Marcio Nucci

Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial

BACKGROUND Invasive candidosis is increasingly prevalent in seriously ill patients. Our aim was to compare micafungin with liposomal amphotericin B for the treatment of adult patients with candidaemia or invasive candidosis. METHODS We did a double-blind, randomised, multinational non-inferiority study to compare micafungin (100 mg/day) with liposomal amphotericin B (3 mg/kg per day) as first-line treatment of candidaemia and invasive candidosis. The primary endpoint was treatment success, defined as both a clinical and a mycological response at the end of treatment. Primary analyses were done on a per-protocol basis. This trial is registered with ClinicalTrials.gov, number NCT00106288. FINDINGS 264 individuals were randomly assigned to treatment with micafungin; 267 were randomly assigned to receive liposomal amphotericin B. 202 individuals in the micafungin group and 190 in the liposomal amphotericin B group were included in the per-protocol analyses. Treatment success was observed for 181 (89.6%) patients treated with micafungin and 170 (89.5%) patients treated with liposomal amphotericin B. The difference in proportions, after stratification by neutropenic status at baseline, was 0.7% (95% CI -5.3 to 6.7). Efficacy was independent of the Candida spp and primary site of infection, as well as neutropenic status, APACHE II score, and whether a catheter was removed or replaced during the study. There were fewer treatment-related adverse events--including those that were serious or led to treatment discontinuation--with micafungin than there were with liposomal amphotericin B. INTERPRETATION Micafungin was as effective as--and caused fewer adverse events than--liposomal amphotericin B as first-line treatment of candidaemia and invasive candidosis.

Fusarium Infections in Immunocompromised Patients

SUMMARY Fusarium species cause a broad spectrum of infections in humans, including superficial, locally invasive, and disseminated infections. The clinical form of fusariosis depends largely on the immune status of the host and the portal of entry, with superficial and localized disease occurring mostly in immunocompetent patients and invasive and disseminated disease affecting immunocompromised patients. Risk factors for severe fusariosis include prolonged neutropenia and T-cell immunodeficiency, especially in hematopoietic stem cell transplant recipients with severe graft-versus-host disease. The most frequent presentation of disseminated fusariosis is a combination of characteristic cutaneous lesions and positive blood cultures, with or without lung or sinus involvement. The prognosis is poor and is determined largely by degree of immunosuppression and extent of infection, with virtually a 100% death rate among persistently neutropenic patients with disseminated disease. These infections may be clinically suspected on the basis of a constellation of clinical and laboratory findings, which should lead to prompt therapy. Treatment options include the lipid formulations of amphotericin B, voriconazole, and posaconazole. Prevention of fusarial infection among high-risk patients should be considered.

Micafungin versus Caspofungin for Treatment of Candidemia and Other Forms of Invasive Candidiasis

BACKGROUND Invasive candidiasis is an important cause of morbidity and mortality among patients with health care-associated infection. The echinocandins have potent fungicidal activity against most Candida species, but there are few data comparing the safety and efficacy of echinocandins in the treatment of invasive candidiasis. METHODS This was an international, randomized, double-blind trial comparing micafungin (100 mg daily) and micafungin (150 mg daily) with a standard dosage of caspofungin (70 mg followed by 50 mg daily) in adults with candidemia and other forms of invasive candidiasis. The primary end point was treatment success, defined as clinical and mycological success at the end of blinded intravenous therapy. RESULTS A total of 595 patients were randomized to one the treatment groups and received at least 1 dose of study drug. In the modified intent-to-treat population, 191 patients were assigned to the micafungin 100 mg group, 199 to the micafungin 150 mg group, and 188 to the caspofungin group. Demographic characteristics and underlying disorders were comparable across the groups. Approximately 85% of patients had candidemia; the remainder had noncandidemic invasive candidiasis. At the end of blinded intravenous therapy, treatment was considered successful for 76.4% of patients in the micafungin 100 mg group, 71.4% in the micafungin 150 mg group, and 72.3% in the caspofungin group. The median time to culture negativity was 2 days in the micafungin 100 mg group and the caspofungin group, compared with 3 days in the micafungin 150 mg groups. There were no significant differences in mortality, relapsing and emergent infections, or adverse events between the study arms. CONCLUSIONS Dosages of micafungin 100 mg daily and 150 mg daily were noninferior to a standard dosage of caspofungin for the treatment of candidemia and other forms of invasive candidiasis.

Epidemiology of Candidemia in Brazil: a Nationwide Sentinel Surveillance of Candidemia in Eleven Medical Centers

ABSTRACT Candidemia studies have documented geographic differences in rates and epidemiology, underscoring the need for surveillance to monitor trends. We conducted prospective candidemia surveillance in Brazil to assess the incidence, species distribution, frequency of antifungal resistance, and risk factors for fluconazole-resistant Candida species. Prospective laboratory-based surveillance was conducted from March 2003 to December 2004 in 11 medical centers located in 9 major Brazilian cities. A case of candidemia was defined as the isolation of Candida spp. from a blood culture. Incidence rates were calculated per 1,000 admissions and 1,000 patient-days. Antifungal susceptibility tests were performed by using the broth microdilution assay, according to the Clinical and Laboratory Standards Institute guidelines. We detected 712 cases, for an overall incidence of 2.49 cases per 1,000 admissions and 0.37 cases per 1,000 patient-days. The 30-day crude mortality was 54%. C. albicans was the most common species (40.9%), followed by C. tropicalis (20.9%) and C. parapsilosis (20.5%). Overall, decreased susceptibility to fluconazole occurred in 33 (5%) of incident isolates, 6 (1%) of which were resistant. There was a linear correlation between fluconazole and voriconazole MICs (r = 0.54 and P < 0.001 [Spearmans rho]). This is the largest multicenter candidemia study conducted in Latin America and shows the substantial morbidity and mortality of candidemia in Brazil. Antifungal resistance was rare, but correlation between fluconazole and voriconazole MICs suggests cross-resistance may occur.

