Prescribing a Green Future: A Review of Antimicrobial Waste in Pediatric Hospitals and Practices to Promote Healthcare Sustainability.

Pediatric hospitals are uniquely positioned to be impacted by antimicrobial waste. To explore this issue, we reviewed the current literature to identify the reasons, costs, and potential solutions to waste. Identified reasons for waste included weight-based dosing, medication order changes due to changing patient status, loss or expiration of doses, and medication errors. The cost of waste included financial costs, promotion of antimicrobial resistance, and generation of greenhouse gases. Proposed interventions to reduce waste included an early switch from intravenous to oral administration, required stop dates, standardized dosing times, and optimization of the pharmacy batching process. However, additional studies are needed to assess the potential correlation between these proposed interventions and waste reduction. Antimicrobial stewardship programs have been identified as a group that can play a crucial role in partnering to implement these interventions to potentially reduce antimicrobial waste and promote better healthcare sustainability.

Clinical impact of pleural fluid Streptococcus pneumoniae PCR testing in children with complicated pneumonia.

BACKGROUND: While Streptococcus pneumoniae (Spn) is the leading cause of pediatric complicated community acquired pneumonia (cCAP), it is infrequently recovered by culture-based methods. We studied the real-world clinical impact of an Spn PCR assay for pleural fluid. METHODS: This pre-post quasi-experimental cohort study compared pathogen detection, antibiotic usage, and outcomes in children hospitalized with cCAP requiring pleural effusion or empyema drainage at Children's Hospital Colorado between 2016 and 2023. Patients were compared across two diagnostic periods: pre-Spn PCR and post-Spn PCR. Cox proportional hazard models compared time from admission to pathogen detection, optimal therapy (narrowest pathogen-directed or guideline-recommended empiric therapy), and MRSA therapy discontinuation between periods. RESULTS: Compared to the pre-Spn PCR cohort (N=149), the post-Spn PCR cohort (N=79) was more likely to have a pathogen detected (73.4% post-PCR vs. 38.9% pre-PCR, p < 0.001), driven by more Spn detections (45.6% vs. 14.1%, p < 0.001). Time to pathogen detection during hospitalization was shorter in the post-Spn PCR period (p < 0.001). The post-PCR cohort was more likely to receive optimal therapy (84.8% vs. 53.0%, p < 0.001), with shorter median times to optimal antibiotics (4.9 vs. 10.0 days, p < 0.001) and MRSA therapy discontinuation (1.5 vs. 2.5 days, p = 0.03). There were no differences in hospital length of stay or readmissions. CONCLUSIONS: Spn molecular testing of pleural fluid in children with cCAP resulted in significantly more microbiologic diagnoses and was associated with the optimization of antibiotics and decreased exposure to MRSA therapy, suggesting its clinical impact for pediatric complicated pneumonia.

At the break point: What needs to change for antimicrobial stewardship program pharmacists?

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.

Time to positivity of blood cultures in a level IV NICU varies based on organism category and population subgroups: is a 36-hour rule out safe?

BACKGROUND: Time to positivity (TTP) of blood cultures and organism characteristics may be different in a Level IV NICU population. METHODS: Retrospective study of 309 Level IV NICU positive blood cultures between January 2012 to December 2018 describing TTP and organism characteristics. RESULTS: Median TTP [IQR] was 21.1 [14.3, 25.2] hours, with 91.2% positive at 36 h, and 96.1% positive at 48 h. Gram negative definite pathogens had the shortest TTP (13.0 [11.4, 15.4] hours) compared to gram positive definite pathogens (16.3 [13.0, 22.4] hours). TTP for treated gram positive commensal organisms (22.3 [20.1, 30.4] hours) and those considered contaminants (23.6 [21.4, 26.0] hours), was significantly longer than both gram positive and negative definite pathogens. CONCLUSION: When antimicrobials are initiated due to concern for bacteremia and blood cultures have not identified a causative pathogen at 36 h, antimicrobials may be safely discontinued in the majority of Level IV NICU patients.

Evaluation of Empiric Voriconazole Dosing and Therapeutic Drug Monitoring in Hospitalized Pediatric Patients.

