Voriconazole: therapeutic review of a new azole antifungal

The new triazole antifungal, voriconazole (Vfend^®, Pfizer Ltd), was developed for the treatment of life-threatening fungal infections in immunocompromised patients. The drug, which is available for both oral and intravenous administration, has broad-spectrum activity against pathogenic yeasts, dimorphic fungi and opportunistic moulds. Unlike fluconazole (Diflucan^®, Pfizer Ltd), voriconazole has potent in vitro activity against Aspergillus spp., Fusarium spp. and Scedosporium apiospermum. In Phase II/III trials, voriconazole was well-tolerated and had excellent clinical efficacy in patients with fluconazole-sensitive and -resistant candida infection, aspergillosis, and various refractory fungal infections. The US Food and Drug Administration approved voriconazole in May 2002 for the treatment of invasive aspergillosis, and serious infections caused by Fusarium and S. apiospermum in patients who are intolerant of, or refractory to, other antifungal agents. In Europe, voriconazole is approved by the European Medicines Agency for the treatment of invasive aspergillosis, serious infections caused by Fusarium and S. apiospermum, and fluconazole-resistant serious invasive candida infections (including C. krusei).     

Open-label, randomized comparison of itraconazole versus caspofungin for prophylaxis in patients with hematologic malignancies

Invasive fungal infection remains the most common cause of infectious death in acute leukemia. In this open-label, randomized study, we compared the efficacy and safety of caspofungin with that of intravenous itraconazole for antifungal prophylaxis in patients undergoing induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome. Of 200 patients, 192 were evaluable for efficacy (86 for itraconazole, 106 for caspofungin). Duration of prophylaxis (median, 21 days [range, 1 to 38 days]), demographics, and prognostic factors were similar in both groups. Ninety-nine patients completed antifungal prophylaxis without developing fungal infection (44 [51%] with itraconazole, 55 [52%] with caspofungin). Twelve patients developed documented invasive fungal infections, five in the itraconazole group (four with candidemia and one with Aspergillus pneumonia), and seven in the caspofungin group (two with candidemia, two with disseminated trichosporon species, two with Aspergillus pneumonia, and one with disseminated Fusarium spp). Two patients in the itraconazole group and four in the caspofungin group died of fungal infection (P = 0.57). Grade 3 to 4 adverse event rates were comparable between groups; the most common event in both was reversible hyperbilirubinemia. No evidence of cardiovascular toxicity from intravenous itraconazole was noted among patients older than 60. In conclusion, intravenous itraconazole and caspofungin provided similar protection against invasive fungal infection during induction chemotherapy, and both drugs were well tolerated.     

New perspectives in the diagnosis of systemic fungal infections

Profound and prolonged neutropenia following chemotherapy is a major risk factor for systemic fungal infections. Mortality associated with disseminated fungal infection is high, and treatment with conventional amphotericin B is complicated by renal toxicity. Candida and Aspergillus are among the major pathogens in these patients. Many patients remaining neutropenic over a prolonged period of time will receive empirical antifungal therapy. The clinical and laboratory diagnoses of these infections are neither sensitive nor specific and are generally limited in the early detection of invasive fungal infection. However, several new approaches to diagnosis are being developed, which should be translated into routine practice, based on a greater understanding of the pathogenesis of systemic fungal infection and virulence determinants of fungal pathogens. These include antigen detection and polymerase chain reaction. Patients with presumed fungal infection require more intense and accurate monitoring for signs of disseminated infection. Early diagnosis may guide appropriate treatment and prevent mortality. Continued development of commercial tests should help achieve the objective of definitive diagnostic tests for systemic fungal infections.     

