High risk neutropenic patient (anticipated duration > 10 days) Send blood twice weekly for Beta -D Glucan Galactomanan Aspergillus PCR

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1 DERBY TEACHING HOSPITALS NHS FOUNDATION TRUST Prophylaxis, diagnosis and treatment of invasive fungal infections in oncology/haematology patients with prolonged neutropenia. High risk neutropenic patient (anticipated duration > 10 days) Give posaconazole prophylaxis -see appendix two Send blood twice weekly for Beta -D Glucan Galactomanan Aspergillus PCR *see below for additional information Note; Galactomanan sensitivity may be reduced in pts on posaconazole or beta lactam antibiotics If patient becomes pyrexial - Start antibiotics as per the neutropenic sepsis guidelines - Look for source (see other investigations below) - Review the fungal screening blood test results Positive fungal screen -start ambisome and arrange HRCT chest Negative fungal screen and persistent pyrexia after 48 hours of antibiotics -switch to second line antibiotics and arrange HRCT chest If suggestive of fungal infection arrange bronchoscopy for BAL HRCT chest, if suggestive of fungal infection arrange bronchoscopy for BAL and start Ambisome If HRCT chest, is clear and negative fungal screen, continue second line antibiotics Other investigations (indicate on the request forms that the patient is neutropenic) Blood cultures central and peripheral (taken simultaneously) MSU Sputum sample Oral swabs for bacterial, fungal and viral cultures if mouth ulcers /mucositis Culture any skin lesions Chest X-ray CT sinuses if symptomatic Consider CT or US abdomen if hepato(splenic) candidiasis is suspected

2 Samples Specimen required One serum sample in a red top bottle with a minimum volume of 1ml (1.5ml is preferred) is required. BAL can also be sent for Galactomanan testing. Days of the week to be sent Twice a week, Monday and Wednesday Test interpretation Galactomanan in serum >0.5 is reported as detected. Confirm the first result with another sample. Galactomanan in BAL >0.5 is reported as detected; however most use a higher value i.e.>1 index as a cut off. Beta-D Glucan in serum >80 pg/ml is reported as detected. Results <60 pg/ml are not detected pg/ml is equivocal. Confirm the first result with another sample. Aspergillus PCR will be reported as detected or not detected. For all tests clinical correlation is advised. Prophylaxis High risk neutropenic patients (AML, high risk myelodysplasia, or where anticipated duration of neutropenia is > 10 days) should be given oral posaconazole for prophylaxis. See appendix two for full information on dosing and monitoring. Fluconazole prophylaxis (100mg daily) can be given to lower risk patients Risk factors for invasive fungal infection (IFI) Of the patients managed in Derby, those at highest risk are patients with AML, prolonged neutropenia, and history of corticosteroid use. Other risk factors are iron overload, treatment with purine analogues or monoclonal antibodies, renal failure, concurrent CMV infection and advanced age. Causative pathogens Until a few years ago, Candida spp were responsible for the majority of invasive fungal infections, but there has been a shift over time in the prevalent pathogens such that moulds are now a more common cause of IFI in severely immunocompromised patients, with Aspergillus spp being the most common. Other moulds causing IFI include Zygomycetes, Fusarium spp, and Scedosporium spp. There has also been a shift from Candida albicans to non-albican Candida spp.

3 Microbiological isolation of fungi is rarely achieved, so treatment is usually empirical, based on the clinical presentation and radiological investigations. The majority of cases will be probable and possible IFI. MICROBIOLOGY HOST FACTORS CLINICAL FACTORS Positive cytology or culture from BAL or sputum or sinus aspirate or other source Prolonged use steroids e.g. at an average min dose equivalent of prednisolone 0.3mg/kg/day for >3 weeks Neutropenia (<0.5 for >10days) Recipient of an allogeneic stem cell transplant T-cell immunosuppressant therapy, e.g Campath, ciclosporin Inherited immunodeficiency disorder, eg. Severe combined immunodeficiency CT chest findings nodules or wedge-shaped infiltrates, halo sign, air crescent sign or cavity Pleural rub or pleurisy or haemoptysis In sinus infection acute localized pain, nasal ulcer, black eschar Opthalmic signs seek ophthalmology review urgently CNS disease focal lesions or meningeal enhancement on CT/ MRI Abscesses in liver and/or spleen PROVEN (Histopathology/ cytopathology/ of fine needle aspirate or biopsy showing yeast or mould OR positive blood culture) PROBABLE 1 microbiological +1 host factor + 1 clinical factor POSSIBLE 1 host +1 clinical factor (but no microbiology evidence) Empirical Treatment Liposomal amphotericin (Ambisome ) (prescribe by brand name - see note 1 below) Dose 3mg/kg/day in 250ml dextrose 5% infused over minutes. Due to the risk of anaphylaxis and allergic reactions, a test dose should be given. Give 1mg of the first dose over 10 minutes. Then wait for 30 minutes, and provided no reaction, the rest of the 3mg/kg dose can be given over minutes. Contra-indications to Liposomal amphotericin (Ambisome ) Hypersensitivity to the active substance or any of its constituents. Cautions with Liposomal amphotericin (Ambisome ) Renal impairment - If clinically significant reduction in renal function occurs, consideration should be given to dose reduction, treatment interruption or discontinuation. Hepatic impairment Pregnancy and breastfeeding - discuss with pharmacist Drug interactions see BNF Notes 1 As a result of fatalities due to confusion between different brands and formulations of amphotericin, always ensure you are certain that you are prescribing, preparing or administering the intended brand, formulation and dose of amphotericin. If there is any doubt, DO NOT PROCEED. Seek advice from medical/nursing and/or pharmacy staff.

