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Russell E. Lewis, Pharm.D., FCCP, BCPS Associate Professor

Intrapulmonary drug distribution & pharmacodynamic interactions of antifungal drugs with host cells. Russell E. Lewis, Pharm.D., FCCP, BCPS Associate Professor University of Houston College of Pharmacy & The University of Texas M.D. Anderson Cancer Center Houston, Texas. UH Anti-Infective

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Russell E. Lewis, Pharm.D., FCCP, BCPS Associate Professor

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  1. Intrapulmonary drug distribution & pharmacodynamic interactions of antifungal drugs with host cells Russell E. Lewis, Pharm.D., FCCP, BCPS Associate Professor University of Houston College of Pharmacy & The University of Texas M.D. Anderson Cancer Center Houston, Texas UH Anti-Infective Research Laboratories

  2. Outline How does the pathophysiology of invasive pulmonary aspergillosis impair drug delivery to the site of infection? Are pharmacokinetic differences among antifungal agents important for the treatment of fungal pneumonia?

  3. Pathology of acute mould infectionsneutropenic hosts Mononuclear and polymorphonuclear cells clear germinating conidia and hyphal forms Angioinvasive growth In tissue with hemorrhage, thrombosis, hypoxia, necrosis, and dissemination Inhalation of conidia Conidia reach distal alveolar space and begin to germinate Impaired by neutropenia, glucocorticoids, metabolic abnormalities, concomitant infections Administer drugs to slow fungal proliferation; and reduce, angioinvasion, and dissemination Figure: R. Lewis

  4. Figure: R. Lewis Pathology of acute mould infectionscorticosteroid and mixed immunosuppression? Angioinvasive growth In tissue with hemorrhage, thrombosis, hypoxia, necrosis, and dissemination Mononuclear and polymorphonuclear cells clear germinating conidia and hyphal forms Inhalation of conidia Conidia reach distal alveolar space and begin to germinate Dysregulated inflammatory response Immunopathology hemorrhage, necrosis Figure: R. Lewis

  5. All treated Voriconazole Amphotericin B Progressive thrombosis- inflammation-necrosis impair drug activity in invasive aspergillosis Discrete nodules (neutropenia) Nodular consolidation (steroids) Coagulation necrosis without Inflammatory cells Encompassing hemorrhage Defined nodules with hemorrhage Solid nodular consolidation with necrotic center Dense neutrophilic infiltrate on periphery ∆ 20% in response ~10 days % Cured Nodular Lesion with Halo Sign (N=143) Nodular lesion without Halo Sign (N=143) Greene et al. Clin Infect Dis 2007;44:373-9. Shibuya et al. J Infect Chemother2004;10:138-45.

  6. Pathogen growth and inflammation in the lung evoke neovascularization and angiogenesis How does the pathogen or host immunosuppression affect the angioplasticity of the lung? Implications for disease pathogenesis? Implications for drug delivery? Lung epithelium TNFα IL-8 Bone marrow derived pro-angiogenic precursors (CD34+, CD 133+) VEGF HIF-1α bFGF Asosingh & Erzuram. Biochem S. Tran 2009;37:805-810.

  7. Invasive pulmonary aspergillosis in neutropenic mice is associated with rapid down-regulation of multiple genes involved in angioneogenesis Relative expression by RT-PCR at 24 hr A. fumigatus uncoupling of inflammatory-angiogenic response in neutropenic animals? corticosteroid only cyclophosphamide + 1 dose cortisone (neutropenic) x fold expression whole lung RNA PCR arrays 84 genes angiogenesis pathway controls: same immunosuppression, no infection Ben-Ami et al. Blood ; Advanced access published 2009

  8. In vivo assessment of the anti-angiogenic effects of Aspergillus infection Will surrounding Aspergillus growth suppress angiogenesis? In vivo Matrigel plug (500 µL)bFGF + heparin myocutaneous model of aspergillosis (neutropenic, non-lethal) D+5 endothelial cell migration capillary tube formation D+7 erythrocyte-filled lacunae Remove and image Ben-Ami et al. Blood ; Advanced access published 2009 a Passanti et al. Lab Invest 1992;67:518-528. injected 10 mm from infection site

  9. A. fumigatus suppress angiogenesis in an in vivo cutaneous infection model Day +7 Matrigel plugs Control AF 293 ∆laeA Masson trichrome stain Ben-Ami et al. Blood; Advanced access published 2009

  10. Are secondary metabolites responsible for this anti-angiogenic effect? In vitro Matrigel experiments (HUVEC) Growth medium Growth medium A. fumigatus culture filtrate ∆laeA culture filtrate ∆laeA complemented culture filtrate ∆glip Ben-Ami et al. Blood; Advanced access published 2009

  11. Gliotoxin suppresses angioneogensis in a dose-dependent fashion In vitro Matrigel experiments (HUVEC) gliotoxin 30 ng/mL gliotoxin 3000 ng/mL gliotoxin 300 ng/mL control *gliotoxin lung concentrations in experimental pulmonary aspergillosis: 1000-4000 ng/gram lung Ben-Ami et al. Blood; Advanced access published 2009 *Lewis et al. Infect Immun 2005;73:635-637.