SUMMARY: Invasive fungal infections are a significant cause of morbidity and mortality in children with immunodeficiencies. Current dosing recommendations for voriconazole often result in subtherapeutic exposure in pediatric patients. In this single-center retrospective study, we reviewed hospitalized pediatric patients receiving voriconazole with at least one inpatient serum trough concentration measured. Patient characteristics and voriconazole dosing courses with associated trough concentrations were summarized for all patients as well as grouped by age (0 to 1 y, 2 to 11 y, and 12 to 18 y). Of 106 included patients, the median age was 9 years (range, 29 d to 18 y). Five hundred ninety courses of voriconazole were administered with 365 associated troughs. Most troughs were subtherapeutic (49%) and 30% of patients never attained a therapeutic trough. The median oral daily dose associated with a therapeutic trough was higher in younger age groups: 21.6 mg/kg 0 to 1 year, 17.9 mg/kg 2 to 11, and 9.5 mg/kg 12 to 18 years ( P <0.001). Patients younger than 2 years had the largest proportion of subtherapeutic troughs and variability in dosing. Attainment of therapeutic voriconazole concentrations was challenging across all pediatric age groups. Higher starting doses for patients younger than 2 years are likely needed.

Letermovir for Cytomegalovirus prophylaxis in pediatric hematopoietic stem cell transplantation.

BACKGROUND: Letermovir (LTV), an antiviral with exclusive activity against Cytomegalovirus (CMV), is approved for prophylaxis of CMV infection and disease in adult hematopoietic cell transplant (HCT) patients. The use of LTV in the pediatric HCT population is off-label, and has limited literature to support its use. PROCEDURE: This was a single-center, retrospective, matched (1:1 LTV:non-LTV) cohort study of allogeneic HCT recipients transplanted at Children's Hospital Colorado from 2015 to 2022. The primary endpoint was clinically significant CMV DNAemia (defined as a CMV viral load >1000 copies/mL or any CMV DNAemia leading to preemptive treatment) through 6 months post transplant. Secondary outcomes included time to clinically significant CMV DNAemia, drug adverse effects, and dose adjustments of concomitant cyclosporine and voriconazole (known drug interactions). RESULTS: We compared 41 patients who received LTV prophylaxis to 41 patients who received no CMV prophylaxis. There was less clinically significant CMV DNAemia through D+180 in the LTV group (9.8% vs. 17.0%, p = .33). Overall, LTV was well tolerated, and 87.8% of patients experienced no adverse effects related to the drug. There was no observed pattern in LTV effect on cyclosporine serum concentrations, but LTV was associated with decreased voriconazole trough levels. CONCLUSIONS: In this retrospective study, the use of LTV prophylaxis in pediatric stem cell patients was associated with reduced clinically significant CMV DNAemia through D+180.

Risk Factors for Venous Thromboembolic Events in Children With Acute Musculoskeletal Infections.

BACKGROUND AND OBJECTIVES: Venous thromboembolic events (VTE) complicate acute hematogenous musculoskeletal infections (MSKIs) among hospitalized children. However, there is limited guidance for which specific MSKI patients are at the greatest VTE risk. This study aimed to identify VTE risk factors for children hospitalized with MSKIs. METHODS: A retrospective chart review was performed of children hospitalized with MSKIs at a single quaternary care pediatric hospital during a 9-year period. Patients with chronic MSKIs, non-hematogenous infections, or significant contributing comorbidities were excluded. Demographic and clinical characteristics were compared between patients with and without VTE using forward stepwise conditional multivariable logistic regression to identify VTE risk factors. RESULTS: Among 335 included patients, 7 (2.1%) developed a VTE. There was no difference in age, sex, or obesity rates for those with or without VTE. Patients with methicillin-resistant Staphylococcus aureus (MRSA) infections and/or critical illness were more likely to develop a VTE with summative adjusted odds ratios of 31.7 and 26.4, respectively. In addition, patients with VTEs had longer hospitalizations (median 4.7 vs. 12.8 d, P <0.001), longer courses of intravenous antimicrobials (median 3.7 vs. 13.5 d, P =0.001), and longer time to fever resolution (median 25.7 vs. 162 h, P =0.004). CONCLUSIONS: VTE prevalence among children with acute MSKIs is low. MRSA infection and critical illness significantly increase the risk for VTE development in these patients. Future prospective studies are needed to determine if VTEs in high-risk MSKI patients can be prevented.

Microbiology Culture Results and Antibiotic Prescribing in Pediatric Patients With Lymphadenitis.

