Site Infection Research Articles

A Targeted Click-to-Release Activation of the Last-Resort Antibiotic Colistin Reduces its Renal Cell Toxicity.

The use of highly potent but very toxic antibiotics such as colistin has become inevitable due to the rise of antimicrobial resistance. We aimed for a chemically-triggered, controlled release of colistin at the infection site to lower its systemic toxicity by harnessing the power of click-to-release reactions. Kinetic experiments with nine tetrazines and three dienophiles demonstrated a fast release via an inverse-electron-demand Diels-Alder reaction between trans-cyclooctene (TCO) and the amine-functionalised tetrazine Tz7. The antibiotic activity of colistin against Escherichia coli was masked by TCO units, but restored upon reaction with d-Ubi-Tz, a tetrazine functionalised with the bacterial binding peptide d-Ubi29-41. While standard TCO did not improve toxicity against human proximal tubular kidney HK-2 cells, the installation of an aspartic acid-modified TCO masking group reduced the overall charge of the peptide and entry to the kidney cells, thereby dramatically lowering its toxicity. The analog Col-(TCO-Asp)1 had favourable pharmacokinetic properties in mice and was successfully activated locally in the lung by d-Ubi-Tz in an in vivo infection model, whereas it remained inactive and non-harmful without the chemical trigger. This study constitutes the first example of a systemically acting two-component antibiotic with improved drug tolerability.

D-[5-11C]-Glutamine Positron Emission Tomography Imaging for Diagnosis and Therapeutic Monitoring of Orthopedic Implant Infections.

Orthopedic implant infections (OIIs) present diagnostic and therapeutic challenges, owing to the lack of methods to distinguish between active infection and sterile inflammation. To address this unmet need, d-amino-acid-based radiotracers with unique metabolic profiles in microorganisms have emerged as a novel class of infection-specific imaging agents. Given the pivotal role of d-glutamine in bacterial biofilm formation and virulence, herein, we explored the potential of positron emission tomography (PET) imaging with d-[5-11C]-Glutamine (d-[5-11C]-Gln) for early detection and treatment monitoring of OIIs. In vitro studies confirmed an active uptake of d-[5-11C]-Gln by Staphylococcus aureus (S. aureus) biofilm commonly associated with OIIs. In vivo evaluations included PET imaging comparisons with d-[5-11C]-Gln vs l-[5-11C]-Gln or 2-deoxy-2-[18F]-fluoroglucose ([18F]-FDG) in a rat OII model with tibial implantation of sterile or S. aureus-colonized stainless-steel screws before and after treatment. These studies demonstrated that the uptake of d-[5-11C]-Gln was significantly higher in the infected screws than that in sterile screws (∼3.4-fold, p = 0.008), which displayed significantly higher infection-to-background muscle uptake ratios (∼2-fold, p = 0.011) with d-[5-11C]-Gln as compared to l-[5-11C]-Gln. Following a 3 week vancomycin treatment, imaging with d-[5-11C]-Gln showed a significant reduction in uptake at the infected sites (∼3-fold, p = 0.0008). Further regression analyses revealed a superior correlation of residual infection-associated radiotracer uptake with the postimaging ex vivo bacterial counts for d-[5-11C]-Gln (k = 0.473, R2 = 0.796) vs [18F]-FDG (k = 0.212, R2 = 0.434), suggesting that d-[5-11C]-Gln PET had higher sensitivity for detecting residual bacterial burden than [18F]-FDG PET. Our results demonstrate the translational potential of d-[5-11C]-Gln PET imaging for noninvasive detection and treatment monitoring of OIIs.

Comparison of efficacy and safety between elacycline and polymyxin for complicated intra-abdominal infections caused by multidrug-resistant bacteria

