Conventional Antifungal Therapy Research Articles

Retrospective analysis of the dosage of amphotericin B lipid complex for the treatment of invasive fungal infections.

To understand the relationship between dosage and therapeutic response of amphotericin B lipid complex (ABLC) by analyzing underlying diseases, types of infections, and therapeutic outcomes with different dosages as second-line antifungal therapy. Retrospective analysis of low-dose (initial dose < or = 3 mg/kg) ABLC from three open-label, clinical, second-line treatment studies. Centers in the United States (204), Canada (3), Australia (1), Mexico (1), and The Netherlands (1). Five hundred fifty-one patients (5 enrolled twice) with invasive fungal infections, of whom 289 failed and 267 were intolerant to conventional antifungal therapy. Patients were to receive the recommended dosage of ABLC 5 mg/kg/day, with dosage reduction for markedly increased serum creatinine. The duration of treatment was 4 weeks; therapy could be extended if the investigator considered additional treatment necessary. Seventy-three patients (13%) received ABLC 3 mg/kg/day (low dosage) instead of the protocol-recommended 5 mg/kg/day Response was 65% and 56%, respectively. Logistic regression analysis revealed that the following patients are most likely to start therapy at the lower dosage: those with candidiasis and other yeast infections, patients with nephrotoxicity due to prior amphotericin B, and those with underlying conditions other than hematologic malignancy. These results suggest that ABLC 3 mg/kg/day may be effective in treating patients with candidiasis who do not have hematologic malignancy.

Native lung pneumonectomy for invasive pulmonary aspergillosis following lung transplantation: a case report

Pulmonary aspergillosis occurs most commonly as a consequence of immunosuppression in recipients of pulmonary transplantation and is associated with a high mortality. It affects the native lung more commonly than the transplanted lung in single lung transplant patients. Infection often progresses despite aggressive medical therapy. The cornerstone of treatment of acute, semi-invasive, and invasive pulmonary aspergillosis (IPA) is medical, with intravenous amphotericin B, and oral itraconazole either as isolated or combined therapy. While newer, and more expensive liposomal forms of amphotericin B have been used to enhance tissue penetration and minimize renal toxicity, an appreciable improvement in clinical outcome has not been reported. The role of surgery in localized pulmonary aspergillus infection is well recognized, but remains undefined in immunosuppressed patients. We report a case where a pneumonectomy was performed for progressive, refractory angioinvasive aspergillosis in a lung transplant recipient whose disease progressed despite conventional antifungal therapy.

EFFICACY AND SAFETY OF AMPHOTERICIN B LIPID COMPLEX INJECTION (ABLC) IN SOLID-ORGAN TRANSPLANT RECIPIENTS WITH INVASIVE FUNGAL INFECTIONS

Background Fungal infections following solid-organ transplantation are a major source of morbidity and mortality. This report describes the efficacy and safety of Amphotericin B Lipid Complex Injection (ABLC) in solid-organ transplant recipients. Methods Three open-label, second-line treatment studies evaluated ABLC as a treatment for severe, life-threatening mycoses in patients who were refractory to or intolerant to conventional antifungal (mostly amphotericin B [AmB]) therapy or had pre-existing renal disease. Results The 79 solid-organ transplant recipients (25 heart, 20 liver, 17 kidney, 11 lung, 5 multiple, 1 pancreas) who received ABLC in these studies had the following fungal infections: aspergillosis (n = 39); candidiasis (n = 20); zygomycosis (n = 8); cryptococcosis and histoplasmosis (n = 3 each); and blastomycosis, cladosporiosis, fusariosis, Bipolaris hawaiiensis, Dactylaria gallopava, and an unspecified fungal infection (n = 1 each). The median duration of ABLC therapy was 28 d (1-178 d). The daily dose ranged between 1.6 and 7.4 mg/kg (median, 4.6 mg/kg). The clinical response rate for the patients who could be assessed was 58% (39/67). Clinical response rates for heart, liver, kidney, and lung recipients were 59, 60, 67, and 40%, respectively; response rates for aspergillosis and candidiasis were 47 and 71%, respectively. Forty-six of the 79 patients (58%) survived for more than 28 d after the last dose of ABLC. Mean baseline serum creatinine was 3.2 mg/dL; 64 patients (81%) had stable (n = 37) or improved (n = 27) serum creatinine at the end of treatment. Conclusions ABLC is safe and effective treatment for fungal infections in solid-organ transplant recipients. Its renal-sparing properties are particularly suited for this high-risk population for renal failure.

