Bennett, J. E., Powers, J., de Pauw, B., Dismukes, W., Galgiani, J., Glauser, M., Herbrecht, R., Kauffman, C., Lee, J., Pappas, P., Rex, J., Verweij, P., Viscoli, C., & Walsh, T. (2003). Forum report: issues in the design of trials of drugs for the treatment of invasive aspergillosis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 36(Suppl 3), S113-6.
A recent trial of drugs for invasive aspergillosis was used as a background for discussing critical features in the design of antifungal trials. The study under discussion allowed stopping either drug without classifying the patient as having treatment failure, so the trial should be understood as a comparison of 2 treatment strategies, not just 2 drugs. Although the study was a noninferiority trial, the outcome permitted a claim of superiority. Use of the category of "probable" in addition to "proven" aspergillosis permitted inclusion of patients for whom the diagnosis was less certain but who were still early enough in the disease progression to respond to therapy. Different opinions still exist about some of the criteria for the diagnosis of "probable" aspergillosis. A blinded data review committee was helpful in evaluating efficacy in this unblinded trial but had limited value in assessing toxicity. An understanding of these features of design of antifungal drug trials is important in applying the results to clinical practice.
DENNING, D. W., LEE, J. Y., HOSTETLER, J. S., PAPPAS, P., KAUFFMAN, C. A., DEWSNUP, D. H., GALGIANI, J. N., GRAYBILL JR, ., SUGAR, A. M., CATANZARO, A., GALLIS, H., PERFECT JR, ., DOCKERY, B., DISMUKES, W. E., & STEVENS, D. A. (1994). NIAID MYCOSES STUDY-GROUP MULTICENTER TRIAL OF ORAL ITRACONAZOLE THERAPY FOR INVASIVE ASPERGILLOSIS. AMERICAN JOURNAL OF MEDICINE, 97(2), 135-144.
Ostrosky-Zeichner, L., Casadevall, A., Galgiani, J. N., Odds, F. C., & Rex, J. H. (2010). An insight into the antifungal pipeline: selected new molecules and beyond. Nature reviews. Drug discovery, 9(9), 719-27.
Invasive fungal infections are increasing in incidence and are associated with substantial mortality. Improved diagnostics and the availability of new antifungals have revolutionized the field of medical mycology in the past decades. This Review focuses on recent developments in the antifungal pipeline, concentrating on promising candidates such as new azoles, polyenes and echinocandins, as well as agents such as nikkomycin Z and the sordarins. Developments in vaccines and antibody-based immunotherapy are also discussed. Few therapeutic products are currently in active development, and progression of therapeutic agents with fungus-specific mechanisms of action is of key importance.
Bennett, J. E., Powers, J., Walsh, T., Viscoli, C., de Pauw, B., Dismukes, W., Galgiani, J., Glauser, M., Herbrecht, R., Kauffman, C., Lee, J., Pappas, P., Rex, J., & Verweij, P. (2003). Forum report: issues in clinical trials of empirical antifungal therapy in treating febrile neutropenic patients. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 36(Suppl 3), S117-22.
There is inferential evidence that some patients with prolonged neutropenia and fever not responding to antibacterial agents are at sufficient risk of deep mycoses to warrant empirical therapy, although superiority of an antifungal agent over placebo has not been conclusively demonstrated. Amphotericin B deoxycholate, liposomal amphotericin B, and intravenous itraconazole followed by oral itraconazole solution are licensed in the United States for this indication. Fluconazole and voriconazole have given favorable results in clinical trials of patients with low and high risk of deep mold infections, respectively. Design features that can profoundly influence outcome of empirical trials are (1) inclusion of low-risk patients, (2) failure to blind the study, (3) obscuration of antifungal effects by changing antibacterial antibiotics, (4) failure to balance both arms of the study in terms of patients with prior antifungal prophylaxis or with severe comorbidities, (5) the merging of end points evaluating safety with those of efficacy, and (6) choice of different criteria for resolution of fever.
Shubitz, L. F., Roy, M. E., Nix, D. E., & Galgiani, J. N. (2013). Efficacy of Nikkomycin Z for respiratory coccidioidomycosis in naturally infected dogs. Medical mycology, 51(7), 747-54.
Nikkomycin Z (NikZ) is a chitin synthase inhibitor with antifungal efficacy against Coccidioides spp. and other endemic fungi. Dogs suffer a rate and range of natural coccidioidomycosis similar to humans and were considered an excellent model for initially testing NikZ against naturally acquired disease. Twelve dogs with coccidioidal pneumonia that had been present for an average of three months were treated with 250 mg (5-15 kg) or 500 mg (> 15-30 kg) twice daily for 60 days. Nine dogs completed the course of treatment and seven dogs had improvement in disease based on radiographs, clinicopathological parameters, physical examination findings, and subjective assessment by owners; three dogs had resolution or near resolution of disease. Based on this small study, NikZ shows efficacy to treat naturally acquired coccidioidomycosis and merits further development for trials in humans.