In-vivo and human evidence for potential efficacy of therapeutic polyclonal RSV neutralizing antibodies for palivizumab-resistant RSV infections.

BACKGROUND: Monoclonal antibody (palivizumab), intravenous immune globulin (IGIV), or respiratory syncytial virus (RSV)-polyclonal-hyperimmune-globulin (RSV-IG as Respigam®, RI-001, RI-002) are used with ribavirin in RSV-infected immunocompromised patients, with debated efficacy. Palivizumab-resistance (PR) can arise during treatment of persistent infections in this population. RSV-IG may confer benefit in PR-RSV infection. METHODS: RSV-IG [RI-001] was provided for an immunocompromised infant with RSV-pneumonitis refractory to ribavirin and palivizumab. RSV-neutralizing antibody, respiratory RSV load (qPCR), and F-gene-sequence-detection of PR was determined. Prophylactic RSV-IG [RI-002] or palivizumab was administered in a cotton-rat model infected with wild-type and PR-RSV. Lung RSV load and neutralizing antibody were measured. RESULTS: As protective RI-001-neutralizing antibody titers waned in the infant, a subpopulation of PR-escape mutants were detected with a fatal RSV-burden in the lungs. In PR-RSV-infected cotton rats, prophylactic RI-002 reduced RSV-load in the lungs (2.45 vs 0.28 log10 PFU/g lung-tissue reduction, respectively, p < 0.05) and provided protective RSV-neutralizing antibody. CONCLUSIONS: RSV-IG and ribavirin use in immunocompromised patients requires further study.

Two Distinct Illnesses Consistent With MIS-C in a Pediatric Patient.

Multisystem inflammatory syndrome in children (MIS-C) is a severe inflammatory response described in children after infection with severe acute respiratory syndrome coronavirus 2. We present a case of a 9-year-old African American boy with 2 distinct illnesses that were both consistent with MIS-C. He first presented in the early stages of our understanding of MIS-C with predominantly neurologic and gastrointestinal symptoms and demonstrated elevated inflammatory markers consistent with MIS-C. He was treated with intravenous immunoglobulin with complete resolution of signs and symptoms. After 7 months of good health, he returned with a second, distinct illness characterized by fever, rash, gastrointestinal symptoms, and elevated inflammatory markers that met the criteria for MIS-C. In addition, we identified new dilatation of the left anterior descending coronary artery. He improved rapidly after treatment with intravenous immunoglobulin, aspirin, and steroids. Our report highlights the need to achieve a better understanding of this entity's pathogenesis and clinical course and to improve anticipatory guidance for children with MIS-C.

How Broad Should Gram-Negative Coverage Be for Febrile Parenteral Nutrition Dependent Short Bowel Syndrome Patients?

ABSTRACT: Broader spectrum Gram-negative antibiotics are commonly utilized empirically for central line-associated bloodstream infections (CLABSI) in febrile short bowel syndrome (SBS) patients receiving home parenteral nutrition compared to those used empirically for inpatient-acquired CLABSI. This analysis reports 57 CLABSI in 22 patients with SBS admitted from the community and 78 inpatient-acquired CLABSI in 76 patients over a 5-year period. Proportional Gram-negative CLABSI was similar between the SBS and inpatient-acquired cohorts (43.8% vs42.3%, respectively, P  = 0.78). 1.8% and 10.3% (P = 0.125) of Gram-negative CLABSI were non-susceptible to ceftriaxone and 0% and 3.8% (P = 0.52) were non-susceptible to ceftazidime in the SBS and inpatient-acquired cohorts, respectively. In the SBS cohort, home ethanol lock therapy and prior culture results impacted Gramnegative pathogen distribution. Broader empiric Gram-negative coverage for CLABSI among SBS patients compared to inpatients is unnecessary. Third-generation cephalosporins represent appropriate empiric Gramnegative agents for febrile SBS patients presenting from the community to our institution.

A Culture Change: Impact of a Pediatric Antimicrobial Stewardship Program Based on Guideline Implementation and Prospective Audit with Feedback.

