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ABSTRACTMucormycoses are life-threatening infections in immunocompromised patients. This study characterizes the response of human mononuclear cells to different Mucorales and Ascomycota. PBMC, monocytes, and monocyte derived dendritic cells (moDCs) from healthy donors were stimulated with resting and germinated stages of Mucorales and Ascomycota. Cytokine response and expression of activation markers were studied. Both inactivated germ tubes and resting spores of Rhizopus arrhizusand other human pathogenic Mucorales species significantly stimulated mRNA synthesis and secretion of proinflammatory cytokines. Moreover, R. arrhizusspores induced the upregulation of co-stimulatory molecules on moDCs and a specific T-helper cell response. Removal of rodlet hydrophobins by hydrofluoric acid treatment of A. fumigatusconidia resulted in enhanced immunogenicity, whereas the cytokine response of PBMCs to dormant R. arrhizusspores was not influenced by hydrofluoric acid. Scanning electron micrographs of Mucorales spores did not exhibit any morphological correlates of rodlet hydrophobins. Taken together, this study revealed striking differences in the response of human mononuclear cells to resting stages of Ascomycota and Mucorales, which may be explained by absence of an immunoprotective hydrophobin layer in Mucorales spores.

ABSTRACTCombined biomarker screening is increasingly used to diagnose invasive aspergillosis (IA) in high-risk patients. In adults, the combination of galactomannan (GM) and fungal DNA detection has proven to be beneficial in the diagnosis of IA. Data in purely pediatric cohorts are scarce. Here, we monitored 39 children shortly before and after allogeneic stem cell transplantation twice weekly by use of a commercial GM enzyme-linked immunosorbent assay (ELISA) and a PCR assay based on amplification of the pan-AspergillusITS1/5.8S ribosomal operon. In addition, clinical data were recorded and classification of IA was performed according to the European Organization for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria. Among the 39 high-risk children, we identified 4 patients (10.3%) with probable and 2 (5.1%) with possible IA. All patients with probable IA were repeatedly positive for both tests (means of 9.5 and 6.8 positive GM and PCR samples, respectively), whereas both possible IA cases were detected by PCR. The sensitivity and specificity were, respectively, 67% and 89% for GM and 100% and 63% for PCR. Positive and negative predictive values were, respectively, 50% and 100% for GM and 27% and 100% for PCR. For the combined testing approach, both values were 100%. The number of positive samples seemed to be lower in patients undergoing antifungal therapy. Sporadically positive tests occurred in 12% (GM) and 42% (PCR) of unclassified patients. In summary, our data show that combined monitoring for GM and fungal DNA also results in a high diagnostic accuracy in pediatric patients. Future studies have to determine whether combined testing is suitable for early detection of subclinical disease and how antifungal prophylaxis impacts assay performance.

Isavuconazole is a novel triazole with broad-spectrum antifungal activity. The SECURE trial assessed efficacy and safety of isavuconazole versus voriconazole in patients with invasive mould disease.

ABSTRACTIsavuconazole is a novel broad-spectrum triazole antifungal agent. This open-label dose escalation study assessed the safety and pharmacokinetics of intravenous isavuconazole prophylaxis in patients with acute myeloid leukemia who had undergone chemotherapy and had preexisting/expected neutropenia. Twenty-four patients were enrolled, and 20 patients completed the study. The patients in the low-dose cohort (n= 11) received isavuconazole loading doses on day 1 (400/200/200 mg, 6 h apart) and day 2 (200/200 mg, 12 h apart), followed by once-daily maintenance dosing (200 mg) on days 3 to 28. The loading and maintenance doses were doubled in the high-dose cohort (n= 12). The mean ± standard deviation plasma isavuconazole areas under the concentration-time curves for the dosing period on day 7 were 60.1 ± 22.3 μg · h/ml and 113.1 ± 19.6 μg · h/ml for the patients in the low-dose and high-dose cohorts, respectively. The adverse events in five patients in the low-dose cohort and in eight patients in the high-dose cohort were considered to be drug related. Most were mild to moderate in severity, and the most common adverse events were headache and rash (n= 3 each). One patient in the high-dose cohort experienced a serious adverse event (unrelated to isavuconazole treatment), and two patients each in the low-dose and high-dose cohorts discontinued the study due to adverse events. Of the 20 patients who completed the study, 18 were classified as a treatment success. In summary, the results of this analysis support the safety and tolerability of isavuconazole administered at 200 mg and 400 mg once-daily as prophylaxis in immunosuppressed patients at high risk of fungal infections. (This study is registered at ClinicalTrials.gov under registration number NCT00413439.)

