Pharmacological evaluation of a 5-fold incremented dosage of the ivermectin+fenbendazole combination against highly resistant Haemonchus contortus in lambs

Abstract

The combination of nematodicidal compounds from different chemical groups has been proposed as a strategy to delay the development of resistance.Previous studies involving ivermectin (IVM) and albendazole demonstrated that the enhanced systemic exposure achieved after their administration at high doses correlated to a significant increment in drug efficacy against resistant Haemonchus contortus. The aims of the current trial were: a) to characterise the plasma pharmacokinetic (PK) behaviour of IVM and fenbendazole (FBZ) administered either alone or co-administered to lambs (therapeutic dose x5) and, b) to compare the clinical efficacy of IVM and FBZ given separately (therapeutic dose x5) or co-administered to lambs naturally infected with gastrointestinal nematodes resistant to both molecules. Forty (40) lambs naturally infected with resistant nematodes were allocated into four groups (n=10) and orally treated either with IVM (1 mg/kg), FBZ (25 mg/kg) or with a combined formulation of IVM+FBZ (at the same x5 dose rate). An untreated control group (n=10) was included to assess the comparative clinical anthelmintic efficacy (14 days post-treatment) of the different treatments by the faecal egg count reduction test (FECRT). Additionally, faecal samples were cultured to determine nematode genus/species. The Kruskal-Wallis test was applied for the statistical comparison (P<0.05). The presence of IVM did not change the systemic availability of oxfendazole, main FBZ plasma metabolite, after the combined administration of IVM+FBZ. However, the IVM plasma systemic exposure (expressed as AUC) obtained after its oral co-administration with FBZ was 50% higher compared to that observed after the IVM alone administration. FECRT values were 55% (IVM), 41% (FBZ) and 67% (IVM+FBZ). No differences (P>0.05) were observed on faecal egg counts among treated animals. The faecal cultures showed H. contortus as the main nematode specie surviving all treatments. The combined administration of IVM+FBZ at 5 times the therapeutic dose did not improve the clinical efficacy against a highly resistant H. contortus strain.