Abstract
Background
We aimed to determine the noninferiority of fosfomycin compared to ciprofloxacin as an oral step-down treatment for Escherichia coli febrile urinary tract infections (fUTIs) in ...women.
Methods
This was a double-blind, randomized, controlled trial in 15 Dutch hospitals. Adult women who were receiving 2–5 days of empirical intravenous antimicrobials for E. coli fUTI were assigned to step-down treatment with once-daily 3g fosfomycin or twice-daily 0.5g ciprofloxacin for 10 days of total antibiotic treatment. For the primary end point, clinical cure at days 6–10 post-end of treatment (PET), a noninferiority margin of 10% was chosen. The trial was registered on Trialregister.nl (NTR6449).
Results
After enrollment of 97 patients between 2017 and 2020, the trial ended prematurely because of the coronavirus disease 2019 pandemic. The primary end point was met in 36 of 48 patients (75.0%) assigned to fosfomycin and 30 of 46 patients (65.2%) assigned to ciprofloxacin (risk difference RD, 9.6%; 95% confidence interval CI: –8.8% to 28.0%). In patients assigned to fosfomycin and ciprofloxacin, microbiological cure at days 6–10 PET occurred in 29 of 37 (78.4%) and 33 of 35 (94.3%; RD, –16.2%; 95% CI: –32.7 to –0.0%). Any gastrointestinal adverse event was reported in 25 of 48 (52.1%) and 14 of 46 (30.4%) patients (RD, 20.8%; 95% CI: 1.6% to 40.0%), respectively.
Conclusions
Fosfomycin is noninferior to ciprofloxacin as oral step-down treatment for fUTI caused by E. coli in women. Fosfomycin use is associated with more gastrointestinal events.
Clinical Trial Registration
Trial NL6275 (NTR6449).
Fosfomycin is noninferior to ciprofloxacin regarding clinical cure as a targeted oral step-down treatment for Escherichia colifebrile urinary tract infections in women. Its use could prevent extended hospitalization in cases of resistance, intolerance, or allergies to existing step-down antibiotics.
Nitrofurantoin is the first-choice antibiotic treatment for uncomplicated urinary tract infections (UTIs) in males according to the Dutch primary care UTI guideline. However, prostate involvement may ...be undetected and renders this treatment less suitable.
To compare the nitrofurantoin failure fraction with that found with use of other antibiotics in adult males diagnosed by their GP with an uncomplicated UTI, as well as GP adherence to the Dutch primary care UTI guideline.
Retrospective observational cohort study using routine healthcare data for males seeking care at GP practices participating in the Julius GP Network from 2014 to 2020.
Medical records were screened for signs and symptoms of complicated UTIs, antibiotic prescriptions, and referrals. Treatment failure was defined as prescription of a different antibiotic within 30 days after initiation of antibiotic therapy and/or acute hospital referral. The effects of age and comorbidities on failure were assessed using multivariable logistic regression.
Most UTI episodes in males were uncomplicated (
= 6805/10 055 episodes, 68%). Nitrofurantoin was prescribed in 3788 (56%) of uncomplicated UTIs, followed by ciprofloxacin (
= 1887, 28%), amoxicillin/clavulanic acid (
= 470, 7%), and trimethoprim/sulfamethoxazole (
= 285, 4%). Antibiotic failure occurred in 25% (95% confidence interval CI = 23 to 26), 10% (95% CI = 9 to 12), 20% (95% CI = 16 to 24), and 14% (95% CI = 10 to 19) of episodes, respectively. The nitrofurantoin failure fraction increased with age. Comorbidities, adjusted for age, were not associated with nitrofurantoin failure.
Nitrofurantoin failure was common in males with uncomplicated UTI and increased with age.
To compare the effectiveness of 5 versus 7 days of nitrofurantoin treatment for urinary tract infection (UTI) in women with diabetes.
Data were collected retrospectively from Dutch general ...practitioners between 2013 and 2020. Nitrofurantoin prescriptions with a duration of 5 days (5DN) or 7 days (7DN) in women with diabetes were included. Inverse propensity weighting was performed to calculate adjusted risk differences (RD) for treatment failure within 28 days. Secondary outcomes were 14-day treatment failure, severe treatment failure and 28-day treatment failure in defined risk groups.
