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PubMed2003

[Guidelines for the treatment of invasive fungal infection. Invasive fungal infection by Candida spp. Invasive Fungal Infection Study Group (MICOMED) and Infection in Transplantation Study Group (GESITRA) of the Spanish Society for Infectious Diseases and Clinical Microbiology (SEIMC)].

These guidelines resume different issues related to the clinical management of invasive candidosis in the immunossuppressed patients. They are based on the recommendations of the different Drug's Agencies.

Antifungal Agents↗

PubMed2004

Recent advances in antifungal pharmacotherapy for invasive fungal infections.

Invasive fungal infections carry significant morbidity and mortality. Candida species have become one of the most frequent causes of bloodstream infections, and infections caused by molds such as Aspergillus are becoming more frequent in immunocompromised patients. As this population grows, more invasive fungal infections can be anticipated. In the past, treatment options have been limited for many of these infections due to toxicity and efficacy concerns with the available antifungals. Fortunately, the past few years have brought exciting developments in antifungal pharmacotherapy. Lipid-based formulations of amphotericin B were introduced in the 1990s to attenuate adverse effects caused by amphotericin B deoxycholate (Fungizone, Bristol-Myers Squibb). Most recently, the echinocandins have been added to our antifungal regimen with the introduction of caspofungin (Cancidas, Merck and Co.) and voriconazole (Vfend, Pfizer), a new triazole, has come to market. The introduction of the echinocandins has invigorated the discussion about combination antifungal therapy. Evidence-based studies using these new agents are accumulating, and they are assuming important roles in the pharmacotherapy of invasive fungal infections in seriously ill and complex patients.

Amphotericin B↗

PubMed2000

New developments in the diagnosis and management of invasive fungal infections.

Invasive fungal infections in cancer patients are on the increase. Candidemia is now the fourth leading cause of bloodstream infections in many intensive care units (ICUs). Although a number of risk factors have been identified, antifungal therapy should not be started in non-neutropenic patients until a diagnosis of invasive candidiasis or candidemia is made or presumed in order to avoid the development of resistance. Even a single positive blood culture should be treated, and requires removal of intravascular lines. Fluconazole is the first line agent for treatment candidemia other than that caused by Candida glabrata or C. krusei. High-resolution CT scan pictures showing a halo sign or crescent air sign are helpful for establishing the diagnosis of invasive aspergillosis. Sandwich ELISA can be used to detect circulating galactomannan in serial serum samples. Polymerase chain reaction (PCR) of blood samples may also be used. There are only a few randomized studies of newly developed antifungal drugs compared to conventional amphotericin B (AmB). So far, both AmB colloidal dispersion and AmB lipid complex have failed to show more favorable efficacy or lesser toxicity rates, except for nephrotoxicity. Liposomal AmB, used during febrile neutropenia, did have a significantly lower toxicity rate. In neutropenic patients with invasive fungal infections liposomal AmB proved to be better than conventional AmB in terms of clinical efficacy, mortality and nephrotoxicity rates. The use of tests to achieve an earlier diagnosis combined with more potent treatment formulations such as liposomal AmB may be significant steps towards successful management of invasive fungal infections.

Antifungal Agents↗

PubMed2003

New approaches to invasive fungal infections.

Invasive fungal infections are typically difficult to prevent, diagnose, and treat; consequently, fungal infection-related mortality has become high, particularly among patients with prolonged neutropenia and severe graft-versus-host disease. However, much recent progress has been made in understanding the immune response to fungi and the epidemiology of infection, and new diagnostic tests and antifungal drugs have become available. This review will describe these most recent developments with the goal of evaluating new approaches to prevent, diagnose, and treat invasive fungal infections.

Antifungal Agents↗

PubMed2007

Antifungal immunity and adjuvant cytokine immune enhancement in cancer patients with invasive fungal infections.

Invasive fungal infections are common in severely immunosuppressed patients with cancer and in recipients of haematopoietic transplants. Response to antifungal therapy alone is often inadequate. Pro-inflammatory cytokines are critical for promoting innate and adaptive cellular antifungal immune responses. Recombinant cytokines, including granulocyte-macrophage-colony stimulating factor and interferon-gamma, have been studied as adjuvant therapies for severely immunosuppressed cancer patients with difficult-to-treat invasive mycoses. The limited clinical experience to date shows a possible benefit of these cytokines, and further controlled clinical trials are needed to validate their routine use in cancer patients and stem-cell transplant recipients with invasive fungal infections who are likely to have a poor response to antifungal drug therapy.