BACKGROUND: Bacterial lymphadenitis is a common reason for antibiotic treatment and hospitalization in children. The literature available addressing the bacterial etiology of lymphadenitis recommends the use of narrow-spectrum agents to cover common pathogens. We suspect that patients at our institution receive unnecessarily broad-spectrum antimicrobial agents. The primary objective of this study was to characterize the microbiology and antibiotic use in lymphadenitis patients. METHODS: Retrospective review of children admitted over a 10-year period with an International Classification of Diseases Ninth or Tenth Edition code for lymphadenitis. Patients were included if they were <18 years old, admitted to the inpatient ward, and had intraoperative lymph node cultures collected. RESULTS: A total of 131 patients admitted with lymphadenitis had lymph node cultures collected and were included. Seventy-two (72/131; 55%) patients had positive lymph node culture results with pathogenic bacteria. The predominant pathogens were Staphylococcus aureus (56/72; 77.8%) and Streptococcus pyogenes (10/72; 13.9%). The most common inpatient empirical regimen was ampicillin-sulbactam. Of the 72 patients with typical pathogens identified, 80.6% were sensitive to a first-generation cephalosporin, whereas 86.1% were sensitive to a ß-lactam/ß-lactamase inhibitor. CONCLUSION: Patients presenting to our institution with acute bacterial lymphadenitis were predominantly found to have methicillin-susceptible S. aureus lymphadenitis that could be empirically treated with cefazolin. At our institution, there is little advantage to the most commonly used broad-spectrum agent, ampicillin-sulbactam.

Identifying predictors for source culture positivity in children with acute musculoskeletal infections.

OBJECTIVES: Identifying the causative bacterial pathogen for children with acute hematogenous musculoskeletal infections (MSKIs) allows for improved care. The purpose of our study was to determine if clinical markers could predict which patients will have a causative pathogen found on source culture alone, thus being highest yield to undergo operative diagnostic procedures. METHODS: A single-center, retrospective cohort study was performed. Medical records for patients between 6 months and 18 years of age admitted between July 2014 and September 2018 with a discharge diagnosis of acute osteomyelitis, septic arthritis, or pyomyositis were reviewed. Patients were stratified based on results of blood and source cultures. Predictors of interest were screened on a univariable basis with significant predictors retained in a multivariate analysis. RESULTS: There were 170 patients included. No predictors were significantly associated with increased odds of having a causative pathogen found on source culture alone. Degree of C-reactive protein elevation and history of fever were associated with decreased odds of being source culture positive, OR (95% CI); 0.92 (0.87, 0.98) and 0.39 (0.19, 0.81), respectively. CONCLUSIONS: Predictive modeling failed to identify children with MSKIs whose causative pathogen was found by source culture alone. It is difficult to predict which MSKI patients will be highest yield for operative diagnostic procedures.

Prolonged Perioperative Antibiotics: A Hidden Problem.

OBJECTIVES: National guidelines generally recommend 24 hours or less of surgical antibiotic prophylaxis. In a freestanding, regional children's hospital, we evaluated the duration of antibiotic surgical prophylaxis to identify targets for standardization of practice. METHODS: All procedures performed in 2017 were extracted from our local data warehouse; those involving an incision were considered a surgical procedure and correlated to antibiotic data. Antibiotic courses were reviewed if administered for >24 hours, or if the duration or indication for prophylaxis was uncertain. Total duration of prophylaxis (including discharge prescriptions) was calculated in hours for all procedures and categorized by department and by the quantity of prophylaxis received: none, single dose, multiple doses within 24 hours, and >24 hours. Percentage of procedures and total days of potential excess were calculated. RESULTS: A total of 15 651 procedures were included; 5009 met criteria for chart review, and after further exclusions, 12 895 procedures were included in the analysis. In total, 55% of all 12 895 procedures received prophylaxis. A single dose was given in 30%. Over 24 hours was administered in 11%, and 14% received multiple doses <24 hours (both potential excess). Results were evaluated by surgical subspecialty and procedure type. There were 5733 cumulative days of surgical prophylaxis administered after 24 hours (potential excess). CONCLUSION: In 2017, up to 25% of procedures received potentially unnecessary perioperative prophylaxis, indicating that national guidance specific to pediatrics would have high impact on antibiotic overuse in the pediatric surgical population.

Characteristics of Children With Culture Negative Acute Hematogenous Musculoskeletal Infections.

