Examining the Evidence for Escalating Antimicrobial Regimens in Febrile Oncology and Hematopoietic Stem Cell Transplant Patients Admitted to the PICU: An Observational Study.

OBJECTIVES: To examine whether escalating antimicrobial treatment in pediatric oncology and hematopoietic cell transplantation (HSCT) patients admitted to the PICU is supported by culture data or affects patient outcomes. DESIGN: Retrospective cross-sectional study. SETTING: Quaternary care PICU. PATIENTS: Patients younger than 18 years old who were admitted to the PICU at Boston Children's Hospital from 2012 to 2017 with a diagnosis of cancer or who had received HSCT and who had suspected sepsis at the time of PICU admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 791 PICU admissions for 544 patients that met inclusion criteria, 71 (9%) had escalation of antimicrobial therapy. Median Pediatric Logistic Organ Dysfunction (PELOD) score was higher in the escalation group (4 vs 3; p = 0.01). There were 14 admissions (20%) with a positive culture in the escalation group and 110 (15%) in the no escalation group ( p = 0.31). In the escalation group, there were only 2 (3%) cultures with organisms resistant to the initial antimicrobial regimen, compared with 28 (4%) cultures with resistant organisms in the no escalation group ( p = 1). Mortality in the escalation group was higher (17%) compared with the nonescalation group (5%; p < 0.001). The escalation group had more acute kidney injury (AKI) (25%) during treatment compared with the no escalation group (15%; p = 0.04), although this difference was not statistically significant when controlling for age, neutropenia, and PELOD-2 score (odds ratio, 1.75; 95% CI, 0.95-3.08; p = 0.06). CONCLUSIONS: Few patients who had escalation of antimicrobials proved on culture data to have an organism resistant to the initial antimicrobials, and more patients developed AKI during escalated treatment. While the escalation group likely represents a sicker population, whether some of these patients would be safer without escalation of antimicrobial therapy warrants further study.

Mixed-methods process evaluation of a respiratory-culture diagnostic stewardship intervention.

OBJECTIVE: To conduct a process evaluation of a respiratory culture diagnostic stewardship intervention. DESIGN: Mixed-methods study. SETTING: Tertiary-care pediatric intensive care unit (PICU). PARTICIPANTS: Critical care, infectious diseases, and pulmonary attending physicians and fellows; PICU nurse practitioners and hospitalist physicians; pediatric residents; and PICU nurses and respiratory therapists. METHODS: This mixed-methods study was conducted concurrently with a diagnostic stewardship intervention to reduce the inappropriate collection of respiratory cultures in mechanically ventilated children. We quantified baseline respiratory culture utilization and indications for ordering using quantitative methods. Semistructured interviews informed by these data and the Consolidated Framework for Implementation Research (CFIR) were then performed, recorded, transcribed, and coded to identify salient themes. Finally, themes identified in these interviews were used to create a cross-sectional survey. RESULTS: The number of cultures collected per day of service varied between attending physicians (range, 2.2-27 cultures per 100 days). In total, 14 interviews were performed, and 87 clinicians completed the survey (response rate, 47%) and 77 nurses or respiratory therapists completed the survey (response rate, 17%). Clinicians varied in their stated practices regarding culture ordering, and these differences both clustered by specialty and were associated with perceived utility of the respiratory culture. Furthermore, group "default" practices, fear, and hierarchy were drivers of culture orders. Barriers to standardization included fear of a missed diagnosis and tension between practice standardization and individual decision making. CONCLUSIONS: We identified significant variation in utilization and perceptions of respiratory cultures as well as several key barriers to implementation of this diagnostic test stewardship intervention.

Antibiotic Indications and Appropriateness in the Pediatric Intensive Care Unit: A 10-Center Point Prevalence Study.

