Chemical formula: C₂₁H₂₄FN₃O₄ Molecular mass: 401.431 g/mol PubChem compound: 152946
Moxifloxacin has in vitro activity 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.
Pharmacodynamic investigations have demonstrated that moxifloxacin exhibits a concentration dependent killing rate. Minimum bactericidal concentrations (MBC) were found to be in the range of the minimum inhibitory concentrations (MIC).
Fluoroquinolones exhibit a concentration dependent killing of bacteria. Pharmacodynamic studies of fluoroquinolones in animal infection models and in human trials indicate that the primary determinant of efficacy is the AUC24/MIC ratio.
The following changes in the intestinal flora were seen in volunteers following oral administration of moxifloxacin: Escherichia coli, Bacillus spp., Enterococcus spp., and Klebsiella spp. were reduced, as were the anaerobes Bacteroides vulgatus, Bifidobacterium spp., Eubacterium spp., and Peptostreptococcus spp.. For Bacteroides fragilis there was an increase. These changes returned to normal within two weeks.
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.
In vitro resistance to moxifloxacin is acquired through a stepwise process by target site mutations in both type II topoisomerases, DNA gyrase and topoisomerase IV. Moxifloxacin is a poor substrate for active efflux mechanisms in Gram-positive organisms.
Cross-resistance is observed with other fluoroquinolones. However, as 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.
EUCAST clinical MIC and disk diffusion breakpoints for moxifloxacin (01.01.2011):
| Organism | Susceptible | Resistant |
|---|---|---|
| Staphylococcus spp. | ≤0.5 mg/l | >1 mg/l |
| ≥24 mm | <21 mm | |
| S. pneumoniae | ≤0.5 mg/l | >0.5 mg/l |
| ≥22 mm | ≥22 mm | |
| Streptococcus Groups A, B, C, G | ≤0.5 mg/l | >1 mg/l |
| ≥18 mm | <15 mm | |
| H. influenzae | ≤0.5 mg/l | ≤0.5 mg/l |
| ≥25 mm | ≥25 mm | |
| M. catarrhalis | ≤0.5 mg/l | >0.5 mg/l |
| ≥23 mm | <23 mm | |
| Enterobacteriaceae | ≤0.5 mg/l | >1 mg/l |
| ≥20 mm | <17 mm | |
| Non-species related breakpoints* | ≤0.5 mg/l | >1 mg/l |
* Non-species related breakpoints have been determined mainly on the basis of pharmacokinetic/pharmacodynamic data and are independent of MIC distributions of specific species. They are for use only for species that have not been given a species-specific breakpoint and are not for use with species where interpretative criteria remain to be determined.
There are no pharmacological data correlated with clinical outcome for moxifloxacin administered as a topical agent. As a result, the European Committee on Antimicrobial Susceptibility Testing (EUCAST) suggests the following epidemiological cut-off values (ECOFF mg/l) derived from MIC distribution curves to indicate susceptibility to topical moxifloxacin:
| Corynebacterium | ND |
|---|---|
| Staphylococcus aureus | 0.25 mg/l |
| Staphylococcus, coag-neg. | 0.25 mg/l |
| Streptococcus pneumoniae | 0.5 mg/l |
| Streptococcus pyogenes | 0.5 mg/l |
| Streptococcus, viridans group | 0.5 mg/l |
| Enterobacter spp. | 0.25 mg/l |
| Haemophilus influenzae | 0.125 mg/l |
| Klebsiella spp. | 0.25 mg/l |
| Moraxella catarrhalis | 0.25 mg/l |
| Morganella morganii | 0.25 mg/l |
| Neisseria gonorrhoeae | 0.032 mg/l |
| Pseudomonas aeruginosa | 4 mg/l |
| Serratia marcescens | 1 mg/l |
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.
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.