Nitrofurantoin was prescribed in 6866 episodes, 3247 (47.3%) episodes with 5DN and 3619 (52.7%) episodes with 7DN. Patients in the 7DN group had more co-morbidities, more diabetes-related complications and were more insulin-dependent. There were 517/3247 (15.9%) failures in the 5DN group versus 520/3619 (14.4%) in the 7DN group. The adjusted RD for failure within 28 days was 1.4% (95% CI –0.6 to 3.4).
We found no clinically significant difference in treatment failure in women with diabetes with UTI treated with either 5DN or 7DN within 28 days. A 5-day treatment should be considered to reduce cumulative nitrofurantoin exposure in DM patients.
Bacillus Calmette-Guerin (BCG) vaccination has been hypothesized to reduce severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, severity, and/or duration via trained immunity ...induction. Health care workers (HCWs) in nine Dutch hospitals were randomized to BCG or placebo vaccination (1:1) in March and April 2020 and followed for 1 year. They reported daily symptoms, SARS-CoV-2 test results, and health care-seeking behavior via a smartphone application, and they donated blood for SARS-CoV-2 serology at two time points. A total of 1,511 HCWs were randomized and 1,309 analyzed (665 BCG and 644 placebo). Of the 298 infections detected during the trial, 74 were detected by serology only. The SARS-CoV-2 incidence rates were 0.25 and 0.26 per person-year in the BCG and placebo groups, respectively (incidence rate ratio, 0.95; 95% confidence interval, 0.76 to 1.21;
= 0.732). Only three participants required hospitalization for SARS-CoV-2. The proportions of participants with asymptomatic, mild, or moderate infections and the mean infection durations did not differ between randomization groups. In addition, unadjusted and adjusted logistic regression and Cox proportional hazards models showed no differences between BCG and placebo vaccination for any of these outcomes. The percentage of participants with seroconversion (7.8% versus 2.8%;
= 0.006) and mean SARS-CoV-2 anti-S1 antibody concentration (13.1 versus 4.3 IU/mL;
= 0.023) were higher in the BCG than placebo group at 3 months but not at 6 or 12 months postvaccination. BCG vaccination of HCWs did not reduce SARS-CoV-2 infections nor infection duration or severity (ranging from asymptomatic to moderate). In the first 3 months after vaccination, BCG vaccination may enhance SARS-CoV-2 antibody production during SARS-CoV-2 infection.
While several BCG trials in adults were conducted during the 2019 coronavirus disease epidemic, our data set is the most comprehensive to date, because we included serologically confirmed infections in addition to self-reported positive SARS-CoV-2 test results. We also collected data on symptoms for every day during the 1-year follow-up period, which enabled us to characterize infections in detail. We found that BCG vaccination did not reduce SARS-CoV-2 infections nor infection duration or severity but may have enhanced SARS-CoV-2 antibody production during SARS-CoV-2 infection in the first 3 months after vaccination. These results are in agreement with other BCG trials that reported negative results (but did not use serological endpoints), except for two trials in Greece and India that reported positive results but had few endpoints and included endpoints that were not laboratory confirmed. The enhanced antibody production is in agreement with prior mechanistic studies but did not translate into protection from SARS-CoV-2 infection.
Urinary Tract Infections (UTIs) are among the most frequently occurring infections in the hospital. Urinalysis and urine culture are the main tools used for diagnosis. Whereas urinalysis is ...sufficiently sensitive for detecting UTI, it has a relatively low specificity, leading to unnecessary treatment with antibiotics and the risk of increasing antibiotic resistance. We performed an evaluation of the current diagnostic process with an expert-based label for UTI as outcome, retrospectively established using data from the Electronic Health Records. We found that the combination of urinalysis results with the Gram stain and other readily available parameters can be used effectively for predicting UTI. Based on the obtained information, we engineered a clinical decision support system (CDSS) using the reliable semi-supervised ensemble learning (RESSEL) method, and found it to be more accurate than urinalysis or the urine culture for prediction of UTI. The CDSS provides clinicians with this prediction within hours of ordering a culture and thereby enables them to hold off on prematurely prescribing antibiotics for UTI while awaiting the culture results.
