|Year : 2019 | Volume
| Issue : 4 | Page : 478-487
A comparative assessment of clinical, pharmacological and antimicrobial profile of novel anti-methicillin-resistant Staphylococcus aureus agent levonadifloxacin: Therapeutic role in nosocomial and community infections
Yamuna Devi Bakthavatchalam1, Shoma Vinay Rao2, Barney Isaac3, Abi Manesh4, Senthur Nambi5, Subramanian Swaminathan6, Vasanth Nagvekar7, Vivek Nangia8, Peter Victor John9, Balaji Veeraraghavan1
1 Department of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Critical Care Unit, Christian Medical College, Vellore, Tamil Nadu, India
3 Department of Pulmonary Medicine, Christian Medical College, Vellore, Tamil Nadu, India
4 Department of Internal Medicine and Infectious Diseases, Christian Medical College, Vellore, Tamil Nadu, India
5 Department of Infectious Disease, Apollo Hospital, Chennai, Tamil Nadu, India
6 Department of Infectious Disease, Global Hospital, Chennai, Tamil Nadu, India
7 Department of Infectious disease, Lilavati Hospital, Mumbai, Maharashtra, India
8 Department of Infectious Disease, Fortis Hospital, New Delhi, India
9 Critical Care Medicine, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Submission||29-Jan-2020|
|Date of Acceptance||30-Mar-2020|
|Date of Web Publication||18-May-2020|
Dr. Balaji Veeraraghavan
Department of Clinical Microbiology, Christian Medical College, Vellore - 632 004, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Staphylococcus aureus is of significant clinical concern in both community- and hospital-onset infections. The key to the success of S. aureus as a pathogen is its ability to swiftly develop antimicrobial resistance. Methicillin-resistant S. aureus (MRSA) is not only resistant to nearly all beta-lactams but also demonstrates resistance to several classes of antibiotics. A high prevalence of MRSA is seen across worldwide. For many decades, vancomycin remained as gold standard antibiotic for the treatment of MRSA infections. In the past decades, linezolid, daptomycin, ceftaroline and telavancin received regulatory approval for the treatment of infections caused by resistant Gram-positive pathogens. Although these drugs may offer some advantages over vancomycin, they also have significant limitations. These includes vancomycin's slow bactericidal activity, poor lung penetration and nephrotxicity;linezolid therapy induced myelosuppression and high cost of daptomycin greatly limits their clinical use. Moreover, daptomycin also gets inactivated by lung naturally occurring surfactants. Thus, currently available therapeutic options are unable to provide safe and efficacious treatment for those patients suffering from hospital-acquired pneumonia, bloodstream infections (BSIs), bone and joint infections and diabetic foot infections (DFI). An unmet need also exists for a safe and efficacious oral option for switch-over convenience and community treatment. Herein, the review is intended to describe the supporting role of anti-staphylococcal antibiotics used in the management of S. aureus infections with a special reference to levonadifloxacin. Levonadifloxacin and its prodrug alalevonadifloxacin are novel benzoquinolizine subclass of quinolone with broad-spectrum of anti-MRSA activity. It has been recently approved for the treatment of complicated skin and soft-tissue infection as well as concurrent bacteraemia and DFI in India.
