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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., (© 2018 Blackwell Verlag GmbH.)

Background: Intravenous bridging strategies increase exposure of antifungal prophylaxis in high-risk hematological patients. The cost-effectiveness of such strategies has not been analyzed., Methods: A recent study compared the impact of oral posaconazole (POS) and oral posaconazole with intravenous micafungin bridging (POS-MIC) as prophylactic antifungal regimens in patients undergoing allogeneic stem cell transplantation (aSCT). Based on data from the Cologne Cohort of Neutropenic Patients (CoCoNut), a health economic evaluation of direct treatment costs was performed to analyze the economic impact of micafungin bridging. Analysis was undertaken based on current guidelines for the German societal perspective with an annual discount rate of 5%, whereby indirect costs were disregarded due to the severity of the underlying disease. Sensitivity analysis of cost calculation with different discount rates was performed to improve robustness of our health economic evaluation., Results: A retrospective case-control analysis of patients undergoing aSCT between 05/2006 and 07/2011 was performed; 106 patients each in the POS and POS-MIC group were included. In the POS and POS-MIC group, mean costs per patient for the treatment on bone marrow transplant ward were €27,228 (95% CI: €24,932-€29,525) vs. €27,894 (95% CI: €26,414-€29,375; P = 0.629), for diagnostic measures €2124 (95% CI: €1823-€2425) vs. €1269 (95% CI: €1168-€1370; P ≤ 0.001), for laboratory findings €10,612 (95% CI: €9681-€11,544) vs. €8836 (95% CI: €8198-€9475; P = 0.002), and for overall antifungal treatment €6105 (95% CI: €4703-€7508) vs. €6943 (95% CI: €5393-€8493; P = 0.428), resulting in mean overall costs per patient of €60,304 (95% CI: €53,969-€66,639) vs. €58,089 (95% CI: €51,736-64,442; P = 0.625)., Conclusions: Our health economic evaluation shows micafungin bridging in aSCT patients did not result in excess cost. Higher acquisition costs of antifungal prophylaxis were balanced by a reduced incidence of possible IFD and lower costs for empirical, preemptive, and targeted antifungal therapy as well as lower costs for diagnostic measures and laboratory tests in the micafungin bridging group., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Prior clinical trials have demonstrated efficacy and effectiveness of posaconazole in the prophylaxis of invasive fungal diseases in high-risk patients. Controversy exists about the cost-effectiveness of this approach. We performed an analysis comparing the direct costs of posaconazole prophylaxis against polyene mouthwash (thrush) prophylaxis in patients with acute myelogenous leukaemia (AML). Data of AML patients receiving remission-induction chemotherapy were extracted from the CoCoNut (Cologne Cohort of Neutropenic Patients) database to compare hospital costs of patients before (2003-2005) and after (2006-2008) introduction of posaconazole prophylaxis. Treatment on general ward, intensive care unit (ICU), mechanical ventilation, diagnostic procedures, and all anti-infectives were calculated. Patient groups were well matched according to age, gender and duration of neutropenia. The mean costs per patient in the posaconazole group (n = 76) and the polyene mouthwash group (n = 81) were €21 040 (95% confidence interval (CI): €18 204-€23 876) and €23 169 (95% CI: €19 402-€26 937) per patient. Antifungal treatment costs were €4580 (95% CI: €3678-€5482) and €4019 (95% CI: €2825-€5214). Duration on the ICU was 2582 (95% CI: 984.1-4181.7) and 5517 (95% CI: 2206-8827.3) min. In our hospital, primary antifungal prophylaxis by posaconazole was cost-effective. There was a trend towards cost savings, which was primarily caused by a shorter overall length of stay and the less frequent ICU treatment., (© 2013 Blackwell Verlag GmbH.)

Antifungal prophylaxis during first remission induction chemotherapy for acute myelogenous leukaemia requires broad spectrum azoles. In a clinical trial, therapeutic drug monitoring (TDM) of antifungal prophylaxis with voriconazole 200 mg bid was evaluated in a population of six patients. High pressure liquid chromatography was applied. Trough levels were obtained 24 h after the last voriconazole dose. Median time of voriconazole exposure prior to sample acquisition was 16 days (range 9-21). The mean voriconazole concentration was 486 μg l(-1) and ranged from 136 μg l(-1) to 1257 μg l(-1). Among possible or probable treatment-related adverse events, elevated liver function tests were the most frequent. Five of six patients developed fever during neutropenia, but none of them developed pulmonary infiltrates or other signs of invasive fungal infection while on voriconazole prophylaxis. Future investigations might aim at identifying drug level thresholds that allow for minimum toxicity and optimum efficacy of antifungal prophylaxis., (© 2009 Blackwell Verlag GmbH.)

