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Objectives: Levonadifloxacin (IV) and alalevonadifloxacin (oral) are novel broad-spectrum anti-methicillin-resistant Staphylococcus aureus ( S. aureus ) agents based on novel benzoquinolizine core. Both are recently approved in India for the treatment of acute bacterial skin and skin structure infections, including diabetic foot infections and concurrent bacteremia. The present investigation reports the findings from preclinical pharmacokinetic (PK) studies that support the development of levonadifloxacin as a treatment option for bone and joint infections (BJIs). Methods: PK profiles of levonadifloxacin were obtained in serum, and/or various anatomical segments of femoral bone such as whole bone (WB), hard bone (HB), and bone marrow (BM) following subcutaneous administration of levonadifloxacin single doses at 50, 100, 200, and 400 mg/kg, as well as multiple doses at 200 mg/kg (BID (two times a day), 6 hours apart) for 5 days in Wistar rats. Results: The distribution of levonadifloxacin in bone was rapid, and the extent of distribution (B/S ratio; bone-to-serum area under the concentration-time curve ratio) was nearly comparable across bone segments. In single-dosage PK studies, the mean B/S ratio in WB, HB, and BM was 0.40, 0.33, and 0.34, respectively; however, in 5 days' repeated dose studies, it increased to 1.01, 1.14, and 0.61, respectively. Conclusions: On the basis of bone PK data in Wistar rat and ever-growing clinical experience in terms of safety and efficacy, levonadifloxacin has the potential to offer a well-differentiated therapy for the treatment of BJIs.

Ketolide antibiotics are known to cause hepatic injury. Nafithromycin, a novel lactone ketolide was therefore assessed for hepatic safety through range of preclinical in vitro (metabolic stability, CYP inhibition/induction assays) and in vivo (mass balance and repeat dose toxicity) studies. Repeat-dose toxicity studies in rat and dog revealed that nafithromycin did not cause adverse hematological, biochemical and histopathological changes suggestive of systemic or hepatobiliary safety concern at exposures 3-8 fold higher than targeted therapeutic exposures. The only histological finding noticed was reversible phospholipidosis, mainly in lung and lymphoid organs but not in liver, indicating lower nafithromycin accumulation in liver. This observation was corroborated with lack of biologically relevant elevation of hepatic enzymes linked to hepatic injury. In vitro studies showed that nafithromycin undergoes moderate CYP3A mediated metabolism. Unlike other ketolides, nafithromycin and its metabolites showed weak inhibition of CYP3A isoform and lacked CYP2D6 inhibition. Due to hydrophilic nature, nafithromycin in addition to hepatic clearance is also eliminated unchanged by kidneys in significant amount, thereby minimizing hepatic burden. Based on the scientifically integrated evidences such as moderate metabolism, weak CYP inhibition, lack of CYP induction, minimal accumulation in liver, nafithromycin showed promising hepatic safety profile suitable for its intended community-based usage., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Nafithromycin is a next generation lactone ketolide antibiotic slated to enter phase III clinical development in India for the treatment of CABP as a shorter 800 mg-OD X3 day therapeutic regimen. Nafithromycin exhibits potent activity against MDR Streptococcus pneumoniae including erythromycin and telithromycin-resistant resistant strains. Older macrolides/ketolides are reported to be potent inhibitors of CYP3A4/5. To facilitate comparative assessment of drug-drug interaction potential, CYP inhibitory activities of nafithromycin was evaluated in comparison with clarithromycin, telithromycin, cethromycin and solithromycin. CYP inhibitory activities were assessed against key CYP isoforms (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and CYP3A4/5) using human liver microsomes. Additionally, time-dependent inhibition (TDI), metabolism-based inhibition (MBI) and k inact /K I activities were also investigated for CYP3A4/5. Nafithromycin did not inhibit key CYP enzymes and was found to be a weak inhibitor of CYP3A4/5. Comparator antibiotics were found to be potent inhibitors with 2- to 50-fold leftward shifts in CYP3A4/5 IC50 values, while such shift was not noted for nafithromycin. k inact /K I ratio of nafithromycin was 3- to 153-fold lower than comparator drugs, further substantiating its lower affinity for CYP3A4/5. In sum, weaker inhibition and lower k inact /K I ratio for CYP3A4/5, points towards nafithromycin's lower propensities towards clinical drug-drug interactions as compared to other macrolides/ketolides antibiotics.

