Levofloxacin

Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone class and is the S (-) enantiomer of the racemic drug substance ofloxacin.

As a fluoroquinolone antibacterial agent, levofloxacin acts on the DNA-DNA-gyrase complex and topoisomerase IV.

PK/PD relationship

The degree of the bactericidal activity of levofloxacin depends on the ratio of the maximum concentration in serum (C_max) or the area under the curve (AUC) and the minimal inhibitory concentration (MIC).

Mechanism(s) of resisance

Resistance to levofloxacin is acquired through a stepwise process by target site mutations in both type II topoisomerases, DNA gyrase and topoisomerase IV. Other resistance mechanisms such as permeation barriers (common in Pseudomonas aeruginosa) and efflux mechanisms may also affect susceptibility to levofloxacin.

Cross-resistance between levofloxacin and other fluoroquinolones is observed. Due to the mechanism of action, there is generally no cross-resistance between levofloxacin and other classes of antibacterial agents.

Breakpoints

The EUCAST recommended MIC breakpoints for levofloxacin, separating susceptible from intermediately susceptible organisms and intermediately susceptible from resistant organisms are presented in the below table for MIC testing (mg/L).

EUCAST clinical MIC breakpoints for levofloxacin (version 2.0, 2012-01-01):

¹ The breakpoints for levofloxacin relate to high dose therapy.
² Low-level fluoroquinolone resistance (ciprofloxacin MICs of 0.12-0.5 mg/l) may occur but there is no evidence that this resistance is of clinical importance in respiratory tract infections with H. influenzae.
³ Strains with MIC values above the susceptible breakpoint are very rare or not yet reported. The identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate must be sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC above the current resistant breakpoint they should be reported resistant.
⁴ Breakpoints apply to an oral dose of 500 mg x 1 to 500 mg x 2 and an intravenous dose of 500 mg x 1 to 500 mg x 2.

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. 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.

Commonly susceptible species

Aerobic Gram-positive bacteria:

Bacillus anthracis
Staphylococcus aureus methicillin-susceptible
Staphylococcus saprophyticus
Streptococci, group C and G
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes

Aerobic Gram-negative bacteria:

Eikenella corrodens
Haemophilus influenzae
Haemophilus para-influenzae
Klebsiella oxytoca
Moraxella catarrhalis
Pasteurella multocida
Proteus vulgaris
Providencia rettgeri

Anaerobic bacteria:

Peptostreptococcus

Other:

Chlamydophila pneumoniae
Chlamydophila psittaci
Chlamydia trachomatis
Legionella pneumophila
Mycoplasma pneumoniae
Mycoplasma hominis
Ureaplasma urealyticum

Species for which acquired resistance may be a problem

Aerobic Gram-positive bacteria:

Enterococcus faecalis
Staphylococcus aureus methicillin-resistant#
Coagulase negative Staphylococcus spp

Aerobic Gram-negative bacteria:

Acinetobacter baumannii
Citrobacter freundii
Enterobacter aerogenes
Enterobacter cloacae
Escherichia coli
Klebsiella pneumoniae
Morganella morganii
Proteus mirabilis
Providencia stuartii
Pseudomonas aeruginosa
Serratia marcescens

Anaerobic bacteria:

Bacteroides fragilis

Inherently resistant Strains

Aerobic Gram-positive bacteria:

Enterococcus faecium

^# Methicillin-resistant S. aureus are very likely to possess co-resistance to fluoroquinolones, including levofloxacin.

Paediatric population

Pharmacodynamic properties are the same in adults and children aged ≥1 year

Absorption

Orally administered levofloxacin is rapidly and almost completely absorbed with peak plasma concentrations being obtained within 1-2 h. The absolute bioavailability is 99-100%.

Food has little effect on the absorption of levofloxacin.

Steady state conditions are reached within 48 hours following a 500 mg once or twice daily dosage regimen.

The maximal plasma concentration (C_max) of levofloxacin following administration by inhalation occurred at approximately 0.5-1 hour post-dose.

