micafungin and Mucormycosis

To review the current literature for the pathogenesis of mucormycosis, discuss diagnostic strategies, and evaluate the efficacy of polyenes, triazoles, and echinocandins as pharmacological treatment options.. An electronic literature search was conducted in PubMed using the MESH terms Rhizopus, zygomycetes, zygomycosis, Mucorales and mucormycosis, with search terms amphotericin B, micafungin, anidulafungin, caspofungin, extended infusion amphotericin B, liposomal amphotericin B, combination therapy, triazole, posaconazole, isavuconazole, diagnosis, and clinical manifestations.. Studies written in the English language from January 1960 to March 2016 were considered for this review article. All search results were reviewed, and the relevance of each article was determined by the authors independently.. Mucormycosis is a rare invasive fungal infection with an exceedingly high mortality and few therapeutic options. It has a distinct predilection for invasion of endothelial cells in the vascular system, which is likely important in dissemination of disease from a primary focus of infection. Six distinct clinical syndromes can occur in susceptible hosts, including rhino-orbital-cerebral, pulmonary, gastrointestinal, cutaneous, widely disseminated, and miscellaneous infection.. Diagnosis of mucormycosis is typically difficult to make based on imaging studies, sputum culture, bronchoalveolar lavage culture, or needle aspirate. Surgical debridement prior to dissemination of infection improves clinical outcomes. Surgery combined with early, high-dose systemic antifungal therapy yields greater than a 1.5-fold increase in survival rates. The Mucorales are inherently resistant to most widely used antifungal agents. Amphotericin B is appropriate for empirical therapy, whereas posaconazole and isavuconazole are best reserved for de-escalation, refractory cases, or patients intolerant to amphotericin B.

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Caspofungin; Debridement; Drug Resistance, Fungal; Echinocandins; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Mucorales; Mucormycosis; Nitriles; Pyridines; Triazoles; Virulence

Micafungin is an echinocandin antifungal drug recently approved for the treatment of candidiasis. The possibility of its clinical use against other invasive mycoses, has aroused the interest of numerous investigators in evaluating its efficacy in different animal models.. To critically review the current data on the use of micafungin in the treatment of invasive mycoses in animal models.. We searched the PubMed/Medline data base (National Library of Medicine) from 2005 to 2008, both inclusive, on the use of micafungin in the experimental treatment of the fungal infection.. Seven, of a total of 18 articles reviewed, were done in animal models of candidiasis and six in animal models of pulmonary or SNC aspergillosis. Similarly to the other echinocandins, caspofungin and anidulafungin, micafungin seems to exert a fungicidal activity against Candida albicans and Candida glabrata and a fungistatic activity against Aspergillus fumigatus. The paradoxical effect observed in lung tissue the experimental caspofungin treatment of aspergillosis has not been seen in the case of micafungin. The available data demonstrate a higher efficacy of micafungin versus fluconazole in the experimental treatment of C. albicans infections caused by strains susceptible in vitro to both drugs. To improve the efficacy of micafungin in the treatment of C. glabrata and A. fumigatus infections, several authors have tested different combined therapies, the combination of micafungin with amphotericin B being that showed the best results.

Topics: Animals; Antifungal Agents; Aspergillosis; Candidiasis; Drug Evaluation, Preclinical; Echinocandins; Fusarium; Immunocompromised Host; Lipopeptides; Micafungin; Mice; Mucormycosis; Mycoses; Rabbits; Rats; Rhizopus; Saccharomycetales; Trichosporon

Posaconazole is a triazole antifungal with activity against Rhizopus, but data on its use and pharmacokinetics in preterm infants are scarce. In this case, a 24 4/7-week neonate's Rhizopus infection is successfully treated with debridement and combination antifungal therapy with amphotericin B, micafungin and enteral posaconazole. This is the first reported posaconazole use in a preterm neonate with Rhizopus.

