Pharmacokinetic analysis driven letermovir dosing in pediatric hematopoietic cell transplantation patients with resistant CMV disease.

BACKGROUND: Reactivation of cytomegalovirus (CMV) in CMV-seropositive patients after haploidentical T-cell receptor αß+ /CD19+ depleted hematopoietic cell transplant (HCT) is common. Due to delayed CMV-specific immune reconstitution, patients may require prolonged antiviral therapy, including secondary prophylaxis (SP). We present our clinical experience with the off-label use of letermovir for SP in a severely immunocompromised 2-year-old toddler with refractory pre-B-cell ALL and bilateral retinitis caused by resistant CMV (A594V UL97 mutation) following a haploidentical TCRαß+ /CD19+ depleted HCT. METHODS: The patient underwent measurement of two separate sets of letermovir serum concentrations, drawn at pre-dose, 1 and 4 h (and 8 h during the second therapeutic drug monitoring) post-dose. Pharmacokinetic parameters, including AUC0-24 were calculated, and dose adjustment was performed based on the drug level. RESULTS: While receiving oral letermovir 240 mg once daily without cyclosporine, the observed AUC0-24 was high (75 815 ng h/mL) with a Cmin of 209 ng/mL. The dose was reduced by 25% to 180 mg once daily. Despite the dose reduction, both AUC0-24 and Cmin values further increased to 119 095 ng h/L and 959 ng/mL, respectively. The patient continued oral letermovir 180 mg once daily for about 3 months, with adequate viral suppression (CMV viral load in plasma <150 IU/mL) and no recurrent CMV end-organ disease or adverse events. CONCLUSIONS: Given limited options for anti-CMV therapy in young children with resistant CMV, letermovir could be considered as an alternative antiviral for SP. Further studies are warranted to evaluate the pharmacokinetics of letermovir in pediatric allogeneic HCT recipients.

Impact of Intravenous Fat Emulsion Choice on Candida Biofilm, Hyphal Growth, and Catheter-Related Bloodstream Infections in Pediatric Patients.

BACKGROUND: Use of mixed-oil (MO) intravenous fat emulsion (IFE) was shown to inhibit Candida albicans biofilm formation and overall rate of catheter-related bloodstream infections (CR-BSIs) compared with soybean-oil (SO) IFE). We aimed to delineate this inhibitory mechanism and impact of IFE choice on distribution of fungal CR-BSIs. METHODS: Transcriptional profiling was conducted on C. albicans grown in SO-IFE, MO-IFE, or SO-IFE with capric acid. Overexpression strains of shared down-regulated genes were constructed using a tetracycline-off system to assess hypha and biofilm formation in IFEs. A 5-year retrospective multicenter cohort study was performed to assess differences in CR-BSIs caused by Candida species based on the IFE formulation received in pediatric patients. RESULTS: Genes significantly down-regulated in MO-IFE and SO-IFE with capric acid included CDC11, HGC1, and UME6. Overexpression of HGC1 or UME6 enabled filamentation in capric acid and MO-IFE. Interestingly, only overexpression of UME6 was sufficient to rescue biofilm growth in MO-IFE. MO-IFE administration was associated with a higher proportion of non-albicans Candida versus C. albicans CR-BSIs (42% vs 33%; odds ratio, 1.22 [95% confidence interval, .46-3.26]). CONCLUSIONS: MO-IFE affects C. albicans biofilm formation and hyphal growth via a UME6-dependent mechanism. A numerical but not statistically significant difference in distribution of Candida spp. among CR-BSIs was observed.

Delivery of carbohydrates, amino acids, and lipids via intravenous catheters is necessary for some patients to supply daily caloric needs. These nutrient-dense parenteral solutions can promote microbial biofilm growth on the catheter surface, which may seed subsequent catheter-related bloodstream infection (CR-BSI). In fact, receipt of parenteral nutrition is an established risk factor for CR-BSI caused by the polymorphic fungal pathogen Candida albicans. New intravenous fat emulsions (IFEs) have gained market share and IFEs containing capric acid (mixed-oil [MO] IFE) compared with those without (soybean-oil [SO] IFE) impair the C. albicans yeast-to-hypha switch­a trait strongly associated with pathogenicity and biofilm formation. In this study, we found that MO-IFE and capric acid reduced expression of a transcriptional regulator involved in hyphal extension (UME6) and down-regulated genes involved in cell partitioning (HGC1). Overexpression of these genes enabled hyphal growth in MO-IFE. Secondly, we sought to determine whether the type of IFE administered was associated with the clinical incidence of CR-BSIs caused by C. albicans or other common non-albicans Candida species. There was a nonsignificant numerical reduction in C. albicans infections in patients administered MO-IFE compared with SO-IFE. Collectively, this work shows that IFEs differentially affect Candida biology with potential infectious consequences for the patient.

