Invasive fungal infections (IFI) are a kind of the most severe complications after hematopoietic stem cell transplantation (HSCT), Candida and Aspergillus are common causes. Because of immunosuppressive therapy, ablative conditioning regimen, acute or chronic graft-versus-host disease, long-term treatment of broad-spectrum antibiotics and cytomegalovirus infection, IFI has increased in the past few years. Invasive mould infection is a major cause of morbidity and mortality in HSCT recipients. Methods for early diagnosis of IFI include clinical and laboratory examinations, as well as characteristic radiography. Voriconazole is the first-line antifungal agent for prevention of IFI. Combination therapy of two antifungal compounds such as azoles or amphotericin B with echinocandins have shown a good effectiveness and may be a promising future strategy for antifungal treatment. In this review, the early diagnosis and treatment of IFI in HSCT recipients are summarized. As for early diagnosis of IFI, the laboratory diagnosis techniques such as GM test, G test and PCR techniques are discussed. As for prophylaxis and treatment of IFI, the prophylaxis treatment, empirical treatment, preemptive treatment, targeted treatment, combined treatment and immunologic treatment are discussed.
Antifungal Agents ; therapeutic use ; Hematopoietic Stem Cell Transplantation ; adverse effects ; Humans ; Mycoses ; diagnosis ; drug therapy

BACKGROUNDInvasive fungal infections such as candidiasis and mold infections cause significant morbidity and mortality in seriously ill patients. Micafungin is an echinocandin antifungal agent with potent activity against most species of Candida and Aspergillus. We did this meta-analysis to clarify whether micafungin offers superior efficacy and safety compared with other antifungal agent for treating infections associated with invasive candidiasis.

METHODSWe did a meta-analysis of randomized controlled trials to examine whether micafungin has superior efficacy and safety compared with other antifungal agents recommended by the treatment guidelines for fungal infection. Seven trials involving 2913 patients were included in this analysis. Odds ratios (OR) and 95% confidence intervals (CI) were calculated.

RESULTSMicafungin was associated with significantly better treatment success compared with the comparator antifungal agents (modified intention to treat, 2851 patients; random-effects model, OR 1.20, 95%CI 1.00 - 1.45, P = 0.0487). In addition, micafungin was more effective than the comparators for antifungal prophylaxis of neutropenic patients undergoing hematopoietic stem cell transplantation (OR 1.47, 95%CI 1.08 - 2.00, P = 0.01). Although there was no significant difference between the compared regimens in terms of the incidence of adverse drug effects (OR 0.94, 95%CI 0.77 - 1.11), fewer patients treated with micafungin withdrew from the studies because of adverse events (OR 0.64, 95%CI 0.44 - 0.94).

CONCLUSIONSMicafungin has a good safety and tolerability profile, with an efficacy at least comparable to the other antifungal agents. Micafungin offers advantages over other agents for antifungal prophylaxis. Micafungin offers an appropriate alternative for antifungal prophylaxis rather than the treatment of invasive candida infections.

Antifungal Agents ; adverse effects ; therapeutic use ; Candidiasis, Invasive ; drug therapy ; Echinocandins ; adverse effects ; therapeutic use ; Humans ; Lipopeptides ; adverse effects ; therapeutic use ; Randomized Controlled Trials as Topic ; Treatment Outcome

PURPOSE: To identify prognostic factors for the outcomes of empirical antifungal therapy, we performed a multicenter, prospective, observational study in immunocompromised patients with hematological malignancies. MATERIALS AND METHODS: Three hundred seventy-six patients (median age of 48) who had neutropenic fever and who received intravenous (IV) itraconazole as an empirical antifungal therapy for 3 or more days were analyzed. The patients with possible or probable categories of invasive fungal disease (IFD) were enrolled. RESULTS: The overall success rate was 51.3% (196/376). Age >50 years, underlying lung disease (co-morbidity), poor performance status [Eastern Cooperative Oncology Group (ECOG) > or =2], radiologic evidence of IFD, longer duration of baseline neutropenic fever (> or =4 days), no antifungal prophylaxis or prophylactic use of antifungal agents other than itraconazole, and high tumor burden were associated with decreased success rate in univariate analysis. In multivariate analysis, age >50 years (p=0.009) and poor ECOG performance status (p=0.005) were significantly associated with poor outcomes of empirical antifungal therapy. Twenty-two patients (5.9%) discontinued itraconazole therapy due to toxicity. CONCLUSION: We concluded that empirical antifungal therapy with IV itraconazole in immunocompromised patients is effective and safe. Additionally, age over 50 years and poor performance status were poor prognostic factors for the outcomes of empirical antifungal therapy with IV itraconazole.
Antifungal Agents/adverse effects/*therapeutic use ; Female ; Hematologic Neoplasms ; Humans ; Immunocompromised Host ; Itraconazole/adverse effects/*therapeutic use ; Male ; Middle Aged ; Prospective Studies ; Republic of Korea

OBJECTIVETo evaluate the incidence of Ketoconazole associated hepatotoxicity and related factor.

