Pharmacology: Cravit is a broad-spectrum quinolone antibacterial agent containing levofloxacin, optically active (-)-S-form of racemate ofloxacin synthesized by Daiichi Pharmaceutical Co., Ltd. It shows broad and potent antibacterial activities against gram-positive bacteria eg, Staphylococcus aureus, Staphylococcus saprophyticus, Streptococcus pneumoniae (including penicillin-resistant strains), Streptococcus pyogenes, Enterococcus faecalis and gram-negative bacteria eg, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, Enterobacter cloacae, Moraxella catarrhalis, Legionella pneumophila and other microorganisms eg, 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 and genitourinary tract, 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 1-2 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 mcg/mL after the 500-mg doses and 8.6±1.9 and 1.1±0.4 mcg/mL after 750-mg doses, respectively.
Distribution: The mean volume of distribution of levofloxacin generally ranges from 74-112 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-fold higher than plasma concentrations and range from approximately 2.4-11.3 mcg/g over 24 hr period after a single 500-mg oral dose.
In vitro, over a clinically relevant range (1-10 mcg/mL) of serum/plasma levofloxacin concentrations, levofloxacin is approximately 24-38% 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. It 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 hrs, whereas <4% of the dose was recovered in feces in 72 hrs. 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 (t½) of levofloxacin ranges from approximately 6-8 hrs following single or multiple doses of levofloxacin given orally. The mean apparent total body clearance and renal clearance range from approximately 144-226 mL/min and 96-142 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 2-fold 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. It 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) and Streptococcus pyogenes.
Aerobic Gram-Negative Microorganisms: Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Legionella pneumophila, Moraxella catarrhalis, Proteus mirabilis and Pseudomonas aeruginosa.
Others: Chlamydia pneumoniae and 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 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 and Serratia marcescens.
Anaerobic Gram-Positive Microorganisms: Clostridium perfringens.