Introduction
Leo Ophthalmic Solution 0.5% is a fluoroquinolone antibiotic and the optical S-(-) isomer of racemic ofloxacin. It reportedly carries 8 to 128-fold more activity against both gram-negative and gram-positive bacteria compared to R-(+)-ofloxacin and remains stereochemically stable following administration (i.e. it does not invert to the inactive isomer). Leo Ophthalmic Solution 0.5%, along with other quinolones such as gatifloxacin and moxifloxacin, is a member of the third generation of fluoroquinolones, colloquially referred to as the "respiratory quinolones" due to improved activity against gram-positive bacteria commonly implicated in respiratory infections.
Uses
Leo Ophthalmic Solution 0.5% is a fluoroquinolone antibiotic used to treat infections caused by susceptible bacteria of the upper respiratory tract, skin and skin structures, urinary tract, and prostate, as well as for post-exposure treatment of inhaled anthrax and the plague.
In oral and intravenous formulations, levofloxacin is indicated in adults for the treatment of various infections caused by susceptible bacteria, including infections of the upper respiratory tract, lower respiratory tract, skin, skin structures, urinary tract, and prostate. The oral formulation is also indicated in both adults and children 6 months of age and older for the post-exposure management of inhalational anthrax caused by Bacillus anthracis and for the treatment and/or prophylaxis of plague caused by Yersinia pestis.
In its ophthalmic formulation, levofloxacin is indicated for the treatment of bacterial conjunctivitis caused by susceptible organisms. An inhalational solution available in Canada is indicated for the management of cystic fibrosis patients aged 18 years or older with chronic pulmonary Pseudomonas aeruginosa infections.
Associated Conditions
Pharmacodynamics
Leo Ophthalmic Solution 0.5% is bactericidal and exerts its antimicrobial effects via inhibition of bacterial DNA replication. It has a relatively long duration of action in comparison with other antibiotics that allows for once or twice daily dosing. Leo Ophthalmic Solution 0.5% is associated with QTc-interval prolongation and should be used with caution in patients with other risk factors for prolongation (e.g. hypokalemia, concomitant medications).
Leo Ophthalmic Solution 0.5% has demonstrated in vitro activity against a number of aerobic gram-positive and gram-negative bacteria and may carry some activity against certain species of anaerobic bacteria and other pathogens such as Chlamydia and Legionella. Resistance to levofloxacin may develop, and is generally due to mutations in DNA gyrase or topoisomerase IV, or via alterations to drug efflux. Cross-resistance may occur between levofloxacin and other fluoroquinolones, but is unlikely to develop between levofloxacin and other antibiotic classes (e.g. macrolides) due to significant differences in chemical structure and mechanism of action.
As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use.
Mechanism of Action
Leo Ophthalmic Solution 0.5%, like other fluoroquinolone antibiotics, exerts its antimicrobial activity via the inhibition of two key bacterial enzymes: DNA gyrase and topoisomerase IV. Both targets are type II topoisomerases, but have unique functions within the bacterial cell. DNA gyrase is an enzyme found only in bacteria that introduces negative supercoils into DNA during replication - this helps to relieve torsional strain caused by the introduction of positive supercoils during replication, and these negative supercoils are essential for chromosome condensation and the promotion of transcription initiation. It is comprised of four subunits (two A subunits and two B subunits) of which the A subunits appear to be the target of fluoroquinolone antibiotics. Bacterial topoisomerase IV, in addition to contributing to the relaxation of positive supercoils, is essential at the terminal stages of DNA replication and functions to “unlink” newly replicated chromosomes to allow for the completion of cell division.
Inhibition of these enzymes by levofloxacin likely occurs via complexation with the topoisomerase enzymes. The end result is a blockade of DNA replication, thus inhibiting cell division and resulting in cell death.
Absorption
Absorption of levofloxacin following oral administration is rapid and essentially complete, with an oral bioavailability of approximately 99%. Due to its nearly complete absorption, the intravenous and oral formulations of levofloxacin may be interchangeable. The Tmax is generally attained 1-2 hours following administration and the Cmax is proportional to the given dose - an intravenous dose of 500mg infused over 60 minutes resulted in a Cmax of 6.2 ± 1.0 µg/mL whereas a 750mg dose infused over 90 minutes resulted in a Cmax of 11.5 ± 4.0 µg/mL. Oral administration with food prolongs the Tmax by approximately 1 hour and slightly decreases the Cmax, but these changes are not likely to be clinically significant.
Systemic absorption following oral inhalation is approximately 50% lower than that observed following oral administration.
Volume of Distribution
Leo Ophthalmic Solution 0.5% is widely distributed in the body, with an average volume of distribution following oral administration between 1.09-1.26 L/kg (~89-112 L). Concentrations in many tissues and fluids may exceed those observed in plasma. Leo Ophthalmic Solution 0.5% is known to penetrate well into skin tissue, fluids (e.g. blisters), lung tissue, and prostatic tissue, amongst others.
Protein Binding
Leo Ophthalmic Solution 0.5% is 24-38% protein-bound in plasma, primarily to albumin. The extent of protein-binding is independent of its plasma concentration.
Route of Elimination
The majority of administered levofloxacin is excreted unchanged in the urine. Following the administration of a single oral dose of levofloxacin, approximately 87% was eliminated unchanged in the urine within 48 hours and less than 4% was eliminated in the feces within 72 hours.
Half Life
The average terminal elimination half-life of levofloxacin is 6-8 hours.
Clearance
The average apparent total body clearance of levofloxacin ranges from 8.64-13.56 L/h, and its renal clearance ranges from 5.76-8.52 L/h. The relative similarity of these ranges indicates a small degree of non-renal clearance.
Toxicity
The LD50 following oral administration in mice and rats is 1803 mg/kg and 1478 mg/kg, respectively.
Leo Ophthalmic Solution 0.5% exhibits low potential for acute toxicity - following a single high dose of levofloxacin in several different test animals (e.g. mice, rats, monkeys) observed symptoms included ataxia, ptosis, decreased motor activity, dyspnea, tremors, and convulsions. Treatment of acute overdosage should involve stomach emptying (e.g. with activated charcoal) and general supportive measures. Consider monitoring of the patient's ECG to ensure QTc values remain within range. Leo Ophthalmic Solution 0.5% is not efficiently removed by dialysis (peritoneal or hemodialysis) and is therefore of little benefit in cases of overdose.
Food Interactions
- Take with or without food. Food slightly alters kinetics but not to any clinically significant extent.
