Abstract Corresponding Author Parichehr Shoureshi, PharmD, Department of Pharmacy, St. Jude Children’s Research Hospital, 262, Danny Thomas Place, Memphis, TN 38105, USA, (301) 395-6226, parichehr.shoureshi@stjude.org Funding No external funding to report. Conflict(s) of Interest All authors report no conflicts of interest. Background Meropenem, a broad-spectrum β-lactam antibiotic, is frequently used in immunocompromised pediatric patients with serious Gram-negative infections. Pediatric meropenem pharmacokinetics are highly variable and influenced by age, renal function, and critical illness, which may result in subtherapeutic or supratherapeutic exposures despite standard dosing. Published data in critically ill children suggest that conventional intermittent infusions may not reliably achieve pharmacodynamic targets. This project evaluated implementation of meropenem therapeutic drug monitoring (TDM) to assess pharmacokinetic/pharmacodynamic (PK/PD) target attainment in an immunocompromised pediatric population at a single specialty center. Methods This prospective, single-center quality improvement project was conducted from August 2025 to April 2026. Pediatric patients receiving meropenem were screened for TDM eligibility. Criteria were initially limited to ICU patients and, beginning February 23, 2026, were expanded to include floor patients with known extended-spectrum β-lactamase-producing organisms, Bacillus cereus, or Infectious Diseases consult service determination that meropenem TDM was indicated. PK/PD target attainment was defined as free meropenem concentrations above the minimum inhibitory concentration for 100% of the dosing interval. Collected variables included demographics, baseline clinical characteristics, renal function, infection details, meropenem dosing regimens, sampling timing, TDM results, and TDM-related recommendations. Process measures included TDM uptake, sampling appropriateness, turnaround time, and pharmacy documentation. Outcomes included PK/PD target attainment and TDM-guided dose modification. Continuous variables were summarized as mean ± standard deviation or median [range], as appropriate, and categorical variables as frequencies and percentages. Results A total of 87 meropenem courses were screened, of which 34 met inclusion criteria; 25 were ICU courses and 9 met criteria after expansion to floor patients. TDM was performed in 9 of 34 courses (26%). The most common barrier to TDM completion was send-out laboratory availability outside business hours (75%). Among courses with TDM performed, end-of-infusion and trough samples were appropriately collected in 9 of 9 courses (100%), while midpoint sampling was appropriate in 8 of 9 courses (89%). TDM results were available by the next business day and clinical pharmacy specialist documentation was completed within 24 hours of result availability in 9 of 9 courses (100%). Seven of 9 courses (78%) achieved the PK/PD target of 100% fT>MIC with standard meropenem dosing; the remaining 2 courses achieved high 80%–90% fT>MIC exposures. No TDM-guided dose adjustments were required, and all trough concentrations remained below the predefined safety threshold. Conclusions Prospective implementation identified meropenem TDM opportunities limited primarily by send-out laboratory business hours, with barriers decreasing after in-house meropenem TDM implementation. Expansion of eligibility criteria to floor patients identified additional missed TDM opportunities, supporting continued pharmacy and medical team education regarding TDM candidacy. Most TDM- evaluated meropenem courses achieved the PK/PD target of 100% fT>MIC with standard dosing. Remaining courses demonstrated near-target exposures, and dose adjustment was not required given clinical stability or improvement.

BACKGROUND:Prophylactic administration of oral third-generation cephalosporins, administered prior to and concurrently with irinotecan, reduces dose-limiting diarrhea and allows higher irinotecan dosing in pediatric patients. The Children's Oncology Group recommends a 10-day cefixime regimen, beginning 2 days prior to irinotecan, continuing throughout the 5-day irinotecan course, and concluding 3 days afterward. Despite its efficacy, compliance with this regimen presents significant logistical challenges. To address these challenges, a multidisciplinary team at St. Jude Children's Research Hospital instituted a standardized 5-day prophylactic regimen in patients receiving irinotecan. This study compared the incidence of severe diarrhea during the first course of irinotecan before and after the implementation of a shortened 5-day course of cefixime. PROCEDURE:A single-center retrospective cohort study was performed for patients who received a 5-day course of irinotecan during the 12 months before and 18 months after implementation of a shortened cefixime prophylaxis regimen. The primary outcome was the incidence of severe diarrhea. Secondary outcomes included provider ordering compliance with prophylactic antibiotic recommendations, the duration of prophylactic antibiotics, and the incidence of Clostridioides difficile infections or ceftriaxone-resistant gram-negative bacterial infections. RESULTS:Data were collected for 85 participants (35 pre-implementation and 50 in the post-implementation period), representing a total of 432 irinotecan courses. Eighty-two percent of courses included intravenous irinotecan. The incidence of severe diarrhea was 5.4% in the pre- and 6.2% in the post-implementation period (p = 0.7255). Provider ordering compliance with the institutional standard improved from 7.2% to 68.4% (p < 0.0001). Three patients developed a C. difficile infection, while no patients developed a microbiologically documented ceftriaxone-resistant gram-negative bacterial infection. CONCLUSIONS:A 5-day course of prophylactic cefixime, starting on the day of irinotecan initiation, was safe, increased provider ordering compliance, and did not lead to increased irinotecan toxicity.

Therapeutic drug monitoring (TDM) is used to optimize drug therapy by ensuring efficacy or preventing toxicity. For a limited number of cytotoxic antineoplastic drugs, for aminoglycoside antibiotics, and for vancomycin the use of TDM is common practice. In this article, we summarize recent advances and indications for the TDM of antineoplastic agents in children, focusing on protein kinase inhibitors and the cytotoxic drug fludarabine. We also summarize recent recommendations for antimicrobial TDM of beta-lactam antibiotics and vancomycin.

Accurate assessment of renal function is essential in treating pediatric patients dosed with nephrotoxic chemotherapy. The validity of the bedside Schwartz, 5-covariate St. Jude (5SJ), CKiD-CysC-U25, combined Cr-CysC-based CysPed, and the serum creatinine-BUN-cystatin C-based CKiD (CKiD Cr-CysC) equations were evaluated in pediatric hematology and oncology patients. A retrospective analysis was conducted comparing estimated glomerular filtration rate (eGFR) to measured GFR (mGFR) obtained from technetium- 99 m diethylenetriaminepentaacetic acid (99 mTc-DTPA) clearance between January 2016 and May 2022. The influence of corticosteroid use and inflammation in our patient population was evaluated for effect on serum cystatin C (CysC) concentrations and mGFR. All equations agreed within 2 SD of the mean difference with mGFR, but the 5SJ equation had the smallest bias followed closely by the CysPed equation. Overall accuracy (P30) was assessed, and the 5SJ, CKiD Cr-CysC, CysPed, and CKiD-Cys-U25 exhibited comparable performance. In our patient population, we did not observe an effect of corticosteroids (cumulative dosage of > 0.5 mg/kg within the past 14 days) or the presence of inflammation (CRP > 1.2 mg/L) on cystatin C concentrations or mGFR. In our pediatric hematology and oncology patient population, no one estimating equation demonstrated superior accuracy and bias overall and in all subgroups. Neither corticosteroid use nor elevated CRP influenced serum CysC concentrations or eGFR.

