Drugs

, Volume 47, Issue 4, pp 677–700

Levofloxacin

A Review of its Antibacterial Activity, Pharmacokinetics and Therapeutic Efficacy
  • Rick Davis
  • Harriet M. Bryson
Drug Evaluation

DOI: 10.2165/00003495-199447040-00008

Cite this article as:
Davis, R. & Bryson, H.M. Drugs (1994) 47: 677. doi:10.2165/00003495-199447040-00008

Summary

Synopsis

Levofloxacin, an oral fluoroquinolone antibacterial agent, is the optical S-(-) isomer of ofloxacin. In vitro it is generally twice as potent as ofloxacin. Levofloxacin is active against most aerobic Gram-positive and Gram-negative organisms and demonstrates moderate activity against anaerobes. Drug penetration into body tissues and fluids is rapid and widespread after oral administration. In clinical trials conducted in Japan, oral levofloxacin has demonstrated antibacterial efficacy against a variety of infections, including upper and lower respiratory tract, genitourinary, obstetric, gynaecological and skin and soft tissue. In comparative trials with ofloxacin, levofloxacin, at half the daily dosage of ofloxacin, showed equivalent efficacy and a reduced incidence of adverse effects in the treatment of lower respiratory tract and complicated urinary tract infections.

Levofloxacin has a tolerability profile similar to that of other oral fluoroquinolones, with gastrointestinal and central nervous system effects reported most commonly. Theophylline dosage adjustment does not appear to be necessary in patients receiving concomitant levofloxacin. Coadministration with antacids or with other drugs containing divalent or trivalent cations reduces levofloxacin absorption.

Thus, levofloxacin has potential as a broad spectrum antibacterial drug in the treatment of a variety of infections. However, clinical trials recruiting non-Japanese patients are in progress and these results will form a basis on which future recommendations for the broader use of levofloxacin can be made.

Pharmacodynamic Properties

The mechanism of action of levofloxacin, like that of other fluoroquinolones, involves inhibition of bacterial deoxyribonucleic acid (DNA) gyrase, a type II topoisomerase. It has a broad range of in vitro activity against most aerobic Gram-negative bacteria, although some strains may show only moderate susceptibility (Providencia rettgeri and Pseudomonas aeruginosa) or resistance (Serratia marcescens). MIC90 values are somewhat higher against Gram-positive bacteria, but these organisms are usually susceptible. Levofloxacin, in common with other available fluoroquinolones, demonstrates only moderate activity against anaerobes

Mean MIC90 values for levofloxacin were about 50% lower than those observed for ofloxacin against both Gram-positive and Gram-negative bacteria and 3 to 4 times lower than those for ciprofloxacin against methicillin-susceptible and methicillin-resistant Staphylococcus aureus. Mean MIC90 values for levofloxacin were approximately 50% higher than those observed for ciprofloxacin against most Gram-negative bacteria. Ciprofloxacin showed greater in vitro activity than levofloxacin against Pseudomonas aeruginosa.

Inhibition of bacterial multiplication by levofloxacin was not influenced by growth medium types while the presence of serum and inoculum size had equivocal effects. Acidic pH or the addition of urine may reduce the in vitro antibacterial activity of levofloxacin. Levofloxacin usually has additive or indifferent effects when combined with other antibacterial agents in vitro, but may occasionally show synergy or antagonism. A postantibiotic effect for levofloxacin has been exhibited against methicillin-susceptible and methicillin-resistant S. aureus, S. epidermidis, Enterococcus faecalis and Escherichia coli.

Resistance to fluoroquinolones occurs at a low rate in vitro and is chromosomally mediated. Changes to the A or B subunits of DNA gyrase or cell membrane porin channels are 3 possible mechanisms of chromosomal mutation which can confer bacterial resistance to the fluoroquinolones. Apart from 1 unconfirmed report in S. aureus, plasmid-mediated resistance has not been noted with fluoroquinolones. Although no specific data regarding its resistance pattern are available, levofloxacin will be likely to display a pattern similar to its racemate, ofloxacin.

Levofloxacin was generally as efficacious or more efficacious than ciprofloxacin, ofloxacin or norfloxacin in protecting mice against experimentally induced systemic infections, lower respiratory tract infections and pyelonephritis. At therapeutic concentrations, the drug penetrates into human phagocytes in vitro without affecting cell viability.

Pharmacokinetic Properties

Following oral administration of levofloxacin 50 to 200mg in healthy volunteers, mean maximum plasma concentrations ranging from 0.57 to 2.04 mg/L were achieved within 0.8 to 2.4 hours; these parameters are linearly related to dose. Food does not appear to affect the absorption of levofloxacin, which has an oral bioavailability approaching 100%. The apparent mean volume of distribution of levofloxacin ranges from 1.09 to 1.26 L/kg after administration of single 50, 100 or 200mg doses to healthy volunteers. Oral levofloxacin penetrates rapidly and efficiently throughout the body, achieving concentrations in tissues or body fluids which are generally higher than those observed in plasma

Within 24 hours of an administered oral dose, about 80 to 85% of the drug is excreted unchanged in the urine. The mean plasma elimination half-life of levofloxacin is 4 to 7 hours. The elimination half-life and the area under the plasma concentration-time curve (AUC) of levofloxacin increase proportionally as creatinine clearance decreases. Therefore, prolongation of the normal dosage interval and/or dosage reduction of levofloxacin is necessary in patients with impaired renal function.

