Source: Health Products Regulatory Authority (IE) Revision Year: 2018 Publisher: Ferrer Internacional, S.A., Gran Vía Carlos III, 94, 08028, Barcelona, Spain
Pharmacotherapeutic group: Antibiotics and chemotherapeutics for dermatological use, Antibiotics for topical use
ATC code: D06AX14
Ozenoxacin is a non-fluorinated quinolone with a dual inhibitory activity against bacterial DNA replication enzymes, DNA gyrase A and topoisomerase IV. This effect is mediated by the ability of quinolones to stabilize complexes of DNA and both DNA gyrase and topoisomerase IV thus, blocking progression of the replication fork.
The bactericidal activity of ozenoxacin has been demonstrated by the mean of kill curves experiments.
The development of quinolone resistance is caused by point mutations in discrete regions of the DNA gyrase (gyrA) and topoisomerase IV (grlA) genes called the Quinolone Resistance-Determining Regions (QRDR).
Ozenoxacin shows a dual target of action, inhibiting DNA gyrase and topoisomerase IV, showing an ability to inhibit both enzymes. As a result of this inhibitory target activity and bactericidal property, ozenoxacin shows a low frequency of selection of spontaneous resistant mutants.
Against Gram-positive organisms Ozenoxacin has shown no cross-resistance with other families of commercial antibacterial, and retains activities below the breakpoints for mutants resistant to other marketed quinolones.
It is worth noting that ozenoxacin shows the same activity against methicillin-sensitive and methicillin-resistant strains of all studied bacterial species.
Ozenoxacin is characterized by its potency and bactericidal activity against clinical bacterial isolates involved in skin infections, including S. aureus and S. pyogenes. The proposed epidemiological cut off (ECOFF) values for S. aureus and S. pyogenes are of 0.008 and 0.06 µg/ml, respectively. However, the differences in sensitivity to the product between populations are not always related to the clinical breakpoints and the therapeutic properties of the product. For this reason, EUCAST assumes that using ECOFF values might underestimate the activity of some agents in topical preparations.
Commonly susceptible species:
Staphylococcus aureus1
Streptococcus pyogenes1
Staphylococcus capitis*
Staphylococcus epidermidis*
Staphylococcus haemolyticus*
Staphylococcus lundunensis*
Staphylococcus warneii*
MR-Staphylococcus aureus (MRSA)*2
MR-Staphylococcus epidermidis*
MR-coagulase-negative staphylococci (MR-CNS)*
MR-Streptococcus pyogenes*
MR-Streptococcus agalactiae
1 Activity has been satisfactorily demonstrated in clinical studies.
2 In vitro, ozenoxacin was equally active against methicillinsusceptible and methicillinresistant strains of S. aureus. In clinical studies in all the cases the patients have achieved clinical improvement/cure.
* In vitro, ozenoxacin was shown to have a wide spectrum of bactericidal activity, especially against gram-positive bacteria. Ozenoxacin activity extends to strains of bacteria resistant to other antibiotics including mupirocin, quinolones and methicillin.
Two multicenter, randomized, blind clinical trials have been performed to compare the efficacy of ozenoxacin 10 mg/g cream to placebo for the treatment of impetigo in adult and paediatric population (one included retapamulin as an internal control).
| Total | Ozenoxacin | Placebo | |
|---|---|---|---|
| N | 723 | 361 | 362 |
| 0-6 months | 4 (0.5%) | 1(0.3%) | 3 (0.8%) |
| 6 months - <2 years | 24 (3.3%) | 11 (3.0%) | 13 (3.6%) |
| 2 years - <12 years | 387 (53.5%) | 196 (54.3%) | 191 (52.8%) |
| 12 years - <18 years | 83 (11.5%) | 42 (11.6%) | 41 (11.3%) |
| ≥18 years | 225 (31.1%) | 111 (30.7%) | 114 (31.5%) |
Clinical Response:
| Ozenoxacin | Placebo | |||
|---|---|---|---|---|
| Study 1 (N=155) n (%) | Study 2 (N=206) n (%) | Study 1 (N=156) n (%) | Study 2 (N=206) n (%) | |
| Primary Efficacy Endpoint | ||||
| Clinical Success at Visit 3 (day 6-7)a | ||||
| Clinical success | 54 (34.8) | 112 (54.4) | 30 (19.2) | 78 (37.9) |
| Clinical failure | 98 (63.2) | 91 (44.2) | 120 (76.9) | 121 (58.7) |
| Unable to determine | 3 | 3 | 6 | 7 |
a The difference in the success rates was very similar in both clinical trials (approximately 0.16) and statistically significant in both cases, confirming a greater clinical success in the ozenoxacin group than in the placebo group at end of therapy.
The difference in the success rates was statistically significant (difference of 0.165; 95% CI 0.070–0.260; p<0.001).