Ashton Bellamy, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, 262 Danny Thomas Pl, Memphis, TN 38105, (903) 530-4509, abellamy@stjude.org Supported, in part, by the National Institutes of Health Cancer Center Support (CORE) grant P30 CA021765 and the American Lebanese Syrian Associated Charities (ALSAC). The authors of this study have no relevant conflicts of interest to declare. Children undergoing hematopoietic cell transplantation (HCT) are at high risk for antimicrobial-resistant infections. For post-HCT febrile events, current guidelines recommend modifying empiric antimicrobial regimens based on prior resistant infections, often leading to broader spectrum therapies being utilized. However, not all febrile episodes are associated with an infection. No high-quality evidence is available to guide the selection of empiric antimicrobials in this setting. The goal of this study is to estimate the proportion of recurrent, cefepime-resistant, Gram-negative infections in febrile post-HCT subjects with a prior cefepime-resistant history, and to investigate associations between clinical characteristics and the risk of recurrent infection. This IRB-approved, retrospective cohort study evaluated infants, children, and adolescents (<24 years) who had a cefepime-resistant Gram-negative bacteremia before or shortly after undergoing HCT between January 2010 and September 2022. We collected patient demographics, primary diagnosis, HCT details, presenting signs and symptoms, microbiological data, and antibiotic information for the initial cefepime-resistant bacteremia episode and for all subsequent post-HCT febrile events, regardless of neutropenic status, up to 100 days post-transplant. Recurrent episodes were excluded if the patient had received empiric treatment antibiotics within 48 hours prior to a new febrile episode. We identified 123 evaluable episodes in 63 unique patients. Sixty-three index episodes and 60 recurrent febrile episodes were included. Demographics are provided in Table 1. Recurrent cefepime-resistant infection occurred in 13/60 (21.7%) post-transplant febrile episodes. Thirty-eight of 60 (63.3%) episodes were culture negative, and 9/60 (15%) episodes were positive for a discordant bacterium (e.g., cefepime-susceptible or Gram-positive). Hypotension and receipt of a fluid bolus were significantly associated with an increased risk of recurrent cefepime-resistant infection (p=.0007 and 0.04, respectively). No other clinical features were associated with an increased risk. Characteristics are shown in Table 2. Children and adolescents with a history of cefepime-resistant bacteremia who present with fever post-HCT are at risk of having another cefepime-resistant infection. Hypotension and receipt of fluid boluses are associated with a higher risk of developing recurrent bacteremia. Further research should aim to validate these findings, with the goal of developing risk stratification models to guide empiric therapy post-transplant.

Introduction:Palivizumab reduces severe respiratory syncytial virus (RSV) infection risk in immunocompromised children. However, guidance on palivizumab prophylaxis for immunocompromised children has remained vague. We developed an institutional program to allocate palivizumab in a predefined high-risk group of patients. Methods:We aimed to increase provider adherence to palivizumab administration in profoundly immunocompromised children through education, identifying clinical pharmacists, and informing primary providers of eligible patients. The primary process metric was palivizumab guideline adherence, indicated by the percentage of patients receiving all recommended doses each season. The primary metric was the percentage of eligible patients receiving monthly follow-up doses. Balancing metrics were the percentage of inappropriate doses and patients not meeting our definition of profoundly immunocompromised who did not receive palivizumab prophylaxis and had severe RSV infection. A statistical process control P-chart analyzed the outcome metric before program implementation (baseline: 2009-2013) and throughout interventions (seasons 1-8; 2014-2021). Results:More than 80% of patients received all expected monthly doses, with 89% (584 of 656) of eligible monthly palivizumab doses administered over 8 RSV seasons. The percentage of eligible patients receiving all recommended palivizumab doses increased from 30% to 99% in season 3, remaining more than 95%. Before intervention, 21 patients received palivizumab without meeting criteria; this decreased to 4 during season 1 postimplementation and to 0 thereafter. No profoundly immunocompromised patients meeting the operational definition or receiving palivizumab experienced severe RSV. Conclusions:We improved adherence to palivizumab administration guidelines for profoundly immunocompromised children over 8 consecutive RSV seasons without increasing RSV infection incidence or severity.

BACKGROUND:Pediatric immunocompromised patients are at an increased risk of severe respiratory syncytial virus (RSV) infection. Here, we aimed to describe the clinical course and outcomes of RSV infection in immunocompromised children. METHODS:This single-center study at St. Jude Children's Research Hospital involved immunocompromised children ≤21 years old with a positive RSV clinical test from 2007 to 2019. Demographic and clinical characteristics, laboratory values, treatment delays for underlying conditions, and outcomes were gathered from electronic medical records. Multivariate models identified risk factors predictive of severe RSV-lower respiratory tract infection (LRTI). RESULTS:A total of 391 patients, predominantly children over 2 years old (median age: 5), were included in the study. Acute lymphoblastic leukemia (ALL) was the most prevalent underlying disease. Most patients (85.7%) exhibited upper respiratory tract infections, while approximately 6% progressed to LRTIs. Over half of the patients (58.8%) required hospitalization, and one-third experienced modifications or delays in their underlying disease treatment due to RSV infection. Severe RSV infections were observed in 15.9% of patients. All-cause mortality was 2.6%, with 0.7% of deaths attributed to RSV. CONCLUSIONS:One-third of patients experienced a delay in treatment for their underlying disease due to RSV infection, a phenomenon not well understood but potentially significant. Many immunocompromised children with RSV require hospitalization, including those over 2 years old. RSV imposes a significant burden on immunocompromised children of all ages, affecting their cancer treatment plans both directly and indirectly.

