Mechanism of Action
The bactericidal action of moxifloxacin results from inhibition of the topoisomerase II (DNA gyrase) and topoisomerase IV required for bacterial DNA replication, transcription, repair, and recombination.
The mechanism of action for fluoroquinolones, including moxifloxacin, is different from that of macrolides, beta-lactams, aminoglycosides, or tetracyclines; therefore, microorganisms resistant to these classes of drugs may be susceptible to moxifloxacin. Resistance to fluoroquinolones occurs primarily by a mutation in topoisomerase II (DNA gyrase) or topoisomerase IV genes, decreased outer membrane permeability or drug efflux. In vitro resistance to moxifloxacin develops slowly via multiple-step mutations. Resistance to moxifloxacin occurs in vitro at a general frequency of between 1.8 x 10 -9 to < 1 × 10 -11 for Gram-positive bacteria.
Cross-resistance has been observed between moxifloxacin and other fluoroquinolones against Gram-negative bacteria. Gram-positive bacteria resistant to other fluoroquinolones may, however, still be susceptible to moxifloxacin. There is no known cross-resistance between moxifloxacin and other classes of antimicrobials.
Moxifloxacin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections [see Indications and Usage (1)].
Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP] 1)
- MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates previously known as PRSP (Penicillin-resistant S. pneumoniae), and are isolates resistant to two or more of the following antibiotics: penicillin (MIC) ≥2 mcg/mL), 2nd generation cephalosporins (for example, cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole.
The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for moxifloxacin against isolates of similar genus or organism group. However, the efficacy of Moxifloxacin Tablets in treating clinical infections due to these bacteria has not been established in adequate and well controlled clinical trials.
Streptococcus viridans group
Susceptibility Tests Methods
For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.
Long term studies in animals to determine the carcinogenic potential of moxifloxacin have not been performed.
Moxifloxacin was not mutagenic in 4 bacterial strains (TA 98, TA 100, TA 1535, TA 1537) used in the Ames Salmonella reversion assay. As with other fluoroquinolones, the positive response observed with moxifloxacin in strain TA 102 using the same assay may be due to the inhibition of DNA gyrase. Moxifloxacin was not mutagenic in the CHO/HGPRT mammalian cell gene mutation assay. An equivocal result was obtained in the same assay when v79 cells were used. Moxifloxacin was clastogenic in the v79 chromosome aberration assay, but it did not induce unscheduled DNA synthesis in cultured rat hepatocytes. There was no evidence of genotoxicity in vivo in a micronucleus test or a dominant lethal test in mice.
Moxifloxacin had no effect on fertility in male and female rats at oral doses as high as 500 mg/kg/day, approximately 12 times the maximum recommended human dose based on body surface area) or at intravenous doses as high as 45 mg/kg/day, approximately equal to the maximum recommended human dose based on body surface area). At 500 mg/kg orally there were slight effects on sperm morphology (head-tail separation) in male rats and on the estrous cycle in female rats.
Fluoroquinolones have been shown to cause arthropathy in immature animals. In studies in juvenile dogs oral doses of moxifloxacin 30 mg/kg/day or more (approximately 1.5 times the maximum recommended human dose based upon systemic exposure) for 28 days resulted in arthropathy. There was no evidence of arthropathy in mature monkeys and rats at oral doses up to 135 and 500 mg/kg/day, respectively.
Moxifloxacin at an oral dose of 300 mg/kg did not show an increase in acute toxicity or potential for CNS toxicity (for example, seizures) in mice when used in combination with NSAIDs such as diclofenac, ibuprofen, or fenbufen. Some fluoroquinolones have been reported to have proconvulsant activity that is exacerbated with concomitant use of NSAIDs.
A QT-prolonging effect of moxifloxacin was found in dog studies, at plasma concentrations about five times the human therapeutic level. The combined infusion of sotalol, a Class III antiarrhythmic agent, with moxifloxacin induced a higher degree of QTc prolongation in dogs than that induced by the same dose (30 mg/kg) of moxifloxacin alone. Electrophysiological in vitro studies suggested an inhibition of the rapid activating component of the delayed rectifier potassium current (I Kr ) as an underlying mechanism.
No signs of local intolerability were observed in dogs when moxifloxacin was administered intravenously. After intra-arterial injection, inflammatory changes involving the peri-arterial soft tissue were observed suggesting that intra-arterial administration of moxifloxacin should be avoided.
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