Mucosal Candidiasis In Patients Research Articles

Double‐Blind Active‐Control Trials: Beware the Comparator You Keep

The indirect impact of the known comparator drug in double-blind comparative clinical trials of novel agents is underappreciated, despite its potentially pernicious effects. This hypothesis-generating analysis illustrates potential spillover effects of a comparator (amphotericin) in the evaluation of the first member (caspofungin) of a novel class (echinocandins) of antifungal drugs. Reported rates of drug-related fever in the first 3 studies of caspofungin for the treatment of mucosal candidiasis in patients with advanced human immunodeficiency virus infection were retrospectively analyzed. We compared patients who received 50 mg of caspofungin per day in a double-blind trial that used fluconazole as the comparator with patients who received the corresponding dosage in 2 similar earlier studies that used amphotericin as the comparator. With respect to the incidence of drug-related fever, the difference between the concurrent caspofungin and fluconazole groups was less than the difference between caspofungin groups from studies that used different comparators. In phase II/III blinded, active-control trials, the reporting of adverse experiences attributed to a first-in-class drug might be confounded to a variable degree by expectations regarding a well-known comparator.

Immunopathogenesis of oropharyngeal candidiasis in human immunodeficiency virus infection.

Oropharyngeal and esophageal candidiases remain significant causes of morbidity in human immunodeficiency virus (HIV)-infected patients, despite the dramatic ability of antiretroviral therapy to reconstitute immunity. Notable advances have been achieved in understanding, at the molecular level, the relationships between the progression of HIV infection, the acquisition, maintenance, and clonality of oral candidal populations, and the emergence of antifungal resistance. However, the critical immunological defects which are responsible for the onset and maintenance of mucosal candidiasis in patients with HIV infection have not been elucidated. The devastating impact of HIV infection on mucosal Langerhans' cell and CD4(+) cell populations is most probably central to the pathogenesis of mucosal candidiasis in HIV-infected patients. However, these defects may be partly compensated by preserved host defense mechanisms (calprotectin, keratinocytes, CD8(+) T cells, and phagocytes) which, individually or together, may limit Candida albicans proliferation to the superficial mucosa. The availability of CD4C/HIV transgenic mice expressing HIV-1 in immune cells has provided the opportunity to devise a novel model of mucosal candidiasis that closely mimics the clinical and pathological features of candidal infection in human HIV infection. These transgenic mice allow, for the first time, a precise cause-and-effect analysis of the immunopathogenesis of mucosal candidiasis in HIV infection under controlled conditions in a small laboratory animal.

Use of Sargramostim (rh-GM-CSF) As Adjunctive Treatment of Fluconazole-Refractory Oropharyngeal Candidiasis in Patients with AIDS: A Pilot Study

Purpose: Fluconazole-refractory mucosal candidiasis is a significant problem in patients with advanced HIV disease. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is postulated to activate neutrophils, enhance phagocytosis, and increase intracellular killing of Candida species. The aim of this study was to evaluate the use of sargramostim (rh-GM-CSF) in combination with fluconazole for refractory mucosal candidiasis in patients with AIDS. Method: Patients with mycologically confirmed fluconazole-refractory oropharyngeal candidiasis who failed fluconazole 400 mg/day for a minimum of 7 days were enrolled, continued on fluconazole (400 mg/day), and received sargramostim 2.5 μg/kg/day for a minimum of 2 weeks. Patients were evaluated for clinical signs and symptoms of oropharyngeal candidiasis, and quantitative fungal cultures were taken at baseline and the end of weeks 1 and 2 of therapy. Results: Eleven patients were entered, 3 out of 11 patients were cured, 6 were unchanged, and 2 were worse at the 2-week evaluation. Mycological response was seen in 7 out of 11 patients. Conclusion: In this small pilot study, sargramostim appears to exert a beneficial effect on the mucosal mycoflora and may be a possible alternative as adjunctive therapy in the management of fluconazole-refractory mucosal candidiasis in advanced HIVpositive patients.

