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Background Little is known about the infrastructure to translate advances in the management of patients at risk to develop invasive opportunistic fungal diseases. To assess the current state of Medical Mycology support in Germany, we conducted a survey among all 36 academic medical centres. Methods The survey consisted of a 3-pages questionnaire sent out in the first half of 2019. Information included details of infrastructure, education and teaching; consultation services and interdisciplinary conferences; research activities and participation in network groups; radiology, microbiology and pharmacology support; publication activity; and European Confederation for Medical Mycology (ECMM) Excellence Center designation, if assigned. Results Information was returned from 24 centres (67%). Thirteen institutions (54%) reported an independent infectious disease, and two a separate Medical Mycology department (8%); a Medical Mycology working group was reported for nine institutions (38%). An infectious disease consultation service was existent in 16 institutions (67%) and a multidisciplinary conference in 13 (54%). Fifteen institutions reported a separate study office with activities in infectious disease studies (63%). Laboratory capability for fungal identification and susceptibility testing was confirmed by all 24 institutions; testing of galactomannan by 23 (96%), cryptococcal antigen by 21 (88%), ss-D-Glucan by 9 (38%), and panfungal and Pneumocystis PCR by 21 and 22 (88% and 92%), respectively. Therapeutic drug monitoring of voriconazole was reported to be available in 15 (63%) institutions with a turnaround of <= 24 h during weekdays in 10 (42%). Two of the 24 University hospitals (8%) reported ECMM Diamond Excellence Status. Conclusions The results of this survey document the continuing need to improve the availability of specialised Medical Mycology support in German academic medical centres.

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.

The incidence of invasive fungal diseases (IFDs) with central nervous system (CNS) involvement is increasing due to the rising numbers of immunocompromised individuals, such as patients receiving chemotherapy, transplantation procedures, or immune-modulating therapies. CNS IFDs cause significant morbidity and mortality, and treatments are complicated by difficulties in identifying fungal pathogens and delivering antifungal agents to the CNS. Isavuconazole is a novel triazole with broad-spectrum activity that has shown good blood-brain barrier penetration in animal models. We present a retrospective analysis of isavuconazole in the treatment of patients with CNS IFDs and who either participated in the phase III VITAL or SECURE clinical trials, or were included in a named-patient program. A total of 36 patients were identified, including 27 patients from the clinical trials. Of these patients, 47.2% had hematologic malignancies, while 13.9% had no identifiable underlying conditions. Mucorales, Aspergillus species, and Cryptococcus species accounted for 30.6%, 22.2%, and 13.9% of infections, respectively. The overall survival rate was 80.6% at day 42 and 69.4% at day 84, and at the end of treatment, a complete or partial clinical response was achieved in 58.3% of patients. Isavuconazole exhibited clinical activity in a variety of CNS IFDs.

In immunocompromised patients with acute leukaemia as well as in allogeneic hematopoietic stem cell transplant patients, pulmonary lesions are commonly seen. Existing guidelines provide useful algorithms for diagnostic procedures and treatment options, but they do not give recommendations on how to evaluate early success or failure and if or when it is best to change therapy. Here, we review the diagnostic techniques currently used in association with clinical findings and propose an approach using a combination of computer tomography, clinical and all available biomarkers and inflammation parameters, especially those positive at baseline, to assess early response in invasive pulmonary aspergillosis. Computed tomography scans should be carried out at regular intervals during early and long-term follow-up. Imaging on day seven, or even earlier in clinically unstable patients, combined with an additional testing of biomarkers and inflammatory markers in between, is needed for a reliable assessment at day 14. If no improvement is seen after 2 weeks of therapy or the clinical condition is deteriorating, a change of antifungal therapy should be considered. Alleged breakthrough infections or treatment failure should undergo early diagnostic workup, including tissue biopsies when possible, to retrieve fungal cultures for resistance testing.

Background: First-line antifungal treatment for invasive mucormycosis (IM) consists of liposomal amphotericin B. Salvage treatment options are limited and often based on posaconazole oral suspension. With the approval of posaconazole new formulations, patients could benefit from improved pharmacokinetics, safety and tolerability. Objectives: Our aim was to assess the effectiveness of posaconazole new formulations for IM treatment. Methods: We performed a case-matched analysis with proven or probable IM patients from the FungiScope (R) Registry. First-line posaconazole new formulations (1st-POSnew) and first-line amphotericin B plus posaconazole new formulations (1st-AMB+POSnew) cases were matched with first-line amphotericin B-based (1st-AMB) treatment controls. Salvage posaconazole new formulations (SAL-POSnew) cases were matched with salvage posaconazole oral suspension (SAL-POSsusp) controls. Each case was matched with up to three controls (based on severity, haematological/oncological malignancy, surgery and/or renal dysfunction). Results: Five patients receiving 1st-POSnew, 18 receiving 1st-AMB+POSnew and 22 receiving SAL-POSnew were identified. By day 42, a favourable response was reported for 80.0% (n=4/5) of patients receiving 1st-POSnew, for 27.8% (n=5/18) receiving 1st-AMB+POSnew and for 50.0% (n=11/22) receiving SAL-POSnew. Day 42 all-cause mortality of patients receiving posaconazole new formulations was lower compared with controls [20.0% (n=1/5) in 1st-POSnew versus 53.3% (n=8/15) in 1st-AMB; 33.3% (n=6/18) in 1st-AMB+POSnew versus 52.0% (n=26/50) in 1st-AMB; and 0.0% (n=0/22) in SAL-POSnew versus 4.4% (n=2/45) in SAL-POSsusp]. Conclusions: Posaconazole new formulations were effective in terms of treatment response and associated mortality of IM. While posaconazole new formulations may be an alternative for treatment of IM, the limited sample size of our study calls for a cautious interpretation of these observations.

