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To ensure the safety of high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT), evidence-based recommendations on infectious complications after HDC/ASCT are given. This guideline not only focuses on patients with haematological malignancies but also addresses the specifics of HDC/ASCT patients with solid tumours or autoimmune disorders. In addition to HBV and HCV, HEV screening is nowadays mandatory prior to ASCT. For patients with HBs antigen and/or anti-HBc antibody positivity, HBV nucleic acid testing is strongly recommended for 6 months after HDC/ASCT or for the duration of a respective maintenance therapy. Prevention of VZV reactivation by vaccination is strongly recommended. Cotrimoxazole for the prevention of Pneumocystis jirovecii is supported. Invasive fungal diseases are less frequent after HDC/ASCT, therefore, primary systemic antifungal prophylaxis is not recommended. Data do not support a benefit of protective room ventilation e.g. HEPA filtration. Thus, AGIHO only supports this technique with marginal strength. Fluoroquinolone prophylaxis is recommended to prevent bacterial infections, although a survival advantage has not been demonstrated.

Aim The aim of this official guideline, published and coordinated by the German (DGGG), Austrian (OEGGG) and Swiss (SGGG) Societies of Gynecology and Obstetrics in collaboration with the DMykG, DDG and AGII societies, was to provide consensus-based recommendations obtained by evaluating the relevant literature for the diagnosis, treatment and management of women with vulvovaginal candidosis. Methods This S2k guideline represents the structured consensus of a representative panel of experts with a range of different professional backgrounds commissioned by the Guideline Committee of the above-mentioned societies. Recommendations This guideline gives recommendations for the diagnosis, management, counseling, prophylaxis and screening of vulvovaginal candidosis.

Aim The multicentre non-interventional AVANTI study assessed safety, effectiveness and patient-reported outcomes with approved first-line bevacizumab-containing regimens for HER2-negative locally recurrent/metastatic breast cancer (LR/MBC) in German routine oncology practice. Methods Eligible patients had HER2-negative LR/MBC, no bevacizumab contraindications and no prior chemotherapy for LR/MBC. Chemotherapy schedule, diagnostics and follow-up were at physicians’ discretion. Data were collected for 1 year after starting bevacizumab, then every 6 months for 1.5 years (maximum follow-up: 2.5 years). Patients and physicians rated treatment satisfaction. Subgroup analyses were prespecified in clinically relevant populations, including triple-negative breast cancer (TNBC). Results Between November 1, 2009 and April 30, 2016, 2065 eligible patients at 346 centres received bevacizumab with paclitaxel or capecitabine. Patients receiving bevacizumab–capecitabine were less likely to have de novo disease and more likely to have TNBC, age ≥60 years and prior anthracycline/taxane and/or endocrine therapy. Median PFS was 12.6 (95% CI 11.9–13.2) months (12.8 with bevacizumab–paclitaxel, 10.5 with bevacizumab–capecitabine); median OS was 23.9 (95% CI 22.2–25.1) months. Outcomes were worse in patients with TNBC, prior anthracycline/taxane or prior endocrine therapy. Grade ≥3 adverse events occurred in 27% of patients. Treatment was discontinued for adverse events in 15%. Treatment satisfaction was rated as good or better by 304/394 responding patients (77%) at week 54 and in 1393/2065 patients (67%) by physicians overall. Conclusions In routine clinical practice, effectiveness and safety of first-line bevacizumab-containing therapy for LR/MBC were consistent with experience from phase III trials. Patient and physician treatment satisfaction showed high concordance., Highlights • AVANTI assessed 1st-line bevacizumab-based therapy for LR/MBC in routine practice. • Median progression-free and overall survival were 12.6 and 23.9 months respectively. • Treatment satisfaction was rated as good or better by 77% of patients at week 54. • Physician- and patient-rated treatment satisfaction showed high concordance. • Effectiveness and safety were consistent with experience from phase III trials.

Contains fulltext : 232415.pdf (Publisher’s version ) (Closed access) The EORTC/MSGERC recently revised and updated the consensus definitions of invasive fungal disease (IFD). These definitions primarily focus on patients with cancer and stem cell or solid-organ transplant patients. They may therefore not be suitable for intensive care unit (ICU) patients. More in detail, while the definition of proven IFD applies to a broad range of hosts, the categories of probable and possible IFD were primarily designed for classical immunocompromised hosts and may therefore not be ideal for other populations. Moreover, the scope of the possible category of IFD has been diminished in the recently revised definitions for classically immunocompromised hosts. Diagnosis of IFD in the ICU presents many challenges, which are different for invasive candidiasis and for invasive aspergillosis. The aim of this article is to review progresses made in recent years and difficulties remaining in the development of definitions applicable in the ICU setting.

Approximately 70‐75% of women will have vulvovaginal candidosis (VVC) at least once in their lifetime. In premenopausal, pregnant, asymptomatic and healthy women and women with acute VVC, Candida albicans is the predominant species. The diagnosis of VVC should be based on clinical symptoms and microscopic detection of pseudohyphae. Symptoms alone do not allow reliable differentiation of the causes of vaginitis. In recurrent or complicated cases, diagnostics should involve fungal culture with species identification. Serological determination of antibody titres has no role in VVC. Before the induction of therapy, VVC should always be medically confirmed. Acute VVC can be treated with local imidazoles, polyenes or ciclopirox olamine, using vaginal tablets, ovules or creams. Triazoles can also be prescribed orally, together with antifungal creams, for the treatment of the vulva. Commonly available antimycotics are generally well tolerated, and the different regimens show similarly good results. Antiseptics are potentially effective but act against the physiological vaginal flora. Neither a woman with asymptomatic colonisation nor an asymptomatic sexual partner should be treated. Women with chronic recurrent Candida albicans vulvovaginitis should undergo dose‐reducing maintenance therapy with oral triazoles. Unnecessary antimycotic therapies should always be avoided, and non‐albicans vaginitis should be treated with alternative antifungal agents. In the last 6 weeks of pregnancy, women should receive antifungal treatment to reduce the risk of vertical transmission, oral thrush and diaper dermatitis of the newborn. Local treatment is preferred during pregnancy.