Fusarium infections in burn patients: a case report and review of the literature

Fusarium species, or saprophytic molds, are important plant pathogens and recognized as agents of human mycotic infections. Frequently superficial, deep-tissue involvement, and dissemination occurs in immunocompromised hosts with hematologic malignancies, aplastic anemia, and chemotherapy treatment. Presented in this work is a burn patient with a fatal disseminated infection in addition to a review of the literature. A 40-year-old white male acquired a 73% grease scald injury at work. His hospital course was interspersed with multiple episodes of Flavobacterium, Fusarium, Candida, Proteus, Enterococcus, coagulase-negative Staphylococcus, and Serratia infections. He underwent nine operative procedures for debridement, excision, and skin grafting. The last operative procedure included bilateral below knee amputations to halt an invasive Fusarium infection that was invading normal unburned skin. The patient died 55 days after injury. Fusarium and Aspergillus infections are frequently confused and do not have characteristic clinical features. With the prolonged survival of severely burned patients, better fungal diagnostic and treatment modalities are needed to improve outcome.     

Paecilomyces lilacinus olecranon bursitis in an immunocompromised host: case report and review

Paecilomyces lilacinus is a little-known mold that causes rare cases of invasive infections in humans regardless of their immune status. We present a unique case in an immunocompromised host with olecranon bursitis because of multidrug-resistant P. lilacinus treated with systemic ketoconazole therapy and surgical debridement. Recognition of this fungus is difficult initially because of its appearance, which can be confused with that of other fungi. Once this organism has been identified, it is recommended that antifungal susceptibility testing be obtained to guide appropriate therapy. Combination of therapeutic modalities requires case-by-case assessment. Surgical debridement and removal of prosthesis may be indicated. Although P. lilacinus can be a laboratory contaminant, in our case, causation was established as the organism grew in repeated cultures, sufficient to confirm a fungal origin for his bursitis.     

Molecular identification of phaeohyphomycosis due to Alternaria infectoria in a patient with acute myeloid leukemia—a case report

We report the case of a 15-year old with acute myeloid leukemia who developed breakthrough invasive fungal rhinitis. The fungus was identified as Alternaria infectoria by polymerase chain reaction (PCR) and successfully treated by surgical excision and combination antifungal therapy, emphasizing the utility of fungal PCR in timely diagnosis of invasive fungal infections.     

Voriconazole: therapeutic review of a new azole antifungal

The new triazole antifungal, voriconazole (Vfend, Pfizer Ltd), was developed for the treatment of life-threatening fungal infections in immunocompromised patients. The drug, which is available for both oral and intravenous administration, has broad-spectrum activity against pathogenic yeasts, dimorphic fungi and opportunistic moulds. Unlike fluconazole (Diflucan, Pfizer Ltd), voriconazole has potent in vitro activity against Aspergillus spp., Fusarium spp. and Scedosporium apiospermum. In Phase II/III trials, voriconazole was well-tolerated and had excellent clinical efficacy in patients with fluconazole-sensitive and -resistant candida infection, aspergillosis, and various refractory fungal infections. The US Food and Drug Administration approved voriconazole in May 2002 for the treatment of invasive aspergillosis, and serious infections caused by Fusarium and S. apiospermum in patients who are intolerant of, or refractory to, other antifungal agents. In Europe, voriconazole is approved by the European Medicines Agency for the treatment of invasive aspergillosis, serious infections caused by Fusarium and S. apiospermum, and fluconazole-resistant serious invasive candida infections (including C. krusei).     

Secondary prophylaxis of invasive fungal infections with combination antifungal therapy and G-CSF-mobilized granulocyte transfusions in three children with hematological malignancies

Fungal infections represent a life-threatening complication for patients receiving chemotherapy or undergoing hematopoietic stem cell transplantation. Historically, antifungal monotherapy is associated with a poor outcome. We treated three children with hematological malignancies and proven fungal infections (one cerebral mold infection, one disseminated Candida infection, one naso-pharyngeal mucor infection) with combination antifungal therapy plus granulocyte-colony-stimulation-factor-mobilized granulocyte transfusions as secondary prophylaxis during subsequent neutropenic episodes. With this approach, the fungal infection was effectively treated, and the anticancer therapy was completed without major delay. All children survived the fungal infection and the underlying malignancy. These experiences illustrate the feasibility of this approach using more than one antifungal agent together with immune-therapy in high-risk patients.     

