Directions for use and doses
Levofloxacin eye drops are instilled into the cavity of the conjunctival sac in the amount of 1-2 drops every two hours during the first two days of therapy. Subsequently, the frequency is reduced to four times a day (for 3-7 days). The duration of treatment is a week. If at the same time the doctor prescribed another drug for topical application, then the interval between medications should be 15 minutes. To prevent contamination of the vial and solution, avoid contact of the dropper tip with non-sterile surfaces.
The safety of Levofloxacin in newborns for the treatment of gonococcal conjunctivitis and corneal ulcers has not been studied. In elderly people, no dosage adjustment or frequency of administration of the drug is required.
In the practice of an otorhinolaryngologist, there are situations when initial empirical antibacterial therapy does not lead to a quick effect. In this case, assessing the patient’s condition after 72 hours, the doctor needs to change the antibiotic to a stronger one with a broad spectrum of action. At the same time, a change is often made to antimicrobial agents of the quinolone class - fluoroquinolones. Drugs in this group have good pharmacokinetic properties and a high degree of penetration into tissues and cells of both humans and microorganisms.
Fluoroquinolones compare favorably with other antibiotics by their properties: inhibition of the enzyme DNA gyrase - a bacterial cell enzyme with a wide spectrum of antimicrobial action (Gram-negative and Gram-positive aerobic bacteria, mycobacteria, Mycoplasma pneumonia, Chlamydia pneumoniae); high degree of bacterial activity; the possibility of creating concentrations of drugs in human tissues and cells that are close to serum concentrations or exceed them; well tolerated and low incidence of side effects. In addition, the long half-life determines the convenient dosing regimen - 1-2 times a day. Thus, the drug of this group, levofoxacin, when taken orally, has a large volume of distribution and reaches high concentrations in tissues, phagocytes and body fluids, in particular in the tissues of the paranasal sinuses, as well as in macrophages [1].
Currently, new drugs of the fluoroquinolone group have been synthesized that exhibit higher activity against gram-positive bacteria, primarily pneumococci, which has made it possible to distinguish them into a separate subgroup - the 2nd generation, or new fluoroquinolones (see table). At the same time, levofloxacin and moxifloxacin are produced in two forms: tablets and for intramuscular administration, which allows them to be used in the form of step-down therapy, which reduces the cost of treatment.
Drugs of this group have a pronounced effect on gram-negative bacteria (Moraxella catarrhalis, Legionella spp.), Haemophilus influenzae (including strains producing β-lactamases) [2].
Drugs from the group of new fluoroquinolones have higher natural activity against Streptococcus pneumoniae compared to earlier fluoroquinolones (for example, levofloxacin - 1 mg/l). In this regard, it is advisable to prescribe them for community-acquired respiratory tract infections. At the same time, the activity of new fluoroquinolones does not differ in relation to penicillin-sensitive and penicillin-resistant strains of pneumococcus. It has now been established that the resistance of pneumococci to new fluoroquinolones is minimal (less than 1%). The high activity of 2nd generation fluoroquinolones against S. pneumoniae is extremely important, because Acute and chronic diseases are now quite often caused by this pathogen.
Drugs from the group of new fluoroquinolones are superior to earlier ones in activity against other streptococci (groups A and C) and staphylococci (Staphylococcus aureus). Against Pseudomonas aeruginosa, the most active fluoroquinolone remains ciprofloxacin; of the new fluoroquinolones, only levofloxacin has real anti-pseudomonas activity.
It has been established that the combined use of a number of drugs (antacids, sucralfate, bismuth salts, calcium, iron supplements) reduces the bioavailability of fluoroquinolones when taken orally, which can lead to a decrease in the effectiveness of the latter. It should be borne in mind that food intake slows down the absorption of fluoroquinolones.
There are restrictions on the use of drugs in this group for pregnant and lactating women, children and adolescents under the age of 16–18 years. This was revealed in an experiment on the damaging effect of fluoroquinolones on the cartilage tissue of immature animals. However, these data have not been confirmed in the clinic. But such a contraindication is justified, because. strictly limits the widespread irrational use of fluoroquinolones in pediatrics until reliable evidence of their safety for patients in this category is obtained.
