Efficacy of Aerosol MP-376, a Levofloxacin Inhalation Solution,in Models of Mouse Lung Infection Due to Pseudomonas aeruginosa

Progressive respiratory failure due to Pseudomonas aeruginosa is the leading cause of morbidity and mortality in patients with cystic fibrosis. The pulmonary delivery of antimicrobial agents provides high concentrations of drug directly to the site of infection and attains pharmacokinetic-pharmacodynamic indices exceeding those which can be achieved with systemic dosing. MP-376 is a new formulation of levofloxacin that enables the safe aerosol delivery of high concentrations of drug to pulmonary tissues. In vivo studies were conducted to demonstrate the efficacy of MP-376 in models of mouse pulmonary infection. The superiority of aerosol dosing over systemic dosing was demonstrated in models of both acute and chronic lung infection. In a model of acute lung infection, aerosol treatment with MP-376 once or twice daily reduced the lung bacterial load to a greater extent than aerosol tobramycin or aztreonam did when they were administered at similar or higher doses. The bacterial killing by aerosol MP-376 observed in the lung in the model of acute pulmonary infection translated to improved survival (P < 0.05). In a model of chronic pulmonary infection, aerosol MP-376 had antimicrobial effects superior to those of aztreonam (P < 0.05) and effects similar to those of tobramycin (P > 0.05). In summary, these data show that aerosol MP-376 has in vivo activity when it is used to treat acute and chronic lung infections caused by P. aeruginosa.Pseudomonas aeruginosa, a gram-negative opportunistic pathogen, remains an important cause of pulmonary infection in patients with cystic fibrosis (CF). A majority of patients with CF become infected with P. aeruginosa by the age of 18 years (5, 11). Chronic infection with P. aeruginosa is associated with morbidity and mortality in patients with CF (7, 8, 14, 17). In addition to chronic infection with P. aeruginosa in patients with CF, recent studies have also demonstrated an important role of chronic infection with P. aeruginosa in patients with chronic obstructive pulmonary disease (COPD) (16, 20).Since achievement of an adequate antimicrobial concentration is a requirement for the successful treatment of chronic pulmonary infections, aerosol antibiotic therapy has become a valuable approach to treatment in patients with CF. Compared to systemic dosing, aerosol treatment provides higher pulmonary concentrations of antibiotics and reduces the systemic level of exposure to the drug (3, 6, 27). Tobramycin inhalation solution is currently the only aerosol antibiotic approved for use for the treatment of bacterial infections in patients with CF. With the aerosol administration of tobramycin, the potential for systemic toxicity is reduced and a clinical benefit has been shown over several cycles of treatment (23); its long-term use, however, has been associated with multiple-antibiotic-resistant P. aeruginosa strains (19, 27). Thus, there is a need for the development of different classes of aerosol antibiotics for the treatment of chronic lung infections in patients with CF.The fluoroquinolone levofloxacin has potent activity against key pathogens in patients with CF, including P. aeruginosa, with no loss of potency in CF sputum (13). Pharmacokinetic (PK)-pharmacodynamic (PD) studies with systemically administered levofloxacin have shown that bactericidal activity and clinical efficacy are linked to the area under the concentration-time curve (AUC)/MIC and maximum concentration of drug in plasma (C_max)/MIC ratios (9, 12, 22). In addition, both in vitro and in vivo studies have shown that high levels of exposure (C_max) relative to the MIC can reduce the rate of selection of drug-resistant bacteria in vivo (12, 13).Since aerosol administration of antibiotics produces drug levels in pulmonary tissues that are higher than those that can be produced with systemic dosing and that these increased local levels are associated with improved efficacy, a novel aerosol formulation of levofloxacin, MP-376, was developed. MP-376 is a levofloxacin solution formulated with divalent cations and permeant ions for inhalational use. The purpose of the studies described here was to determine the efficacy of aerosol MP-376 in models of acute and chronic lung infection due to P. aeruginosa.(This work was presented in part at the 21st and 22nd Annual North American Cystic Fibrosis Conferences, October 2007 and 2008, respectively [25, 26].)     

Herpes simplex virus type 2 (HSV-2) infection in women attending an antenatal clinic in the South Pacific island nation of Vanuatu

OBJECTIVE: The objective of this study was to estimate the prevalence and correlates of herpes simplex virus type 2 infection in women in an antenatal clinic in the South Pacific island nation of Vanuatu. STUDY DESIGN: A prevalence survey of sexually transmitted infections of pregnant women attending an antenatal clinic at Vila Central Hospital was conducted in 1999-2000. Serum samples were tested for HSV-1 and HSV-2 antibodies by enzyme-linked immunosorbent assay. Results for other sexually transmitted infections and demographic and obstetric variables were analyzed for their association with HSV-2 serostatus. RESULTS: HSV-2 serum antibody results were obtained on 535 women and HSV-1 results on 134. The seroprevalence of HSV-2 was 30% and HSV-1 was 100%. On multivariate analysis, the independent predictors of HSV-2 infection were age, marital status, and trichomoniasis. CONCLUSIONS: HSV-2 was common in this sample of sexually active women in Vanuatu. This is the first study of HSV in Vanuatu and one of very few studies in the Pacific region.     

