Anti-infective Drugs Research Articles

Drug-Induced QT Prolongation and Torsade de Pointes in Spontaneous Adverse Event Reporting: A Retrospective Analysis Using the Japanese Adverse Drug Event Report Database (2004-2021).

Drugs with new mechanisms of action are continually being developed, but it is difficult to capture whether a drug induces QT prolongation/torsade de pointes (TdP) in preclinical and preapproval clinical trials. To evaluate drugs associated with drug-induced QT prolongation/TdP using a real-world database in Japan. A search was performed in the Japanese Adverse Drug Event Report (JADER) database for QT prolongation and TdP. The reporting odds ratio (ROR) was calculated to identify potential drug-induced QT prolongation/TdP association. Among the reported 4,326,484 data entries, 3410 patients exhibited QT prolongation/TdP (2707 with QT prolongation, 703 with TdP) with the suspected drugs. Of these patients, 53.9% were females. The highest occurrence was in the 70- to 79-year-old age group (24.7%). The most common types of drugs involved were cardiovascular drugs, central nervous system (CNS) drugs, anticancer drugs, and anti-infective drugs; the rate of overdose was reportedly very low at 1.6%. The highest adjusted RORs were observed for nifekalant (351.41, 95% confidence interval (CI) 235.85-523.59), followed by vandetanib (182.55, 95% CI 108.11-308.24), evocalcet (181.59, 95% CI 132.96-248.01), bepridil (160.37, 95% CI 138.17-186.13), diarsenic trioxide (79.43, 95% CI 63.98-98.62), and guanfacine (78.29, 95% CI 58.51-104.74). Among the drugs launched in Japan during the last decade, vandetanib had the highest adjusted RORs. This study using the JADER database showed that antiarrhythmic drugs, calcium-sensing receptor agonists, small-molecule targeted anticancer drugs, and CNS drugs are associated with QT prolongation/TdP. Further pharmacoepidemiological studies, such as cohort studies using large databases, are needed to prove these causal relationships.

Fatal adverse drug reactions in children: A descriptive study in the World Health Organization pharmacovigilance database, 2010-2019.

Adverse drug reactions (ADRs) represent a significant public health burden. There are few data on fatal ADRs in children. This population is particularly at risk due to metabolic and physiological immaturity, frequent off-label drug use and limited paediatric clinical pharmacology studies. The study investigated the main characteristics of drug-related deaths registered in World Health Organization pharmacovigilance database, during the past decade. Fatal outcomes registered between 2010 and 2019 in children (<18 y) and reported by physicians were investigated. Age, sex and suspected drugs were described and disproportionality analyses investigated differences according to sex, age and continents with calculation of reporting odds ratio and its 95% confidence interval. Among the 1 198 560 reports registered in children, 1585 (0.13%) were fatal. They occurred mainly in boys, aged 28 days-23 months. Reports mostly came from the Americas and Europe and involved, besides anti-infectious drugs (mainly vaccines), central nervous system (vigabatrin, paracetamol, methylphenidate…) and antineoplastic/immunomodulating (mainly thalidomide) and cardiovascular (mainly bosentan) drugs without major differences between boys and girls. Large differences were found according to continents and age. The risk of reporting was higher in boys, in children aged <23 months, in the Americas and Africa. Fatal ADRs represented a small part (around 1/1000) of total registered ADRs, occurred more frequently in boys and during the first 2 years of life. Beside anti-infectious drugs (vaccines), neuropsychiatric drugs were the most frequently involved, with large differences according to continents and classes of age.

Identification of heptapeptides targeting a lethal bacterial strain in septic mice through an integrative approach