An analysis of the Italian pharmacovigilance database showed that the relative risk of side effects with levofloxacin did not differ from that of other classes of oral antibiotics [3].
The most common side effects when using fluoroquinolones include symptoms from the gastrointestinal tract (nausea, vomiting, diarrhea, abdominal pain, changes in taste), but in most cases they are moderate and do not require discontinuation of treatment.
In clinical trials of levofloxacin, the most common side effect was diarrhea, occurring in 4–6%, which is significantly lower than with oral penicillins or cephalosporins [4]. Side effects from the central nervous system (headache, dizziness and sleep disturbances), which are a class effect of fluoroquinolones, were observed less frequently during treatment with levofloxacin (1%).
All fluoroquinolones cause CNS reactions with approximately the same frequency (5–8%), minimal neurotoxicity was observed with ofloxacin and levofloxacin. Reactions from the central nervous system are typical for all drugs of this class. However, they are observed infrequently, they are usually manifested by headache, dizziness, drowsiness, sleep disturbance (these symptoms usually occur on the 1st day of treatment and disappear immediately after discontinuation). The development of seizures is described much less frequently. They occur mainly on the 3rd–4th day of treatment in patients with predisposing factors (epilepsy, brain injury, hypoxia, old age, combined use with theophylline or non-steroidal anti-inflammatory drugs) and resolve spontaneously when the drug is discontinued [5].
The incidence of skin rashes with levofloxacin is 0.2% [6]. The frequency of anaphylactoid reactions during treatment with levofloxacin is comparable to that of most drugs in this group – 1.8–23.0 per 1 million days of treatment [6]. The incidence of anaphylaxis per 1 million daily doses was 0.6 for levofloxacin [7].
In clinical studies of levofloxacin, hepatobiliary lesions occurred in 0.1–1.0% of cases [6]. The incidence of hepatitis, liver necrosis and liver failure during treatment with levofloxacin, according to French Pharmacovigilance data, is <1 case per 5 million prescriptions [8].
Diffuse muscle pain, often in combination with muscle weakness, usually occurs in the first week of fluoroquinolone treatment and in most cases resolves spontaneously within 1–4 weeks after discontinuation.
It has been noted that when exposed to sunlight or UV (ultraviolet) radiation, fluoroquinolones cause phototoxic reactions. Therefore, patients should be warned that they should refrain from using physiotherapeutic procedures associated with UV exposure and from insolation.
While taking drugs of this group in the clinic, an electrocardiogram (ECG) showed a prolongation of the QT interval against the background of sparfloxacin, grepafloxacin, levofloxacin within 10 ms, which has no significant clinical significance and does not increase the risk of dangerous ventricular arrhythmias [9]. However, caution should be exercised when prescribing fluoroquinolones to patients with a history of ventricular arrhythmias or long QT interval syndrome >500 ms, and the combined use of fluoroquinolones with other drugs known to prolong the QT interval should be avoided [10, 11].
In epidemiological studies, the incidence of tendinopathies with the use of fluoroquinolones was 1:2000 [10], according to the FDA (Food and Drug Administration), 1.3–5.6 per 10 thousand patient-years [12]. A five-year follow-up of children (n=6000) taking antibiotics showed that the incidence of tendon or joint injuries with levofloxacin was <1% and comparable to that with azithromycin [13].
In recent years, an increase in the resistance of microorganisms to fluoroquinolones has been observed. There has been an increase in the frequency of isolation of fluoroquinolone-resistant strains of P. aeruginosa and Staphylococcus spp., as well as a decrease in sensitivity in some other microorganisms.
In this regard, it is considered important to strictly justify the prescription of fluoroquinolones in an adequate dose in each specific case.
All currently proposed standards for the treatment of inflammatory diseases of the upper respiratory tract are aimed at destroying planktonic forms of pathogens, while the results of studying biofilms will challenge doctors to develop new standards, especially in the treatment of chronic diseases. Standard laboratory tests do not provide information about the effect of antibiotics on biofilm bacteria. In this regard, it is necessary to develop appropriate molecular diagnostic methods, as well as treatment strategies that affect the mechanisms of formation and functioning of bacterial communities in the form of biofilms.
