Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Accord Healthcare Limited, Sage House, 319, Pinner Road, North Harrow, Middlesex, HA1 4 HF, United Kingdom
Pharmacotherapeutic group: Antiifectives for systemic use – Antibacterials for systemic use – Quinolone antibasterials – Fluoroquinolones
ATC code: J01MA12
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.
The degree of the bactericidal activity of levofloxacin depends on the ratio of the maximum concentration in serum (Cmax) or the area under the curve (AUC) and the minimal inhibitory concentration (MIC).
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.
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):
| Pathogen | Susceptible | Resistant |
|---|---|---|
| Enterobacteriacae | ≤1 mg/L | >2 mg/L |
| Pseudomonas spp. | ≤1 mg/L | >2 mg/L |
| Acinetobacter spp. | ≤1 mg/L | >2 mg/L |
| Staphylococcus spp. | ≤1 mg/L | >2 mg/L |
| S.pneumoniae1 | ≤2 mg/L | >2 mg/L |
| Streptococcus A,B,C,G | ≤1 mg/L | >2 mg/L |
| H.influenzae2,3, M.catarrhalis3 | ≤1 mg/L | >1 mg/L |
| Non-species related breakpoints4 | ≤1 mg/L | >2 mg/L |
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.
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
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
Aerobic Gram-positive bacteria:
Enterococcus faecium
# Methicillin-resistant S. aureus are very likely to possess co-resistance to fluoroquinolones, including levofloxacin.
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.
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.
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.
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.
Following oral and intravenous administration of levofloxacin, it is eliminated relatively slowly from the plasma (t½: 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 obeys linear pharmacokinetics over a range of 50 to 1000 mg.
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:
| Clcr [ml/min] | <20 | 20-49 | 50-80 |
| ClR [ml/min] | 13 | 26 | 57 |
| t1/2 [h] | 35 | 27 | 9 |
There are no significant differences in levofloxacin kinetics between young and elderly subjects, except those associated with differences in creatinine clearance.
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.
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.
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