Gemifloxacin

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Gemifloxacin
Systematic (IUPAC) name
7-[(4Z)-3-(aminomethyl)- 4-methoxyimino-pyrrolidin-1-yl]- 1-cyclopropyl-6-fluoro-4-oxo- 1,8-naphthyridine-3-carboxylic acid
Identifiers
CAS number	175463-14-6
ATC code	J01MA15
PubChem	5464436
DrugBank	APRD00053
Chemical data
Formula	C18H20FN5O4
Mol. mass	389.381 g/mol
Pharmacokinetic data
Bioavailability	71%
Protein binding	60-70%
Metabolism	Limited metabolism by the liver to minor metabolites
Half life	?
Excretion	?
Therapeutic considerations
Pregnancy cat.	C
Legal status	CAP/AECB
Routes	Oral/IV under development

Gemifloxacin mesylate (trade name Factive, Oscient Pharmaceuticals) is an oral broad-spectrum quinolone antibacterial agent used in the treatment of acute bacterial exacerbation of chronic bronchitis and mild-to-moderate pneumonia. Oscient Pharmaceuticals has licensed the active ingredient from LG Life Sciences of Korea.

[edit] Microbiology

Gemifloxacin has been shown to be active against most strains of the following microorganisms:

Aerobic gram-positive microorganisms - Streptococcus pneumoniae including multi-drug resistant Streptococcus pneumoniae (MDRSP). MDRSP includes isolates previously known as PRSP (penicillin-resistant Streptococcus pneumoniae), and are strains resistant to two or more of the following antibiotics: penicillin, 2nd generation cephalosporins, e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole.

Staphylococcus aureus (methicillin-susceptible strains only) and Streptococcus pyogenes

Aerobic gram-negative microorganisms - Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae (many strains are moderately susceptible), Moraxella catarrhalis, Acinetobacter lwoffii, Klebsiella oxytoca, Legionella pneumophila, Proteus vulgaris.

Other microorganisms - Chlamydia pneumoniae, Mycoplasma pneumoniae

Comparative minimum inhibitory concentrations (MICs) (μg/ml) of gemifloxacin versus commonly used fluoroquinolones against major pathogens:

Compared with currently available fluoroquinolones, gemifloxacin demonstrated improved in vitro activity (Gemifloxacin > Garenofloxacin > Moxifloxacin > Gatifloxacin as in following table) against S. pneumoniae (MIC for 90% eradication 0.03 µg/mL) and similar activity against gram-negative respiratory pathogens (Haemophilus influenzae, Moraxella catarrhalis) and atypical pathogens such as Chlamydia pneumoniae, Legionella pneumophila, and Mycoplasma pneumoniae.

It is reported that penicillin-resistant S. pneumoniae clinical isolates, also resistant to ciprofloxacin (MICs, 2 to 64 μg/ml), are highly susceptible to gemifloxacin (MICs, 0.03 to 0.12 μg/ml). It is also reported that other fluoroquinolones like levofloxacin and moxifloxacin (with AUC(0-24)/MIC = 4.4-7.4) provide little or no inhibition of ciprofloxacin-resistant strains, while gemifloxacin is the only fluoroquinolone (with AUC(0-24)/MIC ≥ 32) to eradicate all ciprofloxacin-resistant strains.

As it is obvious from the above, that gemifloxacin is the most potent fluoroquinolone against S. pneumoniae esp. against multidrug resistant-, ciprofloxacin-resistant, and even levofloxacin-resistant strains.

The pharmacokinetics of gemifloxacin are linear over the dose range from 40 mg to 640 mg, thus having predictable pharmacokinetics.

[edit] Mechanism of action

Gemifloxacin acts by inhibiting DNA synthesis through the inhibition of both DNA gyrase and topoisomerase IV (TOPO IV), which are essential for bacterial growth. S. pneumoniae showing mutations in both DNA gyrase and TOPO IV (double mutants) are resistant to most fluoroquinolones.

Gemifloxacin is the only fluoroquinolone which has the ability to inhibit both enzyme systems (dual targeting of both DNA Gyrase & TOPO IV) at therapeutically relevant drug levels in S. pneumoniae, and has MIC values that are still in the susceptible range for some of these double mutants. Inhibitory activities of fluoroquinolones against S. pneumoniae DNA gyrase and topoisomerase IV (TOPO IV)

IC50 (µM)† Fluoroquinolone DNA Gyrase DNA Topoisomerase IV Gemifloxacin 5-10 2.5-5 Moxifloxacin 20 10 Gatifloxacin 20-40 10-20 Levofloxacin 80 40

(†Inhibitory concentration (IC50) is the concentration at which 50% of the activity of a target enzyme is inhibited. The lower the IC50, the greater the inhibitory effect)

Less risk of development of resistance Compared to other fluoroquinolones, resistance to gemifloxacin is low as the resistance is via multistep mutations and efflux. The frequency of spontaneous mutation is low (10^-7 to <10^-10). Some microorganisms resistant to other fluoroquinolones may be susceptible to gemifloxacin.

[edit] Indication and usage

GEMIMAC is indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions listed below. Success has been achieved in the treatment of viral fever with Gemimac with good patient compliance. Acute bacterial exacerbation of chronic bronchitis caused by S. pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or Moraxella catarrhalis. Community-acquired pneumonia (of mild to moderate severity) caused by S. pneumoniae (including multi-drug resistant strains, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, Chlamydia pneumoniae, or Klebsiella pneumoniae.

Dose is 320 mg to be taken orally