Pharmacological, Toxicological, and Dose Range Assessment of OG716, a Novel Lantibiotic for the Treatment of Clostridium difficile-Associated Infection.

Lantibiotics present an attractive scaffold for the development of novel antibiotics. We report here a novel lantibiotic for the treatment of Clostridium difficile infection. The lead compounds were selected from a library of over 700 single- and multiple-substitution variants of the lantibiotic mutacin 1140 (MU1140). The best performers in vitro and in vivo were further used to challenge Golden Syrian hamsters orally in a Golden Syrian hamster model of Clostridium difficile-associated disease (CDAD) in a dose-response format, resulting in the selection of OG716 as the lead compound. This lantibiotic was characterized by a 50% effective dose of 23.85 mg/kg of body weight/day (10.97 µmol/kg/day) in this model. Upon oral administration of the maximum feasible dose (≥1,918 mg/kg/day), no observable toxicities or side effects were noted, and no effect on intestinal motility was observed. Compartmentalization to the gastrointestinal tract was confirmed. MU1140-derived variants offer a large pipeline for the development of novel antibiotics for the treatment of several indications and are particularly attractive considering their novel mechanism of action. Based on the currently available data, OG716 has an acceptable profile for further development for the treatment of CDAD.

Antibacterial activity of the novel semisynthetic lantibiotic NVB333 in vitro and in experimental infection models.

NVB333 is a novel semisynthetic lantibiotic derived from the amide coupling of 3,5-dichlorobenzylamine to the C-terminal of deoxyactagardine B. The in vitro activity of NVB333 includes efficacy against clinically relevant pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp. NVB333 shows no cross-resistance with other antibiotics tested and a very low propensity for resistance development. After intravenous dosing NVB333 has high exposure in mouse plasma and shows generally improved in vivo activity compared with vancomycin in mouse infection models despite modest MIC values. In thigh infection models, promising efficacy was demonstrated against several strains of S. aureus including methicillin-resistant S. aureus (MRSA) and vancomycin-intermediate S. aureus (VISA) strains, and against Enterococcus faecalis UNT126-3. Area under the concentration curve (AUC)/MIC was shown to be the best predictor of efficacy against S. aureus UNT103-3 with an AUC/MIC of 138 (uncorrected for protein binding) achieving a static effect. NVB333 was also effective in a disseminated infection model where it conferred complete survival from the MRSA strain ATCC 33591. NVB333 showed rather modest lung penetration after intravenous dosing (AUC in lung 2-3% of plasma AUC), but because of very high plasma exposure, therapeutic levels of compound were achieved in the lung. Efficacy at least equal to vancomycin was demonstrated against an MRSA strain (UNT084-3) in a bronchoalveolar infection model. The impressive in vivo efficacy of NVB333 and strong resistance prognosis makes this compound an interesting candidate for development for treating systemic Gram-positive infections.

Anatomic fit assessment for the Penn State pediatric ventricular assist device.

This investigation determined the ages and weights of children that could be supported with 12 and 25 ml Penn State pediatric ventricular assist devices (PVADs) using 6, 8, and 10 mm outlet cannulas and grafts. Future patients will be matched to devices based on cardiac output (CO) and ascending aortic diameter (AA). These were calculated for children 0-10 years with regression formulas given as clinical standards [<5 kg, CO = 0.2171(kg) + 0.0703], [>5 kg, CO = 3.06 (m2) + 0.37], [AA = -0.0427 + 14.54 (m2)1/2]. The 12 ml PVAD will be useful for patients from approximately birth to 3-8 months, weighing 2-7 kg, and having 0.5-1.4 L/min CO; the 25 ml PVAD will be for children 2-6 months to 5-9 years old, weighing 6-23 kg, and having 1.3-3.0 L/min of CO. The 6 mm outlet graft will fit children from 0 to 12 months, weighing 2-8 kg; the 8 mm graft from 0 to 47 months, weighing 4-14 kg; and the 10 mm graft for children 4 months to 8 years, weighing 8-21 kg.