Abstract Corresponding author: Thanh Pham, 262 Danny Thomas Pl, Memphis, TN 38105, thanh.pham@stjude.org, 503-380-8576 Alternate corresponding author: Shane Cross, 262 Danny Thomas Pl, Memphis, TN 38105, shane.cross@stjude.org, 901-595-3300 The authors have no conflicts of interest to declare. Background Children receiving chemotherapy or hematopoietic cell transplantation (HCT) are at high risk for life-threatening antibiotic-resistant bacterial infections. Patients who present with febrile neutropenia (FN) following a recent resistant infection may be at uniquely elevated risk of having another resistant infection. Therefore, national and international guidelines recommend clinicians consider modifying initial antibiotic regimens based on prior multidrug-resistant infections. However, broader spectrum empiric therapy has significant risks at the individual and community level, and not all subsequent episodes of FN are associated with another antibiotic resistant infection; some have susceptible infections or no bacterial infection. Therefore, there is uncertainty about appropriate empiric antibiotic regimens during subsequent FN episodes in patients with past resistant infection, and no high-quality published data are available for the absolute risk of recurrent resistant bacteria during FN in this patient population. We aimed to fill this knowledge gap by evaluating the risk of cefepime-resistant bacterial infections during FN episodes occurring within 6 months after cefepime-resistant bacteremia in pediatric patients with cancer. Methods This was an IRB-approved retrospective cohort study of children and adolescents (<25 years) who had an episode of cefepime-resistant Gram-negative bacteremia identified between January 2010 and September 2022 at St. Jude Children’s Research Hospital, a pediatric comprehensive cancer center in Memphis, TN. We abstracted demographic, oncologic information, clinical presentation, laboratory data, microbiology data and antibiotic information for the index bacteremia episode, and for all subsequent discrete FN episodes occurring within 6 months. FN episodes were excluded if they did not meet definition of FN or if there was not at least seven prior days of fever-free without treatment antibiotics or non-standard prophylactic antibiotics. We estimated the proportion of FN episodes with microbiologically-documented caused by cefepime-resistant Gram-negative bacteria with 95% confidence intervals, and identified risk factors for recurrent resistant infection. Results We identified 150 evaluable episodes in 75 participants; 77 index episodes and 73 recurrent episodes. Descriptive data for demographics, clinical presentation and initial outcome data are shown in Table 1. Recurrent cefepime-resistant infection occurred in 29/73 (40%) of FN episodes (95%CI 29-51%). Hypotension, fluid bolus, or chills/rigors were significantly associated with an increased risk of cefepime-resistant infection in recurrent episodes (P = 0.01, P =0.01, and P = 0.046 respectively). The absence of any high-risk clinical features (hypotension, fluid bolus, severe abdominal pain, chills/rigors) markedly reduced the risk (5/28 [18%] vs. 24/45 [53%]; P = 0.003). Conclusions Children and adolescents with cancer presenting with FN after a recent cefepime-resistant bacteremia are at high risk of having another cefepime-resistant infection. Those without high-risk features at presentation are at markedly lower risk. Further research should aim to validate these findings, with the aim of developing risk-stratification models to guide empiric treatment. Table 1. Characteristics of included participants Table 2. Characteristics of recurrent episodes

Background: Continuous infusion vancomycin (CIV) may benefit children who are unable to achieve therapeutic concentrations with intermittent vancomycin dosing and may facilitate outpatient administration by alleviating the burden of frequent dosing intervals. Previous studies have used variable dosing regimens and steady-state concentration goals. The purpose of this study was to evaluate the total daily dose (TDD) of CIV required to achieve therapeutic steady-state concentrations of 15–25 µg/mL in pediatric hematology/oncology patients. Methods: A single-center retrospective study was performed for patients treated with CIV from January 2017 to June 2019. The primary outcome was the TDD required to achieve therapeutic steady-state concentrations on CIV. Secondary outcomes included time to reach therapeutic steady-state concentrations, CIV indications and adverse events associated with CIV. Results: Data were collected for 71 courses of CIV in 60 patients. Median patient age was 4 years (range: 0.4–20 years). The median TDD required to achieve initial therapeutic concentrations was 50.3 mg/kg/d (interquartile range: 38.8–59.2) and was further divided into age-based cohorts. TDD in mg/kg was significantly lower in the older cohort ( P < 0.001), but there was no statistically significant difference between age-based cohorts with TDD in mg/m 2 ( P = 0.97). Median time to achieve first therapeutic concentration was 19.3 hours (range: 8.6–72.3 hours). The most common indication for CIV was ease of outpatient administration (69.0%). Acute kidney injury incidence was minimal (4.2%). Conclusions: CIV is associated with rapid attainment of target concentrations in pediatric hematology/oncology patients and is safe and well tolerated.

OBJECTIVE:To evaluate the association between deficiency of vitamin A or D at diagnosis of pediatric acute lymphoblastic leukemia (ALL) and subsequent infectious complications during induction therapy. STUDY DESIGN:We conducted an institutional review board-approved, retrospective cohort study of children with newly diagnosed ALL from 2007 to 2017 at St. Jude Children's Research Hospital. We measured vitamin D, vitamin D binding protein, retinol binding protein as a surrogate for vitamin A, and immunoglobulin isotypes in serum obtained at ALL diagnosis, and we assessed the association between vitamin deficiencies or levels and infection-related complications during the 6-week induction phase using Cox regression models. RESULTS:Among 378 evaluable participants, vitamin A and D deficiencies were common (43% and 17%, respectively). Vitamin D deficiency was associated with higher risks of febrile neutropenia (adjusted hazard ratio [aHR], 1.7; P = .0072), clinically documented infection (aHR, 1.73; P = .025), and likely bacterial infection (aHR, 1.86; P = .008). Conversely, vitamin A deficiency was associated solely with a lower risk of sepsis (aHR, 0.19; P = .027). CONCLUSIONS:In this retrospective study, vitamin D deficiency was associated with an increased risk of common infection-related complications during induction therapy for ALL. Additional studies are warranted to evaluate whether vitamin D supplementation could mitigate this effect.

From 8 December 2021 to 26 January 2023, tixagevimab-cilgavimab (T-C) was authorized for pre-exposure prophylaxis of COVID-19. During this period, we used a multidisciplinary team to communicate, screen, approach, and administer T-C to eligible patients. Twenty-seven patients were eligible. Of these, 24 (88.9%) received at least one dose of T-C and three patients received two doses. Majority of patients were White, non-Hispanic, and women. Only two patients had COVID-19 prior to receiving T-C. Seventeen (70.8%) had received two or more doses of SARS-CoV-2 vaccine. No serious adverse events were noted. Seven patients developed SARS-CoV-2 infection within 180 days of receiving T-C (median 102 days; range 28-135), and only one patient developed severe COVID-19 requiring intensive mechanical ventilation in the intensive care unit.

