Therapy Of Invasive Fungal Infections Research Articles

The safety of interferon‐γ‐1b therapy for invasive fungal infections after hematopoietic stem cell transplantation

The restoration of normal immune responses, especially of the T-helper type 1 immune response, is an important predictor of fungal infection outcome in patients with malignant disease who undergo hematopoietic stem cell transplantation (HSCT). The authors sought to evaluate the safety of adjuvant recombinant interferon-gamma-1b as an immune-modulatory therapy HSCT recipients. Thirty-two patients received interferon-gamma-1b after undergoing HSCT at the author's institution between 1998 and 2003. A retrospective analysis was undertaken after obtaining permission from the Institutional Review Board. Twenty-six of 32 patients (81%) received allogeneic stem cell grafts. All but 1 patient received interferon-gamma-1b and antifungals to treat infections; the other patients received interferon-gamma-1b to promote autologous graft-versus-tumor effect. Interferon-gamma-1b usually was administered at a dose of 50 mug subcutaneously every other day. The median duration (+/- standard deviation) of interferon-gamma-1b therapy was 6+/-6.5 doses (range, 1-29 doses), and the median cumulative dose was 487+/-453 mug (range, 35-2175 microg). During therapy with interferon-gamma-1b, fever was common (n=9 patients; 28%). In 1 patient (3%), new-onset lymphocytopenia occurred but resolved after cytokine therapy was discontinued; there were no interferon- gamma-1b-related episodes of neutropenia, thrombocytopenia, anemia, or liver dysfunction. Interferon-gamma-1b therapy did not precipitate or exacerbate acute or chronic graft-versus-host disease (GVHD). In fact, in 2 of 7 patients (29%) with acute GVHD and in 3 of 10 patients (30%) with chronic GVHD, significant improvements in GVHD were noted during therapy with interferon-gamma-1b. Among the 26 patients with aspergillosis, 14 patients (54%) died. However, 5 of 10 patients (50%) with presumed pulmonary aspergillosis, 3 of 9 patients (33%) with probable pulmonary aspergillosis, 1 of 2 patients (50%) with definite pulmonary aspergillosis, and 3 of 5 patients (60%) with disseminated aspergillosis responded to antifungals and adjuvant interferon-gamma-1b. Recombinant interferon-gamma-1b was tolerated without serious adverse reactions in HSCT recipients. A large, prospective, randomized study will be needed to evaluate the efficacy of this cytokine in high-risk HSCT recipients who have invasive mycoses.

Voriconazole - applications and perspectives

Voriconazole (Vfend) is a new broadspectrum antifungal agent belonging to the group of triazole drugs. In vitro and in vivo efficacy was demonstrated against a large variety of yeasts with excellent activity against all Candida species but as well against Cryptococcus neoformans. Furthermore, voriconazole has shown excellent activity against many moulds in particular against Aspergillus species, but endemic fungi such as Histoplasma capsulatum are in the spectrum as well. Clinical efficacy was demonstrated in several large phase II/III studies in diseases such as oral and oesophageal candidosis, acute invasive aspergillosis or chronic invasive aspergillosis. New adverse events such as visual disturbancies has been described together with the use of voriconazole, but the majority of adverse events are similar to other triazole drugs and in particular not life-threatening. With the introduction of voriconazole a great progress in the therapy of invasive fungal infections was achieved. In the therapy of invasive aspergillosis, voriconazole is significantly more effective compared to amphotericin B desoxycholate.

Management of fungal infections in neutropenic patients: more doubts than certainties?

An evidence based approach to prophylaxis and therapy of invasive fungal infections depends on the knowledge of epidemiology and of risk factors for these infections, as well as on the appreciation of merits and limitation of the available clinical trials. A progressive increase in the incidence of systemic fungal infections, most often caused by Candida and Aspergillus, in patients with cancer and neutropenia has been observed in recent years. This increase of systemic fungal infections recognizes a multifactorial origin, including host defense impairment and type of underlying disease. The various combinations of these different risk factors make the patients affected by systemic fungal infections a non-homogeneous population and, therefore, the transferability of the results of many clinical trials from one population to another is difficult. Clinical trials on prophylaxis and treatment of systemic fungal infections moreover have many limitations: they are often of small size, are frequently non-comparative, enrol population at different risk for infection, use different criteria to define success or failure of therapy. These limitations make the interpretation of the trial results difficult. As randomised clinical trials and metanalysis are considered the most valuable sources of information on new treatments, it dearly appears that the mentioned difficulties in interpreting available data from the literature may expose patients to an increased risk of receiving an inappropriate or non-optimal treatment. Better designed studies are needed to clarify the many controversial questions in antifungal prophylaxis and therapy.

Therapy of invasive fungal infections

During the past decades, the incidence and severity of invasive fungal infections has been increasing. These events have lead to the development of new antifungal agents, and amphotericin B no longer is the standard therapy for a variety of invasive mycoses. Fluconazole has become the drug of choice for treatment of C. albicans infections in non-neutropenic as well as neutropenic patients. For treatment of cryptococcal meningitis, amphotericin B with flucytosine, followed by fluconazole consolidation therapy is used. For therapy of invasive aspergillosis, the lipid formulations of amphotericin B may be associated with reduced toxicity and allow for larger doses, although the efficacy of each of the formulations still has to be established in randomized trials. Finally, treatment modalities aimed at improving host defense mechanisms, including adjunctive therapy with rG-CSF for disseminated candidiasis and rG-CSF-elicited granulocyte transfusions, are under way.

Recent developments in prophylaxis and therapy of invasive fungal infections in granulocytopenic cancer patients

Recent developments in prophylaxis and therapy of invasive fungal infections in granulocytopenic cancer patients

Fungal Infections in the Immunocompromised Host CATHERINE HAWKINS

Invasive fungal infections cause significant morbidity and mortality in patients with impaired immune defences. Defects in neutrophil function and neutropenia predispose to disseminated Candida, Aspergillus and Mucoraceae infections while altered T-lymphocyte mononuclear phagocyte function predisposes to infection with C. neoformans, Histoplasma and Coccidioides. Fungal infections in the immunocompromised host are difficult to diagnose and difficult to treat successfully. The diagnosis is often missed or delayed because of the non-specific clinical features, the failure to isolate or difficulty in interpreting the presence of the fungus from routine microbiological cultures, and the limited usefulness of available serological tests. The assay for cryptococcal antigen is the only currently available reliable serological test used to diagnose an invasive fungal infection. Definitive diagnosis is made by histopathological demonstration of the fungus in tissue or a positive culture from a sterile body site. Invasive procedures are often necessary to obtain adequate tissue for histology and culture. The treatment of invasive fungal infection in the immunocompromised host is amphotericin B with or without 5FC. The usual recommended dose is 1.5 to 3 g total amphotericin B over 6 to 12 weeks. The optimal dose and duration of therapy for each infection is not known. Treatment failures and relapses are common in patients who do not achieve remission of their underlying disease. Ketoconazole, a new broad-spectrum oral antifungal medication, does not appear to be effective therapy for invasive fungal infection in the immunocompromised patient based on results of small clinical trials. New diagnostic methods and therapeutic approaches are necessary to improve the outcome of these infections. Areas of current research include serological assays for fungal antigens and metabolites which may allow earlier diagnosis, treatment with combinations of antifungal agents, and the development of new antifungal agents.