Effectively killing pathogenic bacteria is key for the treatment of sepsis. Although various anti-infective drugs have been used for the treatment of sepsis, the therapeutic effect is largely limited by the lack of a specific bacterium-targeting delivery system. This study aimed to develop antibacterial peptides that specifically target pathogenic bacteria for the treatment of sepsis. The lethal bacterial strain Escherichia coli MSI001 was isolated from mice of a cecal ligation and puncture (CLP) model and was used as a target to screen bacterial binding heptapeptides through an integrative bioinformatics approach based on phage display technology and high-throughput sequencing (HTS). Heptapeptides binding to E. coli MSI001 with high affinity were acquired after normalization by the heptapeptide frequency of the library. A representative heptapeptide VTKLGSL (VTK) was selected for fusion with the antibacterial peptide LL-37 to construct the specific-targeting antibacterial peptide VTK-LL37. We found that, in comparison with LL37, VTK-LL37 showed prominent bacteriostatic activity and an inhibitive effect on biofilm formation in vitro. In vivo experiments demonstrated that VTK-LL37 significantly inhibited bacterial growth, reduced HMGB1 expression, alleviated lesions of vital organs and improved the survival of mice subjected to CLP modeling. Furthermore, membrane DEGP and DEGQ were identified as VTK-binding proteins by proteomic methods. This study provides a novel strategy for targeted pathogen killing, which is helpful for the treatment of sepsis in the era of precise medicine.

Novel Approaches for the Treatment of Infections Due to Multidrug-Resistant Bacterial Pathogens

Antimicrobial resistance (AMR), which is a major challenge for global healthcare, emerging because of several reasons including overpopulation, increased global migration and selection pressure due to enhanced use of antibiotics. Antibiotics are the widely used therapeutic options to combat infectious diseases; however, unfortunately, inadequate and irregular antibiotic courses are also major contributing factors in the emergence of AMR. Additionally, persistent failure to develop and commercialize new antibiotics has created the scarcity of effective anti-infective drugs. Thus, there is an urgent need for a new class of antimicrobials and other novel approaches to curb the menace of AMR. Besides the conventional approaches, some novel approaches such as the use of antimicrobial peptides, bacteriophages, immunomodulation, host-directed therapy and antibodies have shown really promising potentials.

Clinical characteristics and prognosis analysis of 498 cases with drug-induced liver injury

Objective: To determine the risk factors, clinical characteristics and treatment prognosis, so as to provide reference for clinicians to diagnose, treat and prevent drug-induced liver injury (DILI). Methods: Data of 712 confirmed DILI cases were collected from the Second Affiliated Hospital of Kunming Medical University between 2013 to 2019. Among them, 498 cases were included in the study. All patients medical history, clinical manifestations and classification, laboratory parameters, disease severity, and mortality rate were collected. Statistical analysis was performed using t-test, Mann-Whitney U test/Pearson χ2 test/Fisher's exact test or Spearman's rank test. Results: Among the suspicious drugs causing DILI, single medication accounted for 89.56%, mainly including traditional Chinese medicine (56.43%), anti-tumor and immunomodulatory agents (8.03%), anti-infective drugs (4.42%), antipyretic and analgesic drugs (4.22%) %), etc., while combination medication accounted for 10.44%. The clinical classification was dominated with hepatocyte injury (63.05%), and there was a statistically significant difference in clinical classification among age groups (P<0.001). Age, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and total bile acid (TBA) had statistically significant difference among different suspicious drugs in DILI caused by different drug (P<0.001, 0.003, 0.001, <0.001 and <0.001). Laboratory test results showed that there were statistically significant differences in ALT, AST, ALP, γ-glutamyltransferase (GGT), TBA, international normalized ratio (INR), and eosinophils (P<0.001, <0.001, <0.001, 0.018, 0.003 and 0.019, respectively). Chronic hepatitis was more common in the 54 cases who completed histopathological examination of the liver biopsy. Fibrosis degree was higher in the Western medicine group than Chinese herbal medicine group (P<0.05), and the difference was statistically significant (P<0.05). 96.99% of DILI patients were cured or improved, and 3.01% of patients were uncured. Ordinal logistic regression analysis showed that GGT and INR were independent predictors of poor prognosis. Conclusions: Suspicious drugs for DILI are herbal/dietary supplements, anti-tumor and immunomodulatory, anti-infective, and antipyretic and analgesic. The most common clinical classification is hepatocyte injury. Most patients with DILI have a good prognosis after drug withdrawal and GGT and INR are independent predictors of poor prognosis.

Strategies to Improve the Biosynthesis of β-Lactam Antibiotics by Penicillin G Acylase: Progress and Prospects.

