rifampin and Filariasis

The elimination of filarial diseases such as onchocerciasis and lymphatic filariasis is hampered by the lack of a macrofilaricidal-adult worm killing-drug. In the present study, we tested the in vivo efficacy of AN11251, a boron-pleuromutilin that targets endosymbiotic Wolbachia bacteria from filarial nematodes and compared its efficacy to doxycycline and rifampicin. Doxycycline and rifampicin were previously shown to deplete Wolbachia endosymbionts leading to a permanent sterilization of the female adult filariae and adult worm death in human clinical studies. Twice-daily oral treatment of Litomosoides sigmodontis-infected mice with 200 mg/kg AN11251 for 10 days achieved a Wolbachia depletion > 99.9% in the adult worms, exceeding the Wolbachia reduction by 10-day treatments with bioequivalent human doses of doxycycline and a similar reduction as high-dose rifampicin (35 mg/kg). Wolbachia reductions of > 99% were also accomplished by 14 days of oral AN11251 at a lower twice-daily dose (50 mg/kg) or once-per-day 200 mg/kg AN11251 treatments. The combinations tested of AN11251 with doxycycline had no clear beneficial impact on Wolbachia depletion, achieving a > 97% Wolbachia reduction with 7 days of treatment. These results indicate that AN11251 is superior to doxycycline and comparable to high-dose rifampicin in the L. sigmodontis mouse model, allowing treatment regimens as short as 10-14 days. Therefore, AN11251 represents a promising pre-clinical candidate that was identified in the L. sigmodontis model, and could be further evaluated and developed as potential clinical candidate for human lymphatic filariasis and onchocerciasis.

Topics: Animals; Anti-Bacterial Agents; Boron; Diterpenes; Doxycycline; Female; Filariasis; Filarioidea; Mice, Inbred BALB C; Pleuromutilins; Polycyclic Compounds; Rifampin; Symbiosis; Wolbachia

Antibiotic treatment has emerged as a promising strategy to sterilize and kill filarial nematodes due to their dependence on their endosymbiotic bacteria, Wolbachia. Several studies have shown that novel and FDA-approved antibiotics are efficacious at depleting the filarial nematodes of their endosymbiont, thus reducing female fecundity. However, it remains unclear if antibiotics can permanently deplete Wolbachia and cause sterility for the lifespan of the adult worms. Concerns about resistance arising from mass drug administration necessitate a careful exploration of potential Wolbachia recrudescence. In the present study, we investigated the long-term effects of the FDA-approved antibiotic, rifampicin, in the Brugia pahangi jird model of infection. Initially, rifampicin treatment depleted Wolbachia in adult worms and simultaneously impaired female worm fecundity. However, during an 8-month washout period, Wolbachia titers rebounded and embryogenesis returned to normal. Genome sequence analyses of Wolbachia revealed that despite the population bottleneck and recovery, no genetic changes occurred that could account for the rebound. Clusters of densely packed Wolbachia within the worm's ovarian tissues were observed by confocal microscopy and remained in worms treated with rifampicin, suggesting that they may serve as privileged sites that allow Wolbachia to persist in worms while treated with antibiotic. To our knowledge, these clusters have not been previously described and may be the source of the Wolbachia rebound.

Topics: Animals; Brugia pahangi; Female; Filariasis; Filaricides; Gerbillinae; Rifampin; Wolbachia

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.

Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Drug Therapy, Combination; Filariasis; Filarioidea; Fluoroquinolones; Mice; Moxifloxacin; Rifampin; Tetracyclines; Time Factors; Treatment Outcome; Wolbachia

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

Topics: Albendazole; Animals; Anti-Bacterial Agents; Benzimidazoles; Brugia malayi; Drug Synergism; Female; Filariasis; Male; Mice; Mice, Inbred BALB C; Minocycline; Rifampin; Wolbachia

Doxycycline and rifampicin deplete essential Wolbachia from filarial nematodes that cause lymphatic filariasis or onchocerciasis, resulting in blocked worm development and death. However, doxycycline is contraindicated for children and pregnant/breastfeeding women, as is rifampicin in the latter group with the additional specter of possible resistance development in Mycobacterium spp. Novel antibiotics with a narrower spectrum would aid in eliminating filarial diseases. Corallococcus coralloides synthesizes corallopyronin A, a noncompetitive inhibitor of RNA polymerase ineffective against Mycobacterium spp. Corallopyronin A depleted Wolbachia from infected insect cells (1.89 Thus the antibiotic is effective against intracellular bacteria despite the many intervening surfaces (blood vessels, pleura, worm cuticle) and membranes (worm cell, vesicle, Wolbachia inner and outer membranes). Corallopyronin A is an antibiotic to develop further for filariasis elimination without concern for cross-resistance development in tuberculosis.

