Letermovir as Cytomegalovirus Prophylaxis in a Pediatric Cohort: A Retrospective Analysis.

Letermovir is an attractive cytomegalovirus (CMV) prophylactic agent, but published data in children are scarce. This retrospective chart review aimed to describe our experience using letermovir as CMV prophylaxis in pediatric hematopoietic cell transplantation (HCT) recipients. Pediatric patients (age <20 years) undergoing allogeneic HCT and receiving letermovir prophylaxis in the Mayo Clinic Pediatric Bone Marrow Transplant Program were eligible for inclusion in this retrospective chart review. Medical records were reviewed to evaluate letermovir dosing, CMV levels, laboratory values, and reports of adverse effects. Between October 2020 and April 2022, 9 patients age 4 to 19 years undergoing allogeneic HCT in the Pediatric Bone Marrow Transplant Program received letermovir prophylaxis, either 240 mg or 480 mg daily at a mean and median dose of 10 mg/kg/day. Letermovir was crushed and administered via nasogastric tube in 4 of 9 patients. Two patients received letermovir for secondary CMV prophylaxis after initial treatment with ganciclovir/valganciclovir, and the remaining 7 received letermovir for primary prophylaxis. One patient, a 20-kg 6-year-old female receiving 240 mg (12 mg/kg), experienced low-level CMV viremia while on letermovir. No other patients experienced CMV reactivation while on letermovir prophylaxis. In 2 patients, transient mild transaminitis was noted within the first weeks of letermovir therapy, which resolved without intervention, and its relationship to letermovir could not be clearly established. Letermovir administration was feasible and well tolerated as CMV prophylaxis in our small cohort of pediatric patients undergoing HCT. Larger, prospective studies are warranted to confirm the safety and efficacy of letermovir in children. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Prevention and management of human cytomegalovirus in pediatric HSCT recipients: A review.

Cytomegalovirus (CMV), like other herpesviruses, has the unique ability to establish latent infection with subsequent reactivation during periods of stress and immunosuppression. Herpesviruses cause potentially devastating disease, particularly in hematopoietic stem cell transplant (HSCT) recipients. CMV is especially of concern in HSCT recipients given the high community seroprevalence, high risk of reactivation and high risk of transmission from HSCT donors to recipients causing primary infection after transplantation. The risk of CMV infection and severity of CMV disease varies depending on the underlying disease of the HSCT recipient, donor and recipient CMV status prior to HSCT, type of conditioning therapy in preparation for HSCT, allogeneic versus autologous HSCT, donor graft source, timing of infection in relation to HSCT, and other patient comorbidities. Different strategies exist for prevention (e.g., preemptive therapy vs. universal prophylaxis) as well as management of CMV disease (e.g., antiviral therapy, augmenting immune reconstitution, cytotoxic T-cell therapy). The purpose of this narrative review is to discuss diagnosis, prevention, and management of CMV infection and disease at different stages of HSCT, including key points illustrated through presentations of complex cases and difficult clinical scenarios. Traditional and novel strategies for CMV management will be discussed in the context of these unique clinical cases.

A Quality Improvement Project Aimed at Standardizing the Prescribing of Fluconazole Prophylaxis in a Level IV Neonatal Intensive Care Unit.

Introduction: Invasive candidiasis has a high morbidity and mortality among premature neonates. Antifungal prophylaxis with fluconazole significantly lowers the risk of invasive fungal infection in this population. We noted the use of fluconazole prophylaxis in our level IV neonatal intensive care unit (NICU) was variable and sought to standardize prescribing of prophylactic fluconazole. Methods: We formed a multidisciplinary team to develop an evidence-based protocol using literature and expert consensus to guide appropriate use of fluconazole prophylaxis in our level IV NICU. After determining baseline fluconazole prophylaxis prescribing before protocol implementation, we used plan-do-study-act (PDSA) cycles to introduce protocolized prescribing and incorporate it into daily practice. A 6-month intervention phase was followed by a 2-year control phase, in which monthly audits were performed to evaluate protocol adherence. Results were displayed in a statistical process control chart. Results: Before protocol implementation, fluconazole prophylaxis prescribing adhered to the protocol in 81% of patients. During the first PDSA cycle, adherence increased significantly to 94.5% (86/91 patients), which further increased to 98.7% (74/75 patients) during the second PDSA cycle and remained at 96% (120/125 patients) during the control phase (P < 0.0001). Conclusions: A multidisciplinary group-designed protocol was successful in standardizing fluconazole prophylaxis prescribing for infants in the level IV NICU. Adherence to protocol was high following implementation and was sustained for the duration of the project. There were no cases of invasive candidiasis noted.

