Andrew J Ullmann

Statens Serum Institut, København, Capital Region, Denmark

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Publications (129)673.99 Total impact

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    ABSTRACT: This was a phase 1B, dose-ranging, multicenter, pharmacokinetics and safety study of cyclodextrin-based posaconazole intravenous (IV) solution administered through central line to subjects at high risk for invasive fungal disease (part 1 of a 2-part study [phase 1B/3; NCT01075984]). Initially, safety and tolerability of single-dose posaconazole IV 200 mg (n = 10) were compared with those of placebo (n = 11). Subsequently, 2 doses were evaluated: posaconazole IV 200 mg once daily (qd) (n = 21) and 300 mg qd (n = 24). Subjects received twice-daily (bid) posaconazole IV on day 1, followed by 13 days of posaconazole IV qd, then 14 days of posaconazole oral suspension 400 mg bid. The steady state (day 14) exposure target (average concentration [AUC/24h; Cavg] ≥500 to ≤2500 ng/mL in ≥90% of subjects) was achieved by 94% of subjects for 200 mg posaconazole qd and by 95% of subjects for 300 mg posaconazole qd. The desired exposure target (mean steady state Cavg ∼1200 ng/mL) was 1180 ng/mL in the 200-mg dosing cohort and was exceeded in the 300-mg dosing cohort (1430 ng/mL). Posaconazole IV was well tolerated. Posaconazole IV 300 mg qd was selected for the phase 3 study segment.
    Antimicrobial Agents and Chemotherapy 04/2014; · 4.57 Impact Factor
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    ABSTRACT: This guideline is the second in the line of three for fungal diseases by ESCMID and other societies. The guideline tried to follow the AGREE criteria for the development of clinical guidelines. This guideline serves as a European and potentially world-wide recommendation for the diagnosis and management of rare and emerging fungi. They include mucormycosis, hyalohyphomycosis (Fusarium, Paecilomyces, Scedosporium, etc.), phaeohyphomycosis (Alternaria, Bipolaris, Cladosporium, Rhinocladiella, etc.), and emerging yeasts (Saccharomyces, Trichosporon, Rhodotorula, etc.).
    Clinical Microbiology and Infection 04/2014; 20 Suppl s3:1-4. · 4.58 Impact Factor
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    ABSTRACT: Mycoses summarized in the hyalohyphomycosis group are heterogeneous, defined by the presence of hyaline (non-dematiaceous) hyphae. The number of organisms implicated in hyalohyphomycosis is increasing and the most clinically important species belong to the genera Fusarium, Scedosporium, Acremonium, Scopulariopsis, Purpureocillium and Paecilomyces. Severely immunocompromised patients are particularly vulnerable to infection, and clinical manifestations range from colonization to chronic localized lesions to acute invasive and/or disseminated diseases. Diagnosis usually requires isolation and identification of the infecting pathogen. A poor prognosis is associated with fusariosis and early therapy of localized disease is important to prevent progression to a more aggressive or disseminated infection. Therapy should include voriconazole and surgical debridement where possible or posaconazole as salvage treatment. Voriconazole represents the first line treatment of infections due to members of the genus Scedosporium. For Acremonium spp., Scopulariopsis spp., Purpureocillium spp. and Paecilomyces spp. the optimal antifungal treatment has not been established. Management usually consists of surgery and antifungal treatment, depending on the clinical presentation. This article is protected by copyright. All rights reserved.
