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Patients treated for cancer with chemotherapy and other cytoreductive therapy often develop serious bacterial, viral, and fungal infections due to B- and T-cell depletion, neutropenia and decreased barrier function of mucosal membranes. In patients with neutropenic fever not responding to broad spectrum antibiotic therapy there is a high risk of fungal infection. In a Cochrane Library meta-analysis of the effect of prophylactic and empirical antifungal treatment, amphotericin B was found to be the only drug affecting total mortality. Fluconazole, ketoconazole and itraconazole affected risk of colonization and invasive infection, but not the total risk of death. We agree with these conclusions, but emphasize that the appropriate time to initiate empirical antifungal therapy is still not settled. We also believe that azoles may be of value in the therapy of symptomatic mucositis.
Prognosis of visceral mycosis depends on an early and well-adapted treatment. So, diagnosis must be done as early as possible. The clinician must first think of mycosis in front of a fever resistant to antibiotics or an unusual symptomatology, particularly in patients at risk for this opportunistic infection. The laboratory role is then essential. Isolation of the responsible fungus must be the first step. It leads to confirmation of diagnosis and to the choice of the best antifungal treatment. The search of antibodies and, in immunocompromised patients, of circulating antigens, is of precious help when no fungus is isolated or to confirm its pathogenicity. Unfortunately, diagnosis is often difficult. New molecular biological techniques should improve the quality and delay of mycological diagnosis.
The emergence of new fungal pathogens such filamentous fungi (Scedosporium, Fusarium) or yeast (Trichosporon) is a real problem for doctors who treat immunocompromised patients. These fungi present in our environment (Scedosporium, Fusarium) can also be on the skin (Trichosporon). They are responsible for invasive infections cause of morbidity and mortality because patients are immunocompromised and the fungi are resistant to antifungal treatment. Clinical manifestations are seldom specific, but cutaneous localisations are frequent. They are either the portal of entry of the infection or a metastatic localisation. The role of laboratory for identification of the fungus is essential.
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Fungal infections have increased substantially in patients with acute leukemia as well as in patients receiving allogeneic stem cell transplantations. Most frequently Aspergillus ssp. and Candida ssp. are observed. Despite the recent introduction of new azoles and lipid-based formulations of amphotericin B, there are few randomized, controlled studies on the use of antifungal drugs in patients with proven invasive fungal infections. Conventional Amphotericin B is considered gold standard for the treatment of invasive fungal infections, however is limited by nephrotoxicity and infusion related adverse events. Treatment with azoles, e.g. fluconazole, itraconazole or voriconazole is generally well-tolerated. Fluconazole, however, has no activity against Aspergillus ssp. An additional serious problem is an emerging resistance of non-albicans species to fluconazole. Lipid-formulations of amphotericin B seem to be attractive alternative, but considerably higher medical costs limit broader application of lipid formulations of amphotericin B. The current strategies for the treatment of documented fungal infections as well as the role of new antifungal agents are discussed in this review.
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Fungal infections have been recognized as major cause of morbidity and mortality in neutropenic and non-neutropenic surgical intensive care patients. The incidence of Candida has increased: it is now the fourth most often isolated pathogen in bloodstream infections. The incidence of Aspergillus infection in transplant patients is highest in heart and lung transplants: 19-26%. Most invasive fungal infections in surgical patients are caused by Candida spp. and Aspergillus spp., less by Cryptococcus spp. and may be classified as local or organ-related, as (chronic) disseminated, and as fungemia. There is no highly specific and sensitive routine test for the diagnosis of Candida and Aspergillus infections available; clinical signs of fungal infections are rather unspecific. The significance of colonization remains undetermined. In non-neutropenic surgical patients central venous access and broad-spectrum antibiotics are independent risk factors for the development of fungal infection. Immunsuppression, e.g., transplantation, burn injury, can render patients susceptible to fungal infection. This has lead to the introduction of antifungal prophylaxis in transplant and burned patients which has reduced the mortality for Candida spp. infection significantly. There is no prophylaxis available against Aspergillus spp. and Cryptococcus spp. Treatment of fungal infections consists of surgical and medical treatment for most organ-related infections. Recommendations for the management of fungal infections exist mostly for neutropenic patients, only few reports address the fungal infection of the surgical intensive care patient. Amphotericin B has been recommended as first line treatment for most severe fungal infections with fluconazole as follow-up treatment. In case of the development of toxic side effects of amphotericin B, mostly fluconazole or lipid formulations of amphotericin were favored. However, a shift in Candida strains towards non-albicans spp. and more resistant species was observed during recent years. This has lead to treatment failures in severe Candida and Aspergillus infections. The prognosis for invasive Aspergillus infections remains poor despite amphotericin B treatment. Newer azoles, e.g. voriconazole, demonstrated stable activity against most of these strains and may offer an option in the treatment of refractory fungal infections.
During the past years, progress has been made in the treatment of patients with cancer, and the proportion of patients achieving a complete remission and longer survival has increased. However, fungal infections have become one the leading factors contributing to morbidity and mortalitiy in patient with heamatological malignancies and solid tumours. Most opportunistic fungal infections are caused by Candida and Aspergillus species, but a growing number of less frequent fungal pathogens has been observed in recent years. The management of patients consist of a multidisciplinary approach combining radiology, new techniques in laboratory diagnostics such as serology and PCR as well as use of a growing armentarium of antifungal agents. Therapy of invasive mycosis no more rely on amphotericin B, but newer antifungal agents such as voriconazole and caspofungin have the potential to substitute the current standard therapy.
The past two decades have witnessed an increase in serious fungal infections, without corresponding growth in available antifungal agents. Voriconazole (VRC) is a novel triazole antifungal, recently approved in Europe for treatment of serious infections caused by Aspergillus, Fusarium, Scedosporium, and resistant Candida species. Voriconazole has in vitro activity against yeasts and yeast-like fungi similar, or superior to, fluconazole (FLC), itraconazole (ITC) and amphotericin B (AMB). Candida albicans is generally the most susceptible yeast (VRC MIC subset90 of 0.06 microg/ml); C. krusei often has low MICs even in the face of FLU/ITC resistance. Voriconazole has demonstrated comparable, or better, in vitro activity than ITC and AMB against Aspergillus (mean MICs 0.19-0.58 microg/ml), Ascomycetes, Bipolaris, Fusarium, Blastomyces dermatitidis, Coccidioides immitis, dermatophytes, Histoplasma capsulatum, Malassezia, and Scedosporium angiospermum (P. boydii). The drug possesses potent fungicidal activity against moulds including Aspergillus, Scedosporium, and Fusarium. Fungicidal activity is likely due to the high affinity of VRC for fungal 14-alpha-demethylase, a concept supported by ultrastructural and biochemical analysis. Animal studies confirmed the activity of VRC against infections including pulmonary and invasive aspergillosis (IA); A. fumigatus endocarditis; fusariosis; pulmonary cryptococcosis; and invasive candidiasis. Most importantly, well-designed human clinical trials have confirmed the efficacy of VRC in the treatment of candidal esophagitis, IA, and febrile neutropenia. Smaller studies and case reports have shown VRC is useful for salvage therapy of IA, cerebral aspergillosis, Scedosporium, and other fungal infections. Clinical testing has shown VRC is safe and well tolerated; the most common side effect is benign, self-limited visual disturbance.
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