Higher Weight-Based Doses Are Required to Achieve and Maintain Therapeutic Voriconazole Serum Trough Concentrations in Children.

OBJECTIVE: Children require weight-based voriconazole doses proportionately larger than adults to achieve therapeutic serum trough concentrations (1-6 mcg/mL). The objective of this quality improvement project was to determine the initial dose, proportion of patients achieving target concentrations with initial dosing, and subsequent therapeutic drug monitoring and dose modifications needed to achieve and maintain therapeutic voriconazole concentrations in children. METHODS: This retrospective study evaluated children aged <18 years treated with voriconazole during the study period. Dosing and therapeutic drug monitoring (TDM) values were collected and compared by age. Data are presented as median (IQR), unless otherwise stated. RESULTS: Fifty-nine patients, aged 10.4 (3.7-14.7) years and 49% female, met inclusion criteria; 42 had at least 1 steady-state voriconazole serum trough concentration measured. Twenty-one of 42 (50%) achieved the target concentration at the first steady-state measurement. An additional 13 of 42 (31%) achieved the target following 2 to 4 dose modifications. The dose required to first achieve a value in the target range was 22.3 (18.0-27.1) mg/kg/day in children aged <12 years and 12.0 (9.8-14.0) mg/kg/day in children aged ≥12 years. After reaching the target, 59% and 81% of repeated steady-state measurements were in the therapeutic range in patients aged <12 years and ≥12 years, respectively. CONCLUSIONS: Reaching therapeutic voriconazole serum trough concentrations required doses larger than currently recommended by the American Academy of Pediatrics. Multiple dose adjustments and TDM measurements were required to achieve and maintain therapeutic voriconazole serum concentrations.

A potential cost savings analysis of a penicillin de-labeling program.

Introduction: Over 95% of patients documented as penicillin allergic can tolerate a penicillin without a reaction. Inaccurate documentation of penicillin allergy leads to more expensive alternative antibiotic prescriptions and an increased incidence of resistant infections. Objective: To understand the potential drug cost savings of a penicillin de-labeling program to a healthcare system. Methods: We evaluated patient visits with documented penicillin allergy who presented to the pediatric Emergency Department (PED) and 22 associated primary care clinics. Patients were included if they were discharged home with a non-penicillin antibiotic when the first-line treatment for the diagnosis would have been a penicillin. The potential cost savings were the sum of all visit-level cost differences between the non-penicillin prescription(s) and a counterfactual penicillin prescription. To factor in a 95% successful patient de-labeling rate, we repeatedly sampled 95% from the patients with the eligible visits 10,000 times to produce an estimate of the potential cost savings. Results: Over the 8-year period, 2,034 visits by 1,537 patients to the PED and 12,349 visits by 6,073 patients to primary care clinics satisfied eligibility criteria. If 95% of the patients could have been successfully de-labeled, it would have generated a cost saving of $618,653 (95% CI $618,617-$618,689) for all the corresponding payers in the system. Conclusions: Implementing a penicillin de-labeling program across a healthcare system PED and its associated primary care clinics would bring significant cost savings. Healthcare systems should rigorously evaluate optimal methods to de-label patients with reported penicillin allergy.

Retrospective Comparison of Cefdinir, Cephalexin, and Sulfamethoxazole-Trimethoprim in the Treatment of Outpatient Pediatric Urinary Tract Infections.

This retrospective single-center study included children aged 2 months to 18 years who were prescribed an oral antibiotic for microbiologically confirmed urinary tract infection (UTI). The primary outcomes were re-encounter to the hospital, emergency department, or urgent care within 30 days and modification of the antibiotic regimen within 14 days. Development of Clostridioides difficile (C difficile) infection or new allergic reaction to the antibiotic prescribed was the secondary outcome. The sample included 2685 children. Rates of re-encounter were similar regardless of the initial antibiotic prescribed (P = .88), and patients who received cefdinir had a lower rate of medication changes (5%) compared with both cephalexin (14%) and sulfamethoxazole-trimethoprim (15%) (P ≤ .001). The most common reason for medication change was susceptibility interpretation. Given its low side-effect profile and narrow spectrum compared with the alternatives, cephalexin appears to be a reasonable choice as first-line therapy for the treatment of uncomplicated pediatric UTI.

Extended Infusion ß-Lactams for the Treatment of Gram-Negative Bacteremia in Children.

