Response of drug-susceptible and -resistant Haemonchus contortus larvae to monepantel and abamectin alone or in combination in vitro

Abstract

There is an increasing interest in the use of combination anthelmintic products for the control of intestinal nematode parasites of livestock. These products are seen as attractive options for parasite control in the face of increasing levels of resistance to the different anthelmintic drug classes, as well as a means to slow the rate at which resistance develops to the individual components of the combination. With the recent introduction of an anthelmintic combination product containing abamectin and monepantel (at 1:12.5), we were interested in measuring the response of drug-susceptible and drug-resistant isolates of Haemonchus contortus to these two drugs alone and in combination, using larval development assays. The GWBII isolate showed resistance to abamectin (12-fold) alongside susceptibility to monepantel. The resistance ratio was reduced from 12- to 3.2-fold when the two drugs were combined. The MPL-R isolate was resistant to both drugs, with resistance factors of 6-fold towards abamectin, and 10.6- and 1008-fold towards monepantel in two sub-populations present in the isolate. This isolate showed 6.4-fold resistance to the drug combination. Hence, for both GWBII and MPL-R, the level of resistance towards the combination was reduced compared to the resistance towards abamectin or monepantel alone, respectively, but was not abolished. However, for GWBII, this in vitro resistance to the drug combination would be expected to have no impact on the in vivo efficacy of the combination drench product as the isolate is resistant to only the abamectin component of the drench, with monepantel remaining effective. On the other hand, the observed in vitro resistance to the combination shown by the MPL-R isolate is derived from significant levels of resistance towards both components separately, and hence may impact on in vivo efficacy of the combination. Isobologram analysis did not find any evidence for a synergistic interaction between the two drugs in larval development assays. We examined the predicted effects of varying the abamectin:monepantel ratio in drug combinations, assuming that the two drugs acted in an additive fashion. For GWBII, resistance to the drug combination was reduced to almost zero as the abamectin:monepantel ratio increased from 1:12.5 to 1:100, reflecting its resistance to only the abamectin component of the combination. For MPL-R, on the other hand, the resistance increased as the relative proportion of monepantel in the combination was increased, reflecting the extreme level of in vitro resistance shown by this isolate to monepantel.

Keywords: Abamectin; Anthelmintic; Combination; Haemonchus contortus; In vitro; Monepantel; Resistance.