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-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 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 10.0, 2020-01-01): Pathogen                               Susceptible                 Resistant Enterobacteriales                      ≤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 spp
S.aureus                               ≤0.001 mg/L                 >1 mg/L Coagulase-negative staphylococci ≤0.001 mg/L                       >1 mg/L S.pneumoniae                           ≤0.001 mg/L                 >2 mg/L Streptococcus A,B,C,G                  ≤0.001 mg/L                 >2 mg/L H.influenzae                           ≤0.06 mg/L                  >0.06 mg/L M.catarrhalis                          ≤0.125 mg/L                 >0.125 mg/L H.pylori                               ≤1 mg/L                     >1 mg/L A.sanguinicola and urinae1             ≤2 mg/L                     >2 mg/L (uncomplicated UTI only)
K.kingae                               ≤0.125 mg/L                 >0.125 mg/L Non-species related breakpoints        ≤0.5 mg/L                   >1 mg/L 1. 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 agglomerans
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.

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 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 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


Elderly subjects

There are no significant differences in levofloxacin kinetics 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.