    Clinical Microbiology and Infection 02/2014; · 4.58 Impact Factor
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    ABSTRACT: The etiologic agents of many invasive fungal infections are saprobes and opportunistic pathogens. Some of these fungi are darkly pigmented due to melanin production and traditionally have been named 'dematiaceous'. The melanised fungi cause a wide array of clinical syndromes ranging from superficial to deep-seated infections. Diagnosis relies on histopathological examination of clinical specimens and of examination of cultures. Sequencing is recommended for accurate species identification, especially for unusual or newly described pathogens. In cases of mycetoma and chromoblastomycosis, pathognomonic histological findings are very useful and the Fontana-Masson stain, specific for melanin, usually confirms the diagnosis. There are no standardized therapies but voriconazole, posaconazole and itraconazole demonstrate the most consistent in vitro activity against this group of fungi. Oral itraconazole has been considered the drug of choice, given the extensive clinical experience with this drug. However, voriconazole may presumably be superior for central nervous system infections due to its ability to achieve good cerebrospinal fluid levels. Posaconazole is a well-tolerated alternative drug, backed by less clinical experience but with excellent salvage treatment results after failure of other antifungals. Amphotericin B has been useful as alternative therapy in some cases. Combination antifungal therapy is recommended for cerebral abscesses when surgery is not possible and for disseminated infections in immunocompromised patients. This article is protected by copyright. All rights reserved.
    Clinical Microbiology and Infection 01/2014; · 4.58 Impact Factor
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    ABSTRACT: This ESCMID and ECMM Joint Clinical Guidelines focus on the diagnosis and management of mucormycosis. Only a few of the numerous recommendations can be summarised here. To diagnose mucormycosis, direct microscopy preferably using optical brighteners, histopathology and culture are strongly recommended. Pathogen identification to species level by molecular methods and susceptibility testing are strongly recommended to establish epidemiological knowledge. The recommendation for guiding treatment based on minimal inhibitory concentrations is supported only marginally. Imaging is strongly recommended to determine the extent of disease. To differentiate mucormycosis from aspergillosis in haematological malignancy and stem cell transplantation recipients, identification of the reversed halo sign on computed tomography is advised with moderate strength. For adults and children we strongly recommend surgical debridement in addition to immediate first-line antifungal treatment with liposomal or lipid-complex amphotericin B with a minimum dose of 5 mg/kg/d. Amphotericin B deoxycholate is better avoided due to severe side effects. For salvage treatment we strongly recommend posaconazole 4x200 mg/d. Reversal of predisposing conditions is strongly recommended, i.e. using granulocyte colony stimulating factor in haematologic patients with ongoing neutropaenia, controlling hyperglycaemia and ketoacidosis in diabetic patients, and limiting glucocorticosteroids to the minimum dose required. We recommend against using deferasirox in haematological patients outside of clinical trials, and marginally support a recommendation for deferasirox in diabetic patients. Hyperbaric oxygen is supported with marginal strength only. Finally, we strongly recommend continuing treatment until complete response demonstrated on imaging and permanent reversal of predisposing factors. This article is protected by copyright. All rights reserved.
    Clinical Microbiology and Infection 01/2014; · 4.58 Impact Factor
  • S Leroux, A J Ullmann
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    ABSTRACT: Invasive fungal infections (IFI) are life-threatening conditions that require rapid diagnostic and optimal management to mitigate their high morbidity and mortality rate. They are also associated with a high economic burden owing to the prolonged hospitalisation, need of intensive supportive care, and consumption of costly new antifungal therapy. To address these issues several international organisations proposed guidelines on the management of IFI. The consistency and reliability of these guidelines have rarely been assessed. This paper is a review from the differences between the recommendations of the Infectious Diseases Society of America (IDSA), the European Conference on Infection in Leukaemia (ECIL) and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and will focus on targeted treatment and diagnostic procedures. This article is protected by copyright. All rights reserved.
