Filarial parasites can be targeted by antibiotic treatment due to their unique endosymbiotic relationship with Wolbachia bacteria. This finding has led to successful treatment strategies in both, human onchocerciasis and lymphatic filariasis. A 4–6 week treatment course using doxycycline results in long-term sterility and safe macrofilaricidal activity in humans. However, current treatment times and doxycycline contraindications in children and pregnant women preclude widespread administration of doxycycline in public health control programs; therefore, the search for shorter anti-wolbachial regimens is a focus of ongoing research. We have established an in vivo model for compound screening, using mice infected with Litomosoides sigmodontis. We could show that gold standard doxycycline treatment did not only deplete Wolbachia, it also resulted in a larval arrest. In this model, combinations of registered antibiotics were tested for their anti-wolbachial activity. Administration of rifamycins in combination with doxycycline for 7 days successfully depleted Wolbachia by > 2 log (>99% reduction) and thus resulted in a significant reduction of the treatment duration. Using a triple combination of a tetracycline (doxycycline or minocycline), a rifamycin and a fluoroquinolone (moxifloxacin) led to an even greater shortening of the treatment time. Testing all double combinations that could be derived from the triple combinations revealed that the combination of rifapentine (15mg/kg) and moxifloxacin (2 x 200mg/kg) showed the strongest reduction of treatment time in intraperitoneal and also oral administration routes. The rifapentine plus moxifloxacin combination was equivalent to the triple combination with additional doxycycline (>99% Wolbachia reduction). These investigations suggest that it is possible to shorten anti-wolbachial treatment times with combination treatments in order to achieve the target product profile (TPP) requirements for macrofilaricidal drugs of no more than 7–10 days of treatment.
Over the past years, more attention has been brought to neglected tropical diseases including lymphatic filariasis and onchocerciasis. The latter are caused by helminthic parasites and lead to chronic and debilitating symptoms and present a major health burden that also affects the economy of endemic countries. It has been suggested that disease elimination may be possible but an accelerated implementation of proven and cost-effective interventions are needed if the targets for elimination are to be achieved. Recently, an indirect mode of action has been identified, targeting bacterial Wolbachia endosymbionts within the filariae, which also kills the adult parasites, an advantage over the drug currently used for mass drug administration, i.e. ivermectin. Doxycycline has been successfully used in clinical trials, however due to its long regimen as well as restrictions of use in children and pregnant women new drugs or drug combinations are required that overcome these obstacles. Here, we present the filarial parasite Litomosoides sigmodontis as suitable model for the preclinical testing of anti-wolbachial drugs against filariae and show that combinations of already registered drugs with anti-wolbachial efficacy are able to reduce the treatment time dramatically.