  12. Pathological features affecting drug delivery depend on host immunosuppression Non-neutropenic patient Neutropenic patient immune response Diminished drug delivery/ efficacy? Aspergillus Diminished drug delivery/ efficacy? immune response Aspergillus PMN-mediated tissue damage* inhibition of lung angiogenesis Impact of changing immune function, co-pathogens? *evidence that gliotoxin also exacerbates this effect in corticosteroid-immunosuppressed mice

  13. Effect of amphotericin B on the survival or immunosuppressed mice with invasive pulmonary aspergillosis Corticosteroid Chemotherapy (neutropenic) Balloy et al. Infect Immunity 2005;73:494-503.

  14. Immunomodulatory effects of antifungals in the lung Liposomal amphotericin B Amphotericin B Echinocandins Triazoles Dectin-1 TLR4 TLR2 Exposure or immunogenic epitopes in cell wall Fungal sensitization for phagocytosis Activation of TLR4 Activation of TLR2 relative pro-inflammatory potential in the lung? Ben-Ami et al. Clin Infect Dis 2008;47:226-35.

  15. Outline How does the pathophysiology of invasive pulmonary aspergillosis impair drug delivery to the site of infection? Are pharmacokinetic differences among antifungal agents important for the treatment of fungal pneumonia?

  16. Patterns of drug distribution for currently available antifungals +, ≥50% of serum concentrations. –, <10% of serum concentrations. *Predicted. 1. Dodds-Ashley ES, et al . Clin Infect Dis. 2006;43:S28-S39. 2. Groll AH, et al. Adv Pharmacol. 1998;44:343-500. 3. Eschenauer G, et al. Ther Clin Risk Manag. 2007;3:71-97.

  17. Steady-state concentrations of voriconazole and anidulafungin in plasma, epithelial lining fluid and macrophages in healthy adults Similar data for posaconazole (Conte et al. Antimicrobial Agent Chemother 2009;53:707-7); micafungin (Nicasio et al. Antimicrob Agent Chemother 2009;53:1218-20); itraconazole (Conte et al. Antimicrob Agent Chemother 2004;48:3823-7) Crandon et al. Antimicrob Agent Chemother 2009;Online Publication Sept 21, 2009

  18. Concentration of amphotericin B in lung tissue, ELF, PAMs and PBMs of healthy rabbits after once-daily dosing for 8 daysa a Twenty-four hours after doses of either DAMB, ABCD, ABLC, or LAMB. All values represent the means ± SD from three to seven rabbits in each dosing group. Plasma, concurrent plasma concentrations. P values from comparisons across dosage groups by Kruskal-Wallis nonparametric analysis of variance (ANOVA) were as follows: lung, P = 0.0029; ELF, P = 0.0070; PAMs, P = 0.0246; PBMs, P = 0.4640; and plasma, P = 0.0146. Between-group comparisons using Dunn's correction for multiple comparisons revealed significant differences in lung tissue concentrations between DAMB- and ABLC-treated animals (P < 0.01), in ELF concentrations between DAMB- and LAMB-treated animals (P < 0.01), and in PAM concentrations between ABCD- and ABLC-treated animals (P < 0.05). Groll et al. Antimicrob Agent Chemother 2006;50:3418-23.

  19. Our lipid formulations are engineered to reduce nephrotoxicity, not improve efficacy AMB-d or ABCD 28 days L-AMB 3 mg/kg 100 µg/gram Liver Spleen 50 µg/gram 15 µg/gram Kidney 5-10 µg/gram Lung 0.67 µg/gram 0.1 µg/gram in tissue histologically infected with Aspergillus 1 µg/gram CNS Vogelsinger et al. J Antimicrobial Chemother 2006;57:1153-1160. Paterson et al. J Antimicrob Chemother 2003;52:873-876.

  20. “Corpora non agunt nisi fixata” -Paul Erlich

  21. The way forward? • Earlier detection= wider window for drug delivery to target tissue • Better understanding of the pathobiology that limits drug delivery • Angioneogenesis, tissue repair • Inflammation • Can we engineer solutions? • How can this knowledge be used to improve therapeutic approaches, especially in chronically-infected patients? • Aerosolized, intermittent or novel drug delivery approaches

  22. Acknowledgements • M.D. Anderson Cancer Center • Dimitrios P. Kontoyiannis M.D., Sc.D • Ronen Ben-Ami, M.D. (angioneogensis work) • Nathan Albert, Konstantinos Leventakos, M.D. • Gregory May, Ph.D. (∆glip strain) • NP Keller, Wisconsin (∆laeA) • Funding for angioneogensis studies: • EN Cobb Scholar Award (DPK) • NCI Core Center Grant (CA 16672) • NIH (1RO3AI083733-01) Kontoyiannis

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