The Vehicle of Administration and Prandial State May Reduce the Spectrum of Oral Broad-Spectrum Antibiotics (Oxytetracycline, Fosfomycin and Amoxicillin) Administered to Piglets: A Pharmacokinetic/Pharmacodynamic Approach.

The objective of this study was to assess the impact of the vehicle of administration and the prandial state of post weaning piglets on the indices of therapeutic efficacy for different broad-spectrum antibiotic/pathogen combinations. Pharmacokinetic data were retrieved from previous studies, in which we orally administered oxytetracycline (OTC), fosfomycin (FOS), or amoxicillin (AMX) according to the following treatments: dissolved in soft water to fasted or non-fasted piglets, dissolved in hard water to fasted or non-fasted piglets, and mixed with feed. Minimum inhibitory concentration (MIC) values for susceptible strains of bacteria causing swine diseases were obtained from the database of European Committee on Antimicrobial Susceptibility Testing (EUCAST) for each antibiotic. Pharmacokinetic/pharmacodynamic (PK/PD) indices of therapeutic efficacy-drug exposure over the dosing interval (fAUC/MIC) for OTC and FOS; time that free drug concentration remains above MIC (%fT>MIC) for AMX-were calculated for each antibiotic/pathogen combination under each treatment. After all OTC and in-feed FOS and AMX treatments, the indices of therapeutic efficacy were below the target value for all the study microorganisms. When FOS or AMX were delivered dissolved in soft or hard water, the indices were above the target value over which therapeutic efficacy would be expected for Escherichia coli treated with FOS and, Glaesserella parasuis, Pasteurella multocida, and Actinobacillus pleuropneumoniae treated with AMX. The prandial state of piglets showed no influence on the indices of therapeutic efficacy. Pharmacokinetic profiles of broad-spectrum antibiotics, specifically the ability to achieve target concentrations, may be largely reduced due to drug interactions with components present in feed or water resulting in a discrepancy with PK/PD principles of prudent and responsible use of antibiotics.

Evaluating Antibiotic De-escalation for Autologous Stem Cell Transplant Patients With Febrile Neutropenia in a Real-World Clinical Setting.

Febrile neutropenia (FN) is a complication in approximately 90% of autologous stem cell transplant (SCT) patients. Guidelines support early broad-spectrum antibiotics (BSA) to prevent morbidity and mortality. However, in patients who are clinically stable and deemed to have a fever of unknown origin, the optimal duration of BSA is unknown. Accumulating evidence suggests that de-escalation of BSA in select patients may decrease duration of BSA exposure without compromising clinical outcomes such as infection, recurrent fever, and readmission. With this, a de-escalation protocol was implemented at Vanderbilt University Medical Center (VUMC) to identify autologous SCT patients who may benefit from early de-escalation of BSA. The objectives of this study were to analyze the impact of early empiric antibiotic de-escalation on the duration of BSA as well as its impact on the incidence of recurrent fever and documented infection in autologous SCT patients. This was a single-center, retrospective study evaluating patients older than 18 years of age who underwent autologous SCT and experienced an episode of FN from January 2018 to December 2022 at VUMC (N = 195). The protocol was initiated on January 1, 2020, to de-escalate BSA back to prophylaxis in stable neutropenic patients determined to have a fever of unknown origin. The primary outcome was the number of BSA days within 30 days. Secondary clinical outcomes included recurrent fever, documented infection, readmission, 30-day mortality, and 90-day non-relapsed mortality (NRM). Outcomes were compared across pre- and postprotocol groups with a Wilcoxon rank sum test, Pearson chi-square test, or regression analysis as appropriate. The median BSA duration was 4.7 and 2.7 days in the pre- and postprotocol groups, respectively (P < .001). Recurrent fever (14.2% versus 16.0%, P = .726), documented infection (1.7% versus 6.7%, P = .068), and readmission (13.3% versus 22.7%, P = .091) within 30 days were not significantly different between the two groups. Neither 30-day mortality (0.8% versus 1.3%, P = .736) nor 90-day NRM (0.8% versus 1.3%, P = .736) differed. The implementation of an early de-escalation protocol for autologous SCT patients who develop FN was associated with a reduction in duration of BSA compared to the preprotocol group without a significant difference in readmission, recurrent fevers, and documented infections. This study adds to existing evidence that early de-escalation of BSA in FN patients with a fever of unknown origin who are afebrile and clinically stable is safe and reduces unnecessary antibiotic use.

