Title of Guideline (must include the word Guideline (not protocol, policy, procedure etc) Contact Name and Job Title (author) Directorate & Speciality Clinical Guideline for the prophylaxis and treatment of fungal infections in Haematology patients Dr JL Byrne, Consultant Haematologist Clinical Haematology, CAS Date of submission 9/9/2016 Date on which guideline must be reviewed (this should be one to three years) 1/8/2017 Explicit definition of patient group to which it applies (e.g. inclusion and exclusion criteria, diagnosis) Clinical haematology patients Changes from previous guideline Inclusion of IV posaconazole formulation Version 10 Key Words Antifungal drugs, Haematology Statement of the evidence base of the guideline has the guideline been peer reviewed by colleagues? Evidence base: (1-5) 1a meta analysis of randomised controlled trials 1b at least one randomised controlled trial 2a at least one well-designed controlled study without randomisation 2b at least one other type of well-designed quasiexperimental study 3 well designed non-experimental descriptive studies (ie comparative / correlation and case studies) 4 expert committee reports or opinions and / or clinical experiences of respected authorities 5 recommended best practise based on the clinical experience of the guideline developer Consultation Process Target audience 4 Haematology Consultants. Pharmacists, Senior Haematology nurses FY1/2, CT1/2 and Haematology ST3-ST7 doctors This guideline has been registered with the trust. However, clinical guidelines are guidelines only. The interpretation and application of clinical guidelines will remain the responsibility of the individual clinician. If in doubt contact a senior colleague or expert. Caution is advised when using guidelines after the review date.
Clinical guideline - Review date Aug 2017 Clinical Guideline for the Prophylaxis and Treatment of Fungal Infections Introduction Patients with prolonged neutropenia are at risk of developing both localized fungal infections, mainly involving mucocutaneous Candida species. They are also at risk of invasive fungal infections mainly with Aspergillus and Mucor species, usually of the sinuses and respiratory systems. Prophylaxis with azole antifungal agents can certainly reduce the risk of Candida infections and some of the newer third generation azole drugs also have a broader spectrum of anti- fungal activity including Aspergillus. Patients at risk of invasive fungal infections should have CXRs done for all patients with neutropenic fever. High resolution CT scanning should be performed if there is CXR shadowing suspicious of fungal infection or if there is unremitting fever with no obvious cause and a high CRP > 200. Galactomannan and beta D glucan screening samples should also be sent for patients with unremitting fever before starting antifungal treatment Anti-fungal Prophylaxis according to Risk of Invasive Fungal Infections Haematology patients can be stratified into those with a high risk of invasive fungal infection and those with a standard or low risk of fungal infection depending on the intensity of treatment they are receiving and likely duration of neutropenia and whether or not they have had a previous episode of probable or confirmed invasive fungal infection High Risk Standard Risk Low Risk Patients receiving ALL induction chemotherapy which includes dexamethasone and who are likely to have prolonged period of neutropenia and who cannot have azoles due to vincristine drug interactions Patients who have had previously documented confirmed or highly probable invasive fungal infections and who are undergoing further intensive chemotherapy likely to result in a prolonged period of neutropenia > 10 days eg AML induction chemotherapy or allogeneic or autologous transplant procedure Patients undergoing autologous / allogeneic SCT Prescribe low dose Abelcet or AmBisome 100 mg x 3 per week IV D+1 until ANC > 0.5 Patients undergoing intensive AML/NHL chemotherapy or out patient AML chemotherapy (Note azoles must not be given to patients receiving Myelotarg or AC220) Patients receiving > 10 mg prednisolone for GVHD Oral posaconazole liquid preparation 200 mg tds OR posaconazole gastrresistant tablets 300 mg bd on day 1 as loading dose followed by 300 mg od Patients undergoing out-patient chemotherapy, eg CHOP, VAD or any regimen that includes vinca alkaloids Prescribe fluconazole 50 mg od po 2 1/8/16
Clinical guideline - Review date Aug 2017 Treatment of Invasive Fungal Infections in Neutropenic Patients It is important to try and prove that there is a fungal infection by BAL, high resolution CT scanning or galactomannan / beta D glucan blood tests prior to the initiation of anti- fungal agents. The preferred anti- fungal agent for the treatment of presumed invasive fungal infection depends on the likelihood of such an infection being present and the strength of the evidence for this. Whilst patients are receiving treatment with intra-venous anti- fungal agents their usual azole prophylaxis should be discontinued. 