A Fungal Immunotherapeutic Vaccine (NDV-3A) for Treatment of Recurrent Vulvovaginal Candidiasis-A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial.

Background: Recurrent vulvovaginal candidiasis (RVVC) is a problematic form of mucosal Candida infection, characterized by repeated episodes per year. Candida albicans is the most common cause of RVVC. Currently, there are no immunotherapeutic treatments for RVVC. Methods: This exploratory randomized, double-blind, placebo-controlled trial evaluated an immunotherapeutic vaccine (NDV-3A) containing a recombinant C. albicans adhesin/invasin protein for prevention of RVVC. Results: The study in 188 women with RVVC (n = 178 evaluable) showed that 1 intramuscular dose of NDV-3A was safe and generated rapid and robust B- and T-cell immune responses. Post hoc exploratory analyses revealed a statistically significant increase in the percentage of symptom-free patients at 12 months after vaccination (42% vaccinated vs 22% placebo; P = .03) and a doubling in median time to first symptomatic episode (210 days vaccinated vs 105 days placebo) for the subset of patients aged <40 years (n = 137). The analysis of evaluable patients, which combined patients aged <40 years (77%) and ≥40 years (23%), trended toward a positive impact of NDV-3A versus placebo (P = .099). Conclusions: In this unprecedented study of the effectiveness of a fungal vaccine in humans, NDV-3A administered to women with RVVC was safe and highly immunogenic and reduced the frequency of symptomatic episodes of vulvovaginal candidiasis for up to 12 months in women aged <40 years. These results support further development of NDV-3A vaccine and provide guidance for meaningful clinical endpoints for immunotherapeutic management of RVVC. Clinical Trials Registration: NCT01926028.

Anidulafungin pharmacokinetics and microbial response in neutropenic mice with disseminated candidiasis.

Candidemia is often fatal, especially in patients with persistent neutropenia. New therapies are needed. We performed 24-h pharmacodynamic studies to compare the efficacies of anidulafungin, fluconazole, and amphotericin B in neutropenic mice with disseminated candidiasis caused by one of three strains of Candida glabrata. Anidulafungin produced a maximal fungal kill (E(max)) of 1.4 to 1.9 log(10) CFU/g in kidneys and was not influenced by resistance to either fluconazole or amphotericin B. Fluconazole produced an E(max) of 1.3 log(10) CFU/g in mice infected with fluconazole-susceptible C. glabrata, but the E(max) was 0 for mice infected with a C. glabrata strain that had a fluconazole MIC of >/=32 mg/liter. Amphotericin B achieved an E(max) of 4.2 log(10) CFU/g in mice infected with amphotericin B-susceptible C. glabrata, but the E(max) was 0 for mice infected with a C. glabrata strain with an amphotericin B MIC of 2 mg/liter. In all instances, anidulafungin's maximal microbial kill was superior to that of fluconazole. Next, we performed a 96-h anidulafungin pharmacokinetic-pharmacodynamic study. Anidulafungin exhibited delayed peak concentrations in kidneys compared to those in serum, after which the concentrations declined, with a serum terminal half-life of 21.6 (+/-4.6) h. This was accompanied by a persistent 96-h decrease in the kidney fungal burden after treatment with a single anidulafungin dose of >/=8 mg/kg of body weight. This pharmacokinetic-pharmacodynamic picture of anidulafungin persistence in tissues and the resultant persistent fungal decline should be exploited to improve the efficacy of anidulafungin therapy for candidemia.

Pharmacodynamics of caspofungin in a murine model of systemic candidiasis: importance of persistence of caspofungin in tissues to understanding drug activity.

Pharmacokinetic and pharmacodynamic studies were conducted in a murine model of systemic candidiasis to determine the pharmacodynamic parameter linked with caspofungin efficacy. Additional studies defined the importance of persistent tissue drug concentrations to treatment outcome. The pharmacokinetics of caspofungin were determined in the serum and kidneys of infected mice over 96 h. Population pharmacokinetic analysis demonstrated a serum terminal half-life (t(1/2)) for caspofungin of 20.2 h when only serum concentrations were considered, but the terminal t(1/2) increased to 59.2 h when serum and kidney concentration-time data were co-modeled. In dose-range studies, the dose-response effect was well described by an inhibitory sigmoid curve for the exposure-effect killing caused by the drug (r2 > 0.96; P << 0.001). In dose-fractionation studies, fungal counts in kidneys were not statistically different for total doses given as one, two, or four equally divided doses over 96 h, indicating that the area under the concentration-time curve/MIC is the pharmacodynamic parameter that predicts caspofungin efficacy in our infection model. In a separate study, mice infected with Candida albicans 24 h after serum concentrations of caspofungin fell below the MIC for the fungal isolate had significant reductions in fungal densities in their kidneys compared with the growth of fungi in the kidneys of untreated controls (P = 0.005). This in vivo biological assay demonstrates that therapeutic concentrations of caspofungin persist at the site of infection in kidney tissue well after serum concentrations fall below the MIC, underscoring the primacy of caspofungin levels in tissues on determining treatment outcome.