Use of Sargramostim (rh-GM-CSF) As Adjunctive Treatment of Fluconazole-Refractory Oropharyngeal Candidiasis in Patients with AIDS: A Pilot Study

Purpose: Fluconazole-refractory mucosal candidiasis is a significant problem in patients with advanced HIV disease. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is postulated to activate neutrophils, enhance phagocytosis, and increase intracellular killing of Candida species. The aim of this study was to evaluate the use of sargramostim (rh-GM-CSF) in combination with fluconazole for refractory mucosal candidiasis in patients with AIDS. Method: Patients with mycologically confirmed fluconazole-refractory oropharyngeal candidiasis who failed fluconazole 400 mg/day for a minimum of 7 days were enrolled, continued on fluconazole (400 mg/day), and received sargramostim 2.5 μg/kg/day for a minimum of 2 weeks. Patients were evaluated for clinical signs and symptoms of oropharyngeal candidiasis, and quantitative fungal cultures were taken at baseline and the end of weeks 1 and 2 of therapy. Results: Eleven patients were entered, 3 out of 11 patients were cured, 6 were unchanged, and 2 were worse at the 2-week evaluation. Mycological response was seen in 7 out of 11 patients. Conclusion: In this small pilot study, sargramostim appears to exert a beneficial effect on the mucosal mycoflora and may be a possible alternative as adjunctive therapy in the management of fluconazole-refractory mucosal candidiasis in advanced HIVpositive patients.

Options for the management of mucosal candidiasis in patients with AIDS and HIV infection.

Oropharyngeal candidiasis may be the first manifestation of human immunodeficiency viral (HIV) infection, and more than 90% of patients with the acquired immunodeficiency syndrome (AIDS) develop the disease. Although numerous antifungal agents are available, azoles, both topical (clotrimazole) and systemic (fluconazole, itraconazole), have largely replaced older topical antifungals (gentian violet, nystatin) in the management of the disease in these patients. A concern in these patients is clinical relapse, which appears to be dependent on degree of immunosuppression and is more common with clotrimazole and ketoconazole than with fluconazole or itraconazole. Candida esophagitis is also of concern, since it occurs in more than 10% of patients with AIDS. Fluconazole is an integral part of management. A cyclodextrin oral solution formulation of itraconazole has similar clinical response rates as fluconazole and is an effective alternative. In patients with fluconazole-resistant mucocutaneous candidiasis, treatment options include itraconazole and amphotericin B oral suspension and parenteral preparation.

Refractory mucosal candidiasis in patients with human immunodeficiency virus infection.

Difficult-to-manage mucosal candidal infection has been a hallmark of individuals with advanced infection due to human immunodeficiency virus type 1. In this AIDS Commentary, Drs. Fichtenbaum and Powderly comprehensively review the literature and their experience with refractory candidiasis in such patients. Of interest is their delineation of resistance, a lack of susceptibility to an antifungal agent in vitro among patients with refractory or clinically unresponsive disease. These authors believe that the establishment of resistance should be based upon standards established by the National Committee on Clinical Laboratory Standards, which they propose to define as a failure to respond to systematic therapy with specific doses of itraconazole, fluconazole, or parenterally or orally administered amphotericin B within 14 days. There have been many definitions of "refractory candidiasis," and the one proposed by these authors will be debated; however, this definition has the advantage of establishing a standard by which to judge the efficacy of their proposed algorithm for the treatment of persistent or refractory oropharyngeal candidal infections. Drs. Fichtenbaum and Powderly have performed a useful service in their attempt to bring coherence to the management of this common and often vexing problem.