Infektiologie hat sich in Deutschland als klinische Disziplin nur langsam entwickelt. Die Infektiologendichte und die Zahl der Fachabteilungen in Kliniken hier ist im europäischen Vergleich aber immer noch gering. Zugleich ist aber auch die Zahl anderer Fachärzte im Bereich Infektionsmedizin wie Medizinische Mikrobiologie und Krankenhaushygiene gering. Die Ursachen sind vielfältig, teilweise werden die Rolle und Leistungen des klinischen Infektiologen und auch der Unterschied zur Medizinischen Mikrobiologie gar nicht verstanden. Ein Blick in andere Länder zeigt die enorme Bedeutung besonders der Infektiologie für die klinische Versorgung von komplexen Infektionspatienten, für Behandlungsqualität und Patientensicherheit sowie für strategische Aufgaben im Bereich Sicherstellung rationaler Antibiotikaverordnung (antibiotic stewardship, ABS) und Resistenzminimierung. Der Blick in andere Länder zeigt auch, dass Infektiologen vielerorts Krankenhaushygiene-Funktionen übernehmen können, die Nutzwert moderner mikrobiologischer Diagnostik verbessern und für die translationale Infektionsforschung von außerordentlicher Bedeutung sind. Hochrechnungen ergeben, dass in Deutschland mehr als 1000 zusätzliche Infektiologen gebraucht werden, um eine adäquate Qualität sicherzustellen. Dabei können insbesondere in kleineren Krankenhäusern einige der Funktionen von geschulten ABS-Experten übernommen werden. Mehr Weiterbildungskapazität und Flexibilität für das Training von Infektiologen und von Experten im Bereich ABS und Krankenhaushygiene in Deutschland sind eine dringliche Angelegenheit vor dem Hintergrund der Probleme mit Antibiotikaresistenz.

ABSTRACTThis was a phase 1B, dose-ranging, multicenter, pharmacokinetics, and safety study of cyclodextrin-based posaconazole intravenous (i.v.) solution administered through a central line to subjects at high risk for invasive fungal disease (part 1 of a 2-part study [phase 1B/3]). Initially, the safety and tolerability of single-dose posaconazole i.v. 200 mg (n= 10) were compared with those of a placebo (n= 11). Subsequently, 2 doses were evaluated, posaconazole i.v. 200 mg once daily (q.d.) (n= 21) and 300 mg q.d. (n= 24). The subjects received twice-daily (b.i.d.) posaconazole i.v. on day 1, followed by 13 days of posaconazole i.v. q.d., then 14 days of posaconazole oral suspension 400 mg b.i.d. The steady-state (day 14) exposure target (average concentration [areas under concentration-time curve {AUCs}/24 h, average concentrations at steady state {Cavgs}], of ≥500 to ≤2,500 ng/ml in ≥90% of the subjects) was achieved by 94% of the subjects for 200 mg posaconazole q.d. and by 95% of subjects for 300 mg posaconazole q.d. The desired exposure target (mean steady-state Cavg, ∼1,200 ng/ml) was 1,180 ng/ml in the 200-mg dosing cohort and was exceeded in the 300-mg dosing cohort (1,430 ng/ml). Posaconazole i.v. was well tolerated. Posaconazole i.v. 300 mg q.d. was selected for the phase 3 study segment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01075984.)

