Levofloxacin prophylaxis for pediatric leukemia patients: Longitudinal follow-up for impact on health care-associated infections.

BACKGROUND: Bloodstream infections (BSIs) cause morbidity and mortality in pediatric patients with leukemia. Antibiotic prophylaxis during periods of chemotherapy-induced neutropenia may reduce the incidence of BSIs. PROCEDURE: A levofloxacin prophylaxis guideline was implemented for pediatric patients with acute myeloid leukemia and relapsed acute lymphoblastic leukemia. We conducted a retrospective cohort study over 4 years (2 years pre and 2 years post implementation) of the practice guideline to assess the impact on central line-associated bloodstream infections (CLABSI) and BSI events. Secondary outcomes included incidence of Clostridioides difficile-associated diarrhea, bacteremia due to multidrug-resistant organisms (MDRO), and bacteremia due to levofloxacin nonsusceptible organisms. STATA was used for data analysis. RESULTS: Sixty-three and 72 patients met inclusion criteria for the pre- and postimplementation cohorts, respectively. Demographics were similar between the groups. We observed 60 BSI events in the pre-group versus 49 events in the post-group (p = .1). Bacteremia due to Gram-negative rods (risk ratio [RR] 0.37 [0.21, 0.66], p < .001) and National Healthcare Safety Network (NHSN) CLABSIs (RR 0.62 [0.44, 0.89], p = .01) were significantly reduced in the postimplementation group. The incidences of C. difficile-associated diarrhea and MDRO bacteremia were similar between groups. However, we observed an increase in the incidence of BSI due to Gram-negative rods that were nonsusceptible to levofloxacin (RR 3.38 [0.72, 6.65], p < .001). CONCLUSION: Following implementation of a levofloxacin prophylaxis guideline, we observed a significant decrease in BSIs due to Gram-negative rods and NHSN CLABSIs. Vigilant monitoring of outcomes post guideline implementation is critical to track emergence of resistant organisms.

Investigating Potential Drug-Drug Interactions in Pediatric and Adolescent Patients Receiving Chemotherapy.

INTRODUCTION: Pediatric and adolescent oncology patients admitted to receive chemotherapy are at risk for drug-drug interactions (DDI). While adult literature has quoted this risk to be as high as 95% of encounters, the literature in pediatrics is limited. This is a single-center, retrospective chart review of DDI in hospitalized pediatric oncology patients. METHODS: All patients admitted to Texas Children's Hospital for chemotherapy were included. Medications ordered during the hospitalization were evaluated by Lexicomp® Drug Interactions Tool. Interactions classified as D or X or interactions rated a C including a chemotherapeutic agent were independently reviewed by three clinicians for clinical relevance. Medications associated with central nervous system (CNS) depression or QTc prolongation were counted separately. RESULTS: Of 100 admissions evaluated, 100% had a flagged interaction. There were a total of 12 X-rated interactions, 8 D-rated interactions, and 12 C-rated interactions with a chemotherapeutic agent found to be clinically relevant. Thirty-three percent of admissions had 4 or more QTc prolonging medications ordered. Twenty-four percent of admissions had 3 or more prescribed CNS depressants. In total 49% of admissions were found to have at least 1 clinically-significant DDI. CONCLUSIONS: This study exemplifies the risk of drug-drug interactions in children and young adults admitted to the hospital for chemotherapy. We demonstrated a high rate of flagged interactions with about half of admissions found to have a potentially clinically-significant DDI. Concomitant use of multiple QTc prolonging and CNS depressant medications was also prevalent, indicating a need to evaluate monitoring practices.

Activation of 6-Alkoxy-Substituted Methylenecyclopropane Nucleoside Analogs Requires Enzymatic Modification by Adenosine Deaminase-Like Protein 1.

