NEW! Clinical Practice Guidelines for the Management of Sporotrichosis: 2007 Update by the Infectious Diseases Society of America
CA Kauffman, B Bustamante, SW Chapman, and PG Pappas. Clin Infect Dis. 2007;45:1255-1265.
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Sporotrichosis is caused by the dimorphic fungus, Sporothrix schenckii, and is found throughout the world in decaying vegetation, sphagnum moss, and soil. The most common form of infection is through cutaneous inoculation of the organism, pulmonary and disseminated infections can occur when the organism is inhaled. Dissemination of infection is more likely to occur in patients with a history of alcohol abuse or immunosuppression, particularly patients with AIDS.

Spontaneous resolution of sporotrichosis rarely occurs and treatment with an antifungal agent is required. For life-threatening infections, such as pulmonary, meningeal or disseminated sporotrichosis, a lipid formulation of amphotericin B is the preferred therapeutic choice. Itraconazole may be used for less severe infections as well as step-down therapy from amphotericin B for long-term suppression therapy.

NEW! Posaconazole or Fluconazole for Prophylaxis in Severe Graft-versus-Host Disease
AJ Ullmann, JH Lipton, DH Vesole, P Chandrasekar, A Langston, et al. N Engl J Med. 2007;356:335-47. Click here to learn more about this article!

Invasive fungal infections are a leading cause of death in patients who undergo hematopoietic stem cell transplantation, and those who develop graft-versus-host disease (GVHD) are at greater risk of infection. Given the significant morbidity and mortality associated with invasive fungal infections in these patients, antifungal prophylaxis is a practical approach to prevent these serious infections.

This report describes a randomized, double-blind clinical trial that compared posaconazole with fluconazole for prophylaxis against invasive fungal infections in patients with GVHD. A total of 600 patients were included in the study, and after the 112-day treatment period, posaconazole was found to be as effective as fluconazole in preventing all invasive fungal infections (incidence 5.9% vs 9.0%, respectively; P = .07). However, posaconazole was superior to fluconazole in preventing invasive aspergillosis (2.3% vs 7.0%; P = .001). During the treatment stage, there were significantly fewer breakthrough infections in the posaconazole group (2.4%) compared to fluconazole group (7.6%; P=.004), particularly breakthrough invasive aspergillosis (1.0% vs 5.9%; P = .001). Though overall mortality was similar between the two treatment groups, the mortality rate associated with invasive fungal infections was significantly lower with posaconazole (1.0% vs 4%; P = .046). The safety profiles were similar between the two groups.

The authors conclude that given the superiority of posaconazole over fluconazole in preventing invasive aspergillosis, posaconazole should be considered an option for prophylaxis in patients with severe GVHD.

NEW! Clinical Practice Guidelines for the Management of Patients with Histoplasmosis: 2007 Update by the Infectious Diseases Society of America
LJ Wheat, AG Freifeld, MB Kleinman, JW Baddley, DS McKinsey, et al. Clin Infect Dis. 2007;45:807025. Click here to learn more about this article!

In the United States, histoplasmosis caused by Histoplasma capsulatum variety capsulatum infection has generally been concentrated in the Ohio and Mississippi River valleys. Severity of illness and disease manifestation after inhalation of the organism can vary depending on the intensity of exposure and the immunity of the host. Serious cases can result in severe pneumonitis and respiratory compromise and may require antifungal therapy.

These management guidelines developed by the IDSA provide an update to the previous version released in 2000 and address areas related to the development of newer antifungal agents. For mild-to-moderate cases of acute pulmonary histoplasmosis, antifungal therapy is not recommended in most cases, though itraconazole can be used if symptoms persist for over one month. In moderate-to-severe cases of acute pulmonary histoplasmosis, a regimen of a lipid formulation of amphotericin B followed by itraconazole is recommended, though amphotericin B deoxycholate can be substituted for the lipid formulation in patients at low risk of nephrotoxicity.

Prophylaxis with itraconazole can be used for certain high risk patients (such as those with HIV infection and CD4 cell counts below 150 cells/mm3) in specific areas of endemicity.

Posaconazole vs. Fluconazole or Itraconazole Prophylaxis in Patients with Neutropenia
OA Cornely, J Maertens, DJ Winston, J Perfect, AJ Ullmann, et al. N Engl J Med. 2007;356:348-59.
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Fluconazole prophylaxis has been shown to provide clinical benefits in preventing invasive fungal infections in high risk patients. However, an increase in the number of Candida glabrata and mould infections may diminish the utility of this agent given its limited spectrum of activity. Posaconazole is the latest triazole antifungal agent to become available in the US and exhibits in vitro activity against many important fungal pathogens, including Candida spp., Aspergillus spp., Zygomycetes, and Fusarium spp. In this randomized, multicenter trial where evaluators were unaware of the treatment assignments, posaconazole was compared with fluconazole and itraconazole for prophylaxis in patients with prolonged neutropenia.

