Current issues in the clinical management of invasive candida infections--the AGIHO, DMykG, ÖGMM and PEG web-based survey and expert consensus conference 2009.

The objectives of this study were to identify unsolved issues in the management of invasive candidiasis, identify controversies and achieve consensus. The German Speaking Mycological Society (Deutschsprachige Mykologische Gesellschaft, DMykG e.V.) asked other German infectious diseases (ID) and mycological societies to submit unsolved issues concerning the diagnosis and treatment of fungal infections. Based on these contributions, a digital web-based questionnaire of 12 questions on Candida infections was designed to be completed by experts of the participating societies. Controversial results were identified by a mathematical model and were discussed at a consensus conference during the 43rd Annual Meeting of the DMykG e.V. in Cologne, Germany. Forty-two individuals completed the questionnaire. Analysis showed a strong consensus on treatment indications, choice of antifungals for clinical situations, handling of central venous catheters, duration of treatment and role of susceptibility testing. Opinions diverged on: initial treatment of haemodynamically stable neutropenic and haemodynamically unstable non-neutropenic patients, step down to oral treatment and the differential role of the echinocandins. These questions were presented for discussion at the expert consensus conference. In three of four questions, consensus was achieved. A two-step approach - web-based survey plus classical panel discussion - allows to capture expeditiously the opinions of a large and diverse group of individuals, to identify controversial issues and to resolve them in a personal, interactive setting. Thus, expert consensus was achieved on nine of 12 important questions on how to treat invasive candidiasis.

Current issues in the clinical management of invasive aspergillosis--the AGIHO, DMykG, ÖGMM and PEG web-based survey and expert consensus conference 2009.

The objectives of this study were to identify unsolved issues in the management of invasive aspergillosis, identify controversies and achieve consensus. The German Speaking Mycological Society (Deutschsprachige Mykologische Gesellschaft, DMykG) invited other German infectious diseases (ID) and mycological societies to submit unsolved issues concerning the diagnosis and treatment of invasive aspergillosis. Based on these contributions, a digital web-based questionnaire of 12 questions on Aspergillus spp. was designed to be completed by experts of the participating societies. Controversial results were identified by a mathematical model and were discussed at a consensus conference during the 43rd Annual Meeting of the DMykG in Cologne, Germany. Forty-two individuals completed the questionnaire. Analysis showed a strong consensus on effective preventive measures, choice of antifungal agents for pre-emptive, empiric and targeted treatment, as well as the evaluation of early chest CT control scans as a measure of treatment response assessment. Opinions on the indication for a pulmonary biopsy of a halo sign in high-risk neutropenic patients and on the role of Aspergillus spp. PCR as well as galactomannan from serum in the assessment of treatment duration diverged in spite of discussion such that a consensus could not be reached. Using a recently published two-step approach - web-based survey plus classical panel discussion - expert consensus was achieved on 10 of 12 questions concerning the diagnosis and treatment of invasive aspergillosis.

Environmental and clinical epidemiology of Aspergillus terreus: data from a prospective surveillance study.

Aspergillus terreus may be resistant to amphotericin B and is associated with significant morbidity and mortality in immunocompromised patients. Local incidence is influenced by the density of airborne Aspergillus spp. spores which may in turn depend on meteorological factors. Once-weekly environmental samples were collected prospectively inside and outside the University Hospital of Cologne, Germany (UHC) and haematological patients were screened for nasal Aspergillus spp. colonisation and monitored for invasive fungal disease (IFD). RAPD (rapid amplification of polymorphic DNA)-polymerase chain reaction (PCR) and amphotericin B susceptibility testing were performed on all A. terreus isolates. A total of 4919 colony-forming units (cfu) were isolated (2212 indoors, 2707 outdoors). Further identification revealed A. fumigatus (73.5%), A. niger (4.3%), A. flavus (1.7%), A. terreus (0.2%) and non-Aspergillus fungi (20.3%). RAPD-PCR did not reveal clonal relationships between the A. terreus isolates. All A. terreus isolates displayed complete resistance to amphotericin. The B. Aspergillus spp. conidia exposure was lowest in June and highest in November inside and outside UHC. Conidia load correlated with the season and the relative humidity, with increasing spore counts during dry periods. One out of 855 nasal swabs was positive for A. niger. The patient did not develop IFD. A. terreus is unlikely to be a relevant pathogen at the UHC. Results from RAPD-PCR suggested a wide epidemiological variety of strains rather than a common source of contamination. Nasal swab surveillance cultures for early detection of Aspergillus spp. colonisation were not useful in identifying patients who may develop IFD. The risk of IFD at the UHC may increase in autumn and during dry periods.