Objective:To define better the safety profile of micafungin, an analysis of micafungin clinical trial safety data was undertaken.Research design and methods:Adverse event data were pooled worldwide from 17 clinical efficacy and safety studies. Adverse events were coded using the Medical Dictionary for Regulatory Activities version 5.0.Results:In the pooled clinical trial data set, 3028 patients received at least one dose of micafungin. The mean age of patients was 41.4 years; with 296 (9.8%) children (< 16 years) and 387 (12.8%) elderly patients (≥≥ 65 years). Common underlying conditions were hematopoietic stem cell and other transplantations (26.1%), malignancies (20.8%) and HIV (32.9%). Mean exposure was 18 days for adults and 29 days for children. The most frequently reported treatment-related adverse events were nausea (2.8%), vomiting (2.5%), phlebitis (2.5%), hypokalemia (2.1%), fever/pyrexia (2.1%) and diarrhea (2%), as well as increases in alkaline phosphatase (2.7%), aspartate aminotransferase (2.3%) and alanine aminotransferase (2%). Although elderly adults had a higher incidence of renal impairment (1%) compared with non-elderly adult (0.1%) and pediatric patients (0.3%), there were no clear trends showing an association between higher doses of micafungin or longer treatment durations and increased incidence rates of treatment-related adverse events.Conclusions:Analysis of a large database demonstrated a favorable clinical safety profile for micafungin similar to other echinocandins.

ABSTRACTTwo large studies compared posaconazole and fluconazole or itraconazole for prophylaxis in subjects undergoing allogeneic hematopoietic stem cell transplantation or subjects with acute myelogenous leukemia. To assess the impact of prophylaxis on colonization and the development of resistance in Saccharomycesyeasts, identification and susceptibility testing were performed with yeasts cultured at regular intervals from mouth, throat, and stool samples. Prior to therapy, 34 to 50% of the subjects were colonized with yeasts. For all three drugs, the number of positive Candida albicanscultures decreased during drug therapy. In contrast, the proportion of subjects with positive C. glabratacultures increased by two- and fourfold in the posaconazole and itraconazole arms, respectively. Likewise, in the fluconazole arm the proportion of subjects with positive C. kruseicultures increased twofold. C. glabratawas the species that most frequently exhibited decreases in susceptibility, and this trend did not differ significantly between the prophylactic regimens. For the subset of subjects from whom colonizing C. glabrataisolates were recovered at the baseline and the end of treatment, approximately 40% of the isolates exhibited more than fourfold increases in MICs during therapy. Molecular typing of the C. albicansand C. glabrataisolates confirmed that the majority of the baseline and end-of-treatment isolates were closely related, suggesting that they were persistent colonizers and not newly acquired. Overall breakthrough infections by Candidaspecies were very rare (∼1%), and C. glabratawas the colonizing species that was the most frequently associated with breakthrough infections.

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.

Allogeneic hematopoietic stem cell transplantation (SCT) regimens incorporating the lymphocytotoxic CD52 antibody alemtuzumab demonstrate efficient engraftment and reduced graft-versus-host disease (GVHD). However, these protocols substantially impair posttransplantation antiviral and antitumor immunity. To accelerate immune reconstitution after alemtuzumab-based reduced-intensity SCT, we administered prophylactic CD8-depleted donor lymphocyte infusions (DLIs) starting on days 60 and 120 after transplantation. DLIs were processed in an immunomagnetic good manufacturing practice depletion procedure resulting in a 2.5- to 6-log reduction in CD8 T cells. Of 23 high-risk patients with hematologic malignancies, 11 received a total of 21 CD8-depleted DLIs. Five patients developed transient grade I acute GVHD following transfer. Only 2 patients with HLA-C–mismatched donors showed grade II and III acute GVHD and subsequently progressed to limited chronic GVHD. Following DLIs, 4 patients with declining hematopoietic donor chimerism converted to full chimeras. A 2.1-fold median increase of circulating CD4 T cells was observed within 2 weeks after infusion. Non-DLI patients did not show a comparable rise in CD4 counts. Four patients demonstrated enhanced frequencies of cytomegalovirus-specific CD4 and CD8 T cells following transfer. Our results suggest that prophylactic CD8-depleted DLIs accelerate immune reconstitution after lymphodepleted HLA-matched SCT and carry a low risk of inducing severe GVHD.