4 In patients with hypersensitivity to liposomal amphotericin, or where lipsomal amphotericin is unsuitable use caspofungin Dosing of caspofungin 70mg on first day, then 50mg once daily. If body weight >80kg, continue with 70mg daily. Infuse over 60 minutes in 250ml sodium chloride 0.9%. In moderate liver disease, give 70mg on day one, then reduce to 35mg daily. There is no experience with caspofungin in severe liver disease, so avoid if possible (see note 2 below). Contra-indications to caspofungin Breast feeding, hypersensitivity to the active substance or any of its constituents. Cautions with caspofungin Avoid in pregnancy unless essential toxicity in animal studies. Drug interactions see BNF 2 Anidulafungin is another echinocandin which does not require dosage adjustment in severe hepatic impairment. However, it is only licensed for invasive candidiasis Place in therapy for Voriconazole For the management of suspected invasive fungal infections in patients who are intolerant to or have a documented hypersensitivity to amphotericin and caspofungin or any of their components. OR Proven CNS invasive fungal infection caused by fungi sensitive to voriconazole, due to its superior CNS penetration. OR For the management of patients who have responded well and are fit to discharge but need to finish a treatment course Route Voriconazole intravenous Voriconazole oral (bioavailability 96%) Dose 6mg/kg every 12 hours for 2 doses then 4mg/kg every 12hours by intravenous infusion. If 40kg, 400mg every 12 hours for 2 doses. Then 200mg every 12 hours. If <40kg: 200mg every 12hours for 2doses. Then 100mg every 12 hours Contra-indications Acute porphyria, breast feeding, pregnancy unless potential benefit outweighs risk Cautions Renal Impairment In patients with moderate to severe renal dysfunction (Creatinine clearance <50 ml/min), accumulation of the intravenous vehicle occurs. Oral voriconazole should be administered to these patients, unless an assessment of the risk-benefit to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients and, if increases occur, consideration should be given to changing to oral voriconazole therapy. Hepatic impairment Reduce dose (see SPC). No information in severe cirrhosis. Monitor LFTS increased risk of hepatic reactions in haematological malignancy

5 Arrhythmias or QT interval prolongation Caution with concomitant drugs that prolong QT interval see BNF. Drug Interactions Many significant interactions. See BNF and contact member of pharmacy team for further advice Duration of treatment Duration of therapy should be based on the patient's clinical response Proven, probable or possible invasive fungal infection Discuss duration of treatment with a consultant microbiologist. Generally patients should be treated for a minimum of 14 days and treatment should continue for at least 7 days after neutropenia and clinical symptoms/ signs are resolved. Refractory cases Any radiological changes should have either resolved or shown no deterioration after the minimum 14 days of treatment. If there is inadequate response after this time, or sooner if evidence of progression discuss with a consultant microbiologist regarding increasing the ambisome dose to 5mg/kg, changing treatment, and/or adding a second agent