1. Empiric Therapy for Unremitting Fever A fungal infection may be presumed in neutropenic patients with an unremitting pyrexia which has not resolved within 48-72 hours despite broad spectrum antibiotics It is important to try and prove that there is a fungal infection by either BAL, high resolution CT scanning (galactomannan blood tests are sometimes useful) but anti- fungal agents should be initiated anyway whilst waiting for these results If the high resolution CT scan is not suggestive of a fungal pneumonia and / or if the galactomannan and beta D glucan results are negative then anti-fungal treatment can be discontinued Amphotericin lipid B complex (Abelcet) is a complex of Amphotericin B with 2 phospholipids which has efficacy against Aspergillus and Candida species. Abelcet 1mg/kg is the initial drug of choice in Haematology patients with neutropenic fever unresponsive to broad spectrum antibiotics and with normal renal function and no other risk factors for nephrotoxicity (if available) Dose of Abelcet is 1 mg/kg rounded to nearest 100 mg vial Dose is 100 mg/day if weight is up to 100 kg (i.e. 1mg/kg rounded to nearest 100 mg vial) Dose is 150 mg/day if weight is.> 100 kg (i.e. 1 mg.kg rounded to nearest 100 mg vial) Abelcet is administered as an IV infusion over at least 3 hours at a rate of 2.5 mg/kg/hour after a test dose of 1 mg over 15 minutes then observe patient for 30 minutes before giving the rest of the infusion without chlorpheniramine and hydrocortisone cover. The most common side effects are fever, nausea, chills and vomiting. If reactions occur chlorpheniramine 10 mg IV and paracetamol ig po can be given as premedication. Some patients may require pre-medication with pethidine. Renal function should be monitored daily and if the creatinine increases by 50% then consider switching to an alternative anti-fungal agent A leak of potassium and magnesium may occur and levels should be monitored closely and replacement given IV if necessary Abelcet can also cause abnormal LFT s which should also be monitored daily If reactions occur during the infusion of Abelcet (eg rigors/itching etc) give hydrocortisone and chlorpheniramine IV and consider switching to an alternative anti-fungal agent. 3 1/8/16
Clinical guideline - Review date Aug 2017 If reactions are severe or if renal impairment is developing (i.e. there is a doubling of the baseline creatinine) and the anti- fungal agent needs to be continued then consider switching to AmBisome or IV Voriconazole or Caspofungin 2. Pre-emptive Treatment of Probable Fungal Infection Low doses of Abelcet (1 mg/kg) have been shown to be effective in patients with persisting neutropenic fever but higher doses of 3-5 mg/kg are required for the treatment of confirmed invasive fungal infection. These doses are more likely to cause renal problems Therefore patients with evidence of invasive fungal infection such as CXR changes, high resolution CT scan abnormalities or positive galactomannan test may have their Abelcet dose increased to 3mg/kg or, if renal dysfunction / side-effects, be switched from Abelcet to AmBisome 3mg/kg. IV Voriconazole may be considered if the patient is unable to tolerate the lipid formulations of amphotericin Renal function and LFTs must be monitored daily with both of these drugs. Dose reductions might be needed for IV Voriconazole and levels can be sent. For patients with severe renal impairment Caspofungin should be considered 3. Treatment of Severe Proven (or Strongly Suspected) Fungal Infection - AmBisome / IV Voriconazole / Posaconazole / Caspofungin AmBisome Liposomal amphotericin (AmBisome) should ONLY be prescribed after discussion with the patient s consultant and the use of this drug should be reviewed daily by the consultant Usually AmBisome is reserved for patients with a severe confirmed or highly suspected invasive fungal infection and for proven cases of Mucor infection which is resistant to most other antifungal agents (Alternative is Posaconazole which is given orally as a liquid with a treatment dose of 400 mg bd or as the gastro-resistant tablets at a loading dose of 300 mg bd followed by 300 mg od IV posaconazole 300 mg is now available if the oral route is not possible or absorption is a problem) Dose recommendations for AmBisome are as follows For patients where an Aspergillus infection is suspected but not proven, who have not shown a response to Abelcet, or who have intolerance or renal toxicity, give AmBisome at 1 mg/kg/day initially round to nearest 50 mg vial For patients with proven progressive pulmonary aspergillosis, or if there is evidence of progression, increase the dose of AmBisome to 3 mg/kg/day Doses of 5-10 mg/kg may occasionally be used in severe cases (D/W Consultant) Although this drug has lower renal toxicity, it is still necessary to monitor the U&E daily Patients with impaired renal function may be switched to IV Voriconazole ( but note IV voriconazole should be avoided in those with a CrCl <50ml/min due to accumulation of the 4 1/8/16
