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Guidelines for management of Melody transcatheter pulmonary valve (TPV) infective endocarditis (IE) are lacking. We aimed to identify factors associated with surgical valve removal versus antimicrobial therapy in Melody TPV IE. Multicenter retrospective analysis of all patients receiving Melody TPV from 10/2010 to 3/2019 was performed to identify cases of IE. Surgical explants versus non-surgical cases were compared. Of the 663 Melody TPV implants, there were 66 cases of IE in 59 patients (59/663, 8.8%). 39/66 (59%) were treated with IV antimicrobials and 27/66(41%) underwent valve explantation. 26/59 patients (44%) were treated medically without explantation or recurrence with average follow-up time of 3.5 years (range:1-9). 32% of Streptococcus cases, 53% of MSSA, and all MRSA cases were explanted. 2 of the 4 deaths had MSSA. CART analysis demonstrated two important parameters associated with explantation: a peak echo gradient ≥ 47 mmHg at IE diagnosis(OR 10.6, p  24 mmHg compared to baseline (OR 6.7, p = 0.01). Rates of explantation varied by institution (27 to 64%). In our multicenter experience, 44% of patients with Melody IE were successfully medically treated without valve explantation or recurrence. The degree of valve stenosis at time of IE diagnosis was strongly associated with explantation. Rates of explantation varied significantly among the institutions.

Increasing prevalence of infections caused by antimicrobial-resistant gram-negative bacteria represents a global health crisis, and while several novel therapies that target various aspects of antimicrobial resistance have been introduced in recent years, few are currently approved for children. Ceftazidime-avibactam is a novel β-lactam β-lactamase inhibitor combination approved for adults and children 3 months and older with complicated intra-abdominal infection, and complicated urinary tract infection or hospital-acquired ventilator-associated pneumonia (adults only in the United States) caused by susceptible gram-negative bacteria. Extensive population pharmacokinetic (PK) data sets for ceftazidime and avibactam obtained during the adult clinical development program were used to iteratively select, modify, and validate the approved adult dosage regimen (2,000-500 mg by 2-hour intravenous (IV) infusion every 8 hours (q8h), with adjustments for renal function). Following the completion of one phase I (NCT01893346) and two phase II ceftazidime-avibactam studies (NCT02475733 and NCT02497781) in children, adult PK data sets were updated with pediatric PK data. This paper describes the development of updated combined adult and pediatric population PK models and their application in characterizing the population PK of ceftazidime and avibactam in children, and in dose selection for further pediatric evaluation. The updated models supported the approval of ceftazidime-avibactam pediatric dosage regimens (all by 2-hour IV infusion) of 50-12.5 mg/kg (maximum 2,000-500 mg) q8h for those ≥6 months to 18 years old, and 40-10 mg/kg q8h for those ≥3 to 6 months old with creatinine clearance > 50 mL/min/1.73 m2 .

Amorphous silicates in meteoritic samples are significant as potential surviving interstellar dust from the formation of the Solar System. Amorphous silicate-rich grains called GEMS, glass with embedded metal and sulfides, are abundant in anhydrous interplanetary dust particles and some ultracarbonaceous Antarctic micrometeorites that have high presolar grain abundances. Some GEMS within these objects have been confirmed to be presolar. GEMS-like material, consisting of amorphous silicate with opaque inclusions, has been identified in the matrices of some primitive meteorites. We use specialized thin specimen preparation and transmission electron microscopy methods to compare the GEMS-like material in Paris (CM) and Acfer 094 (ungrouped) chondrites with GEMS in anhydrous, chondritic interplanetary dust particles. Specifically, we compared the amorphous silicate morphology, degree of partial ordering, elemental composition and dominant iron oxidation state. We find that the amorphous silicates in the GEMS-like materials in Paris and Acfer 094 show incipient ordering and are Fe-rich and highly oxidized, while those in GEMS are fully amorphous, Fe-poor, and anhydrous. From examination of various formation routes for the amorphous silicates, we conclude that the GEMS-like material in Paris and Acfer 094 is not GEMS and that it is unlikely that GEMS-like material accreted as primary amorphous material that retained its original amorphous structure since accretion. We also conclude that the presence of GEMS-like amorphous silicates in chondrite matrix is not a reliable indicator for high degrees of primitivity or pristinity since even mild, complex alteration processes may significantly alter silicate structure. Finally, we propose searches for presolar amorphous silicates in chondrite matrix samples that have been precharacterized by transmission electron microscopy methods to enable direct comparisons of presolar amorphous silicate abundances.