WCK 771 (INN: levonadifloxacin) is a novel antibacterial agent belonging to benzoquinolizine subclass of fluoroquinolones which is under clinical development as a parenteral formulation and its prodrug WCK 2349 (INN: alalevonadifloxacin) as an oral option. Both the drugs have been approved recently in India based on phase III trial completed for ABSSSI. In vitro CYP inhibition potential of levonadifloxacin and its sulfate metabolite (WCK 2146) were assessed in this study. The inhibitory effects of levonadifloxacin and its sulfate metabolite were assessed for seven key human liver CYP isoforms 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4 using human liver microsome (HLM) employing validated LC-MS/MS method.The results showed that levonadifloxacin and its metabolite did not inhibit enzyme activity of any of the key CYP isoforms (1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4) even at supra therapeutic concentrations (12-24X, Clinical Cmax: 25-35µg/mL).These in vitro CYP inhibition studies of levonadifloxacin and its sulfate metabolite indicate lack of potential for pharmacokinetic drug interactions of levonadifloxacin when co-administered with drugs which are substrate of these isoforms. Therefore, further clinical studies evaluating CYP mediated drug-drug interactions are not warranted for levonadifloxacin and alalevonadifloxacin.

Introduction: Fungal osteoarticular/soft tissue infections (FOaSI) are an uncommon entity with protracted course due to variability in clinical picture, slow progression; resulting in misdiagnosis with empirical therapy. Recent studies have shown an alarming emergence of FOaSI in immunocompetent individuals with high mortality rates. This study recommends a protocol for managing these complex and confusing scenarios., Methodology: We have retrospectively analysed patients with FOaSI between January 2014 and December 2016, with a minimum 12 months follow up., Results: 8 cases (6 male, 2 female) with a mean age of 42.88 years (26-53) presented to us 45 days (3-365) after initial symptoms. They underwent mean 3 procedures before being diagnosed with a fungal infection. Deep tissue cultures grew 9 fungi and 6 bacteria, commonest fungus being Candida sp (n = 4), treated with appropriate antifungals and antibiotics. Infection remission was achieved in 7/8 (87.5%) cases at 27.1 months (19-45) follow-up with 1 mortality. Excellent functional results as per our criteria were seen in 5 cases (62.5%) with 1 talus excision, 1 ray amputation and 1 mortality., Conclusions: This study highlights the significance of implementing a simple rule such as obtaining fungal cultures in every case of bone and soft tissue infections. Standardisation of treatment may not be the ideal solution, since different fungi have different growth patterns and invasiveness. A simple protocol of customising the medico- surgical treatment with an open ended discussion between the surgeons, microbiologists, pathologists and infectious disease specialists forms the cornerstone to success., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2020 Ravi Chavan, Aditya Menon, Rajeev Soman, Camilla Rodrigues, Anjali Shetty, Ravi Bhadiyadra, Vikas M Agashe.)

