Antimicrobial resistance in patients with COVID-19: a systematic review and meta-analysis.

BACKGROUND: Frequent use of antibiotics in patients with COVID-19 threatens to exacerbate antimicrobial resistance. We aimed to establish the prevalence and predictors of bacterial infections and antimicrobial resistance in patients with COVID-19. METHODS: We did a systematic review and meta-analysis of studies of bacterial co-infections (identified within ≤48 h of presentation) and secondary infections (>48 h after presentation) in outpatients or hospitalised patients with COVID-19. We searched the WHO COVID-19 Research Database to identify cohort studies, case series, case-control trials, and randomised controlled trials with populations of at least 50 patients published in any language between Jan 1, 2019, and Dec 1, 2021. Reviews, editorials, letters, pre-prints, and conference proceedings were excluded, as were studies in which bacterial infection was not microbiologically confirmed (or confirmed via nasopharyngeal swab only). We screened titles and abstracts of papers identified by our search, and then assessed the full text of potentially relevant articles. We reported the pooled prevalence of bacterial infections and antimicrobial resistance by doing a random-effects meta-analysis and meta-regression. Our primary outcomes were the prevalence of bacterial co-infection and secondary infection, and the prevalence of antibiotic-resistant pathogens among patients with laboratory-confirmed COVID-19 and bacterial infections. The study protocol was registered with PROSPERO (CRD42021297344). FINDINGS: We included 148 studies of 362 976 patients, which were done between December, 2019, and May, 2021. The prevalence of bacterial co-infection was 5·3% (95% CI 3·8-7·4), whereas the prevalence of secondary bacterial infection was 18·4% (14·0-23·7). 42 (28%) studies included comprehensive data for the prevalence of antimicrobial resistance among bacterial infections. Among people with bacterial infections, the proportion of infections that were resistant to antimicrobials was 60·8% (95% CI 38·6-79·3), and the proportion of isolates that were resistant was 37·5% (26·9-49·5). Heterogeneity in the reported prevalence of antimicrobial resistance in organisms was substantial (I2=95%). INTERPRETATION: Although infrequently assessed, antimicrobial resistance is highly prevalent in patients with COVID-19 and bacterial infections. Future research and surveillance assessing the effect of COVID-19 on antimicrobial resistance at the patient and population level are urgently needed. FUNDING: WHO.

Addition of anaerobic coverage for treatment of biliary tract infections: a propensity score-matched cohort study.

Objectives: To evaluate whether additional antibiotics that target anaerobes, including Bacteroides spp., are associated with improved clinical outcomes in patients with biliary tract infections (BTIs). Methods: This was a retrospective propensity score-matched cohort of adults aged ≥18 years with BTIs, admitted to hospital between 1 April 2015 and 30 March 2021. Eligible patients treated with antibiotics that provided coverage of anaerobes were compared with those treated with comparable regimens without anaerobic coverage. The primary outcome was a composite of mortality within 30 days or relapse within 90 days of source control or completion of antibiotics. Secondary outcomes included length of stay (LOS), duration of antibiotic therapy and adverse drug reactions. ORs were calculated using a weighted generalized linear regression model with propensity-score matching. Results: Among 398 patients included, 209 were treated without anaerobic coverage and 189 with anaerobic coverage. After propensity-score matching, there was no significant difference in primary outcome between propensity-matched patients who received additional anaerobic coverage and those who did not [adjusted OR (aOR) 1.23; 95% CI 0.69-2.22)]. Those with anti-anaerobic coverage had longer LOS (aOR 4.85; 95% CI 1.68-13.98) and longer duration of antibiotic treatment (aOR 4.14; 95% CI 2.61-6.57) than those who did not receive additional anaerobic therapy, but not more adverse drug reactions (aOR 1.01; 95% CI 0.97-1.05). Conclusions: Omitting anti-anaerobic antibiotics may be a safe antimicrobial stewardship intervention. However, a randomized controlled trial may be warranted to definitively conclude whether additional anaerobic coverage in BTI treatment is necessary.