It is known that the concentrations of antibiotics required to achieve a bactericidal effect for microorganisms structured in a biofilm, in some cases, depending on the nature of the antibiotic, can be 10–100 times higher than for planktonic forms of this pathogen [14]. At the same time, it has been established that fluoroquinolones easily diffuse through the biofilm and very effectively stop its growth [15].
The group of antibiotics that penetrate well into the biofilms of various bacteria includes macrolides, fluoroquinolones, rifampicin, chloramphenicol, etc. It should be noted that antibiotics that are effective against planktonic bacteria often do not have the necessary antimicrobial effect against bacterial biofilms. This is because the choice of antimicrobial agents is based on bacterial culture obtained from planktonic bacteria. Meanwhile, planktonic bacteria differ in behavior and phenotypic forms from bacteria in a biofilm. The ineffectiveness of antimicrobial therapy in the treatment of infection caused by the formation of biofilms can also be explained by the fact that microorganisms in a biofilm grow more slowly, so they are more resistant to antimicrobial drugs that act on actively reproducing bacteria; antimicrobial binding proteins are poorly expressed by bacteria in biofilms; bacteria in the biofilm activate many genes that alter the cell wall, molecular targets, and sensitivity to antimicrobials (intrinsic resistance); Bacteria in a biofilm can survive in the presence of antimicrobial agents at concentrations 1000–1500 times higher than those required to eradicate planktonic cells of the same bacterial species (persister cells) [16].
Drugs of the fluoroquinolone group are capable of eradicating infection caused by the formation of biofilms, provided that a concentration is created that exceeds the minimal inhibitory concentration (MIC) by 32–64 times [17].
The anatomy of the ENT organs itself is favorable for the development of biofilm, and its presence is noted in almost 60% of cases of upper respiratory tract infections [18].
Currently, in otorhinolaryngology, implants are increasingly used for plastic surgery of the paranasal sinuses, face, and nose; reconstructive operations on the middle ear and the introduction of cochlear implants. Implant-associated infections often develop as a result of such surgical interventions. According to some data, the presence of an implant increases the risk of inflammation by 100 times or more, so that even minimal contamination can lead to the development of an abscess [19, 20]. The most common pathogens of implant- and catheter-associated infections include pathogens of opportunistic diseases, such as staphylococci and streptococci, Escherichia coli and P. aeruginosa [21].
Analysis of literature data made it possible to identify microorganisms that most often form biofilms on implants. This can cause chronic inflammation and lead to the need to remove the infected device, including cochlear implants. Almost all species are representatives of the normal microflora of the human body. Thus, the leading positions are occupied by two types of staphylococci: S. aureus and Staphylococcus epidermidis - 49.9%, incl. and methicillin-resistant strains (MRSE - Methicillin-resistant Staphylococcus aureus), followed by Enterococcus faecalis - 6.4%, representatives of non-fermenting gram-negative bacteria (Acinetobacter spp. and P. aeruginosa) - 11%, and representatives of the enterobacteria family (Enterobacter cloacae, Klebsiella pneumoniae , E. coli) – 4.1% (see figure).
It is in the biofilm that intercellular signaling (quorum sensing) is developed to a much greater extent than in planktonic culture, which allows microorganisms to effectively coordinate the rate of reproduction and virulence. There is also a system of non-cellular structures (channels for water and nutrients) [22, 23].
The treatment of chronic infections can no longer be based on the planktonic concept of microbiology. The concept of biofilms is changing approaches to the diagnosis and treatment of infectious lesions in a variety of areas of medicine.
Levofloxacin has excellent pharmacokinetic properties, absolute (100%) bioavailability when taken orally, a fairly long half-life (6–8 hours), providing high concentrations of the drug in the blood exceeding MIC90 (the minimum inhibitory concentration of the antibiotic for 90% of the studied strains) for many microorganisms , including the main causative agents of respiratory tract infections.
The good tolerability of levofloxacin is also evidenced by the results of a pharmacoepidemiological study in the United States, which assessed the frequency of outpatients seeking medical help regarding the side effects of fluoroquinolones [24].
The risk of developing serious side effects with levofloxacin is generally lower than with other fluoroquinolones and can be significantly reduced through rational use of the drug, which involves taking into account the risk factors for developing certain side effects in a particular patient. The rational use of levofloxacin, as well as other fluoroquinolone drugs, will also reduce the rate of increase in antibiotic resistance to them, which is currently causing concern among the medical community.
