Xiflox Mechanism of Action

Pharmacology: Film-coated tablet: Pharmacodynamics: Moxifloxacin is a 8-methoxy-fluoroquinolone antibiotic with a broad spectrum of activity and bactericidal action. Moxifloxacin has in vitro activity against a wide range of gram-positive and gram-negative organisms, anaerobes, acid fast bacteria and atypicals e.g. Chlamydia spp., Mycoplasma spp. and Legionella spp.
The bactericidal action results from the interference with topoisomerase II and IV. Topoisomerases are essential enzymes which control DNA topology and assist in DNA replication, repair and transcription.
Moxifloxacin exhibits concentration dependent bactericidal killing. Minimum bactericidal concentrations are generally similar to minimum inhibitory concentrations.
Moxifloxacin contains the C8-methoxy moiety that augments its antibacterial activity and reduces the possibility of Gram-positive mutations. Because the 8-fluroquinolones use a different mechanism of action than do the aminoglycosides, beta-lactams, macrolides, or tetracyclines, there has been no cross resistance between the quinolones and these antimicrobial agents.
Solution for injection: Mechanism of Action: Moxifloxacin is bactericidal against a wide range of gram positive and gram negative organisms. Such activity arises through the inhibition of DNA gyrase (topoisomerase II) and topoisomerase IV, which bacteria require for DNA replication, transcription, repair, and recombination. Moxifloxacin contains the C8-methoxy moiety that augments its antibacterial activity and reduces the possibility of gram-positive mutations. Because the 8-fluroquinolones use a different mechanism of action than the aminoglycosides, beta-lactams, macrolides, or tetracyclines, there has been no cross resistance between the quinolones and these antimicrobial agents.
Pharmacokinetics: Film-coated tablet: Absorption and Bioavailability: Following oral administration moxifloxacin is rapidly and almost completely absorbed. The absolute bioavailability amounts to approximately 91%.
Pharmacokinetics are linear in the range of 50 - 1200 mg single dose and up to 600 mg once daily dosing over 10 days.
Following a 400 mg oral dose peak concentrations of 3.1 mg/L are reached within 0.5 - 4 h post administration. Peak and trough plasma concentrations at steady-state (400 mg once daily) were 3.2 mg/L and 0.6 mg/L, respectively.
Distribution: Moxifloxacin is distributed very rapidly to extravascular spaces. Exposure to drug in terms of AUC (AUC_norm = 6 kg.h/L) is high with steady-state volume of distribution (V_ss) of approximately 2 L/kg. In saliva peak concentrations higher than those of plasma maybe reached. In vitro and ex vivo experiments over a range of 0.02 to 2 mg/L shows the determination of protein binding of approximately 45% (independent of the concentration of the drug). Moxifloxacin is mainly bound to serum albumin. Due to this low value it shows high free peak concentration > 10x MIC are observed. Moxifloxacin reaches high concentrations in tissues like lung (epithelial fluid, alveolar macrophages, biotic tissues), the sinuses (maxillary and ethmoid sinus, nasal polyps) and inflamed lesions (catharide blister fluid) where total concentrations exceeding those of the plasma concentrations are reached. High free drug concentrations are measured in interstitial body water (saliva, intramuscular, subcutaneous). In addition, high drug concentrations were detected in abdominal tissues and fluids and female genital tract.
The peak concentrations and site vs. plasma concentration ratios for various target tissues yielded comparable results for both modes of drug administration after a single dose of 400 mg moxifloxacin.
Metabolism: Moxifloxacin undergoes Phase II biotransformation and is excreted via renal and biliary/faecal pathways as unchanged drug as well as in the form of a sulpho-compound (M1) and a glucuronide (M2). M1 and M2 are the only metabolites relevant in humans, both are microbiologically inactive.
Elimination: Moxifloxacin is eliminated from plasma with a mean terminal half life of approximately 12 hours. The mean apparent total body clearance following a 400 mg dose ranges from 179 to 246 mL/min. Renal clearance amounted to about 24 - 53 mL/min suggesting partial tubular reabsorption of the drug from the kidneys.
Concomitant administration of moxifloxacin with ranitidine or probenecid did not alter renal clearance of the parent drug.
Mass balance of the mother compound and Phase II metabolites of moxifloxacin yielded an almost complete recovery of approximately 96% - 98% independent from the route of administration with no indication of oxidative metabolism.
Special Population: Geriatric patients: Pharmacokinetics of moxifloxacin are not affected by age.
Gender: Drug absorption of Moxifloxacin is not affected by gender.
Solution for injection: Absorption: After a single 400 mg intravenous 1 hour infusion peak concentrations of approximately 4.1 mg/L were reached in the plasma at the end of infusion which corresponds to a mean increase of approximately 26% relative to the oral application. Following multiple intravenous dosing (1 hour infusion), peak and trough plasma concentrations at steady state (400 mg once daily) were between 4.1 to 5.9 mg/L and 0.43 to 0.84 mg/L respectively.
Distribution: Moxifloxacin is approximately 30-50% bound to serum proteins, independent of drug concentration. The volume of distribution of moxifloxacin ranges from 1.7 to 2.7 L/kg. Moxifloxacin is widely distributed throughout the body, with tissue concentrations often exceeding plasma concentrations. Moxifloxacin has been detected in the saliva, nasal and bronchial secretions, mucosa of the sinuses, skin blister fluid, subcutaneous tissue, skeletal muscle, and abdominal tissues and fluids following intravenous administration of 400 mg.
