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Invasive fungal infection — Clinical Guidelines

Overview

Invasive fungal infections (IFIs) are serious complications in immunocompromised patients, particularly those undergoing chemotherapy or hematopoietic stem cell transplantation, leading to significant morbidity and mortality 3 18.

Diagnosis

Serum biomarkers: 1,3-beta-d-glucan (BDG) testing can aid in early diagnosis 7.

Molecular diagnostics: Mucorales PCR for non-invasive screening of invasive mucormycosis 6.

Culture and histopathology: Essential for definitive diagnosis, though delayed compared to molecular methods 27.

Imaging: Chest CT for pulmonary involvement, particularly in suspected invasive pulmonary aspergillosis (IPA) 16.

Histopathology with immunohistochemistry: Useful but with noted cross-reactivity issues 27.

Management

First-line treatments:

- Azoles: Posaconazole, isavuconazole for prophylaxis and treatment 1 2. - Echinocandins: Micafungin for invasive candidiasis 17 18.

Adjunctive measures:

- Combination therapy: Considered in refractory cases or specific scenarios 5. - Dose optimization: Ensure therapeutic drug levels, especially for posaconazole 4.

Specific scenarios:

- Hypertension management: Monitor for drug interactions, particularly with calcium channel blockers 2.

Special Populations

Pediatrics: Increased incidence of IFIs; combination therapy reported but not universally recommended 5 19.

Elderly: Higher risk due to comorbidities; tailored prophylaxis and monitoring essential 3.

Comorbidities: Patients with solid organ transplants are at risk for Candida and Aspergillus infections 31.

Key Recommendations

Use of broad-spectrum antifungal prophylaxis: Primary mould-active prophylaxis recommended for high-risk hematology patients (Evidence: Strong 8).

Monitoring therapeutic drug levels: Ensure posaconazole trough concentrations exceed 0.7 mg/L in hematology inpatients (Evidence: Moderate 4).

Early diagnosis through biomarkers: Utilize 1,3-beta-d-glucan testing for early detection in high-risk patients (Evidence: Moderate 7).

Consider combination therapy cautiously: In specific refractory cases, combination antifungal therapy may be beneficial, though evidence varies (Evidence: Weak 5).

Implement antifungal stewardship programs: Enhance appropriate antifungal use through education and monitoring (Evidence: Expert opinion 20).

