Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Santen Oy, Niittyhaankatu 20, 33720 Tampere, Finland
Pharmacotherapeutic group: Ophthalmologicals, antiinfectives, fluoroquinolones
ATC code: S01AE05
Levofloxacin is the L-isomer of the racemic drug substance ofloxacin. The antibacterial activity of ofloxacin resides primarily in the L-isomer.
As a fluoroquinolone antibacterial agent, levofloxacin inhibits bacterial type II topoisomerases-DNA gyrase and topoisomerase IV. Levofloxacin preferentially targets DNA gyrase in Gram-negative bacteria and topoisomerase IV in Gram-positive bacteria.
Bacterial resistance to levofloxacin can develop primarily due to two main mechanisms, namely a decrease in the intrabacterial concentration of a drug, or alterations in a drug’s target enzymes. Target site alteration results from mutations in the chromosomal genes encoding the DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE; grlA and grlB in Staphylococcus aureus). Resistance due to low intrabacterial drug concentration follows either from altered outer-membrane porins (OmpF) leading to reduced entry of fluoroquinolones in Gram-negative bacteria or from efflux pumps. Efflux-mediated resistance has been described in pneumococci (PmrA), staphylococci (NorA), anaerobes, and Gram-negative bacteria. Finally, plasmid-mediated resistance to quinolones (determined by the qnr gene) has been reported in Klebsiella pneumoniae and in E. coli.
Cross-resistance between fluoroquinolones may occur. Single mutations may not result in clinical resistance, but multiple mutations generally do result in clinical resistance to all drugs within the fluoroquinolone class. Altered outer-membrane porins and efflux systems may have a broad substrate specificity, targeting several classes of antibacterial agents and leading to multiresistance.
MIC breakpoints separating susceptible from intermediately susceptible organisms and intermediately susceptible from resistant organisms according to breakpoint of EUCAST (European Committee on Antimicrobial Susceptibility Testing) are as follows:
Pseudomonas spp., Staphylococcus spp., Streptococcus A,B,C,G:
Susceptible ≤1 mg/l, resistant >2 mg/l
Streptococcus pneumoniae: Susceptible ≤2 mg/l, resistant >2 mg/l
Haemophilus influenzae, Moraxella catarrhalis: Susceptible ≤1 mg/l, resistant >1 mg/l
All other pathogens: Susceptible ≤1 mg/l, resistant >2 mg/l
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. Therefore the information presented provides only an approximate guidance on probabilities as to whether microorganisms will be susceptible to levofloxacin or not. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
Only those bacterial species that are commonly responsible for external ocular infections, such as conjunctivitis, are presented here in the following table.
Antibacterial spectrum – susceptibility category and resistance characteristics according to EUCAST:
| Category I: Commonly susceptible species | |
|---|---|
| Aerobic Gram-positive micro-organisms | |
| Staphylococcus aureus (MSSA)* | |
| Streptococcus pneumoniae | |
| Streptococcus pyogenes | |
| Viridans group streptococci | |
| Aerobic Gram-negative micro-organisms | |
| Escherichia coli | |
| Haemophilus influenzae | |
| Moraxella catarrhalis | |
| Pseudomonas aeruginosa | (Community isolates) |
| Other micro-organisms | |
| Chlamydia trachomatis | (Treatment of patients with chlamydial conjunctivitis requires concomitant systemic antimicrobial treatment) |
| Category II: Species for which acquired resistance may be a problem | |
| Aerobic Gram-positive micro-organisms | |
| Staphylococcus aureus (MRSA)** | |
| Staphylococcus epidermidis | |
| Aerobic Gram-negative micro-organisms | |
| Pseudomonas aeruginosa | (Hospital isolates) |
* MSSA = methicillin-susceptible strains of Staphylococcus aureus
** MRSA = methicillin-resistant strains of Staphylococcus aureus
Resistance data presented in the table are based on the results of a multicentre surveillance study (Ophthalmic Study) on the prevalence of resistance among bacterial isolates obtained from patients with eye infections in Germany, June-November 2004.
