Linezolid is a bacteriostatic agent with the following pharmacokinetic, pharmacodynamic and safety limitations:
  • Thrombocytopenia and bone marrow suppression
  • Lactic acidosis
  • Serotonin syndrome
  • Peripheral and ocular neuropathies
  • Not indicated for MRSA bacteraemia and endocarditis
  • Not preferred in cancer/neutropenic patients due to bacteriostatic nature
  • On-therapy safety monitoring required
  • Inter-patient pharmacokinetic variability

  • Inactivated by the pulmonary surfactant, thereby limiting its use for MRSA pneumonia
  • Poor clinical outcome in hetero-VISA infections
  • Potential for decreased susceptibility with increased vancomycin MIC and hetero-VISA
  • Dose adjustment required in renal patients
  • Muscle pain and possibly rhabdomyolysis
  • On-therapy safety monitoring is required
  • Narrow spectrum (no coverage of Gram-negatives)
  • No oral option for step down or out-patient treatment
    • Acute bacterial skin and skin structure infections (ABSSSI) and concurrent bacteraemia
    • Diabetic-foot infections.

    The absolute oral bioavailability of EMROK O is >90 %

    EMROK is a L-arginine salt of levonadifl¬oxacin, a novel broad spectrum synthetic benzoquinolizine fl¬uoroquinolone antibacterial agent. The empirical molecular formula for levonadifl¬oxacin L-arginine salt is C25H35FN6O6 .4H2O and the molecular weight is 606.6 g/mol. The chemical structure of levonadifloxacin is shown below.

    EMROK O (alalevonadi¬floxacin mesylate; prodrug of levonadi¬floxacin) is a mesylate salt of L-alanine ester of the active parent drug levonadi¬floxacin for oral administration. The molecular formula of alalevonadi¬floxacin mesylate is C22H26FN3O5•CH3-SO3H and the molecular weight is 527.6 g/mol. The chemical structure of Alalevonadifloxacin is shown below.

    For the treatment of adults (≥ 18 years of age), the recommended dosage regimen is as follows:
    • EMROK: 800 mg every 12 hours by intravenous (IV) infusion over a period of 90 minutes
    • EMROK O: 1000 mg (two tablets of 500 mg each) every 12 hours
    The duration of the treatment is 7 to 14 days or more as prescribed by the physician. As EMROK and EMROK O at recommended dose regimens produce comparable drug exposures, therapy can be switched from IV to oral at the discretion of physician.

    EMROK demonstrates bactericidal activity through dual inhibition of DNA gyrase and topoisomerase IV with DNA gyrase being the primary target. Due to primacy towards DNA gyrase, EMROK causes rapid bactericidal action with minimal propensity for resistance development.

    Yes. The unique 4-hydroxy piperidine side chain at C-8 position of the benzoquinolizine core and anionic nature imparts EMROK with an increased activity under acidic conditions which could be clinically beneficial in pus, abscess, wounds and biofilms.

    EMROK has a broad spectrum activity as listed below.
    • Gram-positive: MRSA/quinolone-resistant S. aureus (QRSA), VISA, hetero-VISA, VRSA, linezolid-non-susceptible S. aureus, macrolide & penicillin-resistant Streptococcus, vancomycin-resistant E. faecalis and vancomycin-susceptible E. faecium
    • Community respiratory Gram-negative pathogens: Haemophilus in¬fluenzae, and Moraxella catarrhalis
    • Atypical respiratory pathogens – Mycoplasma spp., Ureaplasma spp., Chlamydia spp., and Legionella spp.
    • Anaerobes- Bacteroids spp., Prevotella spp., and Clostridium sp
    • Susceptible Gram-negative pathogens: E. coli, K. pneumoniae, Enterobacter spp., Citrobacter spp., Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Burkholderia species and Acinetobacter baumannii

    The unique mechanistic characteristics mentioned below bestow EMROK with superior resistance suppression potential
    • Primary targeting DNA Gyrase, a highly critical enzyme for cell survival
    • Potent activity even against mutated targets thus overcoming quinolone resistance in MRSA
    • Narrow mutant selection window
    • Rapid and high density bacterial killing
    • MRSA biofilm eradication potential

    Depending upon severity of the infection, the recommended duration for the treatment is 7-14 days. However, in the post-marketing use, EMROK has been used up to 3 - 4 weeks and EMROK O up to 4 – 6 weeks without any safety concerns.

