De novo mutations mediate phenotypic switching in an opportunistic human lung pathogen.

Bacteria evolving within human hosts encounter selective tradeoffs that render mutations adaptive in one context and deleterious in another. Here, we report that the cystic fibrosis-associated pathogen Burkholderia dolosa overcomes in-human selective tradeoffs by acquiring successive point mutations that alternate phenotypes. We sequenced the whole genomes of 931 respiratory isolates from two recently infected patients and an epidemiologically-linked, chronically-infected patient. These isolates are contextualized using 112 historical genomes from the same outbreak strain. Within both newly infected patients, diverse parallel mutations that disrupt O-antigen expression quickly arose, comprising 29% and 63% of their B. dolosa communities by 3 years. The selection for loss of O-antigen starkly contrasts with our previous observation of parallel O-antigen-restoring mutations after many years of chronic infection in the historical outbreak. Experimental characterization revealed that O-antigen loss increases uptake in immune cells while decreasing competitiveness in the mouse lung. We propose that the balance of these pressures, and thus whether O-antigen expression is advantageous, depends on tissue localization and infection duration. These results suggest that mutation-driven alternation during infection may be more frequent than appreciated and is underestimated without dense temporal sampling.

Cystic Fibrosis Mice Are Highly Susceptible to Repeated Acute Pseudomonas aeruginosa Pneumonia after Intranasal Inoculation.

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) that controls chloride current. A number of different CFTR transgenic mouse lines have been developed and subjected to both acute and chronic infection models. However, prior studies showed no substantial differences in bacterial clearance between CF and non-CF mice after single inoculations. Here, using F508del transgenic CF mice, we examined the role of repeated acute Pseudomonas aeruginosa (PA) infection, with the second inoculation 7 days after the first. We found that CF mice were more susceptible to PA infection than non-CF mice following the second inoculation, with non-CF mice showing better neutrophil recruitment and effector functions. We further investigated the characteristics of lung immune cells using single-cell RNA sequencing, finding that non-CF lung neutrophils had more prominent upregulation of adhesion molecules including intercellular adhesion molecule-1 (ICAM-1) compared to CF lung neutrophils. Although people with CF are often colonized with bacteria and have high numbers of neutrophils in the airways during chronic infection, these data suggest that CF neutrophils have deficient effector functions in the setting of repeated acute infection.

Stress Ulcer Prophylaxis Versus Placebo-A Blinded Pilot Randomized Controlled Trial to Evaluate the Safety of Two Strategies in Critically Ill Infants With Congenital Heart Disease.

OBJECTIVES: The routine use of stress ulcer prophylaxis (SUP) in infants with congenital heart disease (CHD) in the cardiac ICU (CICU) is controversial. We aimed to conduct a pilot study to explore the feasibility of performing a subsequent larger trial to assess the safety and efficacy of withholding SUP in this population (NCT03667703). DESIGN, SETTING, PATIENTS: Single-center, prospective, double-blinded, parallel group (SUP vs. placebo), pilot randomized controlled pilot trial (RCT) in infants with CHD admitted to the CICU and anticipated to require respiratory support for greater than 24 hours. INTERVENTIONS: Patients were randomized 1:1 (stratified by age and admission type) to receive a histamine-2 receptor antagonist or placebo until respiratory support was discontinued, up to 14 days, or transfer from the CICU, if earlier. MEASUREMENTS AND MAIN RESULTS: Feasibility was defined a priori by thresholds of screening rate, consent rate, timely drug allocation, and protocol adherence. The safety outcome was the rate of clinically significant upper gastrointestinal (UGI) bleeding. We screened 1,426 patients from February 2019 to March 2022; of 132 eligible patients, we gained informed consent in 70 (53%). Two patients did not require CICU admission after obtaining consent, and the remaining 68 patients were randomized to SUP (n = 34) or placebo (n = 34). Ten patients were withdrawn early, because of a change in eligibility (n = 3) or open-label SUP use (n = 7, 10%). Study procedures were completed in 58 patients (89% protocol adherence). All feasibility criteria were met. There were no clinically significant episodes of UGI bleeding during the pilot RCT. The percentage of patients with other nonserious adverse events did not differ between groups. CONCLUSIONS: Withholding of SUP in infants with CHD admitted to the CICU was feasible. A larger multicenter RCT designed to confirm the safety of this intervention and its impact on incidence of UGI bleeding, gastrointestinal microbiome, and other clinical outcomes is warranted.