In patients with hematological malignancies, bronchoalveolar lavage fluid (BALF) specimens are commonly used for the diagnosis of mold infections. However, it is not clear whether the cell pellet (P) or the supernatant fraction (S) of the BALF specimen is optimal for molecular diagnostic testing. Thus, 99 BALF specimens were collected from 96 hematology patients with or without allogeneic hematopoietic stem cell transplant. The cell pellets and supernatants were processed alone and in combination (S/P) for testing by two fungus-specific real-time PCR assays compliant with international recommendations. The results achieved with S/P were revealed to be superior in comparison to those achieved with S and P alone, with the use of each single fraction showing a reduced sensitivity for the detection of Aspergillus DNA (82% and 43% for S and P, respectively). In 57% of the samples, testing of the combination of S and P generated a lower quantification cycle value than testing of S or P alone. Molds would have been missed in 5 and 16 out of 28 samples if only S or P, respectively, was analyzed. No sample was positive by testing of S or P only. Similar results were obtained for the detection of Mucorales DNA in BALF specimens (reduced sensitivity of 67% and 50% for S and P, respectively). Study patients were categorized according to the current European Organization for the Research and Treatment of Cancer/Mycoses Study Group classification for invasive fungal disease (IFD), revealing that 35 patients had proven/probable IFD (36%), 47 patients had possible IFD (49%), and 14 patients had undetermined IFD (15%).

Treatment outcomes in patients with proven/probable vs possible invasive mould disease (IMD; 2008 European Organisation for Research and Treatment of Cancer/Mycoses Study Group [EORTC/MSG] criteria) needed further assessment. The Phase III SECURE trial compared isavuconazole vs voriconazole for treatment of IMD. This post hoc analysis assessed all-cause mortality (ACM) through day 42 (primary endpoint) and day 84, overall and clinical success at end of treatment (EOT), and drug-related treatment-emergent adverse events (TEAEs) in subgroups with proven/probable or possible IMD. Of 516 randomised patients, 304 (58.9%) had proven/probable IMD and 164 (31.8%) had possible IMD as per EORTC/MSG criteria; 48 did not have IMD. Across treatment groups, day 42 and day 84 ACM were numerically lower for possible vs proven/probable IMD (day 42: 17.1% vs 21.1%; P=0.3, day 84: 26.2% vs 32.6%; P=0.15). Overall and clinical success at EOT were significantly higher for possible IMD compared with proven/probable IMD (48.2% vs 36.2%; P=0.01, 75.0% vs 63.1%; P=0.01 respectively). Fewer drug-related TEAEs were reported with isavuconazole compared with voriconazole in patients with either proven/probable or possible IMD. Compared with patients with proven/probable IMD, those with possible IMD demonstrated higher overall and clinical success rates, supporting early initiation of antifungal treatment.

Objectives: A two-part (Phase 1B/3), sequential, open-label, multicentre study evaluated the pharmacokinetics (PK) and safety of intravenous (iv) posaconazole given as antifungal prophylaxis to neutropenic patients with AML or myelodysplastic syndrome (MDS) or to recipients at risk of invasive fungal disease (IFD) after allogeneic HSCT. Methods: Patients (N=237) received 300mg of posaconazole iv twice daily on day 1, followed by 300mg of posaconazole iv once daily for 4-28 days. After at least 5 days, patients were randomly assigned to receive posaconazole oral suspension, 400mg twice daily or 200mg three times daily, to complete a 28 day treatment course. Primary PK parameters were steady-state average concentration over the dosing interval (C-avg) and posaconazole trough levels (C-min). Results: Mean posaconazole C-min was 1320 ng/mL (day 6) and 1297 ng/mL (day 8); steady-state C-min was 1090 ng/mL (day 10). Mean steady-state posaconazole C-avg was 1500 ng/mL (day 10 or 14) and was similar in HSCT recipients (1560 ng/mL) and AML/MDS patients (1470 ng/mL). The most commonly reported treatment-related adverse events were diarrhoea (8%), nausea (5%) and rash (5%). IFD was reported in 3/237 patients (1%; 2 proven, 1 probable). Conclusions: Intravenous posaconazole at 300mg was well tolerated, resulted in adequate steady-state systemic exposure and was associated with a low incidence of IFD in this population at high risk.