Hospital antimicrobial stewardship: profiling the oral microbiome after exposure to COVID-19 and antibiotics.

Introduction: During the COVID-19 Delta variant surge, the CLAIRE cross-sectional study sampled saliva from 120 hospitalized patients, 116 of whom had a positive COVID-19 PCR test. Patients received antibiotics upon admission due to possible secondary bacterial infections, with patients at risk of sepsis receiving broad-spectrum antibiotics (BSA). Methods: The saliva samples were analyzed with shotgun DNA metagenomics and respiratory RNA virome sequencing. Medical records for the period of hospitalization were obtained for all patients. Once hospitalization outcomes were known, patients were classified based on their COVID-19 disease severity and the antibiotics they received. Results: Our study reveals that BSA regimens differentially impacted the human salivary microbiome and disease progression. 12 patients died and all of them received BSA. Significant associations were found between the composition of the COVID-19 saliva microbiome and BSA use, between SARS-CoV-2 genome coverage and severity of disease. We also found significant associations between the non-bacterial microbiome and severity of disease, with Candida albicans detected most frequently in critical patients. For patients who did not receive BSA before saliva sampling, our study suggests Staphylococcus aureus as a potential risk factor for sepsis. Discussion: Our results indicate that the course of the infection may be explained by both monitoring antibiotic treatment and profiling a patient's salivary microbiome, establishing a compelling link between microbiome and the specific antibiotic type and timing of treatment. This approach can aid with emergency room triage and inpatient management but also requires a better understanding of and access to narrow-spectrum agents that target pathogenic bacteria.

Lung Microbiota and Ventilator-Associated Pneumonia in the Neonatal Period.

The lung microbiota is a complex community of microorganisms that colonize the respiratory tract of individuals from, or even before, birth. Although the lungs were traditionally believed to be sterile, recent research has shown that there is a diversity of bacterial species in the respiratory system. Knowledge about the lung microbiota in newborns and its relationship with bacterial infections is of vital importance to understand the pathogenesis of respiratory diseases in neonatal patients undergoing mechanical ventilation. In this article, the current evidence on the composition of the lung microbiota in newborns will be reviewed, as well as the risks that an altered microbiota can impose on premature newborns. Although advances in neonatal intensive care units have significantly improved the survival rate of preterm infants, the diagnosis and treatment of ventilator-associated pneumonia has not progressed in recent decades. Avoiding dysbiosis caused by inappropriate use of antibiotics around birth, as well as avoiding intubation of patients or promoting early removal of endotracheal tubes, are among the most important preventive measures for ventilator-associated pneumonia. The potential benefit of probiotics and prebiotics in preventing infectious, allergic or metabolic complications in the short or long term is not clearly established and constitutes a very important field of research in perinatal medicine.

Can rifaximin for hepatic encephalopathy be discontinued during broad-spectrum antibiotic treatment?

