Otologicals – Corticosteroids and anti-infectives in combination.

The veterinary medicinal product is a fixed combination of three active substances (antibiotic, antifungal and corticosteroid).

Gentamicin is an aminoglycoside bactericidal, concentration dependent antibiotic which acts by inhibiting protein synthesis. Its spectrum of activity includes Gram-positive and Gram-negative bacteria, such as the following pathogenic organism isolated from the ears of dogs: Staphylococcus pseudintermedius.

Bacterial resistance to aminoglycosides can be mediated by aminoglycoside modifying enzymes, such as acetyltransferases, phosphotransferases and nucleotidyltransferases, by reduced drug uptake or active efflux mechanisms and by target modification, such as 16S rRNA methylation. Aminoglycoside resistance determinants are often located on mobile genetic elements.

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

Table 2: MIC range, MIC50 and MIC90 of posaconazole determined for Malassezia pachydermatis isolates (n=50).

All isolates, collected from dogs between 2017 and 2020 in different European countries, were epidemiologically unrelated.

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 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 45, and levels remaining detectable until day 45.