Small-molecule activators of a bacterial signaling pathway inhibit virulence.

The Burkholderia genus encompasses multiple human pathogens, including potential bioterrorism agents, that are often extensively antibiotic resistant. The FixLJ pathway in Burkholderia is a two-component system that regulates virulence. Previous work showed that fixLJ mutations arising during chronic infection confer increased virulence while decreasing the activity of the FixLJ pathway. We hypothesized that small-molecule activators of the FixLJ pathway could serve as anti-virulence therapies. Here, we developed a high-throughput assay that screened over 28,000 compounds and identified 11 that could specifically active the FixLJ pathway. Eight of these compounds, denoted Burkholderia Fix Activator (BFA) 1-8, inhibited the intracellular survival of Burkholderia in THP-1-dervived macrophages in a fixLJ-dependent manner without significant toxicity. One of the compounds, BFA1, inhibited the intracellular survival in macrophages of multiple Burkholderia species. Predictive modeling of the interaction of BFA1 with Burkholderia FixL suggests that BFA1 binds to the putative ATP/ADP binding pocket in the kinase domain, indicating a potential mechanism for pathway activation. These results indicate that small-molecule FixLJ pathway activators are promising anti-virulence agents for Burkholderia and define a new paradigm for antibacterial therapeutic discovery.

Pediatric Ventilator-Associated Events Before and After a Multicenter Quality Improvement Initiative.

Importance: Pediatric ventilator-associated events (PedVAEs, defined as a sustained worsening in oxygenation after a baseline period of stability or improvement) are useful for surveillance of complications from mechanical ventilation. It is unclear whether interventions to mitigate known risk factors can reduce PedVAE rates. Objective: To assess whether adherence to 1 or more test factors in a quality improvement bundle was associated with a reduction in PedVAE rates. Design, Setting, and Participants: This multicenter quality improvement study obtained data from 2017 to 2020 for patients who were mechanically ventilated and cared for in neonatal, pediatric, and cardiac intensive care units (ICUs). These ICUs were located in 95 hospitals participating in the Children's Hospitals' Solutions for Patient Safety (SPS) network in North America. Data analyses were performed between September 2021 and April 2023. Intervention: A quality improvement bundle consisted of 3 test factors: multidisciplinary apparent cause analysis, daily discussion of extubation readiness, and daily discussion of fluid balance goals. This bundle was distributed to a subgroup of hospitals that volunteered to participate in a collaborative PedVAE prevention initiative under the SPS network guidance in July 2018. Main Outcomes and Measures: Each SPS network hospital submitted monthly PedVAE rates from January 1, 2017, to May 31, 2020, and test factor data were submitted from July 1, 2018, to May 31, 2020. Analyses focused on hospitals that reliably submitted PedVAE rate data, defined as outcomes data submission through May 31, 2020, for at least 80% of the baseline and postbaseline periods. Results: Of the 95 hospitals in the SPS network that reported PedVAE data, 21 were grouped in the Pioneer cohort and 74 in the non-Pioneer cohort. Only 12 hospitals (57%) from the 21 Pioneer hospitals and 33 (45%) from the 74 non-Pioneer hospitals were considered to be reliable reporters of outcome data. Among the 12 hospitals, the PedVAE rate decreased from 1.9 to 1.4 events per 1000 ventilator days (absolute rate difference, -0.6; 95% CI, -0.5 to -0.7; P < .001). No significant change in the PedVAE rate was seen among the 33 hospitals that reliably submitted PedVAE rates but did not implement the bundle. Of the 12 hospitals, 3 that reliably performed daily discussion of extubation readiness had a decrease in PedVAE rate from 2.6 to 1.2 events per 1000 ventilator days (absolute rate difference, -1.4; 95% CI, -1.0 to -1.7; P < .001), whereas the other 9 hospitals that did not implement this discussion did not have a decrease. Conclusions and Relevance: This study found that a multicenter quality improvement intervention targeting PedVAE risk factors was associated with a substantial reduction in the rate of PedVAEs in hospital ICUs. The findings suggest that ICU teams seeking to reduce PedVAEs incorporate daily discussion of extubation readiness during morning rounds.