    Clinical Microbiology and Infection 10/2013; · 4.58 Impact Factor
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    ABSTRACT: The mortality associated with invasive fungal infections remains high with that involving rare yeast pathogens other than Candida being no exception. This is in part due to the severe underlying conditions typically predisposing patients to these health-care related infections (most often severe neutropaenia in patients with haematological malignancies), and in part due to the often challenging intrinsic susceptibility pattern of the pathogens that potentially leads to delayed appropriate antifungal treatment. A panel of experts of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Fungal Infection Study Group (EFISG) and the European Confederation of Medical Mycology (ECMM) undertook a data review and compiled guidelines for the diagnostic tests and procedures for detection and management of rare invasive yeast infections. The rare yeast pathogens were defined and limited to the following genus/species: Cryptococcus adeliensis, Cryptococcus albidus, Cryptococcus curvatus, Cryptococcus flavescens, Cryptococcus laurentii and Cryptococcus uniguttulatus (often published under the name Filobasidium uniguttulatum), Malassezia furfur, Malassezia globosa, Malassezia pachydermatis and Malassezia restricta, Pseudozyma spp., Rhodotorula glutinis, Rhodotorula minuta and Rhodotorula mucilaginosa, Sporobolomyces spp., Trichosporon asahii, Trichosporon asteroides, Trichosporon dermatis, Trichosporon inkin, Trichosporon jirovecii, Trichosporon loubieri, Trichosporon mucoides and Trichosporon mycotoxinivorans and ascomycetous ones: Geotrichum candidum, Kodamaea ohmeri, Saccharomyces cerevisiae (incl. S. boulardii) and Saprochaete capitatae (Magnusiomyces (Blastoschizomyces) capitatus formerly named Trichosporon capitatum or Geotrichum (Dipodascus) capitatum) and Saprochaete clavata. Recommendations about the microbiological investigation and detection of invasive infection were made and current knowledge on most appropriate antifungal and supportive treatment reviewed. In addition, remarks about antifungal susceptibility testing were made. This article is protected by copyright. All rights reserved.
    Clinical Microbiology and Infection 09/2013; · 4.58 Impact Factor
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    ABSTRACT: The incidence of invasive candidiasis caused by non-albicans Candida (NAC) spp. is increasing. The aim of this analysis was to evaluate the efficacy of micafungin, caspofungin and liposomal amphotericin B in patients with invasive candidiasis and candidaemia caused by different Candida spp. This post hoc analysis used data obtained from two randomised phase III trials was conducted to evaluate the efficacy and safety of micafungin vs. caspofungin and micafungin vs. liposomal amphotericin B. Treatment success, clinical response, mycological response and mortality were evaluated in patients infected with C. albicans and NAC spp. Treatment success rates in patients with either C. albicans or NAC infections were similar. Outcomes were similar for micafungin, caspofungin and liposomal amphotericin B. Candida albicans was the most prevalent pathogen recovered (41.0%), followed by C. tropicalis (17.9%), C. parapsilosis (14.4%), C. glabrata (10.4%), multiple Candida spp. (7.3%) and C. krusei (3.2%). Age, primary diagnosis (i.e. candidaemia or invasive candidiasis), previous corticosteroid therapy and Acute Physiology and Chronic Health Evaluation II score were identified as potential predictors of treatment success and mortality. Micafungin, caspofungin and liposomal amphotericin B exhibit favourable treatment response rates that are comparable for patients infected with different Candida spp.
    Mycoses 06/2013; · 1.28 Impact Factor
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    ABSTRACT: not appropriate for a letter.
    Haematologica 05/2013; · 5.94 Impact Factor
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    ABSTRACT: In recent years, triazole resistance in human Aspergillus diseases appears to have been increasing in several European countries. However, current data on the prevalence of resistance are based on a small number of studies which are only available from a few European countries. If present, triazole resistance can severely limit treatment options since alternatives, which are only available in intravenous form, have been shown to be associated with more side effects and poorer outcomes. Triazole resistance in Aspergillus spp. can evolve during therapy. Several point mutations, particularly in the cyp51A gene, have been associated with the development of resistance. Increasingly however, resistant isolates are also being detected in azole-naive patients. These isolates tend to have a particular genetic alteration consisting of a 34-base pair tandem repeat in the promoter coupled with a point mutation in the cyp51A target gene. This leads to an amino-acid substitution at codon 98 (TR34/L98H) causing multi-azole resistance. In patients whose Aspergillus isolates have developed