Cravit Mechanism of Action

Pharmacology: Cravit is a broad-spectrum quinolone antibacterial agent containing levofloxacin, optically active (-)-S-form of racemate ofloxacin synthesized by Daiichi Sankyo Co., Ltd. Cravit shows broad and potent antibacterial activities against gram-positive bacteria such as Staphylococcus aureus, Staphylococcus saprophyticus, Streptococcus pneumoniae (including penicillin-resistant strains), Streptococcus pyogenes, Enterococcus faecalis, and gram-negative bacteria such as Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, Enterobacter cloacae, Moraxella catarrhalis, Legionella pneumophila, and other microorganisms such as Chlamydia pneumoniae and Mycoplasma pneumoniae. Cravit, which is transferred rapidly to each tissue in high concentrations without being accumulated there, is mostly excreted in the urine as unchanged form. Cravit shows clinical efficacy on respiratory tract infections, genitourinary tract infections and skin and skin structure infections.
Pharmacokinetics: Absorption and Serum concentration: Levofloxacin is rapidly and essentially completely absorbed after oral administration. Peak plasma concentrations are usually attained one to two hrs after oral dosing. The absolute bioavailability of a 500 mg tablet is approximately 99%, demonstrating complete oral absorption of levofloxacin. Levofloxacin pharmacokinetics is linear and predictable after single and multiple oral dosing regimens. The mean ± SD peak and trough plasma concentrations attained following multiple oral regimens were approximately 5.7 ± 1.4 and 0.5 ± 0.2 μg/mL after the 500 mg doses and 8.6 ± 1.9 and 1.1 ± 0.4 μg/mL after 750 mg doses, respectively.
Distribution: The mean volume of distribution of levofloxacin generally ranges from 74 to 112 L after single and multiple 500 and 750 mg doses, indicating widespread distribution into body tissues. Levofloxacin reaches its peak levels in skin tissue and blister fluid of healthy subjects at approximately 3 hrs after dosing. The skin tissue biopsy to plasma AUC ratio is approximately 2 and the blister fluid to plasma AUC ratio is approximately 1 following multiple oral administration of 750 mg and 500 mg levofloxacin, respectively, to healthy subjects. Levofloxacin also penetrates well into lung tissues. Lung tissue concentrations were generally 2 to 5 folds higher than plasma concentrations and range from approximately 2.4 to 11.3 μg/g over 24 hour period after a single 500 mg oral dose.
In vitro, over a clinical relevant range (1-10 μg/mL) of serum/plasma levofloxacin concentrations, levofloxacin is approximately 24 to 38% bound to serum proteins across all species studied, as determined by the equilibrium dialysis method. Levofloxacin is mainly bound to serum albumin in humans. Levofloxacin binding to serum proteins is independent of the drug concentration.
Metabolism: Levofloxacin is stereochemically stable in plasma and urine and does not invert metabolically to its enantiomer, D-ofloxacin. Levofloxacin undergoes limited metabolism in humans and is primarily excreted as unchanged drug in the urine. Following oral administration, approximately 87% of an administered dose was recovered unchanged drug in urine within 48 hrs, whereas less than 4% of dose was recovered in feces in 72 hours. Less than 5% of an administered dose was recovered in urine as the desmethyl and N-oxide metabolites, the only metabolites identified in humans. These metabolites have little relevant pharmacological activity.
Excretion: Levofloxacin is excreted largely as unchanged drug in the urine. The mean terminal plasma elimination half-life of levofloxacin ranges from approximately 6 to 8 hours following single or multiple doses of levofloxacin given orally. The mean apparent total body clearance and renal clearance range from approximately 144 to 226 mL/min and 96 to 142 mL/min, respectively. Renal clearance in excess of the glomerular filtration rate suggests that tubular secretion of levofloxacin occurs in addition to its glomerular filtration. Concomitant administration of either cimetidine or probenecid result in approximately 24% and 35% reduction in the levofloxacin renal clearance, respectively, indicating that secretion of levofloxacin occurs in the renal proximal tubule. No levofloxacin crystals were found in any of the urine samples freshly collected from subjects receiving levofloxacin.
Microbiology: Levofloxacin is the L-isomer of the racemate, ofloxacin, a quinolone antimicrobial agent. The antibacterial activity of ofloxacin resides primarily in the L-isomer. It is two folds stronger than that of ofloxacin. The mechanism of action of levofloxacin and other fluoroquinolone antimicrobials involves inhibition of bacterial topoisomerase IV and DNA gyrase (both of which are type II topoisomerases), enzymes required for DNA replication, transcription, repair and recombination. Levofloxacin has in vitro activity against a wide range of gram-negative and gram-positive microorganisms. Levofloxacin is often bactericidal at concentrations equal to or slightly greater than inhibitory concentrations.
Fluoroquinolones, including levofloxacin, differ in chemical structure and mode of action from aminoglycosides, macrolides and β-lactam antibiotics including penicillins. Fluoroquinolones may, therefore, be active against bacteria resistant to these antimicrobials.
Resistance to levofloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10^-9 to 10^-10). Although cross-resistance has been observed between levofloxacin and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to levofloxacin.
Levofloxacin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in Indications: Aerobic gram-positive microorganisms: Enterococcus faecalis, Staphylococcus aureus, Staphylococcus saprophyticus, Streptococcus pneumoniae (including penicillin-resistant strains), Streptococcus pyogenes.
Aerobic gram-negative microorganisms: Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Legionella pneumophila, Moraxella catarrhalis, Proteus mirabilis, Pseudomonas aeruginosa.
Other microorganisms: Chlamydia pneumoniae, Mycoplasma pneumoniae.
The following in vitro data are available, but their clinical significance is unknown.
Aerobic gram-positive microorganisms: Staphylococcus epidermidis, Streptococcus (Group C/F), Streptococcus (Group G), Streptococcus agalactiae, Streptococcus milleri, Viridans group streptococci.
Aerobic gram-negative microorganisms: Acinetobacter baumannii, Acinetobacter lwoffii, Bordetella pertussis, Citrobacter (diversus) koseri, Citrobacter freundii, Enterobacter aerogenes, Enterobacter sakazakii, Klebsiella oxytoca, Morganella morganii, Pantoea (Enterobacter) agglomerans, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas fluorescens, Serratia marcescens.
Anaerobic gram-positive microorganisms: Clostridium perfringens.