Bundled Care to Reduce Sepsis Mortality: The Improving Pediatric Sepsis Outcomes (IPSO) Collaborative.

OBJECTIVES: We sought to improve utilization of a sepsis care bundle and decrease 3- and 30- day sepsis-attributable mortality, as well as determine which care elements of a sepsis bundle are associated with improved outcomes. METHODS: Children's Hospital Association formed a QI collaborative to Improve Pediatric Sepsis Outcomes (IPSO) (January 2017-March 2020 analyzed here). IPSO Suspected Sepsis (ISS) patients were those without organ dysfunction where the provider "intended to treat" sepsis. IPSO Critical Sepsis (ICS) patients approximated those with septic shock. Process (bundle adherence), outcome (mortality), and balancing measures were quantified over time using statistical process control. An original bundle (recognition method, fluid bolus < 20 min, antibiotics < 60 min) was retrospectively compared with varying bundle time-points, including a modified evidence-based care bundle, (recognition method, fluid bolus < 60 min, antibiotics < 180 min). We compared outcomes using Pearson χ-square and Kruskal Wallis tests and adjusted analysis. RESULTS: Reported are 24 518 ISS and 12 821 ICS cases from 40 children's hospitals (January 2017-March 2020). Modified bundle compliance demonstrated special cause variation (40.1% to 45.8% in ISS; 52.3% to 57.4% in ICS). The ISS cohort's 30-day, sepsis-attributable mortality dropped from 1.4% to 0.9%, a 35.7% relative reduction over time (P < .001). In the ICS cohort, compliance with the original bundle was not associated with a decrease in 30-day sepsis-attributable mortality, whereas compliance with the modified bundle decreased mortality from 4.75% to 2.4% (P < .01). CONCLUSIONS: Timely treatment of pediatric sepsis is associated with reduced mortality. A time-liberalized care bundle was associated with greater mortality reductions.

Preventing pediatric catheter-associated urinary tract infections utilizing urinary catheter Kamishibai cards (K-cards).

BACKGROUND: We instituted Kamishibai (K-card rounding) with the goals of improving indwelling urinary catheter maintenance bundle reliability and decreasing catheter-associated urinary tract infection (CAUTI) rates. METHOD: In a free-standing children's hospital, we undertook a hospital-wide quality improvement project from January 2019 to June 2021 after developing a K-card based on our urinary catheter maintenance bundle. Auditors used K-cards to ask standardized questions during weekly rounds. Bundle reliability and CAUTI rates were analyzed prospectively. RESULTS: During the study period, 826 K-card audits were performed for 657 unique patients. While overall maintenance bundle reliability remained stable at 84%, there was a statistically significant improvement in reliability to the bundle element "medical discussion of need for the urinary catheter" from 88% to 94% (P = .01). The hospital-wide CAUTI rate significantly decreased (incidence rate ratio, 0.38; 95% CI, 0.15-0.93; P = .04). DISCUSSION: Hospital-wide urinary catheter K-card rounding facilitated standardized data collection, discussion of reliability and real-time feedback to nurses. Maintenance bundle reliability remained stable after implementation, accompanied by a significant decrease in the CAUTI rate. CONCLUSIONS: Implementation of hospital-wide urinary catheter K-card rounding was associated with reduction in CAUTI rates. The project demonstrated likelihood of reproducibility with support of a multidisciplinary team.

Multicomponent Pseudomonas aeruginosa Vaccines Eliciting Th17 Cells and Functional Antibody Responses Confer Enhanced Protection against Experimental Acute Pneumonia in Mice.