β-Lactam antibiotics are widely used anti-infection drugs that are traditionally synthesized via a chemical process. In recent years, with the growing demand for green alternatives, scientists have turned to enzymatic synthesis. Penicillin G acylase (PGA) is the second most commercially used enzyme worldwide with both hydrolytic and synthetic activities toward antibiotics, which has been used to manufacture the key antibiotic nucleus on an industrial level. However, the large-scale application of PGA-catalyzed antibiotics biosynthesis is still in the experimental stage because of some key limitations, such as low substrate concentration, unsatisfactory yield, and lack of superior biocatalysts. This paper systematically reviews the strategies adopted to improve the biosynthesis of β-lactam antibiotics by adjusting the enzymatic property and manipulating the reaction system in recent 20 years, including mining of enzymes, protein engineering, solvent engineering, in situ product removal, and one-pot reaction cascade. These advances will provide important guidelines for the future use of enzymatic synthesis in the industrial production of β-lactam antibiotics.

Plant Alkylbenzenes and Terpenoids in the Form of Cyclodextrin Inclusion Complexes as Antibacterial Agents and Levofloxacin Synergists.

Allylpolyalkoxybenzenes (APABs) and terpenoids from plant essential oils exhibit a range of remarkable biological effects, including analgesic, antibacterial, anti-inflammatory, antioxidant, and others. Synergistic activity with antibiotics of different classes has been reported, with inhibition of P-glycoprotein and impairment of bacterial cell membrane claimed as probable mechanisms. Clearly, a more detailed understanding of APABs’ biological activity could help in the development of improved therapeutic options for a range of diseases. However, APABs’ poor solubility in water solutions has been a limiting factor for such research. Here, we found that complex formation with β-cyclodextrins (CD) is an efficient way to transform the APABs into a water-soluble form. Using a combination of spectroscopic (FTIR, NMR, UV) methods, we have estimated the binding constants, loading capacity, and the functional groups of both APABs and monoterpenes involved in complex formation with CD: ethylene, aromatic, methoxy and hydroxy groups. In the presence of a molar excess of CD (up to 5 fold) it was possible to achieve the complete dissolution of APABs and terpenoids in an aqueous medium (at 90–98% encapsulation) higher by 10–1000 times. Further, we have demonstrated that CD-APABs, if used in combination with levofloxacin (Lev), can be antagonistic, indifferent, additive, or synergistic, mostly depending on the concentration ratio: at high Lev concentration with the addition of APAB is typically neutral or even antagonistic; while at a Lev concentration below MIC, the addition of CD-APAB is either additive or synergistic (according to FICI criteria). An over three-fold increase in Lev antibacterial activity was observed in combination with eugenol (EG), as per the growth inhibition diameter measurement in agar. Interestingly, a synergistic effect could be observed with both Gram-positive and Gram-negative bacteria. So, obviously, the APAB-CD and terpenoid-CD mechanism of action is not limited to their interaction with the bacterial membrane, which has been shown earlier for CDs. Further research may open new prospects for the development of adjuvants to improve the therapeutic regimens with existing, as well as with new anti-infective drugs.

Effects of Shenling Chengqi Decoction on Gastrointestinal Function and Immune Status of Patients with Gastrointestinal Injury in Severe Sepsis.

Objective To investigate the effects of Shenling Chengqi decoction combined with routine treatment on gastrointestinal function and immune status of patients with gastrointestinal injury in severe sepsis. Methods 160 patients with sepsis were randomly divided into a control group (n = 80) and observation group (n = 80). The control group was given routine treatment such as anti-infection and vasoactive drugs. The observation group was treated with Shenling Chengqi decoction on the basis of routine treatment for 7 days. The improvement of gastrointestinal symptoms, nutritional status, gastrointestinal dynamics, inflammatory response, and immune function was observed before and after treatment. The outcome indicators were evaluation of gastrointestinal symptoms, evaluation of disease severity, nutritional status, gastrointestinal dynamic indexes, inflammatory indexes, and immune function indexes. SPSS 22.0 statistical software was used for data processing. The paired t-test was used for comparison before and after treatment. Results Compared with the control group, the disappearance time of reflux, vomiting, and recovery time of bowel sounds in the observation group were significantly shorter (P < 0.05), and the number of defecation per day was significantly higher than that in the control group (P < 0.05). After 3 and 7 days of treatment, the APACHE II score, SIRS score, serum gas, IgA, IgM, serum hs-CRP, TNF, and PCT of the two groups were significantly lower than those before treatment (P < 0.05), and the scores of the observation group were significantly lower than those of the control group (P < 0.05). The levels of SS and MOT were significantly higher than those before treatment (P < 0.05). After 7 days of treatment, the levels of serum Hb, ALB, and PA in the two groups were significantly higher than those before treatment (P < 0.05), and the nutritional status in the observation group was significantly higher than that in the control group (P < 0.05). Conclusion Shenling Chengqi decoction can effectively improve gastrointestinal symptoms, nutritional status, and gastrointestinal dynamics in patients with sepsis. It has high safety and is worthy of clinical promotion.

