Abstract Background Severe COVID-19 can manifest in rapid decompensation and respiratory failure with elevated inflammatory markers, consistent with cytokine release syndrome for which IL-6 blockade is approved treatment. Methods We assessed effectiveness and safety of IL-6 blockade with tocilizumab in a single-center cohort of patients with COVID-19 requiring mechanical ventilation. The primary endpoint was survival probability post-intubation; secondary analyses included an ordinal illness severity scale integrating superinfections. Outcomes in patients who received tocilizumab compared to tocilizumab-untreated controls were evaluated using multivariable Cox regression with propensity score inverse probability weighting (IPTW). Results 154 patients were included, of whom 78 received tocilizumab and 76 did not. Median follow-up was 47 days (range 28-67). Baseline characteristics were similar between groups, although tocilizumab-treated patients were younger (mean 55 vs. 60 years), less likely to have chronic pulmonary disease (10% vs. 28%), and had lower D-dimer values at time of intubation (median 2.4 vs. 6.5 mg/dL). In IPTW-adjusted models, tocilizumab was associated with a 45% reduction in hazard of death [hazard ratio 0.55 (95% CI 0.33, 0.90)] and improved status on the ordinal outcome scale [odds ratio per 1-level increase: 0.58 (0.36, 0.94)]. Though tocilizumab was associated with an increased proportion of patients with superinfections (54% vs. 26%; p<0.001), there was no difference in 28-day case fatality rate among tocilizumab-treated patients with versus without superinfection [22% vs. 15%; p=0.42]. Staphylococcus aureus accounted for ~50% of bacterial pneumonia. Conclusions In this cohort of mechanically ventilated COVID-19 patients, tocilizumab was associated with lower mortality despite higher superinfection occurrence.

Background Although coronavirus disease 2019 (COVID-19) is mild in nearly all children, a small proportion of pediatric patients develop severe or critical illness. Guidance is therefore needed regarding use of agents with potential activity against severe acute respiratory syndrome coronavirus 2 in pediatrics. Methods A panel of pediatric infectious diseases physicians and pharmacists from 18 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of best available evidence and expert opinion. Results Given the typically mild course of pediatric COVID-19, supportive care alone is suggested for the overwhelming majority of cases. The panel suggests a decision-making framework for antiviral therapy that weighs risks and benefits based on disease severity as indicated by respiratory support needs, with consideration on a case-by-case basis of potential pediatric risk factors for disease progression. If an antiviral is used, the panel suggests remdesivir as the preferred agent. Hydroxychloroquine could be considered for patients who are not candidates for remdesivir or when remdesivir is not available. Antivirals should preferably be used as part of a clinical trial if available. Conclusions Antiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For those rare cases of severe or critical disease, this guidance offers an approach for decision-making regarding antivirals, informed by available data. As evidence continues to evolve rapidly, the need for updates to the guidance is anticipated.

Background Severe COVID-19 can manifest in rapid decompensation and respiratory failure with elevated inflammatory markers. This presentation is consistent with cytokine release syndrome in chimeric antigen receptor T cell therapy, for which IL-6 blockade is approved treatment. Methods We assessed effectiveness and safety of IL-6 blockade with tocilizumab in a single-center cohort of patients with COVID-19 requiring mechanical ventilation. The primary endpoint was survival probability post-intubation; secondary analyses included an ordinal illness severity scale integrating superinfections. Outcomes in patients who received tocilizumab compared to tocilizumab-untreated controls were evaluated using multivariable Cox regression with propensity score inverse probability weighting (IPTW). Findings 154 patients were included, of whom 78 received tocilizumab and 76 did not. Median follow-up was 47 days (range 28-67). Baseline characteristics were similar between groups, although tocilizumab-treated patients were younger (mean 55 vs. 60 years), less likely to have chronic pulmonary disease (10% vs. 28%), and had lower D-dimer values at time of intubation (median 2.4 vs. 6.5 mg/dL). In IPTW-adjusted models, tocilizumab was associated with a 45% reduction in hazard of death [hazard ratio 0.55 (95% CI 0.33, 0.90)] and improved status on the ordinal outcome scale [odds ratio per 1-level increase: 0.59 (0.36, 0.95)]. Though tocilizumab was associated with an increased proportion of patients with superinfections (54% vs. 26%; p<0.001), there was no difference in 28-day case fatality rate among tocilizumab-treated patients with versus without superinfection [22% vs. 15%; p=0.42]. Interpretation In this cohort of mechanically ventilated COVID-19 patients, tocilizumab was associated with a decreased likelihood of death despite higher superinfection occurrence. Randomized controlled trials are urgently needed to confirm these findings.