Allogeneic hematopoietic stem cell transplantation (SCT) regimens incorporating the lymphocytotoxic CD52 antibody alemtuzumab demonstrate efficient engraftment and reduced graft-versus-host disease (GVHD). However, these protocols substantially impair posttransplantation antiviral and antitumor immunity. To accelerate immune reconstitution after alemtuzumab-based reduced-intensity SCT, we administered prophylactic CD8-depleted donor lymphocyte infusions (DLIs) starting on days 60 and 120 after transplantation. DLIs were processed in an immunomagnetic good manufacturing practice depletion procedure resulting in a 2.5- to 6-log reduction in CD8 T cells. Of 23 high-risk patients with hematologic malignancies, 11 received a total of 21 CD8-depleted DLIs. Five patients developed transient grade I acute GVHD following transfer. Only 2 patients with HLA-C–mismatched donors showed grade II and III acute GVHD and subsequently progressed to limited chronic GVHD. Following DLIs, 4 patients with declining hematopoietic donor chimerism converted to full chimeras. A 2.1-fold median increase of circulating CD4 T cells was observed within 2 weeks after infusion. Non-DLI patients did not show a comparable rise in CD4 counts. Four patients demonstrated enhanced frequencies of cytomegalovirus-specific CD4 and CD8 T cells following transfer. Our results suggest that prophylactic CD8-depleted DLIs accelerate immune reconstitution after lymphodepleted HLA-matched SCT and carry a low risk of inducing severe GVHD.

This is a clinical review on the current role of polyene antifungals in the treatment of invasive fungal infections. It is timely and relevant because the number of new antifungals being developed has never been greater than today. In addition to re-examining the landmark clinical trials of the past, the more recent findings are put into perspective. The past year has been particularly rich in clinical trials.

New broader spectrum antifungal agents with favorable safety profiles have been available for the last 15 years making prophylaxis feasible. The purpose of this article is to review recent studies in patient populations at high risk for invasive fungal infections.

Objectives: This trial studied the efficacy and safety of itraconazole and fluconazole in the prevention of invasive fungal infections in neutropenic patients with haematological malignancies.Patients and methods: An 8 week, open-label, randomized, parallel-group, multicentre trial comparing itraconazole oral solution (2.5 mg/kg twice daily; N = 248) with fluconazole oral solution or capsules (400 mg daily; N = 246) in 494 patients with anticipated profound neutropenia (i.e. neutrophil count expected to be <500 cells/mm3 for at least 10 days) from tertiary care centres.Results: Invasive fungal infections were reported for 4 out of 248 patients (1.6%) in the itraconazole group and 5 out of 246 patients (2.0%) in the fluconazole group. Invasive Aspergillus infections were proven for 2 out of 248 patients (0.8%) in the itraconazole group and 3 out of 246 patients (1.2%) in the fluconazole group. For both the ITT and profoundly neutropenic populations, no differences were detected between treatment groups in proven or suspected invasive fungal infections or other endpoints. The mortality rates owing to proven invasive fungal infections were 2 out of 248 patients (0.8%) for the itraconazole group and 3 out of 246 patients (1.2%) for the fluconazole group. There was also no difference between treatment groups in the number of patients who recovered from neutropenia or in the duration of neutropenia. More discontinuation of drug intake owing to nausea and more hypokalaemia occurred in the itraconazole group, other adverse events and the total number of adverse events were similar in both groups.Conclusions: In this study there were no differences in the efficacy and safety of itraconazole and fluconazole prophylaxis in neutropenic patients with haematological malignancies.

Purpose To report the histological findings of an eye with severe Aspergillus endophthalmitis after oral treatment with voriconazole. Methods Case report. Results Histopathological examination revealed no fungal elements in choroidal or retinal vessels. The hyphae were mainly restricted to the vitreal side of the preretinal inflammatory infiltrate. Since the treatment with voriconazole had not been completed at the time of enucleation, the clinical course with potential further limitation or regression of the lesion remains unsettled. Conclusions Endogenous Aspergillus endophthalmitis is a devastating condition often associated with immunodeficiency. The pathogenesis of this entity implies the primary invasion of choroidal and retinal vessels. The lack of antifungal drugs with high blood–ocular permeability results in an extremely poor visual prognosis. Our histological examination indicates promising activity and ocular penetration of the new antifungal agent voriconazole.

