Management of fungal infections in high-risk patients

Dr Tan Ban Hock
Senior Consultant
Department of Infectious Diseases
Singapore General Hospital
Singapore

Immunocompromised patients are at risk of invasive fungal infections (IFIs) that can result in death. Dr Tan’s presentation discussed different strategies for the treatment of IFIs in high-risk patients experiencing prolonged febrile neutropenia.

Empirical approach

In the late 1980s, it became obvious that clinical examination and cultures were not sufficiently sensitive for early detection of IFIs. Two pivotal clinical trials demonstrated that the early introduction of antifungals could reduce the frequency of IFI in febrile neutropenic patients, ^{1, 2} leading the Infectious Diseases Society of America (IDSA) to recommend this strategy in their practice guidelines.³ This strategy is known as the empirical approach. Experts today feel that these studies were underpowered, used prophylaxis of dubious value, and did not prove their primary hypothesis.⁴

Diagnostic-driven (pre-emptive) approach

With improved diagnostics, patients can be treated using the diagnostic-driven approach. In this approach, antifungal therapy is initiated when patients exhibit clinical evidence of IFIs. Hence, antifungal treatment and its side effects are obviated in a proportion of patients. As one nonrandomized prospective study found, a diagnosis-driven approach reduced the use of antifungals from an estimated 35% to 7.7%.⁵ In this study, patients received antifungal therapy after they had a positive result from the Aspergillus galactomannan assay or a computed tomography (CT) scan.

In a head-to-head study, patients were randomized to either a standard diagnostic strategy (based on culture and histology) or a biomarker-based diagnostic strategy (Aspergillus galactomannan and polymerase chain reaction [PCR]) to direct antifungal treatment. There were fewer patients who received antifungal therapy in the biomarker-based group compared with the standard diagnosis group (15% vs 32%; p=0.002) (Table 1).⁶ Another group of investigators explored the diagnostic-driven approach, giving antifungal therapy to selected patients with persistent febrile neutropenia. In this study, the overall sensitivity, specificity and negative predictive value (selecting patients who do not need antifungal therapy) for this approach were 100%, 52.4% and 100%, respectively.⁷ These results indicated that the diagnostic driven approach is useful for identifying patients who are not likely to develop IFIs and therefore do not require antifungal therapy. These findings have a clinical and economic impact on the treatment strategy and continue to be a subject of debate and investigation.

Posaconazole prophylaxis

Posaconazole is a triazole antifungal drug that is used to treat IFIs caused by Candida and Aspergillus. Posaconazole is recommended by the IDSA as an antifungal prophylactic against invasive aspergillosis.8 Although posaconazole. is an effective prophylaxis, a consistent proportion (about 30%) of patients still require subsequent systemic antifungal treatment.⁹ A prospective study investigated the impact of posaconazole prophylaxis on subsequent antifungal treatment strategy.⁹ Among patients who received posaconazole prophylaxis and needed systemic antifungal treatment, an empirical approach was utilized in 80% of the patients, a pre-emptive approach in 15% of the patients and targeted treatment in 5% of the patients. There was no difference in IFI-attributable mortality between the empirical and pre-emptive approach (25% vs 21%; p=0.2). The study concluded that posaconazole prophylaxis did not modify the efficacy of subsequent systemic antifungal used, regardless of the treatment approach.

Costs: Empirical vs diagnostic-driven

Diagnostic-driven treatment is not inferior to empirical treatment in terms of survival.¹⁰ Hence cost might be a consideration. According to a study, the reduced use of antifungal agents contributed to the lower cost of the diagnostic-driven strategy compared with an empirical approach (GBP1,561.29 vs GBP2,301.93).¹¹ In addition, more patients are able to avoid the adverse effects caused by antifungal treatment. These results suggested that the diagnostic-driven approach may provide cost-savings for high-risk patients who are neutropenic and have persistent fever.

Clinical pearls

• Both the empirical and diagnostic-driven approaches are common antifungal treatment strategies for high-risk patients
• In the empirical approach, patients are given antifungals based on the fever trend
• In the diagnostic-driven approach, diagnostic assays and CT scans are used to trigger antifungal treatment
• There is a potential for overtreatment of non-fungal fever, resulting in increased toxicity and costs with the empirical approach

Table 1. Comparison of outcomes for standard versus biomarker-based diagnostic strategy to direct antifungal treatment in high-risk hematology patients⁶

	Standard diagnosis group (n=122)	Biomarker-based diagnosis group (n=118)	p
Received antifungal therapy	32%	15%	0.002
Probably invasive aspergillosis	0	14%	0.0001
Mortality	15%	10%	0.31
Invasive aspergillosis-related mortality	15%	10%	0.30
Hepatotoxicity	17%	10%	0.11
Nephrotoxicity	43%	51%	0.20

Highlights of the Medical Mycology Training Network Conference, December 1–3, 2017, Ho Chi Minh City, Vietnam

References

1. EORTC International Antimicrobial Therapy Cooperative Group. Am J Med 1989;86:668.
2. Pizzo PA, et al. Am J Med 1982;72:101.
3. Freifeld AG, et al. Clin Infect Dis 2011;52:e56-e93.
4. Segal BH, et al. Clin Infect Dis 2007;44:402.
5. Maertens J, et al. Clin Infect Dis 2005;41:1242-1250.
6. Morissey CO, et al. Lancet Infect Dis 2013;13:519-528.
7. Aguilar-Guisado M, et al. Haematologica 2012;97:464-471.
8. Patterson TF, et al. Clin Infect Dis 2016;63:e1-e60.
9. Pagano L, et al. J Antimicrob Chemother 2014;49:3142.
10. Cordonnier C, et al. Clin Infect Dis 2009;48:1042-1051.
11. Barnes R, et al. Clin Ther 2015;37:1317-1328.