[The problem of formation of new risks of medicinal resistance of patients with tuberculosis in condition of active use of antibiotics by population under COVID-19].

In pandemic conditions, situation of active and uncontrolled use by population of antimicrobial preparations treating COVID-19 occurs. So, new risks of development of medication resistance among patients with various infectious diseases, tuberculosis included, appear. The purpose of the study is to characterize prevalence of antimicrobial preparations use by population in relationship with development of medication resistance in patients with tuberculosis during COVID-19 pandemic. Material and methods. The analysis of sales of antimicrobial medicines was implemented on the basis of published official data from the joint-stock company DSM Group presenting monthly audit of the Russian pharmaceutical market. The determination of primary antibiotic resistance was carried out in 2018-2020 on 3312 patients with tuberculosis. The modified method of proportions on liquid nutrient medium in system with automated accounting of microorganisms growth, the method of absolute concentrations and the method of polymerase chain reaction with real-time detection were applied. The results of the study. It was established that the most demanding antimicrobial medications among population were ceftriaxone, azithromycin, levofloxacin, moxifloxacin, azithromycin. At the same time, the maximum increase in sales in 2020 up to 150% as compared with of 2019 was determined in medications derived from quinolone moxifloxacin, levofloxacin, which began to be used in treatment of coronavirus infection. At the same time, these medications are traditionally used in tuberculosis treatment. But in 2020, alarming trend was established that limits treatment of tuberculosis patients. The primary resistance of mycobacteria was also established in newly diagnosed tuberculosis patients, also for the same antimicrobial medications of quinolone derivatives, and increasing in proportion of patients with primary medication resistance to levofloxacin, moxifloxacin in 2020 as compared to 2018 was 189-480%. At the same time, increasing of resistance to other antibiotics made up to 60.8% on average. Conclusion. The study results imply alarming scenario of medication resistance shifts towards very virulent and highly medication-resistant genotypes. This trend can result in conditions of successful transmission of deadly medication-resistant mutants that can seriously undermine effectiveness of implemented programs of struggle with tuberculosis worldwide.

Intermittent prophylactic antibiotics for bronchiectasis.