BACKGROUND: Antibiotics are prescribed to most pediatric intensive care unit (PICU) patients, but data describing indications and appropriateness of antibiotic orders in this population are lacking. METHODS: We performed a multicenter point prevalence study that included children admitted to 10 geographically diverse PICUs over 4 study days in 2019. Antibiotic orders were reviewed for indication, and appropriateness was assessed using a standardized rubric. RESULTS: Of 1462 patients admitted to participating PICUs, 843 (58%) had at least 1 antibiotic order. A total of 1277 antibiotic orders were reviewed. Common indications were empiric therapy for suspected bacterial infections without sepsis or septic shock (260 orders, 21%), nonoperative prophylaxis (164 orders, 13%), empiric therapy for sepsis or septic shock (155 orders, 12%), community-acquired pneumonia (CAP; 118 orders, 9%), and post-operative prophylaxis (94 orders, 8%). Appropriateness was assessed for 985 orders for which an evidence-based rubric for appropriateness could be created. Of these, 331 (34%) were classified as inappropriate. Indications with the most orders classified as inappropriate were empiric therapy for suspected bacterial infection without sepsis or septic shock (78 orders, 24%), sepsis or septic shock (55 orders, 17%), CAP (51 orders, 15%), ventilator-associated infections (47 orders, 14%), and post-operative prophylaxis (44 orders, 14%). The proportion of antibiotics classified as inappropriate varied across institutions (range, 19%-43%). CONCLUSIONS: Most PICU patients receive antibiotics. Based on our study, we estimate that one-third of antibiotic orders are inappropriate. Improved antibiotic stewardship and research focused on strategies to optimize antibiotic use in critically ill children are needed.

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.

Study protocol for a two-center test of a nurse-implemented chronotherapeutic restoring bundle in critically ill children: RESTORE Resilience (R2).

Often, pediatric intensive care environments are not conducive to healing the sick. Critically ill children experience disruptions in their circadian rhythms, which can contribute to delayed recovery and poor outcomes. We aim to test the hypothesis that children managed via RESTORE Resilience (R2), a nurse-implemented chronotherapeutic bundle, will experience restorative circadian rhythms compared to children receiving usual care. In this two-phased, prospective cohort study, two separate pediatric intensive care units in the United Sates will enroll a total of 20 baseline subjects followed by 40 intervention subjects, 6 months to less than 18 years of age, requiring invasive mechanical ventilation. During the intervention phase, we will implement the R2 bundle, which includes: (1) a focused effort to replicate the child's pre-hospitalization daily routine, (2) cycled day-night lighting and sound modulation, (3) minimal yet effective sedation (RESTORE), (4) nighttime fasting with bolus enteral daytime feedings, (5) early progressive mobility (PICU Up!), (6) continuity in nursing care, and (7) parent diaries. Our primary outcome is circadian activity ratio post-extubation. We hypothesize that children receiving R2 will experience restored circadian rhythms as evidenced by decreased nighttime activity while in the PICU. Our exploratory outcomes include salivary melatonin levels; electroencephalogram (EEG) slow-wave activity; R2 feasibility, adherence, and system barriers; levels of patient comfort; exposure to sedative medications; time to physiological stability; and parent perception of being well cared for. This paper describes the design, rationale, and implementation of R2. CLINICALTRIALSGOV IDENTIFIER: NCT04695392.

Coronavirus disease 2019 in children.

PURPOSE OF REVIEW: Over the course of the coronavirus disease 2019 (COVID-19) pandemic, it has become clear that the clinical features, epidemiology, and outcomes of COVID-19 are distinct in children relative to adults. In this review, we will present recent pediatric studies informing our current understanding of COVID-19 in children, and review pediatric considerations surrounding disease transmission, currently available therapies, and vaccination. RECENT FINDINGS: Recent studies have shed light on the clinical epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children, identifying a high prevalence of asymptomatic and mild infections, with severe COVID-19 infrequently reported. Several adult clinical trials have informed the use of remdesivir, anti-SARS-CoV-2 monoclonal antibodies, dexamethasone, and tocilizumab in the management of COVID-19. Associations between underlying comorbid medical conditions and severe outcomes, as well as transmission dynamics of SARS-CoV-2 in children, are complex and warrant further study. Finally, highly efficacious vaccines are available for adults and adolescents, with pediatric trials ongoing. SUMMARY: Children generally fare well with acute COVID-19 infection, though critical illness is possible. Future research should focus on clarifying the role of children in SARS-CoV-2 transmission and optimal prevention strategies, particularly in the school setting, as well as evaluating pediatric vaccine candidates.