The most commonly found pathogens were Staphylococcus aureus and Streptococcus pyogenes.
The microbiological success rate was also statistically significant superior for ozenoxacin versus placebo.
The number of patients with bullous impetigo included in ozenoxacin clinical trials was very limited. When the data from the two pivotal trials are pooled, a total of 56 subjects with bullous impetigo were included in the ozenoxacin groups. The pooled clinical response rate in bullous impetigo was 30% (17/56 patients) in the ozenoxacin group and 32% (20/61) in the placebo group. The proportion of subjects in the ozenoxacin 1% cream group who achieved a clinical success in the bullous subgroup was very different among the two studies, 15.6% (5/32) (Study 1) and 50% (12/24) (Study 2), respectively.
Microbiological Response:
| Ozenoxacin | Placebo | |||
|---|---|---|---|---|
| Study 1 (N=154) n (%) | Study 2 (N=125) n (%) | Study 1 (N=152) n (%) | Study 2 (N=119) n (%) | |
| Bacteriological Success (%) at Visit 2 (Day 3-4) | ||||
| Microbiological success | 109 (70.8) | 109 (87.2) | 58 (38.2) | 76 (63.9) |
| Microbiological failure | 37 (24) | 16 (12.8) | 90 (59.2) | 32 (26.9) |
| Unable to determine | 8 | 0 | 4 | 11 |
| Bacteriological Success (%) at Visit 3 (End of Therapy, Day 6-7) | ||||
| Microbiological success | 122 (79.2) | 115 (92) | 86 (56.6) | 87 (73.1) |
| Microbiological failure | 16 (10.4) | 8 (6.4) | 55 (36.2) | 20 (16.8) |
| Unable to determine | 16 | 2 | 11 | 12 |
Few S. aureus infections were resistant to methicillin, ciprofloxacin, mupirocin, fusidic acid, or retapamulin.
No detectable systemic exposure levels were observed in adult healthy volunteers and in adult patients with impetigo following repeated topical application of ozenoxacin 10 mg/g cream for up to 7 days to intact and abraded skin.
Plasma protein binding of [14C]-ozenoxacin was moderate (~80 to 85%) in human and dog plasma and did not appear to be dependent on concentration.
Ozenoxacin was excreted mainly unchanged in animal studies (mini-pigs and rats).
Since no detectable systemic exposure levels were observed in clinical studies, elimination has not been investigated in humans.
No pharmacokinetic data are available in patients with renal or hepatic impairment. However, due to the undetectable systemic plasma levels that have been observed, no safety problems are foreseen.
No detectable systemic exposure levels were observed in any paediatric patient with impetigo (aged >6 months of age) following topical administration of ozenoxacin 10 mg/g cream twice daily for 5 days, with the exception of one patient with blood samples that were very close to the limit of quantitation (0.5 ng/ml).
Topically administered, ozenoxacin was well tolerated. Plasma levels of ozenoxacin after single dermal administration were below LOQ while only low systemic exposure was detected after 28-day dermal administration.
Ozenoxacin was also well tolerated in both intact and abraded skin in minipigs after dermal administration during 28 consecutive days.
In the oral 28-day repeated dose toxicological studies in rats and dogs, where adequate systemic exposure was achieved, the NOAEL was 125 mg/kg/day and 50 mg/kg/day, respectively for each study. Since systemic exposure is negligible, no adverse effects are anticipated.
There was no evidence of mutagenicity/genotoxicity when evaluated in the required standard battery of genotoxicity testing for assessment of the genotoxic potential (Ames test, mouse lymphoma assay and in vivo rat micronucleus assay).
Systemic exposure to ozenoxacin at oral dosages up to 500 mg/kg/day in rats did not induce adverse effects on male or female fertility, parturition, lactation or maternal behavior on F0 generation and did not affect reproductive parameters and growth pattern on F1 generation where quantifiable levels of ozenoxacin in the pup plasma (F1 generation) on day 14 postpartum was demonstrated. In the rabbit, an increase in post-implantation loss and corresponding reduction in live fetuses per litter was observed at 40 mg/kg/day. Furthermore, in rat and rabbit at dosage up to 500 mg/kg/day and 40 mg/kg/day, respectively, during gestation period, a reduction in fetal body weights was observed, which in turn caused delays in skeletal development, but the product did not induce gross, visceral or skeletal fetal anomalies.
In the 2-weeks repeated oral toxicity study in juvenile dogs, where adequate systemic exposure was achieved, the NOAEL was 100 mg/kg/day.
There was no evidence of articular toxicity.
Adverse effects usually related to quinolones, such as phototoxicity, photoallergenic and sensitizer potential have not been observed with ozenoxacin in the non-clinical studies conducted.
Environmental risk assessment studies have shown that ozenoxacin may pose a risk to the aquatic environment.
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