The Gram-negative pathogen Pseudomonas aeruginosa is a common cause of pneumonia in hospitalized patients. Its increasing antibiotic resistance and widespread occurrence present a pressing need for vaccines. We previously showed that a P. aeruginosa type III secretion system protein, PopB, elicits a strong Th17 response in mice after intranasal (IN) immunization and confers antibody-independent protection against pneumonia in mice. In the current study, we evaluated the immunogenicity and protective efficacy in mice of the combination of PopB (purified with its chaperone protein PcrH) and OprF/I, an outer membrane hybrid fusion protein, compared with immunization with the proteins individually either by the intranasal (IN) or subcutaneous (SC) routes. Our results show that after vaccination, a Th17 recall response from splenocytes was detected only in mice vaccinated with PopB/PcrH, either alone or in combination with OprF/I. Mice immunized with the combination of PopB/PcrH and OprF/I had enhanced protection in an acute lethal P. aeruginosa pneumonia model, regardless of vaccine route, compared with mice vaccinated with either alone or adjuvant control. Immunization generated IgG titers against the vaccine proteins and whole P. aeruginosa cells. Interestingly, none of these antisera had opsonophagocytic killing activity, but antisera from mice immunized with vaccines containing OprF/I, had the ability to block IFN-γ binding to OprF/I, a known virulence mechanism. Hence, vaccines combining PopB/PcrH with OprF/I that elicit functional antibodies lead to a broadly and potently protective vaccine against P. aeruginosa pulmonary infections.

An Evidence-Based Guideline Improves Outcomes for Patients With Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome.

OBJECTIVE: To compare clinical outcomes in children with hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) who were managed before and after implementation of an evidence-based guideline (EBG). METHODS: A management algorithm for MAS-HLH was developed at our institution based on literature review, expert opinion, and consensus building across multiple pediatric subspecialties. An electronic medical record search retrospectively identified hospitalized patients with MAS-HLH in the pre-EBG (October 15, 2015, to December 4, 2017) and post-EBG (January 1, 2018, to January 21, 2020) time periods. Predetermined outcome metrics were evaluated in the 2 cohorts. RESULTS: After the EBG launch, 57 children were identified by house staff as potential patients with MAS-HLH, and rheumatology was consulted for management. Ultimately, 17 patients were diagnosed with MAS-HLH by the treating team. Of these, 59% met HLH 2004 criteria, and 94% met 2016 classification criteria for MAS complicating systemic juvenile idiopathic arthritis. There was a statistically significant reduction in mortality from 50% before implementation of the EBG to 6% in the post-EBG cohort (P = 0.02). There was a significant improvement in time to 50% reduction in C-reactive protein level in the post-EBG vs pre-EBG cohorts (log-rank P < 0.01). There were trends toward faster time to MAS-HLH diagnosis, faster initiation of immunosuppressive therapy, shorter length of hospital stay, and more rapid normalization of MAS-HLH-related biomarkers in the patients post-EBG. CONCLUSION: While the observed improvements may be partially attributed to advances in treatment of MAS-HLH that have accumulated over time, this analysis also suggests that a multidisciplinary treatment pathway for MAS-HLH contributed meaningfully to favorable patient outcomes.

Association of Diagnostic Stewardship for Blood Cultures in Critically Ill Children With Culture Rates, Antibiotic Use, and Patient Outcomes: Results of the Bright STAR Collaborative.