Hepatic encephalopathy (HE) is a formidable complication in patients with decompensated cirrhosis, often necessitating the administration of rifaximin (RFX) for effective management. RFX, is a gut-restricted, poorly-absorbable oral rifamycin derived antibiotic that can be used in addition to lactulose for the secondary prophylaxis of HE. It has shown notable reductions in infection, hospital readmission, duration of hospital stay, and mortality. However, limited data exist about the concurrent use of RFX with broad-spectrum antibiotics, because the patients are typically excluded from studies assessing RFX efficacy in HE. A pharmacist-driven quasi-experimental pilot study was done to address this gap. They argue against the necessity of RFX in HE during broad-spectrum antibiotic treatment, particularly in critically ill patients in intensive care unit (ICU). The potential for safe RFX discontinuation without adverse effects is clearly illuminated and valuable insight into the optimization of therapeutic strategies is offered. The findings also indicate that RFX discontinuation during broad-spectrum antibiotic therapy was not associated with higher rates of delirium or coma, and this result remained robust after adjustment in multivariate analysis. Furthermore, rates of other secondary clinical and safety outcomes, including ICU mortality and 48-hour changes in vasopressor requirements, were comparable. However, since the activity of RFX is mainly confined to the modulation of gut microbiota, its potential utility in patients undergoing extensive systemic antibiotic therapy is debatable, given the overlapping antibiotic activity. Further, this suggests that the action of RFX on HE is class-specific (related to its activity on gut microbiota), rather than drug-specific. A recent double-blind randomized controlled (ARiE) trial provided further evidence-based support for RFX withdrawal in critically ill cirrhotic ICU patients receiving broad-spectrum antibiotics. Both studies prompt further discussion about optimal therapeutic strategy for patients facing the dual challenge of HE and systemic infections. Despite these compelling results, both studies have limitations. A prospective, multi-center evaluation of a larger sample, with placebo control, and comprehensive neurologic evaluation of HE is warranted. It should include an exploration of longer-term outcome and the impact of this protocol in non-critically ill liver disease patients.

Long-Term Effects of a Stepwise, Multimodal, Non-Restrictive Antimicrobial Stewardship Programme for Reducing Broad-Spectrum Antibiotic Use in the ICU.

Information on the long-term effects of non-restrictive antimicrobial stewardship (AMS) strategies is scarce. We assessed the effect of a stepwise, multimodal, non-restrictive AMS programme on broad-spectrum antibiotic use in the intensive care unit (ICU) over an 8-year period. Components of the AMS were progressively implemented. Appropriateness of antibiotic prescribing was also assessed by monthly point-prevalence surveys from 2013 onwards. A Poisson regression model was fitted to evaluate trends in the reduction of antibiotic use and in the appropriateness of their prescription. From 2011 to 2019, a total of 12,466 patients were admitted to the ICU. Antibiotic use fell from 185.4 to 141.9 DDD per 100 PD [absolute difference, -43.5 (23%), 95% CI -100.73 to 13.73; p = 0.13] and broad-spectrum antibiotic fell from 41.2 to 36.5 [absolute difference, -4.7 (11%), 95% CI -19.58 to 10.18; p = 0.5]. Appropriateness of antibiotic prescribing rose by 11% per year [IRR: 0.89, 95% CI 0.80 to 1.00; p = 0.048], while broad-spectrum antibiotic use showed a dual trend, rising by 22% until 2015 and then falling by 10% per year since 2016 [IRR: 0.90, 95% CI 0.81 to 0.99; p = 0.03]. This stepwise, multimodal, non-restrictive AMS achieved a sustained reduction in broad-spectrum antibiotic use in the ICU and significantly improved appropriateness of antibiotic prescribing.

The impact of gut microbial signals on hematopoietic stem cells and the bone marrow microenvironment.

Hematopoietic stem cells (HSCs) undergo self-renewal and differentiation in the bone marrow, which is tightly regulated by cues from the microenvironment. The gut microbiota, a dynamic community residing on the mucosal surface of vertebrates, plays a crucial role in maintaining host health. Recent evidence suggests that the gut microbiota influences HSCs differentiation by modulating the bone marrow microenvironment through microbial products. This paper comprehensively analyzes the impact of the gut microbiota on hematopoiesis and its effect on HSCs fate and differentiation by modifying the bone marrow microenvironment, including mechanical properties, inflammatory signals, bone marrow stromal cells, and metabolites. Furthermore, we discuss the involvement of the gut microbiota in the development of hematologic malignancies, such as leukemia, multiple myeloma, and lymphoma.

Vancomycin-Polyguanidino Dendrimer Conjugates Inhibit Growth of Antibiotic-Resistant Gram-Positive and Gram-Negative Bacteria and Eradicate Biofilm-Associated S. aureus.

