EMPIRICAL PRESCRIBING GUIDELINES FOR SYSTEMIC FUNGAL INFECTIONS IN ADULTS - HH (1)/CL(G)/651/13

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1 Hampshire Hospitals NHS Foundation Trust Empirical Antifungal Prescribing Guidelines [INSERT UNIQUE POLICY IDENTIFIER] Due for latest review on January CHECK THE INTRANET FOR LATEST VERSION EMPIRICAL PRESCRIBING GUIDELINES FOR SYSTEMIC FUNGAL INFECTIONS IN ADULTS - HH (1)/CL(G)/651/13 Previous document(s) being replaced: Not applicable Location Document Number Document Name Document Summary These guidelines provide empirical antifungal drug choices for systemic Candidiasis, Neutropenic fungal infections and Cryptococcal meningo-encephalitis. Ownership Author Taryn Keyser Job Title Antimicrobial Pharmacist Consultation Stakeholders Consulted Microbiologists (09/10/12 09/11/12) All Trust Consultants (15/01/13-13/02/13) Document Type Level Level 1 Related Documents Document Details N/A Final Document Approval Committee Antimicrobial Management Team Date Approved 19 February 2013 Final Document Committee Drugs & Therapeutics Committee Ratification Date Ratified 27 February 2013 Authorisation Authoriser Job Title Signature Date Authorised Dissemination Target Audience All Trust Clinical Staff Dissemination Lead Taryn Keyser Review Expiry date March 2016 Review date January 2016 Empirical Antifungal Prescribing Guidelines Version 1. Ratified by the Drugs and Therapeutics Committee19/02/2013

2 Empirical Antifungal Prescribing Guidelines for Adults 2012 EMPIRICAL PRESCRIBING GUIDELINES FOR SYSTEMIC FUNGAL INFECTIONS IN ADULTS Produced by the Antimicrobial Management Team (AMT) Ratified by the Drugs &Therapeutics Committee 27 th Feb 2013 Review date: Jan 2016 Empirical Antifungal Prescribing Guidelines Version 1. Ratified by the Drugs and Therapeutics Committee19/02/2013

3 Consultant Microbiologists BNHH ext 3312, RHCH bleep 178 Dr Kordo Saeed Trust antibiotic lead Dr Matthew Dryden Director of Infection Prevention & Control Dr Jorge Cepeda Dr Fatima El-Bakri Dr Nicki Hutchinison Dr Bobbie Parnaby Antimicrobial Pharmacists Mrs Taryn Keyser (BNHH site) bleep 2435 Mrs Natalie Parker (RHCH site) bleep 396 PRINCIPLES OF PRUDENT ANTIFUNGAL PRESCRIBING This guideline does not cover superficial candidiasis e.g. oral/genital thrush Doses given in these guidelines are for non-pregnant, non-obese with normal kidney and liver function. For more information on these cases and advice about dosing in receiving anti-retroviral agents, consult a pharmacist. Invasive fungal infections are mostly seen in non-neutropenic intensive care and in haematology/oncology with neutropenia or immunosuppression As a general rule, invasive Candidiasis should be treated for 14days after the last negative culture and resolution of symptoms. Therefore blood cultures should be repeated on day 3 of antifungal therapy or as directed by a Microbiologist. A Microbiologist should be consulted for localised candidiasis including infective endocarditis, meningitis, septic arthritis, osteomyelitis, prosthetic device infections, retinitis/endopthalmitis INDEX SECTION PAGE NUMBER Candidiasis (non-neutropenic) 4 Aspergillosis 5 Neutropenic 6 Crytococcal Meningo-encephalitis 7 Empiric Renal Dosing Guide for Common Antifungal Agents 9 Guidelines for Dosing in Obese Patients 9 Useful calculations 10 References 11 Empirical Antifungal Prescribing Guidelines Version 1. Ratified by the Drugs and Therapeutics Committee19/02/2013 Page 3 of 11