Invasive fungal infection is an increasing source of morbidity and mortality in patients with hematologic malignancies, particularly those with prolonged and severe neutropenia (absolute white blood cell count < 100/μL). Early diagnosis of invasive fungal infection is difficult, suggesting that antifungal prophylaxis could be the best approach for neutropenic patients undergoing intensive myelosuppressive chemotherapy. Consequently, antifungal prophylaxis has been extensively studied for more than 20 years. Nonabsorbable polyenes reduce superficial mycoses but are not effective in preventing or treating invasive fungal infections. Intravenous amphotericin B and the newer azoles were used in numerous clinical trials, but the value of antifungal prophylaxis in defined risk groups with cancer is still open to discussion. Recipients of allogeneic stem cell transplants and patients with a relapsed leukemia are high-risk patient populations. In addition, certain risk factors are well defined, for example, neutropenia more than 10 days, corticosteroid therapy, sustained immunosuppression, and graft-versus-host disease. In contrast to study efforts, evidence-based recommendations on the clinical use of antifungal prophylaxis according to risk groups are rare. The objective of this review of 50 studies accumulating more than 9000 patients is to assess evidence-based criteria with regard to the efficacy of antifungal prophylaxis in neutropenic cancer patients.

Invasive fungal infection is an increasing source of morbidity and mortality in patients with hematologic malignancies, particularly those with prolonged and severe neutropenia (absolute white blood cell count < 100/μL). Early diagnosis of invasive fungal infection is difficult, suggesting that antifungal prophylaxis could be the best approach for neutropenic patients undergoing intensive myelosuppressive chemotherapy. Consequently, antifungal prophylaxis has been extensively studied for more than 20 years. Nonabsorbable polyenes reduce superficial mycoses but are not effective in preventing or treating invasive fungal infections. Intravenous amphotericin B and the newer azoles were used in numerous clinical trials, but the value of antifungal prophylaxis in defined risk groups with cancer is still open to discussion. Recipients of allogeneic stem cell transplants and patients with a relapsed leukemia are high-risk patient populations. In addition, certain risk factors are well defined, for example, neutropenia more than 10 days, corticosteroid therapy, sustained immunosuppression, and graft-versus-host disease. In contrast to study efforts, evidence-based recommendations on the clinical use of antifungal prophylaxis according to risk groups are rare. The objective of this review of 50 studies accumulating more than 9000 patients is to assess evidence-based criteria with regard to the efficacy of antifungal prophylaxis in neutropenic cancer patients.

SUMMARYManaging invasive fungal infections often presents a challenge for clinicians in the treatment of immunocompromised patients. Two very different systemic antifungal agents, voriconazole and caspofungin, have recently been introduced into the market place. Voriconazole is a new triazole antifungal, while caspofungin is the first echinocandin antifungal. Voriconazole acts by inhibiting the synthesis of ergosterol in the fungal cell membrane. Caspofungin inhibits β-1,3-D-glucan synthesis in the cell wall, a target present in fungal cells, but absent from mammalian cells. Both agents are broad-spectrum, with efficacy against invasive Aspergillus and Candidainfections. The safety and tolerability profile of caspofungin presented with a low incidence of adverse events in clinical trials. Pending further data, coadministration of cyclosporine has been recommended only if the benefit outweighs the risk for patients. Voriconazole has three important side-effects that the clinician must consider: liver abnormalities, skin abnormalities and visual disturbances. Liver abnormalities in particular should be monitored very carefully. The drug interaction profile of voriconazole also warrants a careful evaluation of the concomitant medication, mainly due to cytochrome P450 metabolism. This article reviews the available data concerning the safety and tolerability profiles of each drug, as well as drug interactions and contraindications.

A retrospective study was performed to collect information regarding efficacy and toxicity of cidofovir (CDV) in allogeneic stem cell transplant patients. Data were available on 82 patients. The indications for therapy were cytomegalovirus (CMV) disease in 20 patients, primary preemptive therapy in 24 patients, and secondary preemptive therapy in 38 patients. Of the patients, 47 had received previous antiviral therapy with ganciclovir, foscarnet, or both drugs. The dosage of CDV was 1 to 5 mg/kg per week followed by maintenance every other week in some patients. The duration of therapy ranged from 1 to 134 days (median, 22 days). All patients received probenecid and prehydration. Ten of 20 (50%) patients who were treated for CMV disease (9 of 16 with pneumonia) responded to CDV therapy, as did 25 of 38 (66%) patients who had failed or relapsed after previous preemptive therapy and 15 of 24 (62%) patients in whom CDV was used as the primary preemptive therapy. Of the patients, 21 (25.6%) developed renal toxicity that remained after cessation of therapy in 12 patients. Fifteen patients developed other toxicities that were potentially due to CDV or the concomitantly given probenecid. No toxicity was seen in 45 (61.6%) patients. Cidofovir can be considered as second-line therapy in patients with CMV disease failing previous antiviral therapy. However, additional studies are needed before CDV can be recommended for preemptive therapy.

