Interaction between bacterial microbiota and nematode parasite communities in sheep's gastrointestinal tract.

The economic impact of gastrointestinal (GI) nematode infections on livestock production is well documented worldwide. Increasing evidence supports the hypothesis that parasite colonization induces significant changes in the GI tract environment and, therefore, in the landscape where the microbiota and parasites occur. Understanding the interactions between bacterial and parasite populations in the digestive tract of livestock may be useful to design parasite control strategies based on microbiota modification. The aims of this work were to investigate the impact of the oxytetracycline-mediated manipulation of the gut microbial community on the composition of GI nematode populations in naturally infected sheep and to explore changes in the GI microbial communities after nematode population treatment with the anthelmintic compound monepantel. Extensive manipulation of the GI microbiota with a therapeutic dose of the long-acting oxytetracycline formulation did not induce significant changes in the GI nematode burden. The gut microbiota of treated animals returned to control levels 17 days after treatment, suggesting strong resilience of the sheep microbial community to antibiotic-mediated microbiota perturbation. A significant decrease of the bacterial Mycoplasmataceae family (Log2FC = -4, Padj = 0.001) and a marked increase of the Methanobacteriaceae family (Log2FC = 2.9, Padj = 0.018) were observed in the abomasum of sheep receiving the monepantel treatment. While a comprehensive evaluation of the interactions among GI mycoplasma, methanobacteria and nematode populations deserves further assessment, the bacteria-nematode population interactions should be included in future control programs in livestock production. Understanding how bacteria and parasites may influence each other in the GI tract environment may substantially contribute to the knowledge of the role of microbiota composition in nematode parasite establishment and the role of the parasites in the microbiota composition.

Comparative assessment of different ivermectin and doramectin formulations for mange control in grazing steers.

Psoroptic mange causes relevant losses of productivity in cattle. Macrocyclic lactones are one of the main pharmacological tools recommended for controlling it. The aim of the current work was to compare the relationship between the pharmacokinetic behavior and the effectiveness of both ivermectin (IVM) and doramectin (DRM) following their administration as either the traditional (1 %) or long-acting (3.15-3.5 %) injectable formulations to cattle naturally infected with Psoroptes ovis. The overall work involved three trials (1, 2 and 3) carried out on commercial beef cattle farms (grazing systems). In Trial 1, 20 grazing steers with active mange infection were allocated into 2 groups (n = 10) and treated subcutaneously (SC) with either IVM (1 %) or DRM (1%) at 0.2 mg/kg. In Trial 2, 16 grazing steers with active mange divided in 2 groups (n = 8) were treated SC with either IVM 1 % (0.2 mg/kg) or IVM 3.15 % long-acting (0.63 mg/kg). In Trial 3, 2 groups of mange infected steers (n = 8) were treated SC with either IVM 3.15 % (0.63 mg/kg) or DRM 3.5 % (0.7 mg/kg). Blood samples were collected of each experimental group and the drug systemic availability was estimated by measuring of IVM/DRM concentrations by HPLC. Skin scraping samples were collected from each animal and mites were counted at 14, 21 and 28 days post-treatment. In Trial 1, the mite density score on day 14 was significantly lower for DRM (0.60) compared to IVM (1.80) (P = 0.019). Based on the number of animals clinically cured (negative to the presence of mites), the efficacy of DRM was higher (80 %) than that obtained for IVM (10 %) (P < 0.05). DRM systemic exposure measured as AUC was 1.37-fold higher compared to IVM. In Trial 2, even though IVM exposure was significantly greater after the long-acting (3.15 %) compared to the traditional formulation (1 %), none of the treatments significantly reduced the mite density score, with a percentage of animals cured between 0 % and 37.5 % after both IVM treatments. In Trial 3, the 100 % of cured animals were achieved at day 21 (IVM 3.15 %) and at day 28 (DRM 3.5 %) post-treatment. In conclusion, DRM treatment could offer some therapeutic advantages in field situations where IVM fails to control mange. Depending on the level of susceptibility of the mite population, long-acting pharmaceutical formulations can be useful to control Psoroptic mange in cattle. The use of macrocyclic lactones for mange control in cattle should be based on appropriate diagnosis on each individual farm.

Pharmacological characterization of geraniol in sheep and its potential use in the control of gastrointestinal nematodes.

Geraniol (GNL) was effective against gastrointestinal nematodes in vitro; nevertheless, the anthelmintic effect of phytochemicals combined with synthetic drugs has been little explored in vivo. This article characterized in vitro / in vivo the pharmacological features of GNL in sheep as well as its pharmacokinetic interaction with albendazole (ABZ). Additionally, the in vivo efficacy of GNL against Haemonchus contortus was evaluated in lambs. Liver microsomes from lambs were incubated in the absence or presence of GNL to analyze CYP1A1, CYP1A2 and FMO metabolic pathways. The effect of GNL on the hepatic sulfoxidation and sulfonation of ABZ and the ruminal sulforeduction of albendazole sulfoxide (ABZSO) was assessed. The in vivo pharmacokinetic interaction of ABZ and GNL was evaluated in lambs. The effect of GNL on the fecal egg count was evaluated in lambs infected with a resistant isolate of H. contortus. In sheep liver microsomes, the presence of 2 mM GNL reduced the CYP1A1, CYP1A2 and FMO pathways by 77.9, 90.8 and 84.5%, respectively, with respect to control (P < 0.05). In the presence of 2 mM GNL, the ABZ sulfoxidation decreased from 114.4 ± 8.49 (control) to 50.24 ± 11.1 nmol/min.mg, and ABZSO2 production decrease from 0.52 ± 0.14 to 0.09 ± 0.03 nmol/h.mg. No changes in the pharmacokinetic behavior of ABZ were observed in the presence of GNL. The in vivo efficacy of four doses of GNL was 40.5%. These findings highlight the importance of integrated in vitro / in vivo pharmaco-parasitological studies to develop new pharmacological tools for controlling gastrointestinal parasites.

Improving the in vitro dissolution rate and pharmacokinetic performance of fenbendazole in sheep using drug nanocrystals.

Benzimidazole methylcarbamate anthelmintics, including fenbendazole (FBZ), have only limited water solubility and small differences in drug solubility may have a major influence on their absorption, pharmacokinetic behavior and anthelmintic efficacy. To improve FBZ water solubility and dissolution rate, novel self-dispersible nanocrystals (SDNCs) of FBZ were recently described. In this work, the pharmacokinetic behavior of the SDNCs of FBZ and Poloxamer 188 was compared against a physical mixture (PM) of its components. The experiment was conducted following a crossover design with two different experimental phases. In phase I, sheep were treated with the SDNC (n = 3) or the PM (n = 3) formulations by the intraruminal route at the same dose rate (5 mg/kg). The treatment groups were reversed after a 7-days washout period. A non-compartmental analysis of the concentration in plasma versus time results showed that the calculated Cmax and AUC0-T were significantly higher (p < 0.05) for FBZ and its metabolites after the SDNC treatment compared to the PM (for FBZ: Cmax 0.346 µg/mL and AUC0-T 10.1 µg.h/mL after the SDNC vs Cmax 0.157 µg/mL and AUC0-T 5.1 µg.h/mL after the PM treatment). Additionally, population pharmacokinetic parameters of FBZ were estimated for the first time in sheep. In conclusion, the formulation of FBZ as SDNCs is a promising approach to improve FBZ dissolution reaching a higher drug plasma exposure in ruminants.