BACKGROUNDMycobacterium tilburgii is an opportunistic pathogen that has only been described 11 times in the literature. Hyperammonemia as a resulting symptom of a mycobacterial infection has only ...been reported once. We describe a patient with a disseminated M. tilburgii infection, leading to hyperammonemia.
CASE PRESENTATIONA 57-year-old man was referred with stupor, rapidly declining to coma. Hyperammonemia was found as the underlying cause. Ammonia-lowering interventions had an overall disappointing effect. Frequent causes of hyperammonemia were excluded. Finally, a disseminated opportunistic M. tilburgii infection was diagnosed by using 16sRNA sequencing. A combination of antimicrobial drugs was started, after which ammonia level declined and consciousness improved. Unfortunately, it failed to eradicate the infection. The patient died od pneumonia and multiorgan failure.
CONCLUSIONSHyperammonemia requires an urgent response to prevent cerebral damage. M. tilburgii is not cultivable and diagnosis is performed using 16S RNA sequencing. Long-term antimicrobial drugs are required for eradication.
Bacille Calmette-Guérin (BCG) induces long-term boosting of innate immunity, termed trained immunity, and decreases susceptibility to respiratory tract infections. BCG vaccination trials for reducing ...SARS-CoV-2 infection are underway, but concerns have been raised regarding the potential harm of strong innate immune responses. To investigate the safety of BCG vaccination, we retrospectively assessed coronavirus disease 2019 (COVID-19) and related symptoms in three cohorts of healthy volunteers who either received BCG in the last 5 years or did not. BCG vaccination is not associated with increased incidence of symptoms during the COVID-19 outbreak in the Netherlands. Our data suggest that BCG vaccination might be associated with a decrease in the incidence of sickness during the COVID-19 pandemic (adjusted odds ratio AOR 0.58, p < 0.05), and lower incidence of extreme fatigue. In conclusion, recent BCG vaccination is safe, and large randomized trials are needed to reveal if BCG reduces the incidence and/or severity of SARS-CoV-2 infection.
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Recent BCG vaccination is safe during the COVID-19 pandemicBCG vaccination is not associated with symptoms of hyperinflammationBCG might be associated with reduced incidence of sickness and extreme fatigueRandomized trials of BCG vaccination for the prevention of COVID-19 are warranted
Moorlag et al. show in a retrospective cohort study that recent BCG vaccination is safe and did not increase disease symptoms during the COVID-19 outbreak. Prospective randomized clinical trials are warranted to assess BCG vaccination effectiveness against SARS-CoV-2 infection.
The objectives of these two separate trials are: (1) to reduce health care workers (HCWs) absenteeism; and (2) to reduce hospital admission among the elderly during the COVID-19 pandemic through BCG ...vaccination.
Two separate multi-centre placebo-controlled parallel group randomized trials PARTICIPANTS: (1) Health care personnel working in the hospital or ambulance service where they will take care of patients with the COVID-19 infection and (2) elderly ≥60 years. The HCW trial is being undertaken in 9 hospitals. The elderly trial is being undertaken in locations in the community in Nijmegen, Utrecht, and Veghel, in the Netherlands, using senior citizen organisations to facilitate recruitment.
For both trials the intervention group will be randomized to vaccination with 0.1 ml of the licensed BCG vaccine (Danish strain 1331, SSI, Denmark, equivalent to 0.075 mg attenuated M. bovis). The placebo group consists of 0.1 ml 0.9% NaCl, which is the same amount, and has the same colour and appearance as the suspended BCG vaccine.
(1) Number of days of unplanned work absenteeism in HCWs for any reason which can be continuously measured on a bi-weekly basis, and (2) the cumulative incidence of hospital admission due to documented COVID-19.
Participants will be randomized to BCG vaccine or placebo (1;1) centrally using a computer- based system, stratified by study centre.
Subjects, investigators, physicians and outcome assessors are blinded for the intervention. Only the pharmacist assistant that prepares- and research personnel that administers- study medicines are unblinded. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): (1) The sample size for the first trial is N=1500 HCWs randomised 1:1 to either BCG vaccine (n=750) and placebo (n=750) and (2) The sample size for the second trial is N=1600 elderly persons randomised to BCG vaccine (n=800) and the placebo group (n=800).