Keywords: Ceftaroline, daptomycin, levonadifloxacin, linezolid, methicillin-resistant Staphylococcus aureus, vancomycin
|How to cite this article:|
Bakthavatchalam YD, Rao SV, Isaac B, Manesh A, Nambi S, Swaminathan S, Nagvekar V, Nangia V, John PV, Veeraraghavan B. A comparative assessment of clinical, pharmacological and antimicrobial profile of novel anti-methicillin-resistant Staphylococcus aureus agent levonadifloxacin: Therapeutic role in nosocomial and community infections. Indian J Med Microbiol 2019;37:478-87
|How to cite this URL:|
Bakthavatchalam YD, Rao SV, Isaac B, Manesh A, Nambi S, Swaminathan S, Nagvekar V, Nangia V, John PV, Veeraraghavan B. A comparative assessment of clinical, pharmacological and antimicrobial profile of novel anti-methicillin-resistant Staphylococcus aureus agent levonadifloxacin: Therapeutic role in nosocomial and community infections. Indian J Med Microbiol [serial online] 2019 [cited 2020 Jul 3];37:478-87. Available from: http://www.ijmm.org/text.asp?2019/37/4/478/284528
| ~ Introduction|| |
Staphylococcus aureus is of significant clinical concern in both community- and hospital-onset infections. In the 1940s, all the S. aureus infections were effectively managed with the introduction of penicillin. Within 2 years of its clinical use, penicillin resistance was reported in S. aureus. Similarly, within 2 years of methicillin use, strains of methicillin-resistant S. aureus (MRSA) were reported. The key to the success of S. aureus as a pathogen is its ability to swiftly develop antimicrobial resistance. MRSA is not only resistant to nearly all beta-lactams but also demonstrates resistance to several classes of antibiotics. In the past 15 years, a high prevalence of MRSA has been seen across the world and led to increased use of vancomycin. This eventually resulted in the emergence of heteroresistant vancomycin-intermediate S. aureus (hVISA) and vancomycin-intermediate S. aureus (VISA) and rarely vancomycin-resistant S. aureus (VRSA).
For many decades, vancomycin remained as gold standard antibiotic for the treatment of MRSA infections. Since the year 2000, linezolid, daptomycin, ceftaroline and telavancin received regulatory approval for the treatment of infections caused by resistant Gram-positive pathogens. Although these drugs may offer some advantages over vancomycin, they also have significant limitations. These includes vancomycin's slow bactericidal activity, poor lung penetration and nephrotxicity;linezolid therapy induced myelosuppression and high cost of daptomycin greatly limits their clinical use. Moreover, daptomycin also gets inactivated by lung naturally occurring surfactants. In India, the prevalence of MRSA is around 40%. Thus, currently available therapeutic options are unable to provide safe and efficacious treatment for those patients suffering from hospital-acquired pneumonia, BSIs, bone and joint infections and diabetic foot infections (DFI). An unmet need also exists for a safe and efficacious oral option for switch-over convenience and community treatment.
Given this high incidence of MRSA infection, there is a need for newer broad-spectrum anti-staphylococcal agent with good efficacy, safety and affordability. Recently, the drug controller general of India has approved a novel anti-MRSA antibiotic, levonadifloxacin, for the treatment of complicated skin and soft-tissue infections (SSTIs) as well as concurrent bacteraemia and DFI. Levonadifloxacin is a broad-spectrum quinolone belonging to the benzoquinolizine subclass, formulated for intravenous (IV) and oral administration.
Ciprofloxacin ( first generation) and levofloxacin (second generation) primarily inhibit DNA topoisomerase IV. A single mutation in this target can affect the binding of ciprofloxacin and levofloxacin to a greater extent. More than 80% of MRSA strains are resistant to ciprofloxacin and mostly carry the mutations S84 L in gyr A and S80F/S80Y in grlA/parC., Levonadifloxacin is superior to other quinolones by demonstrating bactericidal activity through the dual inhibition of DNA gyrase and topoisomerase IV with primacy to DNA gyrase.