Reports analyzing the impact of pediatric antimicrobial stewardship programs (ASP) over long periods of time are lacking. We thus report our ASP experience in a pediatric tertiary referral center over a long-term period from 2011 to 2018. Our ASP was implemented in 2011. The program was based primarily on guideline development with key stakeholders, engaging and educating providers, followed by prospective audit with feedback (PAF). Monitored antibiotics included meropenem, piperacillin-tazobactam, and cefepime, followed by the addition of ceftriaxone, ceftazidime, cefotaxime, ciprofloxacin, levofloxacin, linezolid, and vancomycin at various time points. Specifically, the program did not implemented the core strategy of formulary restriction with prior authorization. Process- and outcome-related ASP measures were analyzed. We saw a 32% decrease in overall antibiotic utilization, a 51% decrease in the utilization of antibiotics undergoing PAF, and a 72% reduction in the use of broad-spectrum antibiotics such as meropenem. There was a concomitant increase in organism susceptibility and a reduction in yearly drug purchasing costs of over USD 560,000 from baseline without changes in sepsis-related mortality. Our study highlights that a pediatric ASP based primarily on the principles of guideline development and PAF can improve antibiotic utilization and institutional bacterial susceptibilities without a detrimental impact on patient outcomes by changing the culture of antimicrobial utilization within the institution.

Analysis of Community-Acquired Urinary Tract Infection Treatment in Pediatric Patients Requiring Hospitalization: Opportunity for Use of Narrower Spectrum Antibiotics.

Background: The most narrow-spectrum antibiotic possible should be used for empiric and definitive treatment of pediatric urinary tract infections (UTIs). Objectives: The objectives of this study were to determine an appropriate narrow-spectrum antibiotic for empiric UTI treatment, factors differentiating empiric first-generation cephalosporin (FGC) versus third-generation cephalosporin (TGC) coverage, and factors associated with unnecessarily broad-spectrum definitive antibiotic treatment. Methods: This was a retrospective chart review of children admitted from 2013 to 2015 who were diagnosed with a UTI and received treatment. Multivariable logistic regression assessed independent factors associated with our outcomes. Results: Of 568 diagnosed UTIs, 88.6% received empiric TGC treatment. Empiric coverage among cultured organisms was only 5.4% lower in FGC versus TGC. Adolescent age group (odds ratio [OR] = 8.83, 95% confidence interval [CI] = 1.47-53.11), uncircumcised males (OR = 4.52, 95% CI = 1.27-16.08), Hispanic ethnicity (OR = 4.37, 95% CI = 1.14-16.82), and hospitalization within the preceding 3 months (OR = 4.73, 95% CI = 1.38-16.23) were associated with FGC nonsusceptibility among TGC susceptible Enterobacteriaceae pathogens. De-escalation occurred in 55.8% of diagnosed UTIs eligible for de-escalation at discharge. Urine white blood cell (WBC) count >5 (OR = 2.89, 95% CI = 1.14-7.21), serum WBC count (OR = 1.04, 95% CI = 1.01-1.07), and having only one narrow-spectrum treatment option (OR = 5.1, 95% CI = 2.43-10.66) were associated with unnecessarily broad-spectrum definitive treatment. Conclusion and Relevance: FGC would be an appropriate narrow-spectrum empiric agent for UTIs at our institution. The factors associated with FGC nonsusceptibility can further stratify empiric treatment decisions. The factors associated with unnecessarily broad-spectrum definitive treatment illustrate areas for educational efforts and future research regarding UTI treatment.

Cytomegalovirus in pediatric inflammatory bowel disease patients with acute severe colitis.