Fluconazole

Fluconazole is a triazole antifungal agent which is now an established part of therapy in patients with immune deficiencies. It is effective against oropharyngeal/oesophageal candidiasis (candidosis) when used orally once daily either as treatment or secondary prophylaxis in patients with AIDS or as treatment or primary prophylaxis in neutropenia associated with cancer therapy. Fluconazole also resolves symptoms in up to 60% of patients with cryptococcal meningitis and AIDS. However, in this infection its efficacy as treatment relative to that of amphotericin B is equivocal, and its major role is as the drug of choice for maintenance therapy following amphotericin B induction. In this regard, fluconazole has been proven superior to amphotericin B and to itraconazole 200 mg/day. Comparisons with other drugs used for the treatment of mucosal candidiasis in patients with AIDS show fluconazole to be superior to nystatin, similar to itraconazole and at least as effective as clotrimazole and ketoconazole; it was more so than the latter azole in 1 study. In patients undergoing chemotherapy or bone marrow transplantation, fluconazole as primary prophylaxis has produced greater clinical benefit than a clotrimazole regimen. The incidence of adverse events appears to be somewhat higher in patients with AIDS compared with HIV-negative cohorts, but the qualitative pattern of events is similar. The most frequent events are gastrointestinal complaints, headache and skin rash: rare exfoliative skin reactions and isolated instances of clinically overt hepatic dysfunction have occurred in patients with AIDS. Issues yet to be clarified include: the use of fluconazole in children with AIDS, in whom results have been promising; its efficacy against other fungal infections encountered in immunocompromised patients; whether the drug influences mortality, as has been suggested by one placebo-controlled trial in patients undergoing bone marrow transplant; and the appropriateness of its potential for use as primary prophylaxis against cryptococcal meningitis in patients with AIDS, where it shows efficacy but there is concern over increasing risk of development of secondary resistance. Notwithstanding these undefined aspects of its clinical profile, fluconazole is now confirmed as an important antifungal drug in the management of fungal infections in patients with immune deficiencies. In patients with AIDS it is the present drug of choice as maintenance therapy against cryptococcal meningitis and is a preferred agent for secondary prophylaxis against candidal infections; it is also a favoured agent for primary prophylaxis in patients at risk because of neutropenia associated with chemotherapy or bone marrow transplantation .

Opportunistic candidal infections in patients infected with human immunodeficiency virus: prevention issues and priorities.

Mucosal candidiasis (oropharyngeal, esophageal, and vulvovaginal candidiasis) has been among the most prominent opportunistic infections in persons infected with human immunodeficiency virus (HIV). Esophageal candidiasis, an AIDS-defining illness, accounted for 15% of the AIDS-defining illnesses in adults and adolescents diagnosed in the United States through 1992. The diagnosis of oropharyngeal and vaginal candidiasis is based on clinically consistent signs and symptoms and a positive culture or a positive gram, KOH, or calcofluor stain, whereas the diagnosis of esophageal and pulmonary candidiasis is based on histopathology. Although a prospective controlled trial showed that prophylaxis with fluconazole can reduce the risk of mucosal candidiasis in patients with advanced HIV disease, routine primary prophylaxis is not recommended because of the effectiveness of therapy for acute disease, the low mortality associated with mucosal candidiasis, the potential for development of drug-resistant candidal infection, and the cost of prophylaxis. The probability of recurrences increases as CD4 counts decline. Nonetheless, many experts do not recommend chronic prophylaxis to prevent recurrent oropharyngeal and vulvovaginal candidiasis, for the same reasons that primary prophylaxis is not recommended. However, if recurrences are frequent or severe following documented esophageal candidiasis, long-term suppressive therapy with fluconazole should be considered.

Clinically Significant Mucosal Candidiasis Resistant to Fluconazole Treatment in Patients with AIDS

Eight cases of severe mucosal candidiasis in patients with AIDS who were taking fluconazole at a dosage of 400-800 mg/d are described. Candida albicans alone or in conjunction with Torulopsis glabrata or Candida stellatoidea was isolated from each patient. In vitro susceptibility testing demonstrated resistance to fluconazole in all eight cases. All tested isolates were susceptible to amphotericin B, and six of eight isolates tested were susceptible to itraconazole. All individuals were severely immunocompromised (CD4 lymphocyte counts: mean, 15/mm3; range, 6-39/mm3) and had been receiving prophylaxis with fluconazole for a mean of only 3 months (range, 1-7 months). The occurrence of candidal mucositis in patients receiving high doses of fluconazole is a matter of concern that requires further study in regard to the causes, prevention, and treatment of the disease.