resistance during azole therapy wildtype isolates, closely related genetically to the resistant isolates, have regularly been recovered from samples taken before the start of therapy or during an earlier phase. To date however, no isogenic isolate with a wild-type phenotype has been recovered from patients infected with an Aspergillus strain carrying the TR34/L98H genetic alteration. This suggests a possible environmental origin of the resistant fungus. This particular resistance mechanism has been observed most frequently in clinical isolates in the Netherlands where it has also been found in the environment. Moreover, the resistance mechanism has been demonstrated in clinical isolates in eight other European countries. Azole fungicides are widely used for crop protection and material preservation in Europe. They protect crops from disease, ensure yields and prevent fungal contamination of produce. It has been proposed that triazole resistance has evolved in the environment and could be driven by the selective pressure of azole fungicides. Although evidence supporting this hypothesis is growing, the link between the environmental use of azole fungicides and the development of triazole resistance in Aspergillus spp. is not yet proven. Triazole therapy has become the established treatment for invasive aspergillosis and is widely used in the treatment of allergic aspergillosis and chronic pulmonary aspergillosis. Antifungal therapy for invasive pulmonary aspergillosis is usually prescribed for a minimum of 6–12 weeks, but often may need to be continued for months depending on the period of immunosuppression. Treatment of allergic aspergillosis and chronic pulmonary aspergillosis may need to continue for years or even throughout a patient’s lifetime. We estimated the burden of allergic, chronic and invasive aspergillosis using population statistics and published literature. Of the 733 million inhabitants in the European region1 [1], at any one time 2 100 000 patients may be suffering from allergic aspergillosis and 240 000 from chronic aspergillosis, that would be an indication for antifungal therapy. For invasive aspergillosis, we have estimated an annual incidence of 63 250 cases, complicating multiple underlying conditions including leukaemia, transplantation, chronic obstructive pulmonary disease (COPD) and medical intensive care. The inability to treat these patients with triazoles due to multi-azole resistance would have significant impact on patient management and associated health costs. Early and thorough investigation of this emerging public health problem is warranted in order to avoid the development and spread of resistance. This report examines current evidence for the environmental origin of resistance in Aspergillus spp. and makes recommendations for further steps to assess the risks and consequences of the environmental usage of azole derivatives. Improved surveillance of clinical isolates, including antifungal susceptibility testing, is the key to a better understanding of the magnitude of this emerging problem. Furthermore, the diagnosis of Aspergillus diseases needs to be improved and molecular methods allowing detection of resistance in culture-negative specimens must be further developed and implemented in laboratory practice. Finally, further environmental and laboratory studies are needed to confirm the environmental hypothesis.
    European Centre for Disease Control Technical Report. 02/2013;
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    ABSTRACT: Clin Microbiol Infect 2012; 18 (Suppl. 7): 38–52 AbstractInvasive candidiasis (IC) is a relatively common syndrome in neonates and children and is associated with significant morbidity and mortality. These guidelines provide recommendations for the prevention and treatment of IC in neonates and children. Appropriate agents for the prevention of IC in neonates at high risk include fluconazole (A-I), nystatin (B-II) or lactoferrin ± Lactobacillus (B-II). The treatment of IC in neonates is complicated by the high likelihood of disseminated disease, including the possibility of infection within the central nervous system. Amphotericin B deoxycholate (B-II), liposomal amphotericin B (B-II), amphotericin B lipid complex (ABLC) (C-II), fluconazole (B-II), micafungin (B-II) and caspofungin (C-II) can all be potentially used. Recommendations for the prevention of IC in children are largely extrapolated from studies performed in adults with concomitant pharmacokinetic data and models in children. For allogeneic HSCT recipients, fluconazole (A-I), voriconazole (A-I), micafungin (A-I), itraconazole (B-II) and posaconazole (B-II) can all be used. Similar recommendations are made for the prevention of IC in children in other risk groups. With several exceptions, recommendations for the treatment of IC in children are extrapolated from adult studies, with concomitant pharmacokinetic studies. Amphotericin B deoxycholate (C-I), liposomal amphotericin B (A-I), ABLC (B-II), micafungin (A-I), caspofungin (A-I), anidulafungin (B-II), fluconazole (B-I) and voriconazole (B-I) can all be used.