Cancer patients frequently require central venous catheters for therapy and parenteral nutrition and are at high risk of central venous catheter–related infections (CRIs). Moreover, CRIs prolong hospitalization, cause an excess in resource utilization and treatment cost, often delay anti-cancer treatment, and are associated with a significant increase in mortality in cancer patients. We therefore summoned a panel of experts by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) and updated our previous guideline on CRIs in cancer patients. After conducting systematic literature searches on PubMed, Medline, and Cochrane databases, video- and meeting-based consensus discussions were held. In the presented guideline, we summarize recommendations on definition, diagnosis, management, and prevention of CRIs in cancer patients including the grading of strength of recommendations and the respective levels of evidence. This guideline supports clinicians and researchers alike in the evidence-based decision-making in the management of CRIs in cancer patients.

Background Invasive fungal diseases remain a major cause of morbidity and mortality in cancer patients undergoing intensive cytotoxic therapy. The choice of the most appropriate antifungal treatment (AFT) depends on the fungal species suspected or identified, the patient's risk factors (eg length and depth of granulocytopenia) and the expected side effects. Objectives Since the last edition of recommendations for 'Treatment of invasive fungal infections in cancer patients' of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) in 2013, treatment strategies were gradually moving away from solely empirical therapy of presumed or possible invasive fungal diseases (IFDs) towards pre-emptive therapy of probable IFD. Methods The guideline was prepared by German clinical experts for infections in cancer patients in a stepwise consensus process. MEDLINE was systematically searched for English-language publications from January 1975 up to September 2019 using the key terms such as 'invasive fungal infection' and/or 'invasive fungal disease' and at least one of the following: antifungal agents, cancer, haematological malignancy, antifungal therapy, neutropenia, granulocytopenia, mycoses, aspergillosis, candidosis and mucormycosis. Results AFT of IFDs in cancer patients may include not only antifungal agents but also non-pharmacologic treatment. In addition, the armamentarium of antifungals for treatment of IFDs has been broadened (eg licensing of isavuconazole). Additional antifungals are currently under investigation or in clinical trials. Conclusions Here, updated recommendations for the treatment of proven or probable IFDs are given. All recommendations including the levels of evidence are summarised in tables to give the reader rapid access to key information.

Invasive fungal diseases (IFD) are a primary cause of morbidity and mortality in patients with haematological malignancies. These infections are mostly life-threatening and an early diagnosis and initiation of appropriate antifungal therapy are essential for the clinical outcome. Most commonly, Aspergillus and Candida species are involved. However, other Non-Aspergillus moulds are increasingly identified in case of documented IFD. For definite diagnosis of IFD, a combination of diagnostic tools have to be applied, including conventional mycological culture and non-conventional microbiological tests such as antibody/antigen and molecular tests, as well as histopathology and radiology. Although varying widely in cancer patients, the risk of invasive fungal infection is highest in those with allogeneic stem cell transplantation and those with acute leukaemia and markedly lower in patients with solid cancer. Since the last edition of Diagnosis of Invasive Fungal Diseases recommendations of the German Society for Hematology and Oncology in 2012, integrated care pathways have been proposed for the management and therapy of IFDs with either a diagnostic driven strategy as opposed to a clinical or empirical driven strategy. This update discusses the impact of this additional evidence and effective revisions.

Neutropenia is linked to the development of invasive candidiasis/candidaemia, for which micafungin has demonstrated efficacy, but evidence in patients with neutropenia is limited. The aim of this study was to evaluate the efficacy of micafungin for the treatment of invasive candidiasis/candidaemia in patients with neutropenia (

Summary We prospectively evaluated a multiplex real-time PCR assay (SeptiFast, SF) in a cohort of patients undergoing allo-BMT in comparison to an in-house PCR method (IH-PCR). Overall 847 blood samples (mean 8 samples/patient) from 104 patients with haematological malignancies were analysed. The majority of patients had acute leukaemia (62%) with a mean age of 52 years (54% female). Pathogens could be detected in 91 of 847 (11%) samples by SF compared to 38 of 205 (18.5%) samples by BC, and 57 of 847 (6.7%) samples by IH-PCR. Coagulase-negative staphylococci (n=41 in SF, n=29 in BC) were the most frequently detected bacteria followed by Escherichia coli (n=9 in SF, n=6 in BC). Candida albicans (n=17 in SF, n=0 in BC, n=24 in IH-PCR) was the most frequently detected fungal pathogen. SF gave positive results in 5% of samples during surveillance vs in 26% of samples during fever episodes. Overall, the majority of blood samples gave negative results in both PCR methods resulting in 93% overall agreement resulting in a negative predictive value of 0.96 (95% CI: 0.95-0.97), and a positive predictive value of 0.10 (95% CI: −0.01 to 0.21). SeptiFast appeared to be superior over BC and the IH-PCR method.

BackgroundMucormycosis is a difficult to diagnose rare disease with high morbidity and mortality. Diagnosis is often delayed, and disease tends to progress rapidly. Urgent surgical and medical intervention is lifesaving. Guidance on the complex multidisciplinary management has potential to improve prognosis, but approaches differ between health care settings.MethodsFrom January 2018, authors from 33 countries in all United Nations regions analysed the published evidence on mucormycosis management and provided consensus recommendations addressing differences between the regions of the world as part of the “One World One Guideline” initiative of the European Confederation of Medical Mycology (ECMM). The author group based in 17 time zones, relied on electronic media including video tutorial on methodology, and central document repository with several daily updates.FindingsSigns and symptoms of mucormycosis depend on organ patterns and underlying conditions. Diagnostic management does not differ greatly between world regions. Upon suspicion of mucormycosis appropriate imaging is strongly recommended to document extent of disease and is followed by strongly recommended surgical intervention. First-line treatment with high-dose liposomal amphotericin B is strongly recommended, while intravenous isavuconazole and intravenous or delayed release tablet posaconazole are recommended with moderate strength. Both triazoles are strongly recommended salvage treatments. Amphotericin B deoxycholate is recommended against, because of substantial toxicity, but may be the only option in resource limited settings.InterpretationManagement of mucormycosis depends on recognising disease patterns and on early diagnosis. Limited availability of contemporary treatments burdens patients in low and middle income settings. Areas of uncertainty were identified and future research directions specified.