Pulmonary mucormycosis in a patient with acute liver failure: A case report and systematic review of the literature

PurposePulmonary mucormycosis is a highly lethal invasive fungal infection usually found in immunocompromised patients. We report herein the case of an adult woman who developed pulmonary mucormycosis with possible systemic dissemination after recovering from acute liver failure secondary to acetaminophen overdose.ResultsOur case developed an invasive pulmonary mucormycosis with probable systemic dissemination. She did not suffer from any immunocompromising disease other than severe acute liver failure. She did not survive the disease, although she received appropriate antifungal treatment. We also performed a systematic review of the literature on pulmonary mucormycosis, with or without dissemination, in immunocompetent patients. We found 16 cases of pulmonary or disseminated mucormycosis in immunocompetent patients. Fifty-seven percent of them died and none occurred after an acute liver failure episode.ConclusionThis case report is the first one to present an invasive pulmonary mucormycosis infection after acute liver failure in an adult patient. The clinical course of this disease is highly lethal, even in immunocompetent adults.     

Virulence and Resistance to Antifungal Therapies of Scopulariopsis Species

Scopulariopsis is an emerging opportunistic fungus characterized by its high resistance to antifungal therapies. We have developed a murine model of disseminated infection in immunosuppressed animals by intravenous inoculation of Scopulariopsis brevicaulis and Scopulariopsis brumptii, the most clinically relevant species, in order to evaluate their virulence and their responses to conventional antifungal treatments. Survival and tissue burden studies showed that S. brumptii was more virulent than S. brevicaulis. The three drugs tested, liposomal amphotericin B, posaconazole, and voriconazole, prolonged the survival of mice infected with S. brumptii, but none showed efficacy against S. brevicaulis. The different therapies were only able to modestly reduce the fungal burden of infected tissue; however, in general, despite the high serum levels reached, they showed poor efficacy in the treatment of the infection. Unfortunately, the most effective therapy for Scopulariopsis infections remains unresolved.     

Disseminated Fusarium infection identified by the immunohistochemical staining in a patient with a refractory leukemia.

The difficulty and uncertainty encountered in diagnosing a systemic mycosis often lead to a delay in starting antifungal therapy. We reported a disseminated infection of multiple fungal isolates including Fusarium species during donor leukocyte transfusion (DLT) after allogeneic bone marrow transplantation in a 20-year-old woman with a refractory leukemia. Skin lesions are the feature of Fusarium and occur in the early period of the infection. In this case, during immunosuppression state after DLT, she presented with the whole body ache and erythematous lesions which appeared rapidly on her trunk and extremities. While administration of amphotericin B was started, her condition was further deteriorated and she died. Autopsy materials revealed that she had multiple fungal infection with different isolates, including Aspergillus and Candida in the brain, lung and liver, but not in the skin. With the immunohistochemical staining with specific antibody, Fusarium or Aspergillus infection was identified from the biopsy skin or autopsy brain, respectively. This rapid and specific immunohistochemical method may be useful for the diagnosis and treatment of invasive fungal infection without delay.     

First case of bloodstream infection of Trichosporon loubieri in a patient with B-cell lymphocytic leukemia in China

Trichosporon loubieri is an opportunistic pathogenic fungus that could causes invasive infections for human, which rarely been reported. In the present study, we reported a case of bloodstream infection from a patient with Ph-positive B-cell acute lymphocytic leukemia (B-ALL) due to Trichosporon loubieri. Trichosporon loubieri was identified by Internal Transcribed Spacer (ITS) gene sequencing. The patient was treated by intravenous voriconazole (VCZ) and amphotericin B (AmB) according to antifungal susceptibility testing and he was still alive so far. To the best of our knowledge, this is the fourth report of human bloodstream infection due to Trichosporon loubieri and the first survival case of its kind in an immunocompromised patient.     

