Protective activity of anti-lipoteichoic acid monoclonal antibody in single or combination therapies in methicillin-resistant Staphylococcus aureus-induced murine sepsis models.

Previously, we generated and screened a panel of monoclonal antibodies (mAbs) against methicillin-resistant Staphylococcus aureus (MRSA) to identify protective mAbs in mouse infection models. One of these mAbs, ZBIA3H, bound to lipoteichoic acid (LTA) and exerted protective effects in a mouse sepsis model. To reinforce the ability of the mAb to protect against infection, combination therapies with the mAb and antibiotics need to be examined. Therefore, herein, we studied the efficacy of ZBIA3H (in combination or alone) in a mouse sepsis model. ZBIA3H improved the survival rate in the mouse models of sepsis induced by highly virulent or refractory S. aureus (community-acquired MRSA strain MW2, vancomycin-intermediate S. aureus strain Mu3, or vancomycin-resistant S. aureus strain VRS1). Furthermore, ZBIA3H remarkably improved the survival rate in combination with antimicrobial agents (vancomycin, daptomycin, or linezolid) in mouse sepsis models. From these results we conclude that anti-LTA mAb ZBIA3H or its humanized form is a promising mAb individually, or in combination with antibiotics, against clinical refractory infection of S. aureus.

Successful selection of an infection-protective anti-Staphylococcus aureus monoclonal antibody and its protective activity in murine infection models.

Recent clinical trials to develop anti-methicillin-resistant Staphylococcus aureus (MRSA) therapeutic antibodies have met unsuccessful sequels. To develop more effective antibodies against MRSA infection, a panel of mAbs against S. aureus cell wall was generated and then screened for the most protective mAb in mouse infection models. Twenty-two anti-S. aureus IgG mAbs were obtained from mice that had been immunized with alkali-processed, deacetylated cell walls of S. aureus. One of these mAbs, ZBIA5H, exhibited life-saving effects in mouse models of sepsis caused by community-acquired MRSA strain MW2 and vancomycin-resistant S. aureus strain VRS1. It also had a curative effect in a MW2-caused pneumonia model. Curiously, the target of ZBIA5H was considered to be a conformational epitope of either the 1,4-ß-linkage between N-acetylmuramic acid and N-acetyl-D-glucosamine or the peptidoglycan per se. Reactivity of ZBIA5H to S. aureus whole cells or purified peptidoglycan was weaker than that of most of the other mAbs generated in this study. However, the latter mAbs did not have the protective activities against S. aureus that ZBIA5H did. These data indicate that the epitopes that trigger production of high-yield and/or high-affinity antibodies may not be the most suitable epitopes for developing anti-infective antibodies. ZBIA5H or its humanized form may find a future clinical application, and its target epitope may be used for the production of vaccines against S. aureus infection.

Effects of foods on the pharmacokinetics and clinical efficacy of quazepam.

The effects of foods on the pharmacokinetics and clinical efficacy of quazepam, a benzodiazepine derivative, in healthy persons were examined. Six healthy Japanese male subjects were randomly divided into three groups and each subject was treated with quazepam under the following three conditions by the crossover method. For the fasting state, subjects were administered 15 mg quazepam 11 hours after a meal. For the postprandial state, subjects were administered 15 mg or 30 mg quazepam 2 hours after a meal. Mean peak plasma concentration (Cmax) of quazepam was significantly higher [1.6-2.8 fold] with administration 2 hours after a meal than 11 hours after a meal. However, in regard to 15 mg of quazepam administration, the area under the curve (AUC) did not differ between administration 2 hours after a meal and 11 hours after a meal. In addition, differences were observed neither in other pharmacokinetic parameters or blood metabolite concentration under all of the study conditions, nor in clinical evaluation of subjective symptoms, complete blood count, or biochemical analyses between administrations 2 and 11 hrs after a meal. The present study showed that administration 2 hours after a meal did not affect subjective symptoms or physical functions so much; therefore it suggested favorable tolerance of this drug. However, it was also suggested that, in actual clinical use, it is important to evaluate the physical function including measurements of vital signs and hematological test results, carefully considering the effects of foods and daily life-style.

A case of general paresis showing marked treatment-associated improvement of cerebellar blood flow by quantitative imaging analysis.

We describe a patient with general paresis who developed progressive dementia and a cerebellar syndrome including wide-based gait, slurred speech, and intention tremor. Quantitative analysis by means of a Patlak plot of single-photon emission computed tomography (SPECT) with 99mTc-ethyl cysteinate dimer showed generally low blood flow in the cerebrum and the cerebellum. After antisyphilitic therapy, blood flow in the brain, especially in the cerebellum, improved noticeably, as did the cognitive disorder and the cerebellar syndrome.