Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic Properties

Mode of action
Pharmacotherapeutic group: fluoroquinolones

ATC code: J01 MA 01
Ofloxacin inhibits bacterial DNA replication in a range of gram-positive and gram- negative pathogenic bacteria by inhibiting bacterial topoisomerases, particularly DNA gyrase and topoisomerase IV.

The NCCLS MIC breakpoint recommendations are as follows:
S ≤ 2 mg/l and R ≥ 8 mg/l
Intermediate susceptibility at 4 mg/l

Haemophilus influenzae and Neisseria gonorrhoea are exceptions with breakpoints at S ≤ 0.25 mg/l and R ≥ 1 mg/l

The BSAC general recommendations are S < 2 mg/l and R > 4 mg/l
According to DIN 58 940, the following limits apply for ofloxacin:
S ≤ 1 mg/L, I =2 mg/L, R ≥ 4 mg/L.

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. This information gives only an approximate guidance on probabilities 
whether micro-organisms will be susceptible to ofloxacin or not.

Only those pathogens relevant to the indications are listed.
European range of acquired bacterial resistance to ofloxacin
Normally susceptible
Aerobic Gram-positive micro organisms
S.aureus -methicillin-sensitive              0.3-12.6%

S.pyogenes                                   2-5%
Aerobic Gram-negative micro organisms
Acinetobacter spp                            0.3-7.3%
Citrobacter spp.                             3-15%
E. Faecalis*
Enterobacter spp.                            2-13%
E. coli                                      1-8%
H. influenzae                                1%
Klebsiella spp.                              1-10%
Moraxella spp.                               0-0.2%
Morganella morganii                          0-6.9%
N. gonorrhoeae                               25%
Proteus spp.                                 1-15%
Serratia marcescens                          2-2.4%
Others
Chlamydia spp
L. pneumophila
Intermediately susceptible
Aerobic Gram-positive micro organisms
S. pneumonia                                 70%
Providentia                                  17.1%
Aerobic Gram-negative micro organisms
E. faecalis                                  50%
P. aeruginosa                                20-30%
Serratia spp.                                20-40%
Stenotrophomonas maltophilia                 5.1-11%
Others
Mycoplasma spp.                              0-5.3%
Ureaplasma spp.                              0-2.1%
Resistant
Anaerobic bacteria
S. aureus - methicillin-resistant            69.2-85.7%
T. pallidum

The main mechanism of bacterial resistance to ofloxacin involves one or more 
mutations in the target enzymes, which generally confer resistance to other active substances in the class. Efflux pump and impermeability mechanisms of resistance have also been described and may confer variable resistance to active substances in other classes.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption:
Ofloxacin is absorbed rapidly and almost completely when administered to fasting volunteers. The mean peak plasma concentration following a single oral dose of 200 mg is 2.6 g/ml and is achieved within an hour. The plasma concentration does not increase significantly with multiple dosing (accumulation factor with twice daily dosage: 1.5).

Distribution:
The apparent volume of distribution is 120 litres. Plasma protein binding is approximately 25%.

Biotransformation:
Ofloxacin is less than 5% bio-transformed. The two principal metabolites found in the urine are N-desmethyl-ofloxacin and ofloxacin-N-oxide. Ofloxacin is found as the glucuronide in the bile.

Elimination:
Elimination is primarily by the renal route in that 80 to 90 % of the dose is excreted unchanged in the urine. The plasma elimination half-life is 5.7 to 7.0 hours, irrespective of dose.

Patients with renal impairment:
The plasma elimination half-life is prolonged in individuals with impaired renal function; total and renal clearance decrease in accordance with creatinine clearance.