Moxifcin Mechanism of Action

Pharmacotherapeutic group: Quinolone antibacterials, fluoroquinolones. ATC code: J01MA14.
Pharmacodynamics: Mechanism of action: Moxifloxacin is active against a wide range of Gram-positive and Gram-negative pathogens.
The bactericidal action of moxifloxacin results from the inhibition of both type II topoisomerases (DNA gyrase and topoisomerase IV) required for bacterial DNA replication, transcription and repair. It appears that the C8-methoxy moiety contributes to enhanced activity and lower selection of resistant mutants of Gram-positive bacteria compared to the C8-H moiety. The presence of the bulky bicycloamine substituent at the C-7 position prevents active efflux, associated with the norA or pmrA genes seen in certain Gram-positive bacteria.
Moxifloxacin exhibits a concentration dependent killing rate.
Mechanism of resistance: Resistance mechanisms that inactivate penicillins, cephalosporins, aminoglycosides, macrolides and tetracyclines do not interfere with the antibacterial activity of moxifloxacin. Other resistance mechanisms such as permeation barriers (common in Pseudomonas aeruginosa) and efflux mechanisms may also effect susceptibility to moxifloxacin.
Moxifloxacin is a poor substrate for active efflux mechanisms in Gram-positive organisms.
Moxifloxacin inhibits both topoisomerase II and IV with similar activity in some Gram-positive bacteria, such bacteria may be resistant to other quinolones, but susceptible to moxifloxacin.
Microbiological Susceptibility: The prevalence of acquired resistance may vary geographically and with time for selected species and local information of resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought where the local prevalence of resistance is such that utility of the agent in at least some types of infections is questionable.
Pharmacokinetics: Absorption and Bioavailability: Following oral administration moxifloxacin is rapidly and almost completely absorbed. The absolute bioavailability amounts to approximately 91%.
Pharmacokinetics are linear in the range of 50 - 800 mg single dose and up to 600 mg once daily dosing over 10 days. Following a 400 mg oral dose peak concentrations of 3.1 mg/l are reached within 0.5 - 4 h post administration. Peak and trough plasma concentrations at steady-state (400 mg once daily) were 3.2 and 0.6 mg/l, respectively. At steady-state the exposure within the dosing interval is approximately 30% higher than after the first dose.
Distribution: Moxifloxacin is distributed to extravascular spaces rapidly; after a dose of 400 mg an AUC of 35 mgh/l is observed. The steady state volume of distribution (Vss) is approximately 2 l/kg. Moxifloxacin shows protein binding of approximately 40 - 42% independent of the concentration of the drug. Moxifloxacin is mainly bound to serum albumin.
Biotransformation: Moxifloxacin undergoes Phase II biotransformation and is excreted via renal and biliary/faecal pathways as unchanged drug as well as in the form of a sulpho-compound (M1) and a glucuronide (M2), both are microbiologically inactive.
Elimination: Moxifloxacin is eliminated from plasma with a mean terminal half-life of approximately 12 hours.
Concomitant administration of moxifloxacin with ranitidine or probenecid did not alter renal clearance of the parent drug.
Elderly and patients with low body weight: Higher plasma concentrations are observed in healthy volunteers with low body weight (such as women) and in elderly volunteers.
Renal impairment: The pharmacokinetic properties of moxifloxacin are not significantly different in patients with renal impairment (including creatinine clearance >20ml/min/1.73m²). As renal function decreases, concentrations of the M2 metabolite (glucuronide) increase by up to a factor of 2.5 (with a creatine clearance of <30ml/min/1.73m²).
Hepatic impairment: On the basis of the pharmacokinetic studies carried out so far in patients with liver failure (Child Pugh A, B), it is not possible to determine whether there are any differences compared with healthy volunteers. Impaired liver function was associated with higher exposure to M1 in plasma, whereas exposure to parent drug was comparable to exposure in healthy volunteers. There is insufficient experience in the clinical use of moxifloxacin in patients with impaired liver function.