Adjuvants, Immunologic↗

PubMed2001

Caspofungin: pharmacology, safety and therapeutic potential in superficial and invasive fungal infections.

Invasive fungal infections are important causes of morbidity and mortality in hospitalised patients. Current therapy with amphotericin B and antifungal triazoles has overlapping targets and is limited by toxicity and resistance. The echinocandin lipopeptide caspofungin is the first of a new class of antifungal compounds that inhibit the synthesis of 1,3-beta-D-glucan. This homopolysaccharide is a major component of the cell wall of many pathogenic fungi and yet is absent in mammalian cells. It provides osmotic stability and is important for cell growth and cell division. In vitro, caspofungin has broad-spectrum antifungal activity against Candida and Aspergillus spp. without cross-resistance to existing agents. The compound exerts prolonged post-antifungal effects and fungicidal activity against Candida spp. and causes severe damage of Aspergillus fumigatus at the sites of hyphal growth. Animal models have demonstrated efficacy against disseminated candidiasis and disseminated and pulmonary aspergillosis, both in normal and in immunocompromised animals. Caspofungin possesses favourable pharmacokinetic properties and is not metabolised through the cytochrome P450 (CYP) enzyme system. It showed highly promising antifungal efficacy in Phase II and III clinical trials in immunocompromised patients with oesophageal candidiasis. Caspofungin was effective in patients with invasive aspergillosis intolerant or refractory to standard therapies. Based on its documented antifungal efficacy and an excellent safety profile, caspofungin has been approved recently by the US Food and Drug Administration for the treatment of invasive aspergillosis in patients who are refractory to or intolerant of other therapies (i.e., amphotericin B, lipid formulations of amphotericin B, and/or itraconazole). Phase III clinical trials in patients with candidaemia and in persistently febrile neutropenic patients requiring empirical antifungal therapy are ongoing. This paper reviews the preclinical and clinical pharmacology of caspofungin and its potential role for treatment of invasive and superficial fungal infections in patients.

Animals↗

PubMed2006

Safety of long-term oral posaconazole use in the treatment of refractory invasive fungal infections.

BACKGROUND: Invasive fungal infections are found most frequently in immunosuppressed and critically ill hospitalized patients. Antifungal therapy is often required for long periods. Safety data from the clinical development program of the triazole antifungal agent, posaconazole, were analyzed. METHODS: A total of 428 patients with refractory invasive fungal infections (n = 362) or febrile neutropenia (n = 66) received posaconazole in 2 phase II/III open-label clinical trials. Also, 109 of these patients received posaconazole therapy for > or = 6 months. Incidences of treatment-emergent, treatment-related, and serious adverse events and abnormal laboratory parameters were recorded during these studies. RESULTS: Treatment-emergent, treatment-related adverse events were reported in 38% of the overall patient population. The most common treatment-related adverse events were nausea (8%) and vomiting (6%). Treatment-related serious adverse events occurred in 8% of patients. Low rates of treatment-related corrected QT interval and/or QT interval prolongation (1%) and elevation of hepatic enzymes (2%) were reported as adverse events. Treatment-emergent, treatment-related adverse events occurred at similar rates in patients who received posaconazole therapy for < 6 months and > or = 6 months. CONCLUSIONS: Prolonged posaconazole treatment was associated with a generally favorable safety profile in seriously ill patients with refractory invasive fungal infections. Long-term therapy did not increase the risk of any individual adverse event, and no unique adverse event was observed with longer exposure to posaconazole.

Adolescent↗

PubMed2001

Clinical microbiology and infectious diseases. Management of fungal infections.

Invasive fungal infections are a major cause of morbidity and mortality in immunocompromised patients. Despite remarkable progress in mycology, many uncertainties and difficulties remain. Invasive fungal infections are difficult to diagnose. Noninvasive, rapid diagnostic tools, such as the detection of Aspergillus galactomannan antigen in serum or of fungal nucleic acids by molecular methods are promising, but are still under investigation. The other difficulty in diagnosis is the lack of standard, consistent criteria. Very recently, diagnostic criteria based on host factors, as well as clinical features and microbiological results, have been proposed. Treatment of invasive fungal infections is also problematic. The development of novel antifungal compounds constitutes a major advance in antifungal therapy. These include novel azoles such as voriconazole (Pfizer), posaconazole (Schering- Plough), and ravuconazole (Eisai/Bristol-Myers Squibb), and novel echinocandins such as caspofungin (Merck), anidulafungin (Eli Lilly), and micafungin (Fujisawa Pharmaceutical). These agents appear more efficacious and less toxic than currently available antifungal drugs. However, immune status of the host remains one of the major determinants of clinical outcome. This property limits the efficiency of in vitro antifungal susceptibility tests in predicting in vivo outcome. Using immune system modifiers such as cytokines in combination with antifungal agents is beneficial in the improvement of immune status, and thus clinical outcome.