The purpose of this review is to discuss the evidence supporting the role of anti-staphylococcal antibiotics used in the management of S. aureus infections with a special reference to levonadifloxacin.
| ~ Vancomycin|| |
Vancomycin was originally discovered as a natural product by the scientists at Eli Lilly and Company. The drug was granted formal approval for clinical use in 1958 2 years before the introduction of methicillin. Its clinical need was realised much later after the emergence and spread of MRSA. Vancomycin is a glycopeptide molecule and an inhibitor of bacterial cell wall synthesis and acts by binding to terminal D-Ala-D-Ala of peptide chain which interlinks glycan polymers. Vancomycin exhibits potent activity against Gram-positive pathogens-staphylococci including MRSA, streptococci, susceptible enterococci and Gram-positive anaerobes. The drug lacks activity against Gram-negative organisms. Since the emergence and spread of hospital MRSA clones, vancomycin has been regarded as the first-line therapy either standalone or in combinations for various MRSA infections such as acute bacterial skin and skin structure infections (ABSSSI), infective endocarditis, bacteraemia, pneumonia and osteoarticular infections.
However, vancomycin is slowly cidal and its activity is hampered against slow-growing bacteria as well as higher inoculum. Moreover, its penetration into various body tissues and lung is poor. The pharmacokinetics (PKs) of vancomycin is significantly altered in patients. Added to these, the minimum inhibitory concentration (MIC) creep (isolates showing MIC of ≥1.5 mg/L) and widespread prevalence of hVISA have a potential to jeopardise the therapeutic outcome., Further, there are a number of challenges in optimising the vancomycin dosing regimen to achieve higher efficacy rates and minimising the toxicity as over exposure of vancomycin leads to kidney toxicity. Given these complications, therapeutic drug monitoring is necessary for vancomycin in special populations such as critically ill, paediatric, elderly, obese, renal impairment, burn and haematologic patients. At the same time, such a facility is not commonly available in middle-income countries such as India.
The area under the curve (AUC)/MIC ratio is the PK/pharmacodynamic (PK/PD) index that drives the efficacy of vancomycin. The general consensus is that an AUC/MIC ratio of ≥400 is necessary for a successful outcome. However, determining AUC of vancomycin in patients requires multiple blood sampling which is not feasible. Therefore, serum trough levels of 15–20 mg/L are considered a surrogate marker of an AUC/MIC ratio of >400 for a MIC of ≤1 mg/L. The trough concentration should be determined at steady-state condition prior to 4th or 5th dose. As mentioned earlier, the potential concern of targeting higher vancomycin trough (>15 mg/L) concentrations and longer duration of therapy is the occurrence of acute kidney injury.,
Rybak et al. have released a revised vancomycin therapeutic guidelines from the Infectious Diseases Society of America. Trough-only therapeutic monitoring of vancomycin is widely used today in clinical practice. Although the guidelines present AUC24/MIC to be the most appropriate PK/PD target for vancomycin, this revised guideline recommends moving away from trough targets to AUC24/MIC for the monitoring of vancomycin. This shift may have been supported due to a significant nephrotoxicity risk when targeting higher vancomycin trough concentration. An effective AUC24/MIC target of 400–600 can be achieved with significantly lower trough concentrations to optimise clinical efficacy and to improve safety. For AUC dosing, MIC should be determined using broth microdilution (BMD) method. An AUC24/MIC ratio is the surrogate marker for clinical efficacy of vancomycin, while trough concentration is required for monitoring safety and the risk of acute kidney injury.
The new guideline recommends Bayesian-derived AUC monitoring for vancomycin dosing. Using this approach, vancomycin concentrations can be determined within 24–48 h and do not require steady-state serum concentration. Bayesian-derived AUC/MICBMD ratio of 400–600 is advocated by assuming vancomycin MICBMD90 of 1 μg/ml. AUC-guided vancomycin dosing and monitoring provides an optimal way to maximise clinical efficacy and minimise toxicity. Trough-only monitoring (15–20 mg/L) is no longer recommended.
| ~ Linezolid|| |
Linezolid has been approved by the Food and Drug Administration (FDA) for the indication of complicated SSTIs (cSSTIs) and pneumonia caused by Gram-positive organisms in 2000. It binds to bacterial 23S rRNA and inhibits protein synthesis. Due to its unique mechanism of action, it lacks cross-resistance to other protein-synthesis inhibitors. Linezolid is available as 2 mg/ml IV infusion and also available as film-coated compressed tablets containing 600 mg of active drug. FDA-recommended dosing regimen is 600 mg every 12 h. This dosing interval can maintain the plasma concentration above the MIC90 for the susceptible target of 4 mg/L. The steady-state peak serum concentration of 15–27 mg/L can be achieved within 0.5–2 h of administration. Irrespective of the route of administration (IV or oral), mean clearance, half-life and volume of distribution have been reported to be similar. Dose adjustment is not required when switching from IV to the oral formulation or in patients with moderate renal or hepatic impairment.
