Streptococcus oralis meningitis in pregnancy.

While pregnancy is a time of relative immunosuppression, infective endocarditis and bacterial meningitis remain rare. We present a case of a pregnant woman with Streptococcus oralis endocarditis and meningitis. This is the first reported case of Streptococcus oralis meningitis in a patient without predisposing risk factors. This case highlights the importance of collecting blood cultures in febrile illness during pregnancy and illustrates that effective management plans can be formulated without performing invasive diagnostic tests such as transesophageal echocardiography.

The challenges of defining the human nasopharyngeal resistome.

The nasopharynx is an important microbial reservoir for the emergence and spread of antibiotic-resistant organisms. The nasopharyngeal resistome is an extensive, adaptable reservoir of antibiotic-resistance genes (ARGs) within this niche. Metagenomic sequencing decodes the genetic material of all organisms within a sample using next-generation technologies, permitting unbiased discovery of novel ARGs and associated mobile genetic elements (MGEs). The challenges of sequencing a low-biomass bacterial sample have limited exploration of the nasopharyngeal resistome. Here, we explore the current understanding of the nasopharyngeal resistome, particularly the role of MGEs in propagating antimicrobial resistance (AMR), explore the advantages and limitations of metagenomic sequencing technologies and bioinformatic pipelines for nasopharyngeal resistome analysis, and highlight the key outstanding questions for future research.

Antifungal Susceptibility Does Not Correlate With Fungal Clearance or Survival in AIDS-Associated Cryptococcal Meningitis.

We investigated the value of susceptibility testing in predicting response in AIDS-associated cryptococcal meningitis using clinical isolates from a randomized controlled trial of antifungal treatment (amphotericin monotherapy, amphotericin with flucytosine, or amphotericin with fluconazole). We found no correlation between antifungal susceptibility and either early or late survival, or fungal clearance.

A phase 1/1b study of PUR1900, an inhaled formulation of itraconazole, in healthy volunteers and asthmatics to study safety, tolerability and pharmacokinetics.

AIMS: Oral itraconazole has variable pharmacokinetics and risks of adverse events associated with high plasma exposure. An inhalation formulation of itraconazole (PUR1900) is being developed to treat allergic bronchopulmonary aspergillosis, an allergic inflammatory disease occurring in asthmatics and patients with cystic fibrosis. METHODS: A 3-part, open-label Phase 1 study was conducted to evaluate safety, tolerability and pharmacokinetics of PUR1900. Healthy volunteers (n = 5-6/cohort) received either single (Part 1) or multiple (Part 2) ascending doses of PUR1900 for up to 14 days. In Part 3 stable, adult asthmatics received a single dose of 20 mg PUR1900 or 200 mg of oral Sporanox (itraconazole oral solution) in a 2-period randomized cross-over design. Itraconazole plasma and sputum concentrations were evaluated. RESULTS: None of the adverse events considered as at least possibly related to study treatment were moderate or severe, and none were classed as serious. The most common was the infrequent occurrence of mild cough. Itraconazole plasma exposure increased with increasing doses of PUR1900. After 14 days, PUR1900 resulted in plasma exposure (area under the concentration-time curve up to 24 h) 106- to 400-fold lower across doses tested (10-35 mg) than steady-state exposure reported for oral Sporanox 200 mg. In asthmatics, PUR1900 geometric mean maximum sputum concentrations were 70-fold higher and geometric mean plasma concentrations were 66-fold lower than with oral Sporanox. CONCLUSION: PUR1900 was safe and well-tolerated under the study conditions. Compared to oral dosing, PUR1900 achieved higher lung and lower plasma exposure. The pharmacokinetic profile of PUR1900 suggests the potential to improve upon the efficacy and safety profile observed with oral itraconazole.

Pharmacodynamics of liposomal amphotericin B and flucytosine for cryptococcal meningoencephalitis: safe and effective regimens for immunocompromised patients.