    Clinical Microbiology and Infection 12/2012; 18(s7). · 4.58 Impact Factor
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    ABSTRACT: Clin Microbiol Infect 2012; 18 (Suppl. 7): 9–18 AbstractAs the mortality associated with invasive Candida infections remains high, it is important to make optimal use of available diagnostic tools to initiate antifungal therapy as early as possible and to select the most appropriate antifungal drug. A panel of experts of the European Fungal Infection Study Group (EFISG) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) undertook a data review and compiled guidelines for the clinical utility and accuracy of different diagnostic tests and procedures for detection of Candida infections. Recommendations about the microbiological investigation and detection of candidaemia, invasive candidiasis, chronic disseminated candidiasis, and oropharyngeal, oesophageal, and vaginal candidiasis were included. In addition, remarks about antifungal susceptibility testing and therapeutic drug monitoring were made.
    Clinical Microbiology and Infection 12/2012; 18(s7). · 4.58 Impact Factor
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    ABSTRACT: Clin Microbiol Infect 2012; 18 (Suppl. 7): 68–77 AbstractMucosal candidiasis is frequent in immunocompromised HIV-infected highly active antiretroviral (HAART) naive patients or those who have failed therapy. Mucosal candidiasis is a marker of progressive immune deficiency. Because of the frequently marked and prompt immune reconstitution induced by HAART, there is no recommendation for primary antifungal prophylaxis of mucosal candidiasis in the HIV setting in Europe, although it has been evidenced as effective in the pre-HAART era. Fluconazole remains the first line of therapy for both oropharyngeal candidiasis and oesophageal candidiasis and should be preferred to itraconazole oral solution (or capsules when not available) due to fewer side effects. For patients who still present with fluconazole-refractory mucosal candidiasis, oral treatment with any other azole should be preferred based on precise Candida species identification and susceptibility testing results in addition to the optimization of HAART when feasible. For vaginal candidiasis, topical therapy is preferred.
    Clinical Microbiology and Infection 12/2012; 18(s7). · 4.58 Impact Factor
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    ABSTRACT: Clin Microbiol Infect 2012; 18 (Suppl. 7): 19–37 AbstractThis part of the EFISG guidelines focuses on non-neutropenic adult patients. Only a few of the numerous recommendations can be summarized in the abstract. Prophylactic usage of fluconazole is supported in patients with recent abdominal surgery and recurrent gastrointestinal perforations or anastomotic leakages. Candida isolation from respiratory secretions alone should never prompt treatment. For the targeted initial treatment of candidaemia, echinocandins are strongly recommended while liposomal amphotericin B and voriconazole are supported with moderate, and fluconazole with marginal strength. Treatment duration for candidaemia should be a minimum of 14 days after the end of candidaemia, which can be determined by one blood culture per day until negativity. Switching to oral treatment after 10 days of intravenous therapy has been safe in stable patients with susceptible Candida species. In candidaemia, removal of indwelling catheters is strongly recommended. If catheters cannot be removed, lipid-based amphotericin B or echinocandins should be preferred over azoles. Transoesophageal echocardiography and fundoscopy should be performed to detect organ involvement. Native valve endocarditis requires surgery within a week, while in prosthetic valve endocarditis, earlier surgery may be beneficial. The antifungal regimen of choice is liposomal amphotericin B +/− flucytosine. In ocular candidiasis, liposomal amphotericin B +/− flucytosine is recommended when the susceptibility of the isolate is unknown, and in susceptible isolates, fluconazole and voriconazole are alternatives. Amphotericin B deoxycholate is not recommended for any indication due to severe side effects.