Importance: Blood culture overuse in the pediatric intensive care unit (PICU) can lead to unnecessary antibiotic use and contribute to antibiotic resistance. Optimizing blood culture practices through diagnostic stewardship may reduce unnecessary blood cultures and antibiotics. Objective: To evaluate the association of a 14-site multidisciplinary PICU blood culture collaborative with culture rates, antibiotic use, and patient outcomes. Design, Setting, and Participants: This prospective quality improvement (QI) collaborative involved 14 PICUs across the United States from 2017 to 2020 for the Bright STAR (Testing Stewardship for Antibiotic Reduction) collaborative. Data were collected from each participating PICU and from the Children's Hospital Association Pediatric Health Information System for prespecified primary and secondary outcomes. Exposures: A local QI program focusing on blood culture practices in the PICU (facilitated by a larger QI collaborative). Main Outcomes and Measures: The primary outcome was blood culture rates (per 1000 patient-days/mo). Secondary outcomes included broad-spectrum antibiotic use (total days of therapy and new initiations of broad-spectrum antibiotics ≥3 days after PICU admission) and PICU rates of central line-associated bloodstream infection (CLABSI), Clostridioides difficile infection, mortality, readmission, length of stay, sepsis, and severe sepsis/septic shock. Results: Across the 14 PICUs, the blood culture rate was 149.4 per 1000 patient-days/mo preimplementation and 100.5 per 1000 patient-days/mo postimplementation, for a 33% relative reduction (95% CI, 26%-39%). Comparing the periods before and after implementation, the rate of broad-spectrum antibiotic use decreased from 506 days to 440 days per 1000 patient-days/mo, respectively, a 13% relative reduction (95% CI, 7%-19%). The broad-spectrum antibiotic initiation rate decreased from 58.1 to 53.6 initiations/1000 patient-days/mo, an 8% relative reduction (95% CI, 4%-11%). Rates of CLABSI decreased from 1.8 to 1.1 per 1000 central venous line days/mo, a 36% relative reduction (95% CI, 20%-49%). Mortality, length of stay, readmission, sepsis, and severe sepsis/septic shock were similar before and after implementation. Conclusions and Relevance: Multidisciplinary diagnostic stewardship interventions can reduce blood culture and antibiotic use in the PICU. Future work will determine optimal strategies for wider-scale dissemination of diagnostic stewardship in this setting while monitoring patient safety and balancing measures.

Strategies to prevent ventilator-associated pneumonia, ventilator-associated events, and nonventilator hospital-acquired pneumonia in acute-care hospitals: 2022 Update.

The purpose of this document is to highlight practical recommendations to assist acute care hospitals to prioritize and implement strategies to prevent ventilator-associated pneumonia (VAP), ventilator-associated events (VAE), and non-ventilator hospital-acquired pneumonia (NV-HAP) in adults, children, and neonates. This document updates the Strategies to Prevent Ventilator-Associated Pneumonia in Acute Care Hospitals published in 2014. This expert guidance document is sponsored by the Society for Healthcare Epidemiology (SHEA), and is the product of a collaborative effort led by SHEA, the Infectious Diseases Society of America, the American Hospital Association, the Association for Professionals in Infection Control and Epidemiology, and The Joint Commission, with major contributions from representatives of a number of organizations and societies with content expertise.

Rapid expansion and extinction of antibiotic resistance mutations during treatment of acute bacterial respiratory infections.

Acute bacterial infections are often treated empirically, with the choice of antibiotic therapy updated during treatment. The effects of such rapid antibiotic switching on the evolution of antibiotic resistance in individual patients are poorly understood. Here we find that low-frequency antibiotic resistance mutations emerge, contract, and even go to extinction within days of changes in therapy. We analyzed Pseudomonas aeruginosa populations in sputum samples collected serially from 7 mechanically ventilated patients at the onset of respiratory infection. Combining short- and long-read sequencing and resistance phenotyping of 420 isolates revealed that while new infections are near-clonal, reflecting a recent colonization bottleneck, resistance mutations could emerge at low frequencies within days of therapy. We then measured the in vivo frequencies of select resistance mutations in intact sputum samples with resistance-targeted deep amplicon sequencing (RETRA-Seq), which revealed that rare resistance mutations not detected by clinically used culture-based methods can increase by nearly 40-fold over 5-12 days in response to antibiotic changes. Conversely, mutations conferring resistance to antibiotics not administered diminish and even go to extinction. Our results underscore how therapy choice shapes the dynamics of low-frequency resistance mutations at short time scales, and the findings provide a possibility for driving resistance mutations to extinction during early stages of infection by designing patient-specific antibiotic cycling strategies informed by deep genomic surveillance.