Objective: To compare the efficacy and safety of eravacycline and polymyxin drugs in the treatment of multidrug-resistant complicated intra-abdominal infections(cIAI). Methods: The cIAI patients diagnosed or highly suspected of multidrug resistant bacterial infection who received eravacycline treatment at Sir Run Run Shaw Hospital and Shulan (Hangzhou) Hospital from June to August 2023 were prospectively included as the elacycline group. The cIAI patients with cIAI caused by multidrug resistant bacteria who received treatment with polymyxin (B or E) from January 2021 to August 2023 were retrospectively collected. The acute physiology and chronic health scores and age were matched with those of the elacrinid group, and they were included in the polymyxin group. The study mainly analyzed the clinical efficacy, microbial clearance rate, comprehensive efficacy, and safety of the two groups at the end of treatment and discharge. Results: A total of 72 patients with cIAI were included in the study, including 53 males and 19 females, aged (56.0±15.4) years. Among them, there were 28 cases in the eravacycline group and 44 cases in the polymyxin group. There was no statistically significant differences in the baseline, the proportion of patients who used combined drugs, the strains, the infection sites and infection conditions of patients between the two groups(all P>0.05).The clinical efficacy rate at the end of treatment [89.3% (25/28) vs 56.8%(25/44), P=0.004] and discharge [(88.5%(23/26) vs 63.6%,(28/44), P=0.024], microbial clearance rate at the end of treatment [(88.9% (24/27) vs 47.6%(20/42), P=0.001] and discharge [(91.3%(21/23) vs 59.5%(25/42), P=0.007], and overall recovery rate at the end of treatment [(89.3%(25/28) vs 52.3%(23/44), P=0.001] and discharge [(88.5%(23/26) vs 63.6%(28/44), P=0.024] in the erythromycin group were higher than those in the polymyxin drug group. In terms of safety, only 2 cases of mild vasculitis were observed in the eravacycline group. Conclusions: Combined regimens based on eravacycline showed better clinical effect in the treatment of cIAI caused by multidrug-resistant bacteria. The clinical effective rate, microbial clearance rate and comprehensive efficacy were significantly higher than those of polymyxin drugs at the end of treatment and discharge with good safety.

Association between malnutrition status and total joint arthroplasty periprosthetic joint infection and surgical site infection: a systematic review meta-analysis

BackgroundMalnutrition is a state resulting from lack of intake or uptake of nutrition. Investigating the association between malnutrition and postoperative complications is essential for enhancing patient outcomes in total joint arthroplasty (TJA). This meta-analysis aimed to investigate the impact of malnutrition on the incidence of surgical site infections (SSIs) and periprosthetic joint infections (PJIs) following TJA.MethodsThe data were searched from databases including PubMed, Embase, Web of Science, and Cochrane Library inception through July 19 2023, without time restrictions. Inclusion criteria focused on studies examining malnutrition as a risk factor for SSIs and PJIs postarthroplasty, providing sufficient data for calculating odds ratios (ORs) and 95% confidence intervals (CIs). Methodological quality was assessed using the Newcastle‒Ottawa Scale, and statistical analyses were executed in Stata version 17.ResultsA total of 1,025 articles were screened, and 9 studies satisfying the predefined inclusion criteria were consequently selected for this meta-analysis. Studies indicated that malnutrition is significant factor to the heightened incidence of both SSIs and PJIs following TJA procedures. Our pooled results yielded aggregated ORs of 2.60 for SSIs and 3.44 for PJIs, with respective 95% CIs of 2.10–3.10 and 2.35–4.53. The heterogeneity of malnutrition as a risk factor for postoperative SSI was I2 = 0.0% (p = 0.592), and for PJI was I2 = 0.0% (p = 0.422). Egger’s linear regression test showed no significant publication bias (p > 0.05).ConclusionsMalnutrition is a significant risk factor for SSIs and potentially PJIs in patients undergoing TJA. Preoperative optimization strategies targeted at malnourished patients are suggested to minimize postoperative complications clinically.

Comparative analysis of non-tuberculous mycobacterial lung disease and lung colonization: a case-control study

BackgroundNon-tuberculous mycobacteria (NTM) are common opportunistic pathogens, and the most common infection site is lung. NTM are found commonly in the environment. Many patients have NTM lung colonization (NTM-Col). NTM lung disease (NTM-LD) have no specific sympotms, though it is hard to differentiate NTM-LD and NTM-Col under this circumstance. The aim of this study is to explore the differences between NTM-LD and NTM-Col for future clinical diagnosis and treatment.MethodsWe retrospectively enrolled patients who had a history of NTM isolated from respiratory specimens in Peking Union Medical College Hospital (PUMCH) from January 1st, 2013 to December 31st, 2022. Patients were classified into NTM-LD group and NTM-Col group. Demographic characteristics, clinical manifestations, laboratory tests and imaging findings of the two groups were compared. Comparative analysis was also performed in peripheral blood lymphocyte subsets among three groups.ResultsA total of 127 NTM-LD patients and 37 NTM-Col patients were enrolled. Proportion of patients with bronchiectasis was higher in NTM-LD group than in NTM-Col group (P = 0.026). Predominant NTM isolates were Mycobacterium avium complex (MAC). NTM-LD group had a higher proportion of Mycobacterium intracellulare (P = 0.004). CD4+ T cells counts was lower in NTM-LD group (P = 0.041) than in NTM-Col group. Imaging finding of bronchiectasis (P = 0.006) was higher in NTM-LD group than in NTM-Col group. Imaging findings of bronchiectasis (OR = 6.282, P = 0.016), and CD4+ T cell count (OR = 0.997, P = 0.012) were independent associated factors for differential diagnosis between NTM-LD and NTM-Col.ConclusionNTM isolates from both NTM-LD and NTM-Col patients were predominantly MAC, with a higher Mycobacterium intracellulare isolation rate in NTM-LD group. Imaging findings of bronchiectasis and lower peripheral blood CD4+ T cell count may be helpful to separate the diagnosis of NTM-LD from NTM-Col.