To determine the mechanism of action of third-generation methylenecyclopropane nucleoside analogs (MCPNAs), DNA sequencing of herpes simplex virus 1 (HSV-1) isolates resistant to third-generation MCPNAs resulted in the discovery of G841S and N815S mutations in HSV-1 UL30. Purified HSV-1 UL30 or human cytomegalovirus (HCMV) UL54 was then subjected to increasing concentrations of MBX-2168-triphosphate (TP), with results demonstrating a 50% inhibitory concentration (IC50) of ∼200 µM, indicating that MBX-2168-TP does not inhibit the viral DNA polymerase. Further metabolic studies showed the removal of a moiety on the guanine ring of MBX-2168. Therefore, we hypothesized that enzymatic removal of a moiety at the 6-position of the guanine ring of third-generation MCPNAs is an essential step in activation. To test this hypothesis, pentostatin (deoxycoformycin [dCF]), an adenosine deaminase-like protein 1 (ADAL-1) inhibitor, was coincubated with MBX-2168. The results showed that dCF antagonized the effect of MBX-2168, with a >40-fold increase in the 50% effective concentration (EC50) at 50 µM dCF (EC50 of 63.1 ± 8.7 µM), compared with MBX-2168 alone (EC50 of 0.2 ± 0.1 µM). Purified ADAL-1 demonstrated time-dependent removal of the moiety on the guanine ring of MBX-2168-monophosphate (MP), with a Km of 17.5 ± 2.4 µM and a Vmax of 0.12 ± 0.04 nmol min-1 Finally, synguanol-TP demonstrated concentration-dependent inhibition of HSV-1 UL30 and HCMV UL54, with IC50s of 0.33 ± 0.16 and 0.38 ± 0.11 µM, respectively. We conclude that ADAL-1 is the enzyme responsible for removing the moiety from the guanine ring of MBX-2168-MP prior to conversion to a TP, the active compound that inhibits the viral DNA polymerase.

Levofloxacin prophylaxis for pediatric leukemia patients: monitoring of outcomes for sustained benefit and consequences.

Levofloxacin prophylaxis reduces bloodstream infections in neutropenic patients with acute myeloid leukemia or relapsed acute lymphoblastic leukemia. A retrospective, longitudinal cohort study compares incidence of bacteremia, multidrug-resistant organisms (MDRO), and Clostridioides difficile (CDI) between time periods of levofloxacin prophylaxis implementation. Benefits were sustained without increasing MDRO or CDI.

Pharmacist-Led Discharge Transitions of Care Interventions for Pediatric Patients: A Narrative Review.

Transitions of care (TOC) before, during, and after hospital discharge are an opportune setting to optimize medication management. The quality standards for pediatric care transitions, however, are lacking, leading to reduced health outcomes in children. This narrative review characterizes the pediatric populations that would benefit from focused, TOC interventions. Different types of medication-focused TOC interventions during hospital discharge are described, including medication reconciliation, education, access, and adherence tools. Various TOC intervention delivery models following hospital discharge are also reviewed. The goal of this narrative review is to help pediatric pharmacists and pharmacy leaders better understand TOC interventions and integrate them into the hospital discharge process for children and their caregivers.

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.

Severe Pediatric COVID-19 Pneumonia Treated With Adjuvant Anakinra.

BACKGROUND AND OBJECTIVES: To compare previous hemophagocytic lymphohistiocytosis criteria with adult coronavirus disease 2019 (COVID-19)-associated hyperinflammatory syndrome (cHIS) criteria for the diagnosis of hyperinflammation in pediatric patients with COVID-19. The secondary objective was to assess treatment response to intravenous (IV) anakinra in these patients. METHODS: This case series included children admitted to the PICU for COVID-19 pneumonia with hyperinflammation and treated with IV anakinra between July 2020 to April 2021. Hyperinflammatory criteria were determined for each patient. Clinical course, chest imaging, and inflammatory marker trends were assessed pre- and post-anakinra treatment. RESULTS: All patients had a cHIS criteria score of ≥5. Two patients met 2004-hemophagocytic lymphohistiocytosis criteria. Only the patient that required extracorporeal membrane oxygenation met the H-Score cut-off value. All but one patient had a decrease in their inflammatory markers and improvement in clinical status with early initiation of adjunctive IV anakinra. CONCLUSIONS: In this case series, adult cHIS criteria were successfully used to identify pediatric COVID-19 patients with hyperinflammation. Ferritin levels decreased after the early initiation of IV anakinra.

Methadone for Cancer Pain in Pediatric End-of-Life Care.

BACKGROUND: The goal of adequate pain control becomes increasingly salient for children with cancer and their families as the patients approach the end of life. Methadone is one option that is particularly desirable in end-of-life care given its long duration of action and NMDA antagonism that may help in controlling pain refractory to conventional opioids. The purpose of this study was to describe a single institution's experience with methadone for the treatment of cancer pain in pediatric end-of-life care. METHODS: This retrospective, observational, single-center study included all patients during a 9-year period who died in the inpatient setting and were receiving methadone in their last 30 days of life. RESULTS: Twenty patients were identified, 18 (90%) of whom received methadone for nociceptive pain. The median duration of methadone use was 32 days (range 2-323 days). Methadone doses ranged from 0.09 to 7.76 mg/kg per day. There were no instances of discontinuing methadone due to an increased QTc interval. No episodes of torsades de pointes were observed. CONCLUSION: In patients with pediatric cancer who are nearing the end of life, methadone is a valuable adjunctive therapy to treat nociceptive and neuropathic pain and to prevent opioid-induced hyperalgesia and opioid tolerance. An individualized approach to dosage and route should be considered based on specific clinical circumstances.