This is partly the focus of the FDA's recent warning to limit the use of fluoroquinolones for acute sinusitis.
Levofloxacin has particular advantages in the case of dysfunction of the natural anastomosis of the paranasal sinuses, as well as in the verification of mixed bacterial infection. There is positive experience in the treatment of patients with various forms of bacterial sinusitis, including the chronic form. The use of levofloxacin in this case has been proven to be effective and safe [25].
It has been established that the number of prescriptions of levofloxacin in the world continues to grow [26]. The basis for the increase in consumption of levofloxacin is its more favorable benefit/risk ratio compared to many other fluoroquinolone drugs, as evidenced by the results of not only clinical, but also pharmacoepidemiological studies currently being widely conducted.
special instructions
Levofloxacin eye drops can only be used topically. The solution cannot be injected into the anterior chamber of the eye or subconjunctivally.
The solution contains benzalkonium chloride, which is a preservative. In this regard, there is no need to use the drug when wearing hydrophilic contact lenses, because in this case eye irritation may occur. If there are signs of bacterial conjunctivitis, then contact methods of refractive correction should be completely abandoned.
Due to the fact that after instillation of the medicine, a temporary decrease in vision may occur, it is not recommended to engage in potentially hazardous activities during this period, in particular, driving a car.
Due to the fact that systemic fluoroquinolols can lead to serious allergic reactions even after a single dose, Levofloxacin eye drops should be discontinued if signs of allergy and hypersensitivity occur.
If you use the drug for a long time, there is a high probability of resistance developing in microorganisms, as well as the growth of fungal flora. If there is a decrease in the effectiveness of Levofloxacin eye drops or an increase in clinical symptoms, then it is necessary to change the medicine to another antibiotic.
Levofloxacin eye drops 5 mg/ml 5 ml with dropper cap No. 1
Name
Levofloxacin solution (supply) 5 mg/ml 5 ml in pack No. 1
Description
Transparent yellowish-green solution.
Main active ingredient
Levofloxacin
Release form
Eye drops
Dosage
5mg/ml
pharmachologic effect
An antimicrobial drug from the fluoroquinolone group, a levorotatory isomer of ofloxacin. Has a wide spectrum of antibacterial (bactericidal) action. Inhibits bacterial DNA gyrase (mainly in gram-negative bacteria) and topoisomerase IV (mainly in gram-positive bacteria), enzymes responsible for replication, transcription, repair and recombination of bacterial DNA. Causes profound morphological changes in the cytoplasm, cell wall and membrane of bacteria. Levofloxacin is active against the following microorganisms according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST): 1. Usually sensitive microorganisms: – Aerobic gram-positive microorganisms: Staphylococcus aureus (MSSA)*, Streptococcus pneumonia, Streptococcus pyogenes, Viridans group of streptococci; – Aerobic gram-negative microorganisms: Escherichia coli, Haemophilus influenza, Moraxella catarrhalis, Pseudomonas aeruginosa (local strains); – Other microorganisms: Chlamydia trachomatis (treatment of patients with chlamydial conjunctivitis requires concomitant systemic antimicrobial therapy). 2. Microorganisms for which the acquisition of resistance may be a problem: – Aerobic gram-positive microorganisms: Staphylococcus aureus (MRSA)**, Staphylococcus epidermidis; – Aerobic gram-negative microorganisms: Pseudomonas aeruginosa (hospital strains). * Methicillin-sensitive strains of Staphylococcus aureus ** Methicillin-resistant strains of Staphylococcus aureus
Indications for use
Local treatment of superficial bacterial infections of the eye caused by microorganisms sensitive to levofloxacin in adults and children aged 1 year and older. Official guidelines on the appropriate use of antibacterial agents should be taken into account.
