How to cite this article: Kalikar M. Levonadifloxacin. Vidarbha J Intern Med 2022;32:55-8.
Methicillin-resistant Staphylococcus aureus (MRSA) is one of the major public health concerns in India, MRSA infections continue to be therapeutically challenging both in hospitals and in the community. The currently available therapeutic options for MRSA are unable to provide safe and efficacious treatment with an option of oral switchover in the treatment of MRSA infections, especially in the community. Levonadifloxacin (LND) is a broad-spectrum benzoquinolizine fluoroquinolone with potent activity against quinolone-resistant S. aureus and MRSA phenotypes developed by an Indian company Wockhardt. LND and its oral prodrug alalevonadifloxacin have been recently approved in India for the treatment of acute bacterial skin and skin structure infections with concurrent bacteraemia and diabetic foot infections.
The emergence of resistance to antibiotics is considered as a threat to the world’s sustainable development. Among various resistant bacterial pathogens isolated around the world, methicillin-resistant Staphylococcus aureus (MRSA) is one of the major public health concerns. In India, MRSA infections continue to be therapeutically challenging both in hospitals and in the community. As per published literature, the incidence of MRSA varies from 25% in the Western part of India to 50% in South India. MRSA infection is encountered in both the hospital and community settings.
The currently available options in India for the treatment of MRSA infections include vancomycin, daptomycin, teicoplanin, and linezolid. All these drugs have limitations such as poor lung penetration and nephrotoxicity with vancomycin, myelosuppression with linezolid, and daptomycin skeletal muscle toxicity. With the exception of linezolid, none of these drugs have an oral option. Thus, the currently available therapeutic options are unable to provide safe and efficacious treatment with an option of oral switchover in the treatment of MRSA infections, especially in the community.
Levonadifloxacin (LND) is a broad-spectrum benzoquinolizine fluoroquinolone with potent activity against quinolone-resistant S. aureus and MRSA phenotypes developed by an Indian company Wockhardt. LND and its oral prodrug alalevonadifloxacin (ALND) have been recently approved in India for the treatment of acute bacterial skin and skin structure infections with concurrent bacteraemia and diabetic foot infections.
LND belongs to the novel benzoquinolizine subclass of quinolone antibiotics and is being developed as a parenteral formulation in the form of L-arginine salt. In addition, the L-alanine ester prodrug of LND and ALND is being developed as a mesylate salt for oral administration. The molecular weight of LND is 606.6 g/mol and that of ALND is 527.6 g/mol. Structurally, LND differs from ciprofloxacin, moxifloxacin, and levofloxacin by having a benzoquinolizine core attached to a non-basic hydroxypiperidine side chain. Because of its non-basic side chain, LND remains in the unionised form in acidic pH, which facilitates its entry into the bacterial cell. As a result, there is a significant increase in the potency of LND in acidic environments.[7-9] This feature could be beneficial for intracellular activity and antibacterial action in infections with an acidic environment.
LND is S-(–)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo; quinolizine-2-carboxylic acid L-arginine salt tetrahydrate is the active S(-) isomer of nadifloxacin recently approved in India. LND exhibits potent in vitro activity against contemporary S. aureus isolates and Bengal Bay Clone, isolates collected from a large Indian tertiary care hospital. The S(-) isomer of nadifloxacin has been shown to be more potent than the R(+) isomer and twice as active as the racemic form of nadifloxacin against Gram-positive and Gram-negative bacteria.
Mechanism of action
The mechanism of the action of fluroquinolone (FQN) is well known. FQNs act on two bacterial DNA enzymes: Gyrase and topoisomerase IV. The supercoiling of the DNA is controlled by DNA gyrase and topoisomerase IV; they act by introducing a break in both the strands of DNA in the bacterial chromosome and then, resealing it to stop the supercoiling. Thus, due to the covalent enzyme-DNA complex stabilisation, DNA is cleaved. After this interaction, depending on the concentration, the death of the bacterial cell occurs in two ways: At low concentration by blocking replication and transcription and at higher concentration (over the minimum inhibitory concentration), when the DNA topoisomerase is dissociated/removed, the DNA strands remain free, which leads to the chromosome fragmentation. Due to simultaneous inhibition of DNA gyrase and topoisomerase IV, both representatives exhibit significant antibacterial activity against Gram-negative and Gram-positive bacteria, with an emphasis on MRSA LND has the advantage of being potent against resistant pathogens with a very low frequency of mutation.[4,11-13]
Various in vitro and in vivo investigations have established LND’s antibacterial spectrum against Gram-positive, Gram-negative, atypical and anaerobic pathogens. Preferential targeting of DNA gyrase by LND is beneficial in providing superior potency, especially against quinolone-resistant S. aureus. The excellent bioavailability of oral formulations can be helpful in the smooth switch from parenteral to oral therapy. Both medication forms have well-established pharmacokinetics and safety; in the Phase I trial, there were no notable severe or unfavourable clinical or laboratory side effects, indicating that both formulations are well tolerated.
SPECTRUM OF ACTIVITY
LND shows potent activity against a variety of Gram-positive aerobic bacteria, including S. aureus resistant to methicillin (i.e., MRSA), vancomycin that is, hetero-vancomycin-intermediate S. aureus and vancomycin-resistant S. aureus and daptomycin-intermediate/-resistant strains, coagulase-negative staphylococci. Activity against quinolone-resistant Staphylococcus epidermidis has also been demonstrated. Moreover, it is active against Streptococcus pneumoniae. Moreover, it is active against other streptococcal species as well.
