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Albendazole and antibiotics synergize to deliver short-course anti-Wolbachia curative treatments in preclinical models of filariasis

  1. Mark J. Taylora
  1. aResearch Centre for Drugs and Diagnostics, Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, United Kingdom;
  2. bTRS Laboratories, Athens, GA 30605
  1. Contributed by Janet Hemingway, September 28, 2017 (sent for review June 16, 2017; reviewed by John Horton and Patrick Lammie)

  1. Fig. 2.

    Schematic of drug treatment protocol (A). Wolbachia loads in B. malayi females immediately following 7-d exposure with MIN or ABZ at indicated doses (B). Box and whiskers are median, minimum/maximum Wolbachia surface protein (wsp) gene copy number, derived from a pool of 10 individual worms, sourced from groups of four SCID mice. Significant differences are assessed by Kruskal–Wallis one-way ANOVA (female worm Wolbachia depletions Kruskal–Wallis statistic: 21.79, P = 0.0002) with Dunn’s multiple tests: *P < 0.05, **P < 0.01. (C) Change in Wolbachia load compared with vehicle control following 7-d exposure to listed compounds (all 5 μM) within an A. albopictus cell line stably infected with wAlbB (C6/36 wAlbB). Bars are mean log-fold change (+SEM) from triplicate wells from two individual experiments.

  2. Fig. 3.

    Schematic of drug treatment protocol (A). Wolbachia loads in B. malayi females (B), Wolbachia loads in B. malayi males (C), and peritoneal B. malayi microfilarial loads per gerbil (D), +8 mo postimplantation of adult filariae and commencement of 15-d vehicle, ABZ, MIN, or MIN+ABZ combination treatments (ABZ administered for final 3 d) at indicated doses. Box and whiskers are median, minimum/maximum Wolbachia surface protein (wsp) gene copy number, adjusted for heterogeneity in filarial age as a ratio to the B. malayi GST (gst) gene, derived from a pool of 10 individual worms, sourced from groups of six gerbils. Significant differences in Wolbachia load are assessed by Kruskal–Wallis one-way ANOVA, female worm Wolbachia depletions Kruskal–Wallis statistic: 21.2, P < 0.0001; male worm Wolbachia depletions Kruskal–Wallis statistic: not significant with Dunn’s multiple comparisons tests. *P < 0.05, ***P < 0.001. Significant differences in peritoneal mf number are assessed by one-way ANOVA with Holm–Sidak’s multiple comparisons tests *P < 0.05.

  3. Fig. 4.

    Schematic of drug treatment protocol (A). Wolbachia loads in B. malayi females (B) or males (C), +13 wk postinfection and +6 wk after commencement of 7-d vehicle, ABZ, RIF, ABZ+RIF combination treatments, or DOX treatment for +42 d at indicated doses. Box and whiskers are median, minimum, and maximum Wolbachia surface protein gene copy number, derived from a pool of 10 individual worms, sourced from groups of three to four mice. Significant differences are assessed by Kruskal–Wallis one-way ANOVA (female worm Wolbachia depletions Kruskal–Wallis statistic: 49.7, P < 0.0001; male worm Wolbachia depletions Kruskal–Wallis statistic: 37.1, P < 0.0001) with Dunn’s multiple tests, indicated as *P < 0.05, **P < 0.01, ***P < 0.001, or ****P < 0.0001 (only tests compared with vehicle are shown).

  4. Fig. 5.

    Quantification of early intrauterine embryonic stages (A) and late intrauterine embryonic stages (B) in B. malayi females and accumulations of mature, motile i.p. B. malayi mf (C), +13 wk postinfection and +6 wk after commencement of 7-d vehicle, ABZ, RIF, or combination treatments at indicated doses. Box and whiskers are median levels, minimum/maximum of indicated uterine stage/s or mature, motile i.p. mf. Embryogram data are derived from a pool of five individual females, sourced from groups of three to four mice; i.p. mf counts are derived from four mice per group (RIF monotherapies), six mice per group (ABZ monotherapy), or eight mice per group (vehicle and RIF+ABZ combinations). Significant differences are assessed by one-way ANOVA with Holm–Sidak’s multiple comparison tests (early-stage embyos/female worm F = 6.537, P = 0.0006) or Kruskal–Wallis one-way ANOVA with Dunn’s multiple comparisons tests (late-stage embryos/female worm Kruskal–Wallis statistic: 19.8, P = 0.0014, peritoneal mf/mouse Kruskal–Wallis statistic: 35.5, P < 0.0001). Significance of multiple comparisons tests are indicated: *P < 0.05, **P < 0.01, or ****P < 0.0001.

  5. Fig. 6.

    Quantification of total (A), female (B), and male (C) B. malayi worm burdens +13 wk postinfection and +6 wk after commencement of 7-d vehicle, ABZ, RIF, or combination treatments at indicated doses. Box and whiskers are median percent recoveries (100 BmL3 infections) and minimum/maximum of mature, motile adult stages from four mice per group (RIF monotherapies) seven mice per group (ABZ monotherapy) or eight mice per group (vehicle and RIF+ABZ combinations). Significant differences are assessed by Kruskal–Wallis one-way ANOVA with Dunn’s multiple comparisons tests (total worm burden Kruskal–Wallis statistic: 12.6, P = 0.0274; female worm Kruskal–Wallis statistic: 11.8, P = 0.0379). Significance of multiple comparisons tests are indicated as *P < 0.05.

  6. Fig. 7.

    Simulated PK profiles (day 1) for (A) 5-d 5 mg/kg bid ABZ regimen. (B) ABZ in ABZ+RIF combination 5-d regimen. (C) The 5-d 5 mg/kg qd RIF regimen (day 1). (D) RIF in ABZ+RIF combination regimen. For the simulated PK profiles the solid line represents the median profile and the red dashed lines represent the 5th and 95th percentile PK profiles and blue circles experimentally sampled concentrations.

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