Levonadifloxacin and its prodrug alalevonadifloxacin are novel broad-spectrum anti-MRSA agents belonging to the benzoquinolizine subclass of quinolone, formulated for intravenous and oral administration, respectively. Various in vitro and in vivo studies have established their antimicrobial spectrum against clinically significant Gram-positive, Gram-negative, atypical, and anaerobic pathogens. The potent activity of levonadifloxacin against MRSA, quinolone-resistant Staphylococcus aureus, and hetero-vancomycin-intermediate strains is an outcome of its welldifferentiated mechanism of action involving preferential targeting to DNA gyrase. Potent antistaphylococcal activity of levonadifloxacin was also observed in clinically relevant experimental conditions such as acidic pH, the intracellular environment, and biofilms, suggesting that the drug is bestowed with enabling features for the treatment of difficult-to-treat MRSA infections. Levonadifloxacin also retains clinically relevant activity against resistant respiratory pathogens such as macrolide-and penicillin-resistant Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, and Moraxella catarrhalis and, in conjunction with clinically established best-in-class human epithelial lung fluid concentration, has promising potential in the management of recalcitrant respiratory infections. Attractive features, such as resistance to NorA efflux, divergent mechanism of action in S. aureus, cidality against high-inoculum cultures, and low mutant prevention concentration, are likely to confer favorable resistance-suppression features to both agents. In vivo studies have shown promising efficacy in models of acute bacterial skin and skin structure infection, respiratory infections, pyelonephritis, and peritonitis at human-equivalent mouse doses. Both formulations were well tolerated in multiple phase I studies and overall showed a dose-dependent exposure. In particular, oral alalevonadifloxacin showed excellent bioavailability (~90%), almost mirroring the pharmacokinetic profile of intravenous levonadifloxacin, indicating the prodrug's seamless absorption and efficient cleavage to release the active parent drug. Hepatic impairment studies showed that clinical doses of levonadifloxacin/alalevonadifloxacin are not required to be adjusted for various degrees of hepatic impairment. With the successful completion of phase II and phase III studies for both levonadifloxacin and alalevonadifloxacin, they represent clinically attractive therapeutic options for the treatment of infections caused by multi-drugresistant Gram-positive organisms. Herein, we review the current evidence on therapeutically appealing attributes of levonadifloxacin and alalevonadifloxacin, which are based on a range of nonclinical in vitro and in vivo investigations and clinical studies.

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Fluoroquinolone (FQ) antibacterials have drawn heightened attention from various international regulatory agencies due to their class-specific side effects.Levonadifloxacin is a novel broad spectrum benzoquinolizine FQ active against methicillin-resistant Staphyloccocus aureus (MRSA). Owing to FQ-associated safety concerns, extensive preclinical safety pharmacology (central nervous system and cardiac safety) and toxicology studies (subacute repeat-dose toxicity, genotoxicity, phototoxicity and chondrotoxicity) of levonadifloxacin were performed at relatively high doses. Intravenous (IV) and oral studies were conducted using WCK 771 (L-arginine salt of levonadifloxacin) and WCK 2349 (L-alanine ester prodrug of levonadifloxacin), respectively. Safety pharmacology studies following single dose revealed no adverse effects on central nervous system (including seizure) in mice and cardiovascular system (hERG and monkey telemetry). In repeat-dose toxicity studies, except for IV bolus dosing related effects in rat (hyperactivity, mild convulsion, polypnoea and injection site irritation) and dog (emesis and salivation), no other adverse findings limiting the dosing duration were observed. No major biochemical, haematological, gross or histopathological changes suggestive of damage to vital organs were observed in either WCK 771-or WCK 2349-treated groups. WCK 771 and WCK 2349 were found to be nongenotoxic; however, they showed weak phototoxicity that was comparable with levofloxacin. WCK 771 showed chondrotoxicity in the Beagle dog pups on repeat-dose administration; however, the severity level was lower than ofloxacin. Overall, preclinical safety studies helped establish wider safety margin for WCK 771 and WCK 2349 that supports administration of higher therapeutic doses in humans by both IV and oral routes, thereby enabling safe anti-MRSA treatment.

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A debilitating complication of diabetes mellitus is diabetic ulcers, which leads to increased overall morbidity in patients. The high growth factor content in Platelet Rich Plasma (PRP) makes it a widely used intervention for the treatment of diabetic foot ulcers. The topical application of Stromal Vascular Fraction (SVF) could possibly enhance wound healing. This study aims at evaluating the efficacy of combining SVF and PRP on wound healing in diabetic rabbit model. Diabetes was induced in New Zealand white rabbits by intravenous injection of 125 mg/Kg Alloxan. After two weeks of alloxan, three 6 mm diameter, full thickness excision wounds were made, on inner side of the right ear pinna. The animals after induction were allocated into 4 groups with [8 Diabetic (treated with SVF+PRP), 4 Diabetic (treated with 10% Povidone Iodine (PI)), 1 non-diabetic (treated with SVF+PRP), 1 non diabetic (treated with 10% PI)]. The effect of combined therapy was evaluated by assessing wound margin closure rate, histo-pathological evaluation, and inflammatory cell infiltration, epithelization of ulcerative region, neo-vascularization, and fibrosis. We observed that the rate of wound closure is enhanced in wounds treated with SVF+PRP as compared to the PI solution. Wound closure and healthy healing were demonstrated by histo-pathological analysis. The analysis clearly indicates that the healing process of PI treated animals is slower than that of SVF + PRP treated animals. In conclusion, based on wound healing assessment and histo-pathological examination, the diabetic rabbits treated with SVF + PRP exhibited early development of granulation tissue and early signs of wound closure as compared to diabetic animals with normal PI dressing

Background: Stromal vascular fraction (SVF) is considered a promising source of stem cells, but potential of treatment of damaged liver has not been fully explored. Aim: In this present study, we sought to evaluate the hepato-regenerative effect of SVF combined with activated platelet rich plasma (aPRP) on carbon tetrachloride (CCl4) induced hepatic injury in Sprague Dawley (SD) rats. Material and Methods: Liver fibrosis was induced using CCl4 in 30 SD rats. Sixteen rats survived and were divided into two groups – control and treated. SVF and aPRP were prepared by standard methods from three normal donor rats. Combination SVF-aPRP was administered intravenously via the lateral tail vein in treated group animals, on Day 0, 7 and 14. Normal saline of same dose volume was administered to the control group. AST and ALT levels were monitored throughout the study duration of 28 days. Gross and histopathological analysis of liver was performed post sacrifice on Day 28. Results: Decrease in the ALT/AST levels over the duration of study was observed in both control and treated groups, with a statistically significant reduction in AST/ALT levels between Control ad Treated groups on Day 28. Gross morphological evaluation, fibrosis and cirrhosis grades also showed reduction between control and treated groups. Conclusion: Observations of enzyme levels, gross and histopathological analyses revealed a reduction in severity of liver fibrosis in the treated group. However, we have identified additional parameters that need to be evaluated to corroborate these research findings.