High-level ceftaroline resistance in a paediatric patient with invasive methicillin-resistant Staphylococcus aureus infection without previous ceftaroline exposure.

WHAT IS KNOWN AN OBJECTIVE: Our objective is to report a paediatric case of high-level ceftaroline resistance without previous ceftaroline exposure. CASE DESCRIPTION: A 20-month-old, 12 kg, female with invasive MRSA infection presented with high-level ceftaroline resistance with no previous ceftaroline exposure. WHAT IS NEW AND CONCLUSION: To our knowledge, our case is the first report of high-level ceftaroline resistance evident in a paediatric patient with invasive infection due to MRSA, without history of prior ceftaroline exposure. This case illustrates the importance of weighing the risk of resistance with the benefits of use when starting therapy empirically prior to susceptibility results, even in patients without previous drug exposure.

Beta-Lactam Allergy De-labeling in a Pediatric Hospital.

OBJECTIVE: To assess the ability to de-label pediatric patients of their beta-lactam allergy by using a newly implemented institutional protocol and to identify potential barriers to the de-labeling process. METHODS: All patients with reported allergies to prespecified beta-lactam antibiotics were eligible for a -beta-lactam allergy interview. Following the interview, patients were grouped into 4 risk categories-no risk, low risk, moderate risk, and high risk-and assessed for intervention eligibility. Potential interventions included de-labeling based on the interview alone or proceeding to an oral amoxicillin challenge with or without penicillin allergy skin testing. RESULTS: Of the 62 patients eligible for beta-lactam allergy interviews, 40% (n = 25) were de-labeled. Among de-labeled patients, 60% (n = 15) were de-labeled on the basis of the interview alone. Additionally, no failures were documented in patients who underwent an oral amoxicillin challenge or penicillin skin testing. Barriers to performing oral amoxicillin challenges or penicillin skin testing included concomitant systemic steroid or antihistamine use, refusal of intervention, and insufficient resources to perform penicillin skin testing. CONCLUSIONS: There was a high frequency of patients de-labeled of their beta-lactam allergies in this study. Increased education to patients, parents, and providers on the de-labeling process, as well as increased personnel available to coordinate and perform de-labeling interventions, may result in more beta-lactam allergy de-labeling.

Whole blood gene expression profiles to assess pathogenesis and disease severity in infants with respiratory syncytial virus infection.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of viral lower respiratory tract infection (LRTI) and hospitalization in infants. Mostly because of the incomplete understanding of the disease pathogenesis, there is no licensed vaccine, and treatment remains symptomatic. We analyzed whole blood transcriptional profiles to characterize the global host immune response to acute RSV LRTI in infants, to characterize its specificity compared with influenza and human rhinovirus (HRV) LRTI, and to identify biomarkers that can objectively assess RSV disease severity. METHODS AND FINDINGS: This was a prospective observational study over six respiratory seasons including a cohort of infants hospitalized with RSV (n = 135), HRV (n = 30), and influenza (n = 16) LRTI, and healthy age- and sex-matched controls (n = 39). A specific RSV transcriptional profile was identified in whole blood (training cohort, n = 45 infants; Dallas, Texas, US) and validated in three different cohorts (test cohort, n = 46, Dallas, Texas, US; validation cohort A, n = 16, Turku, Finland; validation cohort B, n = 28, Columbus, Ohio, US) with high sensitivity (94% [95% CI 87%-98%]) and specificity (98% [95% CI 88%-99%]). It classified infants with RSV LRTI versus HRV or influenza LRTI with 95% accuracy. The immune dysregulation induced by RSV (overexpression of neutrophil, inflammation, and interferon genes, and suppression of T and B cell genes) persisted beyond the acute disease, and immune dysregulation was greatly impaired in younger infants (<6 mo). We identified a genomic score that significantly correlated with outcomes of care including a clinical disease severity score and, more importantly, length of hospitalization and duration of supplemental O2. CONCLUSIONS: Blood RNA profiles of infants with RSV LRTI allow specific diagnosis, better understanding of disease pathogenesis, and assessment of disease severity. This study opens new avenues for biomarker discovery and identification of potential therapeutic or preventive targets, and demonstrates that large microarray datasets can be translated into a biologically meaningful context and applied to the clinical setting. Please see later in the article for the Editors' Summary.

Respiratory viruses identified in an urban children's hospital emergency department during the 2009 influenza A(H1N1) pandemic.

