Serum Pharmacokinetics and Bone Penetration of Novel Broad-Spectrum Anti-MRSA Agent Levonadifloxacin in Wistar Rats.

Levonadifloxacin (IV) and alalevonadifloxacin (oral) are novel broad-spectrum anti-methicillin-resistant () 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).

Transcending the challenge of evolving resistance mechanisms in through β-lactam-enhancer-mechanism-based cefepime/zidebactam.

Compared to other genera of Gram-negative pathogens, is adept in acquiring complex non-enzymatic and enzymatic resistance mechanisms thus remaining a challenge to even novel antibiotics including recently developed β-lactam and β-lactamase inhibitor combinations. This study shows that the novel β-lactam enhancer approach enables cefepime/zidebactam to overcome both non-enzymatic and enzymatic resistance mechanisms associated with a challenging panel of . This study highlights that the β-lactam enhancer mechanism is a promising alternative to the conventional β-lactam/β-lactamase inhibitor approach in combating ever-evolving MDR .

Investigations on Pharmacokinetic/Pharmacodynamic Determinants of Fosfomycin in Murine Thigh and Kidney Infection Models.

Amidst the era of widespread resistance, there has been a renewed interest in older antibiotics such as fosfomycin, owing to its activity against certain resistant Gram-negative pathogens, including multidrug-resistant variants expressing extended spectrum β-lactamases or carbapenemases. The goal of the study was to investigate pharmacokinetic/pharmacodynamic (PK/PD) index and PK/PD targets of fosfomycin in murine thigh and kidney infection models, employing clinical isolates of () and (). Seven isolates of (one wild-type and six clinical isolates) and five isolates of (one wild-type and four clinical isolates) were utilized for PK/PD studies.

WCK 4034: A promising oxazolidinone for treating gram positive infections.

Increased resistance to gram positive infections have highlighted the limitations of currently available drug treatments including penicillins, macrolides and glycopeptides. As an alternative to address these challenges; Linezolid, the first antibiotic from oxazolidinone class, have shown the promising activities against such infections, although associated toxicological issues limiting the use of linezolid for prolonged treatments. In order to circumvent disadvantages allied with the marketed drugs, we herein reporting the synthesis of WCK 4034, an oxazolidinone antibiotic through our structure activity relationship (SAR) program.

WCK 1152, WCK 1153: Discovery and structure activity relationship for the treatment of resistant pneumococcal and staphylococcal respiratory infections.

Novel antibacterial agents needed constantly to counter the ever emergent resistance development to commercially available drugs; one of the effective synthetic antibacterial classes is fluoroquinolone (FQ). This study includes structure activity relationship based design and synthesis of novel fluoroquinolone molecules active against resistant pathogens bearing mutations of DNA gyrase and/or topoisomerase IV which also express efflux pumps. Here, series of compounds were prepared by treating 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid as a core with various 4-substituted-3,3-dialkyl piperidines as side chains, through conventional synthetic approaches.

Ensuring robustness in the quality of antibiotic susceptibility test discs for four novel antibiotics.

Antibiotic susceptibility test (AST) discs are used as an in-vitro diagnostic tool to select the appropriate antibiotic to treat an infection. Generally, the concentration of the drug loaded on to the AST discs is measured by studying its activity against quality control organisms. This methodology has several limitations-it is time consuming, requires trained manpower, has a wider acceptance criteria of zone of inhibitions-causing ambiguity in judging smaller variations in drug concentration.

Design and synthesis of an oral prodrug alalevonadifloxacin for the treatment of MRSA infection.

Levonadifloxacin is a parenteral anti-MRSA benzoquinolizine antibacterial drug recently launched as, EMROK in India to treat acute bacterial skin and skin structure infections (ABSSSI) in hospitalized patients. As a step down therapy an oral form of levonadifloxacin with comparable PK/PD was needed because the levonadifloxacin exhibits very poor oral absorption. To improve the drugability in terms of oral absorption a pro-drug approach was evaluated.

Activity of β-lactam plus β-lactam-enhancer combination cefepime/zidebactam against Klebsiella pneumoniae harbouring defective OmpK35/36 porins and carbapenemases.

Cefepime/zidebactam is a β-lactam/β-lactam-enhancer based novel antibiotic which is in clinical development for treating infections caused by multidrug-resistant Gram-negative bacteria. Here, in vitro activity of cefepime/zidebactam was determined against multicentre Klebsiella pneumoniae clinical isolates co-expressing serine and/or metallo-carbapenemases and defective OmpK35 and OmpK36 porins. The MICs were determined using the reference broth microdilution method.

