micafungin and Neoplasms

Invasive fungal infections have emerged as important causes of morbidity and mortality in profoundly immunocompromised patients with cancer. Current treatment strategies for these infections are limited by antifungal resistance, toxicity, drug interactions, and expense. In order to overcome these limitations, new antifungal compounds are being developed, which may improve our therapeutic armamentarium for prevention and treatment of invasive mycoses in high-risk patients with neoplastic diseases.

Topics: Anidulafungin; Antifungal Agents; Echinocandins; Humans; Immunocompromised Host; Lipopeptides; Lipoproteins; Micafungin; Mycoses; Neoplasms; Opportunistic Infections; Peptides, Cyclic; Pyrimidines; Triazoles; Voriconazole

The aim of this study was to evaluate micafungin efficacy for treatment of invasive candidiasis/candidaemia in patients with cancer. Modified intent-to-treat populations were analysed from two trials: one, in adults and children with confirmed Candida infection, compared micafungin (adults 100 mg day(-1); children 2 mg kg(-1) day(-1)) with liposomal amphotericin B (L-AmB 3 mg kg(-1) day(-1)); and the other, in adults only, compared micafungin (100 or 150 mg day(-1)) with caspofungin (50 mg day(-1); 70 mg loading dose). Primary efficacy endpoint in both trials was treatment success, defined as both clinical and mycological response at end of therapy. In the micafungin/L-AmB trial, 183/489 patients had malignancy (37% neutropenic). In the micafungin/caspofungin trial, 176/572 patients had malignancy (26% neutropenic). Micafungin treatment success rates were generally similar in patients with/without malignancy and to rates observed with L-AmB and caspofungin. Most patients with malignancy and neutropenia were successfully treated by all three drugs. For all drugs, incidence of discontinuations because of treatment-related adverse events was similar for patients with malignancy (≤7.7%) vs. no malignancy (≤8.0%). These results suggest that compared with L-AmB and caspofungin, micafungin was effective and well tolerated in patients with candidiasis/candidaemia with/without malignancy. Further prospective trials are recommended to evaluate comparative outcomes with a primary focus on patients with malignancies and invasive candidiasis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amphotericin B; Antifungal Agents; Candidiasis; Caspofungin; Child; Child, Preschool; Double-Blind Method; Echinocandins; Female; Humans; Infant; Infant, Newborn; Lipopeptides; Male; Micafungin; Middle Aged; Neoplasms; Treatment Outcome; Young Adult

In this dose escalation study, 74 adult cancer patients undergoing bone marrow or peripheral blood stem cell transplantation received fluconazole (400 mg/day) and either normal saline (control) (12 subjects) or micafungin (12.5 to 200 mg/day) (62 subjects) for up to 4 weeks. The maximum tolerated dose (MTD) of micafungin was not reached, based on the development of Southwest Oncology Group criteria for grade 3 toxicity; drug-related toxicities were rare. Commonly occurring adverse events considered related to micafungin were headache (6.8%), arthralgia (6.8%), hypophosphatemia (4.1%), insomnia (4.1%), maculopapular rash (4.1%), and rash (4.1%). Pharmacokinetic profiles for micafungin on days 1 and 7 were similar. The mean half-life was approximately 13 h, with little variance after repeated or increasing doses. Mean maximum concentrations of the drug in serum and areas under the concentration-time curve from 0 to 24 h were approximately proportional to dose. There was no clinical or kinetic evidence of interaction between micafungin and fluconazole. Five of 12 patients (42%) in the control group and 14 of 62 (23%) in the micafungin-plus-fluconazole groups had a suspected fungal infection during treatment which resulted in empirical treatment with amphotericin B. The combination of micafungin and fluconazole was found to be safe in this high-risk patient population. The MTD of micafungin was not reached even at doses up to 200 mg/day for 4 weeks. The pharmacokinetic profile of micafungin in adult cancer patients with blood or marrow transplants is consistent with the profile in healthy volunteers, and the area under the curve is proportional to dose.

Topics: Adolescent; Adult; Antifungal Agents; Area Under Curve; Bone Marrow Transplantation; Chemoprevention; Double-Blind Method; Drug Therapy, Combination; Echinocandins; Female; Fluconazole; Humans; Lipopeptides; Lipoproteins; Male; Micafungin; Middle Aged; Mycoses; Neoplasms; Peptides, Cyclic; Stem Cell Transplantation

Neddylation is a protein modification process similar to ubiquitination, carried out through a series of activating (E1), conjugating (E2), and ligating (E3) enzymes. This process has been found to be overactive in various cancers, leading to increased oncogenic activities. Ubiquitin-conjugating enzyme 2 M (UBE2M) is one of two neddylation enzymes that play a vital role in this pathway. Studies have shown that targeting UBE2M in cancer treatment is crucial, as it regulates many molecular mechanisms like DNA damage, apoptosis, and cell proliferation. However, developing small molecule inhibitors against UBE2M remains challenging due to the lack of suitable druggable pockets. We have discovered that Micafungin, an antifungal agent that inhibits the production of 1,3-β-D-glucan in fungal cell walls, acts as a neddylation inhibitor that targets UBE2M. Biochemical studies reveal that Micafungin obstructs neddylation and stabilizes UBE2M. In cellular experiments, the drug was found to interact with UBE2M, prevent neddylation, accumulate cullin ring ligases (CRLs) substrates, reduce cell survival and migration, and induce DNA damage in gastric cancer cells. This research uncovers a new anti-cancer mechanism for Micafungin, paving the way for the development of a novel class of neddylation inhibitors that target UBE2M.