Pneumocystis jirovecii pneumonia (PJP) is a life-threatening fungal infection affecting immunocompromised patients, especially those with T-cell deficiency or dysfunction. Chemoprophylaxis is almost 100% effective and is critical because exposure seems ubiquitous and treatment is challenging. Epidemiology and Pathophysiology Pneumocystis jirovecii (formerly Pneumocystis carinii) is a fungus with cystic and trophic forms. Each form has a distinct replication cycle and role in infection. The cystic form, characterized by a thick cell wall containing β-1,3-glucan, is the infectious stage, and the trophic form attaches to type-I pneumocytes leading to severe pneumonitis in immunocompromised hosts.1 The previously devasting impact of PJP on children with cancer has significantly improved following routine prophylaxis. Prior to this, PJP was a frequent cause of death in children with leukemia.2 Exposure to the organism is very common; 85% of healthy 2-year-olds have Pneumocystis antibodies, so exposure avoidance seems infeasible.1 Risk Factors The most important risk factors for PJP are T-cell deficiency or dysfunction, but in contrast to HIV, there is no risk cutoff for lymphocyte or CD4 count in patients with cancer. Median CD4 and lymphocyte counts were 250 and 515/mm3, respectively in 1 cohort of children with malignancy-related PJP.3 Corticosteroids (especially >2 mg/kg or >20 mg/day for >14 days) are a specific risk factor. B-cell-depleting agents also increase risk, possibly by inhibiting antigen presentation.1–3 Other risk factors include craniospinal or chest irradiation, myeloablative conditioning for hematopoietic cell transplantation (HCT), high-grade graft-versus-host disease (GVHD) and T-cell-specific therapy (eg, alemtuzumab).1–4 However, all patients receiving myelosuppressive therapy are at some risk.4 DIAGNOSIS AND EVALUATION Clinical Presentation The clinical presentation of PJP in children receiving treatment for cancer or HCT is typically with fever (~80%), hypoxia (~70%), tachypnea (~60%) and nonproductive cough (~50%)2,5,6 Other features include dyspnea, chest pain, pneumothorax, fatigue and shock.2 Auscultation is normal or reveals fine bilateral crackles. Importantly, hypoxia can be absent early and increased work of breathing or cyanosis may be present in more severe disease.2,6 Because prophylaxis is so effective, there are no large modern studies describing pediatric PJP.3 In our experience, features suggestive of PJP are hypoxia (initially without severe respiratory distress, perhaps related to relatively normal lung compliance), severe coughing following deep inspiration, and absence of hemoptysis, productive cough or pleural effusion. Presentation of PJP in patients with cancer or HCT is often abrupt, with only 1–5 days of preceding symptoms. More insidious onset can occur.1,3,4,6 Unlike patients with HIV, acute respiratory distress syndrome is more common in patients with cancer and HCT, who seem to have a lower organism burden and more exuberant inflammatory response.1,3,4 Presentation is often at times of less profound immunosuppression, such as maintenance therapy for ALL, and during or after corticosteroid weaning.3 Although pneumonia is the predominant presentation, extrapulmonary infections in multiple tissues and organs have rarely been described. Complications Untreated PJP progresses almost invariably to hypoxic respiratory failure and death.2 Fever often persists and respiratory symptoms continue to deteriorate for 2–3 days despite appropriate therapy, and this initial deterioration can result in respiratory failure.1–3,7 PJP can also be complicated by coinfections with CMV and other organisms, either at presentation or during therapy. Despite appropriate treatment, mortality from PJP remains high in children with cancer or HCT.6 In a recent case series of pediatric PJP, 2/14 (14%) died from PJP alone, and a further 3/14 (21%) died with coinfections.6 Differential Diagnosis The differential diagnosis includes both infectious and noninfectious syndromes. Almost any lower respiratory tract infection can mimic PJP, including respiratory viruses, herpes viruses, adenovirus, tuberculous or nontuberculous mycobacteria, conventional bacterial or atypical pneumonia, parasites (eg, Toxocara spp.), histoplasmosis or blastomycosis, mold and disseminated candidiasis. Noninfectious syndromes include acute respiratory distress syndrome, transfusion-related acute lung injury, cytokine release syndrome, vaping-associated lung injury, pneumonitis from radiation, GVHD or chemotherapy and pulmonary hemorrhage. Diagnostic Approach Making a definitive diagnosis of PJP is vital to prevent empiric overtreatment, avoid misdiagnosis and encourage adherence to therapy after clinical improvement. The gold standard for diagnosis of PJP is bronchoscopy with bronchoalveolar lavage (BAL). Collection of induced sputum may be effective but is difficult in children, and oral washes appear poorly sensitive and specific in this population.3 Therefore, most patients require a BAL; fluid should be sent for histopathology and P. jirovecii polymerase chain reaction (PCR).1 Direct stains such as Gomori methenamine silver, calcofluor white or immunofluorescent stains have sensitivity as low as 31%, 57% and 48%, respectively, so negative stains do not rule out infection.8 In contrast, BAL PCR has high sensitivity (~97%) and specificity (~94%).1,3,8 Beta-1,3-glucan, a fungal cell wall component present in other fungi and the cystic form of P. jirovecii, is not useful for other fungal infections in children due to poor sensitivity and specificity.9 However, very high elevations (>400 pg/ml) typically seen in PJP are more specific, so this may help indicate the diagnosis.9 Serum lactate dehydrogenase is often elevated in adults with PJP, but is an unreliable predictor of severe PJP in children.1,3 Chest radiograph typically shows bilateral and progressively coalescing interstitial infiltrates with perihilar distribution. Computed tomography usually shows diffuse or patchy ground-glass opacity, but is rarely required for diagnosis, and may be done to look for alternative diagnoses. Atypical imaging findings include unilateral changes, consolidation, nodules or cavities.1 Microbial metagenomic next-generation sequencing from plasma is an emerging diagnostic method that appears sensitive and specific, and provides a more comprehensive evaluation than single tests.10 One study of P. jirovecii-specific plasma cell-free DNA testing demonstrated sensitivity of 100% and specificity of 93%.8 These tests might supplant BAL in the future if supported by additional evidence and, where available, are a reasonable option if BAL is infeasible or delayed. PREVENTION First-line Multiple prophylactic agents are available to prevent PJP in children. (Table 1) Trimethoprim-sulfamethoxazole (TMP-SMX) is the drug of choice for PJP prevention in all immunocompromised populations, based on 2 double-blind, randomized controlled trials showing that TMP-SMX prevented PJP in children with ALL (0% vs. 21%), and that 3 consecutive days per week was as effective and less toxic than daily.1,3,4,11 Other TMP-SMX regimens, including once-weekly or twice-weekly appeared effective in observational studies, with only rare breakthrough infections attributed to poor adherence.3,4 Thrice-weekly TMP-SMX does not adversely affect methotrexate pharmacokinetics or toxicity, is safe in patients with G6PD deficiency, and very rarely causes neutropenia or leukopenia.3,4 In a small study in pediatric patients with cancer or HCT, breakthrough PJP was significantly associated with non-TMP-SMX (dapsone or pentamidine) prophylaxis (OR 6.7, P = 0.02).5 An additional potential benefit of TMP-SMX is the