Topics: Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Humans; Infant, Newborn; Infant, Premature; Male; Micafungin; Microbial Sensitivity Tests; Mucormycosis; Rhizopus; Triazoles

Infection caused by Cunninghamella bertholletiae carries one of the highest mortality rates among mucormycosis, and there are no reported cases that survived from the infection in allogeneic hematopoietic stem cell transplantation recipients occurring before neutrophil engraftment. Here, we present two cases of pulmonary mucormycosis caused by C. bertholletiae occurring before neutrophil engraftment after cord blood transplantation. Both were successfully treated with high-dose liposomal amphotericin B (10 mg/kg/day) combined with micafungin, which was then followed by neutrophil recovery, reduction in immunosuppressive agents, and a subsequent lobectomy. The intensive antifungal therapy immediately administered upon suspicion of mucormycosis greatly suppressed the infection in its early stage and was well tolerated despite its prolonged administration and simultaneous use of nephrotoxic agents after transplantation. Although the synergic effect of micafungin remains unclear, these cases highlight the importance of prompt administration of high-dose lipid polyene when suspecting mucormycosis in highly immunocompromised patients, which enables subsequent diagnostic and therapeutic interventions, resulting in a favorable outcome.

Topics: Adult; Aged; Amphotericin B; Antifungal Agents; Cord Blood Stem Cell Transplantation; Cunninghamella; Drug Therapy, Combination; Echinocandins; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Lipopeptides; Lung; Lung Diseases, Fungal; Male; Micafungin; Mucormycosis; Transplant Recipients; Treatment Outcome

Previously 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.. In 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.. Isavuconazole 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.. Isavuconazole 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.

Topics: Animals; Antifungal Agents; Drug Therapy, Combination; Echinocandins; Lipopeptides; Lung; Male; Micafungin; Mice; Microbial Sensitivity Tests; Mucor; Mucormycosis; Nitriles; Pyridines; Rhizopus; Triazoles

Airway mucormycosis is a deadly opportunistic infection that affects immunocompromised persons, particularly diabetics and those undergoing chemotherapy. Although it is typically a pulmonary or sinonasal infection, mucormycosis can affect the larynx and trachea, with devastating results. We report the case of a 46-year-old man with human immunodeficiency virus infection, hepatitis C infection, neurosyphilis, and recently diagnosed Burkitt lymphoma who presented with dysphonia and stridor after receiving one dose of intrathecal chemotherapy. Flexible laryngoscopy detected the presence of fibrinous material that was obstructing nearly the entire glottis. Surgical debridement revealed a firm mucosal attachment; there was little bleeding when it was removed. After debridement, the patient's dyspnea improved only to recur 2 days later. After an awake tracheotomy, laryngoscopy and bronchoscopy identified necrosis extending from the supraglottic area to the carina tracheae. Biopsies demonstrated hyphal architecture consistent with mucormycosis. Despite continued debridements, the fibrinous material reaccumulated. The patient was placed in hospice care; his airway remained patent, but he died from other causes several weeks after presentation. The management of airway mucormycosis is challenging and complex. Fungal airway infections should be considered in the differential diagnosis of an immunosuppressed patient who presents with dyspnea, dysphonia, and vocal fold immobility. Timely diagnosis and management are critical for a successful outcome, although the prognosis is poor if the infection is widespread, even with the best of efforts.

Topics: Antifungal Agents; Burkitt Lymphoma; Debridement; Dysphonia; Echinocandins; Hepatitis C, Chronic; HIV Infections; Humans; Hyperbaric Oxygenation; Laryngitis; Laryngoscopy; Lipopeptides; Male; Micafungin; Middle Aged; Mucormycosis; Neurosyphilis; Respiratory Distress Syndrome; Respiratory Sounds; Tracheitis; Tracheotomy; Triazoles

Whether isavuconazole, an extended-spectrum triazole, possesses synergistic activity in combination therapy with echinocandins or amphotericin B for the treatment of invasive molds infections has not been studied. Our in vitro combination studies showed that isavuconazole and micafungin are synergistically active against Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, and Cunninghamella bertholletiae. These results suggest that isavuconazole, in combination with micafungin, may have a role in the treatment of invasive aspergillosis and warrants further investigation.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Aspergillus; Cunninghamella; Deoxycholic Acid; Drug Combinations; Drug Interactions; Echinocandins; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Mucormycosis; Nitriles; Pyridines; Triazoles

Topics: Acute Kidney Injury; Adult; Amphotericin B; Antifungal Agents; Debridement; Echinocandins; Humans; Lipopeptides; Lung Diseases, Fungal; Male; Micafungin; Mucormycosis; Pneumonectomy; Triazoles