Linezolid has (i) excellent tissue penetration, (ii) oral bioavailability of 100%, (iii) protein-binding level of approximately 31% and (iv) half-life of 3.4–7.4 h. It has off-label use in the treatment of osteomyelitis, prosthetic joint infections and septic arthritis. PDs parameters of linezolid at the standard dose (600 mg every 12 h) are not influenced by the severity of sepsis. Linezolid has excellent penetration of infected soft tissues, epithelial lining of the lungs and bones. It has enhanced efficacy against strains producing Panton–Valentine leucocidin, α-haemolysin and toxic shock syndrome toxin.
Several studies have reported the superiority of linezolid in the treatment of SSTI and pneumonia [Table 1]. Linezolid showed higher clinical cure and microbiological clearance than vancomycin against suspected MRSA-associated cSSTIs.,, A randomised controlled trial on MRSA-associated hospital-acquired pneumonia has reported a significantly higher rate of clinical (60% vs. 50%) and microbiological cure in the linezolid group, compared to the vancomycin group. The notable adverse event associated with linezolid therapy is the risk of myelosuppression. The incidence of thrombocytopenia has been reported variously between 38.7% and 56.7% in patients treated with more than 14 days., Linezolid efficacy and safety can be maintained with trough concentrations between 3.6 and 8.2 mg/mL. According to the consensus guidelines, linezolid could be preferred when vancomycin MIC was >1 μg/ml. Linezolid-based salvage therapy has been reported to be effective in eradicating S. aureus within 72 h in patients with persistent MRSA bacteraemia. This salvage therapy resulted in the clinical success rate of 88% and reduced S. aureus- related mortality.
|Table 1: Comparative efficacy of linezolid versus vancomycin in treating Methicillin-resistant Staphylococcus aureus infections|
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A global surveillance study has reported that 99.9% of S. aureus are susceptible to linezolid with the MIC50 and MIC90 of 1 and 2 μg/ml, respectively. MIC90 of linezolid is twofold lower than that of the susceptible breakpoint of 4 μg/ml. The mechanisms of linezolid resistance in S. aureus are (i) mutation in 23SrRNA, the most commonly reported mutation is G2576T, (ii) mutation in ribosomal proteins L3 and L4 and/or (iii) acquisition of cfr gene. However, resistance to linezolid is rarely reported in S. aureus.
| ~ Daptomycin|| |
Daptomycin (IV) was initially approved by the US FDA in 2003 for complicated skin and skin structure infections. Subsequently, it obtained the approval for the treatment of S. aureus BSIs (bacteraemia), including those with right-sided infective endocarditis. The molecule is chemically a lipopeptide and discovered as a natural product from Streptomyces roseosporus. The early discovery and following clinical development works were undertaken by Eli Lilly, but the drug giant eventually abandoned the project due to the toxicity surfaced when a higher dose (8 mg/kg) was used twice daily in a Phase 2 study. However, Cubist which in-licensed the molecule continued the clinical development of the molecule. Cubist undertook a detailed evaluation of the in vitro,in vivo bactericidal action and post-antibiotic effects of daptomycin and their impact on the efficacy. These investigations showed that daptomycin is bestowed with concentration-dependent bactericidal action and produced long post antibiotic effect (PAEs) which helped Cubist evolve a novel once-a-day dosing regimen. This regimen not only preserved the efficacy of the drug but also significantly improved the tolerability. Conventionally in clinical practice, higher doses between 6 and 10 mg/kg are used to overcome treatment tolerance development.
