Guest commentary: Emerging resistance, continuous progress in antifungal drug development

In this guest commentary, Dimitrios Kontoyiannis, MD, the Frances King Black Endowed Professor in the department of infectious diseases, The University of Texas MD Anderson Cancer Center, discusses the latest data on invasive fungal infections, including patterns of drug resistance and investigational antifungal therapies in early development.

It has been conservatively estimated that across the world, invasive fungal infections are responsible for the deaths of 1.5 million people each year — a greater global death toll than from malaria and one comparable to tuberculosis. Since a competent immune system has efficient mechanisms that help to reduce the risk for infection with fungal pathogens, the rising incidence of invasive fungal infections is largely being driven by the risks to the increasing numbers of people who have conditions or are receiving treatments that impair the function of the immune system. These at-risk groups include individuals living with HIV/AIDS and primary immune deficiencies, people receiving cancer chemotherapy, especially those with hematologic malignancies, hematopoietic stem-cell transplant or solid-organ transplant recipients; and patients treated with drugs such as corticosteroids that cause the immune system defects.

Dimitrios Kontoyiannis

Antifungal resistance in Candida

The latest data from Fungiscope — Global Registry for Emerging Fungal Infections, a worldwide initiative established in 2003 to gain more information on the epidemiology of emerging invasive fungal infections (IFI) in order to determine clinical patterns and improve diagnostic procedures and therapeutic regimens, suggest that, despite optimal use of currently available antifungal drugs, the outlook remains generally unfavorable for patients with IFI. Reports of changing susceptibility patterns and antifungal drug resistance are, therefore, a cause for concern for both clinicians and at-risk patients. In regards to the most common human mycosis, candidiasis, in recent years there has been a shift toward non-albicans Candida species with lower susceptibility to triazole drugs and the echinocandins. The CDC has found resistance to fluconazole in about 7% of all Candida bloodstream isolates tested. C. glabrata predominates in these isolates, and currently about 1% are resistant to current first-line treatment with the echinocandins.

Prior exposure to echinocandins is known to be an important determinant of resistance to this class, but a study from the University of Pittsburgh suggests that selection pressure imposed by exposure to antifungal drugs, regardless of the specific agent, may promote both a shift to non-albicans Candida strains and lower the threshold for the development of echinocandin resistance. The study by Shields and colleagues evaluated 395 consecutive patients with candidemia from 2009 to 2014, in which prior exposure was defined as at least 3 days of antifungal treatment. Of the 444 strains analyzed, C. albicans was the most common (37%), followed by C. glabrata (36.5%). Other strains isolated were C. parapsilosis (14%), C. tropicalis (8.5%) and other spp. (4%). C. glabrata and C. parapsilosis were more common among patients with a history of antifungal exposure (respectively: 32 to 45%; P = .02 and 10 to 21%; P = .003), and C. albicans was less common (45 to 21%; P < .001); results were consistent for prior azole and echinocandin exposure.

In the overall study population, treatment was more likely to be successful in patients receiving an echinocandin compared with a triazole (70% vs. 58%; P = .02), but success rates were significantly higher in patients who had not been previously exposed to antifungal drugs (71% vs. 52% in previously treated patients; P = .0005).

Novel antifungal therapies

It is encouraging to see early data on investigational antifungal therapies that are now entering early clinical development, and several compounds have generated interest at medical meetings.

CD101 is a novel echinocandin with an extended half-life that may enable once-weekly IV dosing. When compared in vitro with Cancidas (caspofungin, Merck), Mycamine (micafungin, Astellas Pharma) and Eraxis (anidulafungin, Pfizer), CD101 was active against evaluated strains of Candida spp., with potency similar to that of anidulafungin.

F901318 is a representative of the new orotomide class, with a potent activity against Aspergillus spp. In a phase 1, single-ascending dose study, healthy male volunteers aged 18 to 45 years were dosed with F901318 or placebo in 4-hour IV infusions. Overall, F901318 was well-tolerated across the dose range of 0.25 to 4 mg/kg with no observed adverse events.

VT-1161 is an oral inhibitor of CYP51 and blocks the production of ergosterol, an essential component of the fungal cell membrane. In vitro and in vivo studies have shown that VT-1161 has broad-spectrum activity against Candida spp. and dermatophytes, and early clinical trials have demonstrated efficacy in the treatment of vulvovaginal candidiasis and onychomycosis.

A study in immunosuppressed mice reported during ICAAC 2015 assessed VT-1161’s potential use as prophylaxis against the emerging and difficult-to-treat opportunistic mold infection mucormycosis. Two days before the mice were infected with Rhizopus oryzae (day –2), oral treatment was begun with VT-1161 15 mg/kg once daily, posaconazole 30 mg/kg twice daily or placebo (vehicle 0.5% carboxymethyl cellulose), continuing until the day of infection (prophylactic treatment), or started on day –2 and continuing until day 4 (continuous treatment). A comparator delayed-therapy arm comprised mice treated with posaconazole starting 1 day after infection until day 7.

When used in prophylaxis, only VT-1161 improved 21-day survival compared with placebo: 60% vs. 10% for placebo and 20% for posaconazole, with median survival times for placebo, VT-1161 and posaconazole of 8 days, at least 21 days and 12 days, respectively (P < .05). In continuous therapy, VT-1161 enhanced 21-day survival compared to placebo: 80% vs. 10%, with median survival for placebo and VT-1161 being 8 days and at least 21 days, respectively (P < .002). Continuous therapy with posaconazole resulted in 21-day survival of 50% and median survival time of 16 days, with a trend toward significance compared with placebo (P = .06), while posaconazole delayed therapy resulted in 40% survival and median survival time of 15 days (P = .12 compared with placebo).

Conclusion

These studies suggest that in the future, it may be possible to offer an expanded armamentarium of antifungal therapies to patients with IFI. Novel therapies alone, however, will likely not be sufficient to overcome the challenges posed by antifungal drug resistance. I look forward to further data on some of the newest clinical agents presented at recent conferences and further discussion on measures to ensure appropriate use of antifungal therapies, which should be essential components of all institutional antimicrobial stewardship programs. – by Dimitrios Kontoyiannis, MD

References:

Brown GD, et al. Sci Transl Med. 2012;doi:10.1126/scitranslmed.3004404.

Cleveland AA, et al. Clin Infect Dis. 2012;doi:10.1093/cid/cis697.

De Pauw B, et al. Clin Infect Dis. 2008;doi:10.1086/588660.

Gebremariam T, et al. Prophylactic treatment of pulmonary mucormycosis with VT-1161 using immunosuppressed mice. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept. 17-21, 2015; San Diego.

Hall D, et al. Abstract M-852 Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept. 17-21, 2015; San Diego.

Lockhart SR, et al. J Clin Microbiol. 2012;doi:10.1128/JCM.01283-12.

Shields RK, et al. Abstract M-1302. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept. 17-21, 2015; San Diego.

Disclosure: Kontoyiannis reports associations with companies including Astellas, Merck and Pfizer.