4 CANDIDIASIS (NON-NEUTROPENIC) Treatment of candidiasis should take into account history of azole exposure, severity of illness, comorbidities, and likely source of infection. Patients with disseminated Candidiasis should have investigations to rule out Infective Endocarditis and a fundoscopy to rule out endopthalmitis. A Microbiologist should be consulted for localised Candidiasis including infective endocarditis, meningitis, septic arthritis, osteomyelitis, prosthetic device infections, retinitis/endopthalmitis. Central line removal/replacement is recommended if possible as it may act as a reservoir removal has been shown to reduce duration of candidemia and mortality. Condition Useful information First line Second line Duration Blood culture positive for: Yeasts Candida albicans Candida parapsilosis Candida tropicalis No previous azole exposure If previous azole exposure OR haemodynamically unstable OR significant renal impairment. Discuss with a Microbiologist Fluconazole Ω * IV 800mg STAT then 400mg Anidulafungin Ω IV 200mg STAT then 100mg Unless positive cultures for Candida parapsilosis in which case use Amphotericin Anidulafungin Ω IV 200mg STAT then 100mg Liposomal Amphotericin Ω (Ambisome ) IV infusion: initial test dose 1mg over 10minutes, then 3mg/Kg At least 14days after first negative blood culture Blood culture positive for: Candida glabrata Candida krusei May be resistant to azoles, review with sensitivity results Consult Microbiologist if transplant patient/ immunosuppressed Anidulafungin Ω IV 200mg STAT then 100mg Consult Microbiologist if transplant patient/ immunosuppressed Voriconazole Ω R IV 6mg/kg for 2 doses then 4mg/kg Review after 3 days Treat for at least 14days after first negative blood culture Urinary candidiasis Treatment is not recommended unless patient is high-risk for dissemination discuss with Microbiologist. Patients with an indwelling catheter should have this changed/removed At least 7days * Fluconazole may be dosed as 12mg/kg STAT then 6mg/kg for with extremes of weight. Discuss with a Microbiologist/Antimicrobial Pharmacist Amphotericin: monitor renal function and electrolytes daily. IV supplementation of electrolytes likely to be required ρ Seek pharmacist advice on drug interactions f Consider itraconazole suspension if absorption concerns Unlicensed dose supported by evidence base Empirical Antifungal Prescribing Guidelines Version 1. Ratified by the Drugs and Therapeutics Committee19/02/2013 Page 4 of 11

5 CANDIDIASIS (NON-NEUTROPENIC) Treatment of candidiasis should take into account history of azole exposure, severity of illness, comorbidities, and likely source of infection. Patients with disseminated Candidiasis should have investigations to rule out Infective Endocarditis and a fundoscopy to rule out endopthalmitis. A Microbiologist should be consulted for localised Candidiasis including infective endocarditis, meningitis, septic arthritis, osteomyelitis, prosthetic device infections, retinitis/endopthalmitis. Central line removal/replacement is recommended if possible as it may act as a reservoir removal has been shown to reduce duration of candidemia and mortality. Condition Useful information First line Second line Duration Oesophageal candidiasis Immunocompetant Presence of oropharyngeal candidiasis and dysphagia or odynophagia is predictive of oesophageal candidiasis Fluconazole Ω PO/IV mg (3-6mg/kg) If oral therapy inappropriate: Fluconazole Ω * IV 400mg 14days Oesophageal candidiasis Immunocompromised If history of Fluconazole exposure or recent resistant culture: use second line HIV-positive may require long-term suppressive therapy Fluconazole Ω PO/IV 400mg Itraconazole Ω f ρ Oral Solution PO 200mg OR Anidulafungin Ω IV 100mg STAT then 50mg NB. Relapse rate appears higher with echinocandin therapy than with Fluconazole days ASPERGILLOSIS A Consultant Microbiologist should be consulted for treatment options in all cases of presumed/ confirmed Aspergillus infections Reduction of corticosteroid dosage in receiving high-dose glucocorticosteroids is paramount for improved outcome in invasive Aspergillosis, except in the case of Allergic Broncho-pulmonary Aspergillosis. * Fluconazole may be dosed as 12mg/kg STAT then 6mg/kg for with extremes of weight. Discuss with a Microbiologist/Antimicrobial Pharmacist Amphotericin: monitor renal function and electrolytes daily. IV supplementation of electrolytes likely to be required ρ Seek pharmacist advice on drug interactions f Consider itraconazole suspension if absorption concerns Unlicensed dose supported by evidence base Empirical Antifungal Prescribing Guidelines Version 1. Ratified by the Drugs and Therapeutics Committee19/02/2013 Page 5 of 11