prevention of Toxoplasma gondii infection. Although daily TMP-SMX is considered standard for this indication thrice-weekly dosing is likely effective in Toxoplasma seropositive children. TABLE 1. - Suggested Regimens for Prophylaxis or Treatment of PJP Prophylaxis Against PJP Dosing and Frequency Comments First-line therapy Trimethoprim-sulfamethoxazole (TMP-SMX) 75 mg/m2/dose or 2.5 mg/kg/dose TMP (max. 160 mg/dose TMP) orally twice daily 3 days each week Preferred prophylaxis in all patients >1 month of ageProvides coverage for Toxoplasma gondii Second-line therapy Pentamidine Intravenous: 4 mg/kg/dose (max. 300 mg*) every 4 weeksInhaled (age ≥5 years): 300 mg every 4 weeks Ineffective for prevention of Toxoplasma gondii infection Dapsone 2 mg/kg/dose (max. 100 mg) orally once daily or,Age ≥2 years: 4 mg/kg/dose (max. 200 mg) orally once weekly Children ≥1 month of ageProvides coverage for Toxoplasma gondii Contraindicated in G6PD deficiency Atovaquone Age 1 to 3 months: 30 mg/kg/dose orally once dailyAge 4–24 months: 45 mg/kg/dose (max. 1500 mg) orally once dailyAge >24 months: 30 mg/kg/dose (max. 1500 mg) orally once daily Provides coverage for Toxoplasma gondii Take with high-fat mealPoor palatability Treatment of PJP Dosing and frequency Comments First-line therapy TMP-SMX 5 mg/kg/dose, IV or orally every 6 to 8 hours Treatment generally initiated IV; may switch to oral dosing with clinical improvement and assurance of adherence and oral absorption Second-line salvage therapy Pentamidine 4 mg/kg/dose IV once daily Likely effective, but serious toxicity common Third-line or salvage therapy Clindamycin PLUSPrimaquine 10 mg/kg/dose (max. 450 mg) IV or PO every 6 hours0.3 base/kg/dose (max. 30 mg) orally once daily Likely effective for salvage therapyPrimaquine contraindicated in G6PD deficiency Dapsone PLUSTrimethoprim 2 mg/kg/dose (max. 100 mg) orally, once daily5 mg/kg/dose orally every 8 hours Dapsone is contraindicated in G6PD deficiency. Caution is advised in TMP-SMX allergy Atovaquone Age 1 to 3 months: 15–20 mg/kg/dose orally twice dailyAge 2–24 months: 22.5 mg/kg/dose orally twice dailyAge 2 years and above: 15–20 mg/kg/dose (max. 750 mg) orally twice daily Likely inferior to alternatives for initial therapy Adjunctive therapy for PJP Dosing and frequency Comments Prednisone or prednisolone† 0.5–1 mg/kg/dose (max. 40 mg) once or twice daily for ~5 days, then discontinue or wean over ~2–3 weeks Consider in severe disease with hypoxia, but unclear benefit in patients without HIV Caspofungin Age ≥3 months: 70 mg/m2/dose (max. 70 mg) on Day 1 then 50 mg/m2/dose (max. 50 mg) once daily Consider adding to TMP-SMX in severe disease or initial poor response to therapyOther echinocandins might be effective, but less well studied *Not well established; several papers report a max of 300 mg.†Intravenous methylprednisolone may be used at 75% of recommended prednisone dose.PJP indicates Pneumocystis jirovecii pneumonia. Alternatives Alternatives to TMP-SMX, including pentamidine, dapsone and atovaquone, are somewhat effective for PJP prevention and may be considered in cases of true contraindication or shortages affecting TMP-SMX.12 Of 754 children with cancer or HCT receiving pentamidine by aerosolized (n = 158), intravenous (n = 508) or both (n = 88) routes, none had probable or proven PJP, but breakthrough cases are described in ≤9% recipients in other studies.3,5,13 Discontinuation for toxicity, including bronchospasm, hypotension, hypersensitivity, nausea and pancreatitis, occurred in ~3% of patients. Dapsone seems effective for PJP prophylaxis, but hypersensitivity reactions, neutropenia and hemolytic anemia or methemoglobinemia in patients with G6PD deficiency can be challenging.3,5 Similarly, atovaquone prophylaxis seems effective,3,4 but is limited by higher cost, the requirement for coadministration with food and poor palatability. Recommendations We recommend thrice-weekly TMP-SMX as first-line prophylaxis. TMP-SMX can be held for 2 weeks to evaluate the attributability of adverse effects, so second-line prophylaxis is rarely mandatory.3 Alternatives for proven contraindication to TMP-SMX include pentamidine, dapsone or atovaquone, and resumption of TMP-SMX should be regularly reconsidered. We typically continue prophylaxis for 6 weeks after chemotherapy or corticosteroids, 6 months after allogeneic HCT, and longer in patients with prolonged immunosuppression from immunotherapy or GVHD.3 TREATMENT First-line Randomized controlled trial data have established high-dose TMP-SMX as the drug of choice for the treatment of PJP. (Table 1).3,7 Although lower doses of TMP-SMX might be effective, supportive data are from different populations, and pediatric studies had poor outcomes.3 Treatment is generally started intravenously, with an oral switch after improvement to complete 21 days of therapy. Nausea is very common with high-dose oral TMP-SMX, so early antiemetics can help ensure adherence. Secondary prophylaxis is imperative. Alternatives Alternatives for treatment include pentamidine, atovaquone, dapsone plus TMP and primaquine plus clindamycin. Intravenous (and historically intramuscular) pentamidine is effective for the treatment of PJP, but has serious adverse effects, including nephrotoxicity (~40%) and hypoglycemia (~25%).7 Atovaquone or dapsone plus TMP are third-line options. As limited evidence suggests higher failure rates, consider use only in milder cases or where alternatives are contraindicated.3,4 Options for salvage therapy, after ≥4 days of therapy without improvement, include clindamycin plus primaquine or addition of an echinocandin to TMP-SMX. Treatment success with clindamycin plus primaquine salvage therapy was reported in 89% of cases in 1 study.3 Recent promising results for caspofungin plus TMP-SMX require more efficacy data, but the favorable safety profile of echinocandins makes this combination attractive for severe or unresponsive PJP.3,4 Corticosteroids Because respiratory status worsens for 1–2 days after initiation of therapy, adjunctive corticosteroids have been proposed to control inflammation while awaiting response to antimicrobials.1,3,7 Corticosteroids do improve severe PJP outcomes in adults with HIV, but are of unknown benefit in children with cancer or HCT.3 We routinely use short-course corticosteroid therapy in patients with severe PJP and any sign of respiratory failure, aiming to prevent progressive respiratory failure or death (Table 1). Infection Control and Prevention Optimal isolation for patients with PJP is uncertain. PJP outbreaks are reported, and PJP is shed from patients with active infection, so person-to-person spread is possible.3 However, most PJP cases are sporadic without known exposure, and Pneumocystis is shed from people without PJP.3 Therefore, although isolation of children with active infection from other immunocompromised hosts seems reasonable, the absolute benefit is unknown, and prophylaxis for at-risk children is much more important. FUTURE DIRECTIONS More research on the diagnosis, prevention and management of PJP is needed. Utility of noninvasive testing such as plasma PCR or metagenomic sequencing is promising and more data are needed; both targeted and untargeted approaches could improve early detection of PJP and other infections, reducing the need for BAL and preventing unnecessarily broad-spectrum therapy. Rezafungin, a novel once-weekly echinocandin, is under evaluation for the prevention of PJP and other fungal infections (https://clinicaltrials.gov/ct2/show/NCT04368559). Further research is also needed to define the role of other echinocandins, low-dose or shorter-course TMP-SMX, and adjunctive corticosteroids for the treatment of PJP in this population.