Topics: Antifungal Agents; Apoptosis; Cell Nucleus; Cell Proliferation; Micafungin; Neoplasms; Ubiquitin-Conjugating Enzymes

The response rate among 58 patients with cancer and candidemia or deep-seated candidiasis treated with micafungin monotherapy was 81%. Intensive care unit (ICU) stay, concomitant nonfungal infections, and acute kidney injury were significantly associated with the 30-day crude mortality rate. Severe neutropenia was an independent predictor of micafungin failure. The efficacy and safety of micafungin in cancer patients with invasive candidiasis were comparable to those reported for patients without malignancy and for cancer patients treated with caspofungin.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Candidemia; Candidiasis; Candidiasis, Invasive; Echinocandins; Female; Humans; Intensive Care Units; Lipopeptides; Male; Micafungin; Middle Aged; Neoplasms; Neutropenia; Young Adult

The results of a 3-year experience with voriconasole in oncologic practice are presented. Rational schemes for the use of caspofungin and mycofungin in the treatment of oncologic inpatients and the criteria of their use in the therapy of fungal nosocomial infections were developmed. Good clinical and microbiological efficacy of caspofungin and mycofungin against Candida non-albicans was shown.

Topics: Aged; Antifungal Agents; Candida; Candidiasis; Caspofungin; Cross Infection; Drug Resistance, Fungal; Echinocandins; Female; Humans; Intensive Care Units; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Middle Aged; Neoplasms

Invasive fungal infections (IFIs) remain a major cause of infectious morality in neutropenic patients receiving chemotherapy or hematopoietic stem cell transplantation (HSCT). Micafungin exhibits broad antifungal activity against both Aspergillus and Candida species. We performed a retrospective study to determine the efficacy and safety of prophylactic micafungin against IFI in pediatric neutropenic patients during chemotherapy or HSCT.. Forty patients were given micafungin (3 mg/kg/day) intravenously for neutropenia: 131 patient-cycles (39 patients) after chemotherapy and 15 patient-cycles (14 patients) after HSCT. Median duration of neutropenia and micafungin prophylaxis was 13 and 23 days after chemotherapy and HSCT, respectively.. Treatment success rate, defined as absence of proven, probable, possible, or suspected IFIs, was 93.9% (121/131) and 80.0% (12/15) for chemotherapy and HSCT, respectively. Proven or probable IFI was documented in only one patient after HSCT. No adverse events were observed that could be related to micafungin prophylaxis.. These results suggest that prophylactic micafungin is well tolerated and may prevent IFIs in pediatric patients with neutropenia receiving chemotherapy or HSCT.

Topics: Adolescent; Antifungal Agents; Antineoplastic Agents; beta-Glucans; Child; Child, Preschool; Echinocandins; Hematopoietic Stem Cell Transplantation; Humans; Infant; Lipopeptides; Micafungin; Mycoses; Neoplasms; Neutropenia; Retrospective Studies

Paradoxical growth of some Candida isolates occurs at concentrations above the MIC for echinocandins. In 60 Candida bloodstream isolates from cancer patients (20 C. albicans isolates and 10 isolates each of C. parapsilosis, C. tropicalis, C. krusei, and C. glabrata), paradoxical growth was more frequent with caspofungin than micafungin or anidulafungin, was unrelated to MIC, and was strikingly absent in C. glabrata isolates.

Topics: Antifungal Agents; Candida; Candidiasis; Culture Media; Fungemia; Humans; Microbial Sensitivity Tests; Neoplasms; Peptides, Cyclic; Species Specificity

The in vitro activities of voriconazole, posaconazole, ravuconazole and micafungin were compared with those of fluconazole, itraconazole, ketoconazole, flucytosine and amphotericin B against 164 candidaemia isolates recovered from cancer patients in two Canadian centres. The MIC(50) results for ravuconazole, voriconazole, posaconazole and micafungin were 0.01, 0.03, 0.12 and 0.25 mg/L, respectively. The new antifungal agents showed substantial activity against isolates demonstrating in vitro resistance to fluconazole and itraconazole. These results suggest that the newer antifungal agents possess promising activity against invasive Candida isolates, particularly against those with reduced susceptibility to fluconazole and itraconazole.

Topics: Antifungal Agents; Blood; Candida; Candidiasis; Echinocandins; Humans; In Vitro Techniques; Lipopeptides; Lipoproteins; Micafungin; Microbial Sensitivity Tests; Neoplasms; Peptides, Cyclic; Pyrimidines; Thiazoles; Triazoles; Voriconazole