Liposomal amphotericin B (LAmB) combined wither either micafungin or deferasirox was synergistic in previous murine studies with mucormycosis or aspergillosis. We hypothesized that triple therapy using LAmB, micafungin, and deferasirox could further improve outcomes of mucormycosis or aspergillosis. Triple therapy improved survival and reduced tissue fungal burden of mice with mucormycosis and to a lesser extent with aspergillosis. Continued investigation into the use of triple therapy against mucormycosis and aspergillosis is warranted.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Disease Models, Animal; Echinocandins; Iron Chelating Agents; Lipopeptides; Micafungin; Mice; Mice, Inbred BALB C; Mucormycosis; Polyenes; Rhizopus

Mucormycosis is a deadly angioinvasive fungal infection that is increasing in incidence. Gastrointestinal and abdominal involvement is rare, has higher mortality rates, and is frequently diagnosed late.. We report a patient who sustained multiple gunshot wounds to the chest and abdomen and subsequently developed omental and hepatic mucormycosis. He underwent 14 abdominal washouts and several liver debridements, and he received combination therapy with amphotericin B and micafungin.. The patient survived the disease, with negative cultures and pathology at the last washout, and underwent skin grafting. He is clinically improved and remains on oral antifungals as an outpatient.. Mucormycosis should be considered in trauma patients with persistent signs of infection after lavage and antibiotics, especially when necrosis or atypical wound presentations are noted. Approaches such as ours using aggressive surgical management and intensive antifungal administration should be instituted once the diagnosis is suspected.

Topics: Abdominal Injuries; Adult; Amphotericin B; Antifungal Agents; Drug Therapy, Combination; Echinocandins; Humans; Lipopeptides; Male; Micafungin; Mucormycosis; Rhizopus; Wounds, Gunshot

A broth microdilution method was used to evaluate the in vitro activities of seven antifungal agents against 15 clinical strains of Rhizopus microsporus. Amphotericin B (AMB) and posaconazole (POS) were the most active drugs. In a model of disseminated R. microsporus infection in immunosuppressed mice, we studied the efficacy of POS administered once or twice daily against four of the strains previously tested in vitro and compared it with that of liposomal AMB (LAMB). LAMB was the most effective treatment for the two strains with intermediate susceptibility to POS. For the two POS-susceptible strains, LAMB and POS at 20 mg/kg of body weight twice a day orally showed similar efficacies. The in vivo efficacy of POS administered twice a day orally correlated with the in vitro susceptibility data and the serum drug concentrations.

Topics: Amphotericin B; Animals; Antifungal Agents; Brain; Kidney; Male; Mice; Mucormycosis; Rhizopus; Triazoles

We previously found that caspofungin synergized with amphotericin B lipid complex in treating murine mucormycosis. We now report a similarly enhanced activity of liposomal amphotericin combined with micafungin or anidulafungin in mice with disseminated mucormycosis. The efficacy of combination echinocandin-polyene therapy for mucormycosis is a class effect.

Topics: Amphotericin B; Anidulafungin; Animals; Antifungal Agents; Disease Models, Animal; Drug Therapy, Combination; Echinocandins; Humans; Lipopeptides; Lipoproteins; Liposomes; Male; Micafungin; Mice; Mice, Inbred BALB C; Mucormycosis; Polyenes; Rhizopus; Treatment Outcome

We report 2 pediatric cases of cerebral fungal infection. A patient with severe aplastic anemia developed an Aspergillus species brain abscess and pulmonary aspergillosis after peripheral blood stem cell transplantation. Despite administration of micafungin, amphotericin B, and flucytosine, the patient died 2 months after the transplantation because of underlying pulmonary aspergillosis. Another patient with acute myelogenous leukemia developed a huge brain abscess with histopathologic findings suspicious of mucormycosis. This patient was cured with combination therapy of antifungal agents and intensive surgery, without sequelae. It is important to perform aggressive multimodality treatment, when indicated, including surgical intervention, even if in myelosuppression.