Stewardship Intervention to Optimize Central Venous Catheter Utilization in Critically Ill Children.

We aimed to describe utilization and indication(s) for long-term central venous catheters (CVCs) in a pediatric intensive care unit (PICU) and identify potential strategies to decrease CVC utilization. METHODS: We conducted a single-center prospective quality improvement initiative at a 30-bed PICU in a large, freestanding, academic children's hospital. We created an electronic report to identify patients with an indwelling CVC for 7 days and older (defined as long term). We discussed the ongoing need for each long-term CVC with PICU clinicians at weekly interdisciplinary structured "CVC stewardship rounds." We then made recommendations around expedited removal of CVCs. We conducted multiple Plan-Do-Study-Act cycles to categorize CVC indications, identify modifiable factors, and educate PICU clinicians. We hypothesized that CVC stewardship rounds would decrease long-term CVC utilization in our PICU. RESULTS: From October 2016 to September 2017, 607 long-term CVCs were eligible for the stewardship intervention. Compared to the preintervention period, we recorded a significant increase in peripherally inserted central catheters and a decrease in nontunneled CVCs (P < 0.001). Most patients had single- or double-lumen CVCs in both the preintervention and intervention periods (86% and 91%, respectively). The utilization of overall long-term CVC devices, and those with modifiable indications, decreased during the intervention period. CONCLUSIONS: A single-center QI intervention focused on PICU CVC stewardship was associated with a decrease in CVC utilization.

Evolution towards Virulence in a Burkholderia Two-Component System.

Bacteria in the Burkholderia cepacia complex (BCC) are significant pathogens for people with cystic fibrosis (CF) and are often extensively antibiotic resistant. Here, we assess the impacts of clinically observed mutations in fixL, which encodes the sensor histidine kinase FixL. FixL along with FixJ compose a two-component system that regulates multiple phenotypes. Mutations in fixL across two species, B. dolosa and B. multivorans, have shown evidence of positive selection during chronic lung infection in CF. Herein, we find that BCC carrying the conserved, ancestral fixL sequence have lower survival in macrophages and in murine pneumonia models than mutants carrying evolved fixL sequences associated with clinical decline in CF patients. In vitro phosphotransfer experiments found that one evolved FixL protein, W439S, has a reduced ability to autophosphorylate and phosphorylate FixJ, while LacZ reporter experiments demonstrate that B. dolosa carrying evolved fixL alleles has reduced fix pathway activity. Interestingly, B. dolosa carrying evolved fixL alleles was less fit in a soil assay than those strains carrying the ancestral allele, demonstrating that increased survival of these variants in macrophages and the murine lung comes at a potential expense in their environmental reservoir. Thus, modulation of the two-component system encoded by fixLJ by point mutations is one mechanism that allows BCC to adapt to the host infection environment. IMPORTANCE Infections caused by members of the Burkholderia cepacia complex (BCC) are a serious concern for patients with cystic fibrosis (CF) as these bacteria are often resistant to many antibiotics. During long-term infection of CF patients with BCC, mutations in genes encoding the FixLJ system often become prevalent, suggesting that these changes may benefit the bacteria during infection. The system encoded by fixLJ is involved in sensing oxygen and regulating many genes in response and is required for full virulence of the bacteria in a murine pneumonia model. Evolved fixL mutations seen later in infection improve bacterial persistence within macrophages and enhance infection within mice. However, these adaptations are short sighted because they reduce bacterial fitness within their natural habitat, soil.

A Pseudomonas aeruginosa-Derived Particulate Vaccine Protects against P. aeruginosa Infection.

