Cravit IV Mechanism of Action

Pharmacology: Cravit i.v. is a broad spectrum antibacterial agent for intravenous administration 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. The data demonstrate that from pH 0.6 to 5.8, the solubility of Cravit is essentially constant (approximately 100 mg/mL). Cravit is considered soluble to freely soluble in this pH range. Above pH 5.8, the solubility increase rapidly to its maximum at pH 6.7 (272 mg/mL) and is considered freely soluble in this range. Above pH 6.7, the solubility decreases and reaches a minimum value (about 50 mg/mL) at a pH of approximately 6.9. Cravit has the potential to form stable coordinated compounds with many metal ions. This in vitro chelating potential has the following formation order: Al⁺³>Cu⁺²>Zn⁺²>Mg⁺²>Ca⁺².
Pharmacokinetics: Absorption and serum concentration: Following a single 60 minutes and 90 minutes intravenous infusion of 500 mg and 750 mg of levofloxacin to healthy volunteers, the mean peak plasma concentration attained were 6.2 μg/mL and 11.5 μg/mL respectively. Levofloxacin pharmacokinetics is linear and predictable after single and multiple i.v. dosing regimens. Steady-state conditions are reached within 48 hours following a 500 mg or 750 mg once daily regimen. The peak and trough plasma concentrations attained following multiple once daily i.v. 500 mg regimens were approximately 6.4 and 0.6 μg/mL and 12.1 and 1.3 μg/mL after the 750 mg doses, respectively.
The plasma concentration profile of levofloxacin after i.v. administration is similar and comparable in extent of exposure (AUC) to that observed for levofloxacin tablets when equal doses (mg/mg) are administered. Therefore, the oral and i.v. routes of administration can be considered interchangeable.
Distribution: The mean volume of distribution of levofloxacin generally ranges from 74 to 112 L after single and multiple 500 mg or 750 mg doses, indicating widespread distribution into body tissues. Penetration of levofloxacin into blister fluid is rapid and extensive. The blister fluid to plasma AUC ratio is approximately 1. Levofloxacin also penetrates well into lung tissues. Lung tissue concentrations were generally 2 to 5 fold higher than the plasma concentrations and ranged from approximately 2.4 to 11.3 μg/g over a 24 hour period after the single 500 mg oral dose.
In vitro, over the clinically relevant range (1 to 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 as unchanged drug in urine within 48 hours, whereas less than 4% of the dose was recovered in the feces in 72 hours. Less than 5% of an administered dose was recovered in the 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 or intravenously. 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 results 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 involve 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 and Viridans group streptococci.
Aerobic gram-negative microorganisms: Acinetobacter anitratus, Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter lwoffii, Bordetella pertussis, Citrobacter diversus, Citrobacter freundii, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter sakazakii, Klebsiella oxytoca, Morganella morganii, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas fluorescens, Serratia marcescens.
Anaerobic gram-positive microorganisms: Clostridium perfringens.