Immune cells promote paralytic disease in mice infected with enterovirus D68.

Enterovirus D68 (EV-D68) is associated with acute flaccid myelitis (AFM), a poliomyelitis-like illness causing paralysis in young children. However, mechanisms of paralysis are unclear, and antiviral therapies are lacking. To better understand EV-D68 disease, we inoculated newborn mice intracranially to assess viral tropism, virulence, and immune responses. Wild-type (WT) mice inoculated intracranially with a neurovirulent strain of EV-D68 showed infection of spinal cord neurons and developed paralysis. Spinal tissue from infected mice revealed increased levels of chemokines, inflammatory monocytes, macrophages, and T cells relative to controls, suggesting that immune cell infiltration influences pathogenesis. To define the contribution of cytokine-mediated immune cell recruitment to disease, we inoculated mice lacking CCR2, a receptor for several EV-D68-upregulated cytokines, or RAG1, which is required for lymphocyte maturation. WT, Ccr2 -/- , and Rag1 -/- mice had comparable viral titers in spinal tissue. However, Ccr2 -/- and Rag1 -/- mice had significantly less paralysis relative to WT mice. Consistent with impaired T cell recruitment to sites of infection in Ccr2 -/- and Rag1 -/- mice, antibody-mediated depletion of CD4 + or CD8 + T cells from WT mice diminished paralysis. These results indicate that immune cell recruitment to the spinal cord promotes EV-D68-associated paralysis and illuminate new targets for therapeutic intervention.

Nanozyme-Shelled Microcapsules for Targeting Biofilm Infections in Confined Spaces.

Bacterial infections in irregular and branched confinements pose significant therapeutic challenges. Despite their high antimicrobial efficacy, enzyme-mimicking nanoparticles (nanozymes) face difficulties in achieving localized catalysis at distant infection sites within confined spaces. Incorporating nanozymes into microrobots enables the delivery of catalytic agents to hard-to-reach areas, but poor nanoparticle dispersibility and distribution during fabrication hinder their catalytic performance. To address these challenges, a nanozyme-shelled microrobotic platform is introduced using magnetic microcapsules with collective and adaptive mobility for automated navigation and localized catalysis within complex confinements. Using double emulsions produced from microfluidics as templates, iron oxide and silica nanoparticles are assembled into 100-µm microcapsules, which self-organize into multi-unit, millimeter-size assemblies under rotating magnetic fields. These microcapsules exhibit high peroxidase-like activity, efficiently catalyzing hydrogen peroxide to generate reactive oxygen species (ROS). Notably, microcapsule assemblies display remarkable collective navigation within arched and branched confinements, reaching the targeted apical regions of the tooth canal with high accuracy. Furthermore, these nanozyme-shelled microrobots perform rapid catalysis in situ and effectively kill biofilms on contact via ROS generation, enabling localized antibiofilm action. This study demonstrates a facile method of integrating nanozymes onto a versatile microrobotic platform to address current needs for targeted therapeutic catalysis in complex and confined microenvironments.

Immune Dysregulation in the Oral Cavity during Early SARS-CoV-2 Infection.

Tissue-specific immune responses are critical determinants of health-maintaining homeostasis and disease-related dysbiosis. In the context of COVID-19, oral immune responses reflect local host-pathogen dynamics near the site of infection and serve as important "windows to the body," reflecting systemic responses to the invading SARS-CoV-2 virus. This study leveraged multiplex technology to characterize the salivary SARS-CoV-2-specific immunological landscape (37 cytokines/chemokines and 11 antibodies) during early infection. Cytokine/immune profiling was performed on unstimulated cleared whole saliva collected from 227 adult SARS-CoV-2+ participants and 37 controls. Statistical analysis and modeling revealed significant differential abundance of 25 cytokines (16 downregulated, 9 upregulated). Pathway analysis demonstrated early SARS-CoV-2 infection is associated with local suppression of oral type I/III interferon and blunted natural killer-/T-cell responses, reflecting a potential novel immune-evasion strategy enabling infection. This virus-associated immune suppression occurred concomitantly with significant upregulation of proinflammatory pathways including marked increases in the acute phase proteins pentraxin-3 and chitinase-3-like-1. Irrespective of SARS-CoV-2 infection, prior vaccination was associated with increased total α-SARS-CoV-2-spike (trimer), -S1 protein, -RBD, and -nucleocapsid salivary antibodies, highlighting the importance of COVID-19 vaccination in eliciting mucosal responses. Altogether, our findings highlight saliva as a stable and accessible biofluid for monitoring host responses to SARS-CoV-2 over time and suggest that oral-mucosal immune dysregulation is a hallmark of early SARS-CoV-2 infection, with possible implications for viral evasion mechanisms.