OBJECTIVE: The pharmacokinetics of ß-lactam antibiotics favor administration via an extended infusion. Although literature to support extended infusion ß-lactams exists for adults, few data are available in pediatrics, especially among patients with bacteremia. The purpose of this study was to compare clinical outcomes between extended and standard infusions in children with Gram-negative bacteremia. METHODS: This retrospective chart analysis included hospitalized patients ages 0 to 18 years who received at least 72 hours of cefepime, meropenem, or piperacillin-tazobactam between January 1, 2013 and July 30, 2021. Clinical outcomes included duration of antibiotic therapy, hospital length of stay, readmission within 30 days, all-cause mortality, time to blood culture clearance, and time to normalization of inflammatory markers. RESULTS: A total of 124 patients (51 extended infusion, 73 standard infusion) met criteria for evaluation. Duration of antibiotic therapy was shorter in the extended infusion group (6.6 days versus 10.2 days; p = 0.01). There were no differences in hospital length of stay, readmission rates, all-cause mortality, time to normalization of inflammatory markers, or time to blood culture clearance. CONCLUSIONS: Use of extended infusion ß-lactam antibiotics in children with Gram-negative bacteremia was associated with shorter durations of therapy and should be the preferred method of administration when feasible.

Management of Children with Reported Penicillin Allergies.

Penicillin allergy is the most commonly reported medication allergy. Reported allergy is associated with increased morbidity and mortality. Risk categorization tools can help determine the optimal testing strategies to delabel patients with reported allergy. Approaches to allergy removal include oral challenge in low-risk patients and skin testing in high-risk patients. Many different locations may be used to test for allergy, including ambulatory care clinics, inpatient units, and emergency departments. Interventions (eg, use of the electronic medical record) are needed to ensure that once the allergy is removed, this information is effectively transmitted to the patient and appropriate providers.

Extending the Reach of Antimicrobial Stewardship to Pediatric Patients.

Guidance for developing and implementing antimicrobial stewardship programs for children is lacking. This review article describes unique considerations for planning antimicrobial management of children that may impact stewardship strategies. A variety of methods and training tools are described along with metrics specific to measuring antibiotic use and outcomes in children. Handshake stewardship is specifically explained and is considered a best practice. Information on stewardship in unique settings, including the neonatal intensive care unit and outpatient settings, are included.

Extended Infusion of Beta-Lactams Is Associated With Improved Outcomes in Pediatric Patients.

OBJECTIVE: The pharmacokinetics of beta-lactam antibiotics favor administration via an extended infusion. Although literature supporting extended infusion beta-lactams exists in adults, few data are available to guide the practice in pediatrics. The purpose of this study was to compare clinical outcomes between extended and standard infusions in children. METHODS: This retrospective chart analysis included hospitalized patients 0 to 18 years old who received at least 72 hours of cefepime, piperacillin-tazobactam, or meropenem between October 1, 2017, and March 31, 2019. Clinical outcomes of care included hospital length of stay, readmission within 30 days, and all-cause mortality. RESULTS: A total of 551 patients (258 extended infusion, 293 standard infusion) met criteria for evaluation. Clinical outcomes among the entire population were similar. A subanalysis of select populations demonstrated decreased mortality in critical care patients (2.1% vs 19.6%, p = 0.006) and decreased 30-day readmission rates in bone marrow transplant patients (0% vs 50%, p = 0.012) who received the extended infusion compared with a standard infusion. CONCLUSIONS: Outcomes were similar between extended and standard infusions in children. Subgroup analyses suggest a possible mortality benefit in the critically ill and decreased readmission rate in bone marrow transplant patients.

Impact of American Academy of Pediatrics Palivizumab Guidance for Children ≥29 and <35 Weeks of Gestational Age.

OBJECTIVES: To evaluate the impact of the American Academy of Pediatrics revised recommendations (2014) for palivizumab prophylaxis on respiratory syncytial virus (RSV) admissions and severity of illness among children ≥29 weeks and <35 weeks of gestational age. STUDY DESIGN: We evaluated patients hospitalized with RSV infection from October 1, 2012, through April 30, 2017. RSV hospitalizations, community RSV activity, duration of hospitalization, disease severity, and mortality were reviewed. Data were compared before and after implementation of the guideline changes. RESULTS: A total of 91 patients were born at ≥29 weeks and <35 weeks of gestational age and hospitalized within the first year of life during the evaluation period. Gestational age, birth weight, age at diagnosis, and sex remained constant over the seasons evaluated. RSV hospitalizations and activity in the community were unchanged over 5 years. Duration of hospitalization increased. There was no difference in need for intensive care, supplemental oxygen, or mechanical ventilation or mortality. CONCLUSIONS: Implementation of the 2014 American Academy of Pediatrics guidelines regarding eligibility for palivizumab prophylaxis in older infants born preterm did not increase RSV hospitalizations or disease severity among children hospitalized for RSV at our hospital. Our data support continued adherence to the guidelines.