Background: Levonadifloxacin is a novel broad-spectrum anti-MRSA agents belonging to the benzoquinolizine subclass of quinolone. It is developed for oral or intravenous administration for the treatment of infections caused by Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA)., Objectives: To establish the non-inferiority of levonadifloxacin compared with linezolid for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and to compare the safety of the two antimicrobials., Subjects and Methods: This was a Phase 3, multicentre, randomized, open-label, active- comparator study with 500 subjects. Oral levonadifloxacin 1000 mg was compared with oral linezolid 600 mg whereas IV levonadifloxacin 800mg was compared with IV linezolid 600 mg, each treatment was administered twice daily for 7-10 days. Non-inferiority was evaluated by comparing oral levonadifloxacin to oral linezolid and IV levonadifloxacin to IV linezolid for overall clinical response at TOC (Test of Cure) Visit., Results: The clinical cure rates observed at the TOC in the mITT (modified Intent to treat) populations for levonadifloxacin was numerically higher compared to linezolid in the IV sub-group [(91.0% verses 87.8%); treatment difference of 3.2% (95%CI, -4.5 to 10.9)] and in the oral sub-group (95.2% versus 93.6%); treatment difference of 1.6 % [95%CI, -4.2 to 7.3]). As the lowerbound of the 95% CI around the treatment difference was greater than -15% for both subgroups, the primary objective of the study was met. Therefore, both IV levonadifloxacin and oral levonadifloxacin were non-inferior to IV linezolid and oral linezolid, respectively. The majority of subjects in the micro-ITT population had a baseline infection caused by S. aureus with approximately 30% of subjects having MRSA. Levonadifloxacin (IV and oral) had a higher clinical cure rate at TOC for MRSA patients compared with linezolid (IV and oral), (95.0% vs. 89.3% respectively). Levonadifloxacin showed evidence of favourable clinical and microbiological efficacy in subjects with concurrent bacteraemia as well as in subjects with diabetes including diabetic foot infections caused by Gram-positive pathogens including MRSA. Pharmacokinetic analysis showed that bioavailability of oral levonadifloxacin was 90% and similar pharmacokinetic profile of levonadifloxacin by both routes provide an option for IV to oral switch for the treatment of subjects. Incidences of treatment-emergent adverse events (TEAEs) were similar between treatment groups and between IV (20.8% vs. 22.4%, for levonadifloxacin and linezolid, respectively) and oral therapy (16.0% vs. 13.5%, respectively), There were no SAEs or deaths related to study drug and the majority of the AEs observed were mild in nature. Overall, the administration of both IV and oral levonadifloxacin was well-tolerated in subjects with ABSSSI., Conclusions: The results demonstrate that IV and oral levonadifloxacin therapy has excellent clinical activity against MRSA and offers advantage compared to other quinolones which generally lack MRSA coverage. Levonadifloxacin is safe and well tolerated in the treatment of ABSSSI caused by Gram -positive pathogens including MRSA as well as non-inferior to IV and oral linezolid, respectively. Similar pharmacokinetic profile of IV and oral levonadifloxacin provides an option for IV to oral switch for the treatment of subjects. Both oral and IV levonadifloxacin have recently been granted approval in India for the treatment of ABSSSI including diabetic foot infections and concurrent bacteraemia in adults (18 years of age or older). ClinicalTrials.gov Registration: NCT03405064. CTRI No.: CTRI/2017/06/008843., (© Journal of the Association of Physicians of India 2011.)

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 well-differentiated mechanism of action involving preferential targeting to DNA gyrase. Potent anti-staphylococcal 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-drug-resistant Gram-positive organisms. Herein, we review the current evidence on therapeutically appealing attributes of levonadifloxacin and alalevonadifloxacin, which are based on a range of non-clinical in vitro and in vivo investigations and clinical studies., Competing Interests: All the authors are employees of Wockhardt Ltd, Mumbai, India. Dr Sachin S. Bhagwat reports holding Wockhardt shares. The authors report no other conflicts of interest in this work., (© 2019 Bhagwat et al.)