Evaluation of compliance with the 2017 Canadian Paediatric Society Position Statement for the management of newborns at risk for early-onset sepsis: A retrospective cohort study.

INTRODUCTION: Due to the nonspecific clinical presentation, clinicians often empirically treat newborns at risk of early-onset sepsis (EOS). Recently, the Canadian Paediatric Society (CPS) published updated recommendations that promote a more judicious approach to EOS management. OBJECTIVE: To examine the compliance with the CPS statement at a tertiary perinatal site and characterize the types of deviations. METHODS: A retrospective chart review was conducted for all term and late pre-term newborns at risk for sepsis, between January 1 and June 30, 2018. The prevalence of newborns with EOS risk factors was measured during the first month. Management strategies for eligible newborns during the 6-month period were compared to the CPS recommendations to establish the rate of noncompliance. The type of noncompliance, readmission rate, and rate of culture-positive EOS were examined. RESULTS: In the first month, 29% (66 of 228) of newborns had EOS risk factors. Among the 100 newborns born in the 6-month period for whom the CPS recommendations apply, 47 (47%) received noncompliant management. Of those, 51% (N=24) had inappropriately initiated investigations, 17% (N=8) had inappropriate antibiotics, and 32% (N=15) had both. The rate of readmission for a septic workup was 1.6% (N= 2). None had culture-positive sepsis while admitted. CONCLUSION: A large proportion of term and late preterm newborns (29%) had EOS risk factors, but none had culture-confirmed EOS. The rate of noncompliance with the CPS recommendations was high (47%), mainly due to overzealous management. Future initiatives should aim at increasing compliance, particularly in newborns at lower EOS risk.

Increased risk of all-cause mortality associated with domperidone use in Parkinson's patients: a population-based cohort study in the UK.

AIMS: Domperidone is used to treat gastrointestinal symptoms in patients with Parkinson's disease (PD) and is linked to an increased risk of mortality. We sought to examine the risk of all-cause mortality associated with domperidone exposure in PD. METHODS: We conducted a cohort study using data from the Clinical Practice Research Datalink database (1987-2011). The first recorded PD diagnosis defined index date. Time-dependent Cox proportional hazards models estimated hazard ratios (HRs) of all-cause mortality associated with domperidone use. PD patients were stratified by domperidone use (current/recent/past), with never used as the referent. Current domperidone users were stratified by daily dose, domperidone duration and other anti-Parkinson's medications. A secondary analysis compared PD patients to matched (1:1) non-PD patients. RESULTS: A total of 5114 PD patients were identified. Current use of domperidone among PD patients was associated with a two-fold increase in all-cause mortality (HRadj  = 2.00, 95% confidence interval [CI]: 1.64-2.45), as compared to patients never exposed to domperidone. All-cause mortality risk was highest in those starting domperidone in the previous month [HRadj  = 2.97, 95% CI: 2.06-4.27]. When compared to matched non-PD patients, PD was associated with a 43% increased risk of all-cause mortality, yet this increased to a 2.4-fold increased risk among PD patients currently using domperidone. CONCLUSION: Current use of domperidone was associated with a two-fold increased mortality risk in PD patients, as compared to PD patients that never used domperidone. The risk is highest in the first month of use and does not appear to be attributable to PD alone.

FLT1 genetic variation predisposes to neovascular AMD in ethnically diverse populations and alters systemic FLT1 expression.

