galactomannan and posaconazole

At the University Hospital of Cologne, in general two patient groups at high risk for invasive aspergillosis receive posaconazole prophylaxis: Acute myelogenous leukaemia patients during remission induction chemotherapy and allogeneic haematopoietic stem cell transplant recipients. Other patients at risk undergo serum galactomannan testing three times weekly. At 72-96 h of persisting fever despite broad-spectrum antibiotics, or at onset of lower respiratory tract symptoms a thoracic computed tomography (CT) scan is performed. Without lung infiltrates on CT, IPA is ruled out. In lung infiltrates not suggestive for IPA mycological confirmation is pursued. In patients without posaconazole prophylaxis empiric caspofungin will be considered. CT findings typical for IPA prompt targeted treatment, and mycological confirmation. Bronchoalveolar lavage (BAL) is most important for cultural identification and susceptibility testing, and facilitates diagnosing other pathogens. BAL performance is virtually independent of platelet counts. If despite suggestive infiltrates BAL does not yield the diagnosis, CT-guided biopsy follows as soon as platelet counts allow. Surgery can also be beneficial in diagnosis and treatment of IPA. If the diagnosis of IPA is not established, mucormycosis is a valid concern. In patients with breakthrough IPA during posaconazole prophylaxis liposomal amphotericin B is the drug of choice. If no posaconazole prophylaxis was given, voriconazole is the treatment of choice for IPA.

Topics: Antifungal Agents; Aspergillus; Bronchoalveolar Lavage Fluid; Chemoprevention; Fever of Unknown Origin; France; Galactose; Hospitals, University; Humans; Invasive Pulmonary Aspergillosis; Mannans; Microbial Sensitivity Tests; Radiography, Thoracic; Tomography, X-Ray Computed; Triazoles

An established diagnosis of invasive aspergillus is seldom achieved premortem. Conventional laboratory diagnostic methods such as culture and microscopy, although very useful when positive, are insensitive and time-consuming, resulting in late diagnosis and treatment and contributing to high mortality rates. As a result, routine antifungal prophylaxis and early empirical treatment have been recommended. The use of sensitive and rapid non-culture-based diagnostic assays for the detection of Aspergillus antigens (using commercially available tests to detect galactomannan and 1, 3 β-D-glucan) or detection of genomic DNA sequences may allow a shift in emphasis from empirical to preemptive therapy, especially when substantiated by suggestive radiological findings. These new tools may be used to confirm a presumed diagnosis of invasive aspergillosis, or, when used to screen high-risk patients, may identify an infection at an early stage of disease. Their excellent negative predictive value should convince clinicians to withhold antifungal therapy in patients with no other signs of fungal disease. On the other hand, consecutive positive results should at least trigger a complete diagnostic workup. This article will review the diagnostic utility as well as the pitfalls of using these non-culture-based tools for diagnosing invasive aspergillosis.

Topics: Antifungal Agents; Aspergillosis; Aspergillus; beta-Glucans; Bronchoalveolar Lavage Fluid; Galactose; Humans; Mannans; Proteoglycans; Triazoles; Voriconazole

Topics: Aspergillus fumigatus; Galactose; Humans; Invasive Fungal Infections; Mannans; Mass Screening; Mucorales; Real-Time Polymerase Chain Reaction; Retrospective Studies; Triazoles

Galactomannan (GM) detection in biological samples has been shown to predict therapeutic response by azoles and polyenes. In a murine invasive pulmonary aspergillosis model, fosmanogepix or posaconazole treatment resulted in an ∼6- to 7-log reduction in conidial equivalents (CE)/g lung tissue after 96 h versus placebo. Changes in GM levels in BAL fluid and serum mirrored reductions in lung CE, with significant decreases seen after 96 h or 72 h for fosmanogepix or posaconazole, respectively (

Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Biomarkers; Galactose; Immunocompromised Host; Invasive Pulmonary Aspergillosis; Lung; Male; Mannans; Mice; Microbial Sensitivity Tests; Triazoles

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.

Topics: Antibodies, Fungal; Antifungal Agents; Aspergillosis; Aspergillus; Biopsy; Bronchoalveolar Lavage; Disease Management; Early Diagnosis; Flucytosine; Galactose; Humans; Immunocompromised Host; Immunologic Tests; Invasive Pulmonary Aspergillosis; Itraconazole; Leukemia, Myeloid, Acute; Magnetic Resonance Imaging; Mannans; Microbial Sensitivity Tests; Myelodysplastic Syndromes; Nitriles; Pyridines; Tomography, X-Ray Computed; Triazoles; Voriconazole