WCK 4282 is a combination product of cefepime (FEP) and tazobactam (TAZ) in a 1:1 ratio currently under development for the treatment of multidrug-resistant Gram-negative bacterial infections. We investigated the effect of renal impairment on the pharmacokinetics (PK) and safety of WCK 4282 in 48 subjects with various degrees of renal function. Subjects were categorized on the basis of their Cockcroft-Gault equation-estimated creatinine clearance (CL CR ). We enrolled 6 subjects each into those with mild (CL CR , 60 to <90 ml/min), moderate (CL CR , 30 to <60 ml/min), or severe (CL CR , <30 ml/min) renal impairment and those with end-stage renal disease (ESRD) requiring hemodialysis and 24 healthy control subjects (CL CR , ≥90 ml/min). Healthy subjects and subjects with mild and moderate renal impairment received a single 90-min infusion of 4 g of WCK 4282 (2 g FEP and 2 g TAZ). Subjects with severe renal impairment and ESRD received 2 g of WCK 4282 (1 g FEP and 1 g TAZ) over 90 min. The plasma exposure of FEP-TAZ increased as renal function decreased. In subjects with mild, moderate, and severe renal impairment and ESRD, the mean exposure (area under the plasma concentration versus time curve from time zero extrapolated to infinity) of FEP and TAZ increased by 1.3- and 1.2-fold, 2.3- and 2.3-fold, 4.7- and 4.0-fold, and 8.5- and 11.6-fold, respectively. The urinary recovery of FEP and TAZ decreased with increasing renal impairment. There were no adverse events reported during the study. The findings suggest that dose adjustments for WCK 4282 will be required according to the degree of renal impairment. A single infusion of WCK 4282 was found to be safe and well tolerated in subjects with normal and impaired renal function. (This study has been registered at ClinicalTrials.gov under identifier NCT02709382.)., (Copyright © 2019 American Society for Microbiology.)

Levonadifloxacin is a novel benzoquinolizine subclass of fluoroquinolone, active against quinolone-resistant Staphylococcus aureus A phase 3 trial for levonadifloxacin and its oral prodrug was recently completed. The present study identified area under the concentration-time curve for the free, unbound fraction of a drug divided by the MIC ( f AUC/MIC) as an efficacy determinant for levonadifloxacin in a neutropenic murine lung infection model. Mean plasma f AUC/MIC requirement for static and 1 log 10 kill effects against 9 S. aureus were 8.1 ± 6.0 and 25.8 ± 12.3, respectively. These targets were employed in the selection of phase 3 doses., (Copyright © 2019 American Society for Microbiology.)

WCK 5222 is a combination of cefepime and the novel β-lactam enhancer zidebactam being developed for the treatment of serious Gram-negative bacterial infections. The objective of this study was to compare plasma (total), epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of cefepime and zidebactam in healthy adult subjects. The WCK 5222 dosing regimen was 2 g cefepime/1 g zidebactam administered as a 1-h intravenous infusion every 8 h for a total of 7 doses. Subjects were assigned to one bronchoalveolar lavage (BAL) sampling time at 0.5, 1.25, 3, 6, 8, or 10 h after the seventh dose. Noncompartmental pharmacokinetic parameters were determined from serial plasma concentrations collected over 8-hour and 10-hour intervals following the first and seventh doses, respectively. Penetration ratios were calculated from the area under the plasma concentration-time curve from 0 to 8 h (AUC 0-8 ) for plasma, ELF, and AM using mean and median concentrations at each BAL sampling time. The plasma maximum concentration of drug ( C max ) and AUC values of cefepime and zidebactam increased by 8% to 9% after the seventh versus the first dose of WCK 5222. The respective AUC 0-8 values based on mean concentrations of cefepime and zidebactam in ELF were 127.9 and 52.0 mg · h/liter, and 87.9 and 13.2 mg · h/liter in AM. The ELF to total plasma penetration ratios of cefepime and zidebactam based on mean AUC 0-8 values were 0.39 and 0.38, respectively. The AM to total plasma ratios were 0.27 and 0.10, respectively. The observed plasma, ELF, and AM concentrations of cefepime and zidebactam support studies of WCK 5222 for treatment of pneumonia caused by susceptible pathogens., (Copyright © 2018 American Society for Microbiology.)