OBJECTIVES: Two surges in influenza-like illness (ILI) visits to Children's Medical Center Emergency Departments, Dallas and Legacy, occurred in late spring (wave 1) and late summer 2009 (wave 2). This study describes respiratory viruses identified during the first weeks of waves 1 and 2 of the 2009 influenza A(H1N1) pandemic (pH1N1) and compares patients infected with pH1N1 with those infected with other respiratory viruses during wave 1. METHODS: From April 27 to May 7 and August 23 to September 7, 2009, nasopharyngeal swab specimens from all patients with temperature 38.2°C or higher plus 2 or more symptoms of ILI were tested by rapid antigen, direct fluorescent antibody, or multiplex polymerase chain reaction assays. Patients with pH1N1 during wave 1 were classified as cases and 3 age- and sex-matched controls were randomly selected from patients with 1 respiratory virus other than pH1N1. Odds ratios (ORs) and associated 95% confidence intervals (95% CIs) of characteristics associated with patients with pH1N1 were estimated using conditional logistic regression models. RESULTS: During wave 1, single viruses identified in 1023 symptomatic children were confirmed pH1N1 (55, 5.4%), rhinovirus (505, 49.4%), parainfluenza 3 (199, 19.5%), and human metapneumovirus (169, 16.5%). By multivariable analysis, duration of fever (OR, 1.49; 95% CI, 1.02-2.20) and myalgia at presentation (OR, 3.09; 95% CI, 1.09-8.76) were independent predictors associated with pH1N1. During wave 2, 114 (59.7%) of single viruses were pH1N1. CONCLUSIONS: During the epidemic of ILI in Spring 2009, other respiratory viruses were identified more frequently than pH1N1 influenza in children with ILIs. Clinical presentation was similar for all respiratory viruses. Molecular diagnostic testing can define the prevalent viruses during community outbreaks and provide guidance to physicians making treatment decisions in emergency departments.

Implementation of an Automatic 48-Hour Vancomycin Hard-Stop in a Pediatric Community Hospital.

OBJECTIVE: Previous studies evaluating antimicrobial time-outs and required stop dates on antimicrobial orders indicate that these strategies are effective in decreasing antimicrobial duration and cost without a negative impact on patient outcomes. Few have evaluated use of a hard-stop strategy. The purpose of this study was to determine the feasibility and impact of a vancomycin hard-stop at 48 hours of therapy on vancomycin use. METHODS: This retrospective review compared 2 groups, a hard-stop pre-implementation group from April 2018 through March 2019 and a hard-stop post-implementation group from May 2019 through April 2020. The primary outcome was change in days of therapy (DOT) per ordered course of vancomycin therapy. Secondary outcomes included DOT per 1000 patient days (PD), number of courses continued beyond 48 hours, number of vancomycin concentrations drawn and drug acquisition cost. RESULTS: A total of 554 courses of vancomycin were prescribed (228 in the pre-implementation group and 326 in the post-implementation group). The median DOT per ordered course of vancomycin was 1.58 days (IQR, 1.00-2.59) in the pre-implementation group compared with 1.55 days (IQR, 1.00-1.99) in the post-implementation group (p = 0.51). Fewer vancomycin courses continued beyond 48 hours after hard-stop implementation (23% versus 33%) and fewer vancomycin concentrations were obtained in the post-implementation period than in the pre-implementation period despite more ordered courses of vancomycin therapy, 114 concentrations versus 153 concentrations, respectively. Overall, the total yearly drug acquisition cost savings to the pharmacy equated to $3000. CONCLUSIONS: Implementation of a vancomycin hard-stop at 48 hours of therapy is a feasible antimicrobial stewardship tool that may have significant clinical and operational impacts.

Severe Acute Respiratory Syndrome Coronavirus-2 Pneumonia in a Newborn Treated With Remdesivir and Coronavirus Disease 2019 Convalescent Plasma.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel pandemic virus. Mounting evidence supports the possibility of vertical transmission, which at the present time appears to be rare. We report a newborn with vertically acquired SARS-CoV-2 who developed acute respiratory failure and received remdesivir and coronavirus disease 2019 convalescent plasma.

Viral Bacterial Interactions in Children: Impact on Clinical Outcomes.

Respiratory viral infections are associated with significant morbidity and mortality in children < 5 years of age worldwide. Among all respiratory viruses, respiratory syncytial virus (RSV) is the world's leading cause of bronchiolitis and pneumonia in young children. There are known populations at risk for severe disease but the majority of children who require hospitalization for RSV infection are previously healthy. Viral and host factors have been associated with the pathogenesis of RSV disease; however, the mechanisms that explain the wide variability in the clinical presentation are not completely understood. Recent studies suggest that the complex interaction between the respiratory microbiome, the host's immune response and the virus may have an impact on the pathogenesis and severity of RSV infection. In this review, we summarize the current evidence regarding the epidemiologic link, the mechanisms of viral-bacterial interactions, and the associations between the upper respiratory tract microbiome and RSV disease severity.

Whole blood transcriptional profiles as a prognostic tool in complete and incomplete Kawasaki Disease.

