What is known and objective: Epstein-Barr virus (EBV) viraemia and autoimmune cytopenias (AICs) are significant complications that occur following paediatric solid organ transplantation. A variety of treatment methods have been investigated but limited research has focused on the utilization of rituximab in paediatric cardiac transplant recipients for these indications. Rituximab is a monoclonal antibody that binds the CD20 antigen on the surface of B-type lymphocytes resulting in B-cell cytotoxicity. It is considered a second-line therapy for treatment of autoimmune cytopenias and EBV viraemia following adult solid organ transplant (SOT) and haematopoietic stem cell transplant (HSCT). However, data for its use in the paediatric population for treatment of autoimmune cytopenias are lacking. Dosing is based on adult studies, and the frequency and length of therapy associated with resolution of EVB viraemia and AICs in paediatric cardiac transplant recipients is unknown. The objective of this retrospective study was to describe the dosing and length of therapy of expanded off-label use of rituximab for the management of refractory EBV viraemia and AICs, specifically in paediatric cardiac transplant patients.Methods: A retrospective chart review was conducted evaluating children <18 years of age who underwent cardiac transplantation, were diagnosed with EBV viraemia or autoimmune cytopenia, and subsequently received treatment with rituximab between June 1995 and October 2018. Data were analysed descriptively.Results and discussion: Of all (n = 188) paediatric cardiac transplant recipients since 1995, 10 patients met the inclusion/exclusion criteria. Primary diagnoses were EBV viraemia (n = 6), immune haemolytic anaemia (n = 3) and immune thrombocytopenic purpura (n = 1). Complete responses were observed in 83.3% and 100% of patients with EVB viraemia and AICs treated with rituximab, respectively. All patients (n = 10) received rituximab 325 mg/m 2 at weekly intervals. The number of total doses associated with complete resolution was 4-6 doses for EBV viraemia and 2-4 doses for AICs. The most common adverse events reported were neutropenia (n = 3), thrombocytopenia (n = 4), infusion reactions (n = 1) and significant anaemia (n = 2). What is new and conclusion:Although the efficacy of rituximab for treatment of EBV viraemia and autoimmune cytopenia in the paediatric cardiac transplant population How to cite this article: Kiskaddon AL, Landmesser K, Carapellucci J, Wisotzkey B, Asante-Korang A. Expanded utilization of rituximab in paediatric cardiac transplant patients.

Objectives The primary objective of this study was to compare the therapeutic predictive value of area under the curve (AUC24) versus maximum concentration (Cmax) in cystic fibrosis (CF) patients receiving intravenous (IV) tobramycin for a Pseudomonas aeruginosa (PsA) acute pulmonary exacerbation (APE). Acute kidney injury (AKI) incidence and the relationship between time undetectable and efficacy were also assessed. Methods A retrospective review was conducted in patients aged at least 1 month with a diagnosis of CF receiving IV tobramycin for treatment of a PsA APE and admitted to the University of Kentucky between August 2015 and August 2019. Patients were excluded if they had no growth of PsA on sputum culture or if two postdose tobramycin levels were not obtained following a dose adjustment of ≥20%. Results A total of 44 pediatric and 107 adult patient encounters met inclusion criteria. In patients with therapeutic success (n = 91), 75.8% had an AUC24 ≥80% and 80.3% had a Cmax ≥8 times the highest PsA minimal inhibitory concentration. There was a significant correlation between AUC24 and Cmax (r[149] = 0.727; p < 0.001). AKI incidence was significantly higher in patients receiving IV tobramycin dosed multiple times daily versus at least every 24 h (χ2[1, 151] = 3.9; p =  0.047). Conclusions The results of this study indicate that both AUC24 and Cmax serve as relatively accurate predictors of tobramycin efficacy. Additionally, given the significant increase in incidence of AKI, multidaily dosing of IV tobramycin should be avoided in pediatric and adult patients with CF.