Diagnosis and treatment of invasive fungal infections in cancer patients

Fungal infections continue to cause major complications in cancer patients. With the increasing use of aggressive chemotherapy causing prolonged granulocytopenia, and the progress made in the prophylaxis and treatment of bacterial infections, the risk of invasive mycoses has increased, particulaly in patients with hematological malignancies. The prognosis of these infections is poor unless they are diagnosed and treated promptly. Early diagnosis, particularly in neutropenic cancer patients, is often difficult and antifungal therapy is frequently unsuccessful because it is not instituted until the infection is in an advanced, fatal phase. In order to reduce the mortality associated with invasive fungal infections, antifungal therapy, usually amphotericin B, has been empirically carried out in neutropenic patients with fever unresponsive to broadspectrum antibacterial therapy. However, the absence of a marker of the fungal infection, the frequent occurrence in these patients of non-infective fever, which does not require any antimicrobial therapy, and the possible toxicity of amphotericin B represent the major limits of empiric antifungal therapy. In view of the above, the study of improved and less toxic antifungal agents, and the evaluation of new clinical and laboratory methods for an early diagnosis, have been the major goals in research on the opportunistic invasive fungal infections in the last years.Presented as an invited lecture at the 4th International Symposium: Supportive Care in Cancer, St. Gallen, Switzerland, 24–27 February 1993     

Fungemia due to Fusarium solani under low-dose liposomal amphotericin B in a patient after cord blood transplantation

The introduction of the prophylactic use of antifungal drugs caused the increased occurrence of invasive fungal infections due to previously rare molds, such as fusariosis, after allogeneic hematopoietic stem cell transplantation. We herein report the case of a patient with diffuse large B-cell lymphoma who developed fungemia due to Fusarium solani during liposormal amphotericin B on day 25 after cord blood transplantation (CBT). Because Fusarium species might differ in virulence and drug susceptibility, the sequencing of the internal transcribed spacer region of the ribosomal RNA gene accurately identified Fusarium solani to be the cause of fungemia at the species level. This case highlights Fusarium solani as the cause of fungemia in a patient under liposormal amphotericin B treatment after CBT.     

Pulmonary Pseudallescheria boydii infection with cutaneous zygomycosis after near drowning

Pseudallescheria boydii is a ubiquitously occurring fungus. While rarely causing opportunistic infection in humans, it is the most common cause of fungal pneumonia in cases of near drowning, and is associated with high mortality. P. boydii typically causes cutaneous mycetomas but may invade the lungs or brain. P. boydii infections are difficult to treat due to amphotericin B resistance and frequent need for surgical resection. Zygomycetous infections, often referred to as "mucormycoses," usually occur in immunocompromised hosts, trauma or burn victims. Like P. boydii, these organisms are found on decaying vegetation and in soil. Zygomycetous infections generally require debridement and prolonged amphotericin B. We report a case of P. boydii pneumonia with a simultaneous brain lesion and cutaneous mucormycosis in a near drowning patient. The pneumonia responded to treatment with voriconazole and the brain lesion resolved without surgery. The cutaneous mucormycosis responded to surgery and amphotericin B. This is the first documented case of simultaneous invasive P. boydii and cutaneous mucormycosis successfully treated with dual systemic antifungal therapy and resection.     

Infective endocarditis and meningitis due to Scedosporium prolificans in a renal transplant recipient

Scedosporium prolificans is a ubiquitous filamentous fungi that may cause disseminated diseases in neutropenic patients with hematological malignancies. We report a fatal case of renal transplant recipient who developed both infective endocarditis and meningitis due to S. prolificans during treatment with micafungin and itraconazole for chronic necrotizing aspergillosis. Breakthrough Scedosporium infection should be considered among differential diagnosis of invasive fungal diseases in patients with renal transplant recipients receiving antifungal agents.     