Live virus vaccination of pediatric solid organ transplant candidates within 1 month prior to transplantation: A multicenter experience.

BACKGROUND: Solid organ transplant (SOT) recipients are at increased risk of vaccine-preventable illness due to the high degree of immunosuppression required following transplantation. The current recommendation is to vaccinate with live attenuated vaccines, including Measles, Mumps, and Rubella (MMR) and Varicella (VAR) vaccines, at least 4 weeks prior to transplant. However, data to support the time interval between vaccine and transplant are limited. METHODS: We conduct a literature review of the natural history of the viruses and length of viremia following live-attenuated viral vaccines, and we describe a series of 5 cases from 2 pediatric transplant centers in which live attenuated viral vaccines were administered within 21 days prior to SOT. RESULTS: None of the 5 children who received MMR or VAR 8-21 days prior to liver (2) and heart (3) transplant suffered from vaccine-related viral illness after transplant, even in the presence of significant immunosuppression with T-cell-depleting agents. CONCLUSION: These cases support that shorter intervals of live vaccine administration prior to transplant may be safe, allowing the vaccination of a larger cohort of SOT candidates. Increasing pretransplant vaccinations is crucial since, in most cases, live viral vaccines are contraindicated posttransplantation, and the most effective vaccine approaches utilize prime-boost strategies, priming before and boosting after transplant.

Proposed Plasma Ammonia Reference Intervals in a Reference Group of Hospitalized Term and Preterm Neonates.

BACKGROUND: Plasma ammonia is commonly measured in the diagnostic evaluation of hospitalized newborns, but reference values are not well defined. METHODS: We prospectively enrolled newborns admitted to the level III/IV neonatal intensive care unit and level II intermediate special care nursery from January 2017 to January 2018. Infants with inborn errors of metabolism or liver disease were excluded. Plasma ammonia concentrations were measured once within the first week of life and evaluated by sex, gestational age, timing of the draw, blood collection method, and type of nutrition. Reference intervals were calculated. RESULTS: 127 neonates were included; one third (34%) were term infants born at ≥37 weeks gestation, and two thirds (66%) were born preterm at <37 weeks gestation. Median plasma ammonia concentrations were 32 µmol/L (range <10 to 86 µmol/L). Median ammonia concentrations were higher among preterm compared to term infants (35 vs. 28 µmol/L, p = 0.0119), and term female compared to term male infants (34 vs. 26 µmol/L, p = 0.0228). There was no difference in median ammonia concentrations between female and male preterm infants, based on gestational age within the preterm group, timing of the blood draw, presence of hyperbilirubinemia, blood collection method, or type of nutritional intake. CONCLUSIONS: Plasma ammonia concentrations among newborns are higher than the expected adult concentrations and may vary by gestational age and sex. Blood collection method, type of nutrition, hyperbilirubinemia, and timing of the draw do not impact concentrations. We propose a reference limit of ≤82 µmol/L for newborns less than one week of age.

Whole-genome sequencing for methicillin-resistant Staphylococcus aureus (MRSA) outbreak investigation in a neonatal intensive care unit.