BACKGROUND: The prevalence and significance of cytomegalovirus (CMV) colitis in pediatric acute severe colitis is unknown. The aim of this study was to determine the prevalence of CMV in colonic mucosa of children with acute severe refractory colitis and compare the clinical characteristics and outcomes of CMV positive and negative patients. METHODS: In a case-control study, colonic biopsy specimens from children with severe refractory colitis were tested for CMV, and matched with non-refractory IBD controls. We characterized CMV positive patients by assessing laboratory values, concurrent medications, and need for surgery as compared with CMV negative refractory colitis patients. RESULTS: Colonic biopsies from 96 patients were evaluated for CMV; 48 with severe refractory colitis, and 48 non-refractory controls. There was an increased prevalence of CMV in severe refractory colitis [7/48 (14.6%), P < 0.0001]; all were previously CMV negative. Viral DNA burden on immunohistochemistry was not predictive of response to antiviral therapy or need for surgery at 12 months. Lymphopenia was seen in all CMV positive patients, but this did not demonstrate statistical significance (P = 0.09). We did not see an association between azathioprine or infliximab use and the need for surgery at 12 months. CONCLUSIONS: There is an increased prevalence of CMV in colonic biopsies of pediatric patients with severe refractory colitis. Viral burden does not predict clinical outcomes or subsequent need for colectomy.

Importance of Reviewing Antibiotic Courses by 48 Hours: Risk Factors for Third-Generation Cephalosporin Resistance Among AmpC Harboring Organisms in Urine and Respiratory Cultures.

BACKGROUND: Citrobacter, Enterobacter, Morganella, and Serratia (AmpC organisms) species can exhibit third-generation cephalosporin (TGC) resistance after TGC exposure. We aimed to assess if institutional TGC utilization correlated with institutional AmpC organism susceptibility and if prior TGC exposure ≤48 hours were associated with TGC resistance in the first culture of a future infection episode caused by an AmpC organism. METHODS: A 5-year retrospective cohort study was performed, including AmpC organisms isolated from pediatric urinary and respiratory tract cultures at an institution with TGC courses reviewed by the antimicrobial stewardship program at 48 hours. Correlations were assessed by Pearson's correlation. Multivariable logistic regression identified factors independently associated with TGC resistance in a subcohort of infection episodes. RESULTS: Among 654 cultures, AmpC organism TGC susceptibility increased from 74% in 2013 to 89.3% in 2017, and this correlated with a 26.1% decrease in TGC utilization (R = -0.906; P = 0.034). Among 275 AmpC organism infections, 21.1% were resistant. Resistance occurred in 13.6%, 17.4%, and 56.5% of infections with no exposure, ≤48 hours, and >48 hours of TGC exposure in the past 30 days, respectively. TGC exposure ≤48 hours was not associated with resistance (odds ratio [OR], 1.26; 95% confidence interval [CI], 0.32-4.94; P = 0.74), whereas, TGC exposure >48 hours was (OR, 8.7; 95% CI, 3.67-20.6; P < 0.001). Infections in 2017 were less likely to be resistant (OR, 0.25; 95% CI, 0.08-0.8; P = 0.019). CONCLUSIONS: Decreased TGC utilization, likely related to antimicrobial stewardship, correlated with increased AmpC organism susceptibility. Limiting TGC exposure to ≤48 hours when possible may reduce AmpC organism resistance in future infections.

Mediastinal Lymphadenopathy in Children With Histoplasmosis.

BACKGROUND: Mediastinal lymphadenopathy (ML) in children can arise from malignancy, infection, or rheumatic illness among others, and may be found incidentally on imaging or during workup for a variety of symptoms. Our aim was to describe the clinical presentation and natural history of histoplasmosis in children who present to a tertiary care center with ML in an endemic area of the country. METHODS: After institutional review board approval, a retrospective study of all children (aged < 21 y) presenting with proven (positive serologies) or suspected histoplasmosis (negative serologies, negative tuberculosis testing, and benign outcomes in follow-up) over a 5-y period was done. Seventy-four patients were tested; those with another diagnosis (n = 6) or without ML (n = 26) were excluded, for a total cohort of 44 patients. Demographics, clinical presentation, symptoms, laboratory data, treatment course, radiography studies, and inpatient and outpatient visits were examined. RESULTS: Of the 44 patients with ML, 27 had proven histoplasmosis, and 19 had suspected histoplasmosis. The median follow-up by imaging or clinical examination was 6.9 mo (0.3-73.2 mo). Sixteen patients received antifungal therapy with itraconazole, and 15 patients received at least one course of steroids, nearly all for respiratory symptoms; 11 patients (24%) received both. There was no difference in readmission rate (n = 5 versus 2, P = 0.7) or recurrence of symptoms (n = 2 versus 5, P = 0.4) between patients who received an antifungal and those that did not. Receiving steroid therapy was associated with airway narrowing and a higher readmission rate (n =6 versus 2 who were not treated with steroids, P = 0.04), but not with symptom recurrence. Nine lymph node or mass biopsies were performed; however, the pathology only confirmed nonspecific infection in three and was nondiagnostic in the remaining six patients. Twenty-seven patients had at least one confirmatory laboratory test positive for histoplasmosis. Thirty-nine of the 44 patients (84%) with a diagnosis of histoplasmosis (proven or suspected) were asymptomatic by 1-2 mo follow up, with the remainder having intermittent chest pain or reactive airway disease. CONCLUSIONS: ML because of proven or suspected histoplasmosis is usually a self-limiting disease that can be managed with treatment of the child's symptoms. Antifungals and steroids are of unclear benefit and may not alter the natural course of the disease. Biopsies are rarely diagnostic in the setting of ML, and invasive procedures should be avoided.