OBJECTIVES: The primary objective of this study was to compare the therapeutic predictive value of area under the curve (AUC24) versus maximum concentration (Cmax) in cystic fibrosis (CF) patients receiving intravenous (IV) tobramycin for a Pseudomonas aeruginosa (PsA) acute pulmonary exacerbation (APE). Acute kidney injury (AKI) incidence and the relationship between time undetectable and efficacy were also assessed. METHODS: A retrospective review was conducted in patients aged at least one month with a diagnosis of CF receiving IV tobramycin for treatment of a PsA APE and admitted to the University of Kentucky between August 2015 and August 2019 . Patients were excluded if they had no growth of PsA on sputum culture or if two post-dose tobramycin levels were not obtained following a dose adjustment of ≥20%. RESULTS: A total of 44 pediatric and 107 adult patient encounters met inclusion criteria. In patients with therapeutic success (n=91), 75.8% had an AUC24 ≥80 and 80.3% had a Cmax ≥8 times the highest PsA minimal inhibitory concentration (MIC). There was a significant correlation between AUC24 and Cmax (r2 = 0.727; p<0.001). AKI incidence was significantly higher in patients receiving IV tobramycin dosed multiple times daily versus at least every 24 hours (50% versus 28.7%; p=0.047). CONCLUSIONS: The results of this study indicate that both AUC24 and Cmax serve as relatively accurate predictors of tobramycin efficacy. Additionally, given the significant increase in incidence of AKI, multi-daily dosing of IV tobramycin should be used only in select pediatric and adult patients with CF.

Background: Despite the development of new β-lactam agents, gram-negative resistance continues to be an increasing concern in the healthcare setting. The understanding and optimizing antimicrobial pharmacokinetics and pharmacodynamics are essential to enhance activity of appropriate therapy, improve clinical outcomes, and reduce the development of resistance. Methods: A pharmacodynamic analysis was performed for 4 β-lactams (aztreonam, cefepime, piperacillin/tazobactam, and meropenem) and 14 dosage regimens as either intermittent bolus (IB) or prolonged infusion (PI) against 7 gram-negative pathogens: Klebsiella pneumoniae, K. oxytoca, Escherichia coli, Enterobacter cloacae, E. aerogenes, Acinetobacter baumannii, and Pseudomonas aeruginosa. Unit-specific minimum inhibitory concentration (MIC) distribution data were generated using antibiogram data over a decade for 4 intensive care units within our institution: medical ICU, cardiovascular ICU, surgical ICU, and neurosurgical ICU. Published pharmacokinetic parameter estimates in critically ill patients, combined with this MIC distribution data, were utilized to perform Monte Carlo simulations for each antimicrobial regimen. The percentage of time for which the unbound concentration of antibiotic remained above the MIC (ƒT>MIC) was utilized as the pharmacodynamic target for each agent: 40% ƒT>MIC for meropenem, 50% ƒT>MIC for piperacillin/tazobactam, 60% ƒT>MIC for aztreonam, and 70% ƒT>MIC for cefepime. Regimens were modeled using Oracle Crystal Ball software to determine the likelihood of achieving >90% probability of target attainment (PTA). Because resistance rates were significantly higher for P. aeruginosa and A. baumannii, cumulative PTAs for K. pneumoniae, K. oxytoca, E. coli, E. cloacae, and E. aerogenes were analyzed separately to determine the relative PTA for Enterobacterales in each ICU. Results: No intermittent infusion regimens of piperacillin/tazobactam, aztreonam, or cefepime achieved >90% PTA for any organism. Piperacillin/tazobactam 4.5 g infused over 4 hours (PI q6h) and aztreonam 2 g PI q6h failed to achieve adequate PTA for Enterobacterales with only 84% and 85% PTA, respectively. For Enterobacterales, the only regimens to achieve >90% PTA included cefepime 2 g infused over 3 hours (PI q8h) and meropenem 1g IB q8h with 95% and 99% PTA, respectively. Meropenem 2 g PI q8h was the only regimen capable of achieving >90% PTA for both A. baumannii and P. aeruginosa with 97% and 92% PTA, respectively. Conclusions: Although utilization of high doses and prolonged infusions dramatically improve the pharmacodynamics of β-lactam therapy, the only regimen capable of achieving adequate PTA for all organisms analyzed was meropenem 2g PI q8h. To reduce carbapenem use, combination therapy may be considered for critically ill patients receiving aztreonam, cefepime, or piperacillin/tazobactam for empiric treatment of gram-negative infections.Funding: NoDisclosures: None

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