6 NEUTROPENIC PATIENTS An important factor influencing the outcome of candidemia in neutropenic is the recovery of the neutrophils. Persistent neutropenia has been associated with a greater chance of treatment failure. Central line removal should be considered for with persistent candidemia. Condition Useful information First line Second line Duration Unstable, high risk neutropenic. Candida and Aspergillus account for a majority of fungal infections in neutropenic. If fungal infection is suspected discuss with the microbiologist Liposomal Amphotericin Ω (Ambisome ) IV infusion: initial test dose 1mg over 10minutes, then 3mg/Kg OR if oral therapy appropriate: Voriconazole Ω PO Non-Central Nervous System infections only: Caspofungin IV < 80kg: 70mg loading dose then 50mg 80kg: 70mg Review daily Suspected or confirmed neutopenic sepsis < 40Kg 200mg for 2 doses then 100mg 40Kg 400mg for 2 doses then 200mg Previous Aspergillus infection Voriconazole has good oral bioavailability (96%) but drug levels may be required if response is poor Dose adjustment may be required in liver impairment Voriconazole Ω PO <40Kg 200mg for 2 doses then 100mg 40Kg 400mg for 2 doses then 200mg Consider Voriconazole levels if no/poor response If patient unable to have oral therapy: Voriconazole Ω R IV 6mg/kg for 2 doses then 4mg/kg Prophylaxis for neutropenic High risk ALL chemotherapy AML chemotherapy Neutropenic > 5weeks Graft-vs-host disease High dose steroids > 1week Fungal colonisation > 1site Posaconazole Ω PO 200mg 8hourly (with high fat food e.g. ice-cream, or supplement to improve absorption) Licensed for AML or myelodysplasia syndrome Stop when Neutrophils > 0.5 for 7days Start before anticipated neutropenia Amphotericin: monitor renal function and electrolytes at least twice weekly Empirical Antifungal Prescribing Guidelines Version 1. Ratified by the Drugs and Therapeutics Committee19/02/2013 Page 6 of 11

7 CRYPTOCOCCAL MENINGOENCEPHALITIS The Echinocandins (caspofungin, anidulafungin) do not have activity against Crytococcus sp. Measures should be taken to improve immune status e.g. decrease immunosuppressants, introduce HAART at least 4weeks after initiation of antifungal therapy. Monitor for signs/symptoms of raised Intra-Cranial Pressure. Baseline CSF pressure should be measured at lumbar puncture if possible. Elevated CSF pressure (> 25cm) is linked to a high burden of yeast in the CSF. If baseline CSF pressure is high (> 25cm), consider CSF drainage. Medications other than antifungal drugs are not useful in the management of increased intracranial pressure in cryptococcal meningoencephalitis. Secondary sites of infection may include lungs, skin, prostate, eye and bones discuss with a Microbiologist. Condition First line Second line Duration Primary therapy (induction and consolidation) HIV and organ transplant Liposomal Amphotericin Ω (Ambisome ) IV infusion: initial test dose 1mg over 10minutes, then 3-4mg/Kg PLUS Flucytosine * Ω L PO 25mg/kg 6hourly (can be given IV via central line if NBM or severe infection) Treat for 14days FOLLOWED BY: Fluconazole Ω PO mg (6-12mg/kg) Treat for at least 8weeks Liposomal Amphotericin Ω (Ambisome ) IV infusion: initial test dose 1mg over 10minutes, then 3-4mg/Kg PLUS Fluconazole Ω PO 800mg Treat for 4-6 weeks FOLLOWED BY: Fluconazole Ω PO mg (6-12mg/kg) Treat for at least 8weeks Third line: Fluconazole Ω PO 1200mg See regimen PLUS Flucytosine * Ω L PO 25mg/kg 6hourly (can be given IV via central line if NBM or severe infection) Treat for 6 weeks FOLLOWED BY: Fluconazole Ω PO 800mg Treat for at least 8weeks Monitor renal function and FBC at least twice weekly ρ Seek pharmacist advice on drug interactions f Consider itraconazole suspension if absorption concerns L Trough serum levels required 24hours after the first dose (Target 25-50mcg/L). Do not exceed 80mcg/L. Unlicensed dose supported by evidence base Empirical Antifungal Prescribing Guidelines Version 1. Ratified by the Drugs and Therapeutics Committee19/02/2013 Page 7 of 11