Therapeutic drug monitoring (TDM) of antifungal plasma concentrations is increasingly recommended. However, data on antifungal concentrations in the other compartments of the peripheral blood are limited. Hence, we collected 23 blood samples from 14 patients receiving posaconazole for prophylaxis of fungal infections. These samples were separated by double-discontinuous Ficoll-Hypaque density gradient centrifugation. The intracellular posaconazole concentrations of the obtained cells, i.e., the peripheral blood mononuclear cells (PBMCs), polymorphonuclear leukocytes (PMNs), and red blood cells (RBCs), were determined by liquid chromatography-tandem mass spectrometry. The intracellular concentrations of the PBMCs and PMNs were significantly higher than those of surrounding media (P < 0.001). The ratios between the intracellular and extracellular concentrations (C/E) were 22.5 +/- 21.2, 7.66 +/- 6.50, and 0.09 +/- 0.05 for the PBMCs, PMNs, and RBCs, respectively. Posaconazole reaches high concentrations within human PBMCs and PMNs and is, to a lesser extent, present in RBCs. The high intracellular concentrations might contribute to posaconazole efficacy and distribution.

In this review, we aim to compare different early treatment strategies of invasive fungal diseases in patients undergoing induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome. Three treatment approaches--prophylactic, empiric, and preemptive treatment--are subject to continuous discussion among physicians treating patients at risk. Considering the available clinical basis of evidence, we opt for antifungal prophylaxis with posaconazole 200 mg tid po as our primary prophylactic strategy, while the employment of preemptive treatment should be delayed until more accurate diagnostic tools become available. In addition to antifungal prophylaxis, empiric treatment with caspofungin or L-AmB may be administered to patients with fever resistant to broad-spectrum antibiotic treatment and without radiographic findings typical of invasive fungal disease.

Patients surviving invasive fungal disease (IFD) and needing further antineoplastic chemotherapy are at high risk of recurrent fungal infection. In the absence of randomised controlled trials in this area, secondary prophylactic regimens are diverse. From 448 patients registered with the Multinational Case Registry of Secondary Antifungal Prophylaxis, we performed an analysis of patients receiving caspofungin (CAS) or itraconazole (ITC). All patients had an underlying haematological malignancy and had been diagnosed with an episode of IFD earlier in their course of treatment. Data collected comprised demographics, underlying disease, first episode of IFD, antifungal prophylaxis, incidence and outcome of breakthrough IFD and survival. A total of 75 patients were evaluated, comprising 28 receiving CAS and 47 receiving ITC. Patients in the CAS group were more likely to have had progression of underlying disease (32.1% vs. 8.5%; P=0.028) as well as incomplete response of initial IFD at baseline (85.7% vs. 57.4%; P=0.005). Allogeneic stem cell transplantation was more prevalent in patients receiving CAS (46.4% vs. 14.9%; P=0.010). There was no difference in the occurrence of breakthrough IFD between both groups (32.1% vs. 31.9%). Treatment outcomes for recurrent IFD and overall mortality did not differ between groups. Both ITC and CAS were equally effective in preventing second episodes of IFD. Patients with uncontrolled first IFD, uncontrolled underlying disease or those receiving stem cell transplantation were more likely to have received CAS prophylaxis. Despite antifungal prophylaxis, risk of breakthrough IFD was high in both groups.