Multiple dose administration of Quinsair 240 mg twice daily by inhalation results in levofloxacin systemic exposure approximately 50% lower than that observed following systemic administration of comparable doses (see Table 3). However, there is variability in the systemic exposures observed which means that serum levels of levofloxacin following inhalation of Quinsair may sometimes fall within the range of levels observed following systemic administration of comparable doses.

Table 3. Comparison of mean (SD) multiple dose levofloxacin pharmacokinetic parameters following Quinsair administration by inhalation to patients with CF and following oral and intravenous administration of levofloxacin to healthy adult volunteers:

IV = intravenous; QD = quaque die (once a day); BID = bis in die (twice a day)
* Predicted value from population PK analysis in CF patients
** Healthy males 18-53 years old

High levofloxacin concentrations were observed in sputum following Quinsair 240 mg twice daily dosing in patients with CF. The mean post-dose sputum concentrations were approximately 500-1900 µg/ml and were approximately 400-1700 times higher than those observed in serum.

Distribution

Approximately 30-40% of levofloxacin is bound to serum protein. The mean volume of distribution of levofloxacin is approximately 100 l after single and repeated 500 mg doses, indicating widespread distribution into body tissues.

The mean apparent volume of distribution of levofloxacin in serum is approximately 250 L following inhalation of Quinsair 240 mg twice daily.

Penetration into tissues and body fluids

Levofloxacin has been shown to penetrate into bronchial mucosa, epithelial lining fluid, alveolar macrophages, lung tissue, skin (blister fluid), prostatic tissue and urine. However, levofloxacin has poor penetration intro cerebro-spinal fluid.

Biotransformation

Levofloxacin is metabolised to a very small extent, the metabolites being desmethyl-levofloxacin and levofloxacin N-oxide. These metabolites account for <5% of the dose excreted in urine. Levofloxacin is stereochemically stable and does not undergo chiral inversion.

Elimination

Following oral and intravenous administration of levofloxacin, it is eliminated relatively slowly from the plasma (t_½: 6-8 h). Excretion is primarily by the renal route >85% of the administered dose).

The mean apparent total body clearance of levofloxacin following a 500 mg single dose was 175 +/- 29.2 ml/min.

There are no major differences in the pharmacokinetics of levofloxacin following intravenous and oral administration, suggesting that the oral and intravenous routes are interchangeable.

Levofloxacin is systemically absorbed following inhalation and eliminated similarly to levofloxacin following systemic administration. The half-life of levofloxacin following inhalation is approximately 5 to 7 hours. Elimination is primarily by the renal route (>85% of the dose following oral or intravenous administration). The apparent clearance (CL/F) of levofloxacin following inhalation of 240 mg twice daily is 31.8 +/- 22.4 L/hour.

Linearity

Levofloxacin obeys linear pharmacokinetics over a range of 50 to 1000 mg.

Special populations

Subjects with renal insufficiency

The pharmacokinetics of levofloxacin are affected by renal impairment. With decreasing renal function renal elimination and clearance are decreased, and elimination half-lives increased as shown in the table below:

Pharmacokinetics in renal insufficiency following single oral 500 mg dose:

The effects of renal impairment on the pharmacokinetics of levofloxacin administered by inhalation have not been studied. However, dose adjustments were not employed in clinical studies which allowed for the inclusion of patients with mild to moderate renal impairment (estimated creatinine clearance ≥20 ml/min using the Cockcroft-Gault formula in adult patients and ≥20 ml/min/1.73 m² using the Bedside Schwartz formula in patients <18 years old). Studies using systemic administration of levofloxacin show that the pharmacokinetics of levofloxacin are affected by renal impairment; with decreasing renal function (estimated creatinine clearance <50 ml/min), renal elimination and clearance are decreased, and elimination half-life increased.

Therefore, doses of levofloxacin administered by inhalation do not need to be adjusted in patients with mild to moderate renal impairment. However, levofloxacin administered by inhalation is not recommended for use in patients with severe renal impairment (creatinine clearance MODIFIER LETTER LEFT ARROWHEAD (706) 20 ml/min).