The term candidosis or candidiasis comprises several categories of infection: systemic or invasive Candida infections/diseases (IC), such as acute disseminated candidosis, chronic disseminated candidosis (CDC) and candidaemia as well as superficial (muco-cutaneous) Candida infections. According to the recent consensus definition the term “fungal infection” should be replaced by “fungal disease”. Candidaemia is the most frequent manifestation of systemic Candida infection. The serious prognosis associated with candidaemia is highlighted by a recent survey of 60 cases with candidaemia due to C. albicans (n = 38) and non-C. albicans (n = 22): 8% developed severe sepsis and 27% septic shock. The all-cause mortality was 42%. Candidaemia is most often observed in non-granulocytopenic patients after abdominal surgery or catheter-related infection with secondary blood stream infection. Potential further manifestations of invasive disease are Candida oesophagitis (in the past often classified as muco-cutaneous candidosis), peritonitis, urinary tract infections. Less frequently, endocarditis, meningitis/meningoencephalitis or osteomyelitis are manifestations of acute disseminated candidosis.

Patients with hematological cancer have a high risk of invasive fungal diseases (IFDs). These infections are mostly life threatening and an early diagnosis and initiation of appropriate antifungal therapy are essential for the clinical outcome. Most commonly, Aspergillus and Candida species are involved. However, other non- Aspergillus molds are increasingly be identified in cases of documented IFDs. Important risk factors are long lasting granulocytopenia with neutrophil counts below 500/μl for more than 10 days or graft- versus-host disease resulting from allogeneic stem-cell transplantation. For definite diagnosis of IFD, various diagnostic tools have to be applied, including conventional mycological culture and nonconventional microbiological tests such as antibody/antigen and molecular tests, as well as histopathology and radiology. In the last few years, various laboratory methods, like the Aspergillus GM immunoassay ( Aspergillus GM EIA), 1,3-ß-D-glucan (BG) assay or polymerase chain reaction (PCR) techniques have been developed for better diagnosis. Since no single indirect test, including radiological methods, provides the definite diagnosis of an invasive fungal infection, the combination of different diagnostic procedures, which include microbiological cultures, histological, serological and molecular methods like PCR together with the pattern of clinical presentation, may currently be the best strategy for the prompt diagnosis, initiation and monitoring of IFDs. Early start of antifungal therapy is mandatory, but clinical diagnostics often do not provide clear evidence of IFD. Integrated care pathways have been proposed for management and therapy of IFDs with either the diagnostic driven strategy using the preemptive antifungal therapy as opposed to the clinical or empirical driven strategy using the ‘traditional’ empirical antifungal therapy. Antifungal agents preferentially used for systemic therapy of invasive fungal infections are amphotericin B preparations, fluconazole, voriconazole, posaconazole, caspofungin, anidulafungin, micafungin, and most recently isavuconazole. Clinical decision making must consider licensing status, local experience and availability, pharmacological and economic aspects.

Azole prophylaxis has been shown to be effective in preventing invasive fungal infections (IFIs) and increasing survival in patients with prolonged neutropenia after myelosuppressive chemotherapy for haematological malignancies. Similarly, empirical antifungal therapy for persistent neutropenic fever has been shown to reduce IFI-related mortality. However, to date, there is little information with regard to the outcome of patients who receive both strategies. Here, we present our retrospective data on three cohorts of patients receiving empirical or targeted antifungal therapy after different antifungal prophylaxis regimens. All records from patients who received myelosuppressive induction chemotherapy for acute myelogenous leukemia (AML) in our centre from 2004-2010 were analysed. From 2004-2006, itraconazole was used as antifungal prophylaxis; for the first 6 months in 2007, local polyenes and from mid-2007 till 2010, posaconazole. Data of 315 courses of chemotherapy in 211 patients were analysed. Antifungal therapy (empirical or targeted, time point and antifungal agent at the physician's discretion) was initiated in 50/174 (29 %), 7/18 (39 %) and 34/123 courses (28 %, p = 0.615) in the itra cohort, the cohort without systemic prophylaxis and the posa cohort, respectively, and was effective in 24/50 (48 %), 5/7 (71 %) and 22/34 courses (65 %, p = 0.221), respectively. IFI occurred in 25/174 (14 %), 4/18 (22 %) and 16/123 (13 %) courses, respectively (p = 0.580). IFI-related survival was not different in the three cohorts. Antifungal treatment in patients with AML who received azole prophylaxis resulted in the expected efficacy-importantly, prior posaconazole prophylaxis did not render subsequent antifungal treatment less effective than prior itraconazole prophylaxis.

