Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: quinolone antibacterials, fluoroquinolones, ATC code: J01MA12.
Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone class and is the S (-) enantiomer of the racemic active substance ofloxacin.

Mechanism of action
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 (Cmax) or the area under the curve (AUC) and the minimal inhibitory concentration (MIC).

Mechanism of resistance
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 susceptible increased exposure organisms and susceptible increased exposure from resistant organisms are presented in the below table for MIC testing (mg/l).
EUCAST clinical MIC breakpoints for levofloxacin (version 10.0, 2020-01-01): 
Pathogen                  Susceptible Resistant
Enterobacterales              ≤0.5 mg/l   >1 mg/l
Pseudomonas spp.              ≤0.001 mg/l >1 mg/l
Acinetobacter spp.            ≤0.5 mg/l   >1 mg/l
Staphylococcus aureus              ≤0.001 mg/l >1 mg/l

Coagulase-negative staphylococci
Enterococcus spp.1              ≤4 mg/l     >4 mg/l
        Streptococcus pneumoniae            ≤0.001 mg/l >2 mg/l
Streptococcus groups A, B, C and G       ≤0.001 mg/l >2 mg/l
Haemophilus influenzae             ≤0.06 mg/l >0.06 mg/l
Moraxella catarrhalis             ≤0.125 mg/l >0.125 mg/l
Helicobacter pylori             ≤1 mg/l     >1 mg/l
Aerococcus sanguinicola and urinae2       ≤2 mg/l     >2 mg/l
Aeromonas spp.                 ≤0.5 mg/l   >1 mg/l
PK-PD (Non-species related) breakpoints ≤0.5 mg/l       >1 mg/l
1: uncomplicated urinary tract infections only
2: Susceptibility can be inferred from ciprofloxacin susceptibility


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 coresistance to fluoroquinolones, including levofloxacin.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

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.


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.

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 and are 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 (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.

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

Special populations
Subjects with renal insufficiency
The pharmacokinetics of levofloxacin is 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

Elderly subjects
There are no significant differences in levofloxacin pharmacokinetics between young and elderly subjects, except those associated with differences 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.