The global challenge of antibiotic resistance necessitates the introduction of more effective antibiotics. Here we report a potentially general design strategy, exemplified with vancomycin, that improves and expands antibiotic performance. Vancomycin is one of the most important antibiotics in use today for the treatment of Gram-positive infections. However, it fails to eradicate difficult-to-treat biofilm populations. Vancomycin is also ineffective in killing Gram-negative bacteria due to its inability to breach the outer membrane. Inspired by our seminal studies on cell penetrating guanidinium-rich transporters (e.g., octaarginine), we recently introduced vancomycin conjugates that effectively eradicate Gram-positive biofilm bacteria, persister cells and vancomycin-resistant enterococci (with V-r8, vancomycin-octaarginine), and Gram-negative pathogens (with V-R, vancomycin-arginine). Having shown previously that the spatial array (linear versus dendrimeric) of multiple guanidinium groups affects cell permeation, we report here for the first time vancomycin conjugates with dendrimerically displayed guanidinium groups that exhibit superior efficacy and breadth, presenting the best activity of V-r8 and V-R in single broad-spectrum compounds active against ESKAPE pathogens. Mode-of-action studies reveal cell-surface activity and enhanced vancomycin-like killing. The vancomycin-polyguanidino dendrimer conjugates exhibit no acute mammalian cell toxicity or hemolytic activity. Our study introduces a new class of broad-spectrum vancomycin derivatives and a general strategy to improve or expand antibiotic performance through combined mode-of-action and function-oriented design studies.

Antibacterial and biofilm disruptive nonribosomal lipopeptides from Streptomyces parvulus against multidrug-resistant bacterial infections.

BACKGROUND: In recent years, new drugs for the treatment of various diseases, thereby the emergence of antimicrobial resistance tremendously increased because of the increased consumption rate of various drugs. However, the irrational use of antibiotics increases the microbial resistance along with that the frequency of mortality associated with infections is higher. Broad-spectrum antibiotics were effectively against various bacteria and the unrestricted application of antibiotics lead to the emergence of drug resistance. The present study was aimed to detect the antibacterial properties of lipopeptide novel drug producing Streptomyces parvulus. METHODS: A lipopeptide-producing S. parvulus was isolated from the soil sample. The inhibitory effect of lipopeptide was detected against Gram-positive and Gram-negative bacteria. Bactericidal activity and minimum inhibitory concentration (MIC) were assayed. The IC50 value was analysed against ovarian and human melanoma cell lines. The experimental mouse model was infected withKlebsiella pneumoniae and treated with lipopeptide and bactericidal activity was determined. RESULTS: The results indicated that the antibacterial activity of lipopeptide ranges from 13 ± 1 mm to 32 ± 2 mm against Gram-positive and Gram-negative strains. The lowest MIC value was noted as 1.5 ± 0.1 µg/mL against K. pneumoniae and the highest against E. aerogenes (7.5 ± 0.2 µg/mL). The IC50 value was considerably high for the ovarian cell lines and human melanoma cell lines (426 µg/mL and 503 µg/mL). At 25 µg/mL concentration of lipopeptide, only 16.4% inhibition was observed in the ovarian cell line whereas 20.2% inhibition was achieved at this concentration in the human melanoma cell line. Lipopeptide inhibited bacterial growth and was completely inhibited at a concentration of 20 µg/mL. Lipopeptide reduced bacterial load in experimental mice compared to control (p < 0.05). CONCLUSION: Lipopeptide activity and its non-toxic nature reveal that it may serve as a lead molecule in the development of a novel drug.

Outpatient Antibiotic Prescribing Patterns in Children among Primary Healthcare Institutions in China: A Nationwide Retrospective Study, 2017-2019.

There is scarce evidence to demonstrate the pattern of antibiotic use in children in China. We aimed to describe antibiotic prescribing practices among children in primary healthcare institutions (PHIs) in China. We described outpatient antibiotic prescriptions for children in PHIs from January 2017 to December 2019 at both the national and diagnostic levels, utilizing the antibiotic prescribing rate (APR), multi-antibiotic prescribing rate (MAPR), and broad-spectrum prescribing rate (BAPR). Generalized estimating equations were adopted to analyze the factors associated with antibiotic use. Among the total 155,262.2 weighted prescriptions for children, the APR, MAPR, and BAPR were 43.5%, 9.9%, and 84.8%. At the national level, J01DC second-generation cephalosporins were the most prescribed antibiotic category (21.0%, N = 15,313.0), followed by J01DD third-generation cephalosporins (17.4%, N = 12,695.8). Watch group antibiotics accounted for 55.0% of the total antibiotic prescriptions (N = 52,056.3). At the diagnostic level, respiratory tract infections accounted for 67.4% of antibiotic prescriptions, among which prescriptions with diagnoses classified as potentially bacterial RTIs occupied the highest APR (55.0%). For each diagnostic category, the MAPR and BAPR varied. Age, region, and diagnostic categories were associated with antibiotic use. Concerns were raised regarding the appropriateness of antibiotic use, especially for broad-spectrum antibiotics.