    Clinical Microbiology and Infection 12/2012; 18(s7). · 4.58 Impact Factor
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    ABSTRACT: Clin Microbiol Infect 2012; 18 (Suppl. 7): 1–8 AbstractThe process to develop a guideline in a European setting remains a challenge. The ESCMID Fungal Infection Study Group (EFISG) successfully achieved this endeavour. After two face-to-face meetings, numerous telephone conferences, and email correspondence, an ESCMID task force (basically composed of members of the Society’s Fungal Infection Study Group, EFISG) finalized the ESCMID diagnostic and management/therapeutic guideline for Candida diseases. By appreciating various patient populations at risk for Candida diseases, four subgroups were predefined, mainly ICU patients, paediatric, HIV/AIDS and patients with malignancies including haematopoietic stem cell transplantation. Besides treatment recommendations, the ESCMID guidelines provide guidance for diagnostic procedures. For the guidelines, questions were formulated to phrase the intention of a given recommendation, for example, outcome. The recommendation was the clinical intervention, which was graded by a score of A–D for the ‘Strength of a recommendation’. The ‘level of evidence’ received a score of I–III. The author panel was approved by ESCMID, European Organisation for Research and Treatment of Cancer, European Group for Blood and Marrow Transplantation, European Society of Intensive Care Medicine and the European Confederation of Medical Mycology. The guidelines followed the framework of GRADE and Appraisal of Guidelines, Research, and Evaluation. The drafted guideline was presented at ECCMID 2011 and points of discussion occurring during that meeting were incorporated into the manuscripts. These ESCMID guidelines for the diagnosis and management of Candida diseases provide guidance for clinicians in their daily decision-making process.
    Clinical Microbiology and Infection 12/2012; 18(s7). · 4.58 Impact Factor
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    ABSTRACT: Clin Microbiol Infect 2012; 18 (Suppl. 7): 53–67 AbstractFungal diseases still play a major role in morbidity and mortality in patients with haematological malignancies, including those undergoing haematopoietic stem cell transplantation. Although Aspergillus and other filamentous fungal diseases remain a major concern, Candida infections are still a major cause of mortality. This part of the ESCMID guidelines focuses on this patient population and reviews pertaining to prophylaxis, empirical/pre-emptive and targeted therapy of Candida diseases. Anti-Candida prophylaxis is only recommended for patients receiving allogeneic stem cell transplantation. The authors recognize that the recommendations would have most likely been different if the purpose would have been prevention of all fungal infections (e.g. aspergillosis). In targeted treatment of candidaemia, recommendations for treatment are available for all echinocandins, that is anidulafungin (AI), caspofungin (AI) and micafungin (AI), although a warning for resistance is expressed. Liposomal amphotericin B received a BI recommendation due to higher number of reported adverse events in the trials. Amphotericin B deoxycholate should not be used (DII); and fluconazole was rated CI because of a change in epidemiology in some areas in Europe. Removal of central venous catheters is recommended during candidaemia but if catheter retention is a clinical necessity, treatment with an echinocandin is an option (CIIt). In chronic disseminated candidiasis therapy, recommendations are liposomal amphotericin B for 8 weeks (AIII), fluconazole for >3 months or other azoles (BIII). Granulocyte transfusions are only an option in desperate cases of patients with Candida disease and neutropenia (CIII).
    Clinical Microbiology and Infection 12/2012; 18(s7). · 4.58 Impact Factor
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    ABSTRACT: 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.
    Annals of Hematology 05/2012; 91(8):1161-74. · 2.87 Impact Factor
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    ABSTRACT: Invasive fungal disease (IFD) causes increasing morbidity and mortality in haematological cancer patients. Reliable cost data for treating IFD in German hospitals is not available. Objective of the study was to determine the institutional cost of treating the IFD. Data were obtained by retrospective chart review in German hospitals. Patients had either newly diagnosed or relapsed acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS). Direct medical cost was calculated from hospital provider's perspective. A total of 108 patients were enrolled at 5 tertiary care hospitals, 36 IFD patients and 72 controls. The vast majority of IFD patients (74%) were diagnosed with invasive aspergillosis. On average, the hospital stay for IFD patients was 12 days longer than in control patients. All patients in the IFD group and 89% of patients in the control group received antifungal drugs. Mean direct costs per patient were €51 517 in the IFD group and €30 454 in the control group. Incremental costs of €21 063 were dominated by cost for antifungal drugs (36%), hospital stay (32%) and blood products (23%). From the perspective of hospitals in Germany the economic burden of IFD in patients with AML or MDS is substantial. Therefore, prevention of IFD is necessary with respect to both clinical and economic reasons.