Despite numerous efforts to develop an effective vaccine against Pseudomonas aeruginosa, no vaccine has yet been approved for human use. This study investigates the utility of the P. aeruginosa inherently produced polyhydroxyalkanaote (PHA) inclusions and associated host-cell proteins (HCP) as a particulate vaccine platform. We further engineered PHA inclusions to display epitopes derived from the outer membrane proteins OprF/OprI/AlgE (Ag) or the type III secretion system translocator PopB. PHA and engineered PHA beads induced antigen-specific humoral, cell-mediated immune responses, anti-HCP and anti-polysaccharide Psl responses in mice. Antibodies mediated opsonophagocytic killing and serotype-independent protective immunity as shown by 100% survival upon challenge with P. aeruginosa in an acute pneumonia murine model. Vaccines were stable at 4 °C for at least one year. Overall, our data suggest that vaccination with subcellular empty PHA beads was sufficient to elicit multiple immune effectors that can prevent P. aeruginosa infection.

Risk factors for pediatric surgical site infection following neurosurgical procedures for hydrocephalus: a retrospective single-center cohort study.

BACKGROUND: Infection is a major complication following cerebral spinal fluid (CSF) diversion procedures for hydrocephalus. However, pediatric risk factors for surgical site infection (SSI) are currently not well defined. Because a SSI prevention bundle is increasingly introduced, the purpose of this study was to evaluate risk factors associated with SSIs following CSF diversion surgeries following a SSI bundle at a single quaternary care pediatric hospital. METHODS: We performed a retrospective cohort study of patients undergoing CSF diversion procedures from 2017 to 2019. SSIs were identified prospectively through continuous surveillance. We performed unadjusted logistic regression analyses and univariate analyses to determine an association between SSIs and patient demographics, comorbidities and perioperative factors to identify independent risk factors for SSI. RESULTS: We identified a total of 558 CSF diversion procedures with an overall SSI rate of 3.4%. The SSI rates for shunt, external ventricular drain (EVD) placement, and endoscopic third ventriculostomy (ETV) were 4.3, 6.9 and 0%, respectively. Among 323 shunt operations, receipt of clindamycin as perioperative prophylaxis and presence of cardiac disease were significantly associated with SSI (O.R. 4.99, 95% C.I. 1.27-19.70, p = 0.02 for the former, and O.R. 7.19, 95% C.I. 1.35-38.35, p = 0.02 for the latter). No risk factors for SSI were identified among 72 EVD procedures. CONCLUSION: We identified receipt of clindamycin as perioperative prophylaxis and the presence of cardiac disease as risk factors for SSI in shunt procedures. Cefazolin is recommended as a standard antibiotic for perioperative prophylaxis. Knowing that unsubstantiated beta-lactam allergy label is a significant medical problem, efforts should be made to clarify beta-lactam allergy status to maximize the number of patients who can receive cefazolin for prophylaxis before shunt placement. Further research is needed to elucidate the mechanism by which cardiac disease may increase SSI risk after shunt procedures.

Anesthetics isoflurane and sevoflurane attenuate flagellin-mediated inflammation in the lung.

Isoflurane and sevoflurane are volatile anesthetics (VA) widely used in clinical practice to provide general anesthesia. We and others have previously shown that VAs have immunomodulatory effects and may have a significant impact on the progression of disease states. Flagellin is a component of Gram negative bacteria and plays a significant role in the pathophysiology of bacterial pneumonia through its binding to Toll-like Receptor 5 (TLR5). Our results showed that VAs, not an intravenous anesthetic, significantly attenuated the activation of TLR5 and the release of the neutrophil chemoattractant IL-8 from lung epithelial cells. Furthermore, flagellin-induced lung injury was significantly attenuated by VAs by inhibiting neutrophil migration to the bronchoalveolar space. The lungs of cystic fibrosis (CF) patients are highly colonized by Pseudomonas aeruginosa, which causes inflammation. The retrospective study of oxygenation in patients with CF who had received VA versus intravenous anesthesia suggested that VAs might have the protective effect for gas exchange. To understand the interaction between VAs and TLR5, a docking simulation was performed, which indicated that isoflurane and sevoflurane docked into the binding interphase between TLR5 and flagellin.

The Role of Anesthetic Management in Surgical Site Infections After Pediatric Intestinal Surgery.

