Abstract
Background. Invasive candidiasis is a life-threatening infection in patients with hematological malignancies. However, studies of risk factors for candidemia are derived either from non-hematology patients or from single-center, retrospective reviews of hematology patients. The objective of our prospective, multicenter study was to determine incidence, microbiologic characteristics, and clinical outcome of candidemia among hospitalized adult patients with hematological malignancies.Methods. This is a population-based, prospective, multicenter, case-control study of all patients ≥18 years admitted to hematology and/or HSCT units of nine tertiary care Greek hospitals from January 2009 through February 2012. Stepwise logistic regression was used to identify independent predictors of 28-day mortality. Results. Forty hematology patients had candidemia vs. 967 non-hematology patients for an incidence of 1.4 cases/1000 admissions for hematological malignancy vs. 0.83/1000 in non-hematology ...
Background. Invasive candidiasis is a life-threatening infection in patients with hematological malignancies. However, studies of risk factors for candidemia are derived either from non-hematology patients or from single-center, retrospective reviews of hematology patients. The objective of our prospective, multicenter study was to determine incidence, microbiologic characteristics, and clinical outcome of candidemia among hospitalized adult patients with hematological malignancies.Methods. This is a population-based, prospective, multicenter, case-control study of all patients ≥18 years admitted to hematology and/or HSCT units of nine tertiary care Greek hospitals from January 2009 through February 2012. Stepwise logistic regression was used to identify independent predictors of 28-day mortality. Results. Forty hematology patients had candidemia vs. 967 non-hematology patients for an incidence of 1.4 cases/1000 admissions for hematological malignancy vs. 0.83/1000 in non-hematology patients (P<0.001). Candidemia was caused predominantly (35/40, 87.5%) by non-albicans Candida species: C. parapsilosis [20/40, 50%]; C. tropicalis [6/40, 15%]; C. albicans [5/40, 12.5%]; C. glabrata [4/40, 10%]; C. guilliermondii [2/40, 5%]. In vitro resistance to at least one antifungal agent was observed in 60% of Candida isolates. Twenty-one patients (52.5%) developed breakthrough candidemia, while receiving antifungal agents. Crude mortality at day-28 was greater in those with candidemia versus control cases (18/40 (45%) vs. 9/80 (11%) (P< 0.001)). Central venous catheters, hypogammaglobulinemia, and a high APACHE II score were independent risk-factors for the development of candidemia.Conclusions. Despite antifungal prophylaxis, candidemia is a relatively frequent infection associated with high mortality caused by non-albicans Candida spp., especially C. parapsilosis. Central venous catheters and hypogammaglobulinemia are independent risk factors of mortality that provide potential targets for improving outcome.Candida Osteomyelitis in Immunocompromised Patients: Analysis of 119 CasesBackground: The epidemiology, pathogenesis, clinical manifestations, management and outcome of Candida osteomyelitis are not well understood. Methods: Cases of Candida osteomyelitis were reviewed from 1928 through 2011. Underlying conditions, microbiology, mechanisms of infection, clinical manifestations, antifungal therapy (AFT), and outcome were studied in 119 evaluable cases. Results: Median age was 35y (range ≤1mo-88 y) with >2:1 male:female ratio. During the past 4 decades, there was a 4-fold increase of reported cases of Candida osteomyelitis. Localizing pain, tenderness and/or edema were present in 89% of patients. Mechanisms of bone infection followed a pattern of hematogenous dissemination (67%), direct inoculation (25%), and contiguous infection (8%). Coinciding with hematogenous infection, most patients had ≥2 infected bones. When analyzed by age, the most common distribution of infected sites for adults was vertebra (95% CI 0.03, 0.26; OR 0.09)>rib>sternum; whereas, for pediatric patients, (≤18yrs) the pattern was femur (95% CI 8.2, 48.5; OR 20.0)>humerus>vertebra. Non-albicans Candida spp. caused 35% of cases. Bacteria were recovered concomitantly from 12% of cases, underscoring the need for biopsy and/or culture. Candida septic arthritis occurred concomitantly in 23%. Combined surgery and antifungal therapy were used in 46% of cases. The overall complete response rate of Candida osteomyelitis of 31% reflects the difficulty in treating this infection. Conclusions: Candida osteomyelitis is being reported with increasing frequency. Localizing symptoms are usually present. Vertebrae are the most common sites in adults versus femora in children. Management of Candida osteomyelitis remains challenging and often requires combined AFT plus surgery.Phenotypic and Molecular Resistance Patterns of Candida species in Patients with Candidemia and Hematologic Malignancies Background: During a prospective, observational, multicenter study of candidemia in patients with hematological malignancies admitted to Hellenic hospitals from 1-1-09 through 02-28-12, we observed that candidemia emerged commonly during antifungal therapy. The mechanisms underlying these breakthrough infections are not well understood. Methods: In vitro susceptibility profiles were performed by EUCAST microbroth dilution methods on all 30 isolates of Candida spp. causing blood stream infection (BSI). The molecular mechanisms of resistance of 12 of these BSI isolates were further characterized by sequencing specific regions of the FKS1, FKS2, and ERG11 genes. Results: Among the 30 BSI isolates, there were 13 C. parapsilosis (43%), 5 C. albicans (17%), 4 C. glabrata (13%), 3 C. tropicalis (10%), 2 C. guilliermondii (7%), and one (3%) each of C. lusitaniae, C. krusei, and C. famata; 18 (60%) of these isolates caused BSIs during the course of one or more systemic antifungal agents.Eight (27%) emerged during amphotericin B (AmB)therapy. The median MIC for these isolates was 0.25 µg/ml (0.25-1.0 µg/ml); whereas, the median MLC was 2 µg/ml (2-8 µg/ml), and median MLC/MIC ratio was 4 µg/ml (2-8 µg/ml), consistent with resistance to the fungicidal effect of AmB. During the course of an antifungal triazole, breakthrough candidemia occurred in 10 (33%) cases (4 posaconazole, 6 fluconazole). All isolates were susceptible to both triazoles; however, 8 of 10 isolates were C. parapsilosis, suggesting a role for vascular catheters.Breakthrough BSI developed in two patients receiving echinocandins (caspofungin and anidulafungin); both were caused by echinocandin-resistant C. parapsilosis (MIC ≥ 2 mg/L) with the proline-to-alanine amino acid change in the FKS1 protein (P660A). Six other isolates of C. parapsilosis showed phenotypic resistance against echinocandins (MIC range, 2-8 mg/L): 4 C. parapsilosis de novo, 1 C. parapsilosis on fluconazole, 1 C. parapsilosis on AmB. Thus, 8 (62%) of 13 isolates of C. parapsilosis demonstrated phenotypic resistance to echinocandins and 4 of these demonstrated P660A changes in FKS1. By comparison, the multidrug resistant isolate of C. guilliermondii with MICs ≥ 4 mg/L to all echinocandins did not demonstrate any critical FKS1 gene mutations. Conclusions: This study demonstrates new patterns of breakthrough Candida BSIs in patients with hematological malignancies: the emergence of C. parapsilosis and C. guilliermondii; echinocandin resistance with P660A FKS1; high-level resistance to the fungicidal effect of AmB; and emergent candidemia during triazole therapy despite susceptible profiles. These new patterns collectively warrant novel strategies for treatment and prevention of invasive candidiasis in patients with hematological malignancies.
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