Levocin Mechanism of Action

Pharmacology: Mechanism of Action: Levofloxacin is the L-isomer of the racemate, ofloxacin, a quinolone antimicrobial agent. The antibacterial activity of ofloxacin resides primarily in the L-isomer. The main mechanism of action of levofloxacin involves the 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 the following gram-negative and gram-positive microorganisms. It is often bactericidal at concentrations equal to or slightly greater than inhibitory concentrations. It is generally considered to be about twice as active as its isomer, ofloxacin.
Pharmacokinetics: FC tablet: Levofloxacin is rapidly and almost completely absorbed following oral use with peak plasma concentrations achieved within 1 hour of a dose. It is distributed into body tissues including the bronchial mucosa and lungs, but penetration into CSF is relatively poor.
Levofloxacin is approximately 30-40% bound to plasma proteins. It is only metabolised to a small degree to inactive metabolites. The elimination half-life of levofloxacin is 6-8 hours, although this may be prolonged in patients with renal impairment. Levofloxacin is excreted largely unchanged, primarily in the urine. It is not removed by hemodialysis or peritoneal dialysis.
Special Population: Renal Insufficiency: Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in patients with impaired renal function (creatinine clearance <50mL/min), requiring dosage adjustment in such patients to avoid accumulation. Neither hemodialysis nor continuous ambulatory peritoneal dialysis (CAPD) is effective in removal of levofloxacin from the body, indicating that supplemental doses of levofloxacin are not required following hemodialysis or CAPD.
Hepatic insufficiency: Pharmacokinetic studies in hepatically impaired patients have not been conducted. Due to the limited extent of levofloxacin metabolism, the pharmacokinetics of levofloxacin is not expected to be affected by hepatic impairment.
Pediatric: The pharmacokinetics of levofloxacin in pediatric subjects has not been studied.
IV Infusion: Absorption: Following a single intravenous dose of levofloxacin, the mean ±SD peak plasma concentration attained was 6.2±1 μg/mL after a 500 mg dose infused over 60 minutes and 11.5 ± 4.0 μg/mL after a 750 mg dose infused over 90 minutes.
Levofloxacin IV pharmacokinetics are linear and predictable after single and multiple dosing regimens. Steady-state conditions are reached within 48 hours following a 500 mg or 750 mg once daily dosage regimens. The mean ±SD peak and trough plasma concentrations attained following multiple once-daily IV regimens were approximately 6.4±0.8 and 0.6±0.2 μg/mL after the 500 mg doses 12.1 ± 4.1 and 1.3 ±0.71 μg/mL after the 750 mg doses, respectively.
Distribution: The mean volume of distribution generally ranges from 74-112 litres after single and multiple dosing of 500 mg or 750 mg dose, indicating widespread distribution into body tissues. Levofloxacin reaches its peak levels in skin tissues and in body fluid of healthy subjects at approximately 3 hours after dosing.
Levofloxacin is approximately 24 to 38% bound to serum proteins. Levofloxacin is mainly bound to serum albumin in humans. The binding of levofloxacin to serum proteins is independent of the drug concentration.
Metabolism and Elimination: Levofloxacin undergoes limited metabolism in humans and is primarily excreted as unchanged drug in the urine. 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. The mean terminal elimination half-life (t_½) of levofloxacin ranges from approximately 6 to 8 hours following single or multiple doses of levofloxacin. The mean apparent total body clearance and renal clearance range from approx. 144-226 mL/min and 96-142 mL/min, respectively.
Special Populations: Pediatric Patients: The pharmacokinetics of levofloxacin following a single 7 mg/kg intravenous dose in pediatric patients ranging in age from 6 months to 16 years. Pediatric patients cleared levofloxacin faster than adult patients, resulting in lower plasma exposure than adults for a given mg/kg dose, dosage regimen of 8 mg/kg every 12 hours (not to exceed 250 mg per dose) for pediatric patients 6 months to 17 years of age would achieve comparable steady state plasma exposures (AUC_0-24 and C_max) to those observed in adult patients administered 500 mg of levofloxacin once every 24 hours.
Renal Insufficiency: Clearance of levofloxacin is substantially reduced and plasma elimination half life is substantially prolonged in patients with impaired renal function (creatinine clearance <50 mL/min), requiring dosage adjustment in such patients to avoid accumulation. Neither hemodialysis nor continuous ambulatory peritoneal dialysis (CAPD) is effective in removal of levofloxacin from the body, indicating that supplemental doses of levofloxacin are not required following hemodialysis or CAPD.
Hepatic Insufficiency: Pharmacokinetic studies in hepatically impaired patients have not been conducted. Due to the limited extent of levofloxacin metabolism. The pharmacokinetics of levofloxacin are not expected to be affected by hepatic impairment.
Microbiology: FC tablet: Levofloxacin has been shown to be active against most strains of the following micro-organisms both in vitro and in clinical infections.
Aerobic Gram-Positive Microorganisms: Enterococcus faecalis (moderately susceptible), Staphylococcus aureus (methicillin-susceptible strains), Staphylococcus epidermidis (methicillin-susceptible strains), 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, Salmonella species, Moraxella catarrhalis, Proteus mirabilis, Pseudomonas aeruginosa (some strains of Pseudomonas aeruginosa may develop resistance rapidly during treatment with levofloxacin), Serratia marcescens.
Anaerobic Microorganisms: Bacteroides fragilis, Clostridium perfringens, Peptostreptococcus.
Other Microorganisms: Chlamydia pneumoniae, Mycoplasma pneumoniae.
IV Infusion: Commonly susceptible species: Aerobic Gram-Positive Microorganisms: Staphylococcus aureus methicillin-susceptible, Staphylococcus saprophyticus, Streptococci group C and G, Streptococcus agalactiae, Streptoccus pneumoniae, Streptococcus pyogenes.
Aerobic Gram-Negative Microorganisms: Burkholderia cepacia, Eikenella corrodens, Haemophilus influenzae, Haemophilus para-influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis, Pasteurella multocida, Proteus vulgaris, Providencia rettgeri.
Anaerobic Microorganisms: Peptostreptococcus.
Other: Chlamydophila pneumoniae, Chlamydophila psittaci, Chlamydia trachomatis, Legionella pneumophila, Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum.
Species for which acquired resistance may be a problem: Aerobic Gram-positive bacteria: Enterococcus faecalis, Staphylococcus aureus methicillin-resistant, Coagulase negative Staphylococcus spp.
Aerobic Gram-negative bacteria: Acinetobacter baumannii, Citrobacter freundii, Enterobacter aerogenes, Enterobacter agglomerans, Enterobacter cloacae, Escherichia coli, Morganella morganii, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens.
Anaerobic bacteria: Bacteroides fragilis, Bacteroides ovatus, Bacteroides thetaiotamicron, Bacteroides vulgatus, Clostridium difficile.
Levofloxacin has been shown to be active against Bacillus anthracis in vitro.