Assessment of U.S. Pediatrician Knowledge of Toxocariasis.

Toxocariasis, one of a group of parasitic diseases known as neglected parasitic infections, is a disease caused by the larvae of two species of Toxocara roundworms, Toxocara canis, from dogs, and less commonly Toxocara cati, from cats. Although most infected individuals are asymptomatic, clinical manifestations may include fever, fatigue, coughing, wheezing, or abdominal pain (visceral toxocariasis) or vision loss, retina damage, or eye inflammation (ocular toxocariasis). To assess U.S. pediatrician knowledge of toxocariasis, we conducted an electronic survey of American Academy of Pediatrics members. Of the 2,684 respondents, 1,120 (47%) pediatricians correctly selected toxocariasis as the diagnosis in an unknown case presentation with findings typical for toxocariasis; overall 1,695 (85%) stated they were not confident that their knowledge of toxocariasis was current. This knowledge gap suggests a need for improved toxocariasis awareness and education for U.S. pediatricians, especially those caring for children at risk for infection.

A Phase I/II Multicenter, Open-Label Study of the Oral Histone Deacetylase Inhibitor Abexinostat in Relapsed/Refractory Lymphoma.

PURPOSE: Additional targeted therapeutics are needed for the treatment of lymphoma. Abexinostat is an oral pan-histone deacetylase inhibitor (HDACi) displaying potent activity in preclinical models. We conducted a multicenter phase I/II study (N = 55) with single-agent abexinostat in relapsed/refractory lymphoma. EXPERIMENTAL DESIGN: In phase I, 25 heavily pretreated patients with any lymphoma subtype received oral abexinostat ranging from 30 to 60 mg/m(2) twice daily 5 days/week for 3 weeks or 7 days/week given every other week. Phase II evaluated abexinostat at the maximum tolerated dose in 30 patients with relapsed/refractory follicular lymphoma or mantle cell lymphoma. RESULTS: The recommended phase II dose was 45 mg/m(2) twice daily (90 mg/m(2) total), 7 days/week given every other week. Of the 30 follicular lymphoma and mantle cell lymphoma patients enrolled in phase II, 25 (14 follicular lymphoma, 11 mantle cell lymphoma) were response-evaluable. Tumor size was reduced in 86% of follicular lymphoma patients with an investigator-assessed ORR of 64.3% for evaluable patients [intent-to-treat (ITT) ORR 56.3%]. Median duration of response was not reached, and median progression-free survival (PFS) was 20.5 months (1.2-22.3+). Of responding follicular lymphoma patients, 89% were on study/drug >8 months. In mantle cell lymphoma, the ORR was 27.3% for evaluable patients (ITT ORR 21.4%), and median PFS was 3.9 months (range, 0.1-11.5). Grade 3-4 treatment-related adverse events (phase II) with ≥ 10% incidence were thrombocytopenia (20%), fatigue (16.7%), and neutropenia (13.3%) with rare QTc prolongation and no deaths. CONCLUSIONS: The pan-HDACi, abexinostat, was overall well tolerated and had significant clinical activity in follicular lymphoma, including highly durable responses in this multiply relapsed patient population.

Phase 1 study of oral abexinostat, a histone deacetylase inhibitor, in combination with doxorubicin in patients with metastatic sarcoma.