Topics: Aedes; Animals; Cell Line; Contraindications; DNA-Directed RNA Polymerases; Drug Resistance, Bacterial; Enzyme Inhibitors; Female; Filariasis; Filaricides; Filarioidea; Lactones; Mice; Mice, Inbred BALB C; Molecular Conformation; Rifampin; Symbiosis; Wolbachia

The present investigation deals with the evaluation of antifilarial efficacy of liposome entrapped antiwolbachial antibiotics doxycycline and rifampicin (5 doses at 10 mg/kg, subcutaneously for 15 days) alone and/or in combination with standard filaricide diethylcarbamazine (DEC) against human lymphatic filariid Brugia malayi in rodent host Mastomys coucha. The delivery system maintained the sustained release of antibiotics up to 48 h and significantly (P < 0.05) augmented the antifilarial potential of these antibiotics over their free administration. A combination of DEC with each entrapped antibiotics significantly (P<0.05) improved microfilaricidal efficacy, while marginal enhancement was noticed in adulticidal activity. Combination of both antibiotics formulation with DEC demonstrated marginal increase in macrofilaricidal efficacy; however, it was highest ( approximately 75%).

Topics: Animals; Brugia malayi; Diethylcarbamazine; Disease Models, Animal; Doxycycline; Drug Therapy, Combination; Filariasis; Filaricides; Liposomes; Male; Murinae; Rifampin

The symbiosis of filarial nematodes and rickettsial Wolbachia endobacteria has been exploited as a target for antibiotic therapy of filariasis. Depletion of Wolbachia after tetracycline treatment results in filarial sterility because of interruption of embryogenesis and inhibits larval development and adult worm viability. The aim of this study was to investigate if antibiotic intervention of BALB/c mice infected with the rodent filaria Litomosoides sigmodontis with rifampicin or the combination of rifampicin and doxycycline can be used to shorten the treatment period. Both regimens, when given over a period of 14 days initiated with infection, were sufficient to deplete Wolbachia as evidenced by immunohistology and semiquantitative PCR. Worm development and filarial load were significantly reduced in experiments followed up until 63 days p.i. The therapy inhibited embryogenesis and led to filarial sterility. In contrast, treatment with doxycycline alone for 21 days led only to a modest reduction of Wolbachia, filarial growth retardation, worm viability and fertility. In conclusion, the combination of antirickettsial drugs could be used as a suitable tool to explore the minimum duration of therapy required for the depletion of Wolbachia in parasitized hosts subsequent to the onset of patency in human and animal filariasis and the prevention of adverse reactions in human infections.

Topics: Animals; Anti-Bacterial Agents; Doxycycline; Drug Therapy, Combination; Female; Filariasis; Filarioidea; Male; Mice; Mice, Inbred BALB C; Neutrophil Infiltration; Polymerase Chain Reaction; Rickettsiaceae Infections; Rifampin; Symbiosis; Wolbachia

Topics: Animals; Anti-Bacterial Agents; Brugia malayi; Filariasis; Filarioidea; Humans; Onchocerca volvulus; Rifampin; Symbiosis; Tetracycline; Wolbachia; Wuchereria bancrofti

The activity against filarial parasites of the antibiotics rifampicin, oxytetracycline and chloramphenicol was examined. In addition, transmission electron microscopy was used to study the effects of rifampicin and oxytetracycline on filarial tissues and on the endosymbiont bacterium, Wolbachia. When tested in vitro at a concentration of 50.0 microM, each of the three antibiotics significantly reduced the motility levels of male Onchocerca gutturosa. Rifampicin, however, was the most active, virtually immobilizing the parasite by the end of the 40-day trial and producing an 84% reduction in viability (as measured by formazan-based colorimetry). In tests against O. lienalis microfilariae (mff) in CBA mice, the numbers of mff recovered after treatment with oxytetracycline at 100, 25 or 6.5 mg/kg daily, for 15 days, were 56% (P < or = 0.03), 38% (P> 0.05) and 45% (P = 0.05) less than that recovered from the untreated controls, respectively. In another trial in mice, rifampicin (100 mg/kg daily for 15 days) was found to be the most active (causing a 74% reduction in the number of mff recovered--approximately equal to that achieved with the positive control of a single dose of ivermectin at 2 microg/kg), with chloramphenicol also showing significant activity (39% reduction). In further, in-vivo trials, at three dose levels (100, 25 or 6.25 mg/kg daily, for 15 days), all three antibiotics were tested against adult Brugia pahangi in the peritoneal cavities of jirds. None of the antibiotics produced a significant reduction in the numbers of live worms recovered, although a marginal effect was observed in eight of the nine antibiotic-treated groups. A further extended trial with rifampicin and oxytetracycline resulted in 43% and 38% reductions in worm recoveries, respectively (not statistically significant but consistent with a marginal effect); some of these worms appeared less motile and qualitatively in poor condition compared with those recovered from untreated jirds. Ultrastructural studies of these treated worms revealed that virtually all of the endosymbiont bacteria had been cleared from the parasite tissues. The tissues of the adult worms appeared to be largely intact but with a granulomatous response of host cells adhering to some specimens. However, developing uterine forms appeared to be abnormal and extensively damaged, showing an abrogation of embryogenesis. In contrast, worms recovered from control animals contained large numbers of Wolbachia, had n

Topics: Animals; Anti-Bacterial Agents; Brugia pahangi; Cattle; Chloramphenicol; Female; Filariasis; Gerbillinae; Male; Mice; Mice, Inbred CBA; Microscopy, Electron; Onchocerciasis; Oxytetracycline; Rifampin; Treatment Outcome; Wolbachia