Clinical and epidemiological characterization of infections in pediatric hemato-oncology patients with febrile neutropenia in the North of Mexico

Abstract Background Neutropenic fever is the most common complication in patients undergoing chemotherapy, where the choice of empirical antibiotic treatment should be based on the probable focus of infection, the predominant causative microorganisms, and the sensitivity of those organisms to antibiotics, which varies between each hospital and region. Over time, the spectrum of isolated microorganisms in different clinical syndromes of patients presenting during their infectious episode has changed. Our objective is to describe the prevalence of infectious etiology in pediatric patients with neutropenic fever, as well as the clinical characteristics of patients with documented infection. Methods The study design is ambispective, observational, and descriptive of a cohort type. Patients between 0 and 18 years old from the pediatric department of the “Dr. José E. González” University Hospital will be included from May 2019 to June 2023, with hematological-oncological disease during their febrile neutropenia infectious process with a complete medical record. Results A total of 326 episodes of febrile neutropenia were included, of which 15% had microbiological isolation (49 patients). The etiological classification during the events was as follows: bacteria 81%, viruses 14%, and fungi 4%. Five different infection sites were identified. Among these, bacteremia were the most frequent site of infection (10%), followed by gastrointestinal infections (2.4%), respiratory infections (1.5%), skin and soft tissue infections (1.2%), and lastly, urinary tract infections (1%). A total of 45 microorganisms were isolated from different infection sites. Among these, gram-negative bacteria (28 isolates, 62%) were more common and outnumbered gram-positive bacteria (14 isolates, 31%). Among gram-negatives, Escherichia coli (42%) was the most common isolate, followed by Pseudomonas aeruginosa (17%), and Klebsiella pneumoniae (14%). Among gram-positives, Streptococcus mitis (28%), Coagulase-negative Staphylococcus (21%), and Rothia mucilaginosa (14%) were identified. Conclusion Febrile neutropenia at the Hospital Universitario primarily affects 6-year-old males with ALL. The microbiological characterization suggests the intentional search for gram-negative bacteremia, allowing us to direct timely and targeted antibiotic therapy to influence clinical prognosis. It is worthwhile to continue the research line that allows us to identify susceptibility and resistance profiles to address these patients more effectively.

Infectious disease events in people with HIV receiving kidney transplantation: Analysis of the Swiss HIV Cohort Study and the Swiss Transplant Cohort Study

BackgroundSince the implementation of universal antiretroviral therapy, kidney transplantation (K-Tx) has become a valuable option for treatment of end-stage kidney disease for people with HIV (PWH) with similar patient and graft survival as compared to HIV-uninfected patients. Little is known about the hazards and manifestations of infectious disease (ID) events occurring in kidney transplant recipients with HIV.MethodsUsing linked information collected in the Swiss HIV Cohort Study (SHCS) and the Swiss Transplant Cohort Study (STCS), we described in-depth demographical and clinical characteristics of PWH who received a K-Tx since 2008. Further, we performed recurrent time to event analyses to understand whether HIV was an independent risk factor for ID events.ResultsOverall, 24 PWH with 57 ID events were included in this study (100% match of SHCS to STCS). Of these, 17 (70.8%) patients had at least one ID event: 22 (38.6%) viral (HIV not counted), 18 (31.6%) bacterial, one (1.8%) fungal and 16 (28.1%) probable infections. Most ID events affected the respiratory tract (25, 37.3%) or the urinary tract (13, 19.4%). Pathogen types and infection sites were similar in PWH and a matched control group of HIV-uninfected patients. HIV was not an independent risk factor for ID events (adjusted hazard ratio 0.94, p = 0.9).ConclusionBy linking data from two large national Swiss cohorts, we provided in-depth information on ID events in PWH receiving a K-Tx in Switzerland. HIV infection was not associated with an increased hazard for ID events after K-Tx.

Differential transcriptome reprogramming induced by the soybean cyst nematode Type 0 and Type 1.2.5.7 during resistant and susceptible interactions.

