Corrado Girmenia

Invasive Infections Caused by Trichosporon Species and Geotrichum capitatum in Patients with Hematological Malignancies: a Retrospective Multicenter Study from Italy and Review of the Literature

ABSTRACT Trichosporonosis is an uncommon but frequently fatal mycosis in immunocompromised patients. A multicenter retrospective study was conducted to characterize cases of proven or probable invasive trichosporonosis diagnosed over the past 20 years in Italian patients with hematological diseases. Of the 52 cases identified, 17 were classified as Trichosporon sp. infections and 35 were attributed to Geotrichum capitatum. Acute myeloid leukemia accounted for 65.4% of the cases. The incidence rates of Trichosporon sp. and G. capitatum infections in acute leukemia patients were 0.4 and 0.5%, respectively. Overall, 76.9% of cases had positive blood cultures. Pulmonary involvement was documented in 26.9% of cases. Death was reported for 57.1% of G. capitatum infections and for 64.7% of Trichosporon sp. infections. A literature review on trichosporonosis in patients with any underlying disease or condition reveals G. capitatum as a predominantly European pathogen, particularly in certain Mediterranean areas, while Trichosporon sp. infections are seen with similar frequencies on all continents. The majority of published Trichosporon sp. and G. capitatum infections occurred in patients with hematological diseases (62.8 and 91.7%, respectively). Well over half of these were suffering from acute leukemia (68 and 84% of patients with Trichosporon sp. and G. capitatum infections, respectively). Crude mortality rates were 77% for Trichosporon spp. and 55.7% for G. capitatum. The optimal therapy for trichosporonosis has yet to be identified; however, in vitro experiences are providing encouraging evidence of the potential role of the new triazoles, in particular, voriconazole.

Itraconazole Oral Solution as Prophylaxis for Fungal Infections in Neutropenic Patients with Hematologic Malignancies: A Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial

To evaluate the efficacy and safety of itraconazole oral solution for preventing fungal infections, a randomized, placebo-controlled, double-blind, multicenter trial was conducted: 405 neutropenic patients with hematologic malignancies were randomly assigned to receive either itraconazole, 2.5 mg/kg every 12 hours (201 patients), or placebo (204 patients). Proven and suspected deep fungal infection occurred in 24% of itraconazole recipients and in 33% of placebo recipients, a difference of 9 percentage points (95% confidence interval [CI], 0.6% to 22.5%; P = .035). Fungemia due to Candida species was documented in 0.5% of itraconazole recipients and in 4% of placebo recipients, a difference of 3.5 percentage points (95% CI, 0.5% to 6%; P = .01). Deaths due to candidemia occurred in none of the itraconazole recipients compared with 4 placebo recipients, a difference of 2 percentage points (95% CI, 0.05% to 4%; P = .06). Aspergillus infection was documented in four itraconazole recipients (one death) and one placebo recipient (one death). Side effects causing drug interruption occurred in 18% of itraconazole recipients and 13% of placebo recipients. Itraconazole oral solution was well-tolerated and effectively prevented proven and suspected deep fungal infection as well as systemic infection and death due to Candida species.

Species identification of Aspergillus, Fusarium and Mucorales with direct surface analysis by matrix-assisted laser desorption ionization time-of-flight mass spectrometry

Accurate species discrimination of filamentous fungi is essential, because some species have specific antifungal susceptibility patterns, and misidentification may result in inappropriate therapy. We evaluated matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) for species identification through direct surface analysis of the fungal culture. By use of culture collection strains representing 55 species of Aspergillus, Fusarium and Mucorales, a reference database was established for MALDI-TOF MS-based species identification according to the manufacturers recommendations for microflex measurements and MALDI BioTyper 2.0 software. The profiles of young and mature colonies were analysed for each of the reference strains, and species-specific spectral fingerprints were obtained. To evaluate the database, 103 blind-coded fungal isolates collected in the routine clinical microbiology laboratory were tested. As a reference method for species designation, multilocus sequencing was used. Eighty-five isolates were unequivocally identified to the species level (≥99% sequence similarity); 18 isolates producing ambiguous results at this threshold were initially rated as identified to the genus level only. Further molecular analysis definitively assigned these isolates to the species Aspergillus oryzae (17 isolates) and Aspergillus flavus (one isolate), concordant with the MALDI-TOF MS results. Excluding nine isolates that belong to the fungal species not included in our reference database, 91 (96.8%) of 94 isolates were identified by MALDI-TOF MS to the species level, in agreement with the results of the reference method; three isolates were identified to the genus level. In conclusion, MALDI-TOF MS is suitable for the routine identification of filamentous fungi in a medical microbiology laboratory.