Annals of hematology 97(2), 197-207 (2018). doi:10.1007/s00277-017-3196-2, Published by Springer, Berlin ; Heidelberg ; New York

Contains fulltext : 193204.pdf (Publisher’s version ) (Closed access) The European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology and the European Respiratory Society Joint Clinical Guidelines focus on diagnosis and management of aspergillosis. Of the numerous recommendations, a few are summarized here. Chest computed tomography as well as bronchoscopy with bronchoalveolar lavage (BAL) in patients with suspicion of pulmonary invasive aspergillosis (IA) are strongly recommended. For diagnosis, direct microscopy, preferably using optical brighteners, histopathology and culture are strongly recommended. Serum and BAL galactomannan measures are recommended as markers for the diagnosis of IA. PCR should be considered in conjunction with other diagnostic tests. Pathogen identification to species complex level is strongly recommended for all clinically relevant Aspergillus isolates; antifungal susceptibility testing should be performed in patients with invasive disease in regions with resistance found in contemporary surveillance programmes. Isavuconazole and voriconazole are the preferred agents for first-line treatment of pulmonary IA, whereas liposomal amphotericin B is moderately supported. Combinations of antifungals as primary treatment options are not recommended. Therapeutic drug monitoring is strongly recommended for patients receiving posaconazole suspension or any form of voriconazole for IA treatment, and in refractory disease, where a personalized approach considering reversal of predisposing factors, switching drug class and surgical intervention is also strongly recommended. Primary prophylaxis with posaconazole is strongly recommended in patients with acute myelogenous leukaemia or myelodysplastic syndrome receiving induction chemotherapy. Secondary prophylaxis is strongly recommended in high-risk patients. We strongly recommend treatment duration based on clinical improvement, degree of immunosuppression and response on imaging.

In neutropenic patients with lung infiltrates, Aspergillus spp., P. jirovecii, multi-resistant gram-negative pathogens, mycobacteria, viruses and toxic effects from cytotoxic drugs, radiation, or pulmonary involvement by the underlying malignancy should be included into differential diagnosis. Pre-emptive treatment with mould-active systemic antifungal agents improves clinical outcome., Up to 25% of patients with profound neutropenia lasting for >10 days develop lung infiltrates, which frequently do not respond to broad-spectrum antibacterial therapy. While a causative pathogen remains undetected in the majority of cases, Aspergillus spp., Pneumocystis jirovecii, multi-resistant Gram-negative pathogens, mycobacteria or respiratory viruses may be involved. In at-risk patients who have received trimethoprim–sulfamethoxazole (TMP/SMX) prophylaxis, filamentous fungal pathogens appear to be predominant, yet commonly not proven at the time of treatment initiation. Pathogens isolated from blood cultures, bronchoalveolar lavage (BAL) or respiratory secretions are not always relevant for the etiology of pulmonary infiltrates and should therefore be interpreted critically. Laboratory tests for detecting Aspergillus galactomannan, β-d-glucan or DNA from blood, BAL or tissue samples may facilitate the diagnosis; however, most polymerase chain reaction assays are not yet standardized and validated. Apart from infectious agents, pulmonary side-effects from cytotoxic drugs, radiotherapy or pulmonary involvement by the underlying malignancy should be included into differential diagnosis and eventually be clarified by invasive diagnostic procedures. Pre-emptive treatment with mold-active systemic antifungal agents improves clinical outcome, while other microorganisms are preferably treated only when microbiologically documented. High-dose TMP/SMX is first choice for treatment of Pneumocystis pneumonia, while cytomegalovirus pneumonia is treated primarily with ganciclovir or foscarnet in most patients. In a considerable number of patients, clinical outcome may be favorable despite respiratory failure, so that intensive care should be unrestrictedly provided in patients whose prognosis is not desperate due to other reasons.

Summary Fungal infections of the CNS are challenging to treat and their optimal management requires knowledge of their epidemiology, host characteristics, diagnostic criteria, and therapeutic options. Aspergillus and Cryptococcus species predominate among fungal infections of the CNS. Most of these fungi are ubiquitous, but some have restricted geographical distribution. Fungal infections of the CNS usually originate from primary sites outside the CNS (eg, fungal pneumonia) or occur after inoculation (eg, invasive procedures). Most patients with these infections have immunodeficiencies, but immunocompetent individuals can also be infected through heavy exposure. The infecting fungi can be grouped into moulds, yeasts, and dimorphic fungi. Substantial progress has been made with new diagnostic approaches and the introduction of novel antifungal drugs, but fungal infections of the CNS are frequently lethal because of diagnostic delays, impaired drug penetration, resistance to antifungal treatments, and inadequate restoration of immune function. To improve outcomes, future research should advance diagnostic methods (eg, molecular detection and fungus identification), develop antifungal compounds with enhanced CNS-directed efficacy, and further investigate crucial host defence mechanisms.

Fever may be the only clinical symptom at the onset of infection in neutropenic cancer patients undergoing myelosuppressive chemotherapy. A prompt and evidence-based diagnostic and therapeutic approach is mandatory. A systematic search of current literature was conducted, including only full papers and excluding allogeneic hematopoietic stem cell transplant recipients. Recommendations for diagnosis and therapy were developed by an expert panel and approved after plenary discussion by the AGIHO. Randomized clinical trials were mainly available for therapeutic decisions, and new diagnostic procedures have been introduced into clinical practice in the past decade. Stratification into a high-risk versus low-risk patient population is recommended. In high-risk patients, initial empirical antimicrobial therapy should be active against pathogens most commonly involved in microbiologically documented and most threatening infections, including Pseudomonas aeruginosa, but excluding coagulase-negative staphylococci. In patients whose expected duration of neutropenia is more than 7 days and who do not respond to first-line antibacterial treatment, specifically in the absence of mold-active antifungal prophylaxis, further therapy should be directed also against fungi, in particular Aspergillus species. With regard to antimicrobial stewardship, treatment duration after defervescence in persistently neutropenic patients must be critically reconsidered and the choice of anti-infective agents adjusted to local epidemiology. This guideline updates recommendations for diagnosis and empirical therapy of fever of unknown origin in adult neutropenic cancer patients in light of the challenges of antimicrobial stewardship. Electronic supplementary material The online version of this article (doi:10.1007/s00277-017-3098-3) contains supplementary material, which is available to authorized users.