Cervical Necrotizing Fasciitis: A Surgical Outcome Analysis.

Cervical necrotizing fasciitis is an immensely progressive, difficult-to-diagnose soft tissue infection of the fascial planes, skin, and subcutaneous tissue. It has marked morbidity and mortality. In this case report, we analyzed the risk factors, laboratory indices, and treatment modalities that affect the outcome of this fatal disease. This is a retrospective case series of cases admitted within a short span of six months between January and June 23. The cases were followed up monthly for three months, and the diagnosis was made on a clinical, pathological, radiological, and histopathological basis. All the cases were managed with neck exploration and aggressive surgical debridement in an emergency department, dressing of the wound with hydrogen peroxide and betadine twice daily, triple broad-spectrum antibiotic therapy for polymicrobial infection, and tight glycemic control. There were no complications, and all the patients survived. We report our cases of cervical necrotizing fasciitis that had similar presentations but varied outcomes. Here, we would like to advocate the importance of immediate management in the form of neck exploration and debridement at the earliest after the diagnosis has been established. Hyperglycemia should be brought under control, and daily aseptic dressing with removal of the slough and source of infection would greatly affect the outcome of this deadly disease.

Pediatric brainstem abscess successfully treated with stereotactic aspiration: illustrative case.

BACKGROUND: Pediatric brainstem abscesses are rare entities that account for 1% of all brain abscesses and, when diagnosed, constitute a neurosurgical emergency. OBSERVATIONS: A previously healthy 11-year-old male presented with several days of worsening headache, confusion, and ataxia. Brain magnetic resonance imaging (MRI) revealed a midbrain and pons lesion. The patient subsequently had a rapid neurological decline with loss of consciousness and brainstem function. Follow-up MRI revealed significant enlargement of the brainstem lesion with extension into the pons, midbrain, and thalamus, with greater concerns for an abscess rather than a tumor or an inflammatory process. He was taken for an emergent stereotactic aspiration of the abscess, and broad-spectrum antibiotics were initiated. He had neurological improvement, which subsequently declined 5 days later with brain MRI revealing an increase in the brainstem abscess, which required a second stereotactic aspiration. After rehabilitation, he made a significant neurological recovery. LESSONS: Pediatric brainstem abscesses are rare pathologies, and a high index of suspicion is needed in patients presenting with a brainstem lesion mimicking tumor but with rapid neurological decline despite no other evidence of infection or infectious/inflammatory markers. Stereotactic aspiration is required for large lesions to target the antibiotic treatment and as an adjunct to broad-spectrum antibiotics.

The role of gram stain in reducing broad-spectrum antibiotic use: A systematic literature review and meta-analysis.

The number of studies that verify whether Gram stain can help to reduce the use of broad-spectrum antibiotics is relatively limited compared to those evaluating its concordance with culture test results. Thereby, we aimed to evaluate the effectiveness of Gram staining in the reduction of broad-spectrum antibiotics and its impact on clinical outcomes. We systematically reviewed studies having used Gram stain to guide antibiotic selection and evaluated performance measures between 1996 and 2022. We extracted available data on broad-spectrum antibiotic use as a primary outcome of the studies in view of an exploratory meta-analysis designed to estimate the clinical effect of Gram stain. We also evaluated the clinical response and coverage rates of the initial antibiotic therapy. One randomized study and four non-randomized studies were eligible, all of which were conducted in tertiary care hospitals in Japan. Gram stain was associated with reduced broad-spectrum antibiotic use, including antipseudomonal antibiotics (odds ratio [OR], 0.05; 95% confidence interval [CI], 0.01-0.34), anti-methicillin-resistant Staphylococcus aureus antibiotics (OR, 0.21; 95% CI, 0.07-0.63), and carbapenems (OR, 0.07; 95% CI, 0.02-0.19), without impairing clinical outcomes, including clinical response rate (OR, 1.48; 95% CI, 0.95-2.31) and coverage rate of initial antibiotic therapy (OR, 0.70; 95% CI, 0.40-1.22) using random-effects models in our meta-analysis. In conclusion, Gram stain may be useful in guiding initial antibiotic selection without apparent adverse clinical outcomes. However, currently available studies evaluating the clinical usefulness of Gram stain are limited to specific clinical settings.