BACKGROUND: Bronchiectasis is a common but under-diagnosed chronic disorder characterised by permanent dilation of the airways arising from a cycle of recurrent infection and inflammation. Symptoms including chronic, persistent cough and productive phlegm are a significant burden for people with bronchiectasis, and the main aim of treatment is to reduce exacerbation frequency and improve quality of life. Prophylactic antibiotic therapy aims to break this infection cycle and is recommended by clinical guidelines for adults with three or more exacerbations a year, based on limited evidence. It is important to weigh the evidence for bacterial suppression against the prevention of antibiotic resistance and further evidence is required on the safety and efficacy of different regimens of intermittently administered antibiotic treatments for people with bronchiectasis. OBJECTIVES: To evaluate the safety and efficacy of intermittent prophylactic antibiotics in the treatment of adults and children with bronchiectasis. SEARCH METHODS: We identified trials from the Cochrane Airways Trials Register, which contains studies identified through multiple electronic searches and handsearches of other sources. We also searched trial registries and reference lists of primary studies. We conducted searches on 6 September 2021, with no restriction on language of publication. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of at least three months' duration comparing an intermittent regime of prophylactic antibiotics with placebo, usual care or an alternate intermittent regimen. Intermittent prophylactic administration was defined as repeated courses of antibiotics with on-treatment and off-treatment intervals of at least 14 days' duration. We included adults and children with a clinical diagnosis of bronchiectasis confirmed by high resolution computed tomography (HRCT), plain film chest radiograph, or bronchography and a documented history of recurrent chest infections. We excluded studies where participants received high dose antibiotics immediately prior to enrolment or those with a diagnosis of cystic fibrosis, allergic bronchopulmonary aspergillosis (ABPA), primary ciliary dyskinesia, hypogammaglobulinaemia, sarcoidosis, or a primary diagnosis of COPD. Our primary outcomes were exacerbation frequency and serious adverse events. We did not exclude studies on the basis of review outcomes. DATA COLLECTION AND ANALYSIS: We analysed dichotomous data as odds ratios (ORs) or relative risk (RRs) and continuous data as mean differences (MDs) or standardised mean differences (SMDs). We used standard methodological procedures expected by Cochrane. We conducted GRADE assessments for the following primary outcomes: exacerbation frequency; serious adverse events and secondary outcomes: antibiotic resistance; hospital admissions; health-related quality of life. MAIN RESULTS: We included eight RCTs, with interventions ranging from 16 to 48 weeks, involving 2180 adults. All evaluated one of three types of antibiotics over two to six cycles of 28 days on/off treatment: aminoglycosides, ß-lactams or fluoroquinolones. Two studies also included 12 cycles of 14 days on/off treatment with fluoroquinolones. Participants had a mean age of 63.6 years, 65% were women and approximately 85% Caucasian. Baseline FEV1 ranged from 55.5% to 62.6% predicted. None of the studies included children. Generally, there was a low risk of bias in the included studies. Antibiotic versus placebo: cycle of 14 days on/off. Ciprofloxacin reduced the frequency of exacerbations compared to placebo (RR 0.75, 95% CI 0.61 to 0.93; I2 = 65%; 2 studies, 469 participants; moderate-certainty evidence), with eight people (95% CI 6 to 28) needed to treat for an additional beneficial outcome. The intervention increased the risk of antibiotic resistance more than twofold (OR 2.14, 95% CI 1.36 to 3.35; I2 = 0%; 2 studies, 624 participants; high-certainty evidence). Serious adverse events, lung function (FEV1), health-related quality of life, and adverse effects did not differ between groups. Antibiotic versus placebo: cycle of 28 days on/off. Antibiotics did not reduce overall exacerbation frequency (RR 0.92, 95% CI 0.82 to 1.02; I2 = 0%; 8 studies, 1695 participants; high-certainty evidence) but there were fewer severe exacerbations (OR 0.59, 95% CI 0.37 to 0.93; I2 = 54%; 3 studies, 624 participants), though this should be interpreted with caution due to low event rates. The risk of antibiotic resistance was more than twofold higher based on a pooled analysis (OR 2.20, 95% CI 1.42 to 3.42; I2 = 0%; 3 studies, 685 participants; high-certainty evidence) and consistent with unpooled data from four further studies. Serious adverse events, time to first exacerbation, duration of exacerbation, respiratory-related hospital admissions, lung function, health-related quality of life and adverse effects did not differ between study groups. Antibiotic versus usual care. We did not find any studies that compared intermittent antibiotic regimens with usual care. Cycle of 14 days on/off versus cycle of 28 days on/off. Exacerbation frequency did not differ between the two treatment regimens (RR 1.02, 95% CI 0.84 to 1.24; I2 = 71%; 2 studies, 625 participants; moderate-certainty evidence) However, inconsistencies in the results from the two trials in this comparison indicate that the apparent aggregated similarities may not be reliable. There was no evidence of a difference in antibiotic resistance between groups (OR 1.00, 95% CI 0.68 to 1.48; I2 = 60%; 2 studies, 624 participants; moderate-certainty evidence). Serious adverse events, adverse effects, lung function and health-related quality of life did not differ between the two antibiotic regimens. AUTHORS' CONCLUSIONS: Overall, in adults who have frequent chest infections, long-term antibiotics given at 14-day on/off intervals slightly reduces the frequency of those infections and increases antibiotic resistance. Intermittent antibiotic regimens result in little to no difference in serious adverse events. The impact of intermittent antibiotic therapy on children with bronchiectasis is unknown due to an absence of evidence, and further research is needed to establish the potential risks and benefits.

Decreasing ICU-associated Clostridioides difficile infection through fluoroquinolone restriction, the FIRST trial: a study protocol.

INTRODUCTION: Clostridioides difficile infection (CDI) is one of the most common healthcare-associated infections in the USA, having high incidence in intensive care units (ICU). Antibiotic use increases risk of CDI, with fluoroquinolones (FQs) particularly implicated. In healthcare settings, antibiotic stewardship (AS) and infection control interventions are effective in CDI control, but there is little evidence regarding the most effective AS interventions. Preprescription authorisation (PPA) restricting FQs is a potentially promising AS intervention to reduce CDI. The FQ Restriction for the Prevention of CDI (FIRST) trial will evaluate the effectiveness of an FQ PPA intervention in reducing CDI rates in adult ICUs compared with preintervention care, and evaluate implementation effectiveness using a human-factors and systems engineering model. METHODS AND ANALYSIS: This is a multisite, stepped-wedge, cluster, effectiveness-implementation clinical trial. The trial will take place in 12 adult medical-surgical ICUs with ≥10 beds, using Epic as electronic health record (EHR) and pre-existing AS programmes. Sites will receive facilitated implementation support over the 15-month trial period, succeeded by 9 months of follow-up. The intervention comprises a clinical decision support system for FQ PPA, integrated into the site EHRs. Each ICU will be considered a single site and all ICU admissions included in the analysis. Clinical data will be extracted from EHRs throughout the trial and compared with the corresponding pretrial period, which will constitute the baseline for statistical analysis. Outcomes will include ICU-onset CDI rates, FQ days of therapy (DOT), alternative antibiotic DOT, average length of stay and hospital mortality. The study team will also collect implementation data to assess implementation effectiveness using the Systems Engineering Initiative for Patient Safety model. ETHICS AND DISSEMINATION: The trial was approved by the Institutional Review Board at the University of Wisconsin-Madison (2018-0852-CP015). Results will be made available to participating sites, funders, infectious disease societies, critical care societies and other researchers. TRIAL REGISTRATION NUMBER: NCT03848689.