PURPOSE: Current understanding of the genetic risk factors for age-related macular degeneration (AMD) is not sufficiently predictive of the clinical course. The VEGF pathway is a key therapeutic target for treatment of neovascular AMD; however, risk attributable to genetic variation within pathway genes is unclear. We sought to identify single nucleotide polymorphisms (SNPs) associated with AMD within the VEGF pathway. METHODS: Using a tagSNP, direct sequencing and meta-analysis approach within four ethnically diverse cohorts, we identified genetic risk present in FLT1, though not within other VEGF pathway genes KDR, VEGFA, or VASH1. We used ChIP and ELISA in functional analysis. RESULTS: The FLT1 SNPs rs9943922, rs9508034, rs2281827, rs7324510, and rs9513115 were significantly associated with increased risk of neovascular AMD. Each association was more significant after meta-analysis than in any one of the four cohorts. All associations were novel, within noncoding regions of FLT1 that do not tag for coding variants in linkage disequilibrium. Analysis of soluble FLT1 demonstrated higher expression in unaffected individuals homozygous for the FLT1 risk alleles rs9943922 (P = 0.0086) and rs7324510 (P = 0.0057). In silico analysis suggests that these variants change predicted splice sites and RNA secondary structure, and have been identified in other neovascular pathologies. These data were supported further by murine chromatin immunoprecipitation demonstrating that FLT1 is a target of Nr2e3, a nuclear receptor gene implicated in regulating an AMD pathway. CONCLUSIONS: Although exact variant functions are not known, these data demonstrate relevancy across ethnically diverse genetic backgrounds within our study and, therefore, hold potential for global efficacy.

The motility of the chicken embryo: energetic cost and effects of hypoxia.

We estimated the energetic cost of embryonic motility by relating the changes in embryo's motion to the changes in oxygen consumption (VO2). Measurements were conducted on chicken embryos between day 10 and 18 of incubation. Embryonic gross body movement was quantified over ten continuous 3-min periods from the pressure oscillations inside the egg, measured through an implanted catheter, and was correlated to the synchronous changes in VO2, measured by an open-flow methodology. Over the 30 min recording, movements could vary around the mean by up to four folds. The corresponding changes in VO2 were minuscule (0.116 µl O2/mmHg) or, for all age groups combined, only 2.3% of the mean VO2, ranging from ≈ 8% (day 10) to ≈ 0.5% (day 16). At E18, hypercapnia and cold respectively increased and decreased motility. Differently, the effects of hypoxia on motility were variable among embryos. It is concluded that, in chicken embryos over the age period investigated, the cost of motility represents an almost negligible fraction of the total energy budget. Because of its low cost, motility can be maintained in hypoxia; conversely, reduction of motility in hypoxia does not provide an important energy saving.

Aminoimidazole carboxamide ribonucleotide ameliorates experimental autoimmune uveitis.

PURPOSE: To investigate the anti-inflammatory effect of an adenosine monophosphate (AMP) analog, aminoimidazole carboxamide ribonucleotide (AICAR), in experimental autoimmune uveoretinitis (EAU). METHODS: C57BL/6 mice were injected daily with AICAR (200 mg/kg, intraperitoneally [IP]) from day 0, the day of interphotoreceptor retinoid-binding protein (IRBP) immunization, until day 21. The severity of uveitis was assessed clinically and histopathologically. T-cell proliferation and cytokine production of IFN-γ, IL-17, and IL-10 in response to IRBP stimulation were determined. In addition, regulatory T-cell (Treg) populations were measured. Co-stimulatory molecule expression (CD40, 80, 86, and I-Ab) on dendritic cells (DCs) in EAU and on bone marrow-derived dendritic cells (BMDCs) treated with AICAR was measured. RESULTS: AICAR treatment significantly reduced clinical and histologic severity of EAU as well as ocular cytokine production. An anti-inflammatory effect associated with the inhibition of T-cell proliferation and Th1 and Th17 cytokine production was observed. Increases in the Th2 response and Treg population were not observed with AICAR treatment. AICAR did significantly inhibit BMDC maturation by reducing co-stimulatory molecule expression. CONCLUSIONS: AICAR attenuates EAU by preventing generation of Ag-specific Th1 and Th17 cells. Impaired DC maturation may be an underlying mechanism for this anti-inflammatory effect observed with AICAR.