Daptomycin received much attention due to its rapid bactericidal activity against S. aureus which is a reflection of its well-differentiated mechanism of action compared to other peptides such as vancomycin and teicoplanin. It exerts antibacterial activity through disrupting bacterial plasma membrane functions. The antibacterial spectrum includes staphylococci, streptococci and enterococci group of pathogens including vancomycin-resistant enterococci. Daptomycin lacks activity against Gram-negative organisms. The biggest limitation of daptomycin is that the drug is not indicated for the treatment of pneumonia. This was revealed in a Phase 3 clinical trial wherein the death rate and rates of serious cardiorespiratory adverse events were higher in daptomycin-treated patients than in comparator-treated patients. Later investigations revealed that daptomycin is inactivated in the lung environment due to its binding with lung surfactant. Daptomycin is reversibly bound to human plasma proteins, primarily to serum albumin, in a concentration-independent manner.
The overall mean plasma protein binding ranges from 90% to 93%. The Clinical and Laboratory Standards Institute susceptibility breakpoint for S. aureus is ≤1 mg/L. Daptomycin MICs are required to be determined only through BMD test method employing media with the calcium content of 50 mg/L. This is because the membrane-binding action of daptomycin is calcium dependant. The use of the agar dilution method and disc-diffusion test is not recommended for daptomcin. Various published studies show that the MIC90 of daptomycin against MRSA population ranges 0.25–1 mg/L. However, the MIC90 rises up to 4 mg/L against the VISA population. It has been well established that VISA strains show elevated MICs to daptomycin, and therefore, significant proportions of such isolates deemed nonsusceptible to daptomycin (MICs >1 mg/L).
The clinical efficacy of daptomycin has been widely reported. A retrospective assessment showed an overall clinical success rate of 77.2% among 11,557 patients treated with daptomycin. These patients include those suffering from cSSTI (31.2%) and bacteraemia (21.8%). The overall clinical success rate was 79.1% in patients with S. aureus infections (MRSA, 78.1%). Owing to its rapid bactericidal action, daptomycin offers a valuable therapeutic option for the treatment of BSIs and endocarditis. However, it is to be noted that the overall efficacy rates of daptomycin in Phase 3 study of BSI and endocarditis were only 44% versus 42% efficacy for comparator drugs. Thus, there is a significant scope to evolve a newer therapy with superior efficacy for the treatment of MRSA caused BSI. This is an urgent unmet need as none of the other anti-MRSA agents approved till date have been systematically evaluated clinically for the treatment of MRSA BSI. Another concern regarding long-term daptomycin therapy pertains to the development of on-therapy resistance. Daptomycin requires dose adjustment for patients with a creatinine clearance rate of <30 mL/min. The drug has not been evaluated in paediatric patients.
Daptomycin safety has been established for 4 weeks administration but not beyond. The adverse effects associated with daptomycin therapy include myopathy/rhabdomyolysis, eosinophilic pneumonia and anaphylactic hypersensitivity reactions. Daptomycin as a standalone agent is not known to show anti-biofilm activity. The drug has been shown to be active against intracellular S. aureus.