Restrictive Versus Permissive Use of Broad-spectrum Antibiotics in Patients Receiving Allogeneic Stem Cell Transplantation and With Early Fever Due to Cytokine Release Syndrome: Evidence for Beneficial Microbiota Protection Without Increase in Infectious Complications.

BACKGROUND: Intestinal microbiome contributes to the pathophysiology of acute gastrointestinal (GI) graft-versus-host disease (GvHD) and loss of microbiome diversity influences the outcome of patients after allogeneic stem cell transplantation (SCT). Systemic broad-spectrum antibiotics have been identified as a major cause of early intestinal dysbiosis. METHODS: In 2017, our transplant unit at the university hospital in Regensburg changed the antibiotic strategy from a permissive way with initiation of antibiotics in all patients with neutropenic fever independent of the underlying cause and risk to a restrictive use in cases with high likelihood of cytokine release syndrome (eg, after anti-thymocyte globulin [ATG] therapy). We analyzed clinical data and microbiome parameters obtained 7 days after allogeneic SCT from 188 patients with ATG therapy transplanted in 2015/2016 (permissive cohort, n = 101) and 2918/2019 (restrictive cohort, n = 87). RESULTS: Restrictive antibiotic treatment postponed the beginning of antibiotic administration from 1.4 ± 7.6 days prior to 1.7 ± 5.5 days after SCT (P = .01) and significantly reduced the duration of antibiotic administration by 5.8 days (P < .001) without increase in infectious complications. Furthermore, we observed beneficial effects of the restrictive strategy compared with the permissive way on microbiome diversity (urinary 3-indoxylsulfate, P = .01; Shannon and Simpson indices, P < .001) and species abundance 7 days post-transplant as well as a positive trend toward a reduced incidence of severe GI GvHD (P = .1). CONCLUSIONS: Our data indicate that microbiota protection can be achieved by a more careful selection of neutropenic patients qualifying for antibiotic treatment during allogeneic SCT without increased risk of infectious complications.

Identify Drug-Resistant Pathogens in Patients with Community-Acquired Pneumonia.

A substantial increase in broad-spectrum antibiotics as empirical therapy in patients with community-acquired pneumonia (CAP) has occurred over the last 15 years. One of the driving factors leading to that has been some evidence showing an increased incidence of drug-resistant pathogens (DRP) in patients from a community with pneumonia, including methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. Research has been published attempting to identify DRP in CAP through the implementation of probabilistic approaches in clinical practice. However, recent epidemiological data showed that the incidence of DRP in CAP varies significantly according to local ecology, healthcare systems and countries where the studies were performed. Several studies also questioned whether broad-spectrum antibiotic coverage might improve outcomes in CAP, as it is widely documented that broad-spectrum antibiotics overuse is associated with increased costs, length of hospital stay, drug adverse events and resistance. The aim of this review is to analyze the different approaches used to identify DRP in CAP patients as well as the outcomes and adverse events in patients undergoing broad-spectrum antibiotics.

Impact of COVID-19 on broad-spectrum antibiotic prescribing for common infections in primary care in England: a time-series analyses using OpenSAFELY and effects of predictors including deprivation.