BACKGROUND: Identifying the causative pathogen for acute hematogenous musculoskeletal infections (MSKIs) allows for directed antimicrobial therapy and diagnostic confidence. However, 20% to 50% of children with acute MSKIs remain culture negative. The objective of this study was to compare characteristics of culture negative MSKI patients to those where a pathogen is identified. METHODS: Electronic medical records of children admitted between July 2014 to September 2018 to a single quaternary care pediatric hospital with acute MSKIs were retrospectively reviewed. Clinical and demographic characteristics were compared between culture positive and culture negative MSKIs. RESULTS: A total of 170 patients were included of whom 43 (25%) were culture negative. All culture negative patients had at least 1 culture type obtained, and the majority (84%) had both blood and source cultures performed. When compared with patients with a causative pathogen identified, culture negative patients were younger (2.3 vs. 9.8 y), smaller (13.5 vs. 31.6 kg), less likely to be febrile on arrival (56% vs. 77%), less likely to have an abscess on imaging (23% vs. 48%), and were more likely to have uncomplicated septic arthritis (35% vs. 8%). No critically ill patient was culture negative. Seven culture negative patients had additional Kingella kingae testing performed, none of which were positive. CONCLUSIONS: Despite targeted and standardized efforts to identify causative bacteria, 25% of children with acute MSKIs never have a pathogen identified. Culture negative patients are younger, less febrile, are less likely to have an abscess, and more likely to have isolated septic arthritis. LEVEL OF EVIDENCE: This is a retrospective cohort study interested in identifying patient characteristics that predict rate of culture positivity for acute MSKIs. This study meets criteria for Level II evidence.

Pharmacological Management of Pediatric Clostridioides difficile Infection: Clarifying the Controversies.

Clostridioides difficile infection (CDI) is a major public health concern for pediatric and adult patients. The management of pediatric CDI poses a challenge to healthcare providers due to lack of strong randomized controlled trials to guide pharmacological management. Additionally, recent updates to CDI guidelines recommend oral vancomycin over metronidazole for the management of CDI in adults, leaving questions regarding how to best manage pediatric patients. This continuing education pharmacotherapy review describes available evidence for the safety and efficacy of medications used in the treatment and management of pediatric CDI and aims to clarify discrepancies between pediatric and adult recommendations.

Management of an Immunocompromised Pediatric Patient With Multiple Hospitalizations for Symptomatic COVID-19.

Relapse of infection due to SARS-CoV-2 has been rarely described and there is little guidance regarding the management of such cases in immunocompromised hosts. We present a case of an adolescent female with B-cell acute lymphoblastic leukemia hospitalized multiple times for symptomatic SARS-CoV-2 infection who was safely treated with 2 courses of remdesivir (RDV) and has had no additional readmissions to date. Though additional studies are needed to confirm the safety and efficacy of an additional course of RDV in the setting of relapsed or prolonged severe COVID-19, our observations suggest that a second course of RDV may be considered.

IVIG Compared With IVIG Plus Infliximab in Multisystem Inflammatory Syndrome in Children.

OBJECTIVES: To compare initial treatment with intravenous immunoglobulin (IVIG) versus IVIG plus infliximab in multisystem inflammatory syndrome in children (MIS-C). METHODS: Single-center retrospective cohort study of patients with MIS-C who met Centers for Disease Control and Prevention criteria and received treatment from April 2020 to February 2021. Patients were included and compared on the basis of initial therapy of either IVIG alone or IVIG plus infliximab. The primary outcome was need for additional therapy 24 hours or more after treatment initiation. RESULTS: Seventy-two children with MIS-C met inclusion criteria. Additional therapy was needed in 13 of 20 (65%) who received IVIG alone and 16 of 52 (31%) who received IVIG plus infliximab (P = .01). The median (interquartile range) ICU lengths of stay were 3.3 (2.2 to 3.8) and 1.8 (1.1 to 2.1) days, respectively (P = .001). New or worsened left ventricular dysfunction developed in 4 of 20 (20%) and 2 of 52 (4%) (P = .05), and new vasoactive medication requirement developed in 3 of 20 (15%) and 2 of 52 (4%), respectively (P = .13). The median percentage changes in the C-reactive protein level at 24 hours posttreatment compared with pretreatment were 0% (-29% to 66%) and -46% (-62% to -15%) (P < .001); and at 48 hours posttreatment, -5% (-41% to 57%) and -70% (-79% to -49%) respectively (P < .001). There was no significant difference in hospital length of stay, time to fever resolution, vasoactive medication duration, or need for diuretics. CONCLUSIONS: Patients with MIS-C initially treated with IVIG plus infliximab compared with those treated with IVIG alone were less likely to require additional therapy and had decreased ICU length of stay, decreased development of left ventricular dysfunction, and more rapid decline in C-reactive protein levels.

Time to Blood Culture Positivity by Pathogen and Primary Service.

