Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Bayer plc, 400 South Oak Way, Reading RG2 6AD
Pharmacotherapeutic group: Quinolone antibacterials, fluoroquinolones
ATC code: J01MA14
Moxifloxacin inhibits bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) that are required for bacterial DNA replication, transcription and repair.
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.
Resistance to fluoroquinolones can arise through mutations in DNA gyrase and topoisomerase IV. Other mechanisms may include over-expression of efflux pumps, impermeability, and protein-mediated protection of DNA gyrase. Cross resistance should be expected between moxifloxacin and other fluoroquinolones.
The activity of moxifloxacin is not affected by mechanisms of resistance that are specific to antibacterial agents of other classes.
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 | >1mg/l |
| ≥20 mm | <17 mm | |
| Non-species related breakpoints* | ≤0.5 mg/l | >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.
Aerobic Gram-positive micro-organisms:
Staphylococcus aureus*+
Streptococcus agalactiae (Group B)
Streptococcus milleri group* (S. anginosus, S. constellatus and S. intermedius)
Streptococcus pneumoniae*
Streptococcus pyogenes* (Group A)
Streptococcus viridans group (S. viridans, S. mutans, S. mitis, S. sanguinis, S. salivarius, S. thermophilus)
Aerobic Gram-negative micro-organisms:
Acinetobacter baumanii
Haemophilus influenzae*
Legionella pneumophila
Moraxella (Branhamella) catarrhalis*
Anaerobic micro-organisms:
Prevotella spp.
“Other” micro-organismsChlamydophila (Chlamydia) pneumoniae:*
Coxiella burnetii
Mycoplasma pneumoniae*
Aerobic Gram-positive micro-organisms:
Enterococcus faecalis*
Enterococcus faecium*
Aerobic Gram-negative micro-organisms:
Enterobacter cloacae*
Escherichia coli*#
Klebsiella oxytoca
Klebsiella pneumoniae*#
Proteus mirabilis*
Anaerobic micro-organisms:
Bacteroides fragilis*
Aerobic Gram-negative micro-organisms:
Pseudomonas aeruginosa
* Activity has been satisfactorily demonstrated in clinical studies.
+ Methicillin resistant S. aureus have a high probability of resistance to fluoroquinolones. Moxifloxacin resistance rate of >50% have been reported for methicillin resistant S. aureus.
# ESBL-producing strains are commonly also resistant to fluoroquinolones.
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.
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.
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.
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.
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.
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