Clinical guideline - Review date Aug 2017 vehicle.) or alternatively oral or IV posaconazole or IV caspofungin (although Caspofungin has limited activity against moulds) Voriconazole An alternative to AmBisome is IV Voriconazole for patients with probable or proven fungal infections (discuss with Consultant) Loading doses should be used in order to rapidly achieve therapeutic concentrations of the drug. For serious infections, intravenous loading with 2 doses of 6mg/kg IV followed by 4mg/kg IV bd for 7 to 10 days should be given before converting to oral therapy. The oral continuation dose is usually either 200mg bd or 300mg bd. Patients who rapidly metabolise voriconazole will likely have subtherapeutic levels with 200mg bd dosing and conversely those who are slow metabolisers risk toxicity with 300mg bd. Patients with less severe infections can be considered for oral treatment from the outset. However, loading should be performed with 400mg PO bd on day 1 followed by 200mg bd. Dosage escalation to 300mg bd may be required depending on levels (see below). Levels should be taken to guide treatment and determine the need for dosage escalation during the oral phase and doses should generally NOT be withheld pending level results unless overt voriconazole toxicity is suspected. Only pre-dose (trough) levels are required. A first level should be taken 3-4 days into IV therapy. A pre-dose level should be taken within 1 hour prior to the time that the dose is due. This should be sent to microbiology in a red plain top (clotted) blood bottle. Additional levels should then be sent during oral therapy. A level after 3-4 days of oral treatment can be sent followed by at least one other level further into the course of treatment. Levels should also be sent if drugs are commenced that are likely to affect voriconazole metabolism and also if there is a change in patient factors that may affect the level such as an alteration in hepatic function. Levels are referred to Bristol and results can generally be expected within 48 hours of taking the level. Weekends and Bank Holidays may result in longer turnaround times. Pre-dose levels should be > 1.0 to 5.5 mg/l. During the IV phase of treatment, subtherapeutic levels or those towards the bottom end of this range indicate a likely need for a maintenance dose of 300mg bd orally. Levels at the higher end of this range during IV therapy indicate an oral treatment dose of 200mg bd should maintain acceptable levels. Voriconazole is mainly metabolised by the liver and may cause a transient rise in liver enzymes so LFTs should be monitored daily IV Voriconazole dose should be reduced in patients with renal impairment due to accumulation of the carrier protein and should be avoided in patients in whom the CrCl is < 50 ml/min 5 1/8/16
Clinical guideline - Review date Aug 2017 Voriconazole has a number of drug interactions. It should be avoided in patients receiving Vincristine as part of their chemotherapy regimen and for patients on Cyclosporine the dose should be halved and monitored carefully during Voriconazole treatment Posaconazole Oral posaconazole may be considered for patients with suspected Mucor infections (sinus fungal infection). It may be used following a period of IV ambisome to complete the treatment of a confirmed fungal infection There are three formulations of posaconazole available Liquid formulation: the usual treatment dose is 400mg bd (10 ml) with food or 200 mg qds if food not tolerated or risk factors for poor absorption. It is recommended that posaconazole is administered with a high fat meal or nutritional supplement. Administration with food, particularly high-fat food increases the bioavailability. Levels should be sent to microbiology for monitoring Gastro-resistant tablet formulation: this has the advantage of being better absorbed and only once daily. No levels are required. The dose is 300 mg bd as a loading dose on day 1 followed by 300 mg od thereafter IV formulation: once daily dose of 300 mg Posaconazole can be used if oral route is not available It is mainly metabolised by the liver and LFTs should be monitored Like voriconazole it has similar drug interactions eg with cyclosporine A An IV formulation of posaconazole may become available in late 2015 Caspofungin This is an alternative echinocandin anti-fungal agent with a different mode of action. It is active against most Candidal species and some types of Aspergillus It may be used instead of Ambisome / IV Voriconazole for patients with severe documented fungal infection who have renal impairment with Ambisome or rarely in conjunction with AmBisome (eg for the treatment of cerebral Aspergillus, and severe pulmonary Aspergillus) It should be noted that Caspofungin has no activity against Mucor species and that if this is suspected clinically (naso-pharyngeal involvement) then AmBisome is the drug of choice It should be prescribed only with Consultant authorisation If > 80 kg then loading dose is 70 mg followed by 70 mg daily If < 80 kg then loading dose is 70 mg followed by 50 mg daily The infusion should be given over 1 hour LFTs need to be monitored daily 6 1/8/16
Clinical guideline - Review date Aug 2017 Major drug Interactions with ciclosporin (increased caspofungin levels increased liver toxicity) Rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine and dexamethasone reduce caspofungin levels consider increasing the dose. 4. Maintenance Treatment for Proven or Strongly Suspected Fungal Infections Voriconazole or Posaconazole Patients who have responded well to IV anti- fungal therapy and whose counts have regenerated but who have radiological evidence of residual fungal infection should be started on maintenance out-patient therapy using voriconazole 200 mg bd or posaconazole (either 300mg od as the gastroresistant tablets OR liquid formulation 200 mg qds) An initial loading dose of 400 mg bd of voriconazole is required followed by 200 mg bd This should be continued for 2 weeks (NB interacts with CSA so reduce CSA dose to 50%) Alternatively posaconazole may be used in these circumstances If patients cannot tolerate azoles then Abelcet / AmBisome 3mg/kg Mon-Fri on DCU may be considered 7 1/8/16