Therapeutic Etlicacy

The efficacy of oral levofloxacin (mostly 100mg 3 times daily) has been investigated in both noncomparative trials and controlled comparative studies with ofloxacin in Japanese patients with a variety of infections. In comparisons with ofloxacin, levofloxacin was mostly administered at half the daily dosage of ofloxacin

Levofloxacin has proven effective in the treatment of acute or chronic lower respiratory tract infections (bronchitis and pneumonia) and was as effective as ofloxacin in comparative trials. Eradication rates for levofloxacin against common respiratory pathogens [Haemophilus injluenzae, Moraxella (Branhamella) catarrhalis, S. aureus and Streptococcus pneumoniae] were 80 to 100%, while those against P. aeruginosa were lower (about 30%).

In patients with either complicated (upper) or uncomplicated (lower) urinary tract infections, levofloxacin achieved clinical and bacteriological efficacy rates that ranged from 80 to 100%. In women with uncomplicated cystitis, single dose levofloxacin 200mg yielded clinical efficacy rates of 100% on day 3 and 94% on days 7 and 14. Levofloxacin 200 to 300 mg/day displayed clinical and bacteriological efficacy rates comparable to treatment with ofloxacin 400 to 600 mg/day in patients with complicated urinary tract infections. Clinical and bacteriological efficacy rates of 100% were achieved for levofloxacin 200 to 400 mg/day administered for 3 days to patients with gonococcal urethritis and 14 days to patients with nongonococcal (chlamydial) urethritis. Levofloxacin showed clinical efficacy in men with acute prostatitis (100%), chronic prostatitis (74%) and acute or chronic epididymitis (88%). The short duration of levofloxacin therapy (<15 days) used in the treatment of chronic prostatitis may have limited its effectiveness.

Skin and soft tissue infections were responsive to treatment with levofloxacin (clinical efficacy rates 80 and 91% in 2 large trials), while eradication rates for methicillin-susceptible S. aureus and coagulase-negative staphylococci were approximately 90%.

Clinical cure/improvement was observed in 93% of women with various obstetric and gynaecological infections treated with levofloxacin 200 to 300 mg/day. Eradication rates of > 90% were observed for commonly isolated pathogens which included C. trachomatis, E. coli, S. aureus, Streptococcus spp., Peptostreptococcus spp. and E. faecalis.

Clinical efficacy rates of 74 to 92% have been achieved with levofloxacin in noncomparative studies of patients with a variety of ear, nose and throat infections. Overall bacteriological eradication rates were 100% for H. influenzae and M. catarrhalis, 97% for Streptococcus spp. and 93% for methicillin-susceptible and methicillin-resistant S. aureus, with lower rates observed for coagulase- negative staphylococci (75%) and P. aeruginosa (66%). Levofloxacin has also displayed clinical efficacy in bacterial enteritis (97% of patients cured or improved) and in ocular infections (92%), odontogenic infections (83%) and biliary tract infections (73%) investigated in single clinical trials.

Tolerability

Levofloxacin is generally well tolerated, with most adverse effects being mild to moderate in severity and transient in nature. In 5 comparative trials with ofloxacin which recruited a total of 918 patients, a lower incidence of gastrointestinal symptoms (1.2 vs 5.2%) [abdominal discomfort, anorexia or diarrhoea] and central nervous system effects (0.8 vs 2.2%) [insomnia, headache or dizziness] was observed in levofloxacin recipients. In comparative trials, the overall incidence of abnormal laboratory findings (mostly transient elevations of liver function tests, eosinophilia or leucopenia) with levofloxacin (2.4 to 15.5%) was similar to that observed with ofloxacin (4.3 to 18.2%)

Levofloxacin, in common with other fluoroquinolones, has been shown to cause articular damage in animal studies at high dosages. In addition, the phototoxic potential of levofloxacin as assessed in mice appears to be similar to that of ofloxacin and ciprofloxacin and lower than that of lomefloxacin, enoxacin and nalidixic acid.

Dosage and Administration

In Japanese studies, the most frequently used dosage was 100mg 3 times daily for the treatment of a variety of infections, including respiratory, genitourinary, obstetric, gynaecological, skin, oral, ear, nose, throat, enteral, biliary tract and eye infections. Treatment duration ranged from 7 to 14 days, although a shorter duration (3 to 5 days) was sufficient for the treatment of urinary tract infections (uncomplicated and complicated) or gonococcal urethritis. A single 200mg dose has been successfully used for women with uncomplicated cystitis.

Dosage reduction is required in patients with renal impairment. Patients should not receive concomitant levofloxacin and mineral supplements, vitamins with iron or other minerals, antacids, or sucralfate. If required, these drugs should be administered at least 2 hours before or after levofloxacin. The pharmacokinetics of theophylline are not significantly affected by levofloxacin; however, patients receiving this combination should still be monitored for clinical signs of theophylline toxicity.

Copyright information

© Adis International Limited 1994

Authors and Affiliations

  • Rick Davis
    • 1
  • Harriet M. Bryson
    • 1
  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand