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Keywords:

  • antifungal prophylaxis;
  • leukaemia;
  • stem cell transplantation;
  • invasive fungal disease;
  • invasive aspergillosis

Summary

  1. Top of page
  2. Summary
  3. Historical perspective
  4. Evidence for antifungal prophylaxis: randomized studies
  5. Meta-analyses of antifungal prophylaxis
  6. Recommendations of evidence-based guidelines
  7. Continuing debate and future perspectives
  8. References

Antifungal prophylaxis during treatment for haematological malignancies has been studied for 50 years, yet it has not been wholly effective even when using antifungal drugs that exhibit potent activity in vitro against a broad range of fungal pathogens. Trials have demonstrated that it can reduce the incidence of invasive fungal diseases (IFD) and fungal deaths, but only two studies have had an impact on overall mortality. Furthermore, it has not significantly reduced the need for empirical antifungal therapy. Posaconazole was effective in preventing invasive aspergillosis in two studies of high-risk patients, and consensus guidelines grade it as a suitable choice for antifungal prophylaxis of invasive mould disease; however, its bioavailability was compromised by vomiting or diarrhoea so that an alternative parenteral antifungal drug was required. A recent trial of voriconazole prophylaxis after allogeneic stem cell transplantation failed to show superiority over fluconazole. With more accurate definitions of IFD, that utilize fungal biomarkers, such as galactomannan, together with computerized tomographic imaging, there is growing interest in a diagnostic-driven strategy, which could prove to be a more efficacious approach.

Infectious diseases continue to threaten successful treatment of haematological malignancies in spite of considerable progress having been made in recent years with supportive care.

As the threats posed by bacterial and cytomegalovirus infections have receded somewhat, invasive fungal disease (IFD) is now the main infective cause of mortality in this patient population.

To address this challenge we need to know the incidence of the major fungal pathogens in this setting, their ecological niches, routes and timing of entry into the host, together with mechanisms of fungal dissemination. Only then can we develop and validate fully effective preventive strategies. Candida albicans and Aspergillus fumigatus have been the dominant pathogens in recent years (Erjavec et al, 2009), but gaining precise data on their frequencies has been a challenge because of inadequate epidemiological surveillance and diagnostic shortfalls. By combining individual patients’ risk factors, together with clinical and mycological information, 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) have facilitated better documentation of cases of IFD that are not definitively proven by tissue histology (Ascioglu et al, 2002; de Pauw et al, 2008). Adopting these criteria, Pagano et al (2006) undertook a retrospective 18-centre Italian study of 11 802 adult patients who were receiving chemotherapy for different haematological malignancies. Five hundred and 38 patients had a probable or proven IFD (incidence 4·6%); the incidence was 12% in acute myeloid leukaemia (AML) patients – who accounted for the majority of cases with IFD (69%) – and 6·5% in acute lymphoblastic leukaemia (ALL) patients. Invasive aspergillosis (IA) and candidaemia accounted for 58% and 33% of cases, with attributable mortality rates of 42% and 33%, respectively.

The incidence of IFD’s in other types of haematological malignancy was much lower, as was the overall incidence of IFD’s due to other mould and yeast pathogens although it’s worth noting that the highest attributable mortality rates were in cases of zygomycosis (64%) and fusariosis (53%). Further European data highlight the increasing, albeit lower, incidence of these other mould infections in haematological malignancy patients (Lass-Florl, 2009).

In a more recent Italian multi-centre study of 140 AML patients with probable or proven IA, 86% of whom had received antifungal prophylaxis, the greatest proportion of cases occurred during aplasia following initial remission-induction therapy (60%), next were cases occurring after treatment for refractory or relapsed disease (36%). Only 3% occurred in patients having consolidation chemotherapy (Pagano et al, 2010). The overall attributable mortality was 27%.

In a 23-centre prospective US study of 983 IFD’s complicating haematopoietic stem cell transplantation (HSCT) in 875 patients who had been treated between 2001 and 2006 (Kontoyiannis et al, 2010), an analysis of the cumulative 12-month incidence of IFD after first HSCT showed the highest rate was in mismatched related and matched unrelated transplants (7·7–8·1 cases/100 transplants) while the lowest rate was in autologous HSCT recipients (1·2 cases/100 transplants); 43% of cases were IA, 28% invasive candidiasis and 8% zygomycosis. The median time intervals between allogeneic (allo)-HSCT and diagnosis were 61 d for candidiasis and 99 d for IA.

Garcia-Vidal et al (2008) analysed risk factors associated with IFD after HSCT and found that during the early post-transplant period these were principally neutropenia, older age and human leucocyte antigen (HLA) mismatch; while graft-versus-host disease (GVHD) and cytomegalovirus (CMV) disease, together with leucopenia and iron overload, were significant risk factors later after transplant. Both single-centre (Upton et al, 2007) and multi-centre studies (Neofytos et al, 2009) report improving survival rates in cases of IA but continuing high mortality rates from other invasive mould infections and candidiasis.

These studies confirm that IFD has its highest incidence during chemotherapy for AML, in the presence of relapsed disease, and in matched unrelated or mismatched related transplant recipients; by contrast, consolidation chemotherapy, myeloma therapy or autologous HSCT carry a lower risk.

Large randomized comparative empirical antifungal therapy trials of antibiotic-resistant febrile neutropenia have recorded IFD incidences of <5% (Segal et al, 2007); patients in most of the above studies had received different antifungal drugs for prophylaxis and because we know this can reduce the sensitivity of galactomannan (GM) tests (Marr et al, 2005), we can assume that less cases will be recorded as probable IFD so that, according to EORTC/MSG criteria, some will be possible cases or even unclassified. Therefore, it is likely that the rates of IFD of around 5% in the highest risk patients that are reported in the literature, where prophylaxis has been practised, under-represents the true situation.

Candida spp. that cause candidaemia/invasive candidiasis are most commonly endogenous in origin, the main reservoir being the gastrointestinal tract (Nucci & Anaissie, 2001). By contrast, Aspergillus spp, and other mould pathogens are acquired most often by inhalation into the lower respiratory tract. For prophylactic antifungal agents to do their job effectively, they need to reach mucosal surfaces where the earliest interactions between pathogen and host occur. In the case of inhaled Aspergillus spp. the first encounter of fungal conidia with the host is on mucosal surfaces of the upper airways and on alveolar cells (Ben-Ami et al, 2010).

In spite of these insights, an important gap in our knowledge is not knowing how often IA is the result of reactivation of latent Aspergillus infection triggered by new immunosuppression, rather than being a primary infection. The overall approach to prevention of IFD in high-risk leukaemic patients is multifaceted and complex, and has to be based on our knowledge and understanding of how these infections originate. If the aim of primary antifungal prophylaxis is to truly prevent fungal infection before it occurs, then there should be no evidence of previous infection or disease; by contrast, if a patient has previously had the infection then this should be considered suppressive therapy although it is typically referred to as secondary prophylaxis. The traditional approach to antifungal prophylaxis has been to give oral agents with inconsistent bioavailability and tissue distribution, so it is relevant to ask if a more rational approach would be to start prophylaxis with a parenteral agent, or with a combination of oral prophylaxis and inhaled nebulized antifungal, in order to ensure adequate drug levels where they are needed at the pathogen-host interface, and later switch to the oral route once the high-risk period of profound neutropenia has passed or the patient has been discharged from hospital.

A further issue is how long antifungal prophylaxis should be continued. As is evident from the literature, the risk of IFD in allo-HSCT recipients continues for many months, especially in the presence of GVHD that requires steroid or other immunosuppressive therapy, or during ongoing treatment for relapsed disease. Furthermore, beyond 6 months IFD due to zygomycetes and other non-Aspergillus moulds is a risk for some patients although their specific risk factors have not been clearly defined.

Historical perspective

  1. Top of page
  2. Summary
  3. Historical perspective
  4. Evidence for antifungal prophylaxis: randomized studies
  5. Meta-analyses of antifungal prophylaxis
  6. Recommendations of evidence-based guidelines
  7. Continuing debate and future perspectives
  8. References

Nystatin, the first antifungal antibiotic, was discovered in 1951 (Hazen & Brown, 1960) at a time when IFD’s were known to be frequently lethal in patients suffering from leukaemia (Frei et al, 1965) Originally named Fungicidin it was christened after the New York State Department of Health where its discoverers worked and was effective in mucosal Candida infections. It could be given topically in large doses of up to 12 g/d (60 Mu) without apparent ill-effects, but was too toxic for parenteral use. It was already well recognized that patients treated with corticosteroids for leukaemia were at risk of developing oropharyngeal candidiasis and might benefit from prophylaxis with this drug. In 1956 the isolation of amphotericin B (AmB) from Streptomyces nodosus was reported by Gold et al (1956). This polyene had similar antifungal activities to nystatin but was less toxic when given intravenously (Utz et al, 1964). By the start of the 1960’s both polyenes had been used to prevent candidiasis (Stough et al, 1959; Hazen & Brown, 1960).

The imidazole derivative miconazole was synthesized in the Janssen Pharmaceutical laboratory (Van Cutsem & Thienpont, 1972) and by 1980 ketoconazole became available, following which each drug was tested for prophylactic efficacy. Miconazole use was substantially limited to oral administration for topical activity but there was one study of intravenous miconazole for prophylaxis during neutropenia where it was found to be superior to placebo (Wingard et al, 1987). There was a flurry of studies with ketoconazole that were mostly small, randomized, controlled trials according to the standards then current. Whilst some of these showed it had marginally greater efficacy over orally administered non-absorbable AmB or nystatin, others failed to identify a significant advance. Moreover the absorption of ketoconazole was erratic (Hann et al, 1982a) and there were concerns about its interaction with cyclosporine (Shepard et al, 1986). The tone-setting study of Hann et al (1982b) showed that ketoconazole, when compared to non-absorbable polyenes, could prevent oropharyngeal, but not invasive candidiasis. Meanwhile the triazole fluconazole was being developed and was later found to be effective in oral candidiasis complicating cancer chemotherapy even at the relatively low dose of 50 mg/d (Brammer, 1990). Consequently, a randomized open-label study was embarked upon to compare fluconazole at this dose versus a polyene as prophylaxis against candidiasis during leukaemia therapy-induced neutropenia (Philpott-Howard et al, 1993). The results were promising indeed, as the incidence of both oral and invasive candidiasis could be reduced fourfold. The seminal study of Goodman et al (1992), which adopted a higher dose of 400 mg fluconazole, reported a marked reduction in IFD, mostly due to Candida spp, from 15·8% (28/177 patients) in the placebo arm to 2·5% (5/179) in fluconazole recipients. This study heralded a 10-year period of intensive evaluation of fluconazole for prophylaxis of IFD in leukaemic patients. Fluconazole had the advantage of excellent bioavailability when given orally, few side-effects, and availability of an intravenous formulation. This success, however, exposed the lack of effective prophylaxis against mould infections, especially IA.

Itraconazole, another triazole, had begun clinical evaluation before fluconazole and because it had good in vitro activity against moulds, especially Aspergillus spp., it seemed to offer greater potential for antifungal prophylaxis in haematological practice. Its superiority over ketoconazole was suggested in two non randomized studies (Tricot et al, 1987), however it would be another decade before the results of comparisons with fluconazole appeared (Huijgens et al,1999; Morgenstern et al, 1999) The further exploration of itraconazole for prophylaxis was hampered by poor absorption of drug when given in capsules, by the patchy market availability of the oral cyclodextrin suspension, and by adverse drug interactions. The limited success with triazoles may have deterred but did not inhibit exploration of other antifungal agents, and knowing how predictable nephrotoxicity was with intravenous (i.v.) desoxycholate AmB, topical delivery to the lungs by inhalations of either the desoxycholate or lipid formulations (L-AmB) was evaluated in small studies; some suggested a benefit but others no benefit (Schwartz et al, 1999). More recent data suggest this route of administration may have therapeutic validity using liposomal AmB (AmBisome; Rijnders et al, 2008).

Of the new echinocandin class, only micafungin has been formally evaluated – in two randomized trials for antifungal prophylaxis – and has been found to be effective in reducing invasive Candida infections but without evidence of efficacy for preventing IA (van Burik et al, 2004; Hiramatsu et al, 2008).

The publication of two large randomized trials of antifungal prophylaxis (Cornely et al, 2007; Ullmann et al, 2007) with the newest available triazole posaconazole, a structural analogue of itraconazole (Schiller & Fung, 2007), generated new optimism that high-risk patients could be significantly protected from IFD during their treatment, although the lack of a trial to evaluate its efficacy during the early neutropenic period after allo-HSCT was, and continues to be, a clear deficiency. Furthermore, posaconazole has not formally been tested as primary therapy of IA, although it appeared to be at least as effective as any other antifungal agent based on historical efficacy data in a salvage therapy study (Walsh et al, 2007). It is surprising that although voriconazole is widely regarded as the antifungal of choice for primary therapy of IA (Herbrecht et al, 2002), its efficacy for antifungal prophylaxis has only recently been evaluated in two large trials, the results of which have been fully reported (Wingard et al, 2010) or appeared in abstract form (Marks et al, 2009).

Evidence for antifungal prophylaxis: randomized studies

  1. Top of page
  2. Summary
  3. Historical perspective
  4. Evidence for antifungal prophylaxis: randomized studies
  5. Meta-analyses of antifungal prophylaxis
  6. Recommendations of evidence-based guidelines
  7. Continuing debate and future perspectives
  8. References

Table I summarizes the current evidence base for prophylaxis to prevent IFD in patients with profound neutropenia due to haematological malignancy or HSCT. The following sections review recent evidence and where randomized trials are not available, summarize the available data.

Table I.   Studies of antifungal prophylaxis in chemotherapy patients with haematological malignancy and in haematopoietic stem cell transplantation.
ReferenceDesignPopulationAgentsOutcome (IFI, mortality)Comments
  1. IFD, invasive fungal disease; HSCT, haematopoietic stem cell transplant; ANC, absolute neutrophil count; HLA, human leucocyte antigen; AML, acute myeloid leukaemia; MDS, myelodysplastic syndrome; ns, not significant; GVHD, graft versus host disease; IA, invasive aspergillosis; i.v., intravenous; AmB, amphotericin B.

Fluconazole versus comparator
Goodman et al (1992)Randomized double blind single centre n = 356Autologous = allogeneic HSCT. Up to engraftmentFluconazole 400 mg/d vs. PlaceboIFD 2·8% vs. 15·8% Mortality no significant differenceNo survival benefit with fluconazole
Slavin et al (1995)Randomized double blind single centre n = 300Allogeneic > autologous HSCT Up to day 75Fluconazole 400 mg/d vs. placeboIFD 7% vs. 18% Mortality significantly less at day 100Fluconazole survival benefit persisted at 8 year follow-up (Marr et al, 2000)
MacMillan et al (2002)Randomized single centre n = 253Allogeneic (55%) and autologous (45%) Adult and paediatric patientsFluconazole 400 mg vs. 200 mg/dNo difference in systemic IFD at day 50, 4% vs. 1% (P = 0·08)Low incidence of IFD both arms
Menichetti et al, (1994)Randomized controlled multicentre n = 820Acute leukaemia, induction or reinductionFluconazole 150 mg/d vs. AmB 500 mg oral QIDNo difference in IFD Fluconazole (2·6%) vs. AmB (2·5%) 
Winston et al (1993)Randomized, placebo- controlled, double blind multicentre n = 257Acute leukaemia anticipated ANC < 0·5 × 109/l for ≥7 dFluconazole 400 mg/d vs. placeboNo difference in IFD (4% vs. 8%) or mortality 
Rotstein et al (1999)Randomized, double-blind, controlled multicentre n = 304AML/autologous HSCT, intensive chemotherapyFluconazole 400 mg/d vs. placeboProven IFD17% vs. 3% (P < 0·001) No overall survival benefitMost useful in cytarabine/anthracycline for AML induction and autologous HSCT without growth factor support
Kern et al (1998)Randomized, controlled multicentre n = 68Relapsed and refractory AMLFluconazole 400 mg/d vs. placeboNo difference IFD or survival 
Itraconazole versus comparator
Winston et al (2003)Randomized, double blind multicentre n = 140Allogeneic HSCTItraconazole 200 mg bd vs. fluconazoleProven IFD 9% vs. 25% (P = 0·01). IA 4% vs. 12% (ns) Trend towards fewer fungal deaths with itraconazole (9% vs. 18%, P = 0·13, ns)More GVHD in fluconazole arm Gastrointestinal intolerance 24% vs. 9%
Marr et al (2004a)Randomized, double blind single centre n = 299Allogeneic HSCTItraconazole 2·5 mg/kg tds vs. fluconazole 400 mg/dInvasive mould infection 5% vs. 12% (P = 0·03) IFD 7% vs. 15% (P = 0·03) Mortality difference not significantDiscontinuation due to gastrointestinal intolerance 36% vs. 16% (P < 0·001)
Morgenstern et al (1999)Randomized multicentre n = 445 (581 neutropenic episodes)Allogeneic, autologous HSCT and chemotherapy2·5 mg/kg oral solution bd vs. fluconazole 50 mg/dIFD one with itraconazole vs. six with fluconazole (P = 0·06)Note: most infections in the low dose fluconazole arm were due to Candida spp
Nucci et al (2000)Randomized, double-blind two centres n = 210Autologous HSCT, haematological malignancy with expected duration neutropenia >7 dItraconazole capsules 100 mg bd vs. placeboIFD itraconazole 6% vs. 15% placebo (P = 0·03) 
Menichetti et al (1999)Randomized, double-blind multicentre n = 405Autologous HSCT, haematological malignancyItraconazole oral solution 2·5 mg/kg bd vs. placeboProven and suspected IFD itraconazole (24%) vs. placebo (33%) (P = 0·35) No difference in mortality 
Harousseau et al (2000)Randomized double blind multicentre n = 557Autologous HSCT, acute leukaemiaItraconazole oral solution 2·5 mg/kg bd vs. AmB capsules 500 mg QIDNo difference in proven IFD. Itraconazole (2·8%) vs. AmB (4·7%) 
Posaconazole versus comparator
Ullmann et al, 2007Prospective, randomized, double-blind multicentre n = 600Allogeneic HSCT with ≥grade 2 or chronic extensive GVHDPosaconazole 200 mg tds vs. Fluconazole 400 mg/dProven/probable IFD 7% vs. 14% Mortality difference not significantFew patients with most severe form of GVHD (grade 4) at entry Underpowered for itraconazole comparison
Cornely et al, 2007Randomized. not blinded multicentre n = 602AML/MDS with intensive chemotherapyPosaconazole 200 mg tds vs. fluconazole 400 mg/d (n = 240) or itraconazole 200 mg bd (n = 58)Proven/probable IFD 2% vs. 8% (P = 0·0009). Mortality15% vs. 22%P = 0·03 Serious adverse events possibly or probably related to treatment in 19 (6%) posaconazole group and 6 (2%) in the fluconazole or itraconazole group (P = 0·01)Not powered to compare itraconazole. Many of cases diagnosed by positive serum galactomannan
Voriconazole versus comparator
Wingard et al (2010)Randomized, double blind multicentre n = 600Allogeneic HSCT (HLA matched in at least 5/6 loci)Voriconazole 200 mg bd vs. fluconazole 400 mg dailyFungal-free survival at day 180 was not different at 75% and 78% IFD not significantly different voriconazole (7·3%) vs. fluconazole (11·2%)Patients were monitored with serum galactomannan tests twice weekly to day 60, then weekly
Echinocandin versus comparator
van Burik et al (2004)Prospective, randomized, double blind multicentre n = 882Allogeneic slightly >autologous HSCT. During neutropeniaMicafungin 50 mg/d i.v. vs. fluconazole 400 mg/dMicafungin group: Proven/probable/possible IFD 20% vs. 26·5% fluconazole group (CI, 0·9–12%; P = 0·03) Mortality difference not significantTrend towards efficacy against IA with micafungin (n = 1) vs. fluconazole (n = 7); (P = 0·07)
Mattiuzzi et al (2006)Open label, randomized single centre n = 192AML/MDS Induction chemotherapyCaspofungin 50 mg/d i.v. vs. Itraconazole 200 mg i.v. dailyCompleted prophylaxis without IFD: caspofungin (51%) vs. itraconazole (52%); difference not significantNo significant difference in mortality
Amphotericin B versus comparator
Perfect et al (1992)Randomized, blinded single centre n = 182Autologous HSCT During neutropeniaConventional AmB 0·1 mg/kg/d vs. placeboNo difference in IFD. Survival advantage amphotercin B (P = 0·04) 
Riley et al (1994)Double blind, randomized, controlled single centre n = 35Allogeneic > autologous HSCT During neutropeniaConventional AmB 0·1 mg/kg/d vs. placeboNo difference in proven IFD or survival 
Tollemar et al (1993)Randomized, double-blind single centre n = 76Allogeneic and autologous HSCTLiposomal AmB 1 mg/kg/d vs. placeboNo difference in proven IFD or survival 
Kelsey et al (1999)Randomized, double-blind controlled multicentre n = 161Allogeneic > autologous HSCT During neutropeniaLiposomal AmB 2 mg/kg three times per week vs. placeboNo difference in proven IFD or in survival 
Penack et al (2006)Prospective, randomized, open label n = 231Chemotherapy and autologous HSCT neutropenia expected >10 dLiposomal AmB 50 mg alternate days vs. no prophylaxisIFD 4% vs. 20% (P = 0·001) No significant difference in mortality 
Mattiuzzi et al (2004)Comparison of two time periods; non-randomized single centre n = 201AML/MDS Induction chemotherapyAbelcet (n = 131) 2·5 mg/kg given three times a week vs. Liposomal AmB (n = 70) 3 mg/kg three times a weekProven IFD: Abelcet (5%) vs. liposomal AmB (4%). Adverse events similarLiposomal AmB group was a historical control group
Nebulized amphotericin B versus comparator
Rijnders et al (2008)Prospective randomized single centre n = 271Few allogeneic HSCT; autologous HSCT and chemotherapyAerosolized liposomal AmB 12 mg 2 d per week vs. placebo All patients also received fluconazoleInvasive aspergillosis 6/139 vs. 18/132 (P = 0·003). Mortality not significantly different 
Schwartz et al (1999)Randomized unblinded n = 382 multicentreHaematological malignancy/autologous HSCT/solid tumourNebulized AmB 10 mg bd vs. nothingNo difference in IFD Proven, probable, possible IFD 3% vs. 7% No difference in mortality 

Prophylaxis for neutropenia in patients undergoing chemotherapy for haematological malignancy

Cornely et al (2007) conducted a randomized comparison of prophylaxis with posaconazole versus either fluconazole or itraconazole in patients undergoing chemotherapy for AML or myelodysplastic syndrome (MDS). Patients received prophylaxis with each cycle of chemotherapy until recovery from neutropenia and complete remission, occurrence of an IFD according to the original EORTC/MSG definitions (Ascioglu et al, 2002), or for up to 12 weeks, whichever came first. The incidence of proven or probable IFD during treatment was the primary endpoint and although the study was not blinded, the adjudication committee decided proven or probable IFD’s had occurred in seven patients (2%) in the posaconazole group and in 25 patients (8%) in the fluconazole/itraconazole group [absolute reduction in the posaconazole group, −6%; 95% confidence interval (CI), −9·7 to −2·5%; P < 0·001], fulfilling statistical criteria for superiority. Significantly fewer patients in the posaconazole group had IA (1% vs. 7%, P < 0·001), although its diagnosis relied heavily on GM results.

It has been suggested that the higher number of GM-based diagnoses in the fluconazole, or itraconazole, arm (16 vs. 2), which were not always accompanied by radiological or microbiological evidence of infection, might not have all reflected true cases of IA and that what was detected was the ability of posaconazole to suppress GM expression while fluconazole and itraconazole could not do so (de Pauw & Donnelly, 2007). However, survival was significantly longer among recipients of posaconazole than among the fluconazole or itraconazole recipients (P = 0·04) and this is only the second prophylaxis study to demonstrate an impact on overall survival, a more rigorous end-point than death from IFD. Serious adverse events possibly or probably antifungal drug-related were seen in 6% of the posaconazole group and 2% of the fluconazole or itraconazole group (P = 0·01).

The design of the Cornely et al (2007) study, however, does limit our ability to extrapolate its findings as most patients were undergoing their first cycle of chemotherapy. Whether the favourable results also apply to consolidation chemotherapy, when the incidence of IFD is usually lower, is unclear. Also, the study was not powered or designed to separate the potential effect of itraconazole from fluconazole, so it is unclear whether itraconazole would have been as effective as posaconazole. Further, as an i.v. formulation of posaconazole was not available, conventional AmB was substituted for posaconazole for up to 4 d but the patient was discontinued from the study if the requirement for i.v. therapy persisted longer.

In a follow up single-centre study of AML patients undergoing first remission-induction chemotherapy, posaconazole prophylaxis at 200 mg three times daily, was compared with a historical cohort who received oral polyene prophylaxis. Among the 77 posaconazole and 82 polyene recipents who were included in the final analysis the respective incidences of breakthrough IA and IFD were significantly reduced (2·6% vs. 13·4%P = 0·018; 3·9% vs. 19·5%, P = 0·003); however, there was no significant difference in incidence of pneumonia or lung infiltration, attributable or overall mortality (Vehreschild et al, 2010).

Vehreschild et al (2007) had previously evaluated the efficacy of oral voriconazole, 200 mg twice daily, in a prospective randomized, double-blind, placebo controlled trial in AML patients undergoing remission induction chemotherapy. The incidence of pulmonary infiltration up to day 21 after start of chemotherapy was the primary outcome measured. Twenty-five voriconazole recipients had no episodes of pulmonary infiltration compared to 5/15 in the placebo arm (P = 0·06); there were four cases of hepatosplenic candidiasis in the placebo arm. The trial was stopped prematurely because of the reduced mortality reported in the posaconazole study discussed above (Cornely et al, 2007) and the authors’ view that it was unethical to continue with a placebo arm.

In the above studies the majority of IFD’s occurred within 30 d of starting induction chemotherapy. The duration of triazole antifungal prophylaxis ranged from 15·8 ± 4·4 d (Vehreschild et al, 2007) to 29 ± 21 d (Cornely et al, 2007). Interestingly, in the latter study, posaconazole prohylaxis, while significantly reducing the incidence of IFD, also delayed the mean time to onset of IFD to 41 ± 26 d indicating that patients need continuing close monitoring beyond the cessation of prophylaxis.

It should be pointed out that because of the stringent entry criteria for most of the large comparative antifungal prophylaxis trials their findings may not fully reflect clinical practice where variables will include the conditioning regimen, local epidemiology of fungal infections, and status of the underlying disease.

Antifungal prophylaxis for patients with neutropenia after HSCT

The efficacy of fluconazole prophylaxis in HSCT was established in the 1990’s. Fluconazole was protective against IFD and led to a reduction in overall mortality when given for 75 d post-transplant (Slavin et al, 1995) as compared to stopping at the time of engraftment (Goodman et al, 1992). These effects on mortality in allogeneic HSCT recipients persisted after 8 years of follow- up (Marr et al, 2000). At the time of these studies, Candida spp. caused the majority of IFD’s. However since that time, changes in practice, including the use of stem cells (rather than bone marrow), growth factors, and non-myeloablative conditioning regimens have shortened the duration of post-transplant neutropenia and reduced conditioning toxicity and mucositis. Many transplant centres have adopted fluconazole prophylaxis and consequently invasive mould infections, as discussed above, are a greater risk than invasive candidiasis for allogeneic HSCT recipients (Marr et al, 2002; Thursky et al, 2004). The incidence of mould infection, and in particular IA, is still low after autologous transplants, with the exception of some patients with lymphoproliferative disorders receiving fludarabine in whom Gil et al (2009) found this drug to be an independent risk factor for IA (P = 0·008).

Itraconazole and voriconazole have a broader spectrum of activity than fluconazole, offering protection against Aspergillus, some other moulds and Candida spp. Two comparative trials of itraconazole versus fluconazole found that itraconazole was more effective in reducing the incidence of IFD, including IA (Winston et al, 2003; Marr et al, 2004a). However, it is not an ideal drug in view of drug–drug interactions e.g. with cyclophosphamide (Marr et al, 2004b) and vinca alkaloids (Gillies et al, 1998; Harnicar et al, 2009) and consequent toxicity. Approximately 30% of patients ceased itraconazole for toxicity-related reasons, primarily gastrointestinal intolerance and abnormal liver function tests (LFT’s), in the studies of Winston et al (2003), and Marr et al (2004a). The propensity to cause abnormal LFT’s and many of these drug interactions are shared by voriconazole (Brüggemann et al, 2009).

The findings of a randomized double-blind multi-centre trial comparing oral voriconazole with fluconazole prophylaxis in standard risk allogeneic HSCT for 180 d post-transplant has recently been reported (Wingard et al, 2010). Six hundred trial patients were closely monitored for IFD by GM testing and computerized tomography (CT) scan when clinically indicated. Despite there being fewer IFD’s, including IA, in the voriconazole arm there was no difference in fungal-free survival (FFS) or overall survival (OS) at 180 d or 12 months post-transplant (Wingard et al, 2010). The authors of this study noted a similar rate of probable and proven IFDs when compared with another antifungal prophylaxis study of patients with severe GVHD (Ullmann et al, 2007) but a lower incidence when compared to the study of AML patients receiving chemotherapy (Cornely et al, 2007). The number needed to be treated with voriconazole to prevent one IFD at day 180 was 26. Information on serum voriconazole concentrations in study participants was not available to the authors at the time of publication. Another study that has been completed in Europe has compared voriconazole and itraconazole prophylaxis in allo-HSCT recipients over a comparable risk period, again showing similar low rates of IFD in both arms but better tolerability in the voriconazole arm (Marks et al, 2009).

Evaluation of primary posaconazole prophylaxis in this setting is limited to small single centre studies thus far. Sanchez-Ortega et al (2010) studied posaconazole 200 mg thrice daily given to 33 patients in the early time period up to 100 d post allo-HSCT compared to 16 itraconazole recipients studied as a historical control group. Thirteen of 39 posaconazole recipients received T-cell depleted transplants. The incidence of probable/proven IFD was 0% vs. 12% in favour of posaconazole (P = 0·04) with a greater probability of FFS and OS.

In clinical practice the choice of regimen and timing of antifungal prophylaxis is not consistent. A survey of 32 US transplant centres found that there was variability in choice of antifungal, dose, frequency of administration, and, while the start and stop points were consistent for autologous transplants, there was greater variability for allogeneic transplants (Trifilio et al, 2004).

Antifungal Prophylaxis for HSCT recipients with graft-versus-host disease

Both the risk factors and epidemiology of IFD after HSCT have changed. Pre-engraftment, invasive mould infections are less common; most occur in the late post-transplant period, usually in the context of grade 3–4 GVHD and concomitant corticosteroid therapy (Marr et al, 2002; Thursky et al, 2006). Furthermore, the addition of the tumour necrosis factor-alpha inhibitor, infliximab, to steroid treatment of severe GVHD (Marty et al, 2003), or for prophylaxis of acute GVHD (Hamadani et al, 2008) has been reported to increase the incidence of IFD when compared to control patients not receiving infliximab.

In a randomized, double-blind, double dummy study of prophylaxis with posaconazole compared to fluconazole, Ullmann et al (2007) instituted prophylaxis for those with GVHD of grade 2 or greater severity, meeting the criteria for chronic extensive disease or undergoing intensive immunosuppressive therapy. Prophylaxis was continued for 24 weeks and follow-up was for an additional 8 weeks. The primary efficacy end-point was the incidence of proven or probable IFD according to Ascioglu et al (2002), during the 24-week period of prophylaxis. This study demonstrated a reduction in IFD (2·4% vs. 7·6%, P = 0·004), particularly IA (1·0% vs. 5·9%, P = 0·001) without a significant overall mortality benefit in patients receiving posaconazole compared to those receiving fluconazole. It has been suggested that significant benefit from posaconazole prophylaxis in this study was only achieved in the cohort who had a positive serum GM at baseline (Wingard et al, 2010). Posaconazole is only available in oral suspension so patients with severe GVHD involving the gastrointestinal tract were not well represented in this study and most patients had grade 2 or chronic extensive GVHD.

Recently, one centre has reviewed their experience with voriconazole administered either orally or intravenously to allogeneic HSCT recipients receiving at least 1 mg/kg/d of prednisolone for GVHD and reported only two Candida spp infections in 97 patients (Gergis et al, 2009). GVHD was initially graded as grade 3–4 in 31% of these patients. Winston et al (2010) followed 106 allogeneic HSCT recipients receiving posaconazole prophylaxis to day 100 or longer if receiving corticosteroids for prevention or treatment of GVHD. In this cohort, 60% of patients had GVHD of grade 2–4 and breakthrough fungal infections were seen in eight patients (7·5%), with three of these occurring before day 20.

Primary intravenous antifungal prophylaxis in high-risk haematological malignancy patients

Intravenous prophylaxis has to be considered when patients are unable to take oral agents, e.g. because of vomiting, grade 3–4 oral mucositis, GVHD, or infective colitis. For these reasons the intravenous route was incorporated into studies of fluconazole, itraconazole and voriconazole in allo-HSCT (Slavin et al, 1995; Winston et al, 2003; Marr et al, 2004a; Marks et al, 2009; Wingard et al, 2010).

Other intravenous agents have been evaluated for prophylaxis. A prospective, randomized, double-blind comparative trial of micafungin and fluconazole during the neutropenic (i.e., pre-engraftment) phase of HSCT found that the overall success rate was significantly higher for patients in the micafungin arm (80%, compared with 73·5% in the fluconazole arm) with treatment success measured by the absence of proven, probable, or suspected IFD through to the end of prophylaxis and through to the end of the 4-week post-treatment period. Although there was a trend towards reduction of IA in the micafungin arm, its incidence in this study was too low to assess the drug’s potential benefit (van Burik et al, 2004).

Trials of low-dose conventional AmB prophylaxis have been small and inconclusive (Perfect et al, 1992; Riley et al, 1994). There are four studies of L-AmB products administered intermittently. The first was a non-blinded study of 219 neutropenic episodes in 132 patients (predominantly AML but including 29 autologous HSCT recipients). Liposomal AmB (AmBisome), 50 mg on alternate days, was compared with no prophylaxis. Prophylaxis reduced the incidence of IFD, including IA, although most of the Aspergillus infections in the placebo arm were probable, not proven (Penack et al, 2006). The second study compared AmB lipid complex (Abelcet), 2·5 mg/kg, given three times weekly in patients with newly diagnosed AML or high-risk MDS undergoing induction chemotherapy, with a historical control group that had received prophylactic liposomal AmB, 3 mg/kg, three times weekly. The two regimens led to equivalent rates of IFD (Mattiuzzi et al, 2004). The final two studies were small safety studies of liposomal AmB prophylaxis (7·5–10 mg/kg weekly) in either allo-HSCT recipients with GVHD (El-Cheikh et al, 2007) or neutropenic patients with acute leukaemia or allo-HSCT (Cordonnier et al, 2008). However, these doses were not well tolerated in allo-HSCT recipients with infusion-related toxicity (El-Cheikh et al, 2007; Cordonnier et al, 2008) and elevations of serum creatinine (El-Cheikh et al, 2007). An optimal dose and interval for intermittent administration of L-AmB prophylaxis, particularly for HSCT recipients, has not been defined.

Mattiuzzi et al (2011) have compared the efficacy and safety of voriconazole and itraconazole, given i.v., in an open-label randomized study of 123 patients receiving remission-induction or first salvage chemotherapy for AML or high-risk MDS. There were no documented IFD’s in the 71 voriconazole recipients compared to 2 in 52 itraconazole recipients. Side-effects led to the discontinuation of study drug at a high rate in both groups, 21% for voriconazole, mostly due to liver function abnormalities and hallucinations, and 12% for itraconazole. The authors concluded that i.v. voriconazole could nevertheless be used for primary prophylaxis in induction chemotherapy patients where oral administration is contra-indicated.

Aerosolized antifungals as prophylaxis

Conventional AmB was not well tolerated when nebulized for use as prophylaxis (Erjavec et al, 1997; Schwartz et al, 1999). Subsequently, Rijnders et al (2008) performed a randomized, placebo-controlled trial of liposomal AmB or placebo inhalation twice a week in patients with haematological malignancy with neutropenia expected for ≥10 d that included chemotherapy and HSCT patients. Inhalations were given until circulating neutrophil counts increased to >0·3 × 109 cells/l. In subsequent neutropenic episodes, the assigned treatment was restarted. The primary end point was the occurrence of IA according to Ascioglu et al (2002). A total of 271 patients were studied during 407 neutropenic episodes and 18 of 132 patients in the placebo group developed IA versus 6 of 139 patients in the liposomal AmB group [odds ratio (OR), 0·26; 95% CI, 0·09–0·72; P = 0·005] in the intent-to treat analysis, and 13 of 97 patients receiving placebo versus 2 of 91 receiving liposomal AmB developed IA (OR, 0·14; 95% CI, 0·02–0·66; P = 0·007) in the on-treatment analysis. Some adverse effects, but none serious, were reported in the liposomal AmB group, most frequently coughing (16 patients vs. 1 patient; P = 0·002). However, survival was not impacted on and it is unknown how this strategy compares with azole prophylaxis (Perfect, 2008). Recently, inhaled voriconazole i.v. solution (Tolman et al, 2009) and a nanostructured itraconazole (Alvarez et al, 2007) have been evaluated in murine models.

Conceptually, the delivery of prophylactic antifungal drug directly to the respiratory tract, either alone or combined with oral prophylaxis, is attractive for prevention of IA, but more studies are needed before its use can be recommended.

Meta-analyses of antifungal prophylaxis

  1. Top of page
  2. Summary
  3. Historical perspective
  4. Evidence for antifungal prophylaxis: randomized studies
  5. Meta-analyses of antifungal prophylaxis
  6. Recommendations of evidence-based guidelines
  7. Continuing debate and future perspectives
  8. References

The use of meta-analyses to assess antifungal prophylaxis has been contentious. Meta-analysis may be useful to explore endpoints that cannot easily be studied in smaller clinical trials; pooled results increase statistical power; and homogeneous results across studies increase the external validity of their findings. However, their validity is dependent on the quality and selection of studies included in the analysis and often studies in heterogenous patient groups are compared. Publication bias can also lead to the inclusion of more positive trials. The appropriateness of using endpoints such as ‘IFD-related mortality’ versus ‘all-cause mortality’ and the techniques employed (and related conclusions) have been debated (Glasmacher et al, 2005; Gotzsche & Johansen, 2005). For example, a study which demonstrates a decline in IFD rates and/or IFD-related mortality without an all-cause mortality benefit may simply reflect the difficulty of establishing a diagnosis in those receiving prophylaxis, rather than prevention of IFD.