Metabolism: Approximately 52% of an intravenous dose of moxifloxacin is metabolized via glucuronide and sulfate conjugation. The cytochrome P450 system is not involved in moxifloxacin metabolism and is not affected by moxifloxacin. The sulfate conjugate (M1) accounts for approximately 38% of the dose and is eliminated primarily in the feces. While glucuronide conjugate (M2) accounts for approximately 14% of the dose which is excreted exclusively in the urine. Peak plasma concentration of M2 are approximately 40% those of the parent drug, while plasma concentrations of M1 are generally less than 10% those of moxifloxacin.
Excretion: Moxifloxacin is eliminated from plasma with a mean terminal half life of approximately 12 hours. The mean apparent total body clearance following a 400 mg dose ranges from 179 to 246 mL/min. Renal clearance amounted to about 24 - 53 mL/min suggesting partial tubular reabsorption of the medicine from the kidneys. Approximately 45% of intravenous dose of moxifloxacin is excreted as unchanged drug (20% is excreted in the urine and 25% in the feces).
Microbiology: Film-coated tablet: Aerobic Gram-positive micro-organisms: Susceptible: Gardnerella vaginalis, Staphylococcus aureus (methicillin-susceptible strains), Streptococcus agalactiae, Streptococcus milleri group (S. anginosus, S. constellatus and S. intermedius), Streptococcus pneumoniae, Streptococcus pyogenes (Group A), Streptococcus viridans group (S. viridans, S. mutans, S. mitis, S. sanguinis, S. salivarius, S. thermophilus, S. constellatus), Streptococcus dysgalactiae, Coagulase negative Staphylococci (S. cohnii, S. epidermidis, S. haemolyticus, S. hominis, S. saprophyticus, S. simulans) methicillin susceptible strains.
Intermediate: Enterococcus faecalis (Vancomycin, Gentamycin, susceptible strains only), Enterococcus avium, Enterococcus faecium.
Resistant: Staphylococcus aureus (methicillin/ofloxacin resistant strains), Coagulase negative Staphylococci (S. cohnii, S. epidermidis), S. haemolyticus, S. hominis, S. saprophyticus, S. simulans) methicillin resistant strains.
Aerobic Gram-negative micro-organisms: Susceptible: Haemophilus influenzae (including β lactamase negative and positive strains), Haemophilus parainfluenzae, Moraxella catarrhalis (including β lactamase negative and positive strains), Bordetella pertussis, Legionella pneumophila, Acinetobacter baumannii, Proteus vulgaris.
Intermediate: Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Citrobacter freundii, Enterobacter species (E. aerogenes, E. intermedius, E. sakazakii), Enterobacter cloacae, Pantoea agglomerans, Pseudomonas fluorescens, Burkholderia cepacia, Stenotrophomonas maltophilia, Proteus mirabilis, Morganella morganii, Neisseria gonorrhea, Providence species (P. rettgeri, P. stuartii).
Resistant: Pseudomonas aeruginosa.
Anaerobic micro-organisms: Susceptible: Fusobacterium spp., Porphyromonas spp., Prevotella spp., Propionibacterium spp.
Intermediate: Bacteroides sp (B. fragilis, B. distasonis, B. thetaiotaomicron, B. ovatus, B. uniformis, B. vulgaris), Peptostreptococcus spp., Clostridium sp.
Atypicals: Susceptible: Chlamydia pneumoniae, Chlamydia trachomatis, Mycoplasma genitalium, Mycoplasma hominis, Mycoplasma pneumoniae, Coxiella burnetii.
Solution for injection: Spectrum of moxifloxacin is broad and it is active against most strains of the following micro-organisms in both in vitro and in vivo.
Aerobic Gram-positive micro-organisms: Staphylococcus aureus (including methicillin-susceptible strains), Streptococcus pneumoniae (penicillin-susceptible strains only), Streptococcus pyogenes, Streptococcus anginosus, Streptococcus constellatus, Gardnerella vaginalis, Streptococcus milleri, Streptococcus mitior, Streptococcus agalactiae, Streptococcus dysgalactiae, Staphylococcus cohnii, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, Staphylococcus simulans, Corynebacterium diphtheriae, Enterococcus faecalis* (Vancomycin, gentamicin susceptible strains only).
Aerobic Gram-negative micro-organisms: Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis (including β-lactamase negative and positive strains), Enterobacter cloacae, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Bordetella pertussis, Klebsiella oxytoca, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter intermedius, Enterobacter sakazakii, Proteus vulgaris, Morganella morganii, Providencia rettgeri, Providencia stuartii.
Atypicals: Chlamydia pneumoniae, Chlamydia trachomatis, Mycoplasma pneumoniae, Mycoplasma hominis, Mycoplasma genitalium, Legionella pneumophila, Coxiella burnetii.
Anaerobic micro-organisms: Bacteroides distasonis, Bacteroides eggerthii, Bacteroides fragilis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Fusobacterium spp., Peptostreptococcus spp., Porphyromonas spp., Porphyromonas anaerobius, Porphyromonas asaccharolyticus, Porphyromonas magnus, Prevotella spp., Propionibacterium spp., Clostridium perfringens, Clostridium ramosum.