PURPOSE The optimal management of fever without severe neutropenia (absolute neutrophil count [ANC] ≥500/µL) in pediatric patients with cancer is undefined. The previously proposed Esbenshade Vanderbilt (EsVan) models accurately predict bacterial bloodstream infections (BSIs) in this population and provide risk stratification to aid management, but have lacked prospective external validation. MATERIALS AND METHODS Episodes of fever with a central venous catheter and ANC ≥500/µL occurring in pediatric patients with cancer were prospectively collected from 18 academic medical centers. Variables included in the EsVan models and 7-day clinical outcomes were collected. Five versions of the EsVan models were applied to the data with calculation of C-statistics for both overall BSI rate and high-risk organism BSI (gram-negative and Staphylococcus aureus BSI), as well as model calibration. RESULTS In 2,565 evaluable episodes, the BSI rate was 4.7% (N = 120). Complications for the whole cohort were rare, with 1.1% (N = 27) needing intensive care unit (ICU) care by 7 days, and the all-cause mortality rate was 0.2% (N = 5), with only one potential infection-related death. C-statistics ranged from 0.775 to 0.789 for predicting overall BSI, with improved accuracy in predicting high-risk organism BSI (C-statistic 0.800-0.819). Initial empiric antibiotics were withheld in 14.9% of episodes, with no deaths or ICU admissions attributable to not receiving empiric antibiotics. CONCLUSION The EsVan models, especially EsVan2b, perform very well prospectively across multiple academic medical centers and accurately stratify risk of BSI in episodes of non-neutropenic fever in pediatric patients with cancer. Implementation of routine screening with risk-stratified management for non-neutropenic fever in pediatric patients with cancer could safely reduce unnecessary antibiotic use.

