Antifungal Treatments in Adult Haematology Patients - Guidelines for the use of

Publication: 01/03/2009  
Last review: 27/12/2017  
Next review: 27/12/2020  
Clinical Guideline
CURRENT 
ID: 1823 
Approved By: Improving Antimicrobial Prescribing Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2017  

 

This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Guidelines for the use of Antifungal Treatments in Adult Haematology Patients

Summary
Antifungal Treatments in Adult Haematology Patients

  • This guideline applies to adult haematology and/or stem cell transplant patients.
  • The guideline provides advice on diagnosis and treatment of invasive fungal infection in this patient group.
  • The guideline should be used by health care professionals responsible for diagnosis and treatment of this patient group.
  • The guideline does not specify antifungal prophylaxis, which is covered in a separate guideline.

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Background

Invasive fungal disease (IFD)

  • Invasive fungal disease (IFD) is diagnosed according to the revised EORTC/MSG diagnostic criteria (De Pauw et al. 2008). Patients are categorised as having proven, probable or possible IFD according to the flow-chart Evidence Level C

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Clinical Diagnosis

Criteria for proven IFD
Moulds 
Microscopic analysis: sterile material

  • Histopathologic, cytopathologic, or direct microscopic examination of a specimen obtained by needle aspiration or biopsy in which hyphae or melanised yeast-like forms are seen accompanied by evidence of associated tissue damage

Culture

  • Recovery of a mould or “black yeast” by culture of a specimen obtained by a sterile procedure from a normally sterile and clinically or radiologically abnormal site consistent with an infectious disease process, excluding bronchoalveolar lavage fluid, a cranial sinus cavity specimen, and urine
  • blood culture that yields a mould (e.g., Fusarium species) in the context of a compatible infectious disease process (isolation of Aspergillus spp. from blood is considered to represent contamination)

Yeasts
Microscopic analysis: sterile material

  • Histopathologic, cytopathologic, or direct microscopic examination of a specimen obtained by needle aspiration or biopsy from a normally sterile site (other than mucous membranes) showing yeast cells—for example, Cryptococcus species indicated by encapsulated budding yeasts or Candida species showing pseudohyphae or true hyphae.

Culture

  • Recovery of a yeast by culture of a sample obtained by a sterile procedure (including a freshly placed [≤24 h ago] drain) from a normally sterile site showing a clinical or radiological abnormality consistent with an infectious disease process.
  • blood culture that yields yeast (e.g., Cryptococcus or Candida species) or yeast-like fungi (e.g., Trichosporon species).
  • Serological analysis: Cryptococcal antigen in CSF indicates disseminated cryptococcosis.

Criteria for probable and possible IFD (except for endemic mycoses)
Host factors

  • Recent history of neutropenia (<0.5x109 neutrophils/L [<500 neutrophils/mm3] for >10 days) temporally related to the onset of fungal disease
  • Receipt of an allogeneic stem cell transplant
  • Prolonged use of corticosteroids (excluding use for ABPA) at a mean minimum dose of 0.3 mg/kg/day of prednisone equivalent for >3 weeks
  • Treatment with other recognised T-cell immunosuppressants, such as ciclosporin, TNF-α blockers, specific monoclonal antibodies (e.g. alemtuzumab), or nucleoside analogues during the past 90 days
  • Inherited severe immunodeficiency

Clinical criteria (must be consistent with any mycological findings)

  • Lower respiratory tract fungal disease (every reasonable attempt should be made to exclude an alternative aetiology)
    • The presence of 1 of the following 3 signs on CT:
      • Dense, well-circumscribed lesions(s) with or without a halo sign
      • Air-crescent sign
      • Cavity
  • Tracheobronchitis
    • Tracheobronchial ulceration, nodule, pseudomembrane, plaque, or eschar seen on bronchoscopic analysis
  • Sinonasal infection
    • Imaging showing sinusitis plus at least 1 of the following 3 signs:
      • Acute localised pain (including pain radiating to the eye)
      • Nasal ulcer with black eschar
      • Extension from the paranasal sinus across bony barriers, including into the orbit
  • CNS infection
    • 1 of the following 2 signs:
      • Focal lesions on imaging
      • Meningeal enhancement on MRI or CT
  • Disseminated candidiasis
    • At least 1 of the following 2 entities after an episode of candidemia within the previous 2 weeks:
      • Small, target-like abscesses (bull’s-eye lesions) in liver or spleen
      • Progressive retinal exudates on ophthalmologic examination