Development and implementation of an antimicrobial lock therapy guideline in a pediatric hospital.

PURPOSE: The development and implementation of an antimicrobial lock therapy guideline at a large pediatric hospital are described. SUMMARY: Central venous access devices (CVADs) are essential in the medical management of patients requiring long-term total parenteral nutrition, chemotherapy, or hemodialysis. However, the use of a CVAD carries a significant risk of the development of central line-associated bloodstream infection (CLABSI). Antimicrobial lock therapy is indicated for patients with CLABSIs who have no signs of exit site or tunnel infection and for whom catheter salvage is a goal. An antimicrobial lock therapy guideline was developed and implemented at a large pediatric hospital by an interprofessional team consisting of providers specializing in CVAD care. Development and implementation of the guideline included a needs assessment, a literature review, determination of patient selection criteria, addition of compounding formulations, development of administration techniques, and education. In all 10 instances of lock therapy in the 18 months after guideline implementation, the criteria for use were met; in 60% of those instances, patients received care from an infectious diseases physician. Each of the available lock solutions was used at least once during the 18-month period. CONCLUSION: Overall, implementation of a guideline on administration of antimicrobial lock therapy was successful. Nine patients received antimicrobial lock therapy in the 18 months after policy implementation; although 2 had their line removed (1 due to repeated line infections), neither required line replacement.

An Optimized Voriconazole Dosing Strategy to Achieve Therapeutic Serum Concentrations in Children Younger than 2 Years Old.

STUDY OBJECTIVE: To describe our experience with voriconazole in three patients younger than 2 years using an optimized dosing strategy for voriconazole that incorporates intensive therapeutic drug monitoring (TDM). DESIGN: Case series. SETTING: Large pediatric hospital. PATIENTS: Three patients younger than 2 years who received voriconazole therapy and had serum trough concentrations measured between January 1, 2010, and October 31, 2015. MEASUREMENTS AND MAIN RESULTS: A clinical practice guideline developed at our institution was used to standardize initial dosing, appropriate use and timing of TDM, and dosage modifications based on TDM. TDM was used to guide dosing to achieve a target voriconazole serum trough concentration of 2-6 µg/ml. Voriconazole samples were assayed by using a high-performance liquid chromatography analytical method with solid-phase extraction. Initial dosages for the three patients were 9 mg/kg intravenously every 12 hours (one patient) and 9 mg/kg enterally twice/day (two patients). Multiple dose escalations and a more frequent dosing interval were required to achieve trough concentrations within the target range. The final dosages were 12 mg/kg intravenously every 8 hours, 17.7 mg/kg enterally 3 times/day, and 8.5 mg/kg enterally 3 times/day, respectively. In addition to voriconazole trough concentrations, TDM included evaluations for drug toxicities. Visual, neurologic, or hepatic adverse effects were not encountered in the three patients. CONCLUSION: Our data support higher initial doses and perhaps a 3 times/day dosing schedule to achieve voriconazole serum concentrations in the target range for children younger than 2 years. Implementation of a clinical practice guideline with the participation of pharmacists specializing in pharmacokinetics allows for effective use of voriconazole in young children.

Implementation of American Academy of Pediatrics guidelines for palivizumab prophylaxis in a pediatric hospital.

PURPOSE: One hospital's implementation of revised American Academy of Pediatrics (AAP) guidelines for palivizumab prophylaxis of respiratory syncytial virus (RSV) infection is described. METHODS: Revised AAP guidelines for RSV prophylaxis in infants and young children at increased risk for RSV infection recommend that up to five doses of palivizumab be administered during the RSV season. The guidelines also recommend that inpatients not receive monthly palivizumab prophylaxis and that infants and young children eligible for prophylaxis during the RSV season receive a dose of palivizumab two or three days before discharge or promptly after discharge. To ensure compliance with the revised AAP guidelines, a 296-bed hospital implemented a quality-improvement project including (1) efforts by the antimicrobial stewardship pharmacist and the chief medical officer to notify and educate healthcare providers regarding institutional adoption of the guidelines, (2) reinforcement of guideline adherence by clinical pharmacists during daily bedside rounds and via prospective review of all palivizumab orders, and (3) a medication-use evaluation (MUE) to assess adherence to the guidelines. The MUE results showed that during the 2014-15 RSV season (after implementation of the practice changes), the number of palivizumab doses administered at the hospital declined by 56% from the previous RSV season, with 97% of doses administered for appropriate indications. CONCLUSION: Standardized, comprehensive guidelines with defined criteria for palivizumab prophylaxis of RSV infection resulted in $303,227 of cost savings without a discernible change in nosocomial transmission, or morbidity, or mortality. Hospital infection-control practices controlled nosocomial RSV transmission.