Organisms have been classified as levofloxacin-susceptible based on in-vitro susceptibility and plasma concentrations reached after systemic therapy. Topical therapy achieves higher peak concentrations than found in plasma. However, it is not known if or how the kinetics of the drug after topical application to the eye may modify the antibacterial activity of levofloxacin.
Pharmacodynamic properties are the same in adults and children aged ≥1 year.
After ocular instillation, levofloxacin is well maintained in the tear-film.
In a healthy-volunteer study, mean tear-film concentrations of levofloxacin measured four and six hours after topical dosing were 17.0 and 6.6 µg/ml, respectively. Five of six subjects studied had concentrations of 2 μg/ml or above at 4 hours post dose. Four of the six subjects maintained this concentration at 6 hours post dose.
Levofloxacin concentration in plasma was measured in 15 healthy adult volunteers at various time points during a 15-day course of treatment with Oftaquix 5 mg/ml eye drops solution. The mean levofloxacin concentration in plasma 1 hour post-dose ranged from 0.86 ng/ml on Day 1 to 2.05 ng/ml on Day 15. The highest maximum levofloxacin concentration of 2.25 ng/ml was measured on Day 4 following 2 days of dosing every 2 hours for a total of 8 doses per day. Maximum levofloxacin concentrations increased from 0.94 ng/ml on Day 1 to 2.15 ng/ml on Day 15, which is more than 1000 times lower than those reported after standard oral doses of levofloxacin.
As yet, the plasma concentrations of levofloxacin reached after application to infected eyes are not known.
Preclinical effects were observed only at exposures considerably in excess of the maximum human exposure after instillation of Oftaquix 5 mg/ml eye drops, indicating little relevance to clinical use.
Gyrase inhibitors have been shown to cause growth disorders of weight bearing joints in animal studies.
In common with other fluoroquinolones, levofloxacin showed effects on cartilage (blistering and cavities) in rats and dogs after high oral doses.
A cataractogenic potential cannot be ruled out due to the lack of specific investigations.
Visual disorders in animals cannot be ruled out with certainty on the basis of the present data.
Levofloxacin was not teratogenic in rats at oral doses as high as 810 mg/kg/day. Since levofloxacin has been shown to be completely absorbed, the kinetics are linear. No differences were noted in the pharmacokinetic parameters between single and multiple oral doses. Systemic exposure in rats dosed at 810 mg/kg/day is approximately 50,000 times greater than that achieved in humans after doses of 2 drops of Oftaquix 5 mg/ml eye drops to both eyes. In rats the highest dose caused increased foetal mortality and delayed maturation coincident with maternal toxicity. No teratogenic effect was observed when rabbits were dosed orally with up to 50 mg/kg/day or when dosed intravenously as high as 25 mg/kg/day.
Levofloxacin caused no impairment of fertility in rats at oral doses as high as 360 mg/kg/day, resulting in approximately 16,000 times higher plasma concentrations than reached after 8 ocular doses in humans.
Levofloxacin did not induce gene mutations in bacterial or mammalian cells, but did induce chromosome aberrations in Chinese hamster lung (CHL) cells in vitro at or above 100 µg/ml in the absence of metabolic activation. In-vivo tests did not show any genotoxic potential.
Studies in the mouse after both oral and intravenous dosing showed levofloxacin to have phototoxic activity only at very high doses. Neither cutaneous photosensitising potential nor skin phototoxic potential were observed after application of a 3% ophthalmic solution of levofloxacin to the shaven skin of guinea pigs. Levofloxacin did not show any genotoxic potential in a photomutagenic assay, and it reduced tumour development in a photocarcinogenicity assay.
In a long-term carcinogenicity study in rats, levofloxacin exhibited no carcinogenic or tumorigenic potential following daily dietary administration of up to 100 mg/kg/day for 2 years.
The calculated predicted environmental concentration (PECSurfacewater) for Oftaquix 5 mg/ml eye drops is below the action limit 0.01 µg/l and levofloxacin LogKow-value is below action limit 4.5.
It is highly unlikely that Oftaquix 5 mg/ml eye drops would represent a risk to the environment because no other environmental concerns are apparent for this product and its active substance levofloxacin.
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