New Directions in Antifungal Therapy.

Development of antifungal therapy continues to be lively, as we strive to approach the ideal therapy. The newest agents include lipid delivery systems for amphotericin B, which promise relief from some of that drug's side effects. The triazoles, itraconazole and fluconazole, have proven their value as non-toxic and orally effective therapy. Newer members of this class, e. g., SCH 56592 and voriconazole, appear to be promising extensions. To date the triazoles' properties enable new strategies of prophylaxis and of early intervention. Areas needing improvement include treatment for newer fungal pathogens not covered by available therapy, and the need for rapid diagnostic capabilities, comparative clinical trials, and better definitions and scoring in trials. Drugs with new and fungal-specific targets may provide a quantum leap in our weaponry. Examples included drugs targeted at chitin synthase (e. g., nikkomycin Z) or beta glucan synthase (e. g., LY303366). Another approach is immunomodulation, and several cytokines can stimulate the host synergistically with conventional antifungal therapy.

Trends in immunotherapy of fungal infections.

Fungal infections are the primary cause of mortality in patients with severely impaired host defense mechanisms, such as neutropenic patients with acute leukemia or those who have undergone bone marrow transplantation. In view of the unacceptably high mortality due to disseminated candidiasis, it is rational to focus on augmentation of host defense mechanisms in addition to conventional antifungal therapy. In vitro, a variety of immunomodulators, including tumor necrosis factor, interferon-g, and the hematopoietic growth factors, enhance the killing of Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans. Various studies have demonstrated beneficial effects of immunomodulatory therapy in animal models of disseminated candidiasis. For further preclinical and clinical studies, recombinant interferon-g, interleukin-1, granulocyte colony-stimulating factor, and the other hematopoietic growth factors are currently the most promising immunomodulators.

The hematoregulatory peptide, SK&amp;F 107647, in combination with antifungal therapy in murineCandida albicansinfections

SK&amp;F 107647, a novel synthetic low molecular weight peptide, has been shown to be a potent hematoregulatory agent. We have previously demonstrated that SK&amp;F 107647 administration can prolong survival in both immunosuppressed and normal mice challenged with the opportunistic fungal pathogen Candida albicans. Additionally, we have determined the effect of prophylactic SK&amp;F 107647 treatment combined with conventional antifungal therapy on the survival of mice challenged with a lethal dose of C. albicans. Prophylactic treatment with SK&amp;F 107647 or therapeutic treatment with the antifungals fluconazole or amphotericin B significantly increased the survival rates of immunosuppressed mice challenged with a lethal dose of C. albicans. However, the combination of SK&amp;F 107647 treatment followed by antifungal therapy resulted in statistically significant increases in survival over that observed with either therapy alone. These results indicated that the hematoregulatory factor(s) elicited by SK&amp;F 107647 enhance the survival of mice treated with conventional therapies in a model of experimental systemic candidiasis. Key words: SK&amp;F 107647, Candida albicans, hematoregulatory, fluconazole, amphotericin B.