The most recent meta-analysis of antifungal prophylaxis examined the use of any systemic antifungal prophylaxis in patients with cancer (largely haematological) and undergoing HSCT compared to the use of placebo, topical, or no prophylaxis (Robenshtok et al, 2007). In patients receiving prophylaxis there was a significant reduction in all-cause mortality. Allo-HSCT recipients benefited the most, with significant reductions in all-cause and fungal-related mortality, as well as documented IFD, while those with acute leukaemia showed only a borderline significant reduction in all-cause mortality but a significant decrease in fungal-related mortality and documented IFD. The number of autologous HSCT recipients was not large enough to draw firm conclusions despite a trend to reduction in documented IFD and fungal-related mortality. These authors also compared outcomes between drugs. On the basis of the two posaconazole studies described above (Cornely et al, 2007; Ullmann et al, 2007), posaconazole reduced all-cause mortality, fungal-related mortality and documented IFD compared to fluconazole. However, there were not enough patients receiving itraconazole for comparison.

Bow et al (2002) performed a meta-analysis on 38 randomized-controlled trials of antifungal prophylaxis (azoles or intravenous AmB formulations compared with subjects receiving placebo, no treatment, or polyene-based topical therapy) in severely neutropenic chemotherapy recipients. Overall, there were reductions in the use of parenteral antifungal therapy [prophylaxis success: OR, 0·57; 95% CI, 0·48–0·68; relative risk reduction (RRR), 19%; number requiring treatment for this outcome (NNT), 10 patients], invasive fungal infection (OR, 0·44; 95% CI, 0·35–0·55; RRR, 56%; NNT, 22 patients), and fungal infection-related mortality (OR, 0·58; 95% CI, 0·41–0·82; RRR, 47%; NNT, 52 patients). Incidence of IA was unaffected. Overall mortality was not reduced (OR, 0·87; 95% CI, 0·74–1·03) but subgroup analyses showed reduced mortality in patients who had prolonged neutropenia (OR, 0·72; 95% CI, 0·55–0·95) or who underwent HSCT (OR, 0·77; 95% CI, 0·59–0·99). The multivariate meta-regression analyses identified HSCT, prolonged neutropenia, remission-induction therapy with prolonged neutropenia, and higher azole dose as predictors of treatment effect. This meta-analysis also confirmed that efficacy of prophylaxis was highest when the incidence of IFD was approximately 15%.

Two meta-analyses examining the effect of fluconazole prophylaxis have been performed. Vardakas et al (2005) examined five randomized comparative trials of itraconazole and fluconazole in neutropenic patients with haematological malignancy. Although prophylactic fluconazole resulted in significantly more fungal infections [documented and suspected infections combined; (OR = 1·62, CI 1·06–2·48)], there were no statistically significant differences in documented fungal infections (OR = 1·51, CI 0·97–2·35), invasive fungal infections (OR = 1·44, CI 0·96–2·17), or overall mortality (OR = 0·89, CI 0·63–1·24). However, it should be noted that itraconazole capsules were used in several of these studies. Fewer patients were withdrawn due to adverse effects associated with fluconazole when compared with itraconazole (OR = 0·27, 95% CI 0·18–0·41). The approach of Kanda et al (2000) was to examine 16 randomized trials of fluconazole compared to placebo or topical non-absorbed agents. This meta-analysis failed to find an effect of fluconazole on both fatal fungal infection and invasive fungal infection in non-bone marrow transplantation patients. However, prophylactic fluconazole seemed to be effective when the incidence of invasive fungal infection was expected to be >15%.

Glasmacher et al (2003) evaluated itraconazole in 13 randomized controlled studies. Itraconazole significantly reduced the incidence of IFD (mean relative risk reduction, 40 ± 13%; P = 0·002), the incidence of invasive yeast infections (mean, 53 ± 19%; P = 0·004) and the mortality from IFD (mean, 35 ± 17%; P = 0·04). However, the overall mortality was not altered. The incidence of IA was only reduced in trials using the itraconazole cyclodextrin solution (mean, 48 ± 21%; P = 0·02) and not itraconazole capsules (mean, 75 ± 73% increase; P = 0·3). The effect of prophylaxis was clearly associated with the higher bioavailability of oral itraconazole cyclodextrin solution, recommended doses of which are at least 400 mg/d or i.v. itraconazole 200 mg/d.

Johansen and Gotzsche performed two meta-analyses, the first comparing AmB and fluconazole for ‘controlling’ fungal infections in neutropenic cancer patients (Johansen & Gotzsche, 2002). There were no significant differences between fluconazole and AmB, but the confidence intervals were wide and selection of studies questionable with mixing of clinical scenarios, such as prophylaxis and empiric therapy. Amphotericin B has been disfavoured in several trials through their design or analysis, and was associated with greater toxicity than fluconazole. The second meta-analysis compared L-AmB formulations with conventional AmB in cancer patients with neutropenia and showed no mortality benefit (RR 0·83, CI 0·62–1·12), but decreased IFD’s (RR 0·65, CI 0·44–0·97). L-AmB was associated with less nephrotoxicity compared to conventional AmB (RR 0·45, CI 0·37–0·54) and less dropouts from trials (RR 0·78, CI 0·62–0·97). Liposomal AmB showed no mortality benefit (RR 0·74, CI 0·52–1·07) compared to conventional AmB, but a trend towards a decrease in IFDs (RR 0·63, CI 0·39–1·01) (Johansen & Gotzsche, 2000).

In summary, meta-analyses support the use of prophylaxis in allo-HSCT and suggest benefit in some other patients, particularly those where the incidence of IFD is more than 15% and in patients receiving therapy for AML. Itraconazole is more effective than fluconazole for preventing IA but is associated with more side-effects (Glasmacher et al, 2003; Robenshtok et al, 2007) and requires serum levels of >500 ng/ml for efficacy which are more reliably achieved with the oral solution (Glasmacher et al, 2003). Posaconazole was more effective than fluconazole in patients with AML and GVHD but could not be compared directly with itraconazole due to low numbers in that arm of the study (Robenshtok et al, 2007).

Recommendations of evidence-based guidelines

  1. Top of page
  2. Summary
  3. Historical perspective
  4. Evidence for antifungal prophylaxis: randomized studies
  5. Meta-analyses of antifungal prophylaxis
  6. Recommendations of evidence-based guidelines
  7. Continuing debate and future perspectives
  8. References

The European Conference on Infections in Leukaemia (ECIL) have recently published consensus guidelines which include recommendations on antifungal prophylaxis (Maertens et al, 2010). The quality of evidence and strength of recommendations was according to the Infectious Diseases Society of America (IDSA) grading system (Kish, 2001).