Pneumococcal Polysaccharide Vaccination in Pediatric Inflammatory Bowel Disease.

According to current recommendations, in addition to 13-valent pneumococcal conjugate vaccine (PCV13) series, all children with inflammatory bowel disease (IBD) aged ≥2 years, with planned or current immunosuppression, should receive pneumococcal polysaccharide vaccine (PPSV23). The primary aim was to determine the PPSV23 immunization rates in our pediatric IBD patients. The secondary aim was to determine the incidence of invasive pneumococcal disease in these patients. The IBD database at Le Bonheur Children's Hospital was retrospectively reviewed to identify all cases diagnosed from 2003 to 2015. Out of 190 IBD patients, 106 on immunosuppressive drugs, whose immunization records could be obtained from the state database, were included in the study. Medical records were reviewed to determine infections seen in these patients from the time of diagnosis to date. IBD patients in our study ranged from age 2 to 18 years. Only 4 of 106 (3.7%) patients had received PPSV23 vaccine. Only 1 patient (0.9%) had probable pneumococcal disease and none with invasive pneumococcal disease. Clostridium difficile (11 patients) and Cytomegalovirus colitis (4 patients) were more commonly encountered. All our patients received the recommended PCV13 vaccine. The majority of our pediatric IBD patients did not receive PPSV23 vaccine. Fortunately, we did not see a high rate of invasive pneumococcal disease in our patients suggesting that they may be protected by the primary PCV13 vaccine series. Non-pneumococcal infections were more common in this population.

Antimicrobial stewardship impact on Pseudomonas aeruginosa susceptibility to meropenem at a tertiary pediatric institution.

An antimicrobial stewardship program was implemented throughout 2012 at a tertiary pediatric institution with guideline development preceding prospective audit and feedback starting in 2013. Meropenem use decreased over 62% during the next 5 years. Non-cystic fibrosis Pseudomonas aeruginosa isolate susceptibility to meropenem increased from 89% in 2011 to 98% in 2017 (P < .001) and correlated with meropenem use the preceding year (Rs: -0.78, P = .008).

Disseminated histoplasmosis in pediatric kidney transplant recipients-A report of six cases and review of the literature.

BACKGROUND: We report a case series of histoplasmosis in KTx patients in a children's hospital in an endemic area. METHODS: All KTx cases from January 1, 2002, to August 31, 2016, were reviewed to identify those with disseminated histoplasmosis. RESULTS: The attack rate of histoplasmosis among our KTx patients was 6.9 per 100 cases. The median age at the time of diagnosis was 16 years (11-18). Comorbidities included glomerulosclerosis (3), medullary cystic disease (1), and obstructive uropathy (2) and HIV (1). There were 5 deceased and 1 living-related donor transplants, and no patient had a history of rejection prior to histoplasmosis. Median time from transplant to histoplasmosis was 14.8 months (IQR 2.2-38.3) and 33% occurred in the first year after transplant. Urine and/or serum antigens were positive in all patients. They were either treated with amphotericin B and transitioned to an azole or received azole monotherapy. Most (83%) received chronic suppression with itraconazole. No patients died and relapse occurred in 1 patient after repeat transplant. CONCLUSIONS: KTx patients in endemic areas are at risk for disseminated histoplasmosis. Further study is needed to determine which factors portend the need for fungal prophylaxis in this subset of patients.