Invasive and noninvasive ventilation strategies for acute respiratory failure in children with coronavirus disease 2019.

PURPOSE OF REVIEW: Severe Acute Respiratory Syndrome Coronavirus 2 presents as symptomatic coronavirus disease 2019 (COVID-19) disease in susceptible patients. Severe pediatric COVID-19 disease is rare, limiting potential data accumulation on associated respiratory failure in children. Pediatric intensivists and pulmonologists managing COVID-19 patients look to adult guidelines and pediatric-specific consensus statements to guide management. The purpose of this article is to review the current literature and recommended strategies for the escalation of noninvasive and invasive respiratory support for acute respiratory failure associated with COVID-19 disease in children. RECENT FINDINGS: There are no prospective studies comparing COVID-19 treatment strategies in children. Adult and pediatric ventilation management interim guidance is based on evidence-based guidelines in non-COVID acute respiratory distress syndrome, with considerations of (1) noninvasive positive pressure ventilation versus high-flow nasal cannula and (2) high versus lower positive end expiratory pressure strategies related to lung compliance and potential lung recruitability. SUMMARY: Management of acute respiratory failure from COVID-19 requires individualized titration of noninvasive and invasive ventilation modalities with consideration of preserved or compromised pulmonary compliance. Research regarding best practices in the management of pediatric severe COVID-19 with respiratory failure is lacking and is acutely needed as the pandemic surges and vaccination of the pediatric population will be delayed compared to adults.

Practice Improvement for Standardized Evaluation and Management of Acute Tracheitis in Mechanically Ventilated Children.

There is no consensus definition for ventilator-associated tracheitis and limited evidence to guide diagnosis and treatment. To improve acute tracheitis evaluation and management, this quality improvement project aimed to (1) improve the appropriateness of tracheal aspirate cultures while decreasing the number of unnecessary cultures by 20% and (2) decrease antibiotic use for acute tracheitis not consistent with local guidelines by 20% over 12 months among pediatric patients requiring mechanical ventilation. METHODS: All patients admitted to the Medical Intensive Care Unit requiring mechanical ventilation via an artificial airway were included. Tracheal aspirate sampling criteria, technique, and minimum intervals were standardized. Primary outcome measures were the number of tracheal aspirate cultures obtained per 100 ETT/tracheostomy days and ventilator-associated antibiotic days per 100 ETT/tracheostomy days. Improvement cycles included: Implementation of tracheal aspirate sampling criteria, sampling technique standardization, limiting repeat cultures to >72-hour intervals, and standardizing empiric antibiotic therapy. RESULTS: Tracheal aspirate culture rate decreased from 10.70 to 7.10 cultures per 100 ETT/tracheostomy days (P < 0.001). Cultures meeting sampling criteria increased from 28% to 80%. Ventilator-associated antibiotic use decreased from 24.88 to 7.30 ventilator-associated antibiotic days per 100 ETT/tracheostomy days. There were no associated increases in ventilator-associated events or days of mechanical ventilation. CONCLUSIONS: Implementation of standardized criteria for tracheal aspirate sampling, improved tracheal aspirate sampling technique, limiting repeat tracheal aspirate cultures, and utilizing standardized antibiotic treatment guidelines safely decreased resource utilization and antibiotic use among critically ill children requiring mechanical ventilation.

Utilization of cumulative antibiograms for public health surveillance: Trends in Escherichia coli and Klebsiella pneumoniae susceptibility, Massachusetts, 2008-2018.