Journal Article↗

PubMed1994

Epidemiology of invasive fungal infections in bone marrow transplantation. EORTC Invasive Fungal Infections Cooperative Group.

Infections and graft-versus-host disease are the major causes of morbidity and mortality in bone marrow transplantation (BMT). Bacterial infections can nowadays be treated effectively in most instances. The prophylactic and therapeutic armamentarium for viral infections is improving. Fungal infections on the contrary remain a major obstacle for successful outcome in the transplant situation. Invasive fungal infections are mainly caused by Candida and Aspergillus spp. and more seldom by Mucor, Trichosporon and Fusarium. Invasive fungal infections are notoriously difficult to diagnose early and effective non-toxic treatments are still out of reach. Prophylaxis for Candida albicans has become more effective with new triazoles but for species other than albicans and for Aspergillus spp. prophylaxis still remains a major problem. Better treatment modalities, more effective prophylaxis and better knowledge of risk factors are urgently needed. The recently created Invasive Fungal Infections Cooperative Group of the EORTC chaired by Professor F. Meunier runs different surveys to investigate the incidence and nature of invasive fungal infections in cancer patients and in BMT. The group runs different clinical trials on the prophylaxis and treatment of invasive fungal infections.

Bone Marrow Transplantation↗

PubMed2006

Zygomycosis: the re-emerging fungal infection.

Invasive fungal infections are major medical complications in immunocompromised patients. The recent rise in the incidence of cancer and the increased use of newer medical treatment modalities, including organ transplantations, have resulted in growing numbers of highly immunosuppressed individuals. Although aspergillosis and candidiasis are among the most common invasive mycoses in such patients, there is evidence that the incidence of infectious diseases caused by Zygomycetes has risen significantly over the past decade. Patients with diabetes, malignancies, solid organ or bone marrow transplants, or iron overload and those receiving immunosuppressive agents, deferoxamine therapy, or broad-spectrum antimicrobial drugs are at highest risk for zygomycosis. This review details the emergence and importance of zygomycosis in current clinical practice and its manifestations and management. The etiologic species, pathogenesis and risk factors for zygomycosis are reviewed and updated. The clinical spectrum of zygomycosis is now broader, and it can be difficult to distinguish between mucormycosis and enthomophthoramycosis, both of which can manifest as disease ranging from a superficial infection to an angioinvasive infection with high mortality. Finally, the three-part treatment strategy (antifungal drugs, surgery, control of underlying diseases) is reviewed. Lipid formulations of amphotericin B are the antifungal agents of choice for treatment of zygomycosis. A novel antifungal triazole, posaconazole, has been developed and may become approved for treatment of zygomycosis. The clinical experience with adjunctive treatments like colony-stimulating factors, interferon-gamma, and hyperbaric oxygen therapy is still limited.

Amphotericin B↗

PubMedDate not supplied

Newer treatments for fungal infections.

Invasive fungal infections are a significant cause of morbidity and mortality among immunocompromised cancer patients, and until recently, treatment options have been limited. The poor outcomes of these infections, and the increased incidence of disease, particularly due to resistant and less common fungal isolates, necessitate the development of new agents. Antifungal drug development had been a slow process since the release of amphotericin B over 40 years ago. However, since 1995, six new systemic antifungals have been approved: three lipid formulations of amphotericin B, the initial second-generation triazole, and the first two approved agents in a new class of antifungals with a novel mechanism of action, the echinocandins. These newer agents, and several others currently in development, offer improved tolerability and safety profiles and extend the spectrum of coverage to resistant and less-common fungal infections. The authors describe each of these new compounds and discuss how they fit into the overall management of fungal infections in patients with cancer.

Antifungal Agents↗

PubMed2002

Risk factors for invasive fungal infection in neonates.