METHODSLiterature retrieval was conducted by using multi-databases for meta-analysis on Ketoconazole associated hepatotoxicity. The data were collected with a standardized form. Overall estimation of incidence of hepatotoxicity for specific study type was calculated by using a DerSimonian-Laird random-effects model owing to the substantial differences among the studies.

RESULTSTotally 204 eligible studies were included in the analysis. The incidence of Ketoconazole associated hepatotoxicity was 3.6%-4.2%. The dosage and duration specific subgroup analyses did not show any significant difference among groups, while the age specific subgroup analysis showed the incidence in children and people aged >60 years was 1.4% (95% CI: 0.5%-4.2%) and 3.2% (95% CI: 1.1%-8.7%) respectively. Additionally, the incidence of the hepatotoxicity was higher in people who had oral administration of ketoconazole beyond the provisions of the usage instructions, and the incidence was 5.7% (95% CI: 4.5%-7.2%).

CONCLUSIONKetoconazole associated hepatotoxicity was common. Off-label use might increase the risk of liver damage. Well-designed large sample studies are needed to identify the risk factors in future.

Antifungal Agents ; administration & dosage ; adverse effects ; Chemical and Drug Induced Liver Injury ; etiology ; Humans ; Ketoconazole ; administration & dosage ; adverse effects ; Off-Label Use

OBJECTIVETo evaluate the effect of fluconazole in prophylaxis of fungal infection in very low birth weight infants.

METHODSPubMed, EMBASE, Ovid, China National Knowledge Infrastructure, Vip Chinese Periodical Database, Wanfang Chinese Periodical Database and Chinese Bio-medicine Database were searched for the case-control study on the effect of fluconazole in prophylaxis of fungal infection in very low birth weight infants from Jan. 1994 to Jan. 2009. Articles were evaluated according to inclusion criteria. Poor-quality studies were excluded, and RevMan 4.22 software was applied for investigating the heterogeneity among individual studies and calculating the pooled risk ratio (RR) and 95% confidence interval (CI).

RESULTSFive eligible randomized clinical trials were included. Four studies were graded as "A" and one study was graded "B". Meta-analysis based on the included studies showed that the prophylactic fluconazole could significantly reduce the fungal colonization (RR: 0.32 and 95% CI: 0.23 to 0.44, P < 0.00001); and infections (RR: 0.44 and 95% CI: 0.29 to 0.65, P < 0.0001) in very low birth weight neonates. However, there was no statistically significant difference between the infants treated and not treated with prophylactic fluconazole in the neonatal mortality (RR: 0.68 and 95% CI: 0.43 to 1.07, P = 0.09) and the prophylactic use of fluconazole did not show any side-effects on the liver and bilirubin. None of the studies found any significant changes in the minimal inhibitory concentration of fluconazole in fungal isolates during the study period. There were different results about the emergence of resistance to fluconazole.

CONCLUSIONSMeta-analysis of five randomized controlled trials suggest that prophylactic fluconazole reduces the incidence of fungal colonization and invasive fungal infection in very low birth weight infants. Further trials are needed to provide more precise evaluation on efficacy, and to assess the effect on mortality, neurodevelopment and the emergence of resistance to antifungal agents. Different NICU should have different policy on prophylactic fluconazole and also adjust the policy at different time according to the incidence of fungal infection and antifungal drug resistance.

Antifungal Agents ; adverse effects ; therapeutic use ; Fluconazole ; adverse effects ; therapeutic use ; Humans ; Infant, Newborn ; Infant, Very Low Birth Weight ; Mycoses ; prevention & control ; Randomized Controlled Trials as Topic ; Safety

We report a case of 61-yr-old man with stable psoriasis who progressively developed generalized pustular eruption, erythroderma, fever, and hepatic dysfunction following oral terbinafine. Skin biopsy was compatible with pustular psoriasis. After discontinuation of terbinafine and initiating topical corticosteroid and calcipotriol combination with narrow band ultraviolet B therapy, patient's condition slowly improved until complete remission was reached 2 weeks later. The diagnosis of generalized pustular psoriasis (GPP) induced by oral terbinafine was made. To our knowledge, this is the first report of GPP accompanied by hepatic dysfunction associated with oral terbinafine therapy.
Suppuration/chemically induced ; Psoriasis/*chemically induced ; Naphthalenes/*adverse effects ; Middle Aged ; Male ; Liver Diseases/*chemically induced ; Humans ; Antifungal Agents/*adverse effects ; Administration, Oral

