Fleoptic Eye Drops (0.5% levofloxacin): Trusted by Doctors, Safe for Patients

Infectious and inflammatory eye diseases are the most common ophthalmic conditions and the most frequent cause of visits to healthcare providers. According to the literature, approximately 6 million people in the United States develop conjunctivitis each year (Chen F.V. et al., 2018). Acute conjunctivitis is the most common eye disease and accounts for approximately 2% of all outpatient visits (Rietveld R.P. et al., 2004). An even more serious eye disease is keratitis. According to L. Ung et al., microbial keratitis can reach epidemic proportions in some parts of the world, particularly in South, Southeast, and East Asia, and may exceed 2 million cases per year.

The primary cause of inflammatory infections of the anterior segment is bacterial flora, which is detected in >70% of children and in ≈50% of adults with this disease (Rietveld R.P. et al., 2004). According to several authors, the predominant bacterial organisms isolated from patients with acute bacterial conjunctivitis are Staphylococcus aureus, Staphylococcus pneumoniae, and Haemophilus influenzae, with the latter frequently isolated in children (Seal D.V. et al., 1982). Staphylococcus aureus is also considered the primary causative agent of acute blepharoconjunctivitis (Gigliotti F. et al., 1981) . In general, the main causative agents of bacterial keratitis are Staphylococcus spp., Streptococcus spp., Pseudomonas aeruginosa, and Gram-negative intestinal rods (Laspina F. et al., 2004; Keay L. et al., 2006). Gram-negative rods cause most cases of contact bacterial keratitis associated with contact lens wear. Even in a healthy human eye, the bacterial flora of the conjunctiva consists mainly of staphylococci (primarily Staphylococcus epidermidis), corynebacteria (Corynebacterium spp.), and to a lesser extent, streptococci (Streptococcus spp.) and various Gram-negative rods. The leading etiological factors of eye infections are Staphylococcus aureus, coagulase-negative staphylococci, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Pseudomonas aeruginosa, and enterobacteria (Bourcier T. et al., 2003). Although infectious and inflammatory eye diseases are self-limiting, effective local therapy with antibacterial agents can shorten the duration of treatment, reduce the risk of complications, and prevent the epidemic spread of the pathogen (Sheikh A. et al., 2001). In the treatment of any bacterial eye infections, antibiotic therapy is mostly prescribed empirically. That is why the choice of an antibacterial drug for the fastest eradication of typical pathogens is of key importance. Usually, the first-line treatment consists of broad-spectrum antibacterial drugs.

Levofloxacin—a member of the fluoroquinolone group

Fluoroquinolones have been known in ophthalmology since the early 1990s; they have proven their effectiveness in the treatment and prevention of eye infections and are constantly being improved. The first representative of the quinolone class of antibiotics was nalidixic acid, synthesized by Sterling Winthrop Laboratories in 1962, which was used to treat malaria (Lesher G.Y. et al., 1962). Fluoroquinolones differ from nalidixic acid in the presence of fluorine in the molecule. Fluorinated carboxyquinolones have been approved by the Food and Drug Administration (FDA) since 1990 for the treatment of bacterial eye infections (Lichtenstein S.J. et al., 2003). Over the past 30 years, broad-spectrum drugs have been developed that are effective against both Gram-negative and Gram-positive bacteria. Fluoroquinolones are divided into monofluorinated (norfloxacin, ciprofloxacin, ofloxacin, levofloxacin) and difluorinated (lomefloxacin) compounds.
In this review, we will examine in detail a representative of the third generation of the fluoroquinolone class—levofloxacin—which has a broad spectrum of in vitro activity and has demonstrated high efficacy in the treatment of a wide range of community-acquired and hospital-acquired infections (Croom K.F. et al., 2003).
We will examine the microbiological rationale for the use of levofloxacin in the topical treatment of bacterial external eye infections, as well as data from in vitro studies, pharmacokinetics, and clinical trials.
Levofloxacin is the L-isomer of the racemic compound ofofloxacin. The antibacterial activity of ofloxacin is almost entirely concentrated in the L-isomer; therefore, levofloxacin is inherently twice as active as ofloxacin per unit of mass (van Bambeke F. et al., 2005). It has been demonstrated that the antimicrobial activity of the L-isomer is 8–128 times higher than that of the D-isomer, which is attributed to the L-isomer’s higher affinity for the DNA–DNA gyrase complex (Ernst M.E. et al., 1997).