Soybean cyst nematode (SCN, Heterodera glycines) is a serious root parasite of soybean (Glycine max) that induces extensive gene expression changes associated with pleiotropic biological activities in infected cells. However, the impacts of various SCN Hg Types on host transcriptome reprogramming remain largely unknown. Here, we developed and used two recombinant inbred lines (RIL-72 and RIL-137) to profile transcriptome reprogramming in the infection sites during the resistant and susceptible interactions with SCN Hg Type 1.2.5.7 and Type 0. SCN bioassays indicated that RIL-72 was susceptible to Type 1.2.5.7 but resistant to Type 0, whereas RIL-137 was resistant to both types. Comparative analysis of gene expression changes induced by Type 1.2.5.7 in the resistant and susceptible lines revealed distinct transcriptome regulation with a number of similarly and oppositely regulated genes. The expression levels of similarly regulated genes in the susceptible line appeared to be insufficient to mount an effective defense against SCN. The functional importance of oppositely regulated genes was confirmed using virus induced gene silencing and overexpression approaches. Further transcriptome comparisons revealed shared as well as Hg Type- and genotype-specific transcriptome reprogramming. Shared transcriptome responses were mediated through common SCN-responsive genes and conserved immune signaling, whereas genotype-specific responses were derived from genetic variability, metabolic and hormonal differences, and varied regulation of protein phosphorylation and ubiquitination. The conserved defense mechanisms together with genotype-specific responses would enable plants to trigger effective and tailored immune responses to various Hg types and adapt the defense response to their genetic backgrounds.

Antimicrobial Stewardship: A Game Changer in the Fight against Carbapenem-ResistantEnterobacteriaceae (CRE) among Children with Cancer

Abstract Background Carbapenem-resistant Enterobacteriaceae (CRE) is an emerging threat among pediatric cancer patients, with a high mortality rate. A previous study in our center reported that 254 patients with CRE BSI were diagnosed from (2013-2018) with mortality from CRE BSI being 30%. Previous colonization was reported in 35% of those patients. Time to start adequate antibiotics is an independent prognostic factor for patients with CRE BSI, (48%) of patients started active treatment after 48h from culture and associated with higher mortality when compared to patients who started treatment earlier. Our recommendations include antimicrobial stewardship for early detection through routine screening and timely adequate therapy that may impact the outcome for such high-risk patient groups. Methods This prospective study included all pediatric cancer patients with (CRE) bloodstream infections (BSI) at a children’s cancer hospital in Egypt (2020–2022) with adopting antimicrobial stewardship program goals by (1) applying routine screening by rectal swab for high-risk patients and starting active treatment for patients colonized by CRE. (2) Introduction of PCR-based method (Cepheid XpertCarba-R assay) is developed for detecting carbapenemase genes with the availability of results within one hour which can allow for rapid time to start active treatment in less than 48h. Results One hundred and fifty pediatric cancer patients with CRE BSI were identified; 83% had hematological malignancies, and 17% had solid tumors. Acute myeloid leukemia was the most common hematological malignancy (47%). The main clinical features for acquiring CRE-BSI were prolonged neutropenia > 7 days (62%), previous Carbapenem exposure (82%), Quinilone prophylaxis (44%), central venous catheter use (40%), previous colonization with a resistant pathogen (35%) and ICU admission within 90 days (18%). E. coli was the most common isolated pathogen (65%), followed by Klebsiella pneumoniae (31%). Documented site of infection was reported with pneumonia in (32%), typhlitis in 15% skin soft tissue infection (57%), CNS infection (18%), and urinary tract infection in (10%). Time to start active antibiotics in less than 48h was reported in 89% with clinical cure reported in 71% and microbiological clearance was reported in in less than 7 days in 70% of patients. The need for ICU admission as sepsis related to CRE was reported in 29/150 (19%). The Gentopyic profile for CRE in our study reported that class B (69%) with NDM reported in 98/150 (65%) and VIM 6/150 (4%) was the most common carbanamases followed by Oxa-48 in 89/150(59%) of patients while KPC enzyme reported only in 6/150(4%). Day 30 mortality was reported in 23/150(15%). Upon multivariate analysis, patients with Klebsiella pneumoniae BSI, NDM genotype carbapenemases, CRE with aminoglycosides resistance or associated with pneumonia, and CRE patients who developed septic shock with the need for ICU admission were predictors of poor outcome. Conclusion CRE-BSI is a major threat among pediatric cancer patients in limited-resource countries and is considered a barrier against better outcomes. Antimicrobial stewardship through routine screening for colonization detection and Rapid diagnosis by using gene expert with rapid time to start adequate active antibiotics treatment is associated with improvement of outcome and decreasing mortality. Table 1: Comparison between retrospective study and prospective study (after adopting antimicrobial stewardship goals)

Clinical Characteristics, Management, and Outcomes of Bacteremia in Children with Cancer: A Retrospective Study