| ~ Ceftaroline|| |
Ceftaroline is an injectable (600 mg, BID) cephalosporin designed to overcome the penicillin binding protein (PBP2a)-mediated methicillin resistance in S. aureus. In the past, except ceftobiprole, none of the β-lactam class of antibiotics has been shown to overcome methicillin resistance in S. aureus. While ceftobiprole gained approval only in certain European countries, ceftaroline is approved worldwide including the US and EU. Ceftaroline was originally designed by a Japanese company, Takeda, employing an ethoxyimino side chain, which acts as a 'Trojan horse', allosterically opening and facilitating access to the active site of the PBP2a. The PBP-binding studies showed that the ceftaroline affinity for PBP2a is up to 256-fold higher than that of other β-lactams. Ceftaroline fosamil (prodrug of ceftaroline) has been approved for the treatment of ABSSSI and community-acquired bacterial pneumonia (CABP) by both the US FDA (year: 2010) and European Medicines Agency (EMA) (year: 2012). In addition, label expansion of ceftaroline to include treatment of concurrent bacteraemia in patients with ABSSSI caused by susceptible isolates of S. aureus was approved by the US FDA based on a supplemental new drug application filed in 2015. The drug has also obtained paediatric approvals (2 months of age and older) for these indications. However, the drug is not approved for CABP caused by MRSA.
Ceftaroline display activity against MRSA- and penicillin-resistant streptococcal isolates. The antibacterial spectrum also includes respiratory Gram-negative pathogens Haemophilus influenzae and Moraxella catarrhalis. However, the drug lacks activity against β-lactamases (extended-spectrum beta-lactamases) expressing Enterobacterales and also does not demonstrate activity against P. aeruginosa. Being a β-lactam agent, it is not active against atypical respiratory pathogens lacking a cell wall. Therefore, it is not advisable to use ceftaroline as a monotherapy in CABP patients with suspected involvement of atypical respiratory pathogens.
The FDA- and EMA-approved regimen for ABSSI indication in patients with normal renal function is 600 mg, every 12 h (infusion 5–60 min) for 5–14 days or longer. The current FDA breakpoints (mg/L) for S. aureus (skin isolates only) are ≤1 (susceptible), 2 (intermediate) and ≥4 (resistant). The European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints (mg/L) are ≤1 (susceptible) and >1 (resistant). Basically, 1 mg/L is the susceptible breakpoint in both FDA and EUCAST interpretive criteria. All these breakpoints are pertinent to 600 mg BID dose regimen with 5 min to 60 min infusion duration. Despite being a β-lactam, a BID regimen rather than a TID regimen has been chosen considering the utility for CABP indication. In the noninferiority clinical trials of CABP, ceftaroline performed better than ceftriaxone which could be attributed to BID regimen of ceftaroline compared to the OD regimen of ceftriaxone, as more frequent dosing is known to provide a longer %f T>MIC – a PD/clinical efficacy determinant for β-lactams.
The surveillance studies showed that certain regions such as Asia Pacific and Latin America ceftaroline MIC90s could be as high as 2 mg/L for S. aureus and these studies also show the existence of isolates with even higher MIC of 4 mg/L. PK/PD studies have shown that the approved 600 mg BID dosing regimen of ceftaroline is able to provide a consistent coverage of S. aureus only up to the MIC of 1 mg/L. This is a key limitation for ceftaroline standard dose regimen. To overcome this limitation, a Phase 3 study was undertaken wherein 600 mg TID regimen with 2 h infusion time has been evaluated. However, only one clinical S. aureus isolate with >1 mg/L MIC was encountered in this trial; therefore, entirely based on PK/PD target, Monte Carlo Simulation and probability of target attainments, revised breakpoints (mg/L) of ≤1 (susceptible), 2 (intermediate) and >2 (resistant), were granted by the EUCAST. It should be noted that susceptible breakpoint still was retained at 1 mg/L.