A retrospective study was performed to collect information regarding efficacy and toxicity of cidofovir (CDV) in allogeneic stem cell transplant patients. Data were available on 82 patients. The indications for therapy were cytomegalovirus (CMV) disease in 20 patients, primary preemptive therapy in 24 patients, and secondary preemptive therapy in 38 patients. Of the patients, 47 had received previous antiviral therapy with ganciclovir, foscarnet, or both drugs. The dosage of CDV was 1 to 5 mg/kg per week followed by maintenance every other week in some patients. The duration of therapy ranged from 1 to 134 days (median, 22 days). All patients received probenecid and prehydration. Ten of 20 (50%) patients who were treated for CMV disease (9 of 16 with pneumonia) responded to CDV therapy, as did 25 of 38 (66%) patients who had failed or relapsed after previous preemptive therapy and 15 of 24 (62%) patients in whom CDV was used as the primary preemptive therapy. Of the patients, 21 (25.6%) developed renal toxicity that remained after cessation of therapy in 12 patients. Fifteen patients developed other toxicities that were potentially due to CDV or the concomitantly given probenecid. No toxicity was seen in 45 (61.6%) patients. Cidofovir can be considered as second-line therapy in patients with CMV disease failing previous antiviral therapy. However, additional studies are needed before CDV can be recommended for preemptive therapy.

Invasive pulmonary aspergillosis and mucormycosis are life-threatening complications in immunocompromised patients. A rapid diagnosis followed by early antifungal treatment is essential for patient survival. Given the limited spectrum of biomarkers for invasive mold infections, recent studies have proposed the use of radiolabeled siderophores or antibodies as molecular probes to increase the specificity of radiological findings by nuclear imaging modalities. While holding enormous diagnostic potential, most of the currently available molecular probes are tailored to the detection of Aspergillusspecies, and their cost-intensive and sophisticated implementation restricts their accessibility at less specialized centers.