Fluconazole treatment of children with severe fungal infections not treatable with conventional agents

Fluconazole was evaluated prospectively in 173 children aged between 4 months and 16 years in whom conventional antifungal therapy was ineffective or contraindicated. Children entered the study on an individual compassionate request basis for treatment of confirmed or presumed fungal infection or for prophylaxis of fungal infections. Sixty-two children had cancer, 40 had undergone transplantation, 14 had AIDS and 52 had other conditions. The mean fluconazole dosage was 3.4 mg/kg/day (range 0.16-11.1 mg/kg/day) and the mean duration of therapy was 36 days (range 1-340 days). Efficacy was evaluated in 63 children with confirmed fungal infection as documented by the presence of a fungal pathogen at baseline; clinical cure or improvement was achieved in 83% (52/63), pathogen eradication in 73% (43/59). All 173 children were assessed for safety. Related or possibly related adverse events occurred in 6% (11/173) of patients; seven children were withdrawn from therapy because of adverse events. Results of this study demonstrate that the clinical efficacy and safety profile of fluconazole in the treatment of fungal infections in children are favorable, results being similar to those obtained in adults.

Cytokine treatment of central nervous system infection: efficacy of interleukin-12 alone and synergy with conventional antifungal therapy in experimental cryptococcosis.

Cell-mediated immune responses appear to be critical in the outcome of cryptococcosis. Interleukin-12 (IL-12) was studied for its potential use as a therapeutic agent because of its stimulation of natural killer cells and gamma interferon production by stimulated T cells and natural killer cells. Gamma interferon-activated macrophages are important in host resistance against cryptococcosis. In two separate studies, male BALB/c mice were infected intravenously with Cryptococcus neoformans. In the first study, mice received either no treatment, 5.0 mg of fluconazole alone per kg of body weight per day (by gavage twice daily), or IL-12 subcutaneously at 0.01, 0.1, or 1.0 microgram/day once daily (low-dose study) alone or in combination with 5.0 mg of fluconazole per kg/day. In a second study (high dose), the dosages of IL-12 used were 1.0, 2.5, or 5.0 micrograms/day. Therapy was given for 10 consecutive days, and the number of CFU of C. neoformans remaining in various organs was quantitated 1 or 2 days after administration of the last dose. In the low-dose study, IL-12 at 0.1 or 1.0 microgram reduced the level of brain infection by approximately 10-fold (P < 0.05) and IL-12 at 1.0 or 0.1 microgram/day enhanced the efficacy of fluconazole. In liver, both the efficacy of IL-12 alone (0.01 or 0.1 microgram; P < 0.05) and enhancement of the efficacy of fluconazole (P < 0.05) were seen. No efficacy of IL-12 was seen in spleens or lungs, although spleen weights increased fourfold in mice given 1.0 microgram of IL-12 per day. In the high-dose study, all IL-12 doses alone again reduced the levels of brain infection (5- to 8-fold; P < 0.05) when the two were given in combination. No overt toxicities were observed at any dose, and overall, 1.0 microgram of IL-12 per day was found to be the optimal dosage for reducing infection in the brain. To our knowledge, this is the first demonstration of the efficacy of cytokine therapy in systemic and particularly brain infections with C. neoformans. The stimulation of cell-mediated immunity represents a new approach to therapy and can enhance suboptimal antimicrobial chemotherapy. IL-12 should be considered for further study and for clinical trials. These studies suggest that other opportunistic central nervous system pathogens should also be investigated.

Disseminated trichosporonosis in a neutropenic murine model

Life-threatening disseminated infection with Trichosporon beigelii (trichosporonosis) is a rare mycosis most commonly seen in patients with hematologic malignancies made neutropenic by cytotoxic therapy. This infection is usually resistant to conventional antifungal therapies. Poor correlation between therapeutic outcome of trichosporonosis and in vitro susceptibility of clinical isolates of T. beigelii to antifungal agents is often reported. To obtain a better understanding of its pathogenesis, and to aid in the future study of the therapy of this disease, a murine model of trichosporonosis was developed. The in vitro growth of clinical isolates of T. beigelii was first studied. Subsequently, mice made neutropenic with cyclophosphamide were inoculated intravenously with the fungus to produce the disease model. Inoculum size which produced 100% mortality, yet allowed an apparent therapeutic window (6 x 10(6)) was determined. Tissue distribution and burden of organism during the course of infection was examined by viability and histopathologic studies. T. beigelii disseminated rapidly in this model, involving numerous organs including the heart, brain, kidneys, lungs, and liver. The heart and kidneys of the infected animals showed evidence of infection as early as 6 hours following inoculation. Further understanding of the pathogenesis of trichosporonosis in the neutropenic host was imparted by this study. This will aid in the future study of antibiotic treatment of this disease and its untreated progression.