We discuss different strategies for the treatment of invasive fungal infections (IFI) in high risk patients with a focus on patients experiencing profound and prolonged neutropenia, comprising those with acute myelogenous leukaemia (AML) or myelodysplastic syndrome (MDS) during remission induction chemotherapy and on patients undergoing allogeneic haematopoietic stem cell transplantation (SCT). Among these patients, invasive aspergillosis (IA) is the most frequently observed form of IFI, as opposed to high risk intensive care unit (ICU) patients in whom an increased incidence of invasive candidiasis (IC) can be observed. In both groups, initiation of early treatment has a profound impact on mortality rates, but adequate diagnostic tools are lacking. These circumstances have led to the parallel use of different treatment strategies, e.g. prophylaxis, empiric, pre-emptive and targeted treatment of IFI. The optimum treatment strategies for these severe infections are a matter of extensive research and discussion. A review of major clinical trials on the issue reveals that comparisons between different treatment strategies cannot be made. Considering the complexity of the issue, we advocate an eclectic treatment approach that reduces morbidity and mortality from IFI without compromising tolerability. In allogeneic HSCT recipients, patients receiving induction chemotherapy for AML or MDS and those under immunosuppressive medication for graft vs. host disease after allogeneic HSCT, we recommend prophylaxis with posaconazole. For empiric treatment of persistently febrile neutropenic patients, we opt for caspofungin as first and liposomal amphotericin B deoxycholate (L-AmB) as second line choice. If the diagnosis of IA can be established, voriconazole should be favoured over the alternative, liposomal amphotericin B (L-AmB). While high risk ICU patients benefit from fluconazole prophylaxis for IC, the choice of an optimal agent for targeted therapy depends largely on the neutrophil count. In non-neutropenic patients, we recommend an echinocandin as the first line treatment option. Patients with susceptible Candida spp. may be switched to fluconazole. Caspofungin or micafungin might be preferred to anidulafungin in the neutropenic patient. L-AmB is a valuable second line treatment option for both groups of patients.

Invasive fungal infections are frequent and often deadly complications in patients with malignant hematological diseases. Voriconazole is a third generation triazole antifungal with broad activity against most clinically relevant fungal pathogens. Clinical practice often deviates from insights gained from controlled randomized trials. We conducted a multi-centre survey to evaluate efficacy, safety, treatment indications and dosing of voriconazole outside clinical trials. Patients receiving voriconazole were documented via electronic data capturing. An analysis was conducted after submission of 100 episodes from September 2004 to November 2005. Voriconazole was administered for suspected or proven invasive fungal infection (IFI) (57%), as empirical treatment in patients with fever of unknown origin (21%) and secondary (19%) as well as primary (3%) prophylaxis of IFI. Investigators' assessment of fungal infection often diverted from EORTC/MSG 2002 criteria. A favorable response was reported in 61.4% for suspected or proven IFI and 52.4% for empirical treatment. Mortality was 15%, 26.7% of which was attributable to IFI. Breakthrough fungal infections occurred in four (21.1%) patients with voriconazole as secondary prophylaxis. Toxicity and adverse events comprised elevated liver enzymes and visual disturbances. Although indications frequently deviated from clinical evidence and legal approval, voriconazole showed efficacy and safety, comparable to major controlled clinical trials. Data from this survey demonstrate the difficulty of putting drugs to their approved use in IFI.