    Being an amino acid based pro-drug, EMROK O is absorbed from the intestine using amino acid transporters. Upon absorption, the prodrug moiety is cleaved by ubiquitously present esterases to completely release the active levonadifloxacin in to the circulation.

    16.2% of EMROK dose is excreted as unchanged levonadifl¬oxacin (2.3% in urine and 13.9% in faeces) and 72.0% is excreted as anti-bacterially-inactive levonadi¬floxacin sulphate metabolite (50.3% in urine and 21.6% in faeces).

    30.8% of the EMROK O dose is excreted as unchanged levonadi¬floxacin (0.8% in urine and 30.0% in faeces) and remaining 66.7% of dose is excreted as levonadi¬floxacin sulphate metabolite (37.2% in urine and 29.5% in faeces).

    There is no cross resistance observed between EMROK and fluoroquinolones in Gram-positive pathogens. However, among Gram-negative pathogens, cross resistance between EMROK and other fluoroquinolones has been noticed.

    No, the pre-clinical studies showed lack of phototoxic effect of EMROK. Moreover, clinical studies have shown no occurrence of photosensitivity reaction in patients treated with EMROK or EMROK O.

    No. EMROK IV and EMROK O doses are not calculated based on body weight. Thus, the dose adjustment is generally not required for underweight or overweight patients.

    No food effect has been observed with EMROK O and therefore, EMROK O can be administered regardless of fed status

    The national surveillance study conducted by Indian Council of Medical Research (ICMR) reports a hospital MRSA prevalence of 42.6% in 2021. This is a 50% increase over the MRSA prevalence in 2016. In community, the MRSA rates are as high as 27%.

    • Vancomycin (IV)
    • Linezolid (IV and oral)
    • Teicoplanin (IV)
    • Daptomycin (IV)
    • Clindamycin (Oral)
    • Trimethoprim/Sulfamethoxazole (Oral)

  • Dose limiting high rates of nausea/vomiting
  • Bacteriostatic activity
  • No oral option
  • Poor PK/PD due to low dose approval
  • An increase in all-cause mortality has been observed across Phase 3 and 4 clinical trials leading to Black box warning from the U.S. FDA (September 2010)
  • Not effective in treatment of hospital-acquired MRSA pneumonia
  • Dose adjustment required in severe hepatic impairment patients
    • Bone and joint infections
    • Diabetic-foot infections
    • Catheter-related blood stream infections
    • Prosthetic-joint infections
    • Device-associated infections

    The various potential indications are:
    • Community-acquired bacterial pneumonia
    • Bone and joint infections including prosthetic joint infections
    • Febrile neutropenia
    • Device/catheter-associated infections
    • Sepsis

    Studies have shown EMROK’s ability to eradicate MRSA biofilms. This feature suggests EMROK’s uptake and bactericidal potency against biofilm embedded MRSA.

    Linezolid is a bacteriostatic agent with the following pharmacokinetic, pharmacodynamic and safety limitations:
    • Inconsistent coverage of MRSA
    • No bactericidal activity
    • Nearly 45% of MRSA exhibit inducible erm-mediated resistance to clindamycin which could be missed if D test is not performed. These isolates select resistance to clindamycin during therapy
    • Narrow spectrum (no coverage of Gram-negatives)
    • Unproven efficacy for the treatment of invasive MRSA infections
    • Antibiotic-associated diarrhoea

    EMROK has a unique lipophilic tricyclic benzoquinolizine core which provides it with better bacterial cell permeation, enhanced target affinity and ability to overcome efflux pumps in MRSA. Since EMROK is not a substrate of efflux pumps, this helps attain higher intracellular concentrations (unlike ciprofloxacin, norfloxacin) leading to lower potential to select resistance. EMROK has an anionic nature which enables further enhanced bactericidal action against both Gram-positive and Gram-negative pathogens under acidic conditions. Moreover, in non-clinical, clinical studies and post-marketing experience, EMROK has demonstrated a remarkable safety with negligible adverse effects.