We report on the electrical properties of 2.0 eV bandgap (EG) CuInGaS2 (CIGS) solar absorbers integrated on SnO2:F (FTO) substrates and interfaced with CdS buffer layers for multijunction solar cells and photoelectrochemical water splitting devices. The averaged short-circuit photocurrent density measured on nine ITO/ZnO/CdS/CIGS/FTO cells was 10.0 mA cm-2, a value corresponding to 70% of the optical limit for a 2.0 eV-bandgap absorber. However, the averaged power conversion efficiency was low (avg.: 2.4%) and for the most part limited by modest open circuit voltage values (avg.: 587 mV). Solid-state analyses performed at low temperatures revealed poor energetic alignment at the CdS/CIGS top interface. An activation energy (1.1 eV) for the dominant recombination mechanism significantly lower than the CIGS bandgap was measured, implying that recombination takes place near the CdS/CIGS interface. This finding is supported by the large difference found between the quasi Fermi level splitting of the bare absorber (1.17 eV) and the open circuit voltage of the device. Complementary theoretical calculations identified Fermi level pinning as a possible cause for the poor interface energetics through Cd incorporation on both the Cu and the group-III sites, resulting in a large conduction band offset (∼0.9 eV) at the CdS/CIGS interface. This work underlines the need for new EG-tunable buffers coupled with optimized CIGS surface energetics (e.g. ordered vacancy compounds) for future chalcopyrite-based multijunction solar cells and photoelectrochemical water splitting devices. This journal is

BackgroundOsteoarticular infections (OAIs) are frequently encountered in children. Treatment may be guided by isolation of a pathogen; however, operative cultures are often negative. Metagenomic next-generation sequencing (mNGS) allows for broad and sensitive pathogen detection that is culture-independent. We sought to evaluate the diagnostic utility of mNGS in comparison to culture and usual care testing to detect pathogens in acute osteomyelitis and/or septic arthritis in children.MethodsThis was a single-site study to evaluate the use of mNGS in comparison to culture to detect pathogens in acute pediatric osteomyelitis and/or septic arthritis. Subjects admitted to a tertiary children's hospital with suspected OAI were eligible for enrollment. We excluded subjects with bone or joint surgery within 30 days of admission or with chronic osteomyelitis. Operative samples were obtained at the surgeon's discretion per standard care (fluid or tissue) and based on imaging and operative findings. We compared mNGS to culture and usual care testing (culture and polymerase chain reaction [PCR]) from the same site.ResultsWe recruited 42 subjects over the enrollment period. mNGS of the operative samples identified a pathogen in 26 subjects compared to 19 subjects in whom culture identified a pathogen. In 4 subjects, mNGS identified a pathogen where combined usual care testing (culture and PCR) was negative. Positive predictive agreement and negative predictive agreement both were 93.0% for mNGS.ConclusionsIn this single-site prospective study of pediatric OAI, we demonstrated the diagnostic utility of mNGS testing in comparison to culture and usual care (culture and PCR) from operative specimens.

Infections remain a leading cause of death in neonates. The sparse antibiotic development pipeline and challenges in conducting neonatal research have resulted in few effective antibiotics being adequately studied to treat multidrug-resistant (MDR) infections in neonates, despite the increasing global mortality burden caused by antimicrobial resistance. Of 40 antibiotics approved for use in adults since 2000, only four have included dosing information for neonates in their labelling. Currently, 43 adult antibiotic clinical trials are recruiting patients, compared with only six trials recruiting neonates. We review the World Health Organization (WHO) priority pathogens list relevant to neonatal sepsis and propose a WHO multiexpert stakeholder meeting to promote the development of a neonatal priority antibiotic development list. The goal is to develop international, interdisciplinary consensus for an accelerated neonatal antibiotic development programme. This programme would enable focused research on identified priority antibiotics for neonates to reduce the excess morbidity and mortality caused by MDR infections in this vulnerable population. Les infections demeurent l'une des principales causes de deces chez les nouveau-nes. Les rares projets de developpement d'antibiotiques et les defis poses par la recherche neonatale ont entraine une penurie d'antibiotiques efficaces specialement etudies pour traiter les infections multiresistantes (MR) chez les nouveau-nes, en depit d'une mortalite galopante due a une resistance accrue aux antimicrobiens. Sur 40 antibiotiques autorises pour les adultes depuis 2000, quatre a peine sont munis d'un etiquetage indiquant la posologie adaptee aux nouveaunes. Actuellement, 43 essais cliniques portant sur des antibiotiques recrutent des patients du cote des adultes, contre six seulement du cote des nouveau-nes. Dans le present document, nous passons en revue la liste prioritaire d'agents pathogenes etablie par l'Organisation mondiale de la Sante (OMS) pour soigner la septicemie neonatale et proposons de reunir, sous l'egide de l'OMS, des parties prenantes issues de plusieurs domaines d'expertise afin de promouvoir la creation d'une liste prioritaire de developpement d'antibiotiques destines aux nouveaunes. Objectif: parvenir a un consensus international et interdisciplinaire visant a accelerer le programme de mise au point d'antibiotiques a usage neonatal. Ce programme permettrait d'orienter les recherches vers des antibiotiques identifies comme prioritaires pour les nouveau-nes, en vue de faire baisser les taux de morbidite et de mortalite excessifs qu'engendrent les infections MR au sein de cette population vulnerable. Las infecciones siguen siendo una de las principales causas de muerte en los recien nacidos. Debido al escaso desarrollo de los antibioticos y a las dificultades para llevar a cabo la investigacion neonatal, son pocos los antibioticos eficaces que se estudian de manera adecuada para tratar las infecciones multirresistentes (MR) en los recien nacidos, a pesar de la creciente carga de mortalidad mundial causada por la resistencia a los antimicrobianos. De los 40 antibioticos aprobados para su uso en adultos desde el 2000, solo cuatro han incluido informacion sobre la dosis para recien nacidos en su etiquetado. En la actualidad, 43 ensayos clinicos con antibioticos para adultos estan reclutando pacientes, en comparacion con solo seis ensayos que reclutan recien nacidos. Se revisa la lista de patogenos prioritarios de la Organizacion Mundial de la Salud (OMS) relevantes para la sepsis neonatal y se propone una reunion de la OMS con multiples expertos para promover el desarrollo de una lista de antibioticos prioritarios para los recien nacidos. El objetivo es desarrollar un consenso internacional e interdisciplinario para establecer un programa acelerado de desarrollo de antibioticos neonatales. Este programa permitiria centrar la investigacion en los antibioticos prioritarios identificados para los recien nacidos con el fin de reducir el exceso de morbilidad y mortalidad causado por las infecciones MR en esta poblacion vulnerable., Introduction Despite a significant decline in deaths in children younger than 5 years globally in the past three decades, preventable and treatable infectious diseases remain the leading cause of death [...]