Short-term effects of prophylactic intravitreal injection of triamcinolone and moxifloxacin combination after cataract surgery

Background and Aim To evaluate the short-term effects and safety of prophylactic intravitreal injection of triamcinolone–moxifloxacin combination after cataract surgery. Patients and methods This study included 100 eyes of 84 patients who underwent cataract surgery associated with intravitreal injection of triamcinolone–moxifloxacin combination after surgery. The patients were re-assessed at the first day, first week, and then monthly up to 3 months after surgery. The outcome measures included unplanned use of topical anti-inflammatory or anti-infective drugs during the postoperative period, best-corrected visual acuity (BCVA), and intraocular pressure (IOP). The mean age of patients was 55.99±5.20 years. Results The mean BCVA showed a statistically significant difference between the preoperative and the postoperative values, where the mean BCVA improved from 1.21±0.27 logMAR before operation to 0. 83±0.25 logMAR at the first week, 0.46±0.21 logMAR at the first month, and 0.19±0.14 logMAR at the third month. The mean IOP revealed no statistically significant differences between preoperative and postoperative values at the end of the first month (P&lt;0.084). The preoperative IOP ranged from 12 to 19 mmHg, with an average of 15.35±1.60 mmHg and became 14.52±1.11 mmHg at the end of the first month after surgery. There was no evidence of postoperative complications such as endophthalmitis or other complications such as retinal detachment and vitreous hemorrhage. Conclusion Intravitreal injection of triamcinolone–moxifloxacin combination after cataract surgery can be used as an alternative to medications applied topically for prophylaxis against postoperative complications associated with cataract surgery such as infection and inflammation.

The Anti-Histamine Azelastine, Identified by Computational Drug Repurposing, Inhibits Infection by Major Variants of SARS-CoV-2 in Cell Cultures and Reconstituted Human Nasal Tissue.

Background and purpose: The COVID-19 pandemic continues to pose challenges, especially with the emergence of new SARS-CoV-2 variants that are associated with higher infectivity and/or compromised protection afforded by the current vaccines. There is a high demand for additional preventive and therapeutic strategies effective against this changing virus. Repurposing of approved or clinically tested drugs can provide an immediate solution. Experimental Approach: We applied a novel computational approach to search among approved and commercially available drugs. Antiviral activity of a predicted drug, azelastine, was tested in vitro in SARS-CoV-2 infection assays with Vero E6 cells, Vero cells stably overexpressing the human TMPRSS2 and ACE2 proteins as well as on reconstituted human nasal tissue using the predominant variant circulating in Europe in summer 2020, B.1.177 (D614G variant), and its emerging variants of concern; B.1.1.7 (alpha), B.1.351 (beta) and B.1.617.2 (delta) variants. The effect of azelastine on viral replication was assessed by quantification of viral genomes by droplet digital PCR or qPCR. Key results: The computational approach identified major drug families, such as anti-infective, anti-inflammatory, anti-hypertensive, antihistamine, and neuroactive drugs. Based on its attractive safety profile and availability in nasal formulation, azelastine, a histamine 1 receptor-blocker was selected for experimental testing. Azelastine reduced the virus-induced cytopathic effect and SARS-CoV-2 copy numbers both in preventive and treatment settings upon infection of Vero cells with an EC50 of 2.2–6.5 µM. Comparable potency was observed with the alpha, beta and delta variants. Furthermore, five-fold dilution (containing 0.02% azelastine) of the commercially available nasal spray formulation was highly potent in inhibiting viral propagation in reconstituted human nasal tissue. Conclusion and Implications: Azelastine, an antihistamine available as nasal sprays developed against allergic rhinitis may be considered as a topical prevention or treatment of nasal colonization by SARS-CoV-2. A Phase 2 efficacy indicator study with azelastine-containing nasal spray that was designed based on the findings reported here has been concluded recently, confirming accelerated viral clearance in SARS-CoV-2 positive subjects.