BACKGROUND: Early identification of children with Kawasaki Disease (KD) is key for timely initiation of intravenous immunoglobulin (IVIG) therapy. However, the diagnosis of the disease remains challenging, especially in children with an incomplete presentation (inKD). Moreover, we currently lack objective tools for identification of non-response (NR) to IVIG. METHODS: Children with KD were enrolled and samples obtained before IVIG treatment and sequentially at 24 h and 4-6 weeks post-IVIG in a subset of patients. We also enrolled children with other febrile illnesses [adenovirus (AdV); group A streptococcus (GAS)] and healthy controls (HC) for comparative analyses. Blood transcriptional profiles were analyzed to define: a) the cKD and inKD biosignature, b) compare the KD signature with other febrile illnesses and, c) identify biomarkers predictive of clinical outcomes. RESULTS: We identified a cKD biosignature (n = 39; HC, n = 16) that was validated in two additional cohorts of children with cKD (n = 37; HC, n = 20) and inKD (n = 13; HC, n = 8) and was characterized by overexpression of inflammation, platelets, apoptosis and neutrophil genes, and underexpression of T and NK cell genes. Classifier genes discriminated KD from adenovirus with higher sensitivity and specificity (92% and 100%, respectively) than for GAS (75% and 87%, respectively). We identified a genomic score (MDTH) that was higher at baseline in IVIG-NR [median 12,290 vs. 5,572 in responders, p = 0.009] and independently predicted IVIG-NR. CONCLUSION: A reproducible biosignature from KD patients was identified, and was similar in children with cKD and inKD. A genomic score allowed early identification of children at higher risk for non-response to IVIG.

The Effect of 13-Valent Pneumococcal Conjugate Vaccine on the Serotype Distribution and Antibiotic Resistance Profiles in Children With Invasive Pneumococcal Disease.

BACKGROUND: Invasive pneumococcal disease (IPD) continues to be a significant burden in children despite the implementation of two generations of conjugate vaccines. Serotype replacement by nonvaccine serotypes is reported in multiple areas around the world. This study is a continuation of previous studies and describes the incidence, serotype distribution, and antibiotic resistance pattern of Streptococcus pneumoniae serotypes causing IPD at Children's Medical Center Dallas after introduction of 13-valent pneumococcal conjugate vaccine (PCV13). METHODS: Streptococcus pneumoniae isolates from normally sterile sites were collected from January 1, 1999 to June 30, 2014. Demographic and clinical information was extracted for analysis. Incidence of IPD was calculated using inpatient and emergency center admissions to Children's Medical Center of Dallas as the denominator. Isolates were serotyped and penicillin/cefotaxime susceptibilities were determined. Selected nontypeable isolates were further characterized by multilocus sequence typing. A χ2 test and the Cochran-Armitage Trend Test for trend analysis were used to evaluate change in serotype and antibiotic susceptibility patterns over time. RESULTS: Comparison of the different study periods showed a significant reduction in the incidence of IPD in PCV13 era compared with prevaccine era and PCV7 era (P < .05). Children younger than 24 months showed the largest reduction of disease incidence. More than 40% of patients with IPD had a documented comorbidity. Cases of pneumonia continued to decrease in the PCV13 era (P < .002). The most common non-PCV13 serotypes after vaccine introduction were as follows: 23B, 6C, 23A, 9N/L, and 12. Penicillin resistance by meningitis breakpoint decreased significantly in the PCV13 era. CONCLUSIONS: After introduction of PCV13 in Dallas, incidence of IPD caused by strains contained in the vaccine and penicillin resistance continued to decrease. Serotype replacement phenomena and persistence of PCV7 serotypes were documented. Patients with comorbidities represented a large percentage of patients with IPD. Concerns for geographic variation in serotype replacement phenomena arise from the present study.

Aotus lemurinus griseimembra monkeys: a suitable model for Plasmodium vivax sporozoite infection.

This study describes a successful Plasmodium vivax sporozoite infection in Aotus lemurinus griseimembra. Twenty-eight naive or previously infected monkeys, either splenectomized or spleen intact, were inoculated intravenously or subcutaneously with Plasmodium vivax sporozoites of the Salvador I strain or with two wild isolates (VCC-4 and VCC-5; Vivax-Cali-Colombia). The monkeys were successfully infected regardless of the parasite strain, spleen presence, or inoculation route and showed prepatent periods that ranged from 16 to 89 days. Only one monkey inoculated intravenously failed to develop parasitemia. Since immune protection against malaria pre-erythrocytic forms is mediated by both helper and cytolytic T cells that may home in the spleen and P. vivax cultures are not yet available; the use of spleen-intact A. lemurinus griseimembra, susceptible to both adapted and non-adapted strains of P. vivax sporozoites, is a valuable model for evaluation of pre-erythrocytic vaccine candidates.

A Case of Idiopathic Hypereosinophilic Syndrome Causing Mitral Valve Papillary Muscle Rupture.