Antifungal posaconazole prophylaxis for AML patients receiving induction chemotherapy has been routine at our centre since 2009. This retrospective study examined the feasibility and practicability of our prophylaxis guidelines in clinical practice. Data sets of 90 patients undergoing induction-chemotherapy for AML between 2011 and 2014 were evaluated regarding adherence to local guidelines for the administration of antifungal prophylaxis with posaconazole. 75.5% of the 90 patients received posaconazole prophylaxis. All but eight patients received the recommended dosage. A total of 77.95% on prophylaxis had serum galactomannan measured twice weekly. Contradicting our guidelines, 89.70% of patients received concomitant therapy with PPI. Overall, 16.17% of patients had prophylaxis discontinued and started empirical antifungal treatment in the absence of diagnostic criteria for IFI. The breakthrough IFI rate was 36.76% (proven, probable and possible) with 7.35% of infections being classified as proven or probable. Although limited by a small sample size, our study demonstrates the feasibility of local guidelines in a real life setting and outlines areas for improvement in both guidelines and clinical practice. We also highlight the importance of ensuring awareness of guidelines and raise questions about a uniform approach to antifungal prophylaxis in AML patients.

Topics: Adult; Aged; Antifungal Agents; Female; Fluconazole; Galactose; Guideline Adherence; Guidelines as Topic; Humans; Leukemia, Myeloid, Acute; Male; Mannans; Middle Aged; Mycoses; Pre-Exposure Prophylaxis; Retrospective Studies; Triazoles

Topics: Adolescent; Adult; Aged; Antifungal Agents; Female; Fungi; Galactose; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Male; Mannans; Middle Aged; Mycoses; Prospective Studies; Triazoles

A steroid-immunosuppressed rat model of invasive pulmonary aspergillosis was use to examine the usefulness of galactomannan enzyme immunoassay (GM) and quantitative real time PCR (RT-PCR) in evaluating the association between response and exposure after a high dose of prophylactic posaconazole.. Two different strains of Aspergillus fumigatus with different in vitro posaconazole susceptibility were used.. Serum concentrations demonstrated similar posaconazole exposure for all treated animals. However, response to posaconazole relied on the in vitro susceptibility of the infecting strain. After prophylaxis, galactomannan index and fungal burden only decreased in those animals infected with the most susceptible strain.. This study demonstrated that both biomarkers may be useful tools for predicting efficacy of antifungal compounds in prophylaxis.

Topics: Animals; Antifungal Agents; Biomarkers; Galactose; Immunoenzyme Techniques; Mannans; Pulmonary Aspergillosis; Rats; Real-Time Polymerase Chain Reaction; Triazoles

There is a practical need to investigate the performance of the serum galactomannan (GM) assay in hematology patients with a potentially low pretest risk of invasive aspergillosis following effective antimold prophylaxis.. We present a 4-year study with 262 unselected consecutive high-risk episodes, prospectively managed with posaconazole primary prophylaxis and a uniform diagnostic algorithm, including biweekly serum GM quantification for early detection of invasive aspergillosis.. A total of 2972 serum GM tests were performed (median, 11 per episode [range, 3-30]); the vast majority were negative (96.7% of tests and 83.6% of episodes). The incidence of breakthrough invasive aspergillosis was 1.9% (5/262), all with true-positive GM test results. Our study identified 30 false-positive GM evaluable episodes (85.7%; 13.8% of all evaluable episodes), validating with real-life data the low positive predictive value of the assay in this setting (12%). In 26 of these 30 episodes (86.7%), the false-positive result(s) occurred in tests performed as preemptive surveillance only. Conversely, in evaluable cases with positive GM tests and a clinical suspicion of invasive fungal disease, the performance of diagnostic-driven GM tests improved, with a positive predictive value of 89.6%.. The low pretest risk of invasive aspergillosis in the context of effective antimold prophylaxis renders serum GM surveillance of asymptomatic patients unreliable, as all results would be either negative or false positive. The test remains useful to diagnose patients with a clinical suspicion of invasive fungal disease, calling for a more efficient copositioning of effective prophylaxis and GM testing in this clinical setting.

Topics: Antifungal Agents; Antigens, Fungal; Aspergillosis; Galactose; Humans; Mannans; Triazoles

The purpose of this study was to investigate the performance of non-invasive diagnostic tests such as galactomannan enzyme immunoassay and quantitative PCR in the early diagnosis of invasive aspergillosis (IA), and how these tests are impacted upon by the use of different classes of antifungal agents in an in-vivo model of IA.. A standardised rat inhalation model of IA was used to examine the effects of an azole, posaconazole, a polyene, amphotericin B and an echinocandin caspofungin. Daily blood samples were collected for subsequent analysis using a commercially available galactomannan assay and an inhouse qPCR assay.. No significant differences were observed in the CE/g of Aspergillus fumigatus in the lungs of each group. qPCR was statistically more sensitive than galactomannan for both the early detection of infected controls (p=0.045) and for overall detection (p=0.018). However, antifungal treatment significantly reduced the overall sensitivity of qPCR (p=0.020); these effects were due to posaconazole and caspofungin. In the latter stages of infection (days 4 and 5) there were no significant differences in the numbers of infections detected by galactomannan and qPCR; however, the antifungal class used caused significant qualitative differences (p=0.041). Galactomannan showed improved detection in posaconazole-treated animals.. Previous exposure to antifungal therapy must be considered when interpreting either qPCR or galactomannan-based IA diagnostics as this study has shown that individual classes of antifungal agents impact upon the dynamics of antigen and DNA release into the circulation.