In vitro evolution of cefepime/zidebactam (WCK 5222) resistance in Pseudomonas aeruginosa: dynamics, mechanisms, fitness trade-off and impact on in vivo efficacy.

Objectives: To study the dynamics, mechanisms and fitness cost of resistance selection to cefepime, zidebactam and cefepime/zidebactam in Pseudomonas aeruginosa.

Methods: WT P. aeruginosa PAO1 and its ΔmutS derivative (PAOMS) were exposed to stepwise increasing concentrations of cefepime, zidebactam and cefepime/zidebactam.

Activity of Fosfomycin and Nitrofurantoin Against Contemporary Pathogens Isolated from Indian Tertiary Care Hospitals.

In India, multidrug resistance in community and hospital associated Gram-negative pathogens has increased sharply over the past few years. In the absence of novel oral multidrug resistant-pathogen active therapies, the therapeutic situation with regard to community infections is even more challenging. Hence, the focus is now shifting toward potentially expanding the utility of older antibiotics such as fosfomycin and nitrofurantoin beyond their approved pathogen coverage.

In vitro activity of cefepime/zidebactam (WCK 5222) against recent Gram-negative isolates collected from high resistance settings of Greek hospitals.

Cefepime/zidebactam is in clinical development for the treatment of carbapenem-resistant Gram-negative infections. MICs of cefepime/zidebactam (1:1) and comparators against Enterobacterales (n = 563), Pseudomonas (n = 172) and Acinetobacter baumannii (n =181) collected from 15 Greek hospitals (2014-2018) were determined by reference broth microdilution method. The isolates exhibited high carbapenem resistance rates [(Enterobacterales (75%), Pseudomonas (75%) and A.

Structural Characterization of Diazabicyclooctane β-Lactam "Enhancers" in Complex with Penicillin-Binding Proteins PBP2 and PBP3 of Pseudomonas aeruginosa.

Multidrug-resistant (MDR) pathogens pose a significant public health threat. A major mechanism of resistance expressed by MDR pathogens is β-lactamase-mediated degradation of β-lactam antibiotics. The diazabicyclooctane (DBO) compounds zidebactam and WCK 5153, recognized as β-lactam "enhancers" due to inhibition of penicillin-binding protein 2 (PBP2), are also class A and C β-lactamase inhibitors.

Assessment of the cytochrome P450 (CYP) inhibition potential of nafithromycin, a next generation lactone ketolide antibiotic.

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 including erythromycin and telithromycin-resistant resistant strains. Older macrolides/ketolides are reported to be potent inhibitors of CYP3A4/5.

Activity of cefepime/zidebactam against MDR Escherichia coli isolates harbouring a novel mechanism of resistance based on four-amino-acid inserts in PBP3.

Background: Recent reports reveal the emergence of Escherichia coli isolates harbouring a novel resistance mechanism based on four-amino-acid inserts in PBP3. These organisms concomitantly expressed ESBLs or/and serine-/metallo-carbapenemases and were phenotypically detected by elevated aztreonam/avibactam MICs.

Objectives: The in vitro activities of the investigational antibiotic cefepime/zidebactam and approved antibiotics (ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/relebactam and others) were determined against E.

Assessment of inhibitory effects of novel anti MRSA benzoquinolizine fluoroquinolone WCK 771 (levonadifloxacin) and its metabolite on human liver cytochrome P450 enzymes.

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. CYP inhibition potential of levonadifloxacin and its sulfate metabolite (WCK 2146) were assessed in this study.

Levonadifloxacin, a Novel Benzoquinolizine Fluoroquinolone, Modulates Lipopolysaccharide-Induced Inflammatory Responses in Human Whole-Blood Assay and Murine Acute Lung Injury Model.

Fluoroquinolones are reported to possess immunomodulatory activity; hence, a novel benzoquinolizine fluoroquinolone, levonadifloxacin, was evaluated in lipopolysaccharide-stimulated human whole-blood (HWB) and mouse acute lung injury (ALI) models. Levonadifloxacin significantly mitigated the inflammatory responses in an HWB assay through inhibition of proinflammatory cytokines and in the ALI model by lowering lung total white blood cell count, myeloperoxidase, and cytokine levels. The immunomodulatory effect of levonadifloxacin, along with promising antibacterial activity, is expected to provide clinical benefits in the treatment of infections.

