Aspergillus terreus is an uncommon but emerging fungal pathogen, which causes lethal infections that are often refractory to amphotericin B (AmB). In comparison to Aspergillus fumigatus, A. terreus was resistant to the in vitro fungicidal effects of safely achievable concentrations of AmB. These in vitro findings correlated directly with resistance of A. terreus to AmB in experimental invasive pulmonary aspergillosis. Residual fungal pulmonary burden and galactomannan antigenemia demonstrated persistent infection, despite therapy with deoxycholate AmB or liposomal AmB. By comparison, posaconazole and itraconazole resolved GM antigenemia, reduced residual fungal burden, and improved survival. There were no differences in phagocytic host response to A. terreus versus A. fumigatus; however, the rate of conidial germination of A. terreus was slower. The strain of A. terreus with the highest minimum inhibitory and minimum lethal concentration of AmB also had the lowest membrane ergosterol content. The hyphae of A. terreus in vivo displayed distinctive aleurioconidia, which may be a practical microscopic feature for rapid preliminary diagnosis.

The antifungal efficacy, safety, and pharmacokinetics of posaconazole (SCH 56592) (POC) were investigated in treatment and prophylaxis of primary pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Antifungal therapy consisted of POC at 2, 6, and 20 mg/kg of body weight per os; itraconazole (ITC) at 2, 6, and 20 mg/kg per os; or amphotericin B (AMB) at 1 mg/kg intravenously. Rabbits treated with POC showed a significant improvement in survival and significant reductions in pulmonary infarct scores, total lung weights, numbers of pulmonary CFU per gram, numbers of computerized-tomography-monitored pulmonary lesions, and levels of galactomannan antigenemia. AMB and POC had comparable therapeutic efficacies by all parameters. By comparison, animals treated with ITC had no significant changes in outcome variables in comparison to those of untreated controls (UC). Rabbits receiving prophylactic POC at all dosages showed a significant reduction in infarct scores, total lung weights, and organism clearance from lung tissue in comparison to results for UC (P < 0.01). There was dosage-dependent microbiological clearance of A. fumigatus from lung tissue in response to POC. Serum creatinine levels were greater (P < 0.01) in AMB-treated animals than in UC and POC-or ITC-treated rabbits. There was no elevation of serum hepatic transaminase levels in POC-or ITC-treated rabbits. The pharmacokinetics of POC and ITC in plasma demonstrated dose dependency after multiple dosing. The 2-, 6-, and 20-mg/kg dosages of POC maintained plasma drug levels above the MICs for the entire 24-h dosing interval. In summary, POC at >6 mg/kg/day per os generated sustained concentrations in plasma of >1 g/ml that were as effective in the treatment and prevention of invasive pulmonary aspergillosis as AMB at 1 mg/kg/day and more effective than cyclodextrin ITC at >6 mg/kg/day per os in persistently neutropenic rabbits.

Objective Intensive care unit acquired weakness (ICU-AW), comprised of critical illness myopathy (CIM) and critical illness neuropathy (CIN), occurs in a significant proportion of critically ill adults and is associated with high morbidity and mortality. Little is known about ICU-AW among critically ill children. We investigated the incidence of ICU-AW among pediatric intensive care units (PICU) participating in the Virtual PICU Systems (VPS) database. We also sought to identify associated risk factors for ICU-AW and evaluate the hypothesis that ICU-AW is associated with poor clinical outcomes. Design Retrospective cohort study. Setting Pediatric Intensive Care Unit. Measurements VPS was queried for CIM and CIN between 1/2009 and 11/2013. Demographic, admission, and clinical outcome variables including mechanical ventilation days, PICU length of stay (LOS), and discharge disposition were analyzed. The Pediatric Index of Mortality-2 (PIM-2) was used to evaluate and control for illness severity and risk of mortality. Results Among 203,875 admissions there were 55 cases of CIM reported and no cases of CIN, resulting in an incidence of 0.02%. Mechanical ventilation days were higher among patients with ICU-AW versus those that did not develop ICU-AW (31.6 ± 28.9 vs 9.3 ±20.6, p<0.001). In our multivariable analysis, when controlling for PIM-2, ICU-AW was more frequently reported in those with admission diagnoses of respiratory illness and infection, and the need for mechanical ventilation, renal replacement therapy, extracorporeal life support, and tracheostomy. ICU-AW was associated with a longer PICU LOS, episodes requiring mechanical ventilation, and discharge to an intermediate, chronic care, and rehabilitation care unit. ICU-AW was not independently associated with mortality. Conclusions ICU-AW is uncommonly diagnosed among PICU patients reported in VPS. ICU-AW is associated with critical care therapies, invasive procedures and resource utilization. Limitations of our retrospective study include under-recognition of ICU-AW and lack of standardized diagnostic criteria within VPS. Prospective studies are needed to better understand the true incidence, risk factors, and clinical course for patients who develop ICU-AW.