Abstract Background Bacteremia is a common infectious complication among pediatric oncology patients, yet management practices are not standardized. Antibiotic treatment courses as short as seven days are supported by literature and could improve patient quality of life and resource use. However, it is not known if short courses are associated with greater treatment failure in immunocompromised patients. Methods We conducted a retrospective study at St. Jude Children’s Research Hospital, including patients with a laboratory confirmed bloodstream bacterial infection between April 1, 2022, and March 31, 2023. Clinical characteristics such as age, gender, type of malignancy, phase of treatment, underlying chronic conditions, and clinical sites of infection were collected. Antibiotics used, duration of therapy, and route of administration were also gathered to examine clinical management. Clinical outcomes were measured by documenting ICU admission, oxygen, fluid and vasopressor requirements, date of hospital discharge, bacteremia recurrence, and mortality. Results 86 patients contributed 112 bacteremia episodes that met eligibility criteria. Severe neutropenia was present at onset in 68% of all episodes and 32% of patients did not have neutrophil recovery over 500 cells/ml during the episode. Gram-negative organisms accounted for 52% of isolated organisms, with the most common organisms isolated overall being Escherichia coli (19%), followed by Klebsiella pneumoniae (14%), and Viridans group streptococcus (14%). The median length of antibiotic treatment was 12 days. Treatment duration was not associated with oncologic diagnosis or Gram-negative versus Gram-positive infection. Conclusion Bacteremia occurs more frequently in patients who are neutropenic, especially those who are severely neutropenic with an absolute neutrophil count less than 500 cells/mL. Treatment duration is not associated with primary cancer diagnosis or type of bacteremia. In this single high resource setting, bloodstream infections resulted in significant morbidity, resource use, and a mortality rate of 8%, highlighting opportunities for investigation to improve clinical practices.

Bloodstream infections in a Brazilian Pediatric Tertiary Oncology Hospital: 30-month analysis regarding the classification of the infection, distribution of microorganisms and their resistance profile

Abstract Background Infections are a major cause of morbidity and mortality in pediatric oncology patients during their treatment. Bloodstream infections are the main site of infection in these patients. Bacteremia in these patients can be secondary to a primary infectious focus, result from central line associated bloodstream infections (CLABSIs) or mucosal barrier injury laboratory-confirmed bloodstream infection (MBI-LCBI). Methods Descriptive study of bloodstream infections in pediatric patients undergoing oncological treatment and hematopoietic stem cell transplantation in a tertiary pediatric oncology hospital in Brazil from January 1st, 2021 to June 30th, 2023. Infections were classified according to the Centers for Disease Control and Prevention/ National Healthcare Safety Network (CDC/NHSN) criteria into CLABSIs, MBI-LCBIs and secondary bloodstream infections. Among the bloodstream infections that met CDC/NHSN criteria for CLABSI, were analyzed separately those who also met the criteria of catheter-related bloodstream infection (CRBSI) according to Infectious Diseases Society of America (IDSA). Results During this period were diagnosed 335 episodes of bloodstream infection (123 episodes in 2021, 150 in 2022 and 62 episodes in the first 6 months of 2023). There were 378 microorganisms isolated. These infections were classified into: 35% CLABSIs, 27% MBI-LCBIs, 23% CRBSIs, and 15% secondary bloodstream infections. Among the CLABSIs, the most common microorganisms were non-fermenting gram negative bacilli (NFGNB) 38%, enterobacteriaceae 35% and coagulase-negative staphylococcus (CoNS) 11%. Between CRBSIs, there were 31% enterobacteriaceae, 22% CoNS and 19% NFGNB. Among the MBI-LCBIs there were 66% enterobacteriaceae and 23% group viridans streptococci (VGS). Streptococcus pneumoniae (33%) was the most common microorganism in secondary infections followed by Staphylococcus aureus (17%). Assessing all infections together, the main enterobacteriaceae were Klebsiella spp. (40%) and only 50% of them were sensitive to cefepime while 10% were carbapenems resistant. Among NFGNB, 13% of Pseudomonas spp. and 5% of Acinetobacter spp. were carbapenems resistant. Between the gram-positive bacteria, 77% of the S. aureus were methicillin sensitive, the same percentage of the VGS were sensitive to cefepime. Conclusion Among bloodstream infections, there were a predominance of CLABSI followed by MBI-LCBIs. Antimicrobial resistance between gram-positive bacteria, is of little concern in our institution. In the case of gram-negative bacteria, resistance to cefepime is becoming worrying among enterobacteriaceae.