A total of 602 patients were included in the study, with 304 patients receiving posaconazole and 298 patients receiving fluconazole or itraconazole. Proven or probable infection was found in 2% of patients receiving posaconazole compared with 8% receiving fluconazole or itraconazole (P < 0.001). Only 2 patients (1%) in the posaconazole group had invasive aspergillosis compared with 20 (7%) in the comparator group (P < 0.001). A survival benefit was observed for patients who received posaconazole (P = 0.048). However, patients receiving posaconazole were more likely to experience a serious adverse event possibly or probably related to treatment (6% vs 2%; P = 0.01).

The authors conclude that prophylaxis with posaconazole was superior to prophylaxis with fluconazole and itraconazole. The ability of posaconazole to prevent mould infections, particularly invasive aspergillosis, can be significant given the morbidity and mortality associated with those types of infections in severely immunocompromised patients.

Anidulafungin versus Fluconazole for Invasive Candidiasis
AC Reboli, C Rotstein, PG Pappas, SW Chapman, DH Kett, et al. N Engl J Med. 2007;356:2472-82.
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Anidulafungin represents the newest antifungal agent approved for use in the United States. Similar to other echinocandins, this agent exhibits activity against most Candida species. This report describes a randomized, double-blind clinical trial comparing intravenous anidulafungin with intravenous fluconazole for patients with candidemia and invasive candidiasis. All patients could be switched to oral fluconazole after 10 days of intravenous therapy.

A total of 245 patients were enrolled in the study, with 89% having candidemia only and 97% were not neutropenic. At the end of intravenous therapy, the success rate was 75.6% (96 of 127) for those treated with anidulafungin and 60.2% (71 of 118) for fluconazole-treated patients (P = 0.02). The statistical significance of this difference in efficacy disappeared, however, when data from the site with the largest number of patients was excluded. The most common species isolated from the patients was Candida albicans (61.6%) and C. glabrata (20.4%). Fluconazole resistance did not seem to play a role in efficacy results as only five isolates from the fluconazole group had an MIC greater than 16 µg/mL. The frequency of adverse events and the mortality rate for all causes were similar between the two treatment groups.

The authors conclude that anidulafungin is non-inferior to fluconazole in the treatment of invasive Candida infections. This study did use the lower end of fluconazole dosing (400 mg per day), which may have affected efficacy with this agent.

Liposomal Amphotericin B as Initial Therapy for Invasive Mold Infection: A Randomized Trial Comparing a High-Loading Dose Regimen with Standard Dosing (AmBiLoad Trial)
OA Cornely, J Maertens, M Bresnik, R Ebrahimi, AJ Ullmann, et al. Clin Infect Dis. 2007;44:1289-97.
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The pharmacokinetics of liposomal amphotericin B are non-linear and achieve maximal plasma concentration at doses of 10 mg/kg per day, though the approved dosing is 3-5 mg/kg per day for treatment of invasive fungal infections. This prospective, randomized, double-blind trial tested the hypothesis of whether using a higher dose of liposomal amphotericin B could improve outcomes in patients with invasive mould infections.

A total of 201 patients were evaluated, including 107 who received a 3 mg/kg daily dose and 94 who received 10 mg/kg per day for 14 days followed by 3 mg/kg per day. Invasive aspergillosis accounted for 97% of the cases, while 93% of patients had hematologic malignancies and 73% were neutropenic at baseline. No statistically significant difference was observed between treatment groups for response rates at the end of therapy (50% for 3 mg/kg vs 46% for 10 mg/kg). At 12 weeks following study entry, patients receiving the lower dose had a higher survival rate, though not statistically significant (72% vs 59%; P > 0.05). Patients receiving the higher dose of liposomal amphotericin B did report a higher incidence of adverse events, particularly nephrotoxicity (31% vs 14%; P < 0.01) and hypokalemia (30% vs 16%; P = 0.015).

These results support the current dosing regimen for liposomal amphotericin B as a higher dose does not offer additional efficacy benefits but can result in increased rates of drug-related adverse events.

Micafungin versus Liposomal Amphotericin B for Candidaemia and Invasive Candidosis: a Phase III Randomised Double-Blind Trial
ER Kuse, P Chetchotisakd, CA da Cunha, M Ruhnke, C Barrios, et al. Lancet. 2007;369:1519-27.
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This large scale study included 537 patients predominantly from Europe, India, and Brazil to compare micafungin and liposomal amphotericin B for the treatment of invasive Candida infections. Treatment success was observed in 89.6% of patients administered micafungin and 89.5% for those receiving liposomal amphotericin B. Among those who were neutropenic at baseline, success rates were 75% (18 of 24) for those treated with micafungin and 80% (12 of 15) for those treated with liposomal amphotericin B. There were no significant differences in efficacy between treatment groups.

Patients treated with micafungin experienced fewer treatment-related adverse events, including significantly fewer incidences of rigors, increased blood creatinine, back pain, and infusion-related reactions. Treatment discontinuation occurred in 4.9% of the micafungin group compared with 9.0% for those treated with liposomal amphotericin B (P = 0.087).

The authors conclude that the results support the use of micafungin as a first-line treatment option for candidemia and invasive candidosis. The safety profile of micafungin is similar to other echinocandins, such as caspofungin.