Clinical effectiveness of posaconazole prophylaxis in patients with acute myelogenous leukaemia (AML): a 6 year experience of the Cologne AML cohort.

BACKGROUND: Large randomized controlled trials have shown significant decreases in morbidity and mortality in leukaemia patients with posaconazole prophylaxis. However, the value of prophylaxis has been questioned in centres with a low incidence of invasive fungal diseases (IFDs) and pre-emptive treatment strategies. METHODS: We prospectively evaluated the epidemiology of IFDs in acute myelogenous leukaemia (AML) patients undergoing first remission-induction chemotherapy before and after posaconazole prophylaxis had been introduced as a standard of care. Patients admitted from January 2003 to December 2005 received topical polyenes as antifungal prophylaxis (first group), while those admitted between January 2006 and December 2008 received 200 mg of oral posaconazole three times daily (second group). Other diagnostic and therapeutic standard operating procedures remained unchanged. RESULTS: A total of 82 patients in the polyene prophylaxis group and 77 in the posaconazole prophylaxis group were included in the final analysis. Baseline characteristics were well matched between groups. Patients receiving topical polyene prophylaxis were more likely to experience breakthrough IFDs (19.5% and 3.9%; P = 0.003) or breakthrough aspergillosis (13.4% and 2.6%; P = 0.018) than patients receiving systemic posaconazole prophylaxis. They also had more febrile days (mean 10.7 +/- 9.66 and 7.3 +/- 5.73; P = 0.007), longer need for inpatient treatment (mean 53.0 +/- 24.16 and 46.0 +/- 14.39; P = 0.026) and a shorter fungal-free survival (78.7 and 90.4 days; P = 0.024). No significant differences were observed for persistent fever, pneumonia, lung infiltrates indicative of invasive pulmonary aspergillosis, or attributable and overall mortality. CONCLUSIONS: After introduction of posaconazole prophylaxis for patients with AML, the number of febrile days, the incidence rate of IFDs and aspergillosis and the duration of hospitalization decreased significantly.

Factors influencing pharmacokinetics of prophylactic posaconazole in patients undergoing allogeneic stem cell transplantation.

The objectives of the present study were to elucidate the factors influencing the pharmacokinetics of prophylactically administered posaconazole in allogeneic hematopoietic stem cell transplant (SCT) recipients. Between May 2007 and November 2008, clinical data were obtained from all SCT recipients at the University Hospital of Cologne undergoing therapeutic drug monitoring (TDM) of serum prophylactic posaconazole concentrations. The posaconazole concentrations were determined by high-performance liquid chromatography. We developed a population pharmacokinetic model using nonlinear mixed-effect modeling (NONMEM). The list of covariates tested included age; body weight; body height; gender; posaconazole dose; race; coadministration of antineoplastic chemotherapy; day of stem cell transplantation; concomitant ranitidine, pantoprazole, cyclosporine, or tacrolimus administration; coincident fever; diarrhea; and plasma gamma-glutamyltransferase activity. A total of 149 serum posaconazole concentrations from 32 patients were obtained. A one-compartment model with first-order absorption and elimination as the basic structural model appropriately described the data, with the apparent clearance being 75.8 liters/h (95% confidence interval [CI], 65.2 to 86.4 liters/h) and the apparent volume being distribution of 835 liters (95% CI, 559 to 1,111 liters). Among the covariates tested, significant effects were found for age (decrease in the volume of distribution of 123 liters per year of age) and the presence of diarrhea (59% loss of bioavailability). A basis for prediction of the mean posaconazole concentrations in allogeneic SCT recipients with hematological malignancies is provided for a given dose. Corresponding adjustments of the starting dose according to the presence of diarrhea and according to age appear to be justified before TDM results are available.

