LEVOTOP

Indications

• Bacterial infections
• Acute exacerbation of chronic obstructive pulmonary disease
• Community-acquired pneumonia
• Hospital-acquired pneumonia
• Urinary tract infections
• Complicated urinary tract infections
• Prostatitis
• Chronic pulmonary infections due to Pseudomonas aeruginosa
• Helicobacter pylori eradication (in combination with other drugs)

Dosage

Adults: 500 mg once daily for 5-14 days depending on the infection type and severity; for intravenous infusion, 500 mg to be given over at least 60 minutes.

Mechanism of action

Levofloxacin exerts its antimicrobial activity through the inhibition of two key bacterial enzymes: DNA gyrase and topoisomerase IV. DNA gyrase introduces negative supercoils into DNA during replication, while topoisomerase IV is essential for unlinking newly replicated chromosomes, allowing cell division. By inhibiting these enzymes, levofloxacin blocks DNA replication, resulting in cell death.

Pharmacodynamics

Levofloxacin is bactericidal and inhibits bacterial DNA replication. It has a longer duration of action than many other antibiotics, allowing for less frequent dosing. The drug may cause QTc-interval prolongation, necessitating caution in patients with risk factors for this condition. Levofloxacin shows in vitro activity against various bacterial pathogens, and while resistance can develop, it typically arises from mutations in target enzymes or drug efflux mechanisms.

Pharmacokinetics

Levofloxacin is well absorbed following oral administration, with peak plasma concentrations occurring within 1-2 hours. It has a volume of distribution of approximately 100 L and is approximately 30-40% protein bound. The drug is primarily excreted unchanged in the urine, with a half-life of about 6-8 hours, allowing for once or twice daily dosing.

Contra-indications

• Hypersensitivity to levofloxacin or other fluoroquinolones
• History of tendon disorders related to fluoroquinolone use
• Patients with a history of myasthenia gravis

Adverse effects

• Nausea
• Diarrhea
• Headache
• Dizziness
• QT interval prolongation
• Tendon rupture
• Clostridioides difficile-associated diarrhea
• Nephritis tubulointerstitial

Interactions

• Concurrent use with other drugs that prolong the QT interval
• Antacids, sucralfate, metal cations (e.g. magnesium, aluminum, calcium) can reduce absorption
• NSAIDs may increase the risk of CNS stimulation
• Warfarin may have increased anticoagulant effects

Precautions

• Use cautiously in patients with a history of seizures or CNS disorders
• Monitor for signs of tendon damage
• Consider risks in patients with electrolyte disturbances
• Use with caution in patients with renal impairment

Pregnancy

Manufacturer advises use only if potential benefit outweighs risk.

Breast-feeding

Manufacturer advises caution; levofloxacin may be excreted in breast milk.

Storage

Store at room temperature, away from moisture and heat. Protect from light.

Formulations

• 500 mg tablet for oral use
• Solution for intravenous infusion
• Nebuliser solution
• Eye drops

Indications

• Conjunctivitis
• Allergic eye conditions
• Dry eye syndrome
• Glaucoma
• Ocular infections
• Post-surgical inflammation

Dosage

Children: Refer to the BNF for Children for appropriate paediatric dosing, as it is dependent on the specific ophthalmic medication and the condition being treated.

Adults: Refer to specific product information for adult dosing, as it varies widely depending on the condition treated and the formulation used.

Mechanism of action

The mechanism of action of ophthalmic drugs varies widely depending on the active ingredient. Common mechanisms include the inhibition of enzymes involved in inflammation (such as corticosteroids), the reduction of intraocular pressure (such as beta-blockers), and the promotion of tear production (such as cyclosporine). For antibiotics, the mechanism often involves the inhibition of bacterial cell wall synthesis or protein synthesis.

Pharmacodynamics

The pharmacodynamics of ophthalmic medications depend on their specific class and active ingredients. Anti-inflammatory agents like corticosteroids reduce inflammation by inhibiting the migration of leukocytes to the site of inflammation and decreasing the production of inflammatory mediators. Antiglaucoma medications lower intraocular pressure either by reducing aqueous humor production or increasing its outflow. Antibiotics exert their effects by targeting bacterial processes, leading to cell death or inhibiting bacterial growth.

Pharmacokinetics

Ophthalmic drugs are designed for local action, and their pharmacokinetics can be influenced by factors such as formulation, drop size, and drainage from the eye. Generally, after instillation, a significant portion of the drug is lost to systemic circulation through nasolacrimal drainage. The bioavailability is often limited, with peak concentrations occurring shortly after administration. Systemic absorption can occur, particularly with lipophilic drugs, leading to potential side effects. The half-life of ocular drugs can vary, with some lasting for several hours to days, depending on their formulation.

Contra-indications

• Hypersensitivity to any component of the formulation
• Active ocular infection
• Closed-angle glaucoma

Adverse effects

• Burning or stinging sensation in the eye
• Redness of the eye
• Blurred vision
• Allergic reactions
• Dry eyes

Interactions

• May interact with other topical ophthalmic agents leading to altered effects
• Caution should be used when administering with systemic medications that may affect ocular pressure

Precautions

• Use with caution in patients with a history of eye disease
• Monitor for increased intraocular pressure
• Avoid contact with the tip of the dropper to prevent contamination

Pregnancy

Safety during pregnancy has not been established; use only if clearly needed.

Breast-feeding

Caution is advised; it is not known whether the drug is excreted in human milk.

Storage

Store at room temperature, away from light. Do not freeze. Discard after the expiration date.

Formulations

• Ophthalmic drops
• Ophthalmic ointments
• Ophthalmic gels

Mechanism of action

Levofloxacin, 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. 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 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. Fluoroquinolones prolong the QT interval by blocking voltage-gated potassium channels, especially the rapid component of the delayed rectifier potassium current I(Kr), expressed by HERG (the human ether-a-go-go-related gene). According to the available case reports and clinical studies, moxifloxacin carries the greatest risk of QT prolongation from all available quinolones in clinical practice and it should be used with caution in patients with predisposing factors for Torsades de pointes (TdP).

Pharmacodynamics

Levofloxacin 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. Levofloxacin 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). Levofloxacin 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.