Novel antifungal agents as salvage therapy for invasive aspergillosis in patients with hematologic malignancies: posaconazole compared with high-dose lipid formulations of amphotericin B alone or in combination with caspofungin.

In patients with hematologic malignancy, invasive aspergillosis continues to be associated with high mortality even when treated with conventional antifungal therapy. To investigate novel antifungal agents, we compared 53 patients who received posaconazole salvage therapy to 52 contemporary control patients who received high-dose lipid formulation of amphotericin B (HD-LPD/AMB at > or = 7.5 mg kg(-1) per day) and 38 other control patients who received caspofungin plus HD-LPD/AMB. Patients in the three groups had similar. The overall response rate to salvage therapy was 40% for posaconazole, 8% for HD-LPD/AMB (P < or = 0.001) and 11% for combination therapy (P < 0.002). Aspergillosis contributed to the death of 40% of posaconazole group, 65% of the HD-LPD/AMB group and 68% of the combination group (P < or = 0.008). By multivariate analysis, posaconazole therapy independently improved response (9.5; 95% confidence interval, 2.8-32.5; P < 0.001). HD-LPD/AMB alone or in combination was associated with a significantly higher rate of nephrotoxicity (P < or = 0.02) and hepatotoxicity (P < 0.03). In conclusion, posaconazole salvage therapy demonstrated greater efficacy and safety than HD-LPD/AMB alone or in combination with caspofungin in the salvage therapy of invasive aspergillosis in hematologic malignancy.

Fungal osteoarticular infections in patients treated at a comprehensive cancer centre: a 10-year retrospective review.

This study reviewed retrospectively the clinical characteristics of 28 cancer patients with fungal osteoarticular infections (FOAIs) between 1995 and 2005. Most patients (26; 93%) had haematological malignancies (19 had leukaemia); half (14) were allogeneic stem-cell transplant recipients. Twelve patients (43%) had severe neutropenia (< or = 100/mm3) with a mean duration of 65 days (range 10-500 days), and ten (36%) patients had received a significant dose of corticosteroids. Most (19; 68%) FOAIs were caused by contiguous extension, while nine (32%) were associated with haematogenous spread. Pain, joint instability and local drainage were seen in 28 (100%), six (21%), and seven (25%) patients, respectively. Sixteen (57%) patients had symptoms for < 1 month. The sinuses (ten; 36%) and the vertebral spine (six; 21%) were the most common sites involved. Moulds were the predominant pathogens: Aspergillus fumigatus (two); non-fumigatus Aspergillus spp. (eight); non-specified Aspergillus spp. (three); Fusarium spp. (six); Zygomycetes (five); Scedosporium apiospermum (two); and Exserohilum sp. (one). Candida was the causative pathogen in four cases (including two cases of mixed FOAIs). Arthritis and post-operative FOAIs were both uncommon manifestations, occurring in two patients each. All patients received systemic antifungal therapy (combinations in 20 cases), and 19 cases underwent adjunctive surgery. The crude mortality rates (at 12 weeks) were 44% (9/20) in the patients who underwent surgery and antifungal therapy vs. 33% (2/6) in patients who received antifungal therapy alone (p not significant). FOAI is a rare, yet severe, manifestation of localised or systemic mycoses, caused predominantly by moulds, and is seen typically in patients with haematological malignancies.

Fruit flies as a minihost model for studying drug activity and virulence in Aspergillus.

Invasive aspergillosis (IA) is a significant cause of morbidity and mortality in profoundly immunosuppressed patients. The mediocre efficacy of antifungals for IA in clinical practice and an incomplete understanding of the pathogenesis of IA contribute to its overall poor prognosis. Although logistically difficult for large scale use, conventional animal models of IA provide valuable information regarding both antifungal drug efficacy and Aspergillus mutant virulence. However, in the era of introduction of molecular biology techniques for studying Aspergillus and increasing antifungal options, the existing in vivo models of IA might be well complemented by nonvertebrate minihost models such as the Drosophila melanogaster (fruit fly). Drosophila may offer the distinct advantage of performing fast, inexpensive high-throughput screening of compounds for anti-Aspergillus activity and putative Aspergillus mutants for their role in Aspergillus virulence.