Lidocaine Infusions for Pain Management in Pediatrics.

Lidocaine is an amino amide with a well-established role as a local anesthetic agent. Systemic intravenous administration expands its clinical use to include acute and chronic pain circumstances, such as postoperative pain, neuropathic pain, postherpetic neuralgia, hyperalgesia, visceral pain, and centrally mediated pain. For refractory pain that has not responded to conventional therapy or if further escalation of treatment is prevented by contraindications or side effects to standard therapies, a continuous infusion of lidocaine may be considered as a single intervention or as a sequence of infusions. Here, we review and evaluate published data reflecting the use of lidocaine continuous infusions for pain management in the pediatric population.

Evaluation of Aminophylline for the Treatment of Acute Kidney Injury in Pediatric Hematology/Oncology Patients.

OBJECTIVE: The purpose of this study was to compare acute kidney injury (AKI)-related outcomes of patients who received aminophylline in addition to standard of care with matched historical controls who received standard of care alone. METHODS: This was a single center, retrospective, historical control cohort study that included patients treated for AKI. Patients who received aminophylline from January 2017 to June 2018 were matched for age, sex, primary diagnosis, and hematopoietic cell transplant history in a 1:2 ratio to historical controls treated for AKI from July 2015 to September 2016. The primary outcome was improvement in AKI stage at 5 and 10 days from treatment initiation. RESULTS: Twenty-seven patients who received aminophylline were matched to 54 historical controls. Fifty-eight patients (72%) had recently undergone hematopoietic cell transplant. At day 5, improvement in AKI stage was observed in 56% of patients in each group (p = 1.0); at day 10, improvement in AKI stage was observed in 75% of patients in the aminophylline group vs 70% of historical controls (p = 0.76). By day 10, serum creatinine levels had returned to baseline in 21% of patients in the aminophylline group and 34% of patients in the control group (p = 0.37). CONCLUSIONS: Findings of this study demonstrated no difference in the rate of AKI resolution or in the proportion of patients with resolved AKI when aminophylline was added to standard of care for the treatment of AKI in this pediatric hematology/oncology population.

Biosynthesis and half-life of MBX-2168-triphosphate in herpes virus-infected cells.

The third generation of methylenecyclopropane nucleoside analogs (MCPNAs) elicit an anti-viral effect against all three sub-classes of herpes viruses without inducing cytotoxicity in vitro. It has been previously established that the mechanism of action of MCPNAs is similar to that of ganciclovir (GCV) or acyclovir (ACV). However, the activation of MBX-2168, a third generation MCPNA, involves additional and unique enzymatic steps and this process has not been examined in virus-infected cells. To that end, herpes virus-infected cells were incubated with MBX-2168, synguanol, GCV, or ACV. Incubation of HCMV-infected cells with five times the EC50 of MBX-2168 (4.0 µM), synguanol (10.5 µM), or GCV (25 µM) resulted in a time-dependent increase in triphosphate accumulation reaching a maximum of 48.1 ± 5.5, 45.5 ± 2.5, and 42.6 ± 3.7 pmol/106 cells at 120 h, respectively. Additionally, half-lives of these compounds were similar in HCMV-infected cells (GCV-TP = 25.5 ± 2.7 h; MBX-2168-TP/synguanol-TP = 23.0 ± 1.4 h). HSV-1-infected cells incubated with five times the EC50 of MBX-2168 (33.5 µM) or ACV (5.0 µM) demonstrated a time-dependent increase in triphosphate levels reaching a maximum of 12.3 ± 1.5 and 11.6 ± 0.7 pmol/106 cells at 24 h, respectively. ACV-TP and MBX-2168-TP also had similar half-lives under these conditions (27.3 ± 4.8 h and 22.2 ± 2.2 h, respectively). We therefore conclude that although MBX-2168 does not follow the classical route of nucleoside analog activation, the metabolic profile of MBX-2168 is similar to other nucleoside analogs such as GCV and ACV that do.