OBJECTIVES: Initiation and continuation of empirical antimicrobial agents for a 48-72-hour observation period is routine practice in the diagnosis and treatment of infants and children with concern for bacteremia. We examined blood cultures at a freestanding pediatric hospital over a 6-year period to determine the time to positivity. METHODS: Data were extracted for all patients who were hospitalized and had blood cultures drawn between January 2013 and December 2018. Time to positivity was calculated on the basis of date and time culture was collected compared with date and time growth was first reported. RESULTS: Over a 6-year period, 89 663 blood cultures were obtained, of which 6184 had positive results. After exclusions, a total of 2121 positive blood culture results remained, including 1454 (69%) pathogens and 667 contaminants (31%). For all positive blood culture results, the number and percentage positive at 24, 36, and 48 hours were 1441 of 2121 (68%), 1845 of 2121 (87%) and 1970 of 2121 (93%), respectively. One hundred twenty-five (66 pathogens, 59 contaminants) of the 89 663 cultures (0.14%) yielded positive results between 36 and 48 hours, indicating that 719 patients would need to be treated for 48 hours rather than 36 hours to prevent 1 case of antibiotic termination before positive result. Median times to positive result by pathogen and service line are presented. CONCLUSIONS: This study reveals that ≤36 hours may be a sufficient period of observation for infants and children started on empirical antimicrobial agents for concern for bacteremia. These findings highlight opportunities for antimicrobial stewardship to limit antimicrobial .

Etravirine in treatment-experienced HIV-1-infected children 1 year to less than 6 years of age.

OBJECTIVE: To describe the pharmacokinetics, safety, and efficacy of etravirine (ETR) in HIV-infected children 1 to less than 6 years of age. DESIGN: Phase I/II, open-label, multicenter, dose-finding study. METHODS: Antiretroviral therapy (ART)-experienced children in two age cohorts (I: 2 to <6 years; II: 1 to less than 2 years) received weight-based ETR, swallowed whole or dispersed in liquid, with optimized ART including a ritonavir-boosted protease inhibitor. Intensive pharmacokinetics occurred 7-18 days after starting ETR. Participants with ETR AUC12h less than 2350 ng h/ml had a dose increase and repeat pharmacokinetics. RESULTS: Twenty-six children enrolled and 21 (15 in cohort I and 6 in cohort II) had evaluable intensive pharmacokinetics sampling at the final weight-based dose. On the final dose, the geometric mean ETR AUC12h was 3823 ng h/ml for cohort I and 3328 ng h/ml for cohort II. Seven children (33.3%) on the final dose, all taking ETR dispersed, had an AUC12  h less than 2350 ng h/ml and underwent a dose increase. ETR AUC12  h was 3.8-fold higher when ETR was swallowed whole vs. dispersed, P less than 0.0001. On the final dose, 75 and 33.3% in cohorts I and II, respectively, had HIV-1 RNA 400 copies/ml or less or at least 2 log reductions from baseline at week 48. Three children (11.5%) experienced a grade at least 3 adverse event related to ETR but only 1 discontinued. CONCLUSION: ETR was well tolerated. Predefined pharmacokinetics targets were met but overall exposures were low vs. historical data in adults, particularly in young children taking dispersed tablets. A high rate of viral efficacy was observed among those aged 2 to more than 6 years but not in those less than 2 years.

Primary Care Physicians' Perspective on Pharmacists Delivering Vaccines to Adults.

INTRODUCTION: Since 2009, pharmacists in all 50 states have been authorized to provide vaccinations to adults. The objective of this study was to assess primary care physicians' (PCPs) experiences with and attitudes about pharmacists administering vaccinations. METHODS: Internet and mail survey of PCPs representative of American College of Physicians' and American Academy of Family Physicians' memberships. RESULTS: Response rate was 69% (642/926). Ninety-eight percent of respondents agreed (79% "Strongly," 19% "Somewhat") that it is their responsibility to assure their adult patients receive recommended vaccinations. Most respondents agreed that pharmacists either did not have access to patient medical information (33% "Strongly," 45% "Somewhat") or did not have adequate vaccination history (33% "Strongly," 41% "Somewhat"). The majority also agreed that pharmacists did not inform them when vaccinations were given (35% "Strongly," 39% "Somewhat") and did not enter vaccinations administered into immunization information systems (IISs) (20% "Strongly," 37% "Somewhat"). However, 83% agreed (31% "Strongly," 52% "Somewhat") that it is helpful to have pharmacists share the role of vaccinating adults. CONCLUSIONS: PCPs have mixed feelings about pharmacists delivering vaccines. Universal use of IISs by pharmacists could partially address physicians' concerns by providing a systematic way for pharmacists and physicians to share patient vaccination histories.