Emerging Fungal Diseases

The epidemiology of invasive fungal infection is evolving. Yeasts other than Candida albicans and molds other than Aspergillus fumigatus have emerged as significant causes of invasive mycoses in severely immunocompromised patients. Although, in some instances, these changes may be related to medical interventions, such as the use of antifungal agents in prophylaxis, in the majority of cases, they seem to be a consequence of changes in the host, such as more-severe immunosuppression or different types of immunosuppression impacting both risk periods and the infections that occur. These factors have altered the epidemiology of infection in organ transplant recipients, premature newborns, and critically ill patients. This review discusses the epidemiology of some fungal infections that have emerged in the past few years, with an emphasis on the potential factors associated with their emergence and on practical implications of these epidemiological changes.

Cutaneous Infection by Fusarium Species in Healthy and Immunocompromised Hosts: Implications for Diagnosis and Management

Infections by Fusarium species frequently involve the skin, either as the primary or the metastatic site. To better understand the pathophysiology of these infections, 43 new patients with fusariosis were evaluated, and the literature was reviewed. A total of 259 patients (232 immunocompromised and 27 immunocompetent) were identified. Skin involvement was present in 70% of patients, particularly in immunocompromised patients (72% vs. 52%; P=.03). In immunocompetent patients, cutaneous infections were characterized by preceding skin breakdown, localized involvement, slow pace of progression, and good response to therapy. In contrast, skin involvement in immunocompromised patients was only occasionally preceded by skin breakdown and typically was presented as rapidly progressive disseminated lesions at various stages of evolution. Metastatic skin lesions were associated with fungemia, neutropenia, and death. Skin was the single source of diagnosis for the majority of immunocompromised and immunocompetent patients. Recommendations for the prevention of fatal fusariosis originating from skin are presented.

Revisiting the Source of Candidemia: Skin or Gut?

The source of candidemia has been the subject of considerable debate, with some suggesting a origin in the gastrointestinal tract and others suggesting a skin origin. To evaluate the potential sources of candidemia, we performed a computerized search of the MEDLINE database for studies published from January 1966 through September 2000 and we identified relevant abstracts presented at national meetings. We reviewed the literature with special emphasis on studies that used appropriate definitions, evaluated both gut and skin as sources, and conducted molecular-relatedness studies. Among 203 candidemia studies published, we identified 21 that evaluated a specific source for candidemia and only 5 that performed molecular typing. Those studies and additional experimental, epidemiologic, and molecular-relatedness studies strongly suggested that the gut is an important source of candidemia, and studies that supported the skin as a source for this infection were surprisingly incomplete.

Fusarium Infection in Hematopoietic Stem Cell Transplant Recipients

To characterize the epidemiology and prognostic factors of invasive fusariosis in hematopoietic stem cell transplant (HSCT) recipients, the records of HSCT recipients from 9 hospitals (7 in Brazil and 2 in the United States) were retrospectively reviewed. Sixty-one cases were identified: 54 in allogeneic HSCT recipients and 7 in autologous HSCT recipients. The incidence of fusariosis among allogeneic HSCT recipients varied between a range of 4.21-5.0 cases per 1000 in human leukocyte antigen (HLA)--matched related transplant recipients to 20.19 cases per 1000 in HLA-mismatched transplant recipients. The median time period between transplantation and diagnosis of fusariosis was 48 days. Among allogeneic HSCT recipients, a trimodal distribution was observed: a first peak before engraftment, a second peak at a median of 62 days after transplantation, and a third peak >1 year after transplantation. The actuarial survival was 13% (median, 13 days). Persistent neutropenia was the single prognostic factor for death identified by multivariate analysis.

High rate of non-albicans candidemia in Brazilian tertiary care hospitals

In order to evaluate the epidemiology of candidemia in Brazil, we performed a prospective multicenter study conducted in six general hospitals from São Paulo and Rio de Janeiro, We enrolled a total of 145 candidemic patients (85 males) with a median age of 32 years. Non-albicans species accounted for 63% of all episodes and the species most frequently causing candidemia were C. albicans (37%), C. parapsilosis (25%), C. tropicalis (24%), C. rugosa (5%), and C. glabrata (4%). Systemic azoles were used before the onset of candidemia in only six patients. There were no differences in the coexisting exposures or underlying diseases associated with the species most frequently causing candidemia. The overall crude mortality rate was 50%. Nosocomial candidemias in our tertiary hospitals are caused predominantly by non-albicans species, which are rarely fluconazole resistant. This predominance of non-albicans species could not be related to the previous use of azoles.

Epidemiology of Opportunistic Fungal Infections in Latin America

This review discusses the epidemiology of the most clinically relevant opportunistic fungal infections in Latin America, including candidiasis, cryptococcosis, trichosporonosis, aspergillosis, and fusariosis. The epidemiologic features, including incidence, of some of these mycoses are markedly different in Latin America than they are in other parts of the world. The most consistent epidemiologic data are available for candidemia, with a large prospective study in Brazil reporting an incidence that is 3- to 15-fold higher than that reported in studies from North America and Europe. Species distribution also differs: in Latin America, the most common Candida species (other than Candida albicans) causing bloodstream infections are Candida parapsilosis or Candida tropicalis, rather than Candida glabrata.