Hyperbaric oxygen as an adjunctive treatment for zygomycosis.

Zygomycosis is a rare but emerging mycosis. Because of the sub-optimal efficacy of the standard antifungal treatment for this disease, hyperbaric oxygen (HBO) has been used occasionally as an adjunctive therapeutic modality. A review of 28 published cases of zygomycosis indicates that adjunctive HBO may be beneficial in diabetic patients (94% survival), whereas its benefit in the small group of patients with haematological malignancies or bone marrow transplants is doubtful (33% survival; p 0.02). Prolonged courses of HBO were associated with a higher survival (100% survival; p 0.003). Additional studies are required to assess the optimal timing and dose for HBO treatment.

Mycobacterium tuberculosis at a comprehensive cancer centre: active disease in patients with underlying malignancy during 1990-2000.

Thirty HIV-seronegative cancer patients with active tuberculosis were evaluated. Eighteen (60%) were immigrants, 19 (63%) had haematological malignancy, and fever was the most common presentation (97%). Of 19 (63%) patients with pulmonary tuberculosis, 11 (58%) were misdiagnosed initially as suffering from cancer following radiography. Death was attributed to tuberculosis for six (21%) of 29 patients who received anti-mycobacterial therapy. All four patients who had received high-dose systemic corticosteroids within 4 weeks of diagnosis of infection died, whereas two (8%) deaths occurred in 25 individuals without corticosteroid exposure (p < 0.001; OR 8.67). At this institution, active tuberculosis was rare, and was seen mostly in immigrants. Recent high-dose corticosteroid therapy is a significant predictor of mortality in cancer patients with tuberculosis.

High-dose fluconazole therapy for cancer patients with solid tumors and candidemia: an observational, noncomparative retrospective study.

BACKGROUND: Response rates for candidemia treated with standard-dose fluconazole (400 mg/day) are approximately 70%. Higher doses of fluconazole have been recommended for susceptible dose-dependent Candida isolates. Herein, we describe the outcome of 20 patients with solid tumors and candidemia treated with high-dose fluconazole (HDF) at The University of Texas M.D. Anderson Cancer Center (1998-2002). PATIENTS AND METHODS: Patients were identified either by searching the microbiology laboratory database or through direct referral from primary oncology services to the Infectious Diseases Consultative Services. A retrospective review of cases was performed. HDF was defined as > or =600 mg/day. RESULTS: Five patients were treated with 600 mg/day, whereas 15 patients received 800 mg/day. Only one patient was neutropenic. The median APACHE II score at the onset of candidemia was 12 (range 6-24). The most common species identified were Candida albicans (eight patients, 40%) and Candida parapsilosis (seven patients, 35%). Of 19 patients whose quantitative data were available, eight (42%) had high-grade candidemia [> or =200 colony forming units (CFU)/ml]. Fifteen (83%) of 18 isolates were fluconazole susceptible, and two (both Candida glabrata) were fluconazole resistant (MIC 64 each) in vitro. Nineteen patients (95%) responded to HDF therapy. The only HDF failure occurred in a patient with C. glabrata (MIC 64.0) infection. The other patient with C. glabrata (MIC 64.0) infection responded to HDF. Central venous catheters were removed from all patients with > or =10 CFU/ml candidemias. All patients with high-grade candidemias responded to HDF. The median duration of HDF therapy was 16 (range 6-42) days. No significant toxicity occurred. CONCLUSIONS: Although our data are limited, HDF appears to be well tolerated and may be associated with higher response rates than standard-dose fluconazole in a selected group of patients with solid tumors and candidemia caused by species that are susceptible to this triazole.

Systemic mycoses in the immunocompromised host: an update in antifungal therapy.

Despite significant advances in the management of immunosuppressed patients, invasive fungal infections remain an important life-threatening complication. In the last decade several new antifungal agents, including compounds in pre-existing classes (new generation of triazoles, polyenes in lipid formulations) and novel classes of antifungals with a unique mechanism of action (echinocandins), have been introduced in clinical practice. Ongoing and future studies will determine their exact role in the management of different mycoses. The acceleration of antifungal drug discovery offers promise for the management of these difficult to treat opportunistic infections.