PKs studies showed that ceftaroline fosamil prodrug is converted into active drug and primarily excreted through urine. The plasma protein binding is about 20%, while the half-life is about 2 h. The duration of free drug concentrations remaining above MIC (f T > MIC) is the PK/PD driver, and a PK/PD target of 31% f T > MIC for 1 log10 kill has been proposed for S. aureus. Applying this target, >90% PTA for high MIC (4 mg/L) is possible only with TID regimen and not with BID regimen. In essence, the standard dose regimen (600 mg BID) is best left with covering S. aureus isolates with MICs up to 1 or at the most 2 mg/L. Ceftaroline penetrates poorly into the lungs, as only 23% of the administered drug reaches the ELF (plasma unbound 24 h AUC: 72 mg. h/L and epithelial lining fluid (ELF) 24 h AUC: 16 mg. h/L). Therefore, in conjunction with modest bactericidal action, lack of intracellular activity and low lung penetration, ceftaroline is unlikely to offer a consistent clinical efficacy in pneumonia caused by S. aureus, which is a significant unmet need. The therapeutic options for MRSA pneumonia are extremely limited as barring vancomycin and linezolid, and none of the recently introduced anti-MRSA agents are approved for MRSA pneumonia. Although telavancin is approved for MRSA hospital-acquired bacterial pneumonia, it is marred with a number of unacceptable adverse effects. Even vancomycin is associated with poor lung penetration and results in the modest clinical efficacy of only 40%–50% in MRSA pneumonia, highlighting the need for a novel drug with potent bactericidal action and high lung penetration. As compared to vancomycin, linezolid has been shown to offer a better clinical efficacy approaching 60%; however, it has poor tolerability (such as thrombocytopenia) on longer duration therapy. Moreover, linezolid is bacteriostatic and therefore is not recommended for the treatment of BSIs for which pneumonia is a frequent source.
The Phase 3 clinical trial and number of other studies and case reports (post approval) have demonstrated a reasonable clinical utility of ceftaroline in treating hospital invasive MRSA infections such as bacteraemia and orthopaedic infection., However, some of the PD properties that do not favour ceftaroline are poor intracellular concentration (being β-lactam) and lack of potent anti-biofilm activity as outlined earlier.
| ~ Levonadifloxacin|| |
Levonadifloxacin is a broad-spectrum benzoquinolizine (subclass of fluoroquinolone) with the unique structural attribute of a tricyclic core with the absence of conventional amine at the C-8 position of the side chain. These unique structural features have imparted a net acidic charge on the molecule. Owing to its greater affinity for DNA gyrase of S. aureus, the drug is active against MRSA as well as quinolone-resistant S. aureus. The IV levonadifloxacin (EMROK) and its oral prodrug alalevonadifloxacin (EMROK O) have been recently granted approval in India for the indication of ABSSSI including DFI and concurrent bacteraemia. The pharmacological features of levonadifloxacin suggest its potential clinical utility in diverse difficult-to-treat MRSA infections.
Levonadifloxacin exhibits broad-spectrumin vitro activity. It is active against MRSA-, Bengal Bay clone MRSA-, quinolone-resistant staphylococci, coagulase-negative staphylococci (methicillin and or quinolone resistant), hVISA, VRSA, linezolid-resistant staphylococci, quinolone-susceptible streptococci, H. influenzae, atypical respiratory pathogens, anaerobes and quinolone-susceptible Gram-negative pathogens. Severalin vitro studies involving Indian and global MRSA isolates showed consistent activity of levonadifloxacin, with MIC90 being in the range of 0.5–1 mg/L. Levonadifloxacin is 8–16 times more active than levofloxacin against quinolone-resistant S. aureus. Unlike vancomycin and linezolid, levonadifloxacin is highly bactericidal to MRSA- and quinolone-resistant S. aureus even at higher bacterial density. This feature has clinical bearing, particularly in case of bacteraemia where a bactericidal antibiotic is preferred over poorly cidal or bacteriostatic antibiotics [Table 2].