BACKGROUND: Antimicrobial resistance is an urgent public health threat. Identifying trends in antimicrobial susceptibility can inform public health policy at the state and local levels. OBJECTIVE: To determine the ability of statewide antibiogram aggregation for public health surveillance to identify changes in antimicrobial resistance trends. DESIGN: Facility-level trend analysis. METHODS: Crude and adjusted trend analyses of the susceptibility of Escherichia coli and Klebsiella pneumoniae to particular antibiotics, as reported by aggregated antibiograms, were examined from 2008 through 2018. Multivariable regression analyses via generalized linear mixed models were used to examine associations between hospital characteristics and trends of E. coli and K. pneumoniae susceptibility to ciprofloxacin and ceftriaxone. RESULTS: E. coli and K. pneumoniae showed inverse trends in drug susceptibility over time. K. pneumoniae susceptibility to fluoroquinolones increased by 5% between 2008 and 2018 (P < .05). In contrast, E. coli susceptibility declined during the same period to ceftriaxone (6%), gentamicin (4%), and fluoroquinolones (4%) (P < .05). When compared to Boston hospitals, E. coli isolates from hospitals in other regions had a >4% higher proportion of susceptibility to ciprofloxacin and a >3% higher proportion of susceptibility to ceftriaxone (P < .05). Isolates of K. pneumoniae had higher susceptibility to ciprofloxacin (>3%) and ceftriaxone (>1.5%) in all regions when compared to Boston hospitals (P < .05). CONCLUSIONS: Cumulative antibiograms can be used to monitor antimicrobial resistance, to discern regional and facility differences, and to detect changes in trends. Furthermore, because the number of years that hospitals contributed reports to the state-level aggregate had no significant influence on susceptibility trends, other states should not be discouraged by incomplete hospital compliance.

Impact of standardized protocols for cytomegalovirus disease prevention in pediatric solid organ transplant recipients.

End-organ disease caused by CMV is a significant cause of morbidity and mortality in pediatric SOT recipients. Pediatric transplant centers have adopted various approaches for CMV disease prevention in this patient population. We observed significant practice variation in CMV testing, prophylaxis, and surveillance across SOT groups in our center. To address this, we implemented evidence-based standardized protocols and measured outcomes pre- and post-implementation of these protocols. We performed retrospective chart review for SOT recipients from 2009 to 2014 at Boston Children's Hospital. Using descriptive statistics, we measured practice improvement in provision of appropriate prophylaxis, occurrence of neutropenia and associated complications, and occurrence of CMV DNAemia and CMV disease pre- and post-intervention. The pre- and post-intervention periods included 141 and 109 patients, respectively. With the exception of kidney transplant recipients, provision of appropriate valganciclovir prophylaxis improved across SOT groups post-intervention (P < .01). Occurrence of >1 episode of neutropenia was greater in the preintervention period (30% vs 10%, P < .001). In both periods, neutropenia was associated with few episodes of invasive infections. The occurrence of CMV disease did not differ and was overall low. However, due to routine surveillance a significantly greater number of asymptomatic CMV DNAemia episodes were identified and treated in the post-intervention period. Implementation of standardized prevention protocols helped to improve the provision of appropriate prophylaxis to patients at risk for CMV acquisition, increased the diagnosis and treatment of asymptomatic CMV DNAemia, and decreased episodes of recurrent neutropenia in patients receiving prophylaxis.

Whole-Genome Sequences of Staphylococcus aureus Isolates from Cystic Fibrosis Lung Infections.

Staphylococcus aureus is an early colonizer in the lungs of individuals with cystic fibrosis (CF), but surprisingly, only a limited number of genomes from CF-associated S. aureus isolates have been sequenced. Here, we present the whole-genome sequences of 65 S. aureus isolates obtained from 50 individuals with CF.

Acute Pancreatitis in a Patient with Maple Syrup Urine Disease: A Management Paradox.

Maple syrup urine disease (MSUD) is an inborn error of metabolism that causes elevated leucine in the setting of acute illnesses. We describe an 8-year-old boy with MSUD who developed acute pancreatitis and subsequent leucinosis. This case highlights the complexities of fluid management in patients with MSUD.