Background: The COVID-19 pandemic impacted the healthcare systems, adding extra pressure to reduce antimicrobial resistance. Therefore, we aimed to evaluate changes in antibiotic prescription patterns after COVID-19 started. Methods: With the approval of NHS England, we used the OpenSAFELY platform to access the TPP SystmOne electronic health record (EHR) system in primary care and selected patients prescribed antibiotics from 2019 to 2021. To evaluate the impact of COVID-19 on broad-spectrum antibiotic prescribing, we evaluated prescribing rates and its predictors and used interrupted time series analysis by fitting binomial logistic regression models. Findings: Over 32 million antibiotic prescriptions were extracted over the study period; 8.7% were broad-spectrum. The study showed increases in broad-spectrum antibiotic prescribing (odds ratio [OR] 1.37; 95% confidence interval [CI] 1.36-1.38) as an immediate impact of the pandemic, followed by a gradual recovery with a 1.1-1.2% decrease in odds of broad-spectrum prescription per month. The same pattern was found within subgroups defined by age, sex, region, ethnicity, and socioeconomic deprivation quintiles. More deprived patients were more likely to receive broad-spectrum antibiotics, which differences remained stable over time. The most significant increase in broad-spectrum prescribing was observed for lower respiratory tract infection (OR 2.33; 95% CI 2.1-2.50) and otitis media (OR 1.96; 95% CI 1.80-2.13). Interpretation: An immediate reduction in antibiotic prescribing and an increase in the proportion of broad-spectrum antibiotic prescribing in primary care was observed. The trends recovered to pre-pandemic levels, but the consequence of the COVID-19 pandemic on AMR needs further investigation. Funding: This work was supported by Health Data Research UK and by National Institute for Health Research.

Impact of Penicillin Allergy Label on Clinical Outcomes of Pneumonia in Children.

BACKGROUND: Penicillin (PCN) allergy label, reported in approximately 5% of children, influences antibiotic choice and prolongs hospital stay. To our knowledge, the impact of PCN allergy label on clinical outcomes of pneumonia in children is not well characterized. OBJECTIVES: To investigate the impact of PCN allergy label on clinical outcomes of pneumonia in children. METHODS: In this propensity score-matched cohort study, we used the TriNetX research network, a population-based database, to compare the 30-day risk of hospitalization, need for intensive level of care, and acute respiratory failure from pneumonia between pediatric patients (aged 1-17 years) with and without a PCN allergy label after matching the 2 cohorts for demographic and medical comorbidities. Antibiotic prescription patterns were also contrasted. RESULTS: When comparing 3793 pediatric patients with pneumonia labeled with a PCN allergy with matched children without a PCN allergy label, PCN allergy label was associated with a higher risk of hospitalization (relative risk [RR], 1.15; 95% confidence interval [CI], 1.07-1.23), acute respiratory failure (RR, 1.27; 95% CI, 1.17-1.39), and need for intensive level of care (RR, 1.46; 95% CI, 1.15-1.84). PCN allergy label resulted in overutilization of broader-spectrum antibiotics and increased complications including cutaneous drug reactions (RR, 2.43; 95% CI, 1.31-4.52) and Clostridioides difficile infection (RR, 2.25; 95% CI, 1.14-4.44). CONCLUSION: Children with a PCN allergy label are more likely to be hospitalized, receive broader-spectrum antibiotics, and develop acute respiratory failure from pneumonia. Delabeling may offer a way to lessen morbidity from pneumonia in children.

Depletion of gut microbiota resistance in 5×FAD mice enhances the therapeutic effect of mesenchymal stem cell-derived exosomes.

Mesenchymal stem cell-derived exosomes (MSCs-exo) can be used for treating Alzheimer's disease (AD) by promoting amyloid-ß (Aß) degradation, modulating immune responses, protecting neurology, promoting axonal growth, and improving cognitive impairment. Increasing evidence suggests that the alteration of gut microbiota is closely related to the occurrence and development of Alzheimer's disease. In this study, we hypothesized that dysbiosis of gut microbiota might limit the therapy of MSCs-exo, and the application of antibiotics would improve the therapy. METHODS: In this original research study, we used MSCs-exo to treat 5 ×FAD mice and fed them antibiotic cocktails for 1 week to detect cognitive ability and neuropathy. The mice's feces were collected to investigate alterations in the microbiota and metabolites. RESULTS: The results revealed that the AD gut microbiota eliminated the therapeutic effect of MSCs-exo, whereas antibiotic modulation of disordered gut microbiota and associated metabolites enhanced the therapeutic effect of MSCs-exo. CONCLUSIONS: These results encourage the research of novel therapeutics to enhance MSCs-exo treatment for AD, which could benefit a broader range of patients with AD.