Investigation and Analysis of Infection among Inpatients in a Tertiary Hospital in Shanghai.

Objectives This study is aimed at obtaining information about the prevalence of nosocomial infections (NIs) and the use of antibiotics in hospitalized patients and providing relevant references for further understanding, preventing, and controlling NIs. Methods The medical records of adult patients admitted to a hospital in Shanghai from November to December 2021 were analyzed. The patients were divided into the NI group, community-acquired infection (CAI) group, and uninfected or healed group according to their infection status. The survey results were summarized and analyzed. Results A total of 1485 patients were investigated, including 115 patients in the NI group, 172 patients in the CAI group, and 1198 patients in the uninfected or healed group. In the NI group, the main infection site was intra-abdominal tissue (49.6%), followed by lower respiratory tract (unrelated to application of catheters) (13%). There were 73 pathogens detected in the samples submitted from the NI group, mainly including 8 cases (11%) of Escherichia coli, 9 cases (12%) of Klebsiella pneumoniae, and 40 cases (55%) of negative microbiological test results. Thirteen of 115 patients with NIs had infections with drug-resistant bacteria, including 9 cases (69.2%) of CRE (carbapenem-resistant Enterobacteriaceae), 2 cases (15.38%) of VRE (vancomycin-resistant Enterococcus), 1 case (7.69%) of MRSA (methicillin-resistant Staphylococcus aureus), and 1 case (7.69%) of CRAB (carbapenem-resistant Acinetobacter baumannii). In terms of medication, single drug use accounted for the majority of the NI group (66.3%) and CAI group (60.6%); both groups had less frequent quadruple drugs. In the uninfected or healed group, single drug occupied 92.0%, and dual drug use accounted for 8.0%. Cefoperazone/sulbactam was the most commonly used antibacterial drug in the NI group (18.0%) and CAI group (17.6%), and piperacillin/tazobactam accounted for 14.0% and 17.6% in the two groups, respectively. In the uninfected or healed group, cefuroxime accounted for 59.8%, followed by cefoperazone/sulbactam (13.3%). Conclusion This study provides a scientific basis for effective control of NIs. Strict implementation of aseptic techniques, reduction of invasive operations, and rational use of anti-infective drugs can minimize the incidence of nosocomial infection to ultimately achieve effective prevention and control of NIs.

Female Patients with Pneumonia on Intensive Care Unit Are under Risk of Fatal Outcome.

Background and Objectives: The impact of sex on mortality in patients with pneumonia requiring intensive care unit (ICU) treatment is still a controversial discussion, with studies providing heterogeneous results. The reasons for sex differences are widespread, including hormonal, immunologic and therapeutic approaches. This study’s aim was to evaluate sex-related differences in the mortality of ICU patients with pneumonia. Material and Methods: A prospective observational clinical trial was performed at Charité University Hospital in Berlin. Inclusion criteria were a diagnosis of pneumonia and a treatment period of over 24 h on ICU. A total of 436 mainly postoperative patients were included. Results: Out of 436 patients, 166 (38.1%) were female and 270 (61.9%) were male. Significant differences in their SOFA scores on admission, presence of immunosuppression and diagnosed cardiovascular disease were observed. Male patients were administered more types of antibiotics per day (p = 0.028) at significantly higher daily costs (in Euros) per applied anti-infective drug (p = 0.003). Mortalities on ICU were 34 (20.5%) in females and 39 (14.4%) in males (p = 0.113), before correcting for differences in patient characteristics using logistic regression analysis, and afterwards, the female sex showed an increased risk of ICU mortality with an OR of 1.775 (1.029–3.062, p = 0.039). Conclusions: ICU mortality was significantly higher in female patients with pneumonia. The identification of sex-specific differences is important to increase awareness among clinicians and allow resource allocation. The impact of sex on illness severity, sex differences in infectious diseases and the consequences on treatment need to be elucidated in the future.

Antibacterial and Anti-Inflammatory Properties of a Novel Antimicrobial Peptide Derived from LL-37.