Mechanism of Action

Levofloxacin (like other fluoroquinolones) acts by inhibiting two bacterial enzymes that control the topological state of DNA: DNA gyrase, which consists of two A and two B polypeptide subunits, and topoisomerase IV, which consists of two C and two E subunits (Ogawa G.S. et al., 1993). These enzymes are responsible for DNA replication, genetic recombination, and DNA repair. Levofloxacin blocks these enzymes and thereby disrupts bacterial DNA replication (Drlica K., 1999). Both type II DNA topoisomerase enzymes are essential for bacterial growth (Drlica K., 1999; Hooper D.C., 1995; Zhanel G.G. et al., 2002). The primary target of levofloxacin in Gram-negative bacteria, such as Escherichia coli and Neisseria gonorrhoeae, is DNA gyrase, whereas in Gram-positive cocci, such as Staphylococcus aureus and Staphylococcus pneumoniae, it is topoisomerase IV (van Bambeke F. et al., 2005; Zhanel G.G. et al., 2002). The antimicrobial action of levofloxacin (as well as other fluoroquinolones) is characterized by concentration-dependent bactericidal activity and the ability to induce a post-resistance effect against a broad spectrum of bacteria (Croom K.F. et al., 2003; Hooper D.C., 1995). Fluoroquinolones demonstrate higher antibacterial activity compared to gentamicin, tobramycin, chloramphenicol, tetracycline, and erythromycin, as established during the analysis of 1,291 bacterial isolates obtained from patients with various infectious lesions of the eye (Jensen H.G. et al., 1998). Fluoroquinolones and levofloxacin not only kill bacteria but also inhibit their replication for 2–6 hours after exposure. This effect is referred to as post-antibiotic.
Antibacterial spectrum Levofloxacin is characterized by a broad spectrum of in vitro antibacterial activity against Gram-positive and Gram-negative aerobes, as well as so-called atypical bacteria, such as Chlamydia trachomatis, but has limited activity against anaerobic bacteria (Croom K.F. et al., 2003; Hooper D.C., 1995). Clinical breakpoints for minimum inhibitory concentrations (MICs) of levofloxacin against staphylococci, β-hemolytic streptococci, Haemophilus influenzae, Moraxella catarrhalis, members of the Enterobacteriaceae family, and Pseudomonas aeruginosa, according to the recommendations of the European Committee on Antimicrobial Susceptibility Testing (EUCAST), are ≤1 and > 2 mg/L, which distinguishes susceptible organisms from intermediate-susceptible ones and intermediate-susceptible ones from resistant ones, whereas against Staphylococcus pneumoniae – ≤2 and >2 mg/L, respectively. Levofloxacin demonstrates high activity against strains of Pseudomonas aeruginosa (0.063–2 mg/L), Haemophilus influenzae (0.008–0.031 mg/L), Moraxella catarrhalis (0.016–0.063 mg/L), Enterobacteriaceae, including Citrobacter spp., Enterobacter spp., Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis (0.016–0.25 mg/L). Overall, levofloxacin is more active than moxifloxacin (a newer fluoroquinolone) but less active than ciprofloxacin (a relatively early fluoroquinolone) against these Gram-negative species. Levofloxacin also demonstrates good in vitro activity against certain strains of several Gram-positive bacterial species, with MIC values of 0.064–0.5 mg/L for Staphylococcus aureus, 0.5–2 mg/L for Streptococcus pneumoniae, and 0.25–2 mg/L for Streptococcus pyogenes. Ciprofloxacin is less active against Gram-positive bacteria, whereas moxifloxacin exhibits higher in vitro activity (Kahlmeter G. et al., 2022; 2023). Resistance