Antifungal Agents ; therapeutic use ; Humans ; Infant ; Meningitis, Cryptococcal ; drug therapy ; Pyrimidines ; adverse effects ; therapeutic use ; Triazoles ; adverse effects ; therapeutic use ; Voriconazole

PURPOSE: Posaconazole is a second-generation triazole with a broad spectrum. However, there is a lack of data to support a significant role for posaconazole in the treatment of invasive fungal infection (IFI), especially in Korea. Until recently, posaconazole was available only through the Korean Orphan Drug Center. This study was designed to review the use of posaconazole at a single-center in Korea. MATERIALS AND METHODS: Data from patients who received posaconazole treatment at Catholic Blood and Marrow Transplantation Center were retrospectively reviewed between January 2007 and September 2012. RESULTS: A total of 11 cases (3 males and 8 females, median age 52 years) received posaconazole. Five patients were given the drug for mucormycosis, two for invasive aspergillosis, and four for unspecified IFI for which galactomannan (GM) assays were negative. The treatment duration ranged from 4-250 days. Three patients received posaconazole for management refractory IFI, two for intolerance of previous antifungal therapy, and six for long-term maintenance treatment. The overall successful response rate to posaconazole was 55% (six of eleven patients). Five of eleven patients died during the study period. However, only one death was attributed to the progression of IFI. None of the patients discontinued posaconazole therapy due to adverse events. CONCLUSION: Posaconazole is an attractive oral antifungal agent for salvage treatment of IFI, particularly upon diagnosis of mucormycosis or in cases in which mucormycosis cannot be ruled out due to a negative GM.
Adult ; Aged ; Antifungal Agents/adverse effects/*therapeutic use ; Female ; Humans ; Immunocompromised Host ; Male ; Middle Aged ; Mucormycosis/drug therapy ; Mycoses/*drug therapy ; Republic of Korea ; Salvage Therapy/adverse effects ; Triazoles/adverse effects/*therapeutic use

BACKGROUNDAmphotericin B (0.7 mg/kg) with flucytosine is the standard treatment for cryptococcal meningitis. However, the long treatment course can induce adverse reactions in patients; therefore, reducing the dose may decrease such reactions. We performed a retrospective analysis of treatment effects and adverse reactions when amphotericin B (0.4 mg/kg or 0.7 mg/kg per day) and flucytosine were used together to treat HIV-negative patients with cryptococcal meningitis.

METHODSRetrospective analysis was conducted on inpatients at the First Affiliated Hospital, College of Medicine, Zhejiang University (January 2005 to December 2009). Low- or high-dose amphotericin B (0.4 or 0.7 mg/kg per day, respectively) plus flucytosine was used. The negative conversion rate of Cryptococcus in the cerebrospinal fluid (CSF), patient mortality, and the incidence of side effects for the two groups (low- vs. high-dose) were compared immediately after treatment and 2 and 10 weeks later. Data were analyzed by the Student's t test, chi-square tests using SPSS 12.0 statistical software.

RESULTSTwo weeks post-treatment, Cryptococcus negative CSF rates were 78% (18/23) in the low-dose group and 87% (13/15) in the high-dose group (P = 0.28). Ten weeks post-treatment, both groups were negative. The mortality rate was 8% (2/25) in the low-dose group and 17% (3/18) in the high-dose group (P = 0.25). There was a statistically significant difference in the incidence of adverse events between the groups, 48% (12/25) and 78% (14/18) in the low- and high-dose groups, respectively (P = 0.04). Adverse events that required a change in treatment program in the low-dose group were 12% (3/25) compared to 39% (7/18) in the high-dose group (P = 0.04).

CONCLUSIONLow-dose treatment regimens were better tolerated than high-dose ones.

Adolescent ; Adult ; Aged ; Amphotericin B ; adverse effects ; therapeutic use ; Antifungal Agents ; adverse effects ; therapeutic use ; Female ; Flucytosine ; adverse effects ; therapeutic use ; Humans ; Male ; Meningitis, Cryptococcal ; drug therapy ; microbiology ; Middle Aged ; Retrospective Studies ; Young Adult

This is a case report on a 35-year-old man with acute myelogenous leukemia who presented fever and intermittent mucoid loose stool to the emergency center. He had been taking voriconazole for invasive pulmonary aspergillosis. The flexible sigmoidoscopy was consistent with the diagnosis of pseudomembranous colitis.
Adult ; Antifungal Agents/*adverse effects ; Enterocolitis, Pseudomembranous/*chemically induced/pathology ; Humans ; Invasive Pulmonary Aspergillosis/complications/drug therapy ; Leukemia, Myeloid, Acute/complications ; Male ; Opportunistic Infections/complications/drug therapy ; Pyrimidines/*adverse effects ; Triazoles/*adverse effects