    No. EMROK has minimal potential to participate in drug-drug interaction since neither it inhibits nor induces cytochrome (CYP)-enzymes in the liver.

    Yes, EMROK has well-established cardiac safety. Even at a supratherapeutic dose of 2600 mg, EMROK did not cause any clinically significant changes on the electrocardiogram including the QTc interval. Therefore, EMROK shows no risk of QT prolongation and could be considered in individuals at risk of arrhythmias or in those receiving drugs causing QT prolongation.

    Safety and effectiveness of EMROK in paediatric patients below the age of 18 years have not been established, therefore, the use of EMROK in patients under 18 years of age is not recommended.

    No. In pre-clinical toxicological studies, levonadi¬floxacin did not affect the the fertility of male or female rats even at the supra-therapeutic exposures.

    No. In pre-clinical studies, levonadifloxacin did not cause any teratogenic changes in external, visceral, skeletal and soft tissues of foetuses of rats and rabbits

    EMROK does not have any therapeutically relevant activity against M. tuberculosis and therefore, does not pose risk for resistance selection in this pathogen.

    In total 14 Phase I studies have been conducted with both EMROK and EMROK O. Nine studies were conducted in India, while five were conducted in the U.S. Three Phase II studies were completed in India to evaluate the safety and efficacy of EMROK and EMROK O.

    Yes, EMROK can be administered safely without any dose adjustments in patients with hepatic and renal impairment.

    Phase III study has been successfully completed across 40 centres in India with a total of 501 adults being recruited with clinically documented ABSSSI. EMROK (800 mg) and EMROK O (1000 mg) were compared with I.V. Linezolid (600 mg) and oral Linezolid (600 mg), respectively.

    The urinary elimination profile doesn’t support usage of EMROK for UTIs caused by resistant Gram-negative pathogens.

    EMROK immunomodulatory activity was assessed through ex-vivo study by treating human whole blood with lipopolysaccharide (LPS) and also through in vivo studies by injecting LPS to rat and mice. In all of these studies, EMROK showed significant suppression in the levels of pro-inflammatory cytokines like TNF-α, IL-6 and IL-1β. Further in mice, wherein LPS was treated intra-nasally to develop acute lung injury, EMROK showed significant reduction in lung injury which was evident through histopathological observations. The significant reduction in pro-inflammatory cytokine levels by EMROK was depictive of its immunomodulatory effect. However, EMROK should not be used as a treatment for anti-inflammatory effect.

    • Community-acquired bacterial pneumonia (CABP)
    • Hospital- and ventilator-associated bacterial pneumonia (HABP/VABP)
    • Catheter-related blood stream infections (CR-BSI)
    • Complicated skin and soft tissue infections (SSTIs)
    • Febrile neutropenia