Clinical patterns of Fusarium infections in immunocompromised patients

Fusarium is an ubiquitous fungus commonly found in soil and on plants. Human infection usually occurs as a result of inoculation of the organism through the body surface, thus causing skin infection, onychomycosis, keratitis, endophthalmitis and arthritis. Dissemination may occur in subjects with underlying immunodeficiency. Among immunocompromised hosts, Fusarium sp. is an emerging pathogen in neutropenic patients. To our knowledge, since 1973, when the first disseminated fusariosis in a child with acute leukemia was reported, about 80 new cases have been reported, mainly occurring in patients with haematologic malignancies. Specific portals of entry are not well understood, nevertheless the respiratory tract, colonised gastrointestinal tract, onychomycosis, disrupted skin barrier and central venous catheter have been reported as entry sites of deep seated Fusarium infections. Fever, positive blood cultures, severe myalgias, disseminated ecthyma gangrenosum-like skin lesions, ocular symptoms and multiple-organ-system involvement are distinctive features in most cases of disseminated fusariosis. The prognosis is very poor with death generally following despite antifungal therapy, unless an increase in the white blood cell count occurs. All available antifungal drugs show a low activity against the various species of Fusarium. Nevertheless, amphotericin B seems to have the highest in vitro activity and, even if it does not appear to be effective in persistently neutropenic patients, it should be currently considered to be the treatment of choice.

Candida colonization and systemic infection in neutropenic patients. A retrospective study

The results of surveillance cultures in 424 neutropenic patients with hematologic malignancies were analyzed to evaluate the relationship between colonization and infection by Candida species. Eighteen (32%) of 56 patients with multiple noncontiguous colonized sites developed proven (13 cases) or probable (five cases) systemic candidiasis, versus two patients with proven candidiasis (1.2%) of 170 with one colonized site (P < 0.00000001), and one patient with proven candidiasis (0.5%) of 198 without any evidence of Candida colonization (P < 0.00000001). Twenty‐two patients with multiple colonized sites who developed a febrile episode resistant to antibiotics were treated with empiric amphotericin B. Nine of 11 given empiric amphotericin B within day 6 survived versus three of 11 receiving antifungal therapy after day 6 (P = 0.014). The above data seem to justify further prospective studies on Candida colonization as indication to early antifungal therapy in febrile neutropenic patients.

Pneumocystis carinii pneumonia in patients with malignant haematological diseases: 10 years' experience of infection in GIMEMA centres

Summary. A retrospective survey was conducted over a 10‐year period (1990–99) among 52 haematology divisions in order to evaluate the clinical and laboratory characteristics and outcome of patients with proven Pneumocystis carinii pneumonia (PCP) complicating haematological diseases. The study included 55 patients (18 with non‐Hodgkins lymphoma, 10 with acute lymphoblastic leukaemia, eight with acute myeloid leukaemia, five with chronic myeloid leukaemia, four with chronic lymphocytic leukaemia, four with multiple myeloma, three with myelodysplastic syndrome, two with myelofibrosis and one with thalassemia) who developed PCP. Among these, 18 (33%) underwent stem cell transplantation; only two received an oral prophylaxis with trimethroprim/sulphamethoxazole. Twelve patients (22%) developed PCP despite protective isolation in a laminar airflow room. The most frequent symptoms were: fever (86%), dyspnoea (78%), non‐productive cough (71%), thoracic pain (14%) and chills (5%); a severe hypoxaemia was present in 39 patients (71%). Chest radiography or computerized tomography showed interstitial infiltrates in 34 patients (62%), alveolar infiltrates in 12 patients (22%), and alveolar–interstitial infiltrates in nine patients (16%). Bronchoalveolar lavage was diagnostic in 47/48 patients, induced sputum in 9/18 patients and lung biopsy in 3/8 patients. The diagnosis was made in two patients at autopsy. All patients except one started a specific treatment (52 patients trimethroprim/sulphamethoxazole, one pentamidine and one dapsone). Sixteen patients (29%) died of PCP within 30 d of diagnosis. Multivariate analysis showed that prolonged steroid treatment (P < 0·006) and a radiological picture of diffuse lung involvement (P < 0·003) were negative diagnostic factors.

Comparison of the Susceptibilities of Candida spp. to Fluconazole and Voriconazole in a 4-Year Global Evaluation Using Disk Diffusion

ABSTRACT From June 1997 to December 2001, results of in vitro susceptibility tests of yeast isolates from 35 countries were collected. For 2001 alone, fluconazole results were reported for 22,111 yeast isolates from 77 institutions in 30 countries. Of these isolates, 18,569 were also tested for susceptibility to voriconazole. All study sites tested clinical yeast isolates by recently endorsed NCCLS disk diffusion method M44-P. Disk test plates were automatically read and results were recorded with the BIOMIC Image Analysis System. Species, drug, zone diameter, susceptibility category, MIC, and quality control results were electronically submitted by e-mail quarterly for analysis. Duplicate test results (same patient and same species with same sensitivity-resistance profile and biotype results during any 7-day period) and uncontrolled test results were eliminated from this analysis. The proportion of Candida albicans isolates decreased from 69.7% in 1997 to 1998 to 63.0% in 2001, and this decrease was accompanied by a concomitant increase in C. tropicalis and C. parapsilosis. The susceptibility (susceptible [S]or susceptible-dose dependent [S-DD]) of C. albicans isolates to fluconazole was virtually unchanged, from 99.2% in 1997 to 99% in 2001; the C. glabrata response to fluconazole was unchanged, from 81.5% S or S-DD in 1997 to 81.7% in 2001, although the percentage of resistant isolates from blood and upper respiratory tract samples appeared to increase over the study period; the percentage of S C. parapsilosis isolates decreased slightly, from 98% S or S-DD in 1997 to 96% in 2001; and the percentage of S isolates of C. tropicalis increased slightly, from 95.7% in 1997 to 96.9% in 2001. The highest rate of resistance to fluconazole among C. albicans isolates was noted in Ecuador (7.6%, n = 250). Results from this investigation indicate that the susceptibility of yeast isolates to fluconazole has changed minimally worldwide over the 4.5-year study period and that voriconazole demonstrated 10- to 100-fold greater in vitro activity than fluconazole against most yeast species.