Tratamento pelo fluconazol de pacientes imuno-comprometidos com graves infecções fúngicas

Fluconazole therapy was evaluated prospectively in 108 patients with immunosupression and serious fungal infections. Patients were enrolled if they had a life-threatening fungal infection and conventional therapy had failed to eradicate infection, had caused serious toxic reactions, or was contraindicated. Patients were treated with 50 to over 400 mg/day initially. AIDS was underlying risk factor in 66.6% of the patients evaluated in the study and in 92.9% of 57 patients with cryptococcal infection. Satisfactory clinical response was observed in 43 patients with active cryptococcal infection and in 39 patients with active candidiasis, 90.7% and 92.3% respectively. Concerning mycologic response, 63.3% and 80.7% of 30 patients with cryptococcal infection and 26 patients with candidiasis respectively had final negative cultures. Eleven patients (10.2%) had adverse effects possibly due to fluconazole therapy. Fluconazole may be effective in the treatment of cryptococcal infection and candidiasis and can be an alternative to conventional antifungal therapy.

Phase I trial of recombinant human macrophage colony-stimulating factor in patients with invasive fungal infections

A phase I dose escalation trial of recombinant human macrophage colony- stimulating factor (rhM-CSF) in combination with conventional antifungal therapy was conducted in 24 marrow transplant recipients with invasive fungal infection. Daily doses ranged from 100 to 2,000 micrograms/m2/d. Toxicity, such as constitutional symptoms, directly ascribed to rhM-CSF was not observed; however, transient, dose-related thrombocytopenia was observed. Patients who received 2,000 micrograms/m2/d of rhM-CSF had a mean reduction in platelet count of 61,000/mm3 during the rhM-CSF infusion period, which was significant when compared with patients who received lower doses of rhM-CSF (P = .008). Fourteen of the 16 patients who received rhM-CSF after undergoing allogeneic bone marrow transplantation had no change in the severity of graft-versus-host disease (GVHD) while receiving rhM-CSF. One had an increase in the severity of GVHD and one had a decrease. There were no effects on neutrophil, monocyte, or lymphocyte counts. Six patients had resolution of their infections, 12 were not evaluable for response, and six did not respond. Ten patients survived 100 days after initiation of rhM-CSF and 14 died. Further trials with rhM-CSF to assess antifungal activity are indicated.

Phase I Trial of Recombinant Human Macrophage Colony-Stimulating Factor in Patients With Invasive Fungal Infections

A phase I dose escalation trial of recombinant human macrophage colony-stimulating factor (rhM-CSF) in combination with conventional antifungal therapy was conducted in 24 marrow transplant recipients with invasive fungal infection. Daily doses ranged from 100 to 2,000 micrograms/m2/d. Toxicity, such as constitutional symptoms, directly ascribed to rhM-CSF was not observed; however, transient, dose-related thrombocytopenia was observed. Patients who received 2,000 micrograms/m2/d of rhM-CSF had a mean reduction in platelet count of 61,000/mm3 during the rhM-CSF infusion period, which was significant when compared with patients who received lower doses of rhM-CSF (P = .008). Fourteen of the 16 patients who received rhM-CSF after undergoing allogeneic bone marrow transplantation had no change in the severity of graft-versus-host disease (GVHD) while receiving rhM-CSF. One had an increase in the severity of GVHD and one had a decrease. There were no effects on neutrophil, monocyte, or lymphocyte counts. Six patients had resolution of their infections, 12 were not evaluable for response, and six did not respond. Ten patients survived 100 days after initiation of rhM-CSF and 14 died. Further trials with rhM-CSF to assess antifungal activity are indicated.