Invasive zygomycosis accounts for a significant proportion of all invasive fungal diseases (IFD), but clinical data on the clinical course and treatment response is limited.Fungiscope” - A Global Rare Fungal Infection Registry is a university-based case registry that collects data of patients with rare IFD, using a web-based electronic case form at www.fungiscope.net.Fourty-one patients with invasive zygomycosis were registered. Five were pediatric (12.2%), 28 (68.3%) male. Median age was 49 years (range 2-88). Most common underlying conditions were malignancies (n=26; 63.4%), diabetes mellitus (n=7; 17%) and solid organ transplant (n=4; 9.8%). Diagnosis was made by culture in 28 patients (68.3%), by histology in 26 patients (63.4%). Main sites of infection were lungs (n=24; 58.5%), soft tissues (n=8; 19.5%), rhino-sinu-orbital (n=8; 19.5%), brain (n=6; 14.6%). Disseminated infection of >1 non-contiguous sites was seen in 4 patients (9.8%). A favorable response was observed in 23 patients (56.1%). Overall survival was 51.2%. At diagnosis, ten patients (24.4%) were under continuous antifungal prophylaxis with itraconazole (n=1; 2.4%) or posaconazole (n=3; 7.3%). Empiric treatment was administered to 17 patients (41.4%). Survival was significantly improved in patients receiving active (n=7; 17.1%), as opposed to inactive empiric treatment (p=0.036). 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). Additional surgical treatment was performed in 21 patients (51.2%) and was not associated with improved response or survival.Invasive zygomycosis is associated with low response rates to surgical and antifungal therapy. There was a marked amount of breakthrough infections under antifungal prophylaxis, including posaconazole. Only few patients received empiric treatment with activity against zygomycetes. Initial treatment with a polyene was associated with improved survival rates.Rueping: Essex/Schering-Plough: Speakers Bureau. Heinz:Schering-Plough/Essex: Consultancy, Research Funding, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Gilead: Speakers Bureau; Pfizer: Speakers Bureau. Rickerts:Gilead: Research Funding; pfizer: Research Funding. Lass-Floerl:Gilead: Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; MSD: Consultancy, Speakers Bureau. Herbrecht:Pfizer: Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Schering-Plough/Essex: Consultancy, Speakers Bureau. Silling:MSD: Consultancy, Research Funding; Pfizer: Research Funding; Astellas: Research Funding; Janssen-Cilag: Research Funding; Schering-Plough/Essex: Research Funding. Ullmann:Basilea: Consultancy; Aicuris: Consultancy; Pfizer: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Schering-Plough/Essex: Consultancy, Speakers Bureau; Astellas: Consultancy, Speakers Bureau. Maertens:MSD: Consultancy, Research Funding; Pfizer: Research Funding; Astellas: Consultancy; Bio-Rad: Consultancy; Nektar: Consultancy; Schering-Plough/Essex: Consultancy; Zeneus/Cephalon: Consultancy; Viropharma: Consultancy. Maschmeyer:Pfizer: Consultancy, Research Funding, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau. Vehreschild:Schering-Plough/Essex: Speakers Bureau; MSD: Speakers Bureau. Cornely:German Federal Ministry of Research and Education: Support - BMBF Grant 01KN0706; Astellas: Consultancy, Research Funding, Speakers Bureau; Basilea: Consultancy, Research Funding; Bayer: Research Funding; Genzyme: Research Funding; Gilead: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding; Merck/MSD: Consultancy, Research Funding, Speakers Bureau; Optimer: Research Funding; Schering-Plough/Essex: Consultancy, Research Funding, Speakers Bureau; Vicuron: Research Funding; F2G: Consultancy; Mölnlycke: Consultancy; Nektar: Consultancy; Zeneus: Consultancy; SpePharm: Speakers Bureau; United Medical: Speakers Bureau.

Abstract 4736

Background: Pneumococcal infections are causes of death after SCT. The IDWP01 trial compared early (E) vs late (L) pneumococcal immunization after allogeneic SCT, starting either at 3, or at 9 months post-transplant with 3 doses of PCV7 given at 1 month intervals,. This study has shown that the early immunization was not inferior in the proportion of responders one month after the last PCV7 dose. In addition, all patients received one dose of PPV23 after the 3 doses of PCV7 at 12 months and 18 months in the E and L groups, respectively. The goal of this supplementary analysis was to look at the immune response to the PPV23 according to the time of its administration. Methods: 158 patients were randomized in the IDWP01 trial, 75 in the E, and 83 in the L group, of whom 109 received the PPV23 (56 in the E, and 53 in the L group, respectively) and 86 (44 in the E, and 42 in the L group) were followed up to 24 months after SCT. The immune response to PPV23 was assessed by the antibody (Ab) titres, measured by ELISA to pn1 and pn5, which are both included in PPV23 but not in PCV7. Pn1 and pn5 Ab titres were assessed before, and one month after the PPV23 dose, and at 24 months post-SCT. Two cut-off levels for protection were considered for each antigen: □ .15 μg/ml and □ .5 μg/ml. The geometric mean concentrations (GMC) were also analyzed. Additionally, all Ab titres to the 7 PCV7 antigens were measured in parallel. Results: Ab titres to pn1 and pn5 before the PPV23 were not significantly different in the E (at 12 mo post-SCT) and in the L (at 18 mo post-SCT) group. Whatever the cut-off used to evaluating the response, the percentage of responders one month after the PPV23 was not significantly different in both groups: For pn1: □ .15μg/ml: E: 80% vs L: 87%; □ .5μg/ml: E: 42% vs L: 60%; For pn5: □ .15μg/ml: E: 84% vs L: 94%; □ .5μg/ml: E: 62% vs L: 74%). The GMC were not significantly different in the E vs. the L group for pn1. The GMC were significantly higher in the L vs. the E group for pn5 (P=.02). At 24 months post-SCT, there was no significant difference in the GMC of pn1 and pn5 Ab titres but there was a tendency for higher titres in the L group for both antigens. Additionally, among 36 non-responders to the PCV7 at the time of PPV23 administration, 21 remained non-responders, but 15 (42%) responded to all the seven PCV7 antigens 1 month later. Conclusion: Although there was a tendency for a better response rate and for higher GMC for pn1 and pn5 according to the timing of immunization with PPV23 (12 vs. 18 months) in favour of the L group, these differences were not significant. Additionally, PPV23 increase the response rate to the serotypes included in the PCV7. Therefore, we recommend starting PCV7 vaccination early after SCT (3 PCV7 from 3 months). A dose of PPV23 after 3 doses of PCV7 broadens the immune response to pneumococci as well as increases the response rate to the serotypes included in the PCV7 and should therefore be considered at 12 months after SCT. The authors are grateful to the Safety committee: D Engelhard, P Reusser, and P Reinert