Long-term survival after cord blood transplantation for acute myeloid leukemia complicated with disseminated fusariosis

Fusariosis is a critical infectious complication that can develop in immunocompromised hosts, mainly under conditions of prolonged neutropenia, and is often disseminated and associated with a high mortality rate. Disseminated fusariosis developing during the course of hematopoietic stem cell transplantation (HSCT) is a critical condition, and there have been few reports of successful treatment of cases complicated with fusariosis before HSCT. Here, we present a case of acute myeloid leukemia (AML) with the development of fungal endophthalmitis during chemotherapy. Vitrectomy was performed and Fusarium solani infection was confirmed by vitreal culture. The infection was also disseminated to the lung, triceps, and spleen. The splenic lesions disappeared with the administration of antifungal agents, and residual lesions in the lung and triceps were surgically resected. After two courses of consolidation chemotherapy, the patient received cord blood transplantation (CBT) twice because of graft failure in the first transplantation. Antifungal agents were administered continuously during chemotherapy and transplantation. Although Fusarium sinusitis developed after neutrophil engraftment, it was well controlled by surgical resection. Thereafter, the patient has been well without recurrence of fusariosis for more than 2 years since transplantation. A combination of continuous administration of antifungal agents and vigorous surgical intervention may be important for management of disseminated fusariosis in the setting of HSCT.     

Systemic Antifungal Prophylaxis After Hematopoietic Stem Cell Transplantation: A Meta-Analysis

Background

Hematopoietic stem transplant recipients are subject to increased risk for invasive fungal infections.

Objective

This meta-analysis was undertaken to explore the comparative effectiveness of systemic antifungal prophylaxis in hematopoietic stem cell transplant recipients.

Methods

We searched PubMed and The Cochrane Register of Randomized Controlled Trials up to March 2013 for randomized studies on systemic antifungal prophylaxis after hematopoietic stem cell transplantation. We performed a meta-analysis on the relative effectiveness of systemic antifungal prophylaxis on proven or probable invasive fungal infections using direct and indirect effects. Relative effectiveness was reported as odds ratio (OR) for invasive fungal infections, causative agent, empirical antifungal therapy, and withdrawals due to drug adverse events.

Results

Twenty evaluable studies provided data on 4823 patients. The risk for invasive fungal infections while on prophylaxis was 5.1% (95% CI, 3.6−6.8%). In patients receiving fluconazole, risks of proven or probable invasive fungal infections (OR = 0.24; 95% CI, 0.11−0.50; number needed to treat [NNT] = 8), systemic candidiasis (OR = 0.11; 95% CI, 0.05−0.24; NNT = 7), and overall need for empiric antifungal treatment (OR = 0.60; 95% CI, 0.44−0.82; NNT = 8) were reduced compared with patients receiving placebo. Itraconazole was more effective than fluconazole for the prevention of aspergillosis (OR = 0.40; 95% CI, 0.19−0.83; NNT = 23) at the expense of more frequent withdrawals (OR = 3.01; 95% CI, 1.77−5.13; number needed to harm = 6). Micafungin was marginally more effective than fluconazole for the prevention of all mold infections (OR = 0.35; 95% CI, 0.10−1.18; NNT = 79) and invasive aspergillosis (OR = 0.19; 95% CI, 0.03−1.11; NNT = 78) and reducing the need for empiric antifungal treatment (OR = 0.40; 95% CI, 0.13−1.21; NNT = 8). There was a relative lack of comparisons between different antifungal prophylactic strategies, including the newer azoles, voriconazole and posaconazole, in this population. Direct effects derived from single studies showed marginally significant effects for voriconazole compared with fluconazole regarding invasive aspergillosis (OR = 0.50; 95% CI, 0.20−1.20; NNT = 35) and the need for empiric treatment (OR = 0.72; 95% CI, 0.50−1.06; NNT = 15). Voriconazole compared with itraconazole (OR = 0.59; 95% CI, 0.40−0.88; NNT = 8) and posaconazole compared with amphotericin B (OR = 0.28; 95% CI, 0.06−1.24, marginal significance; NNT = 3) were better regarding empirical antifungal treatment.

Conclusions

Even when on antifungal therapy, invasive fungal infection will develop in 1 of 20 patients undergoing hematopoietic stem cell transplantation. There is evidence for the comparable effectiveness of different antifungal drugs used for prophylaxis. Fluconazole is the most widely studied agent, but micafungin might prove to be more effective. There is a relative paucity of studies for the newer azoles, although both voriconazole and posaconazole give proof of their comparative or higher effectiveness to fluconazole in single randomized studies.     

