Quinolone antibacterials, fluoroquinolones. ATC Code:
Moxifloxacin is a fluoroquinolone antibacterial.
Mechanism of action: In vitro,
moxifloxacin has been shown to have activity against a wide range of Gram-positive and Gram-negative pathogens.
The bacterial action results from the interference with topoisomerase II (DNA Gyrase) and IV. Topoisomerases are essential enzymes which play a crucial part in the replication, transcription and repair of bacterial DNA. Topoisomerase IV is also known to influence bacterial chromosome division.
Kinetic investigations have demonstrated that moxifloxacin exhibits a concentration dependent killing rate. Minimum bacterial concentrations (MBC) were found to be the range of the minimum inhibitory concentration (MIC).
See Table 1.
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Interference with culture test:
Moxifloxacin therapy may give false negative culture results for Mycobacterium
spp. By suppression of mycobacterial growth.
Effect on the intestinal flora in humans:
The following changes in the intestinal flora were seen in volunteers following administration of moxifloxacin: E. coli, Bacillus
spp. were reduced, as were the anaerobes Bacteroides vulgatus, Bifidobacterium, Eubacterium,
For B. fragilis
there was an increase. These changes returned to normal within two weeks. There was no selection of Clostridium difficile
2 mg/l) and its toxin under the administration of moxifloxacin. Moxifloxacin is not indicated for the treatment of Clostridium difficile.
The prevalence of resistance may vary geographically and with time for selected species and local area information on resistance is desirable, particularly when treating severe infections. The in vitro
susceptibility information as follows gives only approximate guidance on probabilities whether micro-organisms will be susceptible to moxifloxacin or not.
In vitro Susceptible Data:
Breakpoints S ≤1 mg/l, R >2 mg/l). (See Table 2.)
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Resistance: Resistance mechanisms which inactive penicillins, cephalosporins, aminoglycosides, macrolides and tetracyclines do not interfere with the antibacterial activity of moxifloxacin. Other resistance mechanisms such as permeation barriers (common, for example, in Pseudomonas aeruginosa
) and efflux mechanisms may, however, also effect the sensitivity of corresponding bacteria to moxifloxacin. Apart from there is no cross-resistance between moxifloxacin and aforementioned compound classes. Plasmid-mediated resistance has not been observed. Laboratory tests on the development of resistance against moxifloxacin in Gram-positive bacteria revealed that resistance develops slowly by multiple step mutations and is mediated by target site modifications (i.e. in topoisomerase II and IV) and efflux mechanisms. The frequency of resistance development is low (rate 10-7
Parallel resistance is observed with other quinolones. However, as moxifloxacin inhibits both topoisomerases (II & IV) in Gram-positive organisms, some Gram-positive bacteria and anaerobes that are resistant to other quinolones may be susceptible to moxifloxacin.
Pharmacokinetics: Absorption and Bioavailability:
Following oral administration moxifloxacin is rapidly and almost completely absorbed. The absolute bioavailability amounts to approximately 90% after oral administration of a 400 mg dose.
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.
Moxifloxacin is distributed to extravascular spaces rapidly; after a dose of 400 mg an AUC of 35 mg.h/l is observed. The steady-state volume distribution (Vss) is approximately 2 l/kg. In vitro and ex vivo experiments showed a protein binding of approximately 40-42% independent of the concentration of the drug. Moxifloxacin is mainly bound to serum albumin.
The following peak concentrations (geometric mean) were observed following administration of a single dose of 400 mg moxifloxacin: See Table 3.
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Moxifloxacin undergoes Phase II biotransformation and is excreted via renal and biliary/faecal pathways as unchanged drug as well as in the form of sulpho-compound (M1) and a glucuronide (M2). M1 and M2 are the only metabolites relevant in humans, both are microbiologically inactive.
In clinical Phase I and in vitro
studies no metabolic pharmacokinetic interactions with other drugs under Phase I biotransformation involving Cytochrome P-450 enzymes were observed. There is no indication of oxidative metabolism.