The current antimicrobial market and old (pre-2000) in vitro antimicrobial susceptibility test interpretative criteria (STIC) are not working properly. Malfunctioning susceptibility breakpoints and antimicrobial markets have serious implications for both patients (ie, from a safety and efficacy perspective) and antibiotic-focused pharmaceutical and biotechnology company economic viability. Poorly functioning STIC fail both patients and clinicians since they do not discriminate between likely effective and ineffective antimicrobial regimens. Poor economic viability fails patients and clinicians as it decreases the industry's ability to develop antimicrobial agents that clinicians and patients urgently require now and in the future. Herein, we review how STIC for older antimicrobial agents were determined and how their correction can impact the perceived utility of old relative to new antimicrobial agents. Moreover, we describe the data and analysis needs to systematically reevaluate older STIC values. We call for professional infectious diseases societies, government agencies, and other consensus bodies interested in the appropriate use of antimicrobial agents to join an effort to systematically evaluate and, where warranted, correct STIC for all relevant antimicrobial agents. This effort will amplify the effects of other measures designed to increase appropriate antimicrobial use (ie, good antimicrobial stewardship), development, and regulation.

ObjectivesThe objectives of this study were to 1) define extent and potential clinical impact of increased or decreased renal elimination of meropenem in children with sepsis, based on analysis of renal function during the first 2 days of PICU stay; and 2) estimate the risk of subtherapeutic meropenem exposure attributable to increased renal clearance.MethodsThis retrospective study evaluated patients with a diagnosis of sepsis, receiving meropenem from the PICU at Rady Children's Hospital San Diego from 2015-2017. Meropenem exposure was estimated by using FDA-approved doses (20 and 40 mg/kg/dose) on day 1 and day 2 of PICU stay, based on a population pharmacokinetic (PK) model. For this population with sepsis, we assessed time-above-minimum inhibitory concentration (T>MIC) for pathogen MICs.ResultsMeropenem treatment was documented in 105 episodes of sepsis with a 48% rate of pathogen detection. By day 2, increased eGFR (>120 mL/min/1.73 m2) was documented in 49% of patients, with 17% meeting criteria for augmented renal clearance ([ARC] >160 mL/min/1.73 m2) and 10%, for decreased function. Simulations documented that 80% of PICU patients with ARC did not achieve therapeutic meropenem exposure for Pseudomonas aeruginosa with a MIC of 2, using standard doses to achieve a pharmacodynamic goal of 80% T>MIC.ConclusionsApproximately 3 of every 20 children with sepsis exhibited ARC during the first 48 hours of PICU stay. Simulations documented an increased risk for subtherapeutic meropenem exposure, suggesting that higher meropenem doses may be required to achieve adequate antibiotic exposure early in the PICU course.

Haemophilus influenzae causes common and sometimes severe adult and pediatric disease including chronic obstructive respiratory disease, otitis media and infections of the central nervous system. Serotype b strains, with a b-type capsule, have been the historical cause of invasive disease, and the introduction of a serotype b-specific vaccine has led to their decline. However, unencapsulated or non-b-type H. influenzae infections are not prevented by the vaccine and appear to be increasing in frequency. Here we report two pediatric cases of severe central nervous system H. influenzae infection presenting to the same hospital in San Diego, California during the same week in January 2016. Due to good vaccine coverage in this part of the world, H. influenzae cases are normally rare and seeing two cases in the same week was unexpected. We thus suspected a recent transmission chain, and possible local outbreak. To test this hypothesis, we isolated and sequenced whole genomes from each patient and placed them in a phylogenetic tree spanning the known diversity of H. influenzae. Surprisingly, we found that the two isolates (SD2016_1 and SD2016_2) belonged to distantly related lineages, suggesting two independent transmission events and ruling out a local outbreak. Despite being distantly related, the two isolates belong to two different lineages that have exchanged capsule loci in the recent past. Therefore, as in other bacterial pathogens, capsule switching by horizontal gene transfer may be an important evolutionary mechanism of vaccine evasion in H. influenzae.