OBJECTIVE: To evaluate whole-genome sequencing (WGS) as a molecular typing tool for MRSA outbreak investigation. DESIGN: Investigation of MRSA colonization/infection in a neonatal intensive care unit (NICU) over 3 years (2014-2017). SETTING: Single-center level IV NICU.PatientsNICU infants and healthcare workers (HCWs). METHODS: Infants were screened for MRSA using a swab of the anterior nares, axilla, and groin, initially by targeted (ring) screening, and later by universal weekly screening. Clinical cultures were collected as indicated. HCWs were screened once using swabs of the anterior nares. MRSA isolates were typed using WGS with core-genome multilocus sequence typing (cgMLST) analysis and by pulsed-field gel electrophoresis (PFGE). Colonized and infected infants and HCWs were decolonized. Control strategies included reinforcement of hand hygiene, use of contact precautions, cohorting, enhanced environmental cleaning, and remodeling of the NICU. RESULTS: We identified 64 MRSA-positive infants: 53 (83%) by screening and 11 (17%) by clinical cultures. Of 85 screened HCWs, 5 (6%) were MRSA positive. WGS of MRSA isolates identified 2 large clusters (WGS groups 1 and 2), 1 small cluster (WGS group 3), and 8 unrelated isolates. PFGE failed to distinguish WGS group 2 and 3 isolates. WGS groups 1 and 2 were codistributed over time. HCW MRSA isolates were primarily in WGS group 1. New infant MRSA cases declined after implementation of the control interventions. CONCLUSION: We identified 2 contemporaneous MRSA outbreaks alongside sporadic cases in a NICU. WGS was used to determine strain relatedness at a higher resolution than PFGE and was useful in guiding efforts to control MRSA transmission.

Central Nervous System Blastomycosis in Children: A Case Report and Review of the Literature.

We present a 7-year-old boy with chronic meningitis caused by Blastomyces dermatitidis. A review of the literature revealed 32 cases of central nervous system blastomycosis in children between 1983 and 2016, of which 18 represented parenchymal disease of the brain or spinal cord. Blastomycosis affecting the central nervous system is rare but should be considered in children with chronic meningitis.

Extensive Household Outbreak of Urinary Tract Infection and Intestinal Colonization due to Extended-Spectrum ß-Lactamase-Producing Escherichia coli Sequence Type 131.

BACKGROUND: Reasons for the successful global dissemination of multidrug-resistant Escherichia coli sequence type 131 (ST131) are undefined, but may include enhanced transmissibility or ability to colonize the intestine compared with other strains. METHODS: We identified a household in which 2 young children had urinary tract infection (UTI) caused by an extended-spectrum ß-lactamase (ESBL)-producing, multidrug-resistant ST131 E. coli strain. We assessed the prevalence of ST131 intestinal colonization among the 7 household members (6 humans, 1 dog). Fecal samples, collected 3 times over a 19-week period, were cultured selectively for E. coli. Isolates were characterized using clone-specific polymerase chain reaction to detect ST131 and its ESBL-associated H30Rx subclone, pulsed-field gel electrophoresis, extended virulence genotyping, and antimicrobial susceptibility testing. RESULTS: In total, 8 different E. coli pulsotypes (strains) were identified. The index patient's urine isolate represented ST131-H30Rx strain 903. This was the most widely shared and persistent strain in the household, colonizing 5 individuals at each sampling. In contrast, the 7 non-ST131 strains were each found in only 1 or 2 household members at a time, with variable persistence. The ST131 strain was the only strain with both extensive virulence and antimicrobial resistance profiles. CONCLUSIONS: An ESBL-producing ST131-H30Rx strain caused UTI in 2 siblings, plus asymptomatic intestinal colonization in multiple other household members, and was the household's most extensively detected and persistent fecal E. coli strain. Efficient transmission and intestinal colonization may contribute to the epidemiologic success of the H30Rx subclone of E. coli ST131.

Optimization of vancomycin dosing in very low-birth-weight preterm neonates.

OBJECTIVE: To compare vancomycin serum trough concentrations and 24-hour area under the serum concentration-versus-time curve (AUC24) among very low-birth-weight (VLBW) premature infants before and after implementation of an institution-wide increase in neonatal vancomycin dosing. STUDY DESIGN: We performed a retrospective analysis of vancomycin concentrations among preterm VLBW neonates before (2007-2010) and after (2010-2013) implementation of a new vancomycin dosing protocol consisting of increased vancomycin daily dose and frequency of administration. RESULTS: Neonates weighing < 1,500 g and receiving the new vancomycin dosing regimen had lower rates of undetectable trough concentrations (24 vs. 50%, p = 0.04), higher median trough concentrations (10.8 vs. 5.9 µg/mL, p = 0.003), a higher proportion of goal trough concentrations of 10 to 20 µg/mL (35 vs. 4%, p = 0.005), and a significantly higher vancomycin AUC24 (438 vs. 320 mg·h/L, p = 0.004) compared with historical controls. CONCLUSION: Increasing the vancomycin daily dose and dosing frequency led to an increase in vancomycin trough concentrations and AUC24, and a decrease in the proportion of undetectable (< 5.0 µg/mL) troughs, without an increase in toxicity among VLBW premature neonates.

