Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2016 Publisher: Generics [UK] Limited t/a Mylan, Station Close, Potters Bar, Hertfordshire, EN6 1TL
Pharmacotherapeutic group: Quinolone Antibacterials, Fluoroquinolones
ATC code: J01MA01
Ofloxacin inhibits bacterial DNA replication by inhibiting bacterial topoisomerases, particularly DNA gyrase and topoisomerase IV. It is active after oral administration.
Therapeutic doses of ofloxacin are devoid of pharmacological effects on the voluntary or autonomic nervous system.
The NCCLS MIC breakpoint recommendations are as follows: S ≤ 2 mg/l and R ≥ 1 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% |
| 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. pneumoniae | 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.
The administration of oral doses to fasting volunteers was followed by a rapid and almost complete absorption of ofloxacin. The peak plasma concentration after a single oral dose of 200mg averaged 2.6 µg/ml and was reached within one hour. The plasma elimination half-life was 5.7 to 7.0 hours and was not dose related.
The apparent distribution volume was 120 litres. The plasma concentration did not materially rise with repeat doses (accumulation factor for twice daily dosage: 1.5). The plasma protein binding was approx. 25%.
The biotransformation of ofloxacin was below 5%. The two main metabolites found in the urine were N-desmethyl-ofloxacin and ofloxacin-N-oxide.
Excretion is primarily renal. Between 80 and 90% of the dose were recovered from the urine as unchanged substance.
Ofloxacin was present in the bile in glucuronidised form. The pharmacokinetics of ofloxacin after intravenous infusion are very similar to those after oral doses. The plasma half-life is prolonged in persons with renal insufficiency; total and renal clearance decrease in accordance with the creatinine clearance. In renal insufficiency the dose should be reduced.
No clinically relevant interactions were seen with food and no interaction was found between ofloxacin and theophylline.
Preclinical effects in conventional studies of safety pharmacology, acute toxicity, repeated dose toxicity, reproductive studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Joint toxicity was observed at exposure in the human therapeutic range in juvenile rats and dogs. Ofloxacin exhibits a neurotoxic potential and causes reversible testicular alterations at high doses.
Mutagenicity studies showed no evidence for mutagenicity of ofloxacin. However, like some other quinolones Ofloxacin is phototoxic in animals at exposure in the human therapeutic range. The phototoxic, photomutagenic and photocarcinogenic potential of ofloxacin is comparable with that of other gyrase inhibitors.
Preclinical data from conventional genotoxicity studies reveal no special hazard to humans, carcinogen potential has not be investigated.
Ofloxacin has no effect on fertility, peri- or postnatal development, and therapeutic doses did not lead to any teratogenic or other embryotoxic effects in animals. Ofloxacin crosses the placenta and levels reached in the amniotic fluid are about 30% of the maximal concentrations measured in maternal serum.
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