When and how to treat invasive fungal infections (IFIs) is discussed in this review, with a focus on the two most prevalent non-endemic IFIs, namely invasive aspergillosis and invasive candidiasis. Early treatment initiation in patients with IFIs has a profound impact on mortality rates, but reliable diagnostic measures are lacking. This situation has led to the parallel use of different treatment strategies, e.g. prophylaxis, empirical and pre-emptive treatment, as well as targeted treatment in response to a definite diagnosis of IFI. Identifying high-risk patients is the first step in reducing IFI-related mortality. Patients at risk of invasive aspergillosis comprise (i) those with acute myelogenous leukaemia (AML) or myelodysplastic syndrome (MDS) during remission induction chemotherapy; (ii) patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT); (iii) recipients of solid organ transplants; and (iv) those with other conditions of severe and prolonged immunosuppression. Patients at high risk of invasive candidiasis are less well defined. Risk factors are diverse and include haematological malignancy, neutropenia, age <1 month or >65 years, and recent abdominal surgery. The individual risk further depends on the presence of a variety of other risk factors, including central venous catheters, use of broad spectrum antibacterials, prolonged intensive care unit (ICU) stay, total parenteral nutrition, mucosal Candida spp. colonization and renal failure.Extensive research has been conducted to facilitate the best possible treatment strategies for these severe infections. Optimal timing and choice of antifungal agents largely remain a matter of controversy. After having reviewed the major clinical trials, we conclude that comparisons between different treatment strategies cannot be made, neither at present nor in the near future. The complexity of the clinical problem leads to an eclectic treatment approach to reduce morbidity and mortality from IFIs without compromising tolerability. We recommend prophylaxis with posaconazole for allogeneic HSCT recipients, patients receiving induction chemotherapy for AML or MDS, and those undergoing immunosuppressive therapy for graft-versus-host disease after allogeneic HSCT. For the empirical treatment of persistently febrile neutropenia, caspofungin is our first- and liposomal amphotericin B deoxycholate (LAmB) our second-line choice. Once a diagnosis of invasive aspergillosis has been established, voriconazole should be the preferred treatment option, with LAmB being an alternative. Fluconazole prophylaxis for invasive candidiasis should remain restricted to high-risk ICU patients. Once a diagnosis has been established, the drug of choice for adequate treatment depends largely on neutrophil count and haemodynamic stability. In non-neutropenic patients, an echinocandin should be considered the first-line treatment option, while patients with susceptible Candida spp. may be switched to fluconazole. In neutropenic patients, caspofungin or micafungin might be preferred to anidulafungin as first-line treatment. LAmB is a second-line treatment option in both settings.Early diagnosis of IFIs is imperative to facilitate treatment success. In all patients at risk for IFIs, blood cultures, galactomannan antigen and diagnostic imaging should be rigorously enforced.

Posaconazole is a new drug in the triazole class that has recently been investigated in pivotal Phase III clinical trials. Its antifungal activity is based on the inhibition of the fungal ergosterol synthesis. As demonstrated in vitro, posaconazole exhibits fungicidal activity against Aspergillus spp., Candida spp. and zygomycetes. Currently, posaconazole is only available as an oral suspension. Food consumption affects the bioavailability of posaconazole, while the exposure to posaconazole increases in a dose-proportional manner with a saturation of absorption occurring with a daily dose over 800 mg. Posaconazole is well tolerated without an increase in risk of any treatment-related adverse events during prolonged treatment for 6 or more months (n = 108). Posaconazole has been recently approved by the US FDA and other regulatory bodies for the treatment of oropharyngeal candidiasis, and the prophylaxis of invasive Aspergillus and Candida infections in severely immunocompromised patients. As demonstrated in two pivotal Phase III trials, posaconazole prophylaxis of invasive fungal infection in patients severely immunocompromised by graft-versus-host disease (n = 600) or neutropenia (n = 602) is superior to fluconazole and/or itraconazole prophylaxis. Significantly more patients who received posaconazole, instead of fluconazole, as treatment for oropharyngeal candidiasis sustained clinical success after the treatment was stopped. Preliminary data from a subgroup analysis (n = 24) of two salvage therapy trials for invasive fungal infections, as well as single case reports and series and in vitro studies, suggest that posaconazole might be an attractive oral treatment alternative for zygomycosis.

Zygomycoses are very rare invasive fungal infections (IFI). They primarily occur in the immunocompromised patients and are associated with a high mortality. During the last years, a rising incidence of zygomycosis in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) has been reported, which is probably a part of the trend in the incidence of mould infections that has been going on for decades. Difficulty in diagnosis, especially concerning the differentiation of zygomycosis from the far more common aspergillosis, additionally hampers a reliable assessment of the incidence of zygomycosis. In patients undergoing allogeneic HSCT, changes in the frequency, severity and management of Graft-versus-Host-Disease (GvHD) also favour mould infections, among them zygomycosis. In centres employing voriconazole for prophylaxis of IFI since its approval for treatment in 2001, incidence of aspergillosis has markedly dropped. The assumption that the frequency of zygomycosis has increased since the introduction of voriconazole is not found in prospective trials and therefore needs verification, especially when considering the long ongoing trends in fungal incidence. Currently recruiting multicentre trials on primary prophylaxis of IFI will have to show the preventive effectiveness of antifungals with mould activity and the incidence of zygomycosis under prospectively controlled conditions.