Pretreatment of nafithromycin attenuates inflammatory response in murine lipopolysaccharide induced acute lung injury.

Acute respiratory distress syndrome following an acute lung injury (ALI) is a life threatening inflammatory condition predominantly characterized by vascular protein leakage, neutrophil recruitment and overexpression of proinflammatory cytokines. Pulmonary and systemic bacterial infections are the major cause of ALI wherein the bacterial cell components play a crucial role. Macrolide/ketolide antibiotics are reported to possess immunomodulatory activity; as a result improved survival has been noted in pneumonia patients.

Effective inhibition of PBPs by cefepime and zidebactam in the presence of VIM-1 drives potent bactericidal activity against MBL-expressing Pseudomonas aeruginosa.

Objectives: The combination of cefepime and the novel β-lactam enhancer zidebactam (WCK 5222) is under development for the treatment of difficult-to-treat Gram-negative infections. Against MBL-producing pathogens, cefepime and zidebactam induce cell elongation and spheroplast formation, indicating PBP3 and PBP2 dysfunction, respectively, having a potent bactericidal effect as a combination. The objective of the present study was to determine the mechanistic basis of the bactericidal effect of cefepime/zidebactam on MBL-expressing pathogens.

Levonadifloxacin, a Novel Broad-Spectrum Anti-MRSA Benzoquinolizine Quinolone Agent: Review of Current Evidence.

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 , and hetero-vancomycin-intermediate strains is an outcome of its well-differentiated mechanism of action involving preferential targeting to DNA gyrase.

In vitro activity of a novel antibacterial agent, levonadifloxacin, against clinical isolates collected in a prospective, multicentre surveillance study in India during 2016-18.

Background: Levonadifloxacin is a novel antibiotic belonging to the benzoquinolizine subclass of fluoroquinolones with potent activity against MRSA and quinolone-resistant Staphylococcus aureus. IV levonadifloxacin and its oral prodrug alalevonadifloxacin have recently been approved in India for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) including diabetic foot infections.

Objectives: To investigate the in vitro activity of levonadifloxacin against contemporary clinical isolates collected from multiple tertiary care hospitals across India in the Antimicrobial Susceptibility Profiling of Indian Resistotypes (ASPIRE) surveillance study.

In vitro bactericidal activity of levonadifloxacin (WCK 771) against methicillin- and quinolone-resistant Staphylococcus aureus biofilms.

Purpose: Staphylococcus aureus causes a wide range of infections, such as endocarditis, pneumonia, osteomyelitis, skin and soft tissue infections, and implant/in-dwelling device-related infections. S. aureus poses a significant challenge to clinicians because of its ability to rapidly acquire multi-drug resistance and quickly progress into a recurrent, chronic infection by biofilm formation.

Pharmacokinetic/Pharmacodynamic Targets of Levonadifloxacin against Staphylococcus aureus in a Neutropenic Murine Lung Infection Model.

Levonadifloxacin is a novel benzoquinolizine subclass of fluoroquinolone, active against quinolone-resistant 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 (AUC/MIC) as an efficacy determinant for levonadifloxacin in a neutropenic murine lung infection model. Mean plasma AUC/MIC requirement for static and 1 log kill effects against 9 were 8.

and Activities of β-Lactams in Combination with the Novel β-Lactam Enhancers Zidebactam and WCK 5153 against Multidrug-Resistant Metallo-β-Lactamase-Producing Klebsiella pneumoniae.

Zidebactam and WCK 5153 are novel bicyclo-acyl hydrazide (BCH) agents that have previously been shown to act as β-lactam enhancer (BLE) antibiotics in and The objectives of this work were to identify the molecular targets of these BCHs in and to investigate their potential BLE activity for cefepime and aztreonam against metallo-β-lactamase (MBL)-producing strains and Penicillin binding protein (PBP) binding profiles were determined by Bocillin FL assay, and 50% inhibitory concentrations (ICs) were determined using ImageQuant TL software. MICs and kill kinetics for zidebactam, WCK 5153, and cefepime or aztreonam, alone and in combination, were determined against clinical isolates producing MBLs VIM-1 or NDM-1 (plus ESBLs and class C β-lactamases) to assess the enhancer effect of BCH compounds in conjunction with β-lactams. Additionally, murine systemic and thigh infection studies were conducted to evaluate BLE effects Zidebactam and WCK 5153 showed specific, high PBP2 affinity in The MICs of BLEs were >64 μg/ml for all MBL-producing strains.