Host–Pathogen Interactions in Coccidioidomycosis: Prognostic Clues and Opportunities for Novel Therapies

PurposeCoccidioidomycosis (CM) is a systemic fungal disease caused by the dimorphic fungi Coccidioides immitis and Coccidioides posadasii. In its endemic areas of the United States, CM is growing as a public health challenge with a marked increase in incidence in the last 15 years. Although Coccidioides infection is asymptomatic in most cases, symptomatic pulmonary disease occurs in ~40% and disseminated coccidioidomycosis (DCM) occurs in ~1% of previously healthy children and adults. DCM is markedly more common in immunocompromised people, who often experience life-threatening disease despite use of antifungal medications. Although options for antifungal therapy have improved, lifelong therapy is needed for those who develop coccidioidal meningitis. The purpose of this article was to review the state of antifungal therapy and recent studies of host–pathogen interactions in CM in light of advances in immunomodulatory therapy.MethodsThe study included a review of PubMed and abstracts of the Coccidioidomycosis Study Group (years 2000–2019).FindingsCurrent therapy for CM relies upon azole and polyene antifungal agents. Murine models and studies of DCM in patients with monogenic primary immunodeficiency states and acquired immunodeficiency have revealed the importance of both innate and adaptive immune responses in the control of infections with Coccidioides species. In particular, defects in sensing of fungi and induction of cellular immune responses have been frequently reported. More recently, polymorphisms in key signaling pathways and in the generation of Th17 and Th1 immune responses have been linked with DCM.ImplicationsAntifungal therapy is sufficient to control disease in most cases of CM, but treatment failure occurs in cases of severe pulmonary disease and nonmeningeal disseminated disease. Lifelong therapy is recommended for meningitis in view of the very high risk of recurrence. Corticosteroid therapy is advised by some experts for severe pulmonary disease and for some neurologic complications of DCM. DCM is only rarely the result of a severe monogenic immunodeficiency. Case studies suggest that reorienting cellular immune responses or augmenting effector immune responses may help resolve DCM. Systematic investigation of immunotherapy for coccidioidomycosis is advisable and may help to address the recent marked increase in reports of the disease in endemic areas.     

Murine Model of a Disseminated Infection by the Novel Fungus Fonsecaea monophora and Successful Treatment with Posaconazole

We have evaluated the efficacy of posaconazole, amphotericin B, and itraconazole in a murine model of disseminated infection by Fonsecaea monophora. Of these three antifungal drugs tested, posaconazole prolonged survival significantly and reduced the fungal load in most of the organs tested. Bioassay studies demonstrated the relationship between posaconazole levels and dose escalation in serum and brain tissue. Posaconazole may have a clinical role in the treatment of disseminated infections by F. monophora.The dematiaceous fungus Fonsecaea monophora is a causal agent of cerebral phaeohyphomycosis (10) and chromoblastomycosis (11-13). On the basis of molecular studies (3, 7), this fungus has recently been segregated from Fonsecaea pedrosoi, a traditionally well-known pathogen. Since very little is known about the pathogenicity and antifungal susceptibility of this novel fungus, the aim of this study was to develop a murine model of disseminated infection by F. monophora to evaluate its virulence and compare the therapeutic efficacies of amphotericin B (AMB), itraconazole (ITZ), and posaconazole (PSC).Two clinical strains of Fonsecaea monophora were used: CBS 269.37 and CBS 117236. Their in vitro antifungal susceptibility tests (8) showed MICs of 1 μg/ml for AMB; 0.5 and 0.25 μg/ml for ITZ, respectively; and 0.25 and 0.12 μg/ml for PSC, respectively.Male OF1 mice were immunosuppressed by a single intraperitoneal (i.p.) injection of 200 mg/kg of body weight of cyclophosphamide plus 5-fluorouracil at 150 mg/kg intravenously 1 day prior to the infection.