Intracranial pathologies associated with central diabetes insipidus in infants.

Background Idiopathic central diabetes insipidus (CDI) has been associated with intracranial pathologies that do not involve the structural pituitary gland or hypothalamus. The objective was to study the association between non-structural hypothalamic/pituitary intracranial pathologies (NSHPIP) with CDI and to review etiologies that may be contributory to the development of CDI. Methods A retrospective query of our intra-institutional database from 2006 to 2015. Children admitted diagnosed with diabetes insipidus (DI) (ICD-9 253.5) between the ages of 0-1 year were included. Patient charts were reviewed to include those who have a documented diagnosis of CDI, hypernatremia (>145 mmol/L), high serum osmolality (>300 mOsm/kg), low urine osmolality (<300 mOsm/kg), and brain imaging reports. Diagnoses of nephrogenic DI were excluded. Results Twenty-three infant patients were diagnosed with CDI. Eleven subjects (48%) had NSHPIP. Of those, 18% had cerebral infarction, 27% had intracranial injury and hemorrhage due to traumatic brain injury, 18% had isolated intraventricular hemorrhage, and 27% had meningitis. Hospital prevalence for NSHPIP, age 0-1 year, ranged from 0.05% to 0.3%. Conclusions Rates of NSHPIP in those with CDI are higher than expected hospital rates (p<0.001), suggesting a possible association between CDI and NSHPIP.

Unrecognized prolonged viral replication in the pathogenesis of human RSV infection.

BACKGROUND: Respiratory symptoms in RSV persist long after the virus is no longer detected by culture. Current concepts of RSV pathogenesis explain this by RSV inducing a long-lasting pathogenic immune cascade. We alternatively hypothesized that prolonged unrecognized RSV replication may be responsible and studied this possibility directly in a human wild-type RSV experimental infection model. OBJECTIVE: The objective of the current report was to define the duration of true human RSV replication by studying it directly in immunocompetent adults experimentally infected with a clinical strain of RSV utilizing this previously established safe and reproducible model. STUDY DESIGN: 35 healthy adult volunteers were inoculated with RSV-A (Memphis-37, a low11 passage clinical strain virus, manufactured from a hospitalized bronchiolitic infant) and evaluated over 12 days. Viral load by culture, parallel quantitative PCR (genomic, message) and RSV-specific IgA, were measured twice daily from serially collected nasal washes. RESULTS: After inoculation, 77% (27/35) of volunteers became RSV infected. As expected, culture-detectable RSV ceased abruptly by the 5-6 t h 15 infection day. However, infected volunteers demonstrated prolonged RSV presence by both genomic and message PCR. RSV-specific IgA rose within respiratory secretions of infected volunteers during same time frame. CONCLUSIONS: RSV replication appears to continue in humans far longer than previously thought. The rise in nasal RSV-specific IgA shortly after infection likely neutralizes culture detectable virus producing misleadingly short durations of infection. Prolonged viral replication helps explain RSV's extended disease manifestations and increases the potential utility of antivirals.

Increasing Linezolid-resistant Enterococcus in a Children's Hospital.

We report a reduction in susceptibility to linezolid among Enterococcus isolates (98% in 2007 vs. 46% in 2014) in parallel with a 5-fold increase in linezolid use. A direct association could not be established as the majority of patients with linezolid nonsusceptible isolates did not have prior linezolid exposure. Nosocomial transmission of the nonsusceptible isolates could certainly have contributed.

Angiostrongylus cantonensis Eosinophilic Meningitis in an Infant, Tennessee, USA.

Angiostrongylus cantonensis, the rat lungworm, is the most common infectious cause of eosinophilic meningoencephalitis worldwide. This parasite is endemic to Southeast Asia and the Pacific Islands, and its global distribution is increasing. We report A. cantonensis meningoencephalitis in a 12-month-old boy in Tennessee, USA, who had not traveled outside of southwestern Tennessee or northwestern Mississippi.