Cefiderocol is a novel cephalosporin antibiotic with activity against multidrug-resistant Gram-negative bacteria and limited pediatric experience. This case series describes 3 immunocompromised children receiving blood transfusion who developed benign red or purple urine with administration of cefiderocol. Interaction with iron from blood products is a possible mechanism. It is important to recognize this phenomenon and distinguish it from hematuria to avoid unnecessary diagnostic testing.

Mycolicibacterium neoaurum is a rapidly growing mycobacterium and an emerging cause of human infections. M. neoaurum infections are uncommon but likely underreported, and our understanding of the disease spectrum and optimum management is incomplete. We summarize demographic and clinical characteristics of a case of catheter-related M. neoaurum bacteremia in a child with leukemia and those of 36 previously reported episodes of M. neoaurum infection. Most infections occurred in young to middle-aged adults with serious underlying medical conditions and commonly involved medical devices. Overall, infections were not associated with severe illness or death. In contrast to other mycobacteria species, M. neoaurum was generally susceptible to multiple antimicrobial drugs and responded promptly to treatment, and infections were associated with good outcomes after relatively short therapy duration and device removal. Delays in identification and susceptibility testing were common. We recommend using combination antimicrobial drug therapy and removal of infected devices to eradicate infection.

Neutropenic enterocolitis (NE) is a common and serious condition affecting adults and children with neutropenia. It mostly affects children receiving myelotoxic therapy for cancer or receiving hematopoietic stem cell transplantation (HCT).1–3 Although sometimes called ‘typhlitis’ when limited to the cecum, NE is preferred because it can affect the entire colon, small bowel or rectum.3 NE is important because it can delay chemotherapy, affect nutrition, require prolonged hospitalization or surgery, and has other life-threatening complications. PATHOPHYSIOLOGY AND EPIDEMIOLOGY The proposed pathophysiology of NE is a vicious cycle initiated by gut mucosal injury from chemotherapy (eg, antimetabolites, alkylating agents, anthracyclines and taxanes), malignant infiltration, radiation therapy, graft vs. host disease or infection. Colonizing gastrointestinal flora, including bacteria and sometimes Candida spp., then enter the damaged gut wall and, without neutrophil clearance, cause further mucosal damage.4 Gram-negative, Gram-positive and anaerobic bacteria and Candida, cytomegalovirus (CMV), adenovirus, rotavirus, norovirus, astrovirus, Clostridioides difficile and other enteric pathogens have all been identified in association with NE.4 Other contributing factors include microbiome disruption, intramural bleeding and other immune dysfunction.4 NE affects ~2%–10% of children receiving chemotherapy or HCT in contemporary studies.1,3,5 Risk factors include older age, abdominal radiotherapy, HCT and specific malignancies, such as acute myeloid leukemia, non-Hodgkin’s lymphoma and neuroblastoma.2,3,5 DIAGNOSIS AND EVALUATION Clinical Presentation Clinical presentation of NE is typically with fever, abdominal pain and neutropenia 1–3 weeks after cytotoxic chemotherapy or HCT conditioning.2,3 The pain is often crampy, periumbilical or generalized, and may peak before a bowel movement. More constant or focal pain and tenderness, especially in the right lower quadrant, is seen in ~25%.1 Nausea, vomiting, diarrhea, decreased bowel sounds, abdominal distension and palpable bowel mass are also common but frank gastrointestinal bleeding is rare.1–3,5 The diagnosis is based on clinical presentation in an appropriate host.2,3 Imaging and laboratory tests can support the diagnosis or identify alternative diagnoses and can identify specific infections, complications or prognostic factors. Differential Diagnosis The differential diagnosis for abdominal pain in an immunocompromised child includes appendicitis, ischemic colitis, chemotherapy-associated mucositis, veno-occlusive disease, medication-induced ileus or pancreatitis and infectious syndromes such as infectious gastroenteritis due to norovirus, adenovirus, rotavirus, intestinal parasites, C. difficile, nontyphoidal Salmonella spp., enteropathogenic Escherichia coli, Yersinia enterocolitica, Shigella spp., and Campylobacter spp., ascending cholangitis, cholecystitis and mesenteric adenitis.1 Imaging Studies Ultrasound is preferred to computed tomography (CT) for evaluation of NE because of safety and diagnostic accuracy.3,6 Ultrasound typically shows colonic wall thickening (≥3–4 mm).3,5,6 A maximal measurement of 0.9 mm is associated with longer clinical illness and with mortality.3,6 If the diagnosis is unclear, ultrasound can also evaluate the liver, spleen, gallbladder, kidneys, appendix and retroperitoneum. However, image quality is operator-dependent and bowel evaluation must be specifically requested. Although serial ultrasound is sometimes used to evaluate response to therapy, there is insufficient evidence to modify therapy for increasing wall-thickness alone. Abdominal CT with intravenous contrast is also often used to assess NE; however, wall-thickness-measurement can be challenging in the nondistended colon, and ionizing radiation and intravenous contrast have potential toxicity.3,6 CT is therefore preferred only in patients with large body habitus or who require concurrent evaluation for chest pathology, suspected perforation or intraabdominal complications, and in centers with limited ultrasound expertise.3,6 CT can show bowel wall thickening, intramural pneumatosis, pneumoperitoneum and pericolic fluid collections or mesenteric stranding,3,6 and can also evaluate other alternative or concurrent intraabdominal pathology. Plain radiographs may show extraintestinal free air as a sign of perforation, cecal dilatation, decreased right lower quadrant air, air-fluid levels in ascending colon, pneumatosis intestinalis and small bowel dilatation, but are not routinely indicated because of poor sensitivity and specificity. Gastrointestinal endoscopy is usually contraindicated because of perforation-risk but may be considered if initial therapy fails, or for diagnosis of graft vs. host disease, CMV colitis or fungal infection. Laboratory Tests Blood culture, with added anaerobic culture, should be performed at diagnosis and with any clinical deterioration. This can identify bloodstream infection (BSI) from translocation of gut flora and can guide more specific therapy.2 If all cultures are negative and there is no clinical deterioration, repeating blood cultures >48 hours has little utility, even with persistent symptoms. Other microbiological testing may be considered to identify alternative etiologies for gastrointestinal pathology. If diarrhea is prominent, stool testing for C. difficile, norovirus, adenovirus, rotavirus, intestinal parasites and pathogenic bacteria should be considered. Molecular testing for CMV from blood is reasonable but is negative in ~50% of biopsy-proven cases. Inflammatory markers such as C-reactive protein, Interleukin-8, erythrocyte sedimentation rate and procalcitonin are usually elevated and levels may be associated with the severity of illness or prognosis. COMPLICATIONS OF NEUTROPENIC ENTEROCOLITIS Outcomes of NE in children appear to be superior to adults. Adult mortality is 20%–50%, whereas recent pediatric studies report mortality rates <3%.1,3,5,7,8 Older adolescents (>14 years) appear to be at higher risk than younger children. Other important complications of NE include BSI, sepsis, mechanical complications requiring surgery and gastrointestinal mucormycosis. Bloodstream Infection The most common microbiologically-proven complication of NE is BSI, especially due to E. coli, viridans group streptococci, Pseudomonas aeruginosa, Klebsiella spp. or Enterococcus spp.2,9 Other important pathogens include Clostridium spp., Pasturella haemolytica, Acinetobacter baumanii, Aspergillus spp. and Candida spp. Children with NE have lower BSI rates (~25%) than adults (~40%). Sepsis Death from pediatric NE is most frequently associated with sepsis, a dysregulated response to infection leading to organ dysfunction.1,5 Although severe sepsis requiring intensive care is rare, mild organ dysfunction is common with hypotension reportedly occurring in ~40% of cases.5,7 Early recognition and management of sepsis likely contribute to low mortality rates in recent studies. MANAGEMENT Empiric Antibiotic Therapy Prompt administration of broad-spectrum empiric antibiotics is critical to prevent progressive disease and severe sepsis. (Table 1) Empiric therapy guided by clinical severity usually includes coverage for aerobic Gram-negative and anaerobic bacteria, and may also include coverage for intestinal Gram-positive aerobes or Candida spp.2,3,5,7 The backbone of therapy is usually piperacillin-tazobactam or cefepime plus metronidazole, and some authors have even recommended routine empiric use of carbapenems.3 TABLE 1. - A Risk-stratified Approach to Management of Neutropenic Enterocolitis in Children Patient Characteristics Recommended Empiric Therapy Neutropenic patients with mild abdominal pain and fever Consider treating as per standard fever and neutropenia guidelinesAbdominal imaging to identify patients with enterocolitis Neutropenic patients with fever plus any of the following: Moderate-severe abdominal pain Focal abdominal tenderness Diarrhea Bowel wall thickening between ≥0.3 cm and <0.9 cm PLUS clinical symptoms Metronidazole IV/PO plus Cefepime IVOrPiperacillin-Tazobactam IV Neutropenic patients with moderate-severe abdominal pain plus any of the following: Toxic appearance Rebound tenderness New abdominal mass or local ‘fullness’ on examination Frank or macroscopic blood in stool Bowel wall thickening ≥0.9 cm on ultrasound imaging Metronidazole IV/PO plus Cefepime (or Piperacillin-Tazobactam IV) plus an Aminoglycoside IVConsider addition of fluconazole or micafungin Neutropenic patients with abdominal pain plus: Past colonization or infection with Gram-negative bacteria resistant to cefepime and aminoglycoside AND any of the following: Toxic appearance Rebound tenderness New abdominal mass or local ‘fullness’ on examination Frank or macroscopic blood in stool Bowel wall thickening ≥0.9 cm on ultrasound imaging Consider tailoring empiric therapy to include coverage for resistant bacteria Neutropenic patients with severe abdominal pain plus: Sepsis requiring ICU-level care Meropenem IV plus Aminoglycoside IV plusVancomycin IV plus Fluconazole or Micafungin IV IV indicates intravenous. Broader-spectrum Antimicrobial Therapy Expanded empiric coverage is necessary in select cases. Patients with more severe NE and history of multidrug-resistant Gram-negative infection or colonization may have initial therapy tailored to resistant organisms; options to broaden Gram-negative coverage include adding an aminoglycoside or switching to a carbapenem. Expanded upfront therapy should also be considered in patients requiring critical care support (eg, vasopressor therapy, ventilatory support or severe metabolic acidosis), with signs of peritonitis or an abdominal mass or bowel wall thickening on ultrasound ≥0.9 cm.2,3 In these cases, broader empiric coverage for Gram-positive bacteria, with vancomycin or linezolid, double Gram-negative coverage with an aminoglycoside, and antifungal coverage with fluconazole or an echinocandin should be considered. Indications for Escalation or De-escalation of Antibiotic Therapy Empiric antibiotic therapy should be adjusted as new information becomes available. Patients with documented infection should have antimicrobials tailored to susceptibilities, but broad-spectrum antimicrobials should also be continued because polymicrobial infection of the gut wall is presumed. Patients showing clinical improvement should be considered for de-escalation of therapy after 24–48h, including discontinuation of aminoglycosides, and switching empiric carbapenems to cefepime or piperacillin-tazobactam. Oral metronidazole plus ciprofloxacin can be considered for outpatient management in patients showing clinical improvement and tolerating oral intake. Indications for empiric escalation of therapy include worsening of gastrointestinal symptoms or signs, increasing bowel wall-thickness, sepsis or positive culture with a resistant organism. In these cases, depending on clinical stability, either stepwise escalation of therapy while monitoring for clinical response, or broad escalation with subsequent rationalization can be considered. Ongoing mild-moderate symptoms or fever usually do not require escalation, since they can persist until neutrophil count recovery even with optimal therapy. Duration of Antibiotic Therapy The duration of antibiotic therapy for NE is controversial. Although prolonged therapy after resolution of neutropenia and symptoms has been recommended for adults with uncomplicated NE, our practice is to discontinue antibiotic therapy after count recovery (absolute neutrophil count >500) plus the resolution of symptoms, unless a longer course is indicated for BSI, C. difficile infection, peritonitis or intraabdominal abscess.10 In certain diseases (eg, acute myeloid leukemia or relapsed leukemia), count recovery may be very delayed, and clinicians must balance the risk of continued NE therapy (eg, antibiotic resistance and metronidazole-neurotoxicity) against the benefits. Surgical Management Because mechanical complications, including obstruction, intussusception, perforation and fistulization are rarely described in pediatric NE in the current era,1,5 >90% of pediatric NE cases can be treated conservatively.1,2,5,8 Also, surgery is technically challenging due to friable bowel, surrounding inflammation, impaired healing and bleeding diatheses. Potential indications for surgery include persistent bleeding after correcting thrombocytopenia and coagulopathy, intestinal perforation, intraabdominal abscess or compartment syndrome, and rapid clinical deterioration despite medical management. Clinical signs of perforation include acute sepsis, or the development of focal abdominal pain, tenderness and peritonism. Persistent abdominal pain or fever alone typically does not necessitate surgery. Other Supportive Care Complete ‘bowel-rest’, restricting all oral intake, has often been recommended for NE.2,3,8 However, no controlled trials evaluated this, and many patients are empirically managed with a limited plain diet.7 Indications for bowel rest include impending surgery, suspected perforation, peritonitis or bowel obstruction, severe abdominal pain or nausea and uncontrolled gastrointestinal bleeding. If bowel rest is required, attention to fluid and electrolyte supplementation is important (potassium depletion may occur from large volume diarrhea), and parenteral nutrition should be considered. Neutrophil recovery is required for resolution of NE, so support with granulocyte colony-stimulating factor (G-CSF) is often considered, despite absent high-quality evidence.8 If not contraindicated, we use G-CSF if likely to speed neutrophil recovery without marked leukocytosis. Pain control is also an important component of management. CONCLUSIONS NE is a potentially life-threatening condition affecting neutropenic patients of all ages. Early recognition and appropriate risk-stratified management can prevent surgery, complications, unnecessary antibiotics and mortality. Abdominal ultrasound with colonic wall measurements and other simple investigations can confirm the diagnosis and exclude common differentials. The central pillars of treatment are empiric antibiotic therapy and supportive care, with surgery reserved for intestinal perforation, severe bleeding or fulminant disease. Close monitoring for improvement, deterioration, or development of intraabdominal complications can guide subsequent management. Outcomes are usually good, with rapid resolution after neutrophil recovery. Important future research directions include evaluation of empiric antibiotic approaches, duration of therapy and indications for escalation or de-escalation of empiric antimicrobial treatment.