BACKGROUND: It has been demonstrated that several inhibitors of histone deacetylase (HDAC) can enhance chemotherapy-induced apoptosis and reduce sarcoma tumor volume in preclinical models. The authors sought to determine the maximum tolerated dose, pharmacokinetics/pharmacodynamics, safety, and toxicity of the HDAC inhibitor abexinostat (PCI-24781) when administered with doxorubicin to patients with metastatic sarcomas. METHODS: Participants were enrolled in a standard, phase 1, 3 + 3, dose-escalation study design. Abexinostat was administered on days 1 through 5 with 75 mg/m(2) of doxorubicin administered on day 4 of every 21-day cycle until patients developed disease progression or drug intolerance or reached a cumulative lifetime doxorubicin dose of 450 mg/m(2). Granulocyte-colony-stimulating factor (G-CSF) support was provided at physician discretion on arm A and was provided to all participants in arm B. From 3 to 6 participants initially received abexinostat 30 mg/m(2) twice daily, and subsequent cohorts were administered doses of 15 mg/m(2), 45 mg/m(2), or 60 mg/m(2) twice daily. All patients without progressive disease after receiving a cumulative lifetime doxorubicin dose of 450 mg/m(2) were given the option to continue with abexinostat as a single agent until they developed disease progression. RESULTS: In total, 22 participants (10 who had previously experienced tumor growth after doxorubicin therapy) were enrolled (6 in arm A, 14 in arm B), 20 were evaluable for dose-limiting toxicity (DLT), and 17 were evaluable for radiologic response. In arm A, participants received abexinostat 15 mg/m(2) or 30 mg/m(2) twice daily. DLTs of grade 3 and 4 neutropenia were observed in 2 of 3 participants who received abexinostat 30 mg/m(2) twice daily. Neither of those patients received G-CSF prophylaxis. In arm B, participants received abexinostat at doses of 30 mg/m(2), 45 mg/m(2), or 60 mg/m(2) twice daily, all with mandated G-CSF support. Two DLTs were observed at the 60 mg/m(2) twice-daily dose (grade 3 infection, grade 4 thrombocytopenia). The pharmacokinetics of abexinostat were not affected by doxorubicin. HDAC activity, as measured by histone acetylation in peripheral blood mononuclear cells, was maximally inhibited at the abexinostat 30 mg/m(2) twice-daily dose. Of the 17 participants who were evaluable for radiologic response, 1 patient had a partial response, 9 patients had stable disease, and 7 patients had progressive disease as their best response; and 8 patients completed ≥ 5 cycles. Three of those participants had stable disease as their most recent disease status when the current report was written. Four participants who continued on monotherapy remained in stable disease for a median of 9.8 weeks after completing doxorubicin. The most common toxicities were fatigue, thrombocytopenia, and anemia. No study-related deaths were observed. CONCLUSIONS: The maximum tolerated dose for abexinostat was 45 mg/m(2) twice daily administered on days 1 through 5 when patients received doxorubicin 75 mg/m(2) on day 4 of a 3-week cycle and G-CSF support was mandated. Toxicities were manageable, and tumor responses were observed. Additional studies are needed to further define the specific contributions of HDAC inhibition in patients who receive doxorubicin for the treatment of metastatic sarcoma.

A baseline study of communication networks related to evidence-based infection prevention practices in an intensive care unit.

This study seeks to gain a baseline understanding of the communication network structure, content of communication, and outcomes in a medical intensive care unit experiencing higher-than-expected central line blood stream infection (CLBSI) rates. The communication network structure refers to the direction and frequency of communication on evidence-based CLBSI prevention practices across various professional subgroups and hierarchical levels in the unit, including medical faculty, nurses, residents, students, unit managers, and hospital administrators. The content of communication refers to the type of knowledge (ie, tacit vs explicit knowledge) exchanged on CLBSI prevention practices. Outcomes include (1) compliance with CLBSI prevention practices and (2) hospital-acquired CLBSI rates in the unit. Data on communication network structure and content of communication are collected using communication logs completed weekly for 4 weeks, by individual participants in each professional subgroup and hierarchical level. Outcomes are collected weekly through chart (medical record) review. Study results indicate a sparse communication network structure with minimal interaction across professional subgroups and hierarchical levels. They also indicate that primarily explicit knowledge on general infection topics is being exchanged as against tacit knowledge on specific infection prevention practices. Unit outcomes are poor, with the central line bundle score at zero during all 4 weeks. The study represents an original attempt at developing methods for measuring the communication network structure related to evidence-based infection prevention practices at the unit level. It lays a foundation for testing hypotheses related to effective communication network structures for hospital infection prevention in a larger study. More significantly, the study lays a foundation for generating concrete and context-sensitive strategies for organizational learning and improvement in the context of evidence-based practices. Such insight is critical from the perspective of evidence-based health care management.

The Use of Daptomycin and Linezolid to Treat Vancomycin-Intermediate Staphylococcus haemolyticus Infection in a Premature Infant.