Moxifloxacin is eliminated from plasma with a mean terminal half life of approximately 12 hours. The mean apparent total body clearance following a 400 mg dose range from 179 to 246 ml/min. Renal clearance amounted to about 24-53 ml/min suggesting partial tubular reabsorption of the drug from the kidneys. After a 400 mg dose, recovery from urine (approx. 19% for unchanged drug, approx. 2.5% for M1, and approx. 14% for M2) and faeces (approx. 25% of unchanged drug, approx. 36% for M1, and no recover for M2) totalled to approximately 96%.
Concomitant administration of moxifloxacin with ranitidine or probenecid did not alter renal clearance of the parent drug.
Higher plasma concentrations are observed in healthy volunteers with low body weight (such as women) and in elderly volunteers.
The pharmacokinetic properties of moxifloxacin are not significantly different in patients with renal impairment (including creatinine clearance >20 ml/min/1.73 m2
). As renal function decreases, concentrations of the M2 metabolite (glucuronide) increase by up to a factor of 2.5 (with a creatinine clearance of <30 mL/min/1.73 m2
). No information is available on the use of moxifloxacin in patients with a creatinine clearance of <30 ml/min/1.73 m2
and renal dialysis patients.
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.
Toxicology: Preclinical safety data:
Effects on the haematopoetic system (slight decreases in the number of erythrocytes and platelets) were seen in rats and monkeys. As with other quinolones, hepatotoxicity (elevated liver enzymes and vacuolar degeneration) was seen in rats, monkeys and dogs. In monkeys CNS toxicity (convulsions) occurred. These effect were seen only after treatment with high doses of moxifloxacin or after prolonged treatment.
Moxifloxacin, like other quinolones, was genotoxic in in vitro
test using bacteria or mammalian cells. Since these effects can be explained by an interaction with gyrase in bacteria and - at higher concentrations - by an interaction with the topoisomerase II in mammalian cells, a threshold concentration for genotoxicity can be assumed. In in vivo
tests, no evidence of genotoxicity was found despite the fact that very high moxifloxacin dose were used. Thus, a sufficient margin of safety to therapeutic dose in man can be provided. Moxifloxacin was non-carcinogenic in an initiation-promotion study in rats.
Many quinolones are photo-reactive and can induce phototoxic, photomutagenic and photocarcinogenic effects. In contrast, moxifloxacin was proven to be avoided of phototoxic and photogenotoxic properties when tested in a comprehensive programme of in vitro
and in vivo
studies. Under the same conditions other quinolones induced effects.
At higher concentrations, moxifloxacin is an inhibitor of the delayed rectifier potassium current of the heart and may thus cause prolongations of the QT-INTERVAL Toxicological studies performed in dogs using oral doses of >90 mg/kg leading to plasma concentrations ≥16 mg/l caused QT-prolongations, but arrythmias. Only after very high cumulative intravenous administration of more than 50-fold the human dose (>300 mg/kg), leading to plasma concentrations of ≥200 mg/l (more than 40-fold the therapeutic level), reversible, non-fatal ventricular arrythmias were seen.
Quinolones are known to cause lesions in the cartilage of the major diarthrodial joints in immature animals. The lowest oral dose of moxifloxacin causing joint toxicity in juvenile dogs was four times the maximum recommended therapeutic dose of 400 mg (assuming a 50 kg bodyweight) on a mg/kg basis, with plasma concentrations two to three times higher than those at the maximum therapeutic dose.
Toxicity tests in rats and monkeys (repeated dosing up to six months) revealed no indicating regarding an oculotoxic risk. In dogs, high oral doses (≥60 mg/kg) leading to plasma concentration ≥20 mg/l caused changes in the electroretinogram and isolated cases an atrophy of the retina.
Reproductive studies performed in rats and monkeys indicate that placental transfer of moxifloxacin occurs. Studies in these species did not show evidence of teratogenicity or impairment of fertility following administration of moxifloxacin. Skeletal malformations were observed in rabbits that had been treated with an intravenous dose of 20 mg/kg. This study result is consistent with the known effects of quinolones on skeletal development. There was an increase in the incidence of abortions in monkeys and rabbits at human therapeutic plasma concentrations. In rats, decreased foetal weights, an increased pre-natal loss, a slightly increases duration of pregnancy and increases spontaneous activity of some male and female offspring was observed at doses which were 63 times the maximum recommended dose on a mg/kg basis with plasma concentrations in the range of the human therapeutic dose.