When There Is No Trough: Use and Outcomes of Continuous-Infusion Vancomycin at a Free-Standing Children's Hospital.

OBJECTIVE: There is minimal published literature regarding the use of continuous-infusion vancomycin (CIV) in children. The objective of this study was to describe the use, dosing requirements, and outcomes of CIV at a free-standing children's hospital. METHODS: This is a retrospective review of patients who received CIV while admitted to Nationwide Children's Hospital between July 1, 2010, and June 30, 2020. The total daily dose (TDD) of vancomycin required to attain a target serum vancomycin concentration (SVC) was compared between CIV and intermittent-infusion vancomycin (IIV) administration regimens. Safety outcomes and treatment failure were also explored. RESULTS: Fourteen patients (77% male) with a median age of 7 years (IQR = 1, 10 years) were included. Most patients (71%) were started on CIV in anticipation of outpatient parenteral antimicrobial therapy. The median TDD required to achieve a target SVC was higher with IIV compared with CIV (82.4 mg/kg/day vs 50.5 mg/kg/day; p = 0.02). Despite higher TDD with IIV, median SVC with IIV was similar to SVC with CIV (16.6 mg/L vs 17.6 mg/L; p = 2.00). There were no safety concerns or therapeutic failures identified with CIV. CONCLUSIONS: Continuous-infusion vancomycin was a well-tolerated and effective alternative to IIV for the patients included in this study. The TDD of vancomycin required to achieve a target SVC was lower in patients receiving CIV compared with those receiving IIV.

Empiric Vancomycin Reduction in a Pediatric Intensive Care Unit.

BACKGROUND: At our institution, empirical vancomycin is overused in children with suspected bacterial community-acquired infections (CAIs) admitted to the PICU because of high community rates of methicillin-resistant Staphylococcus aureus (MRSA). Our goal was to reduce unnecessary vancomycin use for CAIs in the PICU. METHODS: Empirical PICU vancomycin indications for suspected CAIs were developed by using epidemiological risk factors for MRSA. We aimed to reduce empirical PICU vancomycin use in CAIs by 30%. After retrospectively testing, the indications were implemented and monthly PICU empirical vancomycin use during baseline (May 2017-April 2018) and postintervention (May 2018-July 2019) periods. Education was provided to PICU providers, vancomycin indications were posted, and the antibiotic order set was revised. Statistical process control methods tracked improvement over time. Proven S aureus infections for which vancomycin was not empirically prescribed and linezolid or clindamycin use were balancing measures. RESULTS: We identified 1620 PICU patients with suspected bacterial CAIs. Empirical vancomycin decreased from a baseline of 73% to 45%, a 38% relative reduction. No patient not prescribed empirical vancomycin later required the addition of vancomycin or other MRSA-targeted antibiotics. There was no change in nephrotoxicity or in the balancing measures. CONCLUSIONS: Development of clear and concise recommendations, combined with clinician education and decision support via an order set, was an effective and safe strategy to reduce PICU vancomycin use. Retrospective validation of the recommendations with local data were key to obtaining PICU clinician buy in.

Implementation of a Pharmacist-Led Antimicrobial Time-Out for Medical-Surgery Services in an Academic Pediatric Hospital.

OBJECTIVE: This report describes a quality improvement initiative to implement a pharmacist-led antimicrobial time-out (ATO) in a large, freestanding pediatric hospital. Our goal was to reach 90% ATO completion and documentation for eligible patients hospitalized on general pediatric medicine or surgery services. METHODS: A multidisciplinary quality improvement team developed an ATO process and electronic documentation tool. Clinical pharmacists were responsible to initiate and document an ATO for pediatric medicine or surgery patients on or before the fifth calendar day of therapy. The quality improvement team educated pharmacists and physicians and provided ATO audit and feedback to the pharmacists. We used statistical process control methods to track monthly rates of ATO completion retrospectively from October 2017 through March 2018 and prospectively from April 2018 through April 2019. Additionally, we retrospectively evaluated the completion of 6 data elements in the ATO note over the final 12-month period of the study. RESULTS: Among 647 eligible antimicrobial courses over the 19-month study period, the mean monthly documentation rate increased from 54.6% to 83.5% (p < 0.001). The mean ATO documentation rate increased from 32.8% to 74.2% (p < 0.001) for the pediatric medicine service and from 65.0% to 88.1% for the pediatric surgery service (p = 0.006). Among 302 notes assessed for completeness, 35.8% had all the required data fields completed. A tentative antimicrobial stop date was the data element completed least often (49.3%). CONCLUSIONS: We implemented a pharmacist-led ATO, highlighting the role pharmacists play in antimicrobial stewardship. Additional efforts are needed to further increase ATO completion rates and to define treatment duration.

