Levonadifloxacin

INTRODUCTION

The emergence of resistance to antibiotics is considered as a threat to the world’s sustainable development.^[1] Among various resistant bacterial pathogens isolated around the world, methicillin-resistant Staphylococcus aureus (MRSA) is one of the major public health concerns.^[2] In India, MRSA infections continue to be therapeutically challenging both in hospitals and in the community.^[3] 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.^[4]

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.^[5] 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.^[6]

CHEMISTRY

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.^[8] LND exhibits potent in vitro activity against contemporary S. aureus isolates and Bengal Bay Clone, isolates collected from a large Indian tertiary care hospital.^[9] 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.

PHARMACOLOGICAL PROPERTIES

SPECTRUM OF ACTIVITY

PHARMACOKINETICS

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.^[11]

CLINICAL ASPECTS

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).^[9] 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.^[7] Recently, the potent in vitro activity (MIC) of LND against contemporary Indian MRSA isolates, including the Bengal Bay clones, has been reported.^[8] 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.^[15] 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.^[4]

CONCLUSION

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.