Infections with staphylococcal species, especially coagulase-negative staphylococci are common after neurosurgical procedures. We report a case of a coagulase-negative staphylococci infection of a ventricular shunt site in a 105-day-old, premature infant born at 25 weeks gestation with multiple medical problems. The patient was successfully treated with a combination of daptomycin and linezolid for the persistent infection, which was increasingly resistant to vancomycin. The patient was initially treated with a combination of vancomycin and rifampin; however, the course of therapy had to be changed when the bacteria was identified as having intermediate resistance to vancomycin. Therapy was initially changed to linezolid monotherapy, but culture results continued to be positive for the bacteria, necessitating removal of an external ventricular drain and combination therapy of daptomycin and linezolid for 2 weeks before insertion of a new ventricular shunt. The patient received 4 weeks of therapy with no further positive results of the culture analysis. To our knowledge, this is the first published case report of the use of daptomycin to successfully treat a central nervous system infection in a premature infant.

Reductase-mediated metabolism of motexafin gadolinium (Xcytrin) in rat and human liver subcellular fractions and purified enzyme preparations.

The biotransformation of motexafin gadolinium (MGd, Xcytrin) was investigated in subcellular rat and human liver fractions. Microsomal MGd metabolism was dependent on NADPH in both species. Cytosolic metabolism in rat and human livers was dependent on NADPH or NADH. Under anaerobic conditions, MGd metabolism increased in liver microsomes and purified enzyme preparations. Cytochrome P450 (CYP450) inhibitors ketoconazole, proadifen, and carbon monoxide increased NADPH-dependent MGd metabolism in microsomes. Treatment of rats with beta-naphthoflavone increased cytosolic metabolism of MGd twofold, but had no effect on microsomal metabolism. Conversely, in liver preparations from phenobarbital treated rats microsomal metabolism of MGd was enhanced twofold, but not in cytosolic preparations. Purified CYP450 reductase from phenobarbital-treated rabbit or untreated human livers metabolized MGd suggesting involvement of CYP450 reductase. Dicumarol, a potent DT-diaphorase inhibitor, inhibited MGd metabolism in both rat and human liver cytosol. These data suggest MGd metabolism in rat liver involves CYP450 reductase and/or DT-diaphorase. In human liver preparations only CYP450 reductase is directly involved in MGd metabolism. A metabolite identified in microsomes and cytosol is a metal-free, reduced form of MGd, indicating that both enzymes generate metabolite 1, which appears to be PCI-0108, a synthetic precursor to MGd.

Double blind placebo-controlled trial of pleconaril in infants with enterovirus meningitis.

BACKGROUND: Enterovirus (EV) meningitis is common in infants and may have neurologic complications. Treatment of older children and adults with pleconaril has been associated with reduced severity and duration of symptoms. This study evaluated the pharmacokinetics, safety and efficacy of pleconaril in infants with EV meningitis. METHODS: Infants < or =12 months old with suspected EV meningitis were randomized 2:1 to receive pleconaril, 5 mg/kg/dose orally three times a day or placebo for 7 days. Evaluations included pharmacokinetic determinations, safety laboratory testing, serial culture and PCR assays and clinical evaluations. RESULTS: Of 21 evaluable subjects 20 were confirmed with EV infection (12 pleconaril, 8 placebo). Among pleconaril-treated subjects 26 of 29 peak and trough pleconaril levels exceeded the 90% inhibitory concentration for EVs. A median 3.5-fold drug accumulation occurred between Days 2 and 7. Pleconaril was well-tolerated, although twice as many adverse events occurred per subject in the pleconaril group. Serial cultures from the oropharynx, rectum and serum had low yield (< or =50%) and positivity generally persisted for <4 days in both groups. Serial PCR assays of culture-negative oropharyngeal and rectal specimens had high positivity rates (generally > or =50%) persisting through Day 14. No significant differences in duration of positivity by culture or PCR, hospitalization or symptoms were detected between groups. CONCLUSIONS: The dose of pleconaril studied provided sufficient plasma levels and was well-tolerated; however, drug accumulation was evident. The low yields of serial viral cultures, relatively short and benign clinical courses and the small number of subjects enrolled precluded demonstration of efficacy. If this medication is to be prescribed in infants, surveillance for toxicity related to drug accumulation will be necessary.

Benzene metabolism in rodents at doses relevant to human exposure from urban air.