|Table 2: Comparative profile of levonadifloxacin, levofloxacin and moxifloxacin|
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The mode of action studies revealed that unlike older fluoroquinolones such as ciprofloxacin and levofloxacin, levonadifloxacin binds preferentially to DNA gyrase of S. aureus. This mechanism endows the drug with potent activity against S. aureus harbouring even two or three mutations in quinolone resistance determining region of S. aureus (Unpublished data, Balaji V). Studies also have shown that levonadifloxacin exhibits low resistance selection potential in S. aureus. The resistance selection window is narrow for levonadifloxacin as the mutation prevention concentration is merely four times the MIC. Another unique feature of levonadifloxacin is that its activity is enhanced at acidic pH, while other quinolones such as ciprofloxacin and moxifloxacin deteriorate in the same condition. This feature has clinical implications as the infection site is acidic in many clinical conditions and levonadifloxacin is expected to act better under this atmosphere. Further, the intracellular environment of phagocytic cells is acidic where S. aureus could remain viable for long and cause relapsing infections. Levonadifloxacin has shown its ability to kill MRSA which is present inside the phagocytic cells. Various reports suggest that anti-biofilm activity is necessary for antibiotics used for treating line infections and also osteoarticular infections involving MRSA. In a comparative study, levonadifloxacin has shown consistent killing of biofilm-embedded MRSA- and quinolone-resistant S. aureus; vancomycin and linezolid were variably bactericidal under the same condition, while daptomycin was not effective even with cation supplementation. Recentin vitro andin vivo studies have established that levonadifloxacin has a potent anti-inflammatory activity which was demonstrated through inhibition of pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin (IL)-6 and IL-1 β. Thus, along with direct antibacterial activity, its' immunomudulatory effect is expected to translate in faster clinical cure along with potent bacterial eradication.
The approved clinical dose regimens of levonadifloxacin and alalevonadifloxacin are 800 mg, BID, 90 min infusion and 1000 mg, BID, oral, respectively. The safety features of levonadifloxacin permit to administer such higher doses leading to potential PK/PD advantages. Compared to other quinolones, levonadifloxacin clinical dose generates the highest plasma exposures and oral alalevonadifloxacin generates comparable exposures. The AUC/MIC of levonadifloxacin required to show efficacy has been established from robustin vivo PK/PD studies employing multiple MRSA- and quinolone-resistant strains. The plasma ACU/MIC of levonadifloxacin achieving bacteriostatic and cidal effects was 8.1 and 25.8, respectively. The population PK modelling-based Monte Carlo simulation revealed that these targets are quite achievable at the approved dose regimens of levonadifloxacin and alalevonadifloxacin. The PK profile of orally administered alalevonadifloxacin is superimposable to that of levonadifloxacin which allows easy IV to oral switch. This helps in early discharge of clinically improved patients continuing with oral therapy without compromising the PK/PD pressure on infecting pathogen. The pulmonary PKs of levonadifloxacin has been well studied. The drug has shown excellent lung permeation leading to the highest ever lung exposures among standard anti-MRSA antibiotics [Table 3]. The AUC/MIC ratio of levonadifloxacin in lung thus exceeds manifolds than AUC/MIC required for killing. The superior lung PK/PD profile is expected to result in favourable clinical outcome in MRSA pneumonia and bacteraemia originated from the lung.
|Table 3: Comparison of efficacy and adverse events between levonadifloxacin with vancomycin, linezolid, daptomycin and ceftaroline|
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| ~ Conclusion|| |
Levonadifloxacin has potent activity against methicillin- and quinolone-resistant S. aureus, hVISA and VRSA isolates. Anti-bacterial activity of levonadifloxacin is retained against the mutations in both DNA gyrase and topoisomerase IV and also biofilm producing S. aureus. In addition, levonadifloxacin is not being a substrate for norA efflux pump which prevents the development of resistance. High level of target attainment ELF and alveolar marcophages indicates the clinical utility of levonadifloxacin and alalevonadifloxacin in the management of respiratory infection. Dose adjustment is not required in patients with hepatic and renal impairment. Superimposed PK/PD of alalevonadifloxacin to levonadifloxacin and excellent bio-availability favour the smooth switch from IV to oral therapy. The results of Phase III clinical trial (Clinical Trials.gov, NCT03405064) shed more light on the clinical utility of this newly approved antibacterials.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]