Metal–phenolic nanozyme based microneedle patch with antibacterial and antioxidant for infected wound healing

Chronic bacterial-infected wound healing is becoming increasingly severe, with high rates of mortality and disability, owing to bacterial film, excessive accumulation of reactive oxygen species (ROS), inflammatory, and traditional therapeutics with poor drug permeability. Herin, a functional Zn-gallic acid nanozyme (Zn-NM) with excellent antibacterial and antioxidant capacity was incorporated with a gelatin-based microneedle patch (Zn-NM@MN) to achieve transdermal and sustained release of the drug at the infected wound site. The Zn-NM displayed the concentration-dependent antibacterial capacity, and 250 μg/mL of Zn-NM simultaneously possessed excellent antibacterial (89.36 ± 0.95 % for Escherichia coli, 92.44 ± 11.03 % for Staphylococcus aureus, and 95.03 ± 1.06 % for Methicillin-resistant Staphylococcus aureus), antioxidant properties and negligible cytotoxicity. After that, Zn-NM@MN could transdermal the epidermis or biofilm to sustain the release of Zn-NM for 3 h (release of 80 % drug). Systematic tissue regeneration assessment on rats’ infected full-thickness skin wounds demonstrated an enhanced wound healing rate. Zn-NM@MN could efficiently kill the bacteria (about 85 %), alleviate oxidant stress, reduce bacterial-induced inflammation, and promote vascular regeneration. This synergetic therapy strategy will pave the way for treating complicated infection wounds.

Identifying Gaps in the International Consensus Case Definitions for Invasive Aspergillosis: A Review of Clinical Cases Not Meeting These Definitions.

International consensus definitions for invasive aspergillosis (IA) in research are rigorous, yet clinically significant cases are often excluded from clinical studies for not meeting proven/probable IA case definitions. To better understand reasons for the failure to meet criteria for proven/probable infection, we herein review 47 such cases for their clinical and microbiological characteristics and outcomes. Data on 47 cases that did not meet consensus IA definitions but were deemed significant were derived from a retrospective, observational, multicenter survey of 382 presumed IA cases across Australasia, of which findings of 221 proven/probable infections were recently published. The clinical, microbiological, and radiologic characteristics of these cases were analyzed. Mortality outcomes were compared with those of 221 proven/probable cases. Of 47 cases studied, 15 lacked classical host factors; 22 exhibited only a single positive Aspergillus polymerase chain reaction result; 7 lacked typical IA radiologic findings on chest computed tomography; and 3 had borderline galactomannan optical density indices (<1.0 but ≥0.5) in bronchoalveolar lavage fluid. The median age of patients was 61 years (IQR, 52-68); 34 were male (72%). Seven patients (15%) required intensive care admission. All patients had lung as the primary site of infection. Antifungal treatment was initiated in 42 patients (89%). All-cause 90-day mortality was 33%, similar to the 30% mortality in the comparative cohort (n = 221). Our findings highlight the limitations of current consensus definitions for IA. Notably, the mortality of patients not meeting these definitions was similar to that of patients with proven/probable IA. Further studies, especially of patients with a single positive Aspergillus polymerase chain reaction result and those without host factors, are needed to determine if future consensus definitions may benefit from modifications.

Stress Responses to Bark Beetle Infestations among Pine (Pinus sylvestris), Fir (Abies alba), and Beech (Fagus sylvatica) Trees

Insect infestation triggers multiple defense responses in plants, both locally at the infection site and systemically throughout the plant, including the production of feeding deterrents, toxins, defensive proteins, enzymes, and secondary metabolites. Our study aimed to compare the endogenous levels of antioxidative enzymes, photosynthetic pigments, phytohormones, total phenols, and flavonoids in bark-beetle-infested and uninfested trees. We evaluated the surviving trees in bark-beetle-infested stands, assessing both the condition and defense of uninfested and infested beech (Fagus sylvatica), pine (Pinus sylvestris), and fir (Abies alba) trees. Sampling was performed at six affected sites in the Czech Republic, targeting trees that were resilient to significant health deterioration caused by abiotic and biotic factors. The results showed different levels of most of the measured compounds in the three species. Among all the tested species, photosynthetic pigment levels showed the strongest association with infestation status, which was generally lower in the infested plants. For chlorophyll a, extremely significant reductions were observed from 123 ± 20.6 to 101 ± 17.9 μg/g dry weight (DW) in pine, from 231 ± 33.1 to 199 ± 22.2 μg/g DW in beech, and from 60 ± 5.66 to 51.3 ± 6.27 μg/g DW in fir. In contrast, enzymatic activities indicated only isolated instances of significant association, whereas antioxidative properties (total phenolic content, flavonoids, and 2,2-diphenyl-1-picrylhydrazyl radical scavenging capacity) were not significantly associated with infestation status. There was a statistically significant increase in glutathione reductase activity in infested fir and pine trees. However, this difference was not statistically significant in beech. In contrast, a significant increase in superoxide dismutase activity was detected in infected beech trees. Phytohormones have emerged as the most diverse group of analyzed compounds. Cytokinins were the most distinct, with many of them being significantly increased in infested pines, whereas both beech and fir showed only one significant association. Additionally, derivatives of jasmonic acid also showed a distinct pattern of change associated with bark beetle infestation, with the levels of three out of the four analyzed jasmonates being significantly decreased in infested pines, whereas no effects were observed in beeches and firs. Notably, many phytohormones were significantly elevated in the infested pine, whereas both beech and fir exhibited only one significant association. Overall, the data showed that pines responded differently to bark beetles than to beeches or firs. The greatest changes in phytohormones were observed in pine, whereas the most significant changes in photosynthetic pigments were observed in beech and fir trees.