    Mycoses 04/2012; 55(6):514-520. · 1.28 Impact Factor
  • Andrew J. Ullmann, Wibke Klaas
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    ABSTRACT: Managing fungal diseases remains a major challenge for clinicians despite the improved armamentarium of antifungal agents. This review identified 19 publications reporting safety data on micafungin. Two of these publications were spin off publications, the remaining 17 (15 prospective, two retrospective) were included in the main assessment. Major adverse events reported which occurred in more than 2% in the study populations were infusion-related, gastro-intestinal and hepatic (LFT parameters elevations). Micafungin demonstrated significantly less renal events compared with liposomal amphotericin B and less hepatic events compared with voriconazole. Compared with fluconazole no significant treatment-related adverse events were found except one trial reporting significantly less somnolence but more chills. Micafungin has a similar favourable safety profile in comparison with other echinocandins or fluconazole.
    Mycoses 04/2012; 55(s1). · 1.28 Impact Factor
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    ABSTRACT: Our objective was to evaluate the maximum tolerated dose of caspofungin for invasive aspergillosis (IA). The safety and pharmacokinetics of escalating dosages of caspofungin were investigated in IA. Eight patients each received caspofungin 70, 100, 150, or 200 mg once a day (QD). Dose-limiting toxicity (DLT) was defined as the same non-hematological treatment-related adverse event of grade ≥ 4 in 2 of 8 patients or ≥ 3 in 4 of 8 patients in a cohort. A total of 46 patients (median age, 61 years; 21 female; 89% with hematological malignancies) received caspofungin (9, 8, 9, and 20 patients in the 70-, 100-, 150-, and 200-mg cohorts) for a median of 24.5 days. Plasma pharmacokinetics were linear across the investigated dosages and followed a two-compartment model, with weight as the covariate on clearance and sex as the covariate on central volume of distribution. Simulated peak plasma concentrations at steady state ranged from 14.2 to 40.6 mg/liter (28%), trough concentrations from 4.1 to 11.8 mg/liter (58%), and area under the concentration-time curve from 175 to 500 mg/liter/h (32%) (geometric mean, geometric coefficient of variation). Treatment was well tolerated without dose-limiting toxicity. The rate of complete or partial responses was 54.3%, and the overall mortality at 12-week follow-up was 28.3%. In first-line treatment of invasive aspergillosis, daily doses of up to 200 mg caspofungin were well tolerated and the maximum tolerated dose was not reached. Pharmacokinetics was linear. Response rates were similar to those previously reported for voriconazole and liposomal amphotericin.
    Antimicrobial Agents and Chemotherapy 09/2011; 55(12):5798-803. · 4.57 Impact Factor

Publication Stats

4k Citations
673.99 Total Impact Points

Institutions

  • 2013
    • Statens Serum Institut
      København, Capital Region, Denmark
    • University of Wuerzburg
      Würzburg, Bavaria, Germany
  • 2004–2013
    • University of Cologne
      • Department of Internal Medicine
      Köln, North Rhine-Westphalia, Germany
    • Evangelic Hospital Bielefeld
      Bielefeld, North Rhine-Westphalia, Germany
  • 2002–2012
    • Johannes Gutenberg-Universität Mainz
      • III. Department of Medicine
      Mayence, Rheinland-Pfalz, Germany
  • 2011
    • Universitätsklinikum Münster
      Muenster, North Rhine-Westphalia, Germany
  • 2010–2011
    • Universitätsmedizin der Johannes Gutenberg-Universität Mainz
      Mayence, Rheinland-Pfalz, Germany
  • 2009
    • Thomas Jefferson University
      • Division of Infectious Diseases
      Philadelphia, PA, United States
  • 2008
    • MSD Animal Health, Germany
      Schleisheim, Bavaria, Germany
  • 2006
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States
    • Technische Universität München
      • Medizinische Klinik und Poliklinik III - Hämatologie/Onkologie
      München, Bavaria, Germany
  • 2002–2003
    • Goethe-Universität Frankfurt am Main
      • Zentrum der Inneren Medizin
      Frankfurt am Main, Hesse, Germany
  • 2001
    • St Anna's Kinderspital
      Wien, Vienna, Austria
  • 2000
    • Hospital de la Santa Creu i Sant Pau
      • Hematology Clinic Services
      Barcelona, Catalonia, Spain