Novel human astroviruses (HAstVs) have recently been implicated as rare causes of fatal encephalitis in immunocompromised patients, for which there is no proven treatment. We report 2 cases from our institution in which HAstV-VA1 was detected in the cerebrospinal fluid by metagenomic next-generation sequencing after the initial evaluation revealed no etiology.

AbstractBackgroundFluoroquinolone antibiotics are frequently utilized in pediatric oncology patients as prophylaxis or step‐down therapy following broad spectrum beta‐lactam therapy for febrile neutropenia. Concerns regarding neurotoxicity limit the use of these agents. No studies have evaluated the association between fluoroquinolone use and neurotoxicity in pediatric oncology patients receiving other neurotoxic agents such as vincristine.MethodsAn observational cohort study comprising patients aged 0‐18 at diagnosis enrolled on a prospective study for treatment of acute lymphoblastic leukemia (ALL) at a pediatric comprehensive cancer center between October 2007 and November 2018. Data for neuropathic pain and sensory or motor neuropathy were collected prospectively, and a Cox proportional hazards regression model was used to evaluate associations between administration of fluoroquinolone antibiotics during induction therapy and subsequent development of vincristine‐induced peripheral neurotoxicity (VIPN).ResultsA total of 598 participants were enrolled, including 338 (57%) who received fluoroquinolones during induction therapy; of these 470 (79%) were diagnosed with VIPN and 139 (23%) were diagnosed with high‐grade (Grade 3+) VIPN. On unadjusted analyses, and analyses adjusted for age and race, there was no evidence of an association between fluoroquinolone exposure and subsequent VIPN (hazard ratio [HR] 0.8, 95% CI 0.5‐1.04, P = .08) or high‐grade VIPN (HR 1.1, 95% CI 0.4‐2.2, P = .87).ConclusionsThe results of this observational study do not show an association between exposure to fluoroquinolone antibiotics during induction therapy for ALL and subsequent development of vincristine‐induced peripheral neuropathies, and suggest that a large increase in VIPN is unlikely.

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.