Contains fulltext : 175113.pdf (Publisher’s version ) (Closed access) A wide array of PCR tests has been developed to aid the diagnosis of invasive aspergillosis (IA), providing technical diversity but limiting standardisation and acceptance. Methodological recommendations for testing blood samples using PCR exist, based on achieving optimal assay sensitivity to help exclude IA. Conversely, when testing more invasive samples (BAL, biopsy, CSF) emphasis is placed on confirming disease, so analytical specificity is paramount. This multicenter study examined the analytical specificity of PCR methods for detecting IA by blind testing a panel of DNA extracted from a various fungal species to explore the range of Aspergillus species that could be detected, but also potential cross reactivity with other fungal species. Positivity rates were calculated and regression analysis was performed to determine any associations between technical specifications and performance. The accuracy of Aspergillus genus specific assays was 71.8%, significantly greater (P < .0001) than assays specific for individual Aspergillus species (47.2%). For genus specific assays the most often missed species were A. lentulus (25.0%), A. versicolor (24.1%), A. terreus (16.1%), A. flavus (15.2%), A. niger (13.4%), and A. fumigatus (6.2%). There was a significant positive association between accuracy and using an Aspergillus genus PCR assay targeting the rRNA genes (P = .0011). Conversely, there was a significant association between rRNA PCR targets and false positivity (P = .0032). To conclude current Aspergillus PCR assays are better suited for detecting A. fumigatus, with inferior detection of most other Aspergillus species. The use of an Aspergillus genus specific PCR assay targeting the rRNA genes is preferential.

Invasive aspergillosis (IA) is a serious hazard to high-risk haematological patients. There are increasing reports of azole-resistant Aspergillus spp. This study assessed the epidemiology of IA and azole-resistant Aspergillus spp. in patients with acute leukaemia in Germany. A prospective multicentre cohort study was performed in German haematology/oncology centres. The incidence of probable and proven aspergillosis according to the revised EORTC/MSG criteria was assessed for all patients with acute leukaemia [acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL)]. Cases were documented into a web-based case report form, and centres provided data on standards regarding prophylactic and diagnostic measures. Clinical isolates were screened centrally for azole resistance and, if applicable, underlying resistance mechanisms were analysed. Between September 2011 and December 2013, 179 cases of IA [6 proven (3.4%) and 173 probable (96.6%)] were diagnosed in 3067 patients with acute leukaemia. The incidence of IA was 6.4% among 2440 AML patients and 3.8% among 627 ALL patients. Mortality at Day 84 was 33.8% (49/145) and attributable mortality was 26.9% (39/145). At Day 84, 53 patients (29.6%) showed a complete response, 25 (14.0%) a partial response and 17 (9.5%) a deterioration or failure. A total of 77 clinical Aspergillus fumigatus isolates were collected during the study period. Two episodes of azole-resistant IA (1.1%) were caused by a TR/L98H mutation in the cyp51A gene. With only two cases of IA due to azole-resistant A. fumigatus, a change of antifungal treatment practices in Germany does not appear warranted currently.

Invasive fungal infections cause substantial morbidity and mortality in immunocompromised patients, particularly in those with haematological malignancies and recipients of allogeneic haematopoietic stem cell transplantation. Difficulties in diagnosing invasive fungal infections and subsequent delays in treatment initiation lead to unfavourable outcomes and emphasise the importance of prophylaxis. Since the recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology in 2009, results of 14 additional clinical studies have been published comprising 2,899 patients and initiating this update. Key recommendations for adult patients are as follows: Posaconazole remains the drug of choice during remission-induction chemotherapy in acute myeloid leukaemia, myelodysplastic syndrome and allogeneic haematopoietic stem cell transplantation with graft versus host disease (AI). In the pre-engraftment period of allogeneic transplantation, several antifungals are appropriate and can be recommended with equal strength: voriconazole (BI), micafungin (BI), fluconazole (BI) and posaconazole (BII). There is poor evidence regarding antifungal prophylaxis in the post-engraftment period of allogeneic haematopoietic stem cell transplantation if no steroids for treatment of graft versus host disease are required. Aerosolised liposomal amphotericin B inhalation in conjunction with fluconazole can be used in patients with prolonged neutropenia (BII).

Background Cancer patients are at increased risk for central venous catheter-related infections (CRIs). Thus, a comprehensive, practical and evidence-based guideline on CRI in patients with malignancies is warranted. Patients and methods A panel of experts by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) has developed a guideline on CRI in cancer patients. Literature searches of the PubMed, Medline and Cochrane databases were carried out and consensus discussions were held. Results Recommendations on diagnosis, management and prevention of CRI in cancer patients are made, and the strength of the recommendation and the level of evidence are presented. Conclusion This guideline is an evidence-based approach to the diagnosis, management and prevention of CRI in cancer patients.

The pharmacokinetics of intravenous anidulafungin in adult intensive care unit (ICU) patients were assessed in this study and compared with historical data from a general patient population and healthy subjects. Intensive plasma sampling was performed over a dosing interval at steady state from 21 ICU patients with candidemia/invasive candidiasis. All patients received the recommended dosing regimen (a 200-mg loading dose on day 1, followed by a daily 100-mg maintenance dose), except for a 54-year-old 240-kg female patient (who received a daily 150-mg maintenance dose instead). Plasma samples were assayed for anidulafungin using a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters in ICU patients were calculated by a noncompartmental method. With the exclusion of the 240-kg patient, the median (minimum, maximum) age, weight, and body mass index (BMI) of 20 ICU patients were 57 (39, 78) years, 65 (48, 106) kg, and 23.3 (16.2, 33.8) kg/m 2 , respectively. The average anidulafungin area under the curve over the 24-hour dosing interval (AUC 0-24 ), maximum concentration ( C max ), and clearance (CL) in 20 ICU patients were 92.7 mg · h/liter, 7.7 mg/liter, and 1.3 liters/h, respectively. The exposure in the 240-kg patient at a daily 150-mg dose was within the range observed in ICU patients overall. The average AUC 0-24 and C max in the general patient population and healthy subjects were 110.3 and 105.9 mg · h/liter and 7.2 and 7.0 mg/liter, respectively. The pharmacokinetics of anidulafungin in ICU patients appeared to be comparable to those in the general patient population and healthy subjects at the same dosing regimen.