The long-term use of antibacterial drugs has led to the emergence of a global problem: antibiotic resistance. Reduced susceptibility to levofloxacin (and other fluoroquinolones) can develop through two main mechanisms: changes in the drug’s target and changes affecting the intracellular concentration of the drug. Changes in the target are associated with mutations in the quinolone resistance-determining region (QRDR) of the gyrA and parC genes (van Bambeke F. et al., 2005; Zhanel G.G. et al., 2002). Research findings indicate that mutations typically arise from errors during chromosome replication, but may also arise through horizontal gene transfer, as observed in Streptococcus pneumoniae and viridans group streptococci (Janoir C. et al., 1999; Ferrandiz M.J. et al., 2000). High levels of resistance to levofloxacin require mutations in more than one gene (Piddock L.J. et al., 1999). The second major mechanism of resistance is associated with a decrease in intracellular concentration and results from changes in the outer membrane of bacteria (limited to Gram-negative bacteria) and/or drug efflux (van Bambeke F. et al., 2005). In the works of A. Robicseket et al., plasmid-mediated genes conferring resistance to quinolones in Escherichia coli and other Enterobacteriaceae species (qnr) have been described. Qnr proteins are capable of protecting DNA gyrase from quinolones. A rise in the level of resistance to fluoroquinolones has been observed worldwide over the past 10–15 years.
Data from the prospective multicenter Ocular TRUST 1 study, conducted in the United States from October 2005 to June 2006, show that the rate of resistance to levofloxacin was 18.9% and 78.8% among isolates of methicillin-susceptible Staphylococcus aureus (MSSA) (n=164) and methicillin-resistant Staphylococcus aureus (MRSA) (n=33), respectively (Asbell P.A. et al., 2008). Results from a 2004 German prospective study, which evaluated 436 Staphylococcus aureus isolates isolated from patients with external eye infections in 35 laboratories, showed a resistance rate to levofloxacin of 5% among MSSA (n=380) and 53.6% among MRSA (n=56) (Kresken M. et al., 2007).
Recent studies indicate the emergence of fluoroquinolone-resistant strains of Streptococcus pneumoniae in some parts of the world, particularly in Southeast Asia (Chen D.K. et al., 1999; Ho P.L. et al., 2001). However, all 49 isolates collected during the Ocular TRUST 1 study were found to be susceptible to levofloxacin.
All 760 archived ocular isolates collected as part of the TRUST surveillance program between 1996 and 2006 were susceptible to levofloxacin, with the exception of one (Asbell P.A. et al., 2008). The results of a study by German epidemiologists (Kresken M. et al., 2007) show that 184/187 (98.4%) isolates were susceptible to levofloxacin. All Haemophilus influenzae isolates collected during the TRUST 1 field study (n=32) were susceptible to levofloxacin, as were 355/356 (99.7%) of the archived TRUST isolates, regardless of β-lactamase production (Asbell P.A. et al., 2008). A German epidemiological study reported that all 164 isolates were susceptible to levofloxacin (Kresken M. et al., 2007). Data from the study on resistance showed that all 46 (100%) Escherichia coli isolates and 6/45 (13.3%) Pseudomonas aeruginosa isolates were not resistant to levofloxacin (Kresken M. et al., 2007).
A study (Kowalski R.P. et al., 2003) examined 177 bacterial isolates obtained from patients with keratitis. The study results indicate that for most ophthalmic pathogens, there are no differences in susceptibility to second-, third-, and fourth-generation fluoroquinolones. It was found that in the treatment of eye infections caused by Gram-negative pathogens, the use of fourth-generation fluoroquinolones (moxifloxacin, gatifloxacin) does not demonstrate advantages over levofloxacin, ofloxacin, and ciprofloxacin. Similar data were obtained by R. Mather et al., who studied strains isolated from patients with endophthalmitis.