8 CRYPTOCOCCAL MENINGOENCEPHALITIS The Echinocandins (caspofungin, anidulafungin) do not have activity against Crytococcus sp. Measures should be taken to improve immune status e.g. decrease immunosuppressants, introduce HAART at least 4weeks after initiation of antifungal therapy. Monitor for signs/symptoms of raised Intra-Cranial Pressure. Baseline CSF pressure should be measured at lumbar puncture if possible. Elevated CSF pressure (> 25cm) is linked to a high burden of yeast in the CSF. If baseline CSF pressure is high (> 25cm), consider CSF drainage. Medications other than antifungal drugs are not useful in the management of increased intracranial pressure in cryptococcal meningoencephalitis. Secondary sites of infection may include lungs, skin, prostate, eye and bones discuss with a Microbiologist. Condition First line Second line Duration Maintenance/ Prophylaxis HIV and organ transplant Fluconazole Ω PO 200mg Treat for 6-12months Transplant : may require higher Fluconazole doses (400mg ) Itraconazole Ω f ρ PO 200mg Discuss with Microbiologist Primary therapy (induction and consolidation) Non-HIV and non-transplant Discuss all cases with a Microbiologist Liposomal Amphotericin Ω (Ambisome ) IV infusion: initial test dose 1mg over 10minutes, then 3-4mg/Kg PLUS Flucytosine * Ω L PO 25mg/kg 6hourly (can be given IV via central line if NBM or severe infection) Treat for at least 4weeks FOLLOWED BY: Fluconazole Ω PO 400mg (6mg/kg) Treat for 8weeks Maintenance/ Prophylaxis Non-HIV and non-transplant Fluconazole Ω PO 200mg Treat for a minimum of 6-12months See regimen Monitor renal function and FBC at least twice weekly ρ Seek pharmacist advice on drug interactions f Consider itraconazole suspension if absorption concerns L Trough serum levels required 24hours after the first dose (Target 25-50mcg/L). Do not exceed 80mcg/L. Unlicensed dose supported by evidence base Empirical Antifungal Prescribing Guidelines Version 1. Ratified by the Drugs and Therapeutics Committee19/02/2013 Page 8 of 11

9 EMPIRIC RENAL DOSING GUIDE FOR COMMON ANTIFUNGALS MEDICATION CrCl 20-50ml/min CrCl 10-20ml/min CrCl <10ml/min AMPHOTERICIN (LIPOSOMAL) No change No change No change ANIDULAFUNGIN No change No change No change CASPOFUNGIN No change No change No change FLUCONAZOLE Normal loading dose then 50% of normal dose Normal loading dose then 50% of normal dose Normal loading dose then 50% of normal dose FLUCYTOSINE 20-40ml/min: 50mg/kg 50mg/kg 50mg/kg STAT then according to levels ITRACONAZOLE No change No change No change VORICONAZOLE PO: No change IV: AVOID PO: No change IV: AVOID PO: No change IV: AVOID GUIDELINES FOR DOSING IN OBESE PATIENTS Some antifungals require dose adjustment when BMI > 30Kg/m2 (or weight > 120% Ideal Body Weight). The list below is not comprehensive but contains some commonly used antifungals dosed by weight: DOSING BASED ON IDEAL BODY WEIGHT Ambisome Flucytosine IV Voriconazole (LBW: see equation below) DOSING ON ACTUAL BODY WEIGHT Fluconazole Voriconazole IV dosing weight For males: LBW 2005 (kg) = For females: LBW 2005 (kg) = 9270 WT (kg) (216 BMI kg.m 2 ) 9270 WT (kg) (244 BMI kg.m 2 ) Monitor renal function and FBC at least twice weekly ρ Seek pharmacist advice on drug interactions f Consider itraconazole suspension if absorption concerns L Trough serum levels required 24hours after the first dose (Target 25-50mcg/L). Do not exceed 80mcg/L. Unlicensed dose supported by evidence base Empirical Antifungal Prescribing Guidelines Version 1. Ratified by the Drugs and Therapeutics Committee19/02/2013 Page 9 of 11