LND shows activity against Acinetobacter baumannii, Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, and Pseudomonas aeruginosa that are comparable to other clinically available quinolones.
Activity against Mycoplasma pneumoniae, Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma spp. (including macrolide-, tetracycline- and levofloxacin-resistant strains), Chlamydophila pneumoniae and Legionella pneumophila is established.
It is active against Gram-positive anaerobes such as Clostridium perfringens and C. difficile. Similarly, Gram-negative anaerobes such as Bacteroides fragilis, Prevotella and Porphyromonas strains, and b-lactamase-producing Fusobacteria were found to be susceptible to LND.
Activity against bioterror pathogens
LND has demonstrated activity against a wide range of bioterror pathogens, including Bacillus anthracis, Burkholderia pseudomallei, Francisella tularensis, Burkholderia mallei, and Yersinia pestis.
The approved clinical dose regimens of LND and ALND are formulated as IV and oral dosage regimen, respectively; their approved clinical dose is 800 mg, BID, 90 min infusion, and 1000 mg, BID, oral, respectively. Studies reveal that on administration through a different route, the drug possesses pharmacokinetic properties that are stated below.
On ingesting the tablet; the prodrug undergoes ester-mediated biotransformation largely in the liver; the active form of the drug gets absorbed at Tmax of 0.5–2 h. The bioavailability of the drug is 90% in fasting condition and food does not much affect the Cmax of the drug.
The drug in systemic circulation gets distributed in all parts of the body and body fluids. The mean apparent volume of distribution for IV and oral administration is 32.7 and 55.44 L respectively, and serum protein binding is 70–90%, the alveolar macrophage concentration is 35.3 which even surpasses the MIC 90 values; hence, studies suggest a potency of drug toward treating respiratory infections.
LND is metabolised through Phase II metabolism or biotransformation and involves very less involvement of cytochrome P450 system, the major metabolite formed about 72% of IV dose and 66.77% of an oral dose is excreted as LND sulphate. Various other metabolites observed are glucuronide conjugates such as O-glucuronide and acyl glucuronide and five oxidative metabolites.
The drug is finally eliminated out of the body either in changed or unchanged form. In oral and intravenous dose administration, the mean elimination half-life of drug LND is 7.35 h and 6.8 h approximately whereas serum clearance is 5.2 L/h and 4.2 L/h, respectively. After IV dose, 88.2% of the dose is recovered in which 16.2% is unchanged drug and 72% is major metabolite; whereas in oral administration, 97% oral dose is recovered out of which 30.8% is unchanged and 66.7% is metabolite LND sulphate.
Indian drug regulator, DCGI has approved Wockhardt LND and ALND for acute bacterial skin and skin structure infections including diabetic foot infections and concurrent bacteraemia. The approval is based on a successfully conducted Phase 3 clinical study comparing LND with linezolid (Clinical Trial Registry India, CTRI/2017/06/008843). These are the first novel chemical entity antibiotics researched and developed in India with various international collaborations across the globe. While the non-clinical and Phase 1 studies have been undertaken in the U.S., Europe, and India, the Phase 2 and Phase 3 clinical studies have been successfully completed in India. LND also shows clinically relevant activities against resistant respiratory pathogens such as macrolide and penicillin-resistant S. pneumoniae, Streptococcus pyogenes, H. influenzae, and Moraxella catarrhalis. It is also active against anaerobic pathogens as well as atypical respiratory pathogens such as C. pneumoniae, L. pneumophila, and M. pneumoniae. Recently, the potent in vitro activity (MIC) of LND against contemporary Indian MRSA isolates, including the Bengal Bay clones, has been reported. In one study, LND showed promising safety and efficacy when used as IV and/or oral therapy for the treatment of secondary bacterial pulmonary infections in COVID-19 patients. The NorA efflux pump does not affect the activity of LND, demonstrating a significant advantage over other quinolones, including ciprofloxacin, norfloxacin, clinafloxacin, and gemifloxacin, which express efflux-mediated fluoroquinolone resistance. LND has undergone extensive clinical development with over 900 patients being exposed to LND at supratherapeutic doses of 2.6 g daily. Moreover, no safety concerns were identified in any study. One study has demonstrated that IV and oral therapy are safe and well tolerated in the treatment of ABSSSI and Gram-positive pathogens including MRSA.
LND shows promising broad-spectrum antibacterial activity toward many bacteria, particularly toward MRSA, where many antibiotics fail. On the other hand, its oral as well as IV doses have a high therapeutic index which has not been reported to produce any toxicity. Multiple attributes, such as not being a substrate for the NorA efflux pump, preferential DNA gyrase activity, and being devoid of potential adverse effects, may offer a valuable therapeutic option for the management of complex and serious bacterial infections.
Declaration of patient consent
Patient’s consent not required as there are no patients in this study.
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Conflicts of interest
There are no conflicts of interest.
- J Assoc Physicians India. 2020;68:30-6.Efficacy and safety of a novel broad-spectrum anti-MRSA agent levonadifloxacin compared with linezolid for acute bacterial skin and skin structure infections: A phase 3, openlabel, randomized study.
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