Department of Hematology
University Hospital Gasthuisberg
Invasive fungal disease (IFD) is a growing challenge in clinical practice, owing to the rising numbers of cancer, transplant and other patients receiving immunosuppressive treatment, and the increasing frequency of non-albicans Candida species of yeast and Zygomycetes and other moulds that are often resistant to many commonly used antifungal drugs.
Recently, European and US guidelines have been published; they recommend the use of different antifungal drugs for prophylaxis for patients receiving chemotherapy for haematological malignancies and those undergoing allogeneic haematopoietic stem cell transplantation (HSCT) with acute or severe chronic graft versus host disease (GVHD).[1,2] These recommendations are gradually being implemented in everyday practice. Indeed, 40% of several hundred participants in a session at the 4th Trends in Medical Mycology (TIMM) congress in 2009 confirmed that they used primary prophylaxis in high risk patients, and nearly 30% said that they used a combination of prophylaxis, empirical and pre-emptive approaches.
Within the next few months, publication of the latest update of European guidance from the 3rd European Conference on Infections in Leukaemia (ECIL-3) will bring healthcare professionals up to date with the latest evidence on which to base decisions for optimal use of antifungal therapy in their high risk patients.
Who needs antifungal prophylaxis?
HSCT and haematological cancer patients have been prioritised for antifungal prophylaxis because of their high IFD rates, with accompanying morbidity and mortality. Rates vary between centres depending on local risk factors and reporting methodology, and it is important to be aware of local epidemiology and microbial sensitivity to commonly used antifungal agents. In Europe, data from the large Italian SEIFEM registry showed an overall incidence of IFD in HSCT recipients of 3.7%, with 2.8% due to moulds and 0.9% due to yeasts. IFI rates were six times higher in patients undergoing allogeneic compared to autologous transplantation – a similar figure to that in a newly published report from the large US TRANSNET registry. In SEIFEM, patients with haematologic malignancies had an IFD rate of 4.6%, with 2.9% caused by moulds (mainly Aspergillus), and 1.6% by yeasts (mainly Candida).
The introduction of effective antifungal drugs is helping to reduce IFD mortality, but European and US studies have shown that fungal infection, especially invasive aspergillosis (IA) is still associated with significant mortality and morbidity.
In the SEIFEM registry, IA mortality was higher in allogeneic than autologous transplant patients (77.2% and 14.3% respectively) and candidaemia was associated with fewer deaths and less variation between the two types of transplant (57.1% and 43.8% respectively). Overall and IFD-attributable mortality rates in patients with haematological malignancies were 2% and 39% respectively, with the highest IFD-attributable mortality rates associated with zygomycosis (64%), fusariosis (53%), aspergillosis (42%), and candidaemia (33%).
An evidence-based approach to prophylaxis
In an effort to further reduce IFD-associated mortality in high risk patients, a number of studies have investigated the best approach to antifungal prophylaxis. A systematic review and meta analysis of 64 good quality randomised controlled trials (RCTs) in cancer patients undergoing chemotherapy or HSCT showed that antifungal prophylaxis significantly decreased all-cause mortality compared to placebo, no treatment, or non-systemic antifungal agents, with a relative risk (RR) of 0.84 (95% CI, 0.74 to 0.95). In allogeneic HSCT recipients, prophylaxis reduced all-cause mortality (RR, 0.62; 95% CI, 0.45 to 0.85), fungal-related mortality, and documented IFD. In acute leukemia patients, there was a significant reduction in fungal-related mortality and documented IFD, whereas the difference in mortality was of borderline significance (RR, 0.88; 95% CI, 0.74 to 1.06).
Further analysis investigated the comparative benefits of individual antifungal agents commonly used for prophylaxis, and demonstrated the advantages of drugs with anti-mould activity. The analysis showed that prophylaxis with itraconazole suspension reduced documented IFD compared with fluconazole, but there was no survival difference between the two treatments, and itraconazole was associated with more adverse events. Posaconazole prophylaxis reduced all-cause mortality (RR, 0.74; 95% CI, 0.56 to 0.98), fungal-related mortality, and IFD when compared with fluconazole.[7,8]
Using results from these and other RCTs, ECIL-2 and US guidelines on antifungal prophylaxis concluded that the strongest evidence supported the use of iv or oral fluconazole 400mg qd or oral posaconazole 200mg tid in patients undergoing allogeneic HSCT with acute or severe chronic GVHD, and the use of oral posaconazole 200mg tid in patients undergoing induction chemotherapy for acute leukaemia.[1,2]
In a subsequent controlled trial of voriconazole and fluconazole prophylaxis in allogeneic blood and marrow transplant patients, a non-significant reduction in proven/probable IFD was seen with voriconazole (p=0.11), with comparable fungal free survival for the two treatments (p=0.72). A prospective European study, comparing voriconazole and itraconazole oral solution prophylaxis in allogeneic HSCT patients, presented at the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting in San Francisco in 2009 (M-1249-a), showed a superior success of antifungal prophylaxis at day 180 for voriconazole (49.1% versus 34.5%; p=0.0004).10 But the better tolerability of voriconazole meant that significantly more patients had sufficient duration of prophylaxis compared with itraconazole (p=0.0014), though there were no significant differences in survival at 100 days and 180 days. On the basis of these two unpublished studies, a provisional recommendation for voriconazole prophylaxis in HSCT recipients was given during ECIL-3.