Repurposing of antibiotics for clinical management of COVID-19: a narrative review.

BACKGROUND: Drug repurposing otherwise known as drug repositioning or drug re-profiling is a time-tested approach in drug discovery through which new medical uses are being established for already known drugs. Antibiotics are among the pharmacological agents being investigated for potential anti-SARS-COV-2 activities. The antibiotics are used either to resolve bacterial infections co-existing with COVID-19 infections or exploitation of their potential antiviral activities. Herein, we aimed to review the various antibiotics that have been repositioned for the management of COVID-19. METHODS: This literature review was conducted from a methodical search on PubMed and Web of Science regarding antibiotics used in patients with COVID-19 up to July 5, 2020. RESULTS: Macrolide and specifically azithromycin is the most common antibiotic used in the clinical management of COVID-19. The other antibiotics used in COVID-19 includes teicoplanin, clarithromycin, doxycycline, tetracyclines, levofloxacin, moxifloxacin, ciprofloxacin, and cefuroxime. In patients with COVID-19, antibiotics are used for their immune-modulating, anti-inflammatory, and antiviral properties. The precise antiviral mechanism of most of these antibiotics has not been determined. Moreover, the use of some of these antibiotics against SARS-CoV-2 infection remains highly controversial and not widely accepted. CONCLUSION: The heavy use of antibiotics during the COVID-19 pandemic would likely worsen antibiotic resistance crisis. Consequently, antibiotic stewardship should be strengthened in order to prevent the impacts of COVID-19 on the antibiotic resistance crisis.

Use of repurposed and adjuvant drugs in hospital patients with covid-19: multinational network cohort study.

OBJECTIVE: To investigate the use of repurposed and adjuvant drugs in patients admitted to hospital with covid-19 across three continents. DESIGN: Multinational network cohort study. SETTING: Hospital electronic health records from the United States, Spain, and China, and nationwide claims data from South Korea. PARTICIPANTS: 303 264 patients admitted to hospital with covid-19 from January 2020 to December 2020. MAIN OUTCOME MEASURES: Prescriptions or dispensations of any drug on or 30 days after the date of hospital admission for covid-19. RESULTS: Of the 303 264 patients included, 290 131 were from the US, 7599 from South Korea, 5230 from Spain, and 304 from China. 3455 drugs were identified. Common repurposed drugs were hydroxychloroquine (used in from <5 (<2%) patients in China to 2165 (85.1%) in Spain), azithromycin (from 15 (4.9%) in China to 1473 (57.9%) in Spain), combined lopinavir and ritonavir (from 156 (<2%) in the VA-OMOP US to 2,652 (34.9%) in South Korea and 1285 (50.5%) in Spain), and umifenovir (0% in the US, South Korea, and Spain and 238 (78.3%) in China). Use of adjunctive drugs varied greatly, with the five most used treatments being enoxaparin, fluoroquinolones, ceftriaxone, vitamin D, and corticosteroids. Hydroxychloroquine use increased rapidly from March to April 2020 but declined steeply in May to June and remained low for the rest of the year. The use of dexamethasone and corticosteroids increased steadily during 2020. CONCLUSIONS: Multiple drugs were used in the first few months of the covid-19 pandemic, with substantial geographical and temporal variation. Hydroxychloroquine, azithromycin, lopinavir-ritonavir, and umifenovir (in China only) were the most prescribed repurposed drugs. Antithrombotics, antibiotics, H2 receptor antagonists, and corticosteroids were often used as adjunctive treatments. Research is needed on the comparative risk and benefit of these treatments in the management of covid-19.