Benzene is both an environmental pollutant and a component of cigarette smoke, gasoline, and automotive emissions. Although occupational exposure to benzene has been shown to cause blood disorders and cancer in humans, the potential health effects resulting from exposure to low levels of benzene are not known. The goals of this project were to determine how well benzene is metabolized and to assess its binding to macromolecules in rodents at doses more closely mimicking human environmental exposure. To determine whether genotoxic metabolites of benzene are produced at environmental exposure levels. various doses of 14C-benzene were given intraperitoneally to male B6C3F1 mice at doses from 5 ng/kg to 500 mg/kg body weight. Samples of urine, plasma, liver, and bone marrow were taken at selected times up to 48 hours after exposure. Individual benzene metabolites in the samples were measured by accelerator mass spectrometry (AMS*). Metabolites were quantified by determining the area under the curve (AUC) for 24 to 48 hours. The major metabolites found in urine were an unidentified radiolabeled metabolite. phenyl sulfate, phenyl glucuronide. and muconic acid (an indicator of muconaldehyde formation). The major metabolites found in plasma, liver, and bone marrow samples were muconic acid and hydroquinone. Only liver showed a dose response for hydroquinone and muconic acid. The kinetics of both DNA and protein adduct formation were assessed over 48 hours at a 14C-benzene dose of 5 microg/kg body weight. A dose-response study was then conducted using 14C-benzene doses from 5 ng/kg to 500 mg/kg body weight in B6C3F1 mice. Adduct levels were determined by AMS in liver and bone marrow. DNA and protein adducts in liver reached maximum levels 30 minutes after benzene administration, whereas those in bone marrow reached maximum levels after six hours. Both protein and DNA adduct AUCs were greater in bone marrow than in liver. Dose-response assessments at both 1 and 12 hours showed that DNA and protein adducts in liver and bone marrow were dose dependent over doses spanning eight orders of magnitude. Consistent with the benzene metabolism data, these data show that reactive forms of benzene were present in liver and bone marrow after exposure to human-relevant benzene levels. Thus, at low doses, benzene was absorbed and metabolized into reactive intermediates capable of binding to DNA and protein. The relation between benzene metabolism and macromolecular binding was examined by comparing benzene macromolecular adduct formation among strains of male mice (B6C3F1, DBA/2, and C57BL/6) and male rats. These animals have been reported to have different metabolic capacities for benzene and also different tumorigenic and cytotoxic responses to benzene exposure. We hypothesized that differences in the capacity to metabolize benzene affect macromolecular adduct formation and that the amount of macromolecular damage is related to benzene's ability to cause cancer and other blood disorders. 14C-benzene was administered intraperitoneally to all rodents (5 microg/kg body weight) and adduct levels were determined by AMS at selected time points up to 48 hours after exposure. AUCs for protein and DNA adducts in bone marrow, the primary target organ for benzene toxicity, decreased in the following order: B6C3F1, DBA/2, C57BL/6, and rats. Similarly, adduct AUCs in liver were greater in B6C3F1 mice than in rats although the trend was less clear for the DBA/2 and C57BL/6 mouse strains. The results of this work are consistent with previously published work showing that the ability to metabolize benzene follows a similar pattern with these animals and is consistent with the tumorigenicity of benzene in mice and rats. Thus, our data suggest that benzene toxicity is related to the ability to produce macromolecular adducts. Preliminary studies were conducted to assess adduct dosimetry after low-dose inhalation of benzene. Inhalation methods were developed to administer a nominal body burden of 5 microg benzene/kg body weight. Then, 14C-benzene was administered to B6C3F1 mice and rats by both intraperitoneal (IP) administration and by inhalation, and DNA and protein adducts in liver and bone marrow were analyzed by AMS. AUCs for adduct levels were greater after IP benzene administration than after inhalation of benzene. Adduct levels were greater in DNA from B6C3F1 mouse bone marrow than in DNA from liver regardless of exposure route. Collectively, these data show that the internally reactive dose was greater when benzene exposure was by IP administration. In summary, the results suggest that benzene is metabolized to reactive forms capable of binding both protein and DNA in target and nontarget organs of rats and mice at doses encountered by humans through environmental exposure. Macromolecular binding was dose-dependent at low doses of benzene and reflected benzene toxicity, based on its carcinogenicity and ability to cause other blood-related disorders. These data are consistent with macromolecular adducts being indicative of benzene exposure and benzene toxicity although much more research is needed to validate this point. Additionally, benzene metabolism varies among species and among strains within a species of rodent. Thus data are needed in humans to understand how to use the rodent data in risk assessment and ultimately to determine whether macromolecular adducts are a useful indicator of exposure and a useful predictor of risk.