Background Although Coronavirus Disease 2019 (COVID-19) is a mild infection in most children, a small proportion develop severe or critical illness. Data evaluating agents with potential antiviral activity continue to expand, such that updated guidance is needed regarding use of these agents in children. Methods A panel of pediatric infectious diseases physicians and pharmacists from 20 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of the best available evidence and expert opinion. Results Given the typically mild course of COVID-19 in children, supportive care alone is suggested for most cases. For children with severe illness, defined as a supplemental oxygen requirement without need for non-invasive or invasive mechanical ventilation or extra-corporeal membrane oxygenation (ECMO), remdesivir is suggested, preferably as part of a clinical trial if available. Remdesivir should also be considered for critically ill children requiring invasive or non-invasive mechanical ventilation or ECMO. A duration of 5 days is appropriate for most patients. The panel recommends against the use of hydroxychloroquine or lopinavir-ritonavir (or other protease inhibitors) for COVID-19 in children. Conclusions Antiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For children with severe or critical disease, this guidance offers an approach for decision-making regarding use of remdesivir.

OBJECTIVESPatients supported on extracorporeal membrane oxygenation (ECMO) have an increased incidence of seizures. Phenobarbital (PB) and fosphenytoin (fos-PHT) are common antiepileptic drugs (AEDs) used to manage seizures in the pediatric population; however, it is unknown what effect ECMO has on the serum concentrations of AEDs. The purpose of this study is to evaluate the effect of ECMO on AED serum concentrations.METHODS A retrospective, matched-cohort study was performed in patients younger than 18 years who received ECMO and were treated with intravenous (IV) PB or fos-PHT at Texas Children's Hospital between 2004 and 2014. Patients receiving IV AED therapy and ECMO were matched, based on age, sex, and weight, with patients receiving IV AED therapy without ECMO. The 24-hour cumulative AED dose, serum concentrations, number of doses per serum concentration drawn ratio, volume of distribution, therapeutic serum concentrations, and time to therapeutic serum concentration were compared between both groups. The fos-PHT and PB groups were analyzed in all patients and in neonates only. CONCLUSION Pediatric patients receiving PB on ECMO and neonatal patients receiving fos-PHT on ECMO required larger doses, and in pediatric patients achieved lower serum concentrations, suggesting the necessity for alternative dosing strategies in these populations.

Objective: To evaluate whether incorporating mandatory prior authorization for Clostridioides difficile testing into antimicrobial stewardship pharmacist workflow could reduce testing in patients with alternative etiologies for diarrhea. Design: Single center, quasi-experimental before-and-after study. Setting: Tertiary-care, academic medical center in Ann Arbor, Michigan. Patients: Adult and pediatric patients admitted between September 11, 2019 and December 10, 2019 were included if they had an order placed for 1 of the following: (1) C. difficile enzyme immunoassay (EIA) in patients hospitalized >72 hours and received laxatives, oral contrast, or initiated tube feeds within the prior 48 hours, (2) repeat molecular multiplex gastrointestinal pathogen panel (GIPAN) testing, or (3) GIPAN testing in patients hospitalized >72 hours. Intervention: A best-practice alert prompting prior authorization by the antimicrobial stewardship program (ASP) for EIA or GIPAN testing was implemented. Approval required the provider to page the ASP pharmacist and discuss rationale for testing. The provider could not proceed with the order if ASP approval was not obtained. Results: An average of 2.5 requests per day were received over the 3-month intervention period. The weekly rate of EIA and GIPAN orders per 1,000 patient days decreased significantly from 6.05 ± 0.94 to 4.87 ± 0.78 (IRR, 0.72; 95% CI, 0.56–0.93; P = .010) and from 1.72 ± 0.37 to 0.89 ± 0.29 (IRR, 0.53; 95% CI, 0.37–0.77; P = .001), respectively. Conclusions: We identified an efficient, effective C. difficile and GIPAN diagnostic stewardship approval model.

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Background Infectious diseases (ID) consultation and optimal antibiotic therapy improve outcomes in Staphylococcus aureus bacteremia (SAB). Data on strategies to improve adherence to these practices in children are limited. Methods This was a quasi-experimental study evaluating the impact of an electronic medical record (EMR)–based best practice advisory (BPA) for SAB, recommending ID consult and optimal antibiotic therapy based on rapid mecA gene detection. Inpatients &lt; 21 years old with SAB before (January 2015–July 2017) and after (August 2017–December 2018) BPA implementation were included. Primary outcome was receipt of ID consult. Secondary outcomes included receipt of optimal therapy, time to ID consult and optimal therapy, recurrent SAB, and 30-day all-cause mortality. ID consultation rates pre- and postimplementation were compared using interrupted time series (ITS) analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) for time to optimal therapy were calculated using Cox regression. Results We included 99 SAB episodes (70 preintervention, 29 postintervention). Preintervention, 48 (68.6%) patients received an ID consult compared to 27 (93.1%) postintervention, but this was not statistically significant on ITS analysis due to a preexisting trend of increasing consultation. Median hours to optimal therapy decreased from 26.1 to 5.5 (P = .03), most notably in patients with methicillin-sensitive S. aureus (MSSA) (42.2 to 10.8; P &lt; .01). On Cox regression, BPA implementation was associated with faster time to optimal therapy (HR, 3.22 [95% CI, 1.04–10.01]). Conclusions Implementation of an EMR-based BPA for SAB resulted in faster time to optimal antibiotic therapy, particularly for patients with MSSA. ID consultation increased throughout the study period and was not significantly impacted by the BPA.