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AIM:To investigate the diagnostic yield, therapeutic efficacy, and rate of adverse events related to flexible fiberoptic bronchoscopy (FFB) in critically ill children. METHODS:We searched PubMed, SCOPUS, OVID, and EMBASE databases through July 2014 for English language publications studying FFB performed in the intensive care unit in children < 18 years old. We identified 666 studies, of which 89 full-text studies were screened for further review. Two reviewers independently determined that 27 of these studies met inclusion criteria and extracted data. We examined the diagnostic yield of FFB among upper and lower airway evaluations, as well as the utility of bronchoalveolar lavage (BAL). RESULTS:We found that FFB led to a change in medical management in 28.9% (range 21.9%-69.2%) of critically ill children. The diagnostic yield of FFB was 82% (range 45.2%-100%). Infectious organisms were identified in 25.7% (17.6%-75%) of BALs performed, resulting in a change of antimicrobial management in 19.1% (range: 12.2%-75%). FFB successfully reexpanded atelectasis or removed mucus plugs in 60.3% (range: 23.8%-100%) of patients with atelectasis. Adverse events were reported in 12.9% (range: 0.5%-71.4%) of patients. The most common adverse effects of FFB were transient hypotension, hypoxia and/ or bradycardia that resolved with minimal intervention, such as oxygen supplementation or removal of the bronchoscope. Serious adverse events were uncommon; 2.1% of adverse events required intervention such as bag-mask ventilation or intubation and atropine for hypoxia and bradycardia, normal saline boluses for hypotension, or lavage and suctioning for hemorrhage. CONCLUSION:FFB is safe and effective for diagnostic and therapeutic use in critically ill pediatric patients.

Pulmonary arteriovenous malformations (PAVMs) are a common source of morbidity after bidirectional superior cavopulmonary anastomosis (Glenn). The diversion of hepatic venous effluent away from the pulmonary circulation after Glenn appears to play a significant role in the pathogenesis of PAVMs. Although the liver is known to produce factors that regulate vascular development, specific hepatic inhibitors of angiogenesis have not been described in the post-Glenn population. Endostatin, produced from its precursor collagen XVIII, is a potent inhibitor of angiogenesis produced by the liver. This study aimed to investigate the hypothesis that endostatin levels decrease in patients after Glenn. Levels of endostatin and its precursor, long-type collagen XVIII, were determined by enzyme-linked immunoassay and immunoprecipitation, respectively, for serum samples from 38 patients undergoing Glenn, total cavopulmonary anastomosis (Fontan), or biventricular repair of cardiac defects. Samples were obtained before surgery and 24 h afterward. In patients undergoing a bidirectional Glenn procedure, endostatin levels decreased after surgery (n = 17; 4.42 vs 3.34 ng/ml; p < 0.001), and long type-collagen XVIII levels increased by 200 % (n = 10; p = 0.0001). However, endostatin levels did not change after surgery in patients undergoing Fontan (n = 13) or biventricular repair (n = 8). In patients undergoing Fontan, long-type collagen XVIII increased by 18 % (p < 0.01), whereas in control subjects, the levels were unchanged. These data suggest that the diversion of hepatic blood flow away from the pulmonary circulation in patients after the Glenn procedure inhibits endostatin production from collagen XVIII, resulting in decreased circulating serum endostatin levels. A decrease in endostatin may promote angiogenesis. The mechanism whereby the pulmonary circulation processes endostatin and its potential role in the pathogenesis of PAVMs warrant further study.