Background: Pneumococcal infections are causes of death after SCT. The IDWP01 trial compared early (E) vs late (L) pneumococcal immunization after allogeneic SCT, starting either at 3, or at 9 months post-transplant with 3 doses of PCV7 given at 1 month intervals,. This study has shown that the early immunization was not inferior in the proportion of responders one month after the last PCV7 dose. In addition, all patients received one dose of PPV23 after the 3 doses of PCV7 at 12 months and 18 months in the E and L groups, respectively. The goal of this supplementary analysis was to look at the immune response to the PPV23 according to the time of its administration.

Introduction: Worldwide, the incidence of nosocomial outbreaks of VRE has increased especially in high-risk patients such as hematology-oncology patients. Outbreaks reported so far, required a minimum of three months to be controlled. Such outbreaks have a serious impact on daily care and treatment of the patients and hospital economics. Patients and Methods: We describe the outcome of a VRE-outbreak in a department with 48 beds (fourteen 2-patient rooms, and 20 single-patient rooms) including allogeneic BMT. Epidemiological evaluation was initiated after two patients in the department for the first time had a blood stream infection (BSI) with VRE within one week. Two goals had to be achieved immediately: 1) Assessment of the outbreak and 2) Implementation of enhanced infection control measures. Screening of all inpatients on a weekly basis became mandatory (stool sample or rectal swab). All patients, regardless of their status, received a single-patient room and had their own assigned restroom. Therefore an additional ward had to be opened. The patients and staff were re-trained in hygiene rules and contact precautions. Positive VRE-tested patients were cohorted in one ward. In addition, spot screening was performed in the outpatient clinic. Due to a low number of restroom facilities and patient rooms, the outpatient clinic was closed for new admissions and reopened within 6 weeks at a new site with improved facilities and more patient rooms. Antibiotic usage was reviewed. Utilization of glycopeptides and cephalosporins was decreased. Pulsed-field gel electrophoresis (PFGE) was performed on all isolates. The outbreak was actively discussed in the local newspapers and television to inform the public of the situation. Results: This is the largest VRE-outbreak in a hematology-oncology department reported to date. Four-hundred-seventy-five patients were evaluated and 1246 tests were performed, resulting in a mean test frequency of 2.6 tests per patient. In this patient population, 34 VRE-colonized patients were identified, 18 within the first 4 weeks of screening. From January through April 2004, a total of 31 VRE-colonized patients were detected. Two additional VRE-BSI occurred. All patients with VRE-BSI were treated successfully with linezolid. PFGE demonstrated a dominant clone indicating a nosocomial transmission mode. After the opening of the new outpatient clinic and normalization of admission policies on the inpatient wards [the extra ward was closed and ID control measures stayed in effect] only 3 additional VRE-colonized patients were detected but PFGE demonstrated different clones. Cutting down on new admissions and actively discussing the outbreak in public was rewarded with back-to-baseline admissions after cessation of the outbreak. Conclusion: Though VRE-infections nowadays can easily be treated with linezolid, its detection indicates an infection control problem. Awareness of the development of resistant microbes especially in the immunocompromised setting requires pragmatic and stringent ID control measures to prevent or to cease early an outbreak of this magnitude.

Introduction: Worldwide, the incidence of nosocomial outbreaks of VRE has increased especially in high-risk patients such as hematology-oncology patients. Outbreaks reported so far, required a minimum of three months to be controlled. Such outbreaks have a serious impact on daily care and treatment of the patients and hospital economics.