UNLABELLED: Invasive fungal infection is an uncommon, but increasing cause of morbidity and mortality in neonates. There are few controlled studies defining risk factors for the development of fungal infection in a contemporary neonatal population. This retrospective case-control study was undertaken to investigate antenatal, demographic and postnatal variables that may be potentially important in the development of fungal infection. Two gestation-matched controls were identified for each index case. Information about perinatal and demographic variables, as well as important neonatal outcomes, was obtained from case notes. Microbiological data collected included the presence of fungal colonization, and organisms responsible for invasive fungal infection. Over a 5-y period, 24 infants with invasive fungal infection and 48 controls were identified. Candida albicans was the organism identified in 75% of cases of fungal septicaemia, and in all cases complicated by fungal meningitis. Preceding fungal colonization, pulmonary haemorrhage and intrauterine growth restriction were factors significantly and independently associated with invasive fungal infection. Fifty-four percent of infants with invasive fungal infection died, and 82% of survivors developed chronic lung disease. CONCLUSION: Some new and potentially important risk factors for the development of invasive fungal infection in a contemporary population of infants admitted to a neonatal intensive care were identified.

Candidiasis↗

PubMed2000

Microbiological diagnosis of invasive fungal infections in transplant recipients.

Invasive fungal infections remain an important cause of morbidity and mortality in transplant recipients. Since conventional diagnostic tools such as culture lack sensitivity and specificity, alternative diagnostic assays have been developed. Among the most promising techniques are the detection of fungal DNA and serology. Fungal DNA can be detected with high sensitivity and specificity when performed with specimens from sterile sites such as blood. Polymerase chain reaction (PCR) assays can be used to detect a broad range of fungal pathogens and combined with species identification. Multicenter diagnostic studies are needed to establish the diagnostic value of PCR but lack of standardization hampers such studies. The serodiagnosis of invasive fungal infections has become an important tool in the management of invasive fungal infections. Especially the detection of circulating galactomannan has been shown to be a sensitive marker for invasive aspergillosis. Both serology and PCR can be used to monitor the response to antifungal therapy. The optimal use of non-culture-based methods is in prospective screening of patients at high risk. Since the incidence of disease greatly influences the positive predictive value, screening should take place only in those patients at very high risk for invasive fungal disease.

Aspergillosis↗

PubMed2003

British Society for Medical Mycology proposed standards of care for patients with invasive fungal infections.

Outcomes for invasive fungal infections have greatly improved in the past decade, and several new antifungal drugs have been or will be licensed in the next few years. Early accurate diagnosis and appropriate treatment have major impact on survival. In a 1995 survey of laboratory practice in the UK for mycology, major disparities were seen, with many laboratories not undertaking even simple diagnostic procedures. Delays in processing and inadequate procedures for handling samples, incomplete or delayed reporting of results, or a combination of these, compromise the care of patients. In randomised trials of antifungal chemotherapy, optimum treatments and good alternatives for others have been defined for some infections. High-quality care requires a multidisciplinary approach to diagnosis and management. In this review, we propose microbiology, histopathology, radiology, and clinical auditing standards, with the evidence base for each reviewed. The standards are absolutes, and, therefore, provide a straightforward basis for improving services to patients if they are all implemented.

Histology↗

PubMed2002

Current status of nonculture methods for diagnosis of invasive fungal infections.

The incidence of invasive fungal infections has increased dramatically in recent decades, especially among immunocompromised patients. However, the diagnosis of these infections in a timely fashion is often very difficult. Conventional microbiologic and histopathologic approaches generally are neither sensitive nor specific, and they often do not detect invasive fungal infection until late in the course of disease. Since early diagnosis may guide appropriate treatment and prevent mortality, there has been considerable interest in developing nonculture approaches to diagnosing fungal infections. These approaches include detection of specific host immune responses to fungal antigens, detection of specific macromolecular antigens using immunologic reagents, amplification and detection of specific fungal nucleic acid sequences, and detection and quantitation of specific fungal metabolite products. This work reviews the current status and recent developments as well as problems in the design of nonculture diagnostic methods for invasive fungal infections.

Antibodies, Fungal↗

PubMed2001

[Fungemia and other invasive fungal infections in Icelandic children. A nationwide study.].