Anidulafungin is the most recent development in the echinocandin class antifungals. Like other echinocandins, it inhibits 1,3-beta-d-glucan synthesis, thus achieving fungicidal activity against many Candida spp. including those resistant to fluconazole as well as fungistatic activity against some clinically important filamentous fungi, especially Aspergillus spp. The drug is well tolerated, even in patients with renal or hepatic impairment. It has a low drug-drug interaction profile as it does not significantly interfere with the cytochrome P450 pathway. Anidulafungin has been approved for treatment of candidaemia, intra-abdominal abscesses, peritonitis and oesophageal candidiasis. Trials have shown non-inferiority of anidulafungin to fluconazole in the treatment of invasive and non-invasive candidiasis. After promising results from animal models, the role of anidulafungin in the treatment of invasive aspergillosis and other filamentous fungi is yet to be cleared. Currently, anidulafungin offers another alternative in the treatment of Candida infections, especially in patients where avoidance of drug-drug interactions is needed. Future investigations may elucidate how anidulafungin performs clinically in comparison with the other echinocandins.

Micafungin is a new drug in the echinocandin class and is currently being investigated in Phase III clinical trials. Like other echinocandins, it inhibits 1,3-beta-D-glucan synthesis, thus achieving fungicidal activity against virtually all Candida spp., including those resistant to fluconazole, and fungistatic activity against Aspergillus spp. Micafungin sodium is available for intravenous administration only. It has a favorable safety and drug-drug interaction profile. Micafungin has been approved by the US FDA for treatment of esophageal candidiasis and for antifungal prophylaxis during the pre-engraftment phase in patients undergoing hematopoietic stem cell transplantation. Considering the competitive pricing as well as the good tolerability and efficacy, at present micafungin seems to be another choice for both of these indications. Current research has proven micafungin sodium to add a rational and effective option to the antifungal armamentarium, especially in esophageal candidiasis refractory to fluconazole treatment, in those intolerant to triazoles or in patients needing concomitant therapy interacting with triazoles. In addition to the current indications, recent uncontrolled clinical trials have demonstrated a marked success in the treatment of candidemia and invasive candidiasis. Results from in vitro studies, animal models, small clinical trials, as well as the obvious comparison with the more established caspofungin, hint at possible future indications such as invasive aspergillosis and empirical antifungal therapy. However, preclinical data on micafungin is inconsistent and published well-designed clinical studies are scarce. More controlled and sufficiently scaled trials are imperative in order to establish micafungin as a reliable and safe option in clinical practice.

We report on the treatment course of a 27-year-old male patient with acute myeloid leukaemia M1 and chronic disseminated candidiasis. After induction chemotherapy, the patient developed oesophageal candidiasis while participating in a voriconazole vs. placebo prophylaxis trial. He was then switched to oral fluconazole 400 mg q.i.d. After 6 days of futile fluconazole therapy he was switched to caspofungin 50 mg q.i.d. Caspofungin dose was later increased to 100 mg q.i.d after disseminated candidiasis with involvement of lung, spleen and liver was diagnosed. Following 63 days of caspofungin without resolution of symptoms, i.e. being persistently febrile, and emergence of soft tissue Candida abscesses, he was included into a trial allowing compassionate use of posaconazole as salvage therapy for refractory invasive fungal infections. Symptoms rapidly resolved under posaconazole 200 mg q.i.d. treatment and the patient was able to undergo allogeneic haematopoietic stem cell transplantation on secondary prophylaxis with posaconazole.

Abstract: Whilst micafungin serum concentrations are well studied, little is known about its concentrations within cellular compartments of the peripheral blood. Hence, in this study blood samples were collected from patients receiving micafungin (n =26). These samples were separated by double-discontinuous Ficoll-Hypaque density gradient centrifugation. Intracellular concentrations within the obtained cells, i.e. peripheral blood mononuclear cells (PBMCs), polymorphonuclear leukocytes (PMNs) and red blood cells (RBCs), were determined by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Within PBMCs and PMNs, the intracellular micafungin concentration was significantly increased compared with the concentration in plasma (P <0.001). The intracellular concentration within RBCs did not significantly differ from the plasma concentration. Micafungin reaches high concentrations in human PBMCs and PMNs and is present in RBCs. In vitro data showed that intracellular uptake of micafungin by PBMCs depends on the albumin concentration of the surrounding medium, but only at non-physiological protein concentrations. [Copyright &y& Elsevier]