The plasma pharmacokinetics of multilamellar liposomal nystatin were studied in normal, catheterized rabbits after single and multiple daily intravenous administration of dosages of 2, 4, and 6 mg/kg of body weight, and drug levels in tissues were assessed after multiple dosing. Concentrations of liposomal nystatin were measured as those of nystatin by a validated high-performance liquid chromatography method, and plasma concentration data were fitted into a two-compartment open model. Across the investigated dosage range, liposomal nystatin demonstrated nonlinear kinetics with more than proportional increases in the AUC(0-24) and decreasing clearance, consistent with dose-dependent tissue distribution and/or a dose-dependent elimination process. After single-dose administration, the mean C(max) increased from 13.07 microg/ml at 2 mg/kg to 41.91 microg/ml at 6 mg/kg (P < 0.001); the AUC(0-24) changed from 11.65 to 67.44 microg. h/ml (P < 0.001), the V(d) changed from 0.205 to 0. 184 liters/kg (not significant), the CL(t) from 0.173 to 0.101 liters/kg. h (P < 0.05), and terminal half-life from 0.96 to 1.51 h (P < 0.05). There were no significant changes in pharmacokinetic parameters after multiple dosing over 14 days. Assessment of tissue concentrations of nystatin near peak plasma levels after multiple dosing over 15 days revealed preferential distribution to the lungs, liver, and spleen at that time point. Substantial levels were also found in the urine, raising the possibility that renal excretion may play a significant role in drug elimination. Liposomal nystatin administered to rabbits was well tolerated and displayed nonlinear pharmacokinetics, potentially therapeutic peak plasma concentrations, and substantial penetration into tissues. Pharmacokinetic parameters were very similar to those observed in patients, thus validating results derived from infection models in the rabbit and allowing inferences to be made about the treatment of invasive fungal infections in humans.

Objective Congenital heart disease (CHD) with increased pulmonary blood flow (PBF) results in progressive pulmonary vascular endothelial dysfunction and associated increased perioperative morbidity. Utilizing our ovine model of CHD with increased PBF, we have previously demonstrated progressive endothelial dysfunction associated with disruption in carnitine homeostasis, mitochondrial dysfunction, decreased nitric oxide (NO) signaling, and enhanced reactive oxygen species (ROS) generation. However, potential alterations in these parameters in patients with CHD have not been investigated. The objective of this study was to test the hypothesis that children with increased PBF will have evidence of altered carnitine homeostasis, mitochondrial dysfunction, decreased NO levels, and increased ROS generation. Design A prospective single center cohort study Setting A tertiary care CICU/PICU Patients Arterial blood samples from 18 patients with CHD associated with increased PBF (ventricular septal defect, VSD), 20 with CHD without increased PBF (tetralogy of Fallot, TOF), and 10 without heart disease (controls) were obtained. Interventions Plasma levels of total carnitine (TC), free carnitine (FC), acylcarnitine (AC); and lactate-to-pyruvate ratios, an indicator of mitochondrial function, were determined and compared. In addition, levels of superoxide and hydrogen peroxide were determined and compared in patients with VSD and controls. Statistical analysis was performed using an unpaired t-test and ANOVA. Measurements and Main Results Baseline AC levels (25.7 ± 13 vs. 12.7 ± 8.3, P<0.05), the AC:FC ratio (0.8 ± 0.1 vs. 0.3 ± 0.05, P<0.05), and the lactate/pyruvate ratio were higher in VSD (27.5 ± 3.8 vs. 11.1 ± 4.1, P<0.05) than TOF; there were no differences between TOF and control. Superoxide and H2O2 levels were also higher in VSD compared to controls, and NOx levels were lower in VSD patients compared to TOF and controls (P<0.05). Conclusions These data suggest that increased PBF from VSD results in altered carnitine and mitochondrial homeostasis, decreased NO signaling, and increased ROS production. These data are consistent with our animal data demonstrating that altered carnitine homeostasis results in mitochondrial dysfunction, increased ROS production, and decreased bioavailable NO. Since disruption of carnitine metabolism may contribute to endothelial dysfunction, carnitine supplementation may attenuate endothelial dysfunction associated with increased PBF and warrants further investigation.