Peri-implantitis is a pathological condition involving tissues around dental implants that are characterized by inflammation of the peri-implant mucosa and progressive loss of supporting bone. We found that the antimicrobial peptide KR-12-3 (KRIVKWIKKFLR) derived from LL-37 had antibacterial properties against Streptococcus gordonii. The purpose of this study was to evaluate its antibacterial and anti-inflammatory activities and its underlying mechanisms. We evaluated the antibacterial activities of antimicrobial peptides in planktonic and biofilm states by measuring their minimum inhibitory concentration, minimum bactericidal concentration, and biofilm susceptibility. The effects of antimicrobial peptides on the production of IL-6 and IL-8 in LPS-stimulated RAW264.7 cells were detected by enzyme-linked immunosorbent assay and other experiments, and their toxicity to MC3T3-E1 cells was also studied. While maintaining low cytotoxicity, KR-12-3 exhibited growth inhibitory effects on S. gordonii in planktonic and biofilm states. Lower concentrations of KR-12-3 treatment reduced the production of inflammatory cytokines in LPS-stimulated RAW264.8 cells. The mechanisms underlying the inhibition of biofilm formation and anti-inflammatory effects have been associated with the low expression of related genes. KR-12-3 may be used to develop an antibacterial, anti-infective, and anti-inflammatory drugs for peri-implantitis.

High-dose versus standard-dose vitamin D supplementation in older adults with COVID-19 (COVIT-TRIAL): A multicenter, open-label, randomized controlled superiority trial.

BackgroundVitamin D supplementation has been proposed as a treatment for Coronavirus Disease 2019 (COVID-19) based on experimental data and data from small and uncontrolled observational studies. The COvid19 and VITamin d TRIAL (COVIT-TRIAL) study was conducted to test whether a single oral high dose of cholecalciferol (vitamin D3) administered within 72 hours after the diagnosis of COVID-19 improves, compared to standard-dose cholecalciferol, the 14-day overall survival among at-risk older adults infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).Methods and findingsThis multicenter, randomized, controlled, open-label, superiority trial involved collaboration of 9 medical centers in France. Patients admitted to the hospital units or living in nursing homes adjacent to the investigator centers were eligible if they were ≥65 years, had SARS-CoV-2 infection of less than 3 days, and at least 1 COVID-19 worsening risk factor (among age ≥75 years, SpO2 ≤94%, or PaO2/FiO2 ≤300 mm Hg). Main noninclusion criteria were organ failure requiring ICU, SpO2 ≤92% despite 5 L/min oxygen, life expectancy <3 months, vitamin D supplementation >800 IU/day during the preceding month, and contraindications to vitamin D supplements. Eligible and consenting patients were randomly allocated to either a single oral high-dose (400,000 IU) or standard-dose (50,000 IU) cholecalciferol administered under medical supervision within 72 hours after the diagnosis of COVID-19. Participants and local study staff were not masked to the allocated treatment, but the Steering Committee and the Data and Safety Monitoring Board were masked to the randomization group and outcome data during the trial. The primary outcome was 14-day overall mortality. Between April 15 and December 17, 2020, of 1,207 patients who were assessed for eligibility in the COVIT-TRIAL study, 254 met eligibility criteria and formed the intention-to-treat population. The median age was 88 (IQR, 82 to 92) years, and 148 patients (58%) were women. Overall, 8 (6%) of 127 patients allocated to high-dose cholecalciferol, and 14 (11%) of 127 patients allocated to standard-dose cholecalciferol died within 14 days (adjusted hazard ratio = 0.39 [95% confidence interval [CI], 0.16 to 0.99], P = 0.049, after controlling for randomization strata [i.e., age, oxygen requirement, hospitalization, use of antibiotics, anti-infective drugs, and/or corticosteroids] and baseline imbalances in important prognostic factors [i.e., sex, ongoing cancers, profuse diarrhea, and delirium at baseline]). The number needed to treat for one person to benefit (NNTB) was 21 [NNTB 9 to ∞ to number needed to treat for one person to harm (NNTH) 46]. Apparent benefits were also found on 14-day mortality due to COVID-19 (7 (6%) deaths in high-dose group and 14 (11%) deaths in standard-dose group; adjusted hazard ratio = 0.33 [95% CI, 0.12 to 0.86], P = 0.02). The protective effect of the single oral high-dose administration was not sustained at 28 days (19 (15%) deaths in high-dose group and 21 (17%) deaths in standard-dose group; adjusted hazard ratio = 0.70 [95% CI, 0.36 to 1.36], P = 0.29). High-dose cholecalciferol did not result in more frequent adverse effects compared to the standard dose. The open-label design and limited study power are the main limitations of the study.ConclusionsIn this randomized controlled trial (RCT), we observed that the early administration of high-dose versus standard-dose vitamin D3 to at-risk older patients with COVID-19 improved overall mortality at day 14. The effect was no longer observed after 28 days.Trial registrationClinicalTrials.gov NCT04344041.