Pharmacokinetic Properties
A study by M.B. Raizman et al. showed that after instilling 1 drop of a 0.5% ophthalmic solution of levofloxacin into each eye of healthy volunteers, the drug concentration in the tear fluid remained >2 mg/L for at least 6 hours.
Topical application of levofloxacin demonstrated the following: the drug effectively penetrates the cornea, and with frequent application (over 1 hour), the concentrations achieved in the anterior chamber of the eye exceeded the MIC of most ocular bacterial pathogens (Bucci F.A. Jr, 2004; Healy D.P. et al., 2004). When topical and oral forms of levofloxacin were used simultaneously, adequate drug levels were also achieved in the vitreous cavity of the eye (Sakamoto H.M. et al., 2007).
A number of authors believe that topically applied fluoroquinolones are more toxic to the corneal epithelium than other antibiotics (Papa, Vincenzo, Leonardi et al., 2006; Pollock G.A. et al., 2003). However, in recently published studies, levofloxacin did not have a negative effect on epithelial wound healing or on the condition of the epithelium following cataract surgery in general (Kim S.-Y. et al., Cornea, 2007; Watanabe R. et al., 2010; Han K.E. et al., 2013). The results of the study by P. Bezwada et al. indicate that levofloxacin is less cytotoxic to human corneal keratocytes and epithelial cells than other fluoroquinolones, including gatifloxacin, moxifloxacin, ciprofloxacin, and ofloxacin.
An important parameter of any antimicrobial agent is its ability to penetrate and accumulate in target organs. It should be noted that the ability to accumulate in tissues is determined by the antibiotic’s solubility. It is known that levofloxacin is 10 times more soluble at neutral pH than ofloxacin, and 400 times more soluble than ciprofloxacin (Ross D.L. et al., 1990), as confirmed by the use of 0.5% levofloxacin eye drops before and after cataract surgery. 0.5% levofloxacin eye drops provide a higher concentration of the active fluoroquinolone than the use of ofloxacin or ciprofloxacin. Due to its broad spectrum of activity and low risk of precipitation at higher concentrations, levofloxacin can be considered the drug of choice compared to ciprofloxacin and ofloxacin for topical use in cataract surgery (Colin J. et al., 2003).