Topics: Adolescent; Amphotericin B; Anti-Bacterial Agents; Antifungal Agents; Aspergillosis; Central Nervous System Fungal Infections; Child; Drug Combinations; Echinocandins; Fatal Outcome; Female; Flucytosine; Follow-Up Studies; Graft Rejection; Hematologic Diseases; Humans; Leukemia, Myeloid, Acute; Lipopeptides; Lipoproteins; Magnetic Resonance Imaging; Male; Micafungin; Mucormycosis; Peripheral Blood Stem Cell Transplantation; Remission Induction; Treatment Outcome

A 59-year-old man was admitted to our hospital with a diagnosis of acute myeloid leukemia in September 2004. He developed invasive pulmonary aspergillosis (IPA) and candidiasis, which were improved by administration of micafungin and amphotericin B (AMPH-B). He received reduced-intensity unrelated cord-blood transplantation without induction chemotherapy. He developed grade IV graft-versus-host disease (GVHD) and the administration of steroids against GVHD was prolonged. Voriconazole (VRCZ) was used for a long period to prevent recurrence of the IPA. Afterwards, infiltrates in the bilateral upper lung fields were detected on a chest CT scan, and a diagnosis of pulmonary mucormycosis was made following detection of Mucor circinelloides from the patient's sputum culture. He then began receiving AMPH-B but died of massive hemoptysis. Mucormycosis usually occurs in immunocompromised hosts such as neutropenic patients with hematologic diseases and is a fatal fungal infection characterized by a rapid and progressive clinical course. Some overseas investigators have recently reported that VRCZ prophylaxis may result in breakthrough mucormycosis in hematopoietic stem cell transplant recipients. These findings suggest that it is very important to pay attention to mucormycosis in hematopoietic stem cell transplant recipients in this country.

Topics: Amphotericin B; Antifungal Agents; Aspergillosis; Cord Blood Stem Cell Transplantation; Echinocandins; Fatal Outcome; Graft vs Host Disease; Humans; Immunocompromised Host; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Lipopeptides; Lipoproteins; Lung Diseases, Fungal; Male; Micafungin; Middle Aged; Mucormycosis; Peptides, Cyclic; Pyrimidines; Transplantation Conditioning; Triazoles; Voriconazole

Invasive rhinocerebral mucormycosis is a rare and often fatal opportunistic fungal infection. It is encountered in immunocompromised hosts exemplified by those with diabetes, human immunodeficiency viruses and particularly haematologic malignancies typically after high-dose chemotherapy and stem cell transplantation. In contrast to the more usual outcome with rapid progression and death. We now describe a successful eradication attributable to the use of a newly available antifungal agent.. Haematology department and bone marrow transplantation unit.. Two patients are contrasted. The first with acute leukaemia developed rapidly progressive facial swelling with mucormycosis proven on biopsy. Treatment over 2 months with maximally tolerated doses of amphotericin failed to halt intracranial extension and death resulted. The second, presented with acute lymphoblastic leukaemia in August 1997, underwent successful autologous bone marrow transplantation in February 1998. Relapse followed in March 1999 and after reinduction and consolidation receive a matched unrelated volunteer allograft in September 1999. A second recurrence was documented in April 2000 and in spite of achieving remission he developed a fever that was managed empirically with intravenous amphotericin and, on discharge, oral itraconazole. Left-sided facial swelling expanded rapidly and biopsy showed extensive invasion of the maxillary sinus with mucormycosis. FK463 was added on 5 June 2000 with gradual reduction in facial pain and within 1 month all clinical signs and resolved. Serial biopsies that included histopathologic investigation and microbiologic cultures confirmed eradication of the invasive mucor. In view of the potential danger of recrudescence this treatment regimen was continued through further chemotherapy and, once again disease-free, a second matched unrelated volunteer allograft took place in August 2000. Full reassessment at the time failed to demonstration any residual fungus. Engraftment was confirmed but neutropenic sepsis resulted in severe inflammatory response syndrome with progression to multiple organ dysfunction to which he succumbed without any evidence of leukaemic or systemic mycosis.. Echinocandin FK463 is of documented value in managing invasive candidiasis and aspergillosis. This is believed to be the first case of successful outcome with one of the angiotrophic zygomycetes.

Topics: Acute Disease; Adolescent; Adult; Amphotericin B; Antifungal Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Combined Modality Therapy; Drug Evaluation; Echinocandins; Fatal Outcome; Female; Humans; Immunocompromised Host; Itraconazole; Leukemia, Myeloid; Lipopeptides; Lipoproteins; Male; Micafungin; Mucormycosis; Multiple Organ Failure; Peptides, Cyclic; Periodontal Abscess; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Sinusitis; Splenectomy; Systemic Inflammatory Response Syndrome; Transplantation, Homologous