After a single 400 mg intravenous 1 hour infusion peak plasma concentrations of approximately 4.1 mg/l were observed at the end of the infusion corresponding to a mean increase of approximately 26% relative to those seen after oral administration (3.1 mg/l). The AUC value of approximately 39 mg•h/l after i.v. administration is only slightly higher than that observed after oral administration (35 mg•h/l) in accordance with the absolute bioavailability of approximately 91%.
In patients, there is no need for age or gender related dose adjustment on intravenous moxifloxacin.
Pharmacokinetics are linear in the range of 50-1200 mg single oral dose, up to 600 mg single intravenous dose and up to 600 mg once daily dosing over 10 days.
Moxifloxacin is distributed to extravascular spaces rapidly. The steady-state volume of 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.
Maximum concentrations of 5.4 mg/kg and 20.7 mg/l (geometric mean) were reached in bronchial mucosa and epithelial lining fluid, respectively, 2.2 h after an oral dose. The corresponding peak concentration in alveolar macrophages amounted to 56.7 mg/kg. In skin blister fluid concentrations of 1.75 mg/l were observed 10 h after intravenous administration. In the interstitial fluid unbound concentration time profiles similar to those in plasma were found with unbound peak concentrations of 1.0 mg/l (geometric mean) reached approximately 1.8 h after an intravenous dose.
The following peak concentrations (geometric mean) were observed following administration of a single oral dose of 400 mg moxifloxacin:
| Tissue | Concentration | Site: Plasma ratio |
|---|---|---|
| Plasma | 3.1 mg/l | - |
| Saliva | 3.6 mg/l | 0.75-1.3 |
| Blister fluid | 1.61 mg/l | 1.71 |
| Bronchial mucosa | 5.4 mg/kg | 1.7-2.1 |
| Alveolar macrophages | 56.7 mg/kg | 18.6-70.0 |
| Epithelial lining fluid | 20.7 mg/l | 5-7 |
| Maxillary sinus | 7.5 mg/kg | 2.0 |
| Ethmoid sinus | 8.2 mg/kg | 2.1 |
| Nasal polyps | 9.1 mg/kg | 2.6 |
| Interstitial fluid | 1.02 mg/l | 0.8-1.42,3 |
| Female genital tract* | 10.24 mg/kg | 1.724 |
* intravenous administration of a single 400 mg dose
1 10 h after administration
2 unbound concentration
3 from 3 h up to 36 h post dose
4 at the end of infusion
Moxifloxacin undergoes Phase II biotransformation and is excreted via renal (approximately 40%) and biliary/faecal (approximately 60%) pathways as unchanged drug as well as in the form of a 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 undergoing Phase I biotransformation involving cytochrome P450 enzymes were observed. There is no indication of oxidative metabolism.
After a 400 mg dose, recovery from urine (approximately 19% for unchanged drug, approximately 2.5% for M1, and approximately 14% for M2) and faeces (approximately 25% of unchanged drug, approximately 36% for M1, and no recovery for M2) totalled to approximately 96%.
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 ranges from 179 to 246 ml/min. Following a 400 mg intravenous infusion recovery of unchanged drug from urine was approximately 22% and from faeces approximately 26%. Recovery of the dose (unchanged drug and metabolites) totalled to approximately 98% after intravenous administration of the drug. Renal clearance amounted to about 24-53 ml/min suggesting partial tubular reabsorption of the drug from the kidneys. Concomitant administration of moxifloxacin with ranitidine or probenecid did not alter renal clearance of the parent drug.
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 ranges 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.
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).
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.
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 effects were seen only after treatment with high doses of moxifloxacin or after prolonged treatment.
Moxifloxacin, like other quinolones, was genotoxic in in vitro tests using bacteria or mammalian cells. Since these effects can be explained by an interaction with the 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 doses were used. Thus, a sufficient margin of safety to the therapeutic dose in man can be provided. Moxifloxacin was non-carcinogenic in an initiation-promotion study in rats.