Topics: Amphotericin B; Animals; Antifungal Agents; Aspergillus fumigatus; Biomarkers; Caspofungin; Disease Models, Animal; DNA, Fungal; Early Diagnosis; Echinocandins; Galactose; Immunoenzyme Techniques; Invasive Pulmonary Aspergillosis; Lipopeptides; Mannans; Microbiological Techniques; Mycological Typing Techniques; Predictive Value of Tests; Rats; Real-Time Polymerase Chain Reaction; Time Factors; Triazoles

Topics: Antifungal Agents; Antineoplastic Agents; Fever; Fungi; Galactose; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Mannans; Mycoses; Neutropenia; Polymerase Chain Reaction; Randomized Controlled Trials as Topic; Retrospective Studies; Triazoles

Cutaneous models have proven useful in studies of the pathogenesis and treatment of Gram-positive bacterial infections. Because cutaneous invasive aspergillosis (IA) occurs in the clinical setting, we sought to develop a nonlethal murine cutaneous model of IA. We induced cutaneous IA in cyclophosphamide-treated nude BALB/c mice by subcutaneous injection of Aspergillus fumigatus conidia. Skin lesion areas correlated well with tissue fungal burdens, allowing dynamic visual monitoring of cutaneous infections. The cutaneous model accurately reflected alterations in A. fumigatus pathogenicity resulting from deletions of recognized virulence genes (pabaA, sidA, and pksP). Moreover, analysis of the roles of conidial and mycelial catalases revealed that the former is required for the initiation of cutaneous aspergillosis, whereas the latter contributes to its propagation. Finally, posaconazole treatment reduced skin lesion areas relative to those of untreated and fluconazole-treated controls. This novel cutaneous model system should be applicable to comparative studies of the pathogenesis, treatment, and tissue specificity of IA.

Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Catalase; Cyclophosphamide; Dermatomycoses; Disease Models, Animal; Female; Galactose; Hyphae; Immunocompromised Host; Immunosuppressive Agents; Mannans; Mice; Mice, Inbred BALB C; Mice, Nude; Mutagenesis; Skin; Spores; Triazoles; Virulence; Virulence Factors

The antifungal efficacy, safety, and pharmacokinetics of posaconazole (SCH 56592) (POC) were investigated in treatment and prophylaxis of primary pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Antifungal therapy consisted of POC at 2, 6, and 20 mg/kg of body weight per os; itraconazole (ITC) at 2, 6, and 20 mg/kg per os; or amphotericin B (AMB) at 1 mg/kg intravenously. Rabbits treated with POC showed a significant improvement in survival and significant reductions in pulmonary infarct scores, total lung weights, numbers of pulmonary CFU per gram, numbers of computerized-tomography-monitored pulmonary lesions, and levels of galactomannan antigenemia. AMB and POC had comparable therapeutic efficacies by all parameters. By comparison, animals treated with ITC had no significant changes in outcome variables in comparison to those of untreated controls (UC). Rabbits receiving prophylactic POC at all dosages showed a significant reduction in infarct scores, total lung weights, and organism clearance from lung tissue in comparison to results for UC (P < 0.01). There was dosage-dependent microbiological clearance of A. fumigatus from lung tissue in response to POC. Serum creatinine levels were greater (P < 0.01) in AMB-treated animals than in UC and POC- or ITC-treated rabbits. There was no elevation of serum hepatic transaminase levels in POC- or ITC-treated rabbits. The pharmacokinetics of POC and ITC in plasma demonstrated dose dependency after multiple dosing. The 2-, 6-, and 20-mg/kg dosages of POC maintained plasma drug levels above the MICs for the entire 24-h dosing interval. In summary, POC at > or =6 mg/kg/day per os generated sustained concentrations in plasma of > or =1 microg/ml that were as effective in the treatment and prevention of invasive pulmonary aspergillosis as AMB at 1 mg/kg/day and more effective than cyclodextrin ITC at > or =6 mg/kg/day per os in persistently neutropenic rabbits.

Topics: Animals; Antibiotic Prophylaxis; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Disease Models, Animal; Female; Galactose; Itraconazole; Lung Diseases, Fungal; Mannans; Neutropenia; Rabbits; Treatment Outcome; Triazoles