Treatment and outcomes of invasive fusariosis: review of 65 cases from the PATH Alliance ® registry

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109347/1/myc12212.pd

Ibrexafungerp, a Novel Triterpenoid Antifungal in Development for the Treatment of Mold Infections

Molds are ubiquitous in the environment, and immunocompromised patients are at substantial risk of morbidity and mortality due to their underlying disease and the resistance of pathogenic molds to currently recommended antifungal therapies. This combination of weakened-host defense, with limited antifungal treatment options, and the opportunism of environmental molds renders patients at risk and especially vulnerable to invasive mold infections such as Aspergillus and members of the Order Mucorales. Currently, available antifungal drugs such as azoles and echinocandins, as well as combinations of the same, offer some degree of efficacy in the prevention and treatment of invasive mold infections, but their use is often limited by drug resistance mechanisms, toxicity, drug-drug interactions, and the relative paucity of oral treatment options. Clearly, there is a need for agents that are of a new class that provides adequate tissue penetration, can be administered orally, and have broad-spectrum efficacy against fungal infections, including those caused by invasive mold organisms. Ibrexafungerp, an orally bioavailable glucan synthase inhibitor, is the first in a new class of triterpenoid antifungals and shares a similar target to the well-established echinocandins. Ibrexafungerp has a very favorable pharmacokinetic profile for the treatment of fungal infections with excellent tissue penetration in organs targeted by molds, such as the lungs, liver, and skin. Ibrexafungerp has demonstrated in vitro activity against Aspergillus spp. as well as efficacy in animal models of invasive aspergillosis and mucormycosis. Furthermore, ibrexafungerp is approved for use in the USA for the treatment of women with vulvovaginal candidiasis. Ibrexafungerp is currently being evaluated in clinical trials as monotherapy or in combination with other antifungals for treating invasive fungal infections caused by yeasts and molds. Thus, ibrexafungerp offers promise as a new addition to the clinician's armamentarium against these difficult-to-treat infections.Experiments reported in this manuscript were funded by Scynexis and support for mucormycosis research was provided by the NIH/NIAID under Contract No. HHSN272201700039I (Task order A34-HHSN27200003).S

Oral Ibrexafungerp for Vulvovaginal Candidiasis Treatment: An Analysis of VANISH 303 and VANISH 306

Background: Ibrexafungerp is a novel antifungal treatment for acute vulvovaginal candidiasis (VVC). Using pooled data from two phase three studies (VANISH 303 and 306) in the treatment of acute VVC, this analysis sought to determine the effectiveness of ibrexafungerp in various patient subgroups that may impact outcomes. Materials and Methods: Data from VANISH 303 (NCT03734991) and VANISH 306 (NCT03987620) evaluating ibrexafungerp 300 mg twice daily (BID) for 1 day versus placebo, were pooled and analyzed to determine clinical cure rate, clinical improvement, and mycological cure at the test-of-cure visit (day 11 ± 3) and symptom resolution at the follow-up visit (day 25 ± 4) in the overall population. Patient subgroups analyzed included race, body mass index (BMI), baseline vulvovaginal signs and symptoms (VSS) score, and Candida species. Results: At the test-of-cure visit, patients receiving ibrexafungerp, compared with those who received placebo, had significantly higher rates of clinical cure (56.9% [214/376 patients] vs. 35.7% [65/182 patients]), clinical improvement (68.4% [257/376 patients] vs. 45.1% [82/182 patients]), and mycological cure (54.0% [203/376 patients] vs. 24.2% [44/182 patients]; all p \u3c 0.0001). At the follow-up visit, patients receiving ibrexafungerp had sustained responses with higher symptom resolution rates (66.8% [251/376 patients]) versus placebo (48.4% [88/182 patients]; p \u3c 0.0001). Race, BMI, baseline VSS score (including VSS severity score 13-18), and Candida species infection did not adversely affect clinical cure rates. Safety analysis results were consistent with the individual studies. Conclusions: Ibrexafungerp provides a safe and well-tolerated first-in-class fungicidal, 1-day oral treatment for patients with acute VVC, the first new therapy in \u3e20 years. Clinical Trial Registration Number: NCT03734991

Insect Destroyer

Patent for an insect destroyer. Illustration included

Monotherapy or combination therapy of isavuconazole and micafungin for treating murine mucormycosis.

ObjectivesPreviously we demonstrated the benefit of isavuconazole in treating murine mucormycosis due to Rhizopus. We wanted to determine the efficacy of isavuconazole in treating murine mucormycosis caused by Mucor, the second most common cause of the disease. Furthermore, because we previously determined that Rhizopus possesses the target enzyme for echinocandins and micafungin has activity against murine mucormycosis, we compared the activity of combination therapy (isavuconazole + micafungin) with placebo, either drug alone or standard therapy of liposomal amphotericin B (LAmB) in treating pulmonary murine mucormycosis caused by Rhizopus delemar.MethodsIn vitro susceptibility to isavuconazole of Mucorales was evaluated using the CLSI M38-A2 method. Immunosuppressed mice were intratracheally infected with either Mucor circinelloides or R. delemar. Treatment with isavuconazole (orally), micafungin (intraperitoneally), a combination of both or LAmB (intravenously) was compared, with survival and tissue fungal burden serving as primary and secondary endpoints, respectively.ResultsIsavuconazole was as effective as LAmB in prolonging survival of mice infected with M. circinelloides. Against R. delemar-induced mucormycosis, all monotherapy treatments significantly improved survival of mice versus placebo without showing superiority over one another. However, LAmB was superior in lowering fungal burden in target organs. Although combination therapy of isavuconazole + micafungin did not enhance survival of mice over monotherapy, antagonism was not detected between the two drugs.ConclusionIsavuconazole is effective in treating pulmonary murine mucormycosis due to Mucor. In addition, combination therapy of isavuconazole + micafungin does not demonstrate synergy and it is not antagonistic against Rhizopus-induced mucormycosis

Epidemiology and outcomes of invasive candidiasis due to non-albicans species of Candida in 2,496 patients: data from the Prospective Antifungal Therapy (PATH) registry 2004-2008.