BACKGROUND: Although surgical site infections (SSIs) remain a significant health care issue, a limited number of studies have analyzed risk factors for SSIs in children, particularly the role of intraoperative anesthetic management. Pediatric patients are less likely to have major adult risk factors for SSIs such as smoking and diabetes. Thus children may be more suitable as a cohort for examining the role of intraoperative anesthetics in SSIs. AIM: We examined an association between SSI incidence and anesthetic management in children who underwent elective intestinal surgery in a single institution. METHODS: We performed a retrospective study of 621 patients who underwent elective intestinal surgery under general anesthesia between January 2017 and September 2019, with primary outcome as the incidence of SSIs. We compared patients who were dichotomized in accordance with the median of the sevoflurane dose. We used propensity score (PS) pairwise matching of these patients to avoid selection biases. PS matching yielded 204 pairs of patients. RESULTS: We found that higher doses of sevoflurane were associated with a higher incidence of SSIs (9.8% versus 3.9%, P = 0.019). We adjusted for intraoperative factors that were not included in the PS adjustment factors, and multivariate regression analysis after PS matching showed compatible results (odds ratio: 2.58, 95% confidence interval: 1.11-6.04, P = 0.028). CONCLUSIONS: Higher doses of sevoflurane are associated with increased odds of SSIs after pediatric elective intestinal surgery. A randomized controlled study of volatile anesthetic-based versus intravenous anesthetic-based anesthesia will be needed to further determine the role of anesthetic drugs in SSI risk.

Stress ulcer prophylaxis versus placebo-a blinded randomized control trial to evaluate the safety of two strategies in critically ill infants with congenital heart disease (SUPPRESS-CHD).

BACKGROUND: Critically ill infants with congenital heart disease (CHD) are often prescribed stress ulcer prophylaxis (SUP) to prevent upper gastrointestinal bleeding, despite the low incidence of stress ulcers and limited data on the safety and efficacy of SUP in infants. Recently, SUP has been associated with an increased incidence of hospital-acquired infections, community-acquired pneumonia, and necrotizing enterocolitis. The objective of this pilot study is to investigate the feasibility of performing a randomized controlled trial to assess the safety and efficacy of withholding SUP in infants with congenital heart disease admitted to the cardiac intensive care unit. METHODS: A single center, prospective, double-blinded, randomized placebo-controlled pilot feasibility trial will be performed in infants with CHD admitted to the cardiac intensive care unit and anticipated to require respiratory support for > 24 h. Patients will be randomized to receive a histamine-2 receptor antagonist (H2RA) or placebo until they are discontinued from respiratory support. Randomization will be performed within 2 strata defined by admission type (medical or surgical) and age (neonate, age < 30 days, or infant, 1 month to 1 year). Allocation will be a 1:1 ratio using permuted blocks to ensure balanced allocations across the two treatment groups within each stratum. The primary outcomes include feasibility of screening, consent, timely allocation of study drug, and protocol adherence. The primary safety outcome is the rate of clinically significant upper gastrointestinal bleeding. The secondary outcomes are the difference in the relative and absolute abundance of the gut microbiota and functional microbial profiles between the two study groups. We plan to enroll 100 patients in this pilot study. DISCUSSION: Routine use of SUP to prevent upper gastrointestinal bleeding in infants is controversial due to a low incidence of bleeding events and concern for adverse effects. The role of SUP in infants with CHD has not been examined, and there is equipoise on the risks and benefits of withholding this therapy. In addition, this therapy has been discontinued in other neonatal populations due to the concern for hospital-acquired infections and necrotizing enterocolitis. Furthermore, exploring changes to the microbiome after exposure to SUP may highlight the mechanisms by which SUP impacts potential microbial dysbiosis of the gut and its association with hospital-acquired infections. Assessment of the feasibility of a trial of withholding SUP in critically ill infants with CHD will facilitate planning of a larger multicenter trial of safety and efficacy of SUP in this vulnerable population. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03667703. Registered 12 September 2018, https://clinicaltrials.gov/ct2/show/NCT03667703?term=SUPPRESS+CHD&draw=2&rank=1 . All WHO Trial Registration Data Set Criteria are met in this manuscript.