As antifungal prophylaxis has become more commonly used in clinical practice, growing experience has confirmed the findings of key clinical trials. For example, at the 36th Annual Meeting of the European Group for Blood and Marrow Transplantation (EBMT) in March, clinical experience reported from a large cancer centre in Mainz, Germany, showed that nearly two thirds of 52 allogeneic HSCT patients undergoing posaconazole prophylaxis remained free from IFD (no sign of infiltrates), while 29% had possible and 8% probable disease. Survival rates were higher in those without infiltrates, and patients who escaped infection had higher blood levels of posaconazole and better compliance rates than those who became infected.
A recent survey of 55 HSCT centres in Spain also reported at EBMT showed that clinicians are well aware of European and US recommendations for IFD prevention but that they are offering antifungal prophylaxis to a wider range of HSCT patients than those highlighted in the guidance. Fluconazole was the drug of choice for prophylaxis in autologous HSCT patients, while there was a shift towards use of mould-active agents, such as posaconazole, in allogeneic HSCT patients.
A future role for pre-emptive therapy
Despite the obvious benefits of antifungal prophylaxis for high risk patients, such an approach does inevitably mean that many patients receive unnecessary treatment. There is also evidence that use of fluconazole prophylaxis has increased the frequency of non-albicans strains of Candida infection and that pre-exposure of cancer patients to amphotericin B or triazoles is associated with increased frequency of non-fumigatus Aspergillus species.
Taking an empirical approach to antifungal therapy and treating only those high risk patients with evidence of persistent fever would scarcely reduce the number of patients exposed to treatment, as fever is such a common finding in this group. But there is considerable optimism surrounding pre-emptive or directed treatment based on clinical signs, high resolution CT (HRCT) scans, results of biomarker tests for galactomannan (GM) and[1,3] beta-D-glucan fungal antigens, and polymerase chain reaction (PCR) fungal DNA assays.
Growing evidence suggests that such an approach to pre-emptive treatment is associated with similar survival to that seen with empirical therapy, with less use of antifungal drugs.[11-13] In one study, pre-emptive therapy in high risk patients based on GM, HRCT and bronchosocopy with lavage (BAL) resulted in a 78% reduction in antifungal therapy. In a second study, high risk, febrile neutropenic patients who had pre-emptive treatment for IFD based on clinical, imaging, or GM evidence had more IFD (9.1% vs. 2.7%) but similar survival (95.1% vs. 97.3%) compared to those who had empirical therapy. Pre-emptive treatment decreased the costs of antifungal therapy by 35%.
Where GM testing is not available, pre-emptive treatment guided by the results of HRCT has also been shown to reduce the need for antifungal drugs while not jeopardising survival. In a study of 99 allogeneic transplant patients with antibiotic-resistant neutropenic fever at 72 hours, 53 would normally have received empirical antifungal therapy. But when treatment was administered based on HRCT, only 17 patients received treatment – equivalent to a 68% reduction in antifungal usage. No subsequent diagnoses of IFD occurred within 100 days in patients with a negative HRCT.
A major EORTC study comparing empirical and pre-emptive antifungal therapy in haematological patients is currently in the final planning stages, and will also provide an important opportunity to validate PCR testing according to recently published standards, alongside GM and HRCT.
Although pre-emptive therapy holds considerable promise for future IFD management, antifungal prophylaxis is likely to continue to form the basis of our efforts to minimise the burden of fungal infection among our haemato-oncology patients for the foreseeable future. In addition, as fungal infection increasingly spreads beyond our oncology and intensive care units into more general medical and surgical wards, we may soon be asking whether prophylaxis should be extended to other vulnerable populations, and how this may be achieved without significantly increasing resistance levels and jeopardising the efficacy of the antifungal drugs on which we depend.
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10. Marks DI, Kibbler C, et al. 49th Interscience Conference on Antomicrobial Agents and Chemotherapy, San Francisco, CA, September 12-15, 2009 Abstract M-1249a
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14. White PL, Bretagne S, et al. J Clin Microbiol 2010; doi:10.1128/JCM.01767-09 epub 10 February 2010.