Picturins and Pictuseptins, two novel antimicrobial peptide families from the skin secretions of the Chachi treefrog, Boana picturata

The Imbabura treefrog (Boana picturata) is an underexplored source of bioactive peptides. The combination of molecular cloning and mass spectrometry allowed us to identify three new peptide families, named “Picturins” (PTR), “Pictuseptins” (PTS), and “Boanins” (BNS). PTR is composed of three 25-mer peptides, characterized by the N-terminal sequence: GVFKDALKQ and the C-terminal sequence: AANALKPK. The sequences of PTR-1, −2 and − 3 are highly conserved only showing two divergent sites: (L/F) in position 10 and (K/Q) in position 17. PTS gathers six peptides. PTS -1, −2 and − 4 have 22 amino acid residues in length, while PTS -3, −5 and − 6 are composed of 26 residues. Whereas BNS are four 28–37 mer peptides, showing two conserved regions: the N-terminal sequence FLGAL and the C-terminal sequence KALNP. PTR-1 to 3 and PTS -1 to −3 were chemically synthetized and their antimicrobial and haemolytic activity was assessed. PTR displayed moderate activity against Escherichia coli (MIC 24.80 to 48.95 μM), while PTS showed a broad antimicrobial and antifungal effect. PTS-1 was the most active peptide against E. coli (6.8 μM) followed by PTS-3 (11.7 μM) and PTS-2 (14.24 μM). These peptides also showed low haemolytic activity, pointing to a favorable selectivity. Overall, new unique non-hemolytic and cationic peptide sequences were characterized that could be valuable for the next-generation of anti-infective drugs. Future functional studies should explore the pharmacological potential of Boanins to include them as antimicrobial scaffolds. Biological significanceNature-inspired solutions have shown their importance mainly for the development of the pharmaceutical industry. Frog skin peptides are excellent examples of the biomedical potential of naturally evolved molecules for specific targets, including multi-resistant bacteria. The characterization of new chemical entities from poorly studied skin secretions of Ecuadorian biodiversity, such as B. picturata, represents an unprecedented opportunity to identify candidates to tackle global concerns, for instance, antibiotic resistance.

Allergic Adverse Drug Events After Alert Overrides in Hospitalized Patients.

This study aimed to assess how often overridden drug allergy alerts (ODAAs) lead to allergic adverse drug events (All-ADEs) and to evaluate the frequency with which drug allergy alerts (DAAs) were overridden and the reasons, as well as appropriateness of these overrides. A retrospective observational study of DAA generated between 2014 and 2016 was conducted. The corresponding DAA records were reviewed to determine the frequency of alert overrides. A chart review was performed on a subset of 194 ODAA (the first of every 3 chronologically ordered ODAA) to identify All-ADEs and to evaluate the override reasons and the appropriateness of these overrides. A total of 2044 DAAs were overridden (override rate of 44.8%). Most were triggered by a nonexact match (93.81%), when ordering nervous system (21.1%) and cardiovascular system (19.6%) drugs and were generated by physicians (72.7%). The main override reason was that the patient was already taking the drug or had previously tolerated the drug. Only 9.28% of ODAAs were inappropriately overridden. Six All-ADEs (3.09%) were identified and were due to anti-infective (1), antineoplastic (1), and iodinated-contrast (4) drug administration. Most All-ADEs were cutaneous and were mild. None was life-threatening or fatal. The All-ADEs rate was higher among inappropriately ODAA (15.79%, P = 0.013). Alert overrides are not exempt from clinical consequences, although few are associated with All-ADEs. It is necessary to identify the drugs involved in those reactions and to update allergy lists to generate only specific and important DAA and to avoid the negative consequences of overrides.