Directions for use and doses
For all patients. Instill 1-2 drops into the affected eye(s) every 2 hours up to 8 times a day while awake for the first 2 days, then 4 times a day for the next 3-5 days. The duration of treatment depends on the severity of the disease, the clinical and bacteriological course of the infection. Usually the duration of treatment is 5 days. Elderly patients. No dosage adjustment is required. Children. For children aged 1 year and older, the dosage regimen is the same as for adults. Safety and effectiveness in children under 1 year of age have not been established. Safety and effectiveness in the treatment of corneal ulcers and neonatal blenorrhea have not been studied. Directions for use: For local ophthalmic use. The drug is instilled into the conjunctival sac, after which it is recommended to lightly press the inner corner of the eye to close the nasolacrimal duct or slightly close the eyelids. This may reduce systemic absorption and the risk of systemic adverse effects. When using several ophthalmic drugs for topical use simultaneously, it is necessary to maintain at least a 15-minute interval between instillations. To avoid contamination of the tip of the dropper and the solution, it is not recommended to touch the tip of the dropper to the eyelids and tissues around the eye. Recommendations for the use of bottles with a dropper cap: Before use, carefully read this section and sequentially perform the operations presented below in the text and in Figures 1-6. 1. Remove the bottle from the package. 2. Place the scissors at an angle of 45 degrees to the lid, pick up its lower edge, and with an upward motion, remove the aluminum cap along with the rubber lid. 3. Remove the dropper from the package and place it tightly on the bottle. 4. Turn the bottle strictly vertically to remove the air bubble and wait a few seconds. In the case of a large bubble, return the bottle to its original position, and then slowly repeat the action, gently tapping the bottom of the bottle. 5. Apply instillation by pressing the pipette with your index finger and thumb. 6. Turn the bottle over and close the pipette with a special stopper. Recommendations for using dropper tubes: before using the medicine, remove the protective cap from the dropper tube and cut off the membrane of the body neck with scissors without damaging the threaded part. Turn the body of the dropper tube with the medicine neck down and gently press the body of the dropper tube, using it as a pipette. After using the dose recommended by the doctor or indicated in the instructions for use of the medicinal product, turn the body of the dropper tube over with the threaded part up and screw on the protective cap. Wash your hands before using eye drops. Do not touch the dropper or pipette to your eyes or hands.
Use during pregnancy and lactation
Contraindicated.
Impact on the ability to drive vehicles and other potentially dangerous mechanisms
Due to possible visual impairment that occurs immediately after instillation, you should stop driving and driving potentially dangerous machinery until your vision normalizes.
Precautionary measures
The drug should not be administered subconjunctivally; direct instillation into the anterior chamber of the eye should be avoided. Eye drops contain benzalkonium chloride as a preservative, which can cause eye irritation and change the color of soft contact lenses. Contact of the drug with soft contact lenses should be avoided. You should not wear contact lenses of any type if you have symptoms of bacterial conjunctivitis. Fluoroquinolones for systemic use can cause allergic reactions (accompanied by cardiovascular disorders, swelling of the larynx, pharynx and face, and difficulty breathing) even after a single use. If an allergic reaction to levofloxacin occurs, you should stop using eye drops. Long-term use of levofloxacin in the form of eye drops can lead to the growth of resistant microorganisms, as well as fungi. If the clinical picture worsens or does not improve, the drug should be discontinued and treatment with other drugs should be prescribed.
Interaction with other drugs
No specific interaction studies have been conducted with levofloxacin eye drops. Since the maximum plasma concentration of levofloxacin after topical administration is 1000 times less than after oral administration, interaction effects with other drugs are unlikely.
Contraindications
Hypersensitivity to levofloxacin or to other quinolones, to benzalkonium chloride; pregnancy, lactation period, children under 1 year.
Compound
active substance: levofloxacin (in the form of levofloxacin hemihydrate) – 5 mg/ml excipients: benzalkonium chloride, sodium chloride, disodium edetate, hydrochloric acid 1 M solution, water for injection.
Overdose
An overdose of the drug in the form of eye drops is unlikely. Symptoms: tissue irritation (burning, redness, swelling, pain, lacrimation). Treatment: rinse with clean (tap) water at room temperature; in the presence of severe side effects, use symptomatic therapy.
Side effect
The frequency of side effects is given in the following gradation: very often (? 1/10); often (?1/100,
Storage conditions
In a place protected from light at a temperature not exceeding 25 ° C. Keep out of the reach of children. Store the opened bottle in a place protected from light at a temperature of 15 ° C to 25 ° C for 4 weeks.