Patients with hepatic impairment

Pharmacokinetic studies in patients with hepatic impairment have not been conducted. Due to the limited extent of levofloxacin metabolism in the liver, the pharmacokinetics of levofloxacin are not expected to be affected by hepatic impairment.

Paediatric population

The safety and efficacy of Quinsair in children aged MODIFIER LETTER LEFT ARROWHEAD (706) 18 years old have not yet been established.

The pharmacokinetics of levofloxacin following inhalation of 240 mg twice daily were investigated in paediatric patients with CF aged 12 years and older and weighing ≥30 kg. A population PK model based on sparse sampling determined that levofloxacin serum concentrations were comparable between paediatric and adult patients following 28 days of treatment. Higher sputum concentrations were observed in adults compared to paediatric patients in Study 207; similar sputum concentrations were observed in adult and paediatric patients in Study 209.

In addition, the pharmacokinetics of weight-based doses of levofloxacin administered by inhalation once daily for 14 days in paediatric patients with CF (≥6 to <12 years old, n=14 and ≥12 to <17 years old, n=13) were evaluated in Study 206. Patients weighing 22 to 30 kg received 180 mg levofloxacin/day and patients weighing ˃30 kg received 240 mg levofloxacin/day. The weight-based dosing scheme resulted in consistent serum and sputum PK exposure across the range of ages (7 to 16 years old) and weights (22 to 61 kg) observed in the study. Serum PK exposures were similar when comparing children receiving the weight-based regimen and adults receiving levofloxacin 240 mg once daily. Sputum PK exposure in children aged 7 to 16 years old was approximately one-third of adult exposure.

Elderly patients (≥65 years old)

There are no significant differences in levofloxacin kinetics between young and elderly subjects, except those associated with differences in creatinine clearance.

The pharmacokinetics of levofloxacin administered by inhalation have not been studied in the elderly. Following systemic administration, there were no significant differences in levofloxacin pharmacokinetics between young and elderly subjects except those associated with age-related decreases in creatinine clearance.

Gender differences

Separate analysis for male and female subjects showed small to marginal gender differences in levofloxacin pharmacokinetics. There is no evidence that these gender differences are of clinical relevance.

Race

The effects of race on the pharmacokinetics of levofloxacin administered by inhalation have not been studied. Following systemic administration, the effect of race on levofloxacin pharmacokinetics was examined through a covariate analysis performed on data from 72 subjects: 48 white and 24 non-white. The apparent total body clearance and apparent volume of distribution were not affected by the race of the subjects.

PK/PD relationship

The degree of the bactericidal activity of levofloxacin depends on the ratio of the maximum concentration in serum (C_max) or the area under the curve (AUC) and the minimal inhibitory concentration (MIC).

Ocular administration

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 levofloxacin 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.

Non-clinical data reveal no special hazard for humans based on conventional studies of single dose toxicity, repeated dose toxicity, carcinogenic potential and toxicity to reproduction and development.

Levofloxacin caused no impairment of fertility or reproductive performance in rats and its only effect on fetuses was delayed maturation as a result of maternal toxicity.

Levofloxacin did not induce gene mutations in bacterial or mammalian cells but did induce chromosome aberrations in Chinese hamster lung cells in vitro. These effects can be attributed to inhibition of topoisomerase II. In vivo tests (micronucleus, sister chromatid exchange, unscheduled DNA synthesis, dominant lethal tests) did not show any genotoxic potential.

Studies in the mouse showed levofloxacin to have phototoxic activity only at very high doses. Levofloxacin did not show any genotoxic potential in a photomutagenicity assay, and it reduced tumour development in a photocarcinogenity study.

In common with other fluoroquinolones, levofloxacin showed effects on cartilage (blistering and cavities) in rats and dogs. These findings were more marked in young animals.

Preclinical effects were observed only at exposures considerably in excess of the maximum human exposure after instillation of levofloxacin eye drops, indicating little relevance to clinical use.

Gyrase inhibitors have been shown to cause growth disorders of weight bearing joints in animal studies.

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.

Reproductive toxicity

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 levofloxacin 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.

Genotoxicity

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.

Phototoxic 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.

Carcinogenic potential

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.