Background: Cytotoxic extravasation is a rare but potentially serious and painful complication of intravenous drug administration in oncology. Literature is anecdotal, and systematic clinical trials are scarce. The German working group for Supportive Care in Cancer (ASORS) has prepared an expert opinion for the diagnosis, prophylaxis and management of cytotoxic extravasation based on an interdisciplinary expert panel. Material and Methods: A Pubmed search was conducted for diagnosis, risk factors, symptoms, prophylaxis, and treatment of extravasation by the respective responsible expert. A writing committee compiled the manuscript and proposed the level of recommendation. In a consensus meeting, 13 experts reviewed and discussed the current practice in diagnosis and management of cytotoxic extravasation. In a telephone voting among the experts, the level of recommendation by ASORS was determined. Results: Every effort should be made to reduce the risk of extravasation. Staff training, patient education, usage of right materials and infusion techniques have been identified to be mandatory to minimalize the risk of extravasation. Extravasation must be diagnosed as soon as possible, and specific therapy including antidotes dependent on the extravasated drug should be initiated immediately. An extravasation emergency set should be available wherever intravenous cytotoxics are applied. Documentation and post-treatment follow-up are recommended. Conclusion: We have developed a literature- and expert-based consensus recommendation to avoid cytotoxic extravasation. It also provides practical management instructions which should help to avoid surgery and serious late effects.

Post hoc analysis of a non-comparative, prospective, multicentre, phase IIIb study was performed to compare efficacy and safety of anidulafungin in elderly (>= 65 years) versus non-elderly (= 1 of the following criteria were enrolled: post-abdominal surgery; solid tumour; renal/hepatic insufficiency; solid organ transplantation; neutropenia; age >= 65 years. Patients received anidulafungin (200 mg on Day 1, 100 mg/day thereafter) for >= 10 days followed by optional azole step-down therapy for a total treatment duration of 14-56 days. The primary efficacy endpoint was global (clinical and microbiological) response at the end of all therapy (EOT). Primary efficacy analysis was performed in the modified intent-to-treat (mITT) population (n = 170), excluding unknown and missing responses. In total, 80 patients (47.1%) were aged >= 65 years and 90 (52.9%) were aged, This study was sponsored by Pfizer. Editorial support was provided by Leigh Prevost at PAREXEL and was funded by Pfizer International Operations. There were no restrictions from the study sponsor in terms of the analyses presented in this paper. Whilst all statistical analyses were conducted by employees of the study sponsor, this was done according to definitions and specifications jointly agreed on by the authors. No other source provided funding for the actual clinical study or the analyses presented in this paper.; GD has received research funding, funds for speaking and funds for advisory board membership from Pfizer; J-AP has received research funding, funds for speaking and funds for advisory board membership from MSD, Novartis and Pfizer; WM has received research funding from MSD and Pfizer, funds for speaking from MSD, and funds for advisory board membership from Pfizer; IG has received funds for speaking from Abbott, Astra-Zeneca, Bayer, Eli Lilly, Fresenius, Merck and Pfizer, and funds for advisory board membership from Pfizer; GS has received funds for speaking and funds for advisory board membership from Pfizer; PM has received funds for speaking and funds for advisory board membership from Astellas, MSD and Pfizer; GA has received funds for speaking and funds for advisory board membership from Pfizer; MBS has received funds for speaking from Astellas, Astra-Zeneca and Pfizer; PJM, TM and MK are employees of Pfizer; MR has received research funding from MSD, Pfizer and Stifterverband fur die Deutsche Wissenschaft as well as funds for speaking and funds for advisory board membership from Astellas, Essex, Gilead, MSD and Pfizer. JP declares no competing interests.

Diagnosis of CNS infections remains a great challenge in patients with hematological disorders since symptoms might both be masked and be mimicked by other conditions such as metabolic disturbances or consequences from antineoplastic treatment. Thus, awareness of this complication is crucial and any suspicion of a CNS infection should lead to timely and adequate diagnostics and treatment to improve the outcome in this population., Infections of the central nervous system (CNS) are infrequently diagnosed in immunocompetent patients, but they do occur in a significant proportion of patients with hematological disorders. In particular, patients undergoing allogeneic hematopoietic stem-cell transplantation carry a high risk for CNS infections of up to 15%. Fungi and Toxoplasma gondii are the predominant causative agents. The diagnosis of CNS infections is based on neuroimaging, cerebrospinal fluid examination and biopsy of suspicious lesions in selected patients. However, identification of CNS infections in immunocompromised patients could represent a major challenge since metabolic disturbances, side-effects of antineoplastic or immunosuppressive drugs and CNS involvement of the underlying hematological disorder may mimic symptoms of a CNS infection. The prognosis of CNS infections is generally poor in these patients, albeit the introduction of novel substances (e.g. voriconazole) has improved the outcome in distinct patient subgroups. This guideline has been developed by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) with the contribution of a panel of 14 experts certified in internal medicine, hematology/oncology, infectious diseases, intensive care, neurology and neuroradiology. Grades of recommendation and levels of evidence were categorized by using novel criteria, as recently published by the European Society of Clinical Microbiology and Infectious Diseases.

Hepatic Candida infection (HCI; known as chronic disseminated candidosis or CDC) is a distinct form of disseminated Candida infection with predominant involvement of the liver. Diagnosis of HCI is usually made on clinical suspicion together with multiple lesions in liver on ultrasound (US), CT and/or MRI scan. Fungal elements may not always be visible in liver tissue and mycological culture is frequently negative, making the evidence for proven fungal disease difficult. We studied a novel commercially available low-cost and density-array (LCD) chip technique for a molecular diagnosis of HCI. This is a two-step procedure with PCR amplification after DNA extraction followed by hybridization on a small chip provided by the manufacturer (Fungi 2.1, Chipron GmbH). The analysis of DNA from 45 fungal control strains showed an excellent specificity and sensitivity. The DNA from 11 liver biopsies of patients with haematological malignancies suffering from CDC was analysed on the LCD chip and overall 11 fungal pathogens could be detected in eight liver biopsies, supporting the clinical diagnosis of HCI/CDC. Analysis of liver biopsies from controls was negative for fungal DNA in all samples studied. In conclusion, the novel LCD chip technique examined in our study was able to detect fungal pathogens in liver biopsies from patients with haematological malignancies and suspected HCI/CDC but was negative in control biopsies.

