Antifungal Treatment in the BMT Setting – Perspectives from Clinical Experience


open-label study of 45 adult allogeneic HSCT patients with previous proven or probable IFI within the 12 months prior to transplantation.17 Median duration of voriconazole treatment was 94 days, and a secondary infection rate of 7% was recorded.


Prophylaxis – The German Experience Ullmann presented data from his own practice on 52 allogeneic HSCT patients who received posaconazole prophylaxis for the first 100 days after transplantation during 2008. Of this group, almost two-thirds had no evidence of fungal infiltrates, while one-quarter had possible IFD and fewer than one-tenth had probable IFD. Among patients whose blood levels of posaconazole were measured, the mean level was higher in patients without infiltrates. Mortality was higher in those with proven/probable infection (more than half of the patients) than in those without infiltrates.


Ullmann concluded that good compliance apparently correlated with lower levels of IFD, and suggested that, despite the preliminary nature of the data, higher levels of drug exposure may give better protection. He added that there appeared to be a link between a lack of infiltrates and better survival.


Prophylaxis – The Spanish Experience de la Cámara discussed the results of a recent survey in 55 HSCT centres in Spain, which showed that clinicians are well aware of European and US recommendations for IFD prevention but are offering antifungal prophylaxis to a wider range of HSCT patients than those highlighted in the guidance. Thirty-eight per cent of responders felt that universal IFD prophylaxis was justified when there was an IFI incidence of 6–10%, and 44% felt that universal prophylaxis was justified when the IFI incidence was 11–15%.


Fluconazole was the drug of choice for prophylaxis in autologous HSCT patients, while there was a shift towards use of mould-active agents in allogeneic HSCT patients. For acute myeloid leukaemia patients undergoing allogeneic HSCT, 40% of respondents used posaconazole, 27% itraconazole prophylaxis and 19% fluconazole. For patients undergoing allogenic HSCT with ≥grade II GvHD, 80% used posaconazole and 11% voriconazole. There was strong support within Spanish HSCT centres for monitoring plasma levels of azoles, with 69% supporting measurements for selected cases and 15% considering that it should be performed for all patients.


de la Cámara also presented the results of a study of antifungal prophylaxis use in 198 HSCT patients undergoing treatment at the same 55 Spanish centres, which showed the reality of clinical practice. Ninety-three per cent of allogeneic and 78% of autologous HSCT patients had antifungal prophylaxis and, despite the strong support for mould-active drugs in allogeneic patients in the original survey, 46% of this group were receiving fluconazole and 54% antimould agents.


Results of a further study of 135 allogeneic HSCT patients treated at 10 Spanish hospitals with posaconazole prophylaxis confirmed in ‘real life’ the findings from previous studies – notably that IFI and survival rates were comparable to those seen in posaconazole randomised prophylaxis trials. Proven/probable IFI was demonstrated in 3.5% of 112 patients treated with posaconazole as primary or secondary prophylaxis and possible IFI in 7%. IFI-related mortality in the total group of 135 patients was 3% and overall mortality was 30%.


EUROPEAN ONCOLOGY


The Role of Empirical and Pre-emptive Therapies for Neutropenic Patients Despite the reductions in IFD and IFD-related mortality that have been achieved with antifungal prophylaxis, improved strategies are still needed for the prompt treatment of possible IFD in neutropenic patients with persistent fever despite broad-spectrum antibiotics.


Craddock reviewed the widespread use of empirical antifungal therapy for such patients and highlighted the lack of consensus on the optimal approach. Current European guidelines support the use of a wide range of antifungal agents for empirical therapy, with the strongest evidence in support of caspofungin and liposomal amphotericin B.18


Craddock drew attention to the growing interest in pre-emptive therapy based on the results of non-culture-based tests, such as galactomannan (GM), (1-3)-β-D-glucan, polymerase chain reaction (PCR) and high-resolution CT (HRCT).


He reviewed a series of recent studies suggesting that the pre-emptive approach may reduce the number of patients who are treated with antifungal therapy in response to persistent fever. In a study of pre-emptive therapy in high-risk neutropenic patients based on GM, HRCT and bronchoscopy with lavage (BAL), antifungal therapy was reduced by 78%.19


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 versus 2.7%) but similar survival rates (95.1 versus 97.3%) compared with those who received empirical therapy.20


However, as Craddock pointed out, considerable variability has been reported in the results of non-culture-based diagnostic tests, and it can be difficult to determine the applicability of the results of pre-emptive studies to clinical practice at other centres. In addition, it can be difficult for clinicians to obtain funding for new diagnostic services such as GM or PCR testing.


The UK Experience


Craddock showed that in the UK, where GM testing is not widely available, pre-emptive treatment guided by the results of HRCT has been shown to reduce the need for antifungal drugs without jeopardising survival.21


He reported the results of pre-emptive treatment in 99 consecutive patients in whom HRCT was used as the diagnostic test to predict need for treatment. All patients received itraconazole prophylaxis (or voriconazole if they had a previous infection), and those who developed neutropenic fever >72 hours afterwards or in whom there was suspicion of IFI received HRCT. Those with negative HRCT received no additional antifungal treatment, while patients with a positive HRCT were switched from their azole to caspofungin. HRCT was repeated after 10–14 days and, if worse, patients were transferred to liposomal amphotericin B. Patients whose HRCT improved were switched to voriconazole.


Seventeen of the 99 patients (17%) received pre-emptive antifungal treatment based on their HRCT results. This compared with 53 of 99 (54%) who would have received empirical treatment based on their neutropenic fever and suspicion of IFD. Craddock reported that the HRCT-guided pre-emptive approach therefore resulted in a 68% reduction in antifungal usage in the early post-transplant period.


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