Forty-one recent cases of invasive zygomycosis from a global clinical registry.

BACKGROUND: Invasive zygomycosis accounts for a significant proportion of all invasive fungal diseases (IFD), but clinical data on the clinical course and treatment response are limited. PATIENTS AND METHODS: Fungiscope-A Global Rare Fungal Infection Registry is an international university-based case registry that collects data of patients with rare IFD, using a web-based electronic case form at www.fungiscope.net. RESULTS: Forty-one patients with invasive zygomycosis from central Europe and Asia were registered. The most common underlying conditions were malignancies (n = 26; 63.4%), diabetes mellitus (n = 7; 17.1%) and solid organ transplantation (n = 4; 9.8%). Diagnosis was made by culture in 28 patients (68.3%) and by histology in 26 patients (63.4%). The main sites of infection were the lungs (n = 24; 58.5%), soft tissues (n = 8; 19.5%), rhino-sinu-orbital region (n = 8; 19.5%) and brain (n = 6; 14.6%). Disseminated infection of more than one non-contiguous site was seen in six patients (14.6%). Mycocladus corymbifer was the most frequently identified species (n = 10, 24.4%). A favourable response was observed in 23 patients (56.1%). Overall survival was 51.2% (n = 21). At diagnosis, four patients (9.8%) were on continuous antifungal prophylaxis with itraconazole (n = 1; 2.4%) or posaconazole (n = 3; 7.3%). Initial targeted treatment with activity against zygomycetes was administered to 34 patients (82.9%). Liposomal amphotericin B was associated with improved response (P = 0.012) and survival rates (P = 0.004). CONCLUSIONS: Pathogen distribution and, consequently, drug susceptibility seem to vary across different geographic regions. Furthermore, protection from invasive zygomycosis for patients on posaconazole prophylaxis is not absolute. Our findings indicate that the use of liposomal amphotericin B as first-line treatment for patients diagnosed with zygomycoses merits further investigation, preferably in the form of a clinical trial.

Current experience in treating invasive zygomycosis with posaconazole.

The treatment of zygomycosis has two cornerstones, namely, surgery and antifungal drugs. In many patients, both need to be applied to achieve treatment success; without treatment, the mortality rate of zygomycosis approaches 100%. Because treatment options are limited, no well-designed randomized clinical trial has been conducted and data are predominantly derived from compassionate-use programmes or case reports. Amphotericin B (AmB) lipid complex (ABLC) was clinically evaluated for efficacy against zygomycosis in a single series and resulted in cure or improvement in 52% and in the stabilizing of disease in 20% of patients. Liposomal AmB (L-AmB) is frequently used, but no large series have yet been published. Posaconazole has demonstrated in vitro and in vivo activity against Zygomycetes. Two series demonstrated salvage treatment response rates of 60% and 79%, respectively. Antifungal combinations have not been evaluated thoroughly enough to warrant recommendations outside of clinical trials. Survival is usually associated with surgical debridement and improvement in underlying diseases. Currently, surgical debridement should be performed. Antifungal treatment should consist of either ABLC > or =5 mg/kg once per day or L-AmB > or =3 mg/kg once per day. When toxicity occurs or stable fungal disease is achieved, treatment can be switched to oral posaconazole 200 mg four times per day. If impaired kidney function is overt or expected on the grounds of, for example, uncontrolled diabetes, primary treatment of zygomycosis with posaconazole is an option.