Candida infections are a permanent threat to immunocompromised individuals such as cancer patients, and Candida glabrata has emerged as a major problem in recent years. Resistance may develop during lengthy antifungal therapies and is often mediated by upregulation of fungal drug efflux pumps. During chemotherapy the yeast cell is also exposed to cytotoxic agents that may affect its drug susceptibility. Four C. glabrata isolates, three susceptible and one resistant to fluconazole (FLU), were incubated with 20 μg/ml of doxorubicin (DOX) for 90 min. In a second experiment, the isolates were cultured with DOX for ten days. Samples were taken on subsequent days to determine the minimal inhibitory concentration (MIC) of FLU and to analyze expression of CgCDR1, CgCDR2, CgSNQ2 and CgPDR1. Samples were also used to assess the petite phenotype. Short-term DOX exposure did not induce efflux pump gene expression, but genes were consistently overexpressed in FLU-susceptible isolates during long-term exposure. An increase in MIC values on day 6 in two of the isolates coincided with the first occurrence of petite mutants in all susceptible isolates. The respiratory deficiency of selected petite mutants was confirmed by culturing mutants on agar containing glycerol as the sole carbon source. FLU MIC values for respiratory-deficient clones were ≥64 μg/ml, and efflux pump gene expression was greatly increased. The resistant isolate did not develop mitochondrial dysfunction. In summary, the cytotoxic agent DOX selects for FLU-resistant respiratory-deficient C. glabrata mutants, which may affect antifungal therapy.

Acutely ill patients with candidemia frequently suffer from renal insufficiency. Voriconazole's intravenous formulation with sulfobutylether beta-cyclodextrin (SBECD) is restricted in patients with renal insufficiency. We evaluated the use of intravenous voriconazole formulated with SBECD in candidemic patients with renal insufficiency and compared treatment outcome and safety to those who received a short course of amphotericin B deoxycholate followed by fluconazole. We reviewed data on treatment outcome, survival, safety, and tolerability from the subset of patients with moderate (creatinine clearance [CrCl], 30 to 50 ml/min) or severe (CrCl

More than 18,000 autolgous transplantation were performed in Europe in the year 2009. It as a routine procedure in experienced centres. Even if there is a low mortality rate, infections are a major issue after transplantation, occurring in more than 60 % of the patients. In this review we discuss all aspects of infections after autologous stem transplantation, including epidemiology, diagnostics, therapeutic algorithms, prophylaxis and supportive therapy.

Summary Despite PCR per se being a powerful and sensitive technique, regarding the detection of fungi in patients’ blood, no consensus for a standardised PCR protocol yet exists. To complement other ongoing or accomplished studies which tackle this problem, the German Reference Center for Systemic Mycoses conducted an interlaboratory comparison starting with blood samples spiked with fungal cell elements. Altogether, six laboratories using in-house PCR-protocols from Germany and Austria participated in the trial. Blood samples were spiked with vital cells of Candida albicans or Aspergillus fumigatus. Candida was used in the yeast form, whereas Aspergillus cells were either spiked as conidia or as very young germlings, also known as smoo cells. Spiked blood samples contained between 10 and 10 000 cells ml−1. Depending on the techniques used for fungal cell disruption and DNA-amplification, detection quality was variable between laboratories, but also differed within single laboratories in different trials particularly for samples spiked with less than 100 cells ml−1. Altogether, at least regarding the detection of A. fumigatus, two of six laboratories showed constant reliable test results also with low fungal cell number spiked samples. Protocols used by these labs do not differ substantially from others. However, as particularities, one protocol included a conventional phenol chloroform extraction during the DNA preparation process and the other included a real time PCR-protocol based on FRET probes. Other laboratory comparisons on the basis of clinical samples should follow to further evaluate the procedures. The difficulties and problems of such trials in general are discussed.

Invasive aspergillosis (IA), the most life-threatening form of aspergillosis, has become a major opportunistic fungal disease in immunocompromised patients. In high-risk patients with hematologic malignancies, IA appears to decline with the use of mold-active antifungal prophylaxis, but the situation is less clear in other patient groups at risk for IA, and precise epidemiologic data from patients treated in intensive care units (ICUs) are lacking. Most Aspergillus culture isolates from nonsterile body sites do not represent disease, but isolation of Aspergillus in critically ill patients is a marker of poor prognosis and is associated with high mortality regardless of invasion or colonization. This review presents current information on epidemiology, risk factors, and diagnosis, and discusses treatment options for patients with IA in the ICU.

An early diagnosis of an invasive fungal infection is essential for the initiation of a specific antifungal therapy and to avoid unnecessary discontinuation of a baseline therapy for haematological or oncological diseases. A real-time PCR assay for the detection and strain identification of Aspergillus species from culture strains was evaluated. DNA preparation was evaluated in contaminated culture media, urine and serum. A LightCycler PCR to differentiate various Aspergillus species was established. A real-time PCR assay for the detection of Aspergillus species was improved and was able to detect and differentiate medically important Aspergillus spp. The sensitivity of the test was