6 References 1. British Committee for Standards in Haematology (2008) Guidelines on the management of invasive fungal infection during therapy for haematological malignancy Johansen HK, Gøtzsche P Amphotericin B lipid soluble formulations versus amphotericin B in cancer patients with neutropenia (Cochrane review 2000, last updated 2007) 3. Oto et al (2007) Amphotericin B deoxycholate use in cases with febrile neutropenia and fungal infections: lower toxicity with suitable premedication. Mycoses 2007;50(2): Walsh T, Sable C, de Pauw, Donowitz G, Maertans J, Baden L, Bourque M, Lupinacci R, Nguyen BY, Teppler H(2004) Liposomal Amphoteracin B for empirical therapy in patients with persistent fever and neutropenia. New England Journal of Medicine, 351, Walsh T, Sable C, de Pauw B, Donowitz G, Maertens J, Baden L, Bourque M, Lupinacci R, Nguyen BY, Teppler H. (2004) Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. New England Journal of Medicine, 351, Journal of Antimicrobial Chemotherapy Pathways for managing invasive fungal disease in immunocompromised patients 2011:66(supp 1) De Pauw et al revised definitions of invasive fungal disease from the EORTC/MSG consensus group Clinical Infectious Disease 2008;46: Documentation control Development of Guidelines: Approved By; Consultant microbiologists Consultant haematologists Antimicrobial D+T subgroup Approval Date: July 2015 Review history and changes Reviewed 26/11/2014 and review date extended to 30/4/15 pending review of the testing and diagnostic strategy and impending change to prophylaxis regime. Appendix II updated in line with itraconazole updated guideline. 2/2/15 posaconazole replaced itraconazole for prophylaxis. Included as an appendix in this guideline Next review Date: July 2016 July new diagnostic algorithm to incorporate galactomanan and BD-glucan screening. Key Contact: Dr Allotey consultant haematologist Dr Milind Khare Consultant microbiologist

7 Appendix I Posaconazole Dosing and monitoring Information for prophylactic use in selected haematology patients Patient group Primary prophylaxis in patients with prolonged neutropenia due to chemotherapy for Acute Myeloid Leukaemia and High risk Myelodysplasia Primary prophylaxis post autograft (these patients are currently managed in Nottingham) Preparation: Dose for tablets Duration Side effects (For full list see BNF and SPC) Drug Interactions (See BNF and SPC for full list) Dosing in renal and hepatic impairment Commence on admission for chemotherapy and continue for 7 days after neutrophils recover to >0.5 Posaconazole 100mg TABLETS (Note: tablets are preferred as they achieve much better plasma levels than the suspension. The suspension should only be used in patients who cannot take tablets. THE DOSE IS NOT THE SAME see section on suspension below) 300mg twice daily on day one, then 300mg once daily. With the tablets, it does not matter when the dose is taken in relation to food Continue for 7 days after neutrophils recover to >0.5 To be stopped if a patient develops a breakthrough fungal infection and commences treatment for this. In such scenarios it would then be more appropriate for secondary prophylaxis during further courses of chemotherapy to be with Ambisome 1mg/kg Mon, Wed and Fri. Particular adverse effects to note are; Gastrointestinal e.g. nausea, abdominal pain, diarrhoea. Posaconazole may cause hepatotoxicity. Monitor LFTs before and during treatment. Patient should be told how to recognise signs of liver disorder Posaconazole is extensively metabolised by the CYP 34A system. There are many significant drug interactions with posaconazole. The patient s concurrent medication list should be checked carefully against Appendix 1 of the BNF and /or the SPC before prescribing posaconazole. For further advice discuss with a pharmacist. Posaconazole may prolong the QT interval and should be used with caution with other drugs known to do this. In addition, potassium, calcium and magnesium levels should be monitored before and during treatment. No dosage adjustment required, but use with caution in hepatic impairment.

8 Posaconazole suspension Monitoring of levels The suspension is not interchangeable with the tablets and should only be used in patients who cannot take tablets as it is not as well absorbed and does not reach such high plasma levels. The dose of suspension is 200mg three times a day, and it must be taken during or immediately after a meal. Absorption is much better following a high fat meal. Levels are not necessary in patients taking tablets unless; There are particular concerns about absorption e.g. vomiting and diarrhoea. The patient is on concomitant medication which may significantly affect the levels. The patient weighs >120kg Due to erratic absorption of posaconazole from the suspension formulation, levels should be checked to ensure they have reached a therapeutic level. If a level is needed, it should be taken pre-dose on day 5-7. Levels are sent to Bristol and will usually take 2-3 days to be reported. The target pre-dose level for prophylaxis is >0.7mg/l Development of Guidelines: Consultation With: Approved By; Dr Allotey Consultant haematologist Julia Lacey Antimicrobial Pharmacist Consultant haematologists Consultant microbiologists Drugs and Therapeutics Committee Version 1 approval Date: 26/1/2015 Review Date: Key Contact: 1/2/2016 Audit: After 12 months of implementation, an audit of tolerance and effectiveness will be carried out. Dr Allotey Consultant haematologist Julia Lacey Antimicrobial Pharmacist References (for posaconazole) BNF No 68 Summary of Product Characteristics accessed 14/1/15 Mycology reference laboratory service users guide PHE Bristol July 2014