Synthesis of new 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one derivatives as anti-MRSA and anti-H. pylori agents

In this work, we have synthesized twenty five new 2-(5-(5-nitrofuran-2-yl)-1,3,4-thiadiazol-2-ylimino)thiazolidin-4-one derivatives bearing an aryl or heteroaryl methylene group on position 5 of thiazolidinone and evaluated their antimicrobial activity against Gram-positive and -negative bacteria as well as three metronidazole resistant Helicobacter pylori strains. Most of the compounds were very potent towards tested Gram-positive bacteria and showed an antibacterial efficacy substantially greater than ampicillin as the reference drug. However, no effectiveness was observed for the Gram-negative microorganisms. The compounds 9, 20 and 29 exhibited strong antimicrobial activity against Helicobacter pylori strains (inhibition zone > 30 mm) in 100 μg/disc and (inhibition zone > 20 mm) in 50 μg/disc. Taking these findings together, it seems that these potent antibacterial derivatives could be considered as promising agents for developing new anti-infectious drugs against microorganisms resistant to currently available antibiotics.Graphical

Paeonol Interferes With Quorum-Sensing in Pseudomonas aeruginosa and Modulates Inflammatory Responses InVitro and In Vivo.

Developing quorum-sensing (QS) based anti-infection drugs is one of the most powerful strategies to combat multidrug-resistant bacteria. Paeonol has been proven to attenuate the QS-controlled virulence factors of P. aeruginosa by down-regulating the transcription of QS signal molecules. This research aimed to assess the anti-virulence activity and mechanism of paeonol against P. aeruginosa infection in vitro and in vivo. In this study, paeonol was found to reduce the adhesion and invasion of P.aeruginosa to macrophages and resist the cytotoxicity induced by P.aeruginosa. Paeonol reduced the expression of virulence factors of P.aeruginosa by inhibiting QS, thereby reducing the LDH release and damage of P.aeruginosa-infected macrophages. Paeonol can inhibit bacterial virulence and enhance the ability of macrophages to clear P.aeruginosa. In addition, paeonol exerts anti-inflammatory activity by reducing the expression of inflammatory cytokines and increasing the production of anti-inflammatory cytokines. Paeonol treatment significantly inhibited the activation of TLR4/MyD88/NF-κB signaling pathway and decreased the inflammation response of P. aeruginosa-infected macrophages. Paeonol also significantly reduced the ability of P.aeruginosa to infect mice and reduced the inflammatory response. These data suggest that paeonol can inhibit the virulence of P.aeruginosa and decrease the inflammation response in P.aeruginosa-infected macrophages and mice, which can decrease the damage induced by P.aeruginosa infection and enhance the ability of macrophages to clear bacteria. This study supports the further development of new potential anti-infective drugs based on inhibition of QS and virulence factors.

Tools for Identifying Potentially Inappropriate Prescriptions for Children and Their Applicability in Clinical Practices: A Systematic Review

Background: Drug use safety in children is a global public health problem. The potentially inappropriate prescription screening tools are expected to reduce adverse drug reactions and promote rational drug use. Objectives: To systematically evaluate children’s potentially inappropriate prescription screening tools and validation studies on these tools. Methods: We systematically searched six databases PubMed, Embase, Cochrane Library, CNKI, VIP and Wanfang Data. Two reviewers independently selected articles by the eligible criteria and extracted data. Then we evaluated the coverage of diseases or drugs in these tools and the consistency of items between tools. Results: Five children’s potentially inappropriate prescription screening tools were identified, most tools were formed by Delphi expert consensus and focused on respiratory system drugs, anti-infective drugs, and gastrointestinal drugs. The coincidence rates of items between the POPI and the POPI Int, the POPI and the POPI United Kingdom, the POPI United Kingdom and the POPI int, and the POPI United Kingdom and the PIPc were 82.0, 55.1, 51.0 and 2.2% respectively, and the KIDs List did not overlap other four tools. Only the POPI tool developed by French experts was comprehensively validated by studies and most tools have not been validated. Conclusion: The development of screening tools for potentially inappropriate prescribing in children is a neglected field and most tools lack studies to validate clinical applicability. More researchers need to form their national potentially inappropriate prescription screening tools for children based on the best available clinical evidence and the actual clinical situation in their countries.

Anti-infective drugs

Anti-infective drugs