Abstract
Elimination of filariasis requires a macrofilaricide treatment that can be delivered within a 7-day period. Here we have identified a synergy between the anthelmintic albendazole (ABZ) and drugs depleting the filarial endosymbiont Wolbachia, a proven macrofilaricide target, which reduces treatment from several weeks to 7 days in preclinical models. ABZ had negligible effects on Wolbachia but synergized with minocycline or rifampicin (RIF) to deplete symbionts, block embryogenesis, and stop microfilariae production. Greater than 99% Wolbachia depletion following 7-day combination of RIF+ABZ also led to accelerated macrofilaricidal activity. Thus, we provide preclinical proof-of-concept of treatment shortening using antibiotic+ABZ combinations to deliver anti-Wolbachia sterilizing and macrofilaricidal effects. Our data are of immediate public health importance as RIF+ABZ are registered drugs and thus immediately implementable to deliver a 1-wk macrofilaricide. They also suggest that novel, more potent anti-Wolbachia drugs under development may be capable of delivering further treatment shortening, to days rather than weeks, if combined with benzimidazoles.
Highlights
Elimination of filariasis requires a macrofilaricide treatment that can be delivered within a 7-day period
The use of IVM is problematic in geographical regions where L. loa is coendemic, as this can result in severe adverse reactions (SAEs) caused by druginduced death and associated inflammation of blood-borne L. loa mf in the brain [11]
Our data reveal a pharmacological drug synergy between registered classes of antibiotics when combined with the standard antifilarial drug ABZ in targeting the filarial symbiont Wolbachia
Summary
Elimination of filariasis requires a macrofilaricide treatment that can be delivered within a 7-day period. We provide preclinical proof-of-concept of treatment shortening using antibiotic+ABZ combinations to deliver anti-Wolbachia sterilizing and macrofilaricidal effects. Our data are of immediate public health importance as RIF+ABZ are registered drugs and immediately implementable to deliver a 1-wk macrofilaricide They suggest that novel, more potent anti-Wolbachia drugs under development may be capable of delivering further treatment shortening, to days rather than weeks, if combined with benzimidazoles. A clinical trial administering a single triple-dose combination of IVM/DEC/ABZ has shown superior microfilaremia suppression in bancroftian filariasis for up to a year [4] These promising results have the potential to accelerate LF elimination goals, in situations where the absence of Loa loa and/or O. volvulus coendemicity precludes the risk of severe adverse events. This synergy enables the shortening of treatment duration of macrofilaricidal anti-Wolbachia based treatments from 4 wk to 7 d with registered drugs ready for clinical testing
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