Fungemia in Patients with Leukemia

A nine-year retrospective study on fungemia in patients with leukemia was conducted. A total of 79 episodes of fungemia in 77 patients with leukemia were documented. Candida parapsilosis fungemia was associated more frequently with the presence of a central venous line and to the use of parenteral nutrition than the other fungal species (p = 0.00026 and p = 0.01, respectively). The same fungus was isolated from both blood and surveillance cultures in 95% of Candida albicans and in 89% of Candida tropicalis fungemia (p < 0.01 and p = 0.02, respectively). The neutropenia and fungus colonization that resulted was associated significantly with the presence of invasive disease (p = 0.0024 and p = 0.0028, respectively). Conversely, central venous catheterization and parenteral nutrition appeared to be associated with episodes without deep tissue invasion (p = 0.000037 and p = 0.001, respectively). Invasive mycosis due to the fungus isolated from blood was documented in 51 patients with a mortality rate of 6970, whereas in 20 patients without invasive mycosis, mortality rate was 21% (p = 0.000059). In patients with fungemia, related or unrelated to the presence of a central venous catheter, mortality was 24% and 6470, respectively (p = 0.00042). Mortality was highest with C. tropicalis (p = 0.0017) and lowest with C. parapsilosis (p = 0.057). Severe neutropenia (polymorpho-nuclears < 100/mmc) appeared associated with a higher mortality rate (p = 0.012), whereas the recovery of neutropenia was related adversely to a fatal outcome (p < 0.01). With antifungal therapy, there was no statistically significant difference whether antifungal therapy was given or not. This study confirms the major roles of neutropenia, previous colonization, and the central venous catheter as predisposing factors in the development of fungemia in patients with leukemia. The prognosis of patients with fungemia depends on the presence of a deep infection, on the recovery of neutropenia, and on the species of fungus involved.

Aspergillus Galactomannan Enzyme-Linked Immunosorbent Assay Cross-Reactivity Caused by Invasive Geotrichum capitatum

ABSTRACT We report three cases of invasive Geotrichum capitatum infection in patients with acute leukemia for which an enzyme-linked immunosorbent assay (ELISA) for Aspergillus galactomannan was positive, with no evidence of aspergillosis. Supernatants obtained from suspensions of 17 G. capitatum strains gave positive reactions with the Aspergillus galactomannan ELISA. These clinical and laboratory data seem to suggest that G. capitatum produces a soluble antigen that is cross-reactive with Aspergillus galactomannan.

Clinically Driven Diagnostic Antifungal Approach in Neutropenic Patients: A Prospective Feasibility Study

PURPOSE Preemptive strategies in neutropenic patients based on serum galactomannan (GM) -guided triggering of diagnostic work-up may be time-consuming and expensive when applied to the entire population. We have assessed the feasibility of a clinically driven diagnostic strategy without GM screening. PATIENTS AND METHODS Patients with neutropenic fever underwent a baseline diagnostic work-up (BDWU; three blood cultures and other examinations as indicated). An intensive diagnostic work-up (IDWU; GM for 3 days, chest computed tomography and other examinations as indicated) was reserved for patients with 4 days of persisting or relapsing fever or with other clinical findings possibly related to an invasive fungal diseaser (IFD). Antifungal therapy was administered to patients diagnosed with IFD and empirically (negative IDWU) only to those with persisting neutropenic fever and worsening clinical conditions. RESULTS Of 220 neutropenia episodes, fever occurred in 159 cases and recurred in 28 cases. Overall, 49 IFDs were diagnosed (two by BDWU and 47 by IDWU) during 48 episodes (21.8%). Diagnostic-driven therapy was administered to 48 patients with IFDs; one patient with zygomycosis died without treatment. Only one patient received empirical therapy. IDWU was required in 40% of neutropenia episodes, and only 1.4 mean blood samples per neutropenia episode were tested for GM. Our strategy allowed a 43% reduction in antifungal treatments compared with a standard empirical approach. At 3-month follow-up, 63% of patients with IFD survived, and no undetected IFDs were found. CONCLUSION A clinically driven diagnostic approach in selected neutropenia episodes offered effective antifungal control and reduced the exposure to unnecessary antifungal treatment.