BACKGROUND: Cryptococcal meningoencephalitis is a lethal infection with relatively few therapeutic options. The optimal dosage of liposomal amphotericin B (LAmB) alone or in combination with flucytosine is not known. METHODS: A murine model of cryptococcal meningoencephalitis was used. The fungal density in the brain was determined using quantitative cultures. Pharmacokinetic-pharmacodynamic relationships were determined for LAmB and flucytosine administered alone. The effect of the combination was described using the Greco model and a mathematical model. The results were bridged to humans. RESULTS: Inoculation resulted in hematogenous dissemination and logarithmic growth within the central nervous system. There was histological evidence of multifocal infection throughout the brain. Both LAmB and flucytosine produced a dose-dependent reduction in fungal burden. The effect of the combination of agents in the brain was additive. Bridging studies suggested that a human dosage of LAmB 3 mg/kg/d resulted in a submaximal antifungal effect. Regimens of LAmB 6 mg/kg/d alone, LAmB 3 mg/kg/d plus flucytosine 50 mg/kg/d, and LAmB 3 mg/kg/d plus flucytosine 100 mg/kg/d all resulted in near-maximal antifungal activity. CONCLUSIONS: Potential regimens for further study in clinical trials include LAmB 6 mg/kg/d alone, LAmB 3 mg/kg/d plus flucytosine 50 mg/kg/d, and LAmB 3 mg/kg/d plus flucytosine 100 mg/kg/d.

Image-defined resolution following radiosurgery for hypothalamic hamartoma.

The authors present the rare case of complete image-defined resolution of a hypothalamic hamartoma (HH) following Gamma Knife surgery (GKS). A 9-month-old girl presented with an episode of generalized tonic-clonic seizures. Magnetic resonance imaging revealed a left-sided HH, which remained radiologically stable. By 3 years of age the patient had a development delay of 12 months, and experienced 8 gelastic seizures per day while on 2 antiepileptic medications. Thirty-one months after presentation, the patient underwent elective GKS to treat the HH. She has since been seizure free for 22 months, while receiving 3 antiepileptic medications. Twelve months after radiosurgery, MRI revealed complete radiological resolution of the lesion. The authors discuss alternative management options for HH, including microsurgical resection, endoscopic disconnection, stereotactic radiofrequency thermocoagulation, and interstitial radiosurgery. Gamma Knife surgery is a minimally invasive procedure associated with a lower morbidity rate than that of published surgical results. The present case demonstrates the potential for complete image-defined resolution of an HH post-GKS, without long-term neurological sequelae, emphasizing the safety and efficacy of this therapeutic option for the control of epileptic seizures produced by small-volume, surgically inaccessible HHs.

Galectin-3 interaction with Thomsen-Friedenreich disaccharide on cancer-associated MUC1 causes increased cancer cell endothelial adhesion.

Patients with metastatic cancer commonly have increased serum galectin-3 concentrations, but it is not known whether this has any functional implications for cancer progression. We report that MUC1, a large transmembrane mucin protein that is overexpressed and aberrantly glycosylated in epithelial cancer, is a natural ligand for galectin-3. Recombinant galectin-3 at concentrations (0.2-1.0 microg/ml) similar to those found in the sera of patients with metastatic cancer increased adhesion of MUC1-expressing human breast (ZR-75-1) and colon (HT29-5F7) cancer cells to human umbilical vein endothelial cells (HUVEC) by 111% (111 +/- 21%, mean +/- S.D.) and 93% (93 +/- 17%), respectively. Recombinant galectin-3 also increased adhesion to HUVEC of MUC1 transfected HCA1.7+ human breast epithelial cells that express MUC1 bearing the oncofetal Thomsen-Friedenreich antigen (Galbeta1,3 GalNAc-alpha (TF)) but did not affect adhesion of MUC1-negative HCA1.7-cells. MUC1-transfected, Ras-transformed, canine kidney epithelial-like (MDE9.2+) cells, bearing MUC1 that predominantly carries sialyl-TF, only demonstrated an adhesive response to galectin-3 after sialidase pretreatment. Furthermore, galectin-3-mediated adhesion of HCA1.7+ to HUVEC was reduced by O-glycanase pretreatment of the cells to remove TF. Recombinant galectin-3 caused focal disappearance of cell surface MUC1 in HCA1.7+ cells, suggesting clustering of MUC1. Co-incubation with antibodies against E-Selectin or CD44H, but not integrin-beta1, ICAM-1 or VCAM-1, largely abolished the epithelial cell adhesion to HUVEC induced by galectin-3. Thus, galectin-3, by interacting with cancer-associated MUC1 via TF, promotes cancer cell adhesion to endothelium by revealing epithelial adhesion molecules that are otherwise concealed by MUC1. This suggests a critical role for circulating galectin-3 in cancer metastasis and highlights the functional importance of altered cell surface glycosylation in cancer progression.