This analysis describes the epidemiology and outcomes of invasive candidiasis caused by non-albicans species of Candida in patients enrolled in the Prospective Antifungal Therapy Alliance (PATH Alliance) registry from 2004 to 2008. A total of 2,496 patients with non-albicans species of Candida isolates were identified. The identified species were C. glabrata (46.4%), C. parapsilosis (24.7%), C. tropicalis (13.9%), C. krusei (5.5%), C. lusitaniae (1.6%), C. dubliniensis (1.5%) and C. guilliermondii (0.4%); 111 infections involved two or more species of Candida (4.4%). Non-albicans species accounted for more than 50% of all cases of invasive candidiasis in 15 of the 24 sites (62.5%) that contributed more than one case to the survey. Among solid organ transplant recipients, patients with non-transplant surgery, and patients with solid tumors, the most prevalent non-albicans species was C. glabrata at 63.7%, 48.0%, and 53.8%, respectively. In 1,883 patients receiving antifungal therapy on day 3, fluconazole (30.5%) and echinocandins (47.5%) were the most frequently administered monotherapies. Among the 15 reported species, 90-day survival was highest for patients infected with either C. parapsilosis (70.7%) or C. lusitaniae (74.5%) and lowest for patients infected with an unknown species (46.7%) or two or more species (53.2%). In conclusion, this study expands the current knowledge of the epidemiology and outcomes of invasive candidiasis caused by non-albicans species of Candida in North America. The variability in species distribution in these centers underscores the importance of local epidemiology in guiding the selection of antifungal therapy

Prior antifungal therapy.

<p>*other species includes: <i>C. kefyr</i> (nine isolates), <i>C. famata</i> (four isolates), <i>C. rugosa</i> (three isolates), <i>C. utilis</i> (two isolates) and one isolate each of <i>C. fennica</i>, <i>C. fermentati</i>, <i>C. lipolytica</i>, and <i>Torulopsis</i> spp.</p>†<p>multiple species include <i>C. parapsilosis+C. glabrata</i> (n = 30), <i>C. tropicalis+C. glabrata</i> (n = 21), <i>C. krusei+C. glabrata</i> (n = 8), <i>C. dubliniensis+C. glabrata</i> (n = 3), <i>C. lusitaniae+C. glabrata</i> (n = 4), other <i>Candida</i> spp.<i>+C. glabrata</i> (n = 3), unknown <i>Candida spp.+C. glabrata</i> (n = 3), <i>C. guilliermondii+C. glabrata</i> (n = 2), <i>C. parapsilosis+C. krusei</i> (n = 5), <i>C. lusitaniae+C. krusei</i> (n = 2), <i>C. tropicalis+C. dubliniensis</i> (n = 1), <i>C. tropicalis+C. guilliermondii</i> (n = 1), <i>C. tropicalis+C. krusei</i> (n = 4), other <i>Candida</i> spp.+<i>C. guilliermondii.</i></p

90-day survival stratified by non-<i>albicans Candida</i> species.

<p>90-day survival stratified by non-<i>albicans Candida</i> species.</p

Antifungal treatment administered by species on infection day 3.

<p>*Other species includes: <i>C. kefyr</i> (nine isolates), <i>C. famata</i> (four isolates), <i>C. rugosa</i> (three isolates), <i>C. utilis</i> (two isolates) and one isolate each of <i>C. fennica</i>, <i>C. fermentati</i>, <i>C. lipolytica</i>, and <i>Torulopsis</i> spp.</p>†<p>multiple species include <i>C. parapsilosis+C. glabrata</i> (n = 30), <i>C. tropicalis+C. glabrata</i> (n = 21), <i>C. krusei+C. glabrata</i> (n = 8), <i>C. dubliniensis+C. glabrata</i> (n = 3), <i>C. lusitaniae+C. glabrata</i> (n = 4), other <i>Candida</i> spp.<i>+C. glabrata</i> (n = 3), unknown <i>Candida spp.+C. glabrata</i> (n = 3), <i>C. guilliermondii+C. glabrata</i> (n = 2), <i>C. parapsilosis+C. krusei</i> (n = 5), <i>C. lusitaniae+C. krusei</i> (n = 2), <i>C. tropicalis+C. dubliniensis</i> (n = 1), <i>C. tropicalis+C. guilliermondii</i> (n = 1), <i>C. tropicalis+C. krusei</i> (n = 4), other <i>Candida</i> spp.+<i>C.</i> guilliermondii (n = 1), unknown <i>Candida</i> spp.+C. <i>dubliensis</i> (n = 1), <i>C. glabrata+C. krusei+C. lusitaniae</i> (n = 1), <i>C. dubliniensis+C.glabrata+C.guilliermondii</i> (n = 1).</p>§<p>patients in this category were in a blinded clinical trial.</p>‡<p>Other combination therapies included lipid amphotericin B +5-fluorocytosine (n = 7), lipid amphotericin B+fluconazole (n = 10), amphotericin B deoxycholate+lipid amphotericin B (n = 1), amphotericin B deoxycholate+fluconazole (n = 2), echinocandins +5-fluorocytosine (n = 1), echinocandins+amphotericin B deoxycholate (n = 9), echinocandins+fluconazole (n = 1), echinocandins+itraconazole (n = 1), fluconazole+blinded (n = 1), fluconazole+voriconazole (n = 8).</p