Covalent DNA Binding Is Essential for Gram-Negative Antibacterial Activity of Broad Spectrum Pyrrolobenzodiazepines.

It is urgent to find new antibiotic classes against multidrug-resistant bacteria as the rate of discovery of new classes of antibiotics has been very slow in the last 50 years. Recently, pyrrolobenzodiazepines (PBDs) with a C8-linked aliphatic-heterocycle have been identified as a new broad-spectrum antibiotic class with activity against Gram-negative bacteria. The active imine moiety of the reported lead pyrrolobenzodiazepine compounds was replaced with amide to obtain the non-DNA binding and noncytotoxic dilactam analogues to understand the structure-activity relationship further and improve the safety potential of this class. The synthesised compounds were tested against panels of multidrug-resistant Gram-positive and Gram-negative bacteria, including WHO priority pathogens. Minimum inhibitory concentrations for the dilactam analogues ranged from 4 to 32 mg/L for MDR Gram-positive bacteria, compared to 0.03 to 2 mg/L for the corresponding imine analogues. At the same time, they were found to be inactive against MDR Gram-negative bacteria, with a MIC > 32 mg/L, compared to a MIC of 0.5 to 32 mg/L for imine analogues. A molecular modelling study suggests that the lack of imine functionality also affects the interaction of PBDs with DNA gyrase. This study suggests that the presence of N10-C11 imine moiety is crucial for the broad-spectrum activity of pyrrolobenzodiazepines.

Effects of rearing system and antibiotic treatment on immune function, gut microbiota and metabolites of broiler chickens.

BACKGROUND: In China, cage systems with a high space utilization have gradually replaced ground litter systems, but the disease incidence of chickens in cages is higher. Broilers in the ground litter pens may be stimulated by more environmental microbes during the growth process and show strong immune function and status, but knowledge of which microbes and their metabolites play an immunomodulatory role is still limited. This study aimed to explore the differences and correlations in the immune function, gut microbiota and metabolites and the importance of gut microbiota of broilers raised in cages and ground litter pens. METHODS: The experiment involved a 2 × 2 factorial arrangement, with rearing systems (cages or ground litter pens) and antibiotic treatment (with or without broad-spectrum antibiotics in drinking water) as factors. RESULTS: The results showed that, compared with the cage group, the ground litter broilers had stronger nonspecific immune function (Macrophages% and NO in blood), humoral immune function (IgG in blood, LPS stimulation index in ileum) and cellular immune function (T%, Tc%, ConA stimulation index and cytokines in blood). Antibiotic (ABX) treatment significantly reduced nonspecific immune function (Macrophages% and NO in blood, iNOS and Mucin2 mRNA expression in ileum), humoral immune function (IgG in blood and sIgA in ileum) and cellular immune function (T% and cytokines in blood, Th and Tc ratio, TLRs and cytokines mRNA expression in ileum). Furthermore, the ground litter broilers had higher α diversity of microbiota in ileum. The relative abundance of Staphylococcus, Jeotgalicoccus, Jeotgalibaca and Pediococcus in the ileum of ground litter broilers were higher. ABX treatment significantly reduced the α diversity of ileal microbiota, with less Chloroplast and Mitochondria. In addition, the levels of acetic acid, isobutyric acid, kynurenic acid and allolithocholic acid in the ileum of ground litter broilers were higher. Spearman correlation analysis showed that Jeotgalibaca, Pediococcus, acetic acid, kynurenic acid and allolithocholic acid were related to the immune function. CONCLUSIONS: There were more potential pathogens, litter breeding bacteria, short-chain fatty acids, kynurenine, allolithocholic acid and tryptophan metabolites in the ileum of broilers in ground litter pens, which may be the reason for its stronger immune function and status.