Mycological criteria

  • Direct test (cytology, direct microscopy, or culture)
    • Mould in sputum, bronchoalveolar lavage fluid, bronchial brush, or sinus aspirate samples, indicated by 1 of the following:
      • Presence of fungal elements indicating a mould
      • Recovery by culture of a mould (e.g., Aspergillus, Fusarium, Zygomycetes, or Scedosporium species)
  • Indirect tests (detection of antigen or cell-wall constituents)
    • Aspergillosis
      • Galactomannan antigen detected in plasma, serum, bronchoalveolar lavage fluid, or CSF (NB: β-D-glucan and CSF galactomannan testing are not available at LTHT)
    • Invasive fungal disease other than cryptococcosis and zygomycosis
      • β-d-glucan detected in serum

THE STRENGTH OF DIAGNOSIS OF IFD SHOULD BE DOCUMENTED IN THE PATIENT’S NOTES AS “PROVEN”, “PROBABLE or “POSSIBLE”.

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Investigation
  • Mycological investigations:
    • Aspergillus galactomannan EIA test is used as a diagnostic test (i.e. in febrile neutropenia or where there is other clinical suspicion of fungal infection) and may be carried out on blood (clotted), or BAL fluid. Evidence Level B
    • Beta-D-glucan test is used to detect a wide range of fungal infections (including Aspergillosis, Candidosis and Pneumocystis pneumonia) and can be carried out on blood (clotted). Evidence level B
    • Microscopy and culture of samples from potentially-infected sites, including respiratory secretions, BAL fluid, blood, skin lesions, sinus aspirates and biopsy material. All such specimens must be submitted with clinical details and a specific request for fungal culture. Evidence Level B
      • All yeast isolates thought to be responsible for an episode of IFD will be speciated and tested for antifungal susceptibility. Therapy need not wait for the results of these tests but may be modified by them. B
      • All significant mould isolates will be speciated. Susceptibility testing will be carried out where a resistant mould is grown or suspected. C
      • Fungal PCR is not available at LTHT, and Aspergillus antibody detection is inappropriate for this patient group.
  • Non-mycological investigations
    • Histopathological examination of biopsy material Evidence Level C
      • All such specimens must be submitted with clinical details and a specific request for fungal staining (methenamine silver or PAS).
    • High-resolution CT scan of chest Evidence Level B
      • Clinical features consistent with IFD, with or without supportive microbiological evidence and regardless of CXR appearances, justify an urgent chest CT scan because the earlier a CT scan is performed the more likely it is to show the early IFD-predictive halo sign. CT scan should be performed within 24 hours wherever possible. Evidence Level C

Patients with inconclusive clinical or microbiological evidence of IFD and negative, non-progressive nodular changes or non-specific initial CT findings, should have a repeat CT scan after no more than 7 days Evidence Level C

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Treatment
Empirical Antimicrobial Treatment
  • The overall scheme for treatment is shown in the treatment algorithm. The entry point for the algorithm is neutropenia (as described under host factors, above) and fever >38°C for 5 days.
  • Amphotericin B deoxycholate (conventional AmB) is not recommended for use in haematology patients in LTHT. Evidence Level C
  • The lipid-associated formulation of AmB used in LTHT is Ambisome. It is used at 1 mg/kg/day empirically and at 1-3 mg/kg/day where there is possible IFD and at 3mg/kg in proven or probable IFD Evidence Level C
  • Caspofungin is recommended for use as “salvage therapy” i.e. where there is refractory IFD or intolerance to alternative antifungal therapy. Evidence Level B
  • Voriconazole is the drug of choice for treatment of proven/probable fungal infections caused by Aspergillus terreus, Scedosporium spp., and Fusarium spp., and is widely considered to be the drug of choice for aspergillosis caused by any species (Patterson et al 2016). For treatment (as opposed to prophylaxis) voriconazole should be started intravenously at a loading dose of 6 mg/kg 12 hourly for 1 day, followed by 4 mg/kg 12 hourly thereafter. Evidence Level B
  • Voriconazole is the drug of choice where a patient with a diagnosis of aspergillosis continues to require antifungal therapy (as opposed to prophylaxis) and is clinically stable, whether or not there is a plan for discharge. It should be administered orally unless absorption is believed to be impaired. Evidence Level B
  • Itraconazole oral suspension (2.5mg/kg 12 hourly) is the drug of choice where secondary prophylaxis is required after full clinical and radiological resolution and neutrophil recovery in a patient with aspergillosis. If there is intolerance to itraconazole, or levels of ≥0.5 mg/L are not achieved, posaconazole (200 mg 8 hourly) should be used for this indication (use of posaconazole in this setting obviates the need for monitoring hepatic and ophthalmic toxicity, which would be required with voriconazole) Evidence Level C
  • Isavuconazole should be used in cases where voriconazole is not tolerated or expected to be tolerated (e.g. Patients with poor liver function) or where there is a known risk for mucoraceous mould infection. Evidence Level B
  • Posaconazole is the drug of choice for proven/probable fungal infections where predicted or reported sensitivity patterns suggest that it is likely to be an appropriate option (e.g. Fusarium spp., Mucoraceous moulds (Rhizopus etc) and the disease is refractory to, or the patient is intolerant of, other antifungal agents. The gastro-resistant tablet formulation provides best absorption. Evidence Level C
  • There is very little evidence on which to base recommendations on treatment duration for fungal infections in haematology patients. Most experts attempt to treat pulmonary infection until resolution or stabilization of all clinical and radiographic manifestations. Other factors include site of infection (e.g., osteomyelitis), level of immunosuppression, and extent of disease. Reversal of immunosuppression, if feasible, is important for a favorable outcome for invasive aspergillosis. Evidence Level C
  • All antifungal decisions not covered by the treatment algorithm should be made in conjunction with a LTHT Consultant Microbiologist or Mycologist.