Recombinant Human Interferon- as Adjunct Therapy for Aspergillus Infection in a Patient with Chronic Granulomatous Disease

The hallmark of chronic granulomatous disease (CGD) is defective killing of ingested microorganisms by phagocytic cells. Invasive aspergillosis in CGD patients is particularly virulent and has a mortality rate of approximately 50%. A patient with autosomal recessive CGD was identified who had progressive pulmonary aspergillosis that was unresponsive to conventional antifungal therapy. She was treated with recombinant human interferon-gamma (rHuIFN-gamma) and had a dramatic improvement in clinical symptoms, sedimentation rate, and radiographic scans. No consistent improvement in bactericidal function or neutrophil oxidative capacity could be demonstrated. However, serum neopterin levels, a measure of macrophage activation, increased in a dose-dependent manner with rHuIFN-gamma therapy; increased levels mirrored the improved clinical parameters. This patient's treatment illustrates the usefulness of the single-photon emission computed tomography (SPECT) gallium scan for following pulmonary inflammatory lesions in the presence of fibrosis and indicates that rHuIFN-gamma may be of benefit to CGD patients with serious infections unresponsive to conventional therapy.

Candidal Endocarditis and Treatment with Fluconazole and Granulocyte-Macrophage Colony-Stimulating Factor

Excerpt To the Editor:The use of colony-stimulating factors associated with conventional antifungal therapy has recently been advocated to treat systemic fungal infections (1). We report the first ...

Fluconazole for Life-Threatening Fungal Infections in Patients Who Cannot Be Treated with Conventional Antifungal Agents

Fluconazole therapy was evaluated prospectively in patients with serious fungal infections who failed to respond to or could not tolerate conventional antifungal therapy. Patients were enrolled if they had a life-threatening fungal infection and conventional therapy had failed to eradicate the infection, had caused serious toxic reactions, or was contraindicated. Patients were treated with 200 mg/day, a dosage that could be increased to 400 mg/d if the initial response was not satisfactory. AIDS was the underlying risk factor in 65% of 232 patients evaluated in the study and in 85% of 151 patients with cryptococcal infection. Fifty-eight patients had active cryptococcal infection; 74% had a satisfactory clinical response, and 75% of 44 patients became culture-negative. Patients with inactive infection had a relapse rate of 4.5/1,000 patient-weeks. Twenty-three of 30 patients with coccidioidal infection and 10 of 14 patients with candidiasis or another mycosis were clinically improved. Five patients (2%) discontinued fluconazole therapy because of adverse effects possibly attributable to therapy. Fluconazole may be effective in the treatment of serious fungal infections in patients who cannot continue conventional antifungal therapy.

Treatment of invasive aspergillus sinusitis with liposomal‐amphotericin B

Invasive sinonasal aspergillosis is a severe and frequently fatal infection in immunosuppressed patients with hematologic malignancies. Seven patients with sinonasal aspergillosis who failed to respond to conventional amphotericin B (AmpB) were treated with liposomal AmpB (L-AmpB).AmpB was incorporated into multilamellar vesicles consisting of dimyristoyl phosphatidyl-choline and dimyristoyl phosphatidylglycerol in a 7:3 molar ratio. Five patients had underlying hematologic malignancies, one patient had aplastic anemia, and one patient had no underlying disease. All patients had biopsy-proven invasive Aspergillus sinusitis, and had failed conventional antifungal therapy including AmpB. Five patients were cured and two did not respond to treatment. Fever and chills were infrequent and, when they occurred, mild, and responded well to conventional management. No severe renal or central nervous system toxicity was observed. L-AmpB is effective and less toxic than conventional AmpB in the treatment of invasive Aspergillus sinusitis.

High dose ketoconazole in the treatment of cerebral aspergilloma

A 32-year-old Chinese woman with bilateral occipital aspergilloma was treated successfully with high dose ketoconazole (1200 mg/day) for six months in conjunction with amphotericin B and 5-fluorocytosine. No unacceptable side effects occurred. The use of high dose ketoconazole could be considered in CNS aspergillosis unresponsive to conventional anti-fungal therapy.