References

1 Nakano Y, Kotake K, Asai Y, Murata M, Uchiyama M, Shimono N et al.. Adverse effects of posaconazole on adrenal steroid biosynthesis: An integrative approach using FAERS-based pharmacovigilance and systematic review with meta-analysis of randomised controlled trials. International journal of antimicrobial agents 2026. link 2 Zhou J, Xiao B, Wei Z, Jia M, Luo X, Wei H et al.. Isavuconazole and Calcium Channel Blocker for Invasive Fungal Disease Accompanied With Hypertension: Evidence From the FAERS and PBPK/PD Model. CPT: pharmacometrics & systems pharmacology 2025. link 3 Calle-Miguel L, Garrido-Colino C, Santiago-García B, Moreno Santos MP, Gonzalo Pascual H, Ponce Salas B et al.. Changes in the epidemiology of invasive fungal disease in a Pediatric Hematology and Oncology Unit: the relevance of breakthrough infections. BMC infectious diseases 2023. link 4 Bui J, Gellatly R, Othman J, Lindsay J. Subtherapeutic concentrations of posaconazole tablet: determining risk factors and effectiveness of a standardized dose adjustment in hematology inpatients. Leukemia & lymphoma 2022. link 5 Lignieres G, Guitard J, Alby-Laurent F, Rambaud J, Bigot J, Morand K et al.. Antifungal combination therapy for invasive fungal infections in a paediatric oncology and haematology department: A retrospective analysis of practice. Journal de mycologie medicale 2022. link 6 Aerts R, Bevers S, Beuselinck K, Schauwvlieghe A, Lagrou K, Maertens J. Blood Mucorales PCR to track down . Frontiers in cellular and infection microbiology 2022. link 7 Garnham K, Halliday CL, Rai NJ, Jayawardena M, Hasan T, Kok J et al.. Introducing 1,3-beta-d-glucan for screening and diagnosis of invasive fungal diseases in Australian high-risk haematology patients: is there a clinical benefit?. Internal medicine journal 2022. link 8 Coussement J, Lindsay J, Teh BW, Slavin M. Choice and duration of antifungal prophylaxis and treatment in high-risk haematology patients. Current opinion in infectious diseases 2021. link 9 Fernando SS, Paige EK, Dendle C, Weinkove R, Kong DCM, Omond P et al.. Consensus guidelines for improving patients' understanding of invasive fungal disease and related risk prevention in the haematology/oncology setting, 2021. Internal medicine journal 2021. link 10 Chang CC, Blyth CC, Chen SC, Khanina A, Morrissey CO, Roberts JA et al.. Introduction to the updated Australasian consensus guidelines for the management of invasive fungal disease and use of antifungal agents in the haematology/oncology setting, 2021. Internal medicine journal 2021. link 11 Bupha-Intr O, Butters C, Reynolds G, Kennedy K, Meyer W, Patil S et al.. Consensus guidelines for the diagnosis and management of invasive fungal disease due to moulds other than Aspergillus in the haematology/oncology setting, 2021. Internal medicine journal 2021. link 12 Koehler P, Denis B, Denning DW, Gangneux JP, Hoenigl M, Kontoyiannis DP et al.. European confederation of medical mycology expert consult-An ECMM excellence center initiative. Mycoses 2020. link 13 Santiago-García B, Rincón-López EM, Ponce Salas B, Aguilar de la Red Y, Garrido Colino C, Martínez Fernández-Llamazares C et al.. Effect of an intervention to improve the prescription of antifungals in pediatric hematology-oncology. Pediatric blood & cancer 2020. link 14 Lagrou K, Duarte RF, Maertens J. Standards of CARE: what is considered 'best practice' for the management of invasive fungal infections? A haematologist's and a mycologist's perspective. The Journal of antimicrobial chemotherapy 2019. link 15 de Kort EA, Maertens J, Verweij PE, Rijnders BJA, Blijlevens NMA. Diagnostic-driven management of invasive fungal disease in hematology in the era of prophylaxis and resistance emergence: Dutch courage?. Medical mycology 2019. link 16 Mercier T, Schauwvlieghe A, de Kort E, Dunbar A, Reynders M, Guldentops E et al.. Diagnosing Invasive Pulmonary Aspergillosis in Hematology Patients: a Retrospective Multicenter Evaluation of a Novel Lateral Flow Device. Journal of clinical microbiology 2019. link 17 Muilwijk EW, Maertens JA, van der Velden WJFM, Ter Heine R, Colbers A, Burger DM et al.. Pharmacokinetics of extended dose intervals of micafungin in haematology patients: optimizing antifungal prophylaxis. The Journal of antimicrobial chemotherapy 2018. link 18 Tissot F, Agrawal S, Pagano L, Petrikkos G, Groll AH, Skiada A et al.. ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients. Haematologica 2017. link 19 Morgan JE, Hassan H, Cockle JV, Lethaby C, James B, Phillips RS. Critical review of current clinical practice guidelines for antifungal therapy in paediatric haematology and oncology. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 2017. link 20 Valerio M, Muñoz P, Rodríguez-González C, Sanjurjo M, Guinea J, Bouza E. Training should be the first step toward an antifungal stewardship program. Enfermedades infecciosas y microbiologia clinica 2015. link 21 Bartlett A, Goeman E, Vedi A, Mostaghim M, Trahair T, O'Brien TA et al.. A Pilot Study of a Computerized Decision Support System to Detect Invasive Fungal Infection in Pediatric Hematology/Oncology Patients. Infection control and hospital epidemiology 2015. link 22 Gheith S, Saghrouni F, Bannour W, Ben Youssef Y, Khelif A, Normand AC et al.. Characteristics of invasive aspergillosis in neutropenic haematology patients (Sousse, Tunisia). Mycopathologia 2014. link 23 Pagano L, Lumb J. Update on invasive fungal disease. Future microbiology 2011. link 24 Ananda-Rajah MR, Cheng A, Morrissey CO, Spelman T, Dooley M, Neville AM et al.. Attributable hospital cost and antifungal treatment of invasive fungal diseases in high-risk hematology patients: an economic modeling approach. Antimicrobial agents and chemotherapy 2011. link 25 Hahn J, Stifel F, Reichle A, Holler E, Andreesen R. Clinical experience with posaconazole prophylaxis--a retrospective analysis in a haematological unit. Mycoses 2011. link 26 Maertens J, Bryan J. Managing invasive fungal disease in immunocompromised patients. Future microbiology 2010. link 27 Schuetz AN, Cohen C. Aspergillus immunohistochemistry of culture-proven fungal tissue isolates shows high cross-reactivity. Applied immunohistochemistry & molecular morphology : AIMM 2009. link 28 Crassard N, Hadden H, Piens MA, Pondarré C, Hadden R, Galambrun C et al.. Invasive aspergillosis in a paediatric haematology department: a 15-year review. Mycoses 2008. link 29 Meletiadis J, Chanock S, Walsh TJ. Defining targets for investigating the pharmacogenomics of adverse drug reactions to antifungal agents. Pharmacogenomics 2008. link 30 Krishna G, Sansone-Parsons A, Kantesaria B. Drug interaction assessment following concomitant administration of posaconazole and phenytoin in healthy men. Current medical research and opinion 2007. link 31 Singh N. Fungal infections in the recipients of solid organ transplantation. Infectious disease clinics of North America 2003. link00067-3) 32 Horn CR, Wood NC, Hughes JA. Invasive aspergillosis following post-influenzal pneumonia. British journal of diseases of the chest 1983. link

Invasive fungal infection