ATCvet code: QS02CA91
Pharmacodynamic properties
The veterinary medicinal product is a fixed combination of three active substances (antibiotic, antifungal and corticosteroid).
Gentamicin is an aminoglycoside bactericidal, concentration-dependent antibiotic. Its mechanism of action involves inhibition of bacterial protein synthesis by binding to 30S ribosomes. In S. pseudintermedius, the most common mechanism of antimicrobial resistance is the production of aminoglycoside modifying enzymes encoded by the transposon-borne resistance genes, aac(6')-aph(2"), conferring cross-resistance to all aminoglycosides with the exception of streptomycin. In addition, co-resistance selection of resistance against other classes of antibiotics is commonly seen (including tetracyclines, oxacillin (MRSP), macrolides etc) in various bacterial species including S. pseudintermedius (e.g. MRSP).
Posaconazole is a broad-spectrum triazole antifungal agent. The mechanism by which posaconazole exerts fungicidal action involves the selective inhibition of the enzyme lanosterol 14-demethylase (CYP51) involved in ergosterol biosynthesis in yeasts and filamentous fungi. In in vitro tests, posaconazole has shown fungicidal activity against most of the approximately 7,000 strains of yeast and filamentous fungi tested. Posaconazole is 40 – 100 times more potent in vitro against Malassezia pachydermatis than clotrimazole, miconazole, nystatin and terbinafine.
The most common mechanisms of resistance to azoles in clinical isolates are alterations in lanosterol 14α-demethylase biosynthesis (e.g. by mutations), increased production of this enzyme or increased efflux (e.g. by ABC transporters or major facilitators). Posaconazole is not an MDR1 major facilitator substrate.
Mometasone furoate is a corticosteroid with high topical potency, but few systemic effects. Like other topical corticosteroids, it has anti-inflammatory and anti-pruritic properties.
Table 1:
Minimum Inhibitory Concentration (MIC) range, MIC50 and MIC90 of gentamicin determined for Staphylococcus pseudintermedius isolates (n=50).
Species | MIC range μg/ml | MIC50 μg/ml | MIC90 μg/ml |
Staphylococcus pseudintermedius pseudintermedius isolates (n=50). | ≤ 0.063 - 16 | 0.125 | 0.25 |
Table 2:
MIC range, MIC50 and MIC90 of posaconazole determined for Malassezia pachydermatis isolates (n=50).
Species | MIC range | MIC50 | MIC90 |
Malassezia pachydermatis | ≤ 0.016 | ≤0.016 | ≤0.016 |
All isolates were collected from dogs between 2017 and 2020 in different European countries and were epidemiologically unrelated.
Pharmacokinetic particulars
Systemic absorption and depletion from the ear wax of the three active substances was determined after a single administration of the recommended dose into both ear canals of healthy beagle dogs. Plasma and ear wax concentrations were measured at 1, 7, 14, 21, 30, and 45 days post-administration.
Systemic exposure was only detected at 1-day post-administration with low plasma concentrations (≤ 7.9 ng/ml) of gentamicin and posaconazole. At 14 days and 45 days post-administration, only one dog out of eight was found to have a detectable amount of gentamicin and posaconazole in the plasma, respectively. Plasma concentrations for all other time points for gentamicin and posaconazole were below the limit of quantification. Plasma concentrations of mometasone furoate were below the limit of quantification at every time point.
Gentamicin, posaconazole, and mometasone furoate were detected in ear wax throughout the 45 day study with depletion occurring progressively. From days 1 to 14, concentrations of all three active substances were detectable in all animals. The number of animals with concentrations of active ingredients below the limit of quantification gradually increased (depending on the active ingredient) from one or two animals on day 21 to most of the animals on day 45 days post-administration.
Gentamicin concentrations were above ten times the MIC90 of S. pseudintermedius in the majority of samples for 30 days post treatment.
The extent of transcutaneous absorption of topical medications is determined by many factors including the integrity of the epidermal barrier. The influence on the absorption of the veterinary medicinal product by factors such as inflammation and skin atrophy associated with prolonged treatment with glucocorticoids has not been established.