HCW: version 4.0, 24-04-2020. Recruitment began 25-03-2020 and was completed on the 23-04-2020. Elderly: version 3.0, 04-04-2020. Recruitment began 16-04- 2020 and is ongoing.
The HCWs trial was registered 31-03-2020 at clinicaltrials.gov (identifier: NCT04328441) and registered 20-03-2020 at the Dutch Trial Registry (trialregister.nl, identifier Trial NL8477). The elderly trial was registered 22-04-2020 at the Dutch trial registry with number NL8547.
The full protocols will be attached as additional files, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
Febrile Urinary Tract Infection (FUTI) is frequently treated initially with intravenous antibiotics, followed by oral antibiotics guided by clinical response and bacterial susceptibility patterns. ...Due to increasing infection rates with multiresistant Enterobacteriaceae, antibiotic options for stepdown treatment decline and patients more frequently require continued intravenous antibiotic treatment for FUTI. Fosfomycin is an antibiotic with high bactericidal activity against Escherichia coli and current resistance rates are low in most countries. Oral Fosfomycin-Trometamol 3000 mg (FT) reaches appropriate antibiotic concentrations in urine and blood and is considered safe. As such, it is a potential alternative for stepdown treatment.
The FORECAST study (Fosfomycin Randomized controlled trial for E.coli urinary tract infections as Alternative Stepdown Treatment) is a randomized, double-blind, double-dummy, non-inferiority trial in which 240 patients will be randomly allocated to a stepdown treatment with FT or ciprofloxacin (standard of care) for FUTI, caused by Escherichia coli with in vitro susceptibility to both antibiotics. The study population consists of consenting female patients (≥18 years) with community acquired E. coli FUTI. After intravenous antibiotic treatment during at least 48 (but less than 120) hours, and if eligibility criteria for iv-oral switch are met, patients receive either FT (3 g every 24 h) or ciprofloxacin (500 mg every 12 h) for a total antibiotic duration of 10 days. The primary endpoint is clinical cure (resolution of symptoms) 6-10 days post-treatment. Secondary endpoints are microbiological cure 6-10 days post-treatment, clinical cure, mortality, ICU admittance, relapse, reinfection, readmission, additional antibiotic use for UTI, early study discontinuation, adverse events, days of hospitalization and days of absenteeism within 30-35 days post-treatment. The sample size is based on achieving non-inferiority on the primary endpoint, applying a non-inferiority margin of 10%, a two-sided p-value of < 0.05 and a power of 80%.
The study aims to demonstrate non-inferiority of oral fosfomycin, compared to oral ciprofloxacin, in the stepdown treatment of E. coli FUTI.
Registered at the Nederlands trial register (Dutch trial register) on 4-10-2017.
NTR6449 . Secondary ID (national authority): NL60186.041.17.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
SARS-CoV-2 infections elicit antibodies against the viral spike (S) and nucleocapsid (N) proteins; COVID-19 vaccines against the S-protein only. The BCG-Corona trial, initiated in March 2020 in ...SARS-CoV-2-naïve Dutch healthcare workers, captured several epidemic peaks and the introduction of COVID-19 vaccines during the one-year follow-up. We assessed determinants of systemic anti-S1 and anti-N immunoglobulin type G (IgG) responses using trial data. Participants were randomised to BCG or placebo vaccination, reported daily symptoms, SARS-CoV-2 test results, and COVID-19 vaccinations, and donated blood for SARS-CoV-2 serology at two time points. In the 970 participants, anti-S1 geometric mean antibody concentrations (GMCs) were much higher than anti-N GMCs. Anti-S1 GMCs significantly increased with increasing number of immune events (SARS-CoV-2 infection or COVID-19 vaccination): 104.7 international units (IU)/mL, 955.0 IU/mL, and 2290.9 IU/mL for one, two, and three immune events, respectively (p < 0.001). In adjusted multivariable linear regression models, anti-S1 and anti-N log10 concentrations were significantly associated with infection severity, and anti-S1 log10 concentration with COVID-19 vaccine type/dose. In univariable models, anti-N log10 concentration was also significantly associated with acute infection duration, and severity and duration of individual symptoms. Antibody concentrations were not associated with long COVID or long-term loss of smell/taste.