Trichuris suis and Oesophagostomum dentatum Show Different Sensitivity and Accumulation of Fenbendazole, Albendazole and Levamisole In Vitro

Background The single-dose benzimidazoles used against Trichuris trichiura infections in humans are not satisfactory. Likewise, the benzimidazole, fenbendazole, has varied efficacy against Trichuris suis whereas Oesophagostomum dentatum is highly sensitive to the drug. The reasons for low treatment efficacy of Trichuris spp. infections are not known. Methodology We studied the effect of fenbendazole, albendazole and levamisole on the motility of T. suis and O. dentatum and measured concentrations of the parent drug compounds and metabolites of the benzimidazoles within worms in vitro. The motility and concentrations of drug compounds within worms were compared between species and the maximum specific binding capacity (B-max) of T. suis and O. dentatum towards the benzimidazoles was estimated. Comparisons of drug uptake in living and killed worms were made for both species. Principal findings The motility of T. suis was generally less decreased than the motility of O. dentatum when incubated in benzimidazoles, but was more decreased when incubated in levamisole. The B-max were significantly lower for T. suis (106.6, and 612.7 pmol/mg dry worm tissue) than O. dentatum (395.2, 958.1 pmol/mg dry worm tissue) when incubated for 72 hours in fenbendazole and albendazole respectively. The total drug concentrations (pmol/mg dry worm tissue) were significantly lower within T. suis than O. dentatum whether killed or alive when incubated in all tested drugs (except in living worms exposed to fenbendazole). Relatively high proportions of the anthelmintic inactive metabolite fenbendazole sulphone was measured within T. suis (6-17.2%) as compared to O. dentatum (0.8-0.9%). Conclusion/Significance The general lower sensitivity of T. suis towards BZs in vitro seems to be related to a lower drug uptake. Furthermore, the relatively high occurrence of fenbendazole sulphone suggests a higher detoxifying capacity of T. suis as compared to O. dentatum. Author Summary The human whipworm Trichuris trichiura is together with the roundworm Ascaris lumbricoides and the hookworms Ancylostoma duodenale and Necator Americanus the most common intestinal worms worldwide. Together they place more than 5 billion people at risk of infection. The current global control strategy against these worms is regular administration of anthelmintic drugs, mostly albendazole and mebendazole, both belonging to the drug-class benzimidazoles. Both drugs have a low effect against T. trichiura infections, but the reasons for this are not known. We evaluated the in vitro effect of two benzimidazoles; i.e., albendazole, fenbendazole, and another type of anthelmintic, levamisole, on the whipworm (T. suis) and the nodular worm (Oesophagostomum dentatum) of the pig. Oesophagostomum dentatum is highly sensitive towards benzimidazoles in comparison to T. suis. We measured and compared the drug uptake in both species in both living and killed worms. Our results suggest that the reason for the difference in sensitivity is due to a lower drug uptake into T. suis as compared to O. dentatum. Furthermore, T. suis was able to metabolise fenbendazole into an inactive metabolite to a much larger extent than O. dentatum, suggesting a higher detoxifying capacity of T. suis as compared to O. dentatum.