Idiopathic Hypereosinophilic Syndrome (IHES) is a rare disease that can be difficult to diagnose as the differential is broad. This disease can cause significant morbidity and mortality if left untreated. Our patient is a 17-year-old adolescent female who presented with nonspecific symptoms of abdominal pain and malaise. She was incidentally found to have hypereosinophilia of 16,000 on complete blood count and nonspecific colitis and pulmonary edema on computed tomography. She went into cardiogenic shock due to papillary rupture of her mitral valve requiring extreme life support measures including intubation and extracorporal membrane oxygenation (ECMO) as well as mitral valve replacement. Pathology of the valve showed eosinophilic infiltration as the underlying etiology. The patient was diagnosed with IHES after the exclusion of infectious, rheumatologic, and oncologic causes. She was treated with steroids with improvement of her symptoms and scheduled for close follow-up. In general patients with IHES that have cardiac involvement have poorer prognoses.

Culture Negative Stent Infection in an Infant with Hypoplastic Left Heart and Persistent Fever.

We present an infant with hypoplastic left heart with persistent fever despite two courses of antibiotics and repeatedly negative blood cultures. He eventually underwent surgical extraction of two stents. The stent cultures became positive; he was treated with 4 weeks of antibiotics and the fever resolved.

Host immune transcriptional profiles reflect the variability in clinical disease manifestations in patients with Staphylococcus aureus infections.

Staphylococcus aureus infections are associated with diverse clinical manifestations leading to significant morbidity and mortality. To define the role of the host response in the clinical manifestations of the disease, we characterized whole blood transcriptional profiles of children hospitalized with community-acquired S. aureus infection and phenotyped the bacterial strains isolated. The overall transcriptional response to S. aureus infection was characterized by over-expression of innate immunity and hematopoiesis related genes and under-expression of genes related to adaptive immunity. We assessed individual profiles using modular fingerprints combined with the molecular distance to health (MDTH), a numerical score of transcriptional perturbation as compared to healthy controls. We observed significant heterogeneity in the host signatures and MDTH, as they were influenced by the type of clinical presentation, the extent of bacterial dissemination, and time of blood sampling in the course of the infection, but not by the bacterial isolate. System analysis approaches provide a new understanding of disease pathogenesis and the relation/interaction between host response and clinical disease manifestations.

Consistent safety and infectivity in sporozoite challenge model of Plasmodium vivax in malaria-naive human volunteers.

A safe and reproducible Plasmodium vivax infectious challenge method is required to evaluate the efficacy of malaria vaccine candidates. Seventeen healthy Duffy (+) and five Duffy (-) subjects were randomly allocated into three (A-C) groups and were exposed to the bites of 2-4 Anopheles albimanus mosquitoes infected with Plasmodium vivax derived from three donors. Duffy (-) subjects were included as controls for each group. Clinical manifestations of malaria and parasitemia were monitored beginning 7 days post-challenge. All Duffy (+) volunteers developed patent malaria infection within 16 days after challenge. Prepatent period determined by thick smear, was longer for Group A (median 14.5 d) than for Groups B and C (median 10 d/each). Infected volunteers recovered rapidly after treatment with no serious adverse events. The bite of as low as two P. vivax-infected mosquitoes provides safe and reliable infections in malaria-naive volunteers, suitable for assessing antimalarial and vaccine efficacy trials.

Immune responses and protection of Aotus monkeys immunized with irradiated Plasmodium vivax sporozoites.

A non-human primate model for the induction of protective immunity against the pre-erythrocytic stages of Plasmodium vivax malaria using radiation-attenuated P. vivax sporozoites may help to characterize protective immune mechanisms and identify novel malaria vaccine candidates. Immune responses and protective efficacy induced by vaccination with irradiated P. vivax sporozoites were evaluated in malaria-naive Aotus monkeys. Three groups of six monkeys received two, five, or ten intravenous inoculations, respectively, of 100,000 irradiated P. vivax sporozoites; control groups received either 10 doses of uninfected salivary gland extract or no inoculations. Immunization resulted in the production low levels of antibodies that specifically recognized P. vivax sporozoites and the circumsporozoite protein. Additionally, immunization induced low levels of antigen-specific IFN-γ responses. Intravenous challenge with viable sporozoites resulted in partial protection in a dose-dependent manner. These findings suggest that the Aotus monkey model may be able to play a role in preclinical development of P. vivax pre-erythrocytic stage vaccines.

Concomitant respiratory viral infections in children with Kawasaki disease.

The role of respiratory viruses in the pathogenesis of Kawasaki disease (KD) remains controversial. In this study, we showed that 8.8% of patients with KD had documented respiratory viral infections. Patients with concomitant viral infections had a higher frequency of coronary artery dilatations and were significantly more often diagnosed with incomplete KD. The presence of a concomitant viral infection should not exclude the diagnosis of KD.