Many quinolones are photoreactive and can induce phototoxic, photomutagenic and photocarcinogenic effects. In contrast, moxifloxacin was proven to be devoid 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 high concentrations, moxifloxacin is an inhibitor of the rapid component 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 no arrhythmias. Only after very high cumulative intravenous administration of more than 50fold the human dose (>300 mg/kg), leading to plasma concentrations of ≥200 mg/l (more than 40fold the therapeutic level), reversible, non-fatal ventricular arrhythmias 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 indication regarding an oculotoxic risk. In dogs, high oral doses (≥60 mg/kg) leading to plasma concentrations ≥20 mg/l caused changes in the electroretinogram and in isolated cases an atrophy of the retina.
Reproductive studies performed in rats, rabbits and monkeys indicate that placental transfer of moxifloxacin occurs. Studies in rats (p.o. and i.v.) and monkeys (p.o.) did not show evidence of teratogenicity or impairment of fertility following administration of moxifloxacin. A slightly increased incidence of vertebral and rib malformations was observed in foetuses of rabbits but only at a dose (20 mg/kg i.v.) which was associated with severe maternal toxicity. 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 prenatal loss, a slightly increased duration of pregnancy and an increased 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.
In conventional repeated dose studies moxifloxacin revealed haematological and hepatic toxicity in rodents and non-rodents. Toxic effects on the CNS were observed in monkeys. These effects occurred after the administration of high doses of moxifloxacin or after prolonged treatment.
In dogs, high oral doses (≥60 mg/kg) leading to plasma concentrations ≥ 20 mg/l caused changes in the electroretinogram and in isolated cases an atrophy of the retina.
After intravenous administration findings indicative of systemic toxicity were most pronounced when moxifloxacin was given by bolus injection (45 mg/kg) but they were not observed when moxifloxacin (40 mg/kg) was given as slow infusion over 50 minutes.
After intra-arterial injection inflammatory changes involving the peri-arterial soft tissue were observed suggesting that intra-arterial administration of moxifloxacin should be avoided.
Moxifloxacinwas genotoxic in in vitro tests using bacteria or mammalian cells. In in vivo tests, no evidence of genotoxicity was found despite the fact that very high moxifloxacin doses were used. Moxifloxacin was non-carcinogenic in an initiation-promotion study in rats.
In vitro, moxifloxacin revealed cardiac electrophysiological properties that can cause prolongation of the QT interval, even though at high concentrations.
After intravenous administration of moxifloxacin to dogs (30 mg/kg infused over 15, 30 or 60 minutes) the degree of QT prolongation was clearly depending on the infusion rate, i.e. the shorter the infusion time the more pronounced the prolongation of the QT interval. No prolongation of the QT interval was seen when a dose of 30 mg/kg was infused over 60 minutes.
Reproductive studies performed in rats, rabbits and monkeys indicate that placental transfer of moxifloxacin occurs. Studies in rats (p.o. and i.v.) and monkeys (p.o.) did not show evidence of teratogenicity or impairment of fertility following administration of moxifloxacin. A slightly increased incidence of vertebral and rib malformations was observed in foetuses of rabbits but only at a dose (20 mg/kg i.v.) which was associated with severe maternal toxicity. There was an increase in the incidence of abortions in monkeys and rabbits at human therapeutic plasma concentrations.
Quinolones, including moxifloxacin, are known to cause lesions in the cartilage of the major diarthrodial joints in immature animals.
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure following administration to the eye indicating little relevance to clinical use.
As with other quinolones, moxifloxacin was also genotoxic in vitro in bacteria and mammalian cells. As these effects can be traced to the interaction with bacterial gyrase and in considerably higher concentrations to the interaction with topoisomerase II in mammalian cells, a threshold level for genotoxicity can be assumed. In in vivo tests, no evidence of genotoxicity was found, despite high doses of moxifloxacin. The therapeutic doses for human use therefore provide adequate safety margin. No indication of a carcinogenic effect was observed in an initiation promotion model in rats.
Unlike other quinolones, moxifloxacin showed no phototoxic or photogenotoxic properties in extensive in vitro and in vivo studies.
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