Prevalence of rectal colonization with multidrug-resistant Enterobacteriaceae among international patients hospitalized at Mayo Clinic, Rochester, Minnesota.

Rectal colonization with multidrug-resistant Enterobacteriaceae was found in 23 of 94 consecutively enrolled international patients hospitalized at Mayo Clinic, Rochester, Minnesota. No carbapenemase producers were detected. Twenty-one isolates were extended-spectrum ß-lactamase-producing Escherichia coli. Colonization was associated with gastrointestinal disease and central venous catheter placement within the antecedent year.

The effect of age and weight on vancomycin serum trough concentrations in pediatric patients.

BACKGROUND: Vancomycin treatment failure has been associated with low serum vancomycin trough concentrations, prompting recommendations to increase the daily doses in adults and children. Despite more aggressive vancomycin dosing, there continues to be significant variability in vancomycin trough concentrations in pediatric patients. METHODS: To determine if vancomycin trough concentrations in pediatric patients differ by age and weight, we reviewed records of hospitalized patients who received vancomycin between 2008 and 2012. Patients were divided into groups that received vancomycin 40 mg/kg/day (2008-2009) or 60 mg/kg/day (2010-2012). Vancomycin trough concentrations were compared between groups and within the 60 mg/kg/day group, stratified by patient age and weight. RESULTS: After increasing the vancomycin dose from 40 to 60 mg/kg/day, initial trough concentrations increased significantly in patients younger than 2 and greater than 6 years of age, but not in patients between the ages of 2 and 5 years. In the 60 mg/kg/day group, only 16.7% of patients between 2 and 5 years of age had initial trough concentrations in the therapeutic range (10-20 µg/ml). Initial trough concentrations were therapeutic in a greater proportion of patients ages 6-12 years (38.7%) and 13-18 years (63.0%). Patients between the ages of 13 and 18 had the highest proportion of supratherapeutic initial vancomycin trough concentrations (14.8%). Patients weighing over 50 kg had significantly higher trough concentrations than patients  50 kg or less (17.1 µg/ml vs 9.3 µg/ml, p<0.001). CONCLUSION: Although increasing the vancomycin dose from 40 to 60 mg/kg/day led to a significant increase in vancomycin trough concentrations, a large proportion of patients receiving 60 mg/kg/day of vancomycin had trough concentrations outside of the therapeutic range. Specifically, patients younger than 6 years tended to have low trough concentrations, whereas adolescents and children over 50 kg were more likely to have elevated trough concentrations. Vancomycin dosing strategies in pediatric patients should consider age and weight as well as renal function and indication.

Characteristics and outcomes of outpatient parenteral antimicrobial therapy at an academic children's hospital.

BACKGROUND: Use of outpatient parenteral antimicrobial therapy (OPAT) in pediatrics is widespread and may be increasing. Recent data quantifying use and characteristics of pediatric OPAT are lacking. METHODS: To evaluate the number of children receiving OPAT each year and their associated characteristics and outcomes, we conducted a retrospective review of all patients discharged with OPAT from the Mayo Clinic Children's Hospital between August 1, 2010 and December 31, 2011. RESULTS: During the study period, there were 126 pediatric hospital discharges with OPAT (2.5% of all discharges). OPAT was used most commonly to treat bone and joint (21%), bloodstream (15%), intra-abdominal (13%) and soft tissue (9%) infections. A positive culture or serology result was found in 86 (68%) OPAT courses. The most frequently used antibiotics were ceftriaxone (17%), cefazolin (16%) and cefepime (13%). The median duration of OPAT was 12 days. Thirty-six courses (29%) resulted in catheter- or antibiotic-associated complications. Weekly laboratory monitoring was more common when OPAT was managed by the infectious disease service (88%) versus other services (20%). Among 123 courses with follow-up, 109 (89%) resulted in cure, and 13 (11%) were treatment failures. CONCLUSION: At our children's hospital, 2.5% of hospitalized patients were discharged with OPAT. In one-third of OPAT courses children developed catheter- or antibiotic-associated complications. Opportunities to increase the role of pediatric infectious disease in OPAT initiation and management should be explored.