Summary Invasive Candida infections are important causes of morbidity and mortality in immunocompromised and hospitalised patients. This article provides the joint recommendations of the German-speaking Mycological Society (Deutschsprachige Mykologische Gesellschaft, DMyKG) and the Paul-Ehrlich-Society for Chemotherapy (PEG) for diagnosis and treatment of invasive and superficial Candida infections. The recommendations are based on published results of clinical trials, case-series and expert opinion using the evidence criteria set forth by the Infectious Diseases Society of America (IDSA). Key recommendations are summarised here: The cornerstone of diagnosis remains the detection of the organism by culture with identification of the isolate at the species level; in vitro susceptibility testing is mandatory for invasive isolates. Options for initial therapy of candidaemia and other invasive Candida infections in non-granulocytopenic patients include fluconazole or one of the three approved echinocandin compounds; liposomal amphotericin B and voriconazole are secondary alternatives because of their less favourable pharmacological properties. In granulocytopenic patients, an echinocandin or liposomal amphotericin B is recommended as initial therapy based on the fungicidal mode of action. Indwelling central venous catheters serve as a main source of infection independent of the pathogenesis of candidaemia in the individual patients and should be removed whenever feasible. Pre-existing immunosuppressive treatment, particularly by glucocorticosteroids, ought to be discontinued, if feasible, or reduced. The duration of treatment for uncomplicated candidaemia is 14 days following the first negative blood culture and resolution of all associated symptoms and findings. Ophthalmoscopy is recommended prior to the discontinuation of antifungal chemotherapy to rule out endophthalmitis or chorioretinitis. Beyond these key recommendations, this article provides detailed recommendations for specific disease entities, for antifungal treatment in paediatric patients as well as a comprehensive discussion of epidemiology, clinical presentation and emerging diagnostic options of invasive and superficial Candida infections.

Two Candida albicans isolates were collected from a HIV-positive patient with recurrent oropharyngeal candidosis (OPC). One isolate was taken during the first episode of oral candidosis [fluconazole susceptible (FLU-S), minimal inhibitory concentration (MIC) = 0.25 mg l(-1) ] and the second after the patient developed refractory OPC and resistance to fluconazole (FLU-R, MIC = 64 mg l(-1)). Both isolates were clonally identical. Different in vitro studies were carried out to assess putative virulence factors of both isolates. Gene expressions of efflux pumps and CSH1 were determined as well as adherence to human epithelial cells, determination of proteinase secretion and biofilm formation activity. Virulence was studied using a disseminated mouse model. All mice challenged with the FLU-S isolate survived the experiment when FLU was given. However, when FLU was absent, the mortality of the FLU-S isolate was higher than that of the FLU-R isolate with no mice surviving the experiment. In vitro studies showed pronounced growth rates of the FLU-S isolate and a more intense biofilm-building activity compared with the FLU-R isolate. The FLU-R isolate highly up-regulated MDR1 and CSH1. This isolate also adhered stronger to the epithelial cell line. The results showed that FLU-S and FLU-R isolates exhibit different virulence factors, which enable the survival of both isolates in adapted environments.

Immunocompromised patients have a high risk for invasive fungal diseases (IFDs). These infections are mostly life-threatening and an early diagnosis and initiation of appropriate antifungal therapy are essential for the clinical outcome. Empirical treatment is regarded as the standard of care for granulocytopenic patients who remain febrile despite broad-spectrum antibiotics. However, this strategy can bear a risk of overtreatment and subsequently induce toxicities and unnecessary treatment costs. Pre-emptive antifungal therapy is now increasingly used to close the time gap between delayed initiation for proven disease and empirical treatment for anticipated infection without further laboratory or radiological evidence of fungal disease. Currently, some new non-invasive microbiological and laboratory methods, like the Aspergillus-galactomannan sandwich-enzyme immunoassay (Aspergillus GM-ELISA), 1,3-β-D-glucan assay or PCR techniques have been developed for a better diagnosis and determination of target patients. The current diagnostic approaches to fungal infections and the role of the revised definitions for invasive fungal infections, now IFDs, will be discussed in this review as well as old and emerging approaches to empirical, pre-emptive and targeted antifungal therapies in patients with haemato-oncological malignancies.

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.

Candida albicans is one of the most important opportunistic fungal pathogens. It can cause serious fungal diseases in immunocompromised patients, including those with cancer. Treatment failures due to the emergence of drug-resistant C. albicans strains have become a serious clinical problem. Resistance incidents were often mediated by fungal effl ux pumps which are closely related to the human ABC transporter P-glycoprotein (P-gp). P-gp is often overexpressed in cancer cells and confers resistance to many cyto- toxic drugs. We examined whether cytotoxic drugs commonly used for cancer treatment (doxorubicin and cyclophosphamide) could alter the expression of genes responsible for the development of fl uconazole resistance in Candida cells in the way they can infl uence homologous genes in cancer cell lines. ABC transporters ( CDR1 and CDR2 ) and other resistance genes ( MDR1 and ERG11) were tested by real-time PCR for their expres- sion in C. albicans cells at the mRNA level after induction by antineoplastic drugs. The results were confi rmed by a lacZ gene reporter system and verifi ed at the protein level using GFP and immunoblotting. We showed that doxorubicin is a potent inducer of CDR1/CDR2 expression in C. albicans at both the mRNA and protein level and thus causes an increase in fl uconazole MIC values. However, cyclophosphamide, which is not a substrate of human P-gp, did not induce ABC transporter expression in C. albicans . Neither doxorubicin nor cyclophosphamide could infl uence the expression of the other resistance genes ( MDR1 and ERG11) . The induction of CDR1/CDR2 by doxorubicin in C. albicans and the resulting alteration of antifungal susceptibility might be of clinical relevance for the antifungal treatment of Candida infections occurring after anticancer chemotherapy with doxorubicin.

Resveratrol is a natural stilbene synthesised by plants. This compound has been shown to inhibit the growth of Candida albicans TIMM 1768 efficiently. Till date, no information is available for other Candida species. The evaluation of the antimicrobial activity of resveratrol was analysed by the inhibition of the growth and metabolism assays. Our data indicate that resveratrol is not effective against Candida albicans and non-C. albicans species (C. dubliniensis, C. glabrata, C. tropicalis, C. parapsilosis and C. krusei) in vitro. The potential candidacidal activity could not be confirmed.