SYN-004 (ribaxamase), an oral beta-lactamase, mitigates antibiotic-mediated dysbiosis in a porcine gut microbiome model.

AIM: To evaluate an antibiotic inactivation strategy to protect the gut microbiome from antibiotic-mediated damage. METHODS AND RESULTS: SYN-004 (ribaxamase) is an orally delivered beta-lactamase intended to degrade penicillins and cephalosporins within the gastrointestinal tract to protect the microbiome. Pigs (20 kg, n = 10) were treated with ceftriaxone (CRO) (IV, 50 mg kg-1 , SID) for 7 days and a cohort (n = 5) received ribaxamase (PO, 75 mg, QID) for 9 days beginning the day before antibiotic administration. Ceftriaxone serum levels were not statistically different in the antibiotic-alone and antibiotic + ribaxamase groups, indicating ribaxamase did not alter systemic antibiotic levels. Whole-genome metagenomic analyses of pig faecal DNA revealed that CRO caused significant changes to the gut microbiome and an increased frequency of antibiotic resistance genes. With ribaxamase, the gut microbiomes were not significantly different from pretreatment and antibiotic resistance gene frequency was not increased. CONCLUSION: Ribaxamase mitigated CRO-mediated gut microbiome dysbiosis and attenuated propagation of the antibiotic resistance genes in pigs. SIGNIFICANCE AND IMPACT OF THE STUDY: Damage of the microbiome can lead to overgrowth of pathogenic organisms and antibiotic exposure can promote selection for antibiotic-resistant micro-organisms. Ribaxamase has the potential to become the first therapy designed to protect the gut microbiome from antibiotic-mediated dysbiosis and reduce emergence of antibiotic resistance.

A young child with bilateral diaphragmatic palsy after bilateral bidirectional Glenn shunt.

A 13-months old boy was admitted in National Heart Foundation Hospital and Research Institute on 3 August 2011 with the diagnosis of Dextrocardia, A-V discordance, DORV, large perimembranous VSD, severe infundibular and valvular PS, bilateral SVC. He was operated on 10 August 2011. Bilateral bidirectional Glenn shunt was done off pump along with interruption of PDA. Antegrade pulmonary blood flow was minimized by tight PA banding. Baby was extubated 3 hours after surgery but had to reintubate immediately due to intense respiratory distress. Subsequent three trials of extubation failed. Chest x-ray revealed elevation of both the hemidiaphragm. Ultrasonogram of abdomen and Bronchogram along with fluoroscopy done and bilateral diaphragmatic palsy was diagnosed. Tracheostomy was done on 25th August 2011. Plication of left hemidiaphragm was done on 27th August and right hemidiaphragm plication was done on 10th September 2011. Though it took long period of time we managed to take him out of ventilator on 57th postoperative day. He was oxygen dependent for a period of time and finally he managed to take his own breath without tracheostomy tube from 67th postoperative day. After a long eventful postoperative hospital stay he was discharged home on 78th postoperative day. Discharge Chest x-ray revealed well expanded lung with flattened diaphragm. Echo revealed well functioning bilateral Glenn shunt. Tracheostomy wound healed nicely and there was no evidence of tracheal stenosis.

Efficacy of sublingual verapamil in patients with severe essential hypertension: comparison with sublingual nifedipine.

Ninety patients, 50 males and 40 females, and their ages ranged between 42 and 70 years, with severe hypertension were treated by either sublingual verapamil tablets 40 mg (30 patients) or 80 mg (30 patients) or sublingual nifedipine capsules 10 mg (30 patients). Blood pressure and heart rate were measured before and 15, 30, 60, 90 and 120 mins after administration of the drugs. - Results showed that sublingual verapamil 40 mg caused significant drop of blood pressure after 60 min (200 +/- 11.6 / 127 +/- 8.7 to 177 +/- 13.8 / 95.4 +/- 11.8, P <0.05) and in 10/30 patients blood pressure was less than 150/90 mmHg. Verapamil 40 mg decreased heart rate in 16 patients, elevated in 5 patients and unchanged heart rate in 9 patients. Verapamil 80 mg caused significant reduction of blood pressure after 30 min (201 +/- 16 / 129 +/- 7.5 to 182 +/- 13 / 105 +/- 10.7, P <0.05) and the blood pressure was dropped to less than 150/90 mmHg in 18/30 patients. Sublingual verapamil 80 mg caused significant decrease in heart rate in 21/30 patients and peak decrease was recorded at 90 min (92.6 +/- 7.2 beats/min to 82 +/- 9, P <0.05). It alleviated headache in 8 patients including 2 patients with migraine. Sublingual nifedipine caused significant drop of elevated blood pressure at each time intervals and the peak drop was at 60 min (from 199 +/- 13.8 / 126 +/- 13.2 to 142.8 +/- 15 / 80. 9 +/- 9, P <0.05). In 22/30 patients blood pressure dropped to less than 150/90 mmHg after 60 min. Nifedipine elevated heart rate in 22/30 patients and peak elevation was at 30 min (from 91.6 +/- 7.8 to 105.6 +/- 6.1 beats/min, P <0.05). It caused headache in 8 patients and flushing in other 2 patients. Therefore, as compared to sublingual verapamil, sublingual nifedipine caused rapid lowering of elevated blood pressure and elevation of heart rate in most of the patients treated. The differences in proportions of patients whom blood pressure was dropped to less than 150/90 mmHg between nifedipine group and verapamil 40 mg group and between verapamil 80 mg and verapamil 40 mg groups were significant (P <0.05). - It might be concluded that sublingual verapamil caused significant lowering of blood pressure in hypertensive patients, decreased heart rate in most of the treated patients and alleviated headache in symptomatic hypertensive patients.

The influence of predegenerated nerve grafts on axonal regeneration from prelesioned peripheral nerves.

Recent in vitro work has indicated that predegenerated segments of peripheral nerve are more capable of supporting neurite growth from adult neurons than fresh segments of nerve, whereas previous in vivo studies which investigated whether predegenerated nerve segments used as grafts are capable of enhancing axonal regeneration produced conflicting results. We have reinvestigated this question by using predegenerated nerve grafts in combination with conditioning lesions of the host nerve to determine the optimal conditions for obtaining the maximal degree of regeneration of myelinated axons. The sciatic nerve of adult Dark Agouti rats were sectioned at midthigh level, and the distal portion was allowed to predegenerate for 0, 6 or 12 d in situ. 10-15 mm lengths of these distal nerve segments were then syngenically grafted onto the central stumps of sciatic nerves which had themselves received a conditioning lesion 0, 6, and 12 d previously, making a total of 9 different donor-host combinations. The grafts were assessed histologically 3 or 8 wk after grafting. Axonal regeneration in the 9 different donor-host combinations was determined by counting the numbers of myelinated axons in transverse sections through the grafts. All grafts examined contained regenerating myelinated axons. The rats given a 3 wk postgrafting survival period had an average of between 1400 and 5300 such axons. The rats given an 8 wk postgrafting survival period had between about 13,000 and 25,000 regenerating myelinated axons. Analysis of variance revealed significant main effects for both the Donor and Host conditions as well as Weeks (i.e. survival period after grafting). These results indicate that both a conditioning lesion of the host neurons and the degree of predegeneration of peripheral nerve segments to be used as grafts are of importance in influencing the degree of axonal regeneration. Of these 2 factors the conditioning lesion of the host appears to have the greater effect on the final number of regenerating myelinated axons.