INTRODUCTION: Invasive fungal infections are increasing in incidence. Among those who are at increased risk of fungal blood stream infections (fungemia) and disseminated fungal infections are premature infants and immunosuppressed children. These infections are associated with high morbidity and mortality. Invasive fungal infections have not yet been studied in Iceland. MATERIAL AND METHODS: We studied all cases of fungemia and/or disseminated fungal infections in Icelandic children (16 years) during a 20 year period. Histopathology reports and autopsies were reviewed. Information on predisposing factors, symptoms, treatment and outcome was collected. All obtainable fungal blood stream isolates were subcultured and their susceptibility to common antifungals determined. RESULTS: In the 20 year period from 1980-1999, 19 episodes of invasive fungal infections were diagnosed in 18 infants and children in Iceland. Twelve episodes of fungemia occured in 11 children and the nationwide annual incidence increased from 0.28 to 1.90 cases/100,000/year (p=0.037) during the study period. Half of the children were premature infants. All patients had a central venous catheter at the time of blood culture and most had received intravenous antibiotics or corticosteroids. Candida albicans was the most commonly isolated species (nine of 12 episodes, 75%). In addition to patients with fungemia, three children were diagnosed with disseminated fungal infection by histology or autopsy. Two cases of fungal meningitis, without fungemia, were identified. Furthermore, two children had invasive infections with Aspergillus fumigatus and both patients survived. Three children (3/16; 19%) with invasive Candida-infections died. CONCLUSIONS: In this study of invasive fungal infections among Icelandic children we demonstrate that the incidence of fungemia has risen significantly in the past 20 years. Diagnosis of invasive fungal infections can be complicated and negative blood cultures do not exclude disseminated infection. Given the high attributable mortality, timely diagnosis and aggressive treatment is extremely important.

English Abstract↗

PubMed2006

Association of hepatic iron overload with invasive fungal infection in liver transplant recipients.

Invasive fungal infection is a serious complication of orthotopic liver transplantation, but its risk factors remain incompletely defined. Iron overload has already been associated with increased risk of fungal infections, but it has not yet been assessed as a risk factor in liver transplantation. We retrospectively studied a cohort of 153 consecutive patients who underwent their first liver transplantation at a single center and who survived at least 7 days after transplantation. The association between various pretransplant patient characteristics, including hepatic explant iron and risk of invasive fungal infections, was analyzed by univariate and multivariate models. Iron in the hepatic explant was assessed by Perl's Prussian blue stain by a pathologist blinded to clinical outcome. During the first year after transplantation, 28 of 153 patients developed a total of 31 invasive fungal infections, of which 21 (68%) were caused by Candida, 7 (23%) by Aspergillus, 2 (6%) by Cryptococcus, and 1 (3%) by Saccharomyces. Stainable iron in the hepatic explant was found in 48 patients (31%). Stainable iron in the hepatic explant was found to be strongly and independently associated with posttransplantation fungal infections in multivariate analysis (hazard ratio 3.09; 95% confidence interval 1.45-6.56; P = 0.003). Hepatic iron overload is strongly and independently associated with posttransplantation invasive fungal infections. Studies to confirm this finding in other centers and define the mechanism are warranted.

Adolescent↗

PubMed2004

Systemic antifungal drugs for invasive fungal infection in preterm infants.

BACKGROUND: Invasive fungal infection is an increasingly common cause of mortality and morbidity in preterm infants. In addition to amphotericin B, a variety of newer antifungal drugs and drug preparations are available for treatment. There is a need to assess their relative merits. OBJECTIVES: In preterm infants with suspected or confirmed invasive fungal infection, does treatment with newer systemic antifungal drugs or drug preparations, versus conventional amphotericin B alone, reduce mortality and adverse neurodevelopmental outcomes? SEARCH STRATEGY: We used the standard search strategy of the Cochrane Neonatal Review Group. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2003), MEDLINE (1966 - August 2003), EMBASE (1980 - August 2003), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised and quasi-randomised control trials comparing one antifungal agent or combination of agents with another in preterm infants with suspected or confirmed invasive fungal infection. DATA COLLECTION AND ANALYSIS: We extracted the data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by each author, and synthesis of data using relative risk and risk difference. The pre-specified outcomes were death prior to hospital discharge, longer term neurodevelopment, and adverse drug reactions resulting in discontinuation of therapy. MAIN RESULTS: We identified only one small trial. This study compared the use of fluconazole with amphotericin B (5-Fluorocytosine added if fungal meningitis present). Three of 11 infants who were treated with fluconazole died and four of 10 infants who were treated with amphotericin B died : Relative risk: 0.68 (95% confidence interval 0.20, 2.33), Risk Difference -0.13 (95% confidence interval -0.53, 0.27) There were not any data on longer term outcomes. REVIEWER'S CONCLUSIONS: From this one small study there are insufficient data to favour one antifungal agent or combination to reduce mortality and adverse neurodevelopmental outcomes in preterm infants with suspected or confirmed invasive fungal infection. A large randomised controlled trial is required to compare the newer antifungal preparations with conventional amphotericin B. Further research may also determine the relative convenience and cost effectiveness of the available drugs.

Amphotericin B↗