Cryptosporidium PI(4)K inhibitor EDI048 is a gut-restricted parasiticidal agent to treat paediatric enteric cryptosporidiosis

Diarrhoeal disease caused by Cryptosporidium is a major cause of morbidity and mortality in young and malnourished children from low- and middle-income countries, with no vaccine or effective treatment. Here we describe the discovery of EDI048, a Cryptosporidium PI(4)K inhibitor, designed to be active at the infection site in the gastrointestinal tract and undergo rapid metabolism in the liver. By using mutational analysis and crystal structure, we show that EDI048 binds to highly conserved amino acid residues in the ATP-binding site. EDI048 is orally efficacious in an immunocompromised mouse model despite negligible circulating concentrations, thus demonstrating that gastrointestinal exposure is necessary and sufficient for efficacy. In neonatal calves, a clinical model of cryptosporidiosis, EDI048 treatment resulted in rapid resolution of diarrhoea and significant reduction in faecal oocyst shedding. Safety and pharmacological studies demonstrated predictable metabolism and low systemic exposure of EDI048, providing a substantial safety margin required for a paediatric indication. EDI048 is a promising clinical candidate for the treatment of life-threatening paediatric cryptosporidiosis.

Functional plasticity shapes neutrophil response to Leishmania major infection in susceptible and resistant strains of mice.

Neutrophils rapidly infiltrate sites of infection and possess several microbicidal strategies, such as neutrophil extracellular traps release and phagocytosis. Enhanced neutrophil infiltration is associated with higher susceptibility to Leishmania infection, but neutrophil effector response contribution to this phenotype is uncertain. Here, we show that neutrophils from susceptible BALB/c mice (B/c) produce more NETs in response to Leishmania major than those from resistant C57BL/6 mice (B6), which are more phagocytic. The absence of neutrophil elastase contributes to phagocytosis regulation. Microarray analysis shows enrichment of genes involved in NET formation (mpo, pi3kcg, il1b) in B/c, while B6 shows upregulation of genes involved in phagocytosis and cell death (Arhgap12, casp9, mlkl, FasL). scRNA-seq in L. major-infected B6 showed heterogeneity in the pool of intralesional neutrophils, and we identified the N1 subset as the putative subpopulation involved with phagocytosis. In vivo, imaging validates NET formation in infected B/c ears where NETing neutrophils were mainly uninfected cells. NET digestion in vivo augmented parasite lymphatic drainage. Hence, a balance between NET formation and phagocytosis in neutrophils may contribute to the divergent phenotype observed in these mice.

Modulating Immune Responses: The Double-Edged Sword of Platelet CD40L.

The CD40-CD40L receptor ligand pair plays a fundamental role in the modulation of the innate as well as the adaptive immune response, regulating monocyte, T and B cell activation, and antibody isotype switching. Although the expression and function of the CD40-CD40L dyad is mainly attributed to the classical immune cells, the majority of CD40L is expressed by activated platelets, either in a membrane-bound form or shed as soluble molecules in the circulation. Platelet-derived CD40L is involved in the communication with different immune cell subpopulations and regulates their functions effectively. Thus, platelet CD40L contributes to the containment and clearance of bacterial and viral infections, and additionally guides leukocytes to sites of infection. However, platelet CD40L promotes inflammatory cellular responses also in a pathophysiological context. For example, in HIV infections, platelet CD40L is supportive of neuronal inflammation, damage, and finally HIV-related dementia. In sepsis, platelet CD40L can induce extensive endothelial and epithelial damage resulting in barrier dysfunction of the gut, whereby the translocation of microbiota into the circulation further aggravates the uncontrolled systemic inflammation. Nevertheless, a distinct platelet subpopulation expressing CD40L under septic conditions can attenuate systemic inflammation and reduce mortality in mice. This review focuses on recent findings in the field of platelet CD40L biology and its physiological and pathophysiological implications, and thereby highlights platelets as vital immune cells that are essential for a proper immune surveillance. In this context, platelet CD40L proves to be an interesting target for various inflammatory diseases. However, either an agonism or a blockade of CD40L needs to be well balanced since both the approaches can cause severe adverse events, ranging from hyperinflammation to immune deficiency. Thus, an interference in CD40L activities should be likely done in a context-dependent and timely restricted manner.