There are at least two published comparisons of different doses of Ambisome in treating IFD. One of these demonstrates similar efficacy for Ambisome at 1 mg/kg/day vs. 4 mg/kg/day (Ellis et al. 1998) and the other shows no difference in outcome between Ambisome at 3 and 10 mg/kg/day (Cornely et al. 2007). Although the licensed dose for Ambisome in proven/probable fungal infection is 1-3 mg/kg/day, the licensed dose in febrile neutropenia, in which most patients do not have a fungal infection, is 3 mg/kg/day (presumably based on Prentice et al., 1997). Given the evidence of similar efficacy between Ambisome at 1 and 4 mg/kg/day an empiric Ambisome dose of 1 mg/kg/day is recommended in this guideline, whilst awaiting further results.

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Duration of Treatment

It is recommended that treatment of IPA be continued for at least 6–12 weeks, largely dependent on the degree and duration of immunosuppression, site of disease, and evidence
of disease improvement.
For patients with successfully treated IPA and requiring further immunosuppression, secondary prophylaxis should be started to prevent recurrence. (Patterson et al 2016)

Treatment Failure

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Treatment Failure
Please contact Microbiology if the patient is not responding to the recommended antimicrobial regimens.

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Provenance

Record: 1823
Objective:
  • To provide evidence-based recommendations for the appropriate investigation of possible fungal infection.
  • To provide evidence-based recommendations for appropriate empirical and directed antifungal therapy.
  • To recommend appropriate dose, route of administration and duration of antifungal agents.
  • To optimise the diagnosis and treatment of invasive fungal infections in haematology and/or stem cell transplant patients.
Clinical condition: Use of antifungal agents in adult haematology patients
Target patient group: Adults
Target professional group(s): Secondary Care Doctors
Adapted from:

Evidence base

Evidence base

  • Ascioglu S, Rex JH, De Pauw B, Bennett JE, Bille J, Crokaert F et al. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clinical Infectious Diseases, 2002;34:7-14.
  • Cornely, O. A., et al. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomised trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial). Clinical Infectious Diseases 2007;44:1289-97.
  • De Pauw et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group Clinical Infectious Diseases 2008;46:1813-21.
  • Ellis, M., et al. An EORTC international multicenter randomized trial (EORTC number 19923) comparing two dosages of liposomal amphotericin B for treatment of invasive aspergillosis. Clinical Infectious Diseases 1998;27:1406-12.
  • Prentice AG, Glasmacher A, Hobson RP, Schey S , Barnes RA, Donnelly JP, Jackson G. Guidelines on the management of invasive fungal infection during therapy for haematological malignancy. British Committee for Standards in Haematology 2008; published on line at http://www.bcshguidelines.com/pdf/IFI_therapy.pdf 
  • Prentice, H. G., et al. A randomized comparison of liposomal versus conventional amphotericin B for the treatment of pyrexia of unknown origin in neutropenic patients. British Journal of Haematology1997;98;711-18.
  • Walsh, T. J., et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. New England Journal of Medicine 1999;340: 764-71.
  • Patterson, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clinical Infectious Diseases 63(4):e1-e60.
  • Maertens JA, et al. 2016 Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 387:760-9

Evidence levels:
A. Meta-analyses, randomised controlled trials/systematic reviews of RCTs
B. Robust experimental or observational studies
C. Expert consensus.
D. Leeds consensus. (where no national guidance exists or there is wide disagreement with a level C recommendation or where national guidance documents contradict each other)

Approved By

Improving Antimicrobial Prescribing Group

Document history

LHP version 1.0

Related information

Appendix 1. Application of EORTC/MSD Diagnostic Criteria

Appendix 2. Treatment algorithm for invasive fungal infection (IFD) in haematology/BMT patients

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