    The need to develop a newer antimicrobial agent stems out of the limitation with the currently available anti-MRSA agents which are listed below.
  • Safety concerns with current anti-MRSA agents like nephrotoxicity with vancomycin and thrombocytopenia with linezolid
  • Non-availability of a safe oral anti-MRSA bactericidal agent
  • Narrow spectrum of coverage of current anti-MRSA agents
  • Poor lung penetration
  • Poor bactericidal activity
  • Requirement of dose adjustment in renal/hepatic impairment
  • Limited options available for MRSA biofilm infections
  • Absence of anti-MRSA drug with longer duration treatment potential as required in bone and joint infections, diabetic-foot infections and febrile neutropenia
  • Following features of EMROK favour its usage for the treatment of lower respiratory tract infections
    • Best-in-class lung concentrations (7.6 times higher than plasma) that remain higher than the MIC90 of MRSA and all the community-respiratory pathogens throughout the dosing duration
    • High potency against MRSA and all the multi-drug resistant community respiratory pathogens
    • Higher intracellular concentration in alveolar macrophages favouring activity against intracellular pathogens like MRSA and atypical respiratory pathogens
    • Potent bactericidal action
    • Anti-inflammatory activity as demonstrated from in vivo and ex vivo models

    In the Phase III study, the most common adverse event related to EMROK and EMROK O treatment was constipation (3.6%) of mild intensity.

    The study was designed for a non-inferiority margin of -15%. However, the clinical cure rates (efficacy end point) observed for EMROK or EMROK O at the test-of-cure were numerically higher compared to linezolid IV and oral, respectively. The treatment difference between EMROK and linezolid in IV group at 95% CI was -4.5 to 10.9% (91.0% versus 87.8%) and in the oral group, the difference was -4.2 to 7.3% (95.2% versus 93.6%). Thus, the actual results demonstrated non-inferiority at > -5%.

    A large multi-center, retrospective, post-marketing, real-world, observational study (PIONEER study) was conducted for assessment of safety and efficacy of EMROK and EMROK O in treating various bacterial infections. The data of 1299 patients from 117 hospitals across India was collected. Data of 1229 patients who received treatment for various bacterial infections was collected. EMROK and EMROK O showed very high efficacy and received remarkable safety ratings from the clinicians in this study. Both the agents were successfully used for the treatment of several indications such as ABSSI, pneumonia, COVID19 secondary bacterial pneumonia, BJIs, febrile neutropenia, CR-BSI, septicaemia etc. The clinical success rates were up to 96.8%.

    None. In the Pioneer study, out of 1229 patients, none experienced EMROK/EMROK O-linked serious adverse events. Only 9 patients reported adverse events which were mild intensity of nausea, vomiting, constipation.

    • Acute bacterial skin and skin structure infection (ABSSSI)
    • Diabetic-foot infection (DFI)
    • Community-acquired bacterial pneumonia (CABP)
    • Bone and joint infection (BJI)
    • Device/catheter-associated infection
    • Blood stream infection (BSI)
    • Hospital- and ventilator-associated bacterial pneumonia (HABP/VABP)
    • Endocarditis
    • Burns

    There is no clinical experience of using EMROK/EMROK O in patients with tendon disorders. Even though EMROK/EMROK O belongs to benzoquinolizine sub-class of fluoroquinolone, owing to certain common moieties in the structure, EMROK/EMROK O may not be preferred in patients with tendon disorders. However, in clinical studies and post marketing real-world observations, EMROK has not been reported to cause tendon disorders even when administered in older patients. Moreover, owing to the previously known class effect of quinolones interaction corticosteroids, EMROK should not be administered in concomitance with steroids. However, in real world use of EMROK, no such clinical incidence of drug-drug interaction has been reported.

    Due to feasibility challenges, concentrations of EMROK in human bones were not estimated. However, a surrogate marker, bone penetration study was conducted in rats. The bone penetration of EMROK relative to plasma was 5x. It means that the concentration of EMROK in bones remained above MIC90 for MDR Gram-positive pathogens including MRSA throughout the dosing interval. Moreover, in vitro and in vivo studies have shown the activity of EMROK against Staphylococcus biofilms. This is a crucial and enabling feature in treating bone and joint infections wherein involvement of biofilms is common. In a translational biofilm model study in mice, conducted at University of North Texas, at therapeutic exposures, EMROK killed biofilm embedded S. aureus better than that of rifampicin. Thus excellent bone penetration coupled with activity against biofilms augurs well for EMROK to be a choice of treatment for bone and joint infections