Intravenous Ribavirin for Parainfluenza and Respiratory Syncytial Virus in an Infant Receiving Extracorporeal Membrane Oxygenation and Continuous Renal Replacement Therapy.

BACKGROUND: Viral bronchiolitis remains a significant cause of hospitalization as well as morbidity and mortality during the first year of life, with treatment options beyond supportive care being limited. In cases of severe illness, ribavirin may offer therapeutic benefit. OBJECTIVE: We report the use of intravenous (IV) ribavirin in an infant requiring concomitant venovenous extracorporeal membrane oxygenation (VV-ECMO) and continuous venovenous hemofiltration (CVVH) for respiratory syncytial virus (RSV) and parainfluenza virus (PIV) coinfection. PATIENTS AND METHODS: A 5-week-old male former 33-week preterm infant was admitted with respiratory failure and subsequently tested positive for RSV and PIV-type 1 infection. Progressive clinical deterioration subsequently required the initiation of both VV-ECMO and CVVH. Although the patient received combined VV-ECMO and CVVH, IV ribavirin was administered, and serial plasma and ultrafiltrate samples were obtained for pharmacokinetic analyses after the first dose (collection period 1) and again after an estimated 5 half-lives (collection period 2). RESULTS: Pharmacokinetics for collection period 1 demonstrated a calculated Cmax of 11.99 mg/L, an AUC0-24 of 43.32 mg·hr/L, ke 0.26 hr-1, t½ 2.69 hr, Vd 10.04 L (2.92 L/kg, using patient's dosing weight 3.43 kg), CLT 43.47 mL/min, and CLCVVH 6.75 mL/min. Pharmacokinetics for collection period 2 demonstrated a calculated Cmax of 10.31 mg/L, AUC0-6 of 52.55 mg· hr/L, ke 0.06 hr-1, t½ 10.69 hr, Vd 17.5 L (5.1 L/kg), and CLT 17.44 mL/min. The sieving coefficient during collection period 1 was 1.17 (range, 1.07-1.37). The percent decline between prefilter and postfilter oxygenator was 19.1%. CONCLUSION: Our patient demonstrated therapeutic concentrations of ribavirin, despite drug removal via CVVH and the ECMO oxygenator. Standard ribavirin dosing used and resultant concentrations achieved were associated with viral clearance and clinical improvement.

Central catheter-associated bloodstream infection reduction with ethanol lock prophylaxis in pediatric intestinal failure: broadening quality improvement initiatives from hospital to home.

IMPORTANCE: Children with intestinal failure are at high risk for developing central catheter-associated bloodstream infections (CCABSIs) owing to children's chronic dependence on central venous catheters for parenteral nutrition. OBJECTIVE: To evaluate the effectiveness and safety of the addition of ethanol lock prophylaxis to a best-practice CCABSI prevention bundle on hospital and ambulatory CCABSI rates in children with intestinal failure. DESIGN, SETTING, AND PARTICIPANTS: Quality improvement and statistical process control analysis that took place at a tertiary care pediatric hospital and patient homes. Participants included children who were 18 years or younger with intestinal failure requiring a central venous catheter. INTERVENTIONS: Central catheter-associated bloodstream infection prevention bundle that included daily ethanol lock prophylaxis. MAIN OUTCOMES AND MEASURES: Central catheter-associated bloodstream infection rates and safety outcomes (central catheter insertions, repairs, and hospitalizations) before (January 1, 2011-January 31, 2012) and after (February 1, 2012-December 31, 2013) ethanol lock prophylaxis bundle implementation. RESULTS: Twenty-four children with intestinal failure received the ethanol lock prophylaxis CCABSI prevention bundle for a median of 266 days (range, 12-635 days). Rates of CCABSI decreased from 6.99 CCABSIs per 1000 catheter days at baseline to 0.42 CCABSI per 1000 catheter days after ethanol lock prophylaxis bundle implementation, despite an increase in the total number of catheter days. A subset of 14 children who received prolonged ethanol lock prophylaxis (≥3 months) had fewer median (range) central catheter insertions 0 (0-2) vs 3 (0-6); P = .001. The pre-ELP intervention CCABSI rates in this subset was 7.01 per 1000 catheter days vs 0.64 per 1000 catheter days for post-ELP intervention (P = .004). There were no significant differences in the total number of hospital admissions; however, there were fewer hospitalizations for fever and CCABSI (P = .003). CONCLUSIONS AND RELEVANCE: A best-practice CCABSI prevention bundle that included ethanol lock prophylaxis in both the hospital and home was successfully implemented, well tolerated, and demonstrated a significant and sustained reduction in preventable harm in the form of CCABSIs in children with intestinal failure.