Medulloepithelioma masquerading as chronic anterior granulomatous uveitis

CASE REPORT: We report a rare clinical case of unilateral ciliary body teratoid medulloepithelioma presented first with infantile cataract, subsequently masquerading as chronic granulomatous anterior uveitis, followed by appearance of a tumour over the iris surface. COMMENTS: Diagnosis of the tumour in the early stages allows proper management and avoids enucleation.     

Biochemical abnormalities and excitotoxicity in Huntington's disease brain

The physiological role of huntingtin and the mechanisms by which the expanded CAG repeat in ITI5 and its polyglutamine stretch in mutant huntingtin induce Huntington's disease (HD) are unknown. Several techniques have now demonstrated abnormal metabolism in HD brain; direct measurement of respiratory chain enzyme activities has shown severe deficiency of complex II/III and a milder defect of complex IV. We confirm that these abnormalities appear to be confined to the striatum within the HD brain. Analysis of complex II/III activity in HD fibroblasts was normal, despite expression of mutant huntingtin. Although glyceraldehyde 3-phosphate dehydrogenase (a huntingtin binding protein) activity was normal in all areas studied, aconitase activity was decreased to 8% in HD caudate, 27% in putamen, and 52% in cerebral cortex, but normal in HD cerebellum and fibroblasts. We have demonstrated that although complexes II and III are those parts of the respiratory chain most vulnerable to inhibition in the presence of a nitric oxide (NO^•) generator, aconitase activity was even more sensitive to inhibition. The pattern of these enzyme deficiencies and their parallel to the anatomical distribution of HD pathology support an important role for NO^• and excitotoxicity in HD pathogenesis. Furthermore, based on the biochemical defects we have described, we suggest that NO^• generation produces a graded response, with aconitase inhibition followed by complex II/III inhibition and the initiation of a self-amplifying cycle of free radical generation and aconitase inhibition, which results in severe ATP depletion. We propose that these events are important in determining neuronal cell death and are critical steps in the pathogenesis of HD. Ann Neurol 1999;45:25–32     

Simultaneous determination of five systemic azoles in plasma by high-performance liquid chromatography with ultraviolet detection

A simple, specific and automatable HPLC assay was developed for a simultaneous determination of systemic azoles (fluconazole, posaconazole, voriconazole, itraconazole and its metabolite hydroxyl-itraconazole, and ketoconazole) in plasma. The major advantage of this assay was sample preparation by a fully automatable solid phase extraction with Varian Plexa cartridges. C6-phenyl column was used for chromatographic separation, and UV detection was set at a wavelength of 260 nm. Linezolid was used as an internal standard. The assay was specific and linear over the concentration range of 0.05 to 40 μg/ml excepted for fluconazole which was between 0.05 and 100 μg/ml, and itraconazole between 0.1 and 40 μg/ml. Validation data for accuracy and precision for intra- and inter-day were good and satisfied FDA's guidance: CV between 0.24% and 11.66% and accuracy between 93.8% and 108.7% for all molecules. This assay was applied to therapeutic drug monitoring on patients hospitalized in intensive care and onco-hematologic units.     

Short-term Mortality Associated with Definitive Chemoradiotherapy Versus Radical Cystectomy for Muscle-invasive Bladder Cancer

BackgroundMuscle-invasive bladder cancer (MIBC) may be managed with radical cystectomy (RC) or chemoradiotherapy (CRT). Because patient selection for RC is important to avoid treatment-related mortality, this study addressed a knowledge gap by quantifying short-term mortality with both approaches, as well as predictors thereof.Materials and MethodsThe National Cancer Database was queried (2004-2014) for clinically staged T2-4aN0M0 MIBC that received either CRT or RC. Statistics included cumulative incidence comparisons of 30- and 90-day mortality between patients treated with either CRT or RC and Cox regression to evaluate predictors thereof.ResultsOf 16,658 patients, 15,208 (91.3%) underwent RC and 1450 (8.7%) CRT. Crude rates of post-treatment mortality at 30 days were 2.7% versus 0.6% (P < .001) and at 90 days were 7.5% versus 4.5% (P = .017) for patients treated with RC and CRT, respectively. When stratifying by age, worse 30- and 90-day mortality with RC was observed for patients aged ≥ 76 years.ConclusionsThis study describes 30- and 90-day mortality following RC versus CRT. Both approaches yield statistically similar treatment-related mortality rates in patients ≤ 75 years of age; however, worse post-treatment mortality was observed with use of RC in patients ≥ 76 years of age. These results may be utilized to better inform shared decision-making between patients and providers when weighing both RC and CRT for MIBC.     

Use of mobile health (mHealth) technologies in ophthalmology patients in Alberta

Objective

This study aims to quantify the proportion of ophthalmology patients using information technology for finding information on their eye condition(s).