS: MLST analysis showed that 87.5% of individuals whose C. concisus belonged to Cluster I had inflammatory enteric diseases (six IBD and one with bloody diarrhea), which was significantly higher than that in the remaining individuals (28.6%) (P<0.05). Enteric invasive C. concisus (EICC) oral strain was detected in 50% of patients with IBD and none of the controls. All EICC strains were in Cluster 1. The C. concisus strain colonizing intestinal tissues of patient No. 1 was closely related to the oral C. concisus strain from patient No. 6 and had gene recombination with the patient's own oral C. concisus. The oral and intestinal C. concisus strains of patient No. 3 were the same strain. Some individuals were colonized with multiple oral C. concisus strains that have undergone natural recombination. CONCLUSIONS: This study provides the first evidence that patients with IBD are colonized with specific oral C. concisus strains, with some being EICC strains. C. concisus colonizing intestinal tissues of patients with IBD at least in some instances results from an endogenous colonization of the patient's oral C. concisus and that C. concisus strains undergo natural recombination