10 USEFUL CALCULATIONS Creatinine Clearance The Cockcroft & Gault equation should be used to calculate estimated Creatinine Clearance. NB ideal body weight should be used if the patient is clinically obese (>20% over IBW; see table below) Estimated CrCl = [140-age (years)] x weight (kg) x f Serum creatinine (µmol/l) where f = 1.23 for men and 1.04 for women Ideal Body Weight The AMT endorses the following methods of calculating Ideal Body Weight for Adults: Devine Formula (should only be used for over 5feet in height): IBW (kg) = (2.3 x inches over 5feet) + F The following table utilises the Devine formula: Obese if weight greater than where F = 50 for men and 45.5 for women WOMEN HEIGHT MEN IBW (kg) Feet & inches cm IBW (kg) Obese if weight greater than Empirical Antifungal Prescribing Guidelines Version 1. Ratified by the Drugs and Therapeutics Committee19/02/2013 Page 10 of 11

11 References 1. Amsden JR and Slain D. Antifungal dosing in obesity: a review of the literature. Curr Fungal Infect Rep (2011) 5: Cockcroft D, Gault MD. Prediction of creatinine clearance from serum creatinine. Nephron (1976) 16: Devine BJ. Gentamicin therapy. Drug Intell Clin Pharm (1974) 8: Janmahasatian S et al. Quantification of lean body weight. Clin Pharmacokinet (2005) 44: Kaplan JE et al. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR (2009) 58(4) 6. Kucer s Use of Antibiotics (online from Medicines Complete, last accessed 31 st December 2012) 7. Limper AH et al. An official American Thoracic Society statement: Treatment of fungal infections in adult pulmonary and critical care. Am J Respir Crit Care Med (2011) 183: Maertans J et al. European guidelines for antifungal management in leukaemia and hematopoietic stem cell transplant recipients: summary of the ECIL update. Bone Marrow Transplantation (2011) 46: Nelson M, Dockrell DH and Edwards S. British HIV Association and British Infection Association Guidelines for the Treatment of Opportunistic Infection in HIV-seropositive Individuals HIV Medicine (2011) 12(suppl.2): Pai MP and Lodise TP. Steady-state plasma pharmacokinetics of oral voriconazole in obese adults. Antimicrobial Agents and Chemotherapy (2011) 55(6): Pappas PG et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis (2009) 48: Perfect JR et al. Clinical Practice Guidelines for the Management of Cryptococcal Disease: 2010 Update by the Infectious Diseases Society of America. Clin Infect Dis (2010) 50: Raoult D. European expert opinion on the management of invasive candidiasis in adults. Clin Microbiol Infect (2011) 17(Suppl 5): Slavin MA et al. Antifungal prophylaxis in adult stem cell transplantation and haematological malignancy. Int Med J (2008) 38: Summary of Product Characteristics for Ancotil 2.5g/250ml Solution for Infusion online at ICAL_PARTS Last accessed on 31 st December The Renal Handbook 2009, 3 rd Edition. Radcliffe Publishing Ltd, Oxford 17. Therapeutic Guidelines in Systemic Fungal Infections, 2007, 4 th Edition. Remedica Medical Education and Publishing, London 18. Thursky KA et al. Recommendations for the treatment of established fungal infections. Int Med J 2008) 38: WHO Rapid Advice: Diagnosis, Prevention and Management of Cryptococcal Disease in HIV infected Adults, Adolescents and Children December 2011 last accessed on 31st December 2012 online at Worth LJ et al. Optimizing antifungal drug dosing and monitoring to avoid toxicity and improve outcomes in with haematological disorders. Int Med J (2008) 38: Empirical Antifungal Prescribing Guidelines Version 1. Ratified by the Drugs and Therapeutics Committee19/02/2013 Page 11 of 11