Clinical Use The first 0.5% levofloxacin eye drops appeared on the European market in 2002. Levofloxacin’s broad antibacterial spectrum and high corneal permeability explain its widespread use in ophthalmology.
The main indications for the use of levofloxacin eye drops are bacterial infections of the anterior segment of the eye, such as blepharitis, conjunctivitis, keratitis, and scleritis, as well as infections of the posterior segment—uveitis and endophthalmitis. This is confirmed by clinical studies conducted by a number of authors. Indeed, in many studies, a 0.5% ophthalmic solution of levofloxacin proved effective for bacterial conjunctivitis and keratitis (Hwang D.G. et al., 2003; Schwab I.R. et al., 2003; Duggirala A. et al., 2007). Levofloxacin eye drops are used to prevent infectious complications following surgical procedures (Kresken M. et al., 2008). Clinical studies have demonstrated that levofloxacin reduces the bacterial load on the conjunctiva, which is the primary source of bacteria causing postoperative infections; furthermore, it achieves drug concentrations in the eye capable of preventing infection in the event of contamination (Bucci, 2004; Healy D.P. et al., 2004; Cantor L.B. et al., 2008; de Kaspar H.M. et al., 2008). As a prophylaxis for intraocular surgery, levofloxacin has proven effective and acted synergistically in combination with standard conjunctival povidone-iodine irrigation (Ta C.N. et al., 2007). The efficacy of using 0.5% levofloxacin just 1 day prior to vitreoretinal surgery (6 times daily) has been demonstrated to minimize the use of prophylactic antibiotics (Li X. et al., 2017). In addition to conjunctival instillations of a 0.5% levofloxacin solution, the safety and efficacy of intracameral administration of this solution (only in the absence of preservatives) during cataract surgery to prevent the development of endophthalmitis have been demonstrated (Espiritu C.R.G. et al., 2017).
According to the results of a postmarketing study conducted by Y. Kanda et al., it has been demonstrated that 0.5% levofloxacin eye drops are safe and have minimal side effects. Specifically, data were collected on 6,760 patients who received levofloxacin for the treatment of various ocular conditions. The drug was well tolerated: adverse reactions were reported in 42 of 6,686 patients (0.63%). The main adverse reactions were blepharitis, local eye irritation, and punctate keratitis. The incidence of adverse reactions did not differ significantly by age, but was significantly higher in women (0.82%) compared to men (0.36%; p=0.028). A clinical response was observed in 95.5% of patients receiving levofloxacin, with no difference in response across the three time periods. The response rate to levofloxacin for bacterial diseases ranged from 97.4% for keratitis to 88.3% for dacryocystitis. This rate was lower in patients with dacryocystitis, as well as in elderly patients, those with a long duration of illness, and during relapses (all p<0.001). This post-marketing study was conducted over 4 years and confirmed the safety and efficacy of levofloxacin with regular clinical use. The authors emphasize that levofloxacin is a promising treatment for various external ocular bacterial infections. It should be noted that levofloxacin preparations are widely used in pediatric practice (children aged >1 year). A study conducted by S.J. Lichtenstein et al. demonstrated better outcomes after 5 days of treatment with 0.5% ophthalmic levofloxacin solution for bacterial conjunctivitis conjunctivitis in children compared to 0.3% ofloxacin: the eradication rate of Haemophilus influenzae and Streptococcus pneumoniae during treatment with levofloxacin was significantly higher. The authors noted that the most common side effects of both fluoroquinolones studied were a temporary burning sensation (2%) and fever (3%). According to the results of a study by G. Hwang et al., it was demonstrated that following the use of topical levofloxacin in children aged 2–11 years, complete eradication was achieved in 88% of participants and in only 24% of patients in the placebo group. The authors assert that a 5-day course of treatment with levofloxacin is pharmacologically more effective than a 7-day course of therapy with second-generation fluoroquinolones, specifically ciprofloxacin.
It should be noted that the treatment regimen with levofloxacin eye drops allows for and requires mandatory overnight breaks during which levofloxacin is not administered. This is justified by the fact that a therapeutic concentration of 0.5% levofloxacin in tears is maintained for >6 hours after instillation (Raizman M.B. et al., 2002).
The developer of levofloxacin—Rioji Noyori, Director of the Research Center at Nagoya University (Japan)—was awarded the Nobel Prize in Chemistry in 2001 for developing a method of catalytic asymmetric synthesis in the production of levofloxacin.
Currently, Kyiv Vitamin Plant JSC manufactures the drug Fleoptik—preservative-free eye drops containing a 0.5% solution of levofloxacin.
It is important to note the main advantages of the drug:

• broad-spectrum antibacterial activity;
• efficacy against Pseudomonas aeruginosa;
• high susceptibility of pathogens causing inflammatory diseases of the conjunctiva and cornea to levofloxacin;
• rapid and effective penetration through the cornea;
• minimal keratotoxicity;
• convenient dosing regimen and administration schedule;
• safety in pediatric practice (approved for children from 1 year of age).

Fleoptik (0.5% levofloxacin eye drops) is the drug of choice for local empirical antibiotic therapy and the optimal therapeutic strategy in most cases of bacterial eye infections.
Fleoptik eye drops (0.5% levofloxacin) offer a broad spectrum of antibacterial activity, a robust evidence base, a high safety profile, and comfort for patients of all ages.