For prophylaxis during induction chemotherapy for leukaemia, oral posaconazole, itraconazole and fluconazole were graded respectively, A-I, C-I and C-I, while the combination of aerosolized liposomal AmB and oral fluconazole was graded BI. During the neutropenic phase following allogeneic HSCT oral fluconazole and itraconazole were graded A-I and B-I respectively, while oral voriconazole was given a provisional A-I grade pending full publication of trial data (Marks et al, 2009; Wingard et al, 2010). Oral fluconazole with aerosolized L-AmB was graded BII, while i.v. micafungin and L-AmB were individually graded C-I. For prophylaxis during the GVHD phase post-HSCT posaconazole was graded A-I and voriconazole was provisionally graded A-I.

The IDSA have published guidelines on management of candidiasis (Pappas et al, 2009) and aspergillosis (Walsh et al, 2008). For prophylaxis of candidiasis during chemotherapy-induced neutropenia they recommend fluconazole (A-I), posaconazole (A-I) or caspofungin (B-II); itraconazole although graded A-I was less favoured than the other triazoles because it is less well tolerated. For neutropenic HSCT patients fluconazole, posaconazole and micafungin were each graded A-I. For prophylaxis of aspergillosis an A-I graded recommendation is only made for posaconazole in AML and MDS patients receiving chemotherapy, and in HSCT patients with GVHD. Other published guidelines (Cornely et al, 2009; Marr et al, 2009)) and reviews (Slavin et al, 2008; Wirk & Wingard, 2009; Leventakos et al, 2010; Kontoyiannis, 2011)) are broadly in line with the above recommendations.

Continuing debate and future perspectives

  1. Top of page
  2. Summary
  3. Historical perspective
  4. Evidence for antifungal prophylaxis: randomized studies
  5. Meta-analyses of antifungal prophylaxis
  6. Recommendations of evidence-based guidelines
  7. Continuing debate and future perspectives
  8. References

In light of these epidemiological and clinical trial data the case for using antifungal prophylaxis should be well established (see Table II). Yet there remain significant questions over the available evidence and how to apply it in clinical practice. Documented complications with some of the antifungal agents used for prophylaxis include drug-induced toxicity, and drug–drug interactions that may compromise efficacy, or increase toxicity (Rogers & Frost, 2009), and a further concern is induction of drug resistance in the target pathogens or selection of multi-drug resistant fungi which cause breakthrough infections (Marr et al, 2001; Marty et al, 2004; Kontoyiannis et al, 2005; Chamilos & Kontoyiannis, 2006; Tong et al, 2007).

Table II.   Keypoints for antifungal prophylaxis of IFD in haematological malignancy patients.
  1. IFD, invasive fungal disease; HSCT, haematopoietic stem cell transplant; HLA, human leucocyte antigen; ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; GVHD, graft-versus-host disease; ECIL, European Conference on Infections in Leukaemia.

Epidemiology of IFD
 Highest incidence of IFD is in AML remission induction chemotherapy (c.12%), with most infections occurring during the neutropenic period; followed by HLA unrelated, or mismatched donor HSCT, and then standard HLA matched allograft where proportionally more IFD occur after engraftment (c. 8%)
 Incidence of IFD after ALL remission induction chemotherapy c. 6%; after consolidation chemotherapy for acute leukaemia and autoHSCT <5%
 Invasive aspergillosis accounts for 60% of IFD, invasive candidiasis 30%, other mould infections 10%
 Median time of IFD onset after alloHSCT: Invasive candidiasis 60 d, invasive aspergillosis 90 d, other mould infections >6 months
 Attributable mortality from invasive aspergillosis and invasive candidiasis is 30–50%
Risk factors for IFD
 Duration of profound neutropenia (3 weeks or longer) after remission induction chemotherapy
 Inclusion of fludarabine in regimen for autologous HSCT
 Alemtuzumab use in treatment of some lymphoproliferative disorders
 Early after alloHSCT: Duration of profound neutropenia, older age, HLA mismatch
 Late after alloHSCT: GVHD, corticosteroid therapy, infliximab therapy, cytomegalovirus infection, iron overload
Antifungal prophylaxis
 Most significant benefit is where incidence of IFD is 10–15%; minimal benefit if incidence is <5%
 Meta-analyses most strongly support antifungal prophylaxis after AML remission induction chemotherapy and alloHSCT
 Only two trials have shown a reduction in overall mortality associated with antifungal prophylaxis
 ECIL evidence-based guidelines give highest grade (AI) to posaconazole for AML remission induction chemotherapy; fluconazole during the neutropenic phase after alloHSCT, and posaconazole during GVHD phase after HSCT

The preferred route of administration has been oral yet it is recognized that with several of the mould-active triazoles there are bioavailability issues, which, if not addressed, may lead to sub-optimal serum and tissue concentrations thereby creating a window of opportunity for breakthrough fungal disease. On the basis of pharmacokinetic data generated from the two large trials of posaconazole prophylaxis (Cornely et al, 2007; Ullmann et al, 2007) there is an inverse relationship between average steady state plasma concentrations and clinical failure rate; steady state takes 1 week to achieve and determination of drug plasma concentration is recommended in order to confirm a target concentration of 700 ng/ml has been reached (Jang et al, 2010). Pascual et al (2008) found therapeutic drug monitoring improved the safety and efficacy of voriconazole during its therapeutic use and this approach is recommended for both posaconazole and voriconazole. There have been far fewer studies evaluating intravenously administered prophylaxis yet this route would ensure that during the initial high-risk period of profound neutropenia adequate drug levels would be achieved. The lack of wider enthusiasm for this approach relates to the greater likelihood of drug-induced toxicity and budgetary costs. These disadvantages are assumed to be obviated by giving antifungals orally but this assumption has never been tested in a formal study.

After HSCT, the duration of neutropenia is likely to be longer if stem cells are from a matched unrelated donor or from cord blood, and consequently the incidence of IFD may be greater in the early post-transplant period in this patient group. However, there have been no prophylaxis studies specific to these higher risk clinical settings.

Some leukaemia chemotherapy regimens may also impart a high risk for IFD but the role of prophylaxis is not well evaluated. For example, alemtuzumab use causes profound T-cell immunosuppression (as opposed to neutropenia), and has been associated with an IFD rate >10% in patients with lymphoproliferative disorders (Thursky et al, 2006). Chemotherapy for ALL may span many months and entail high doses of corticosteroids and regular vinca alkaloids, which can make triazoles difficult to administer due to the likelihood of drug–drug interactions (Harnicar et al, 2009). Similar difficulties may occur when choosing antifungal prophylaxis for salvage regimens for lymphoma.

A further challenge is to identify an appropriate secondary prophylaxis regimen in patients receiving further immunosuppressive therapy at high risk of recurrence or relapse as a result of a previously documented IFD, and to date this has only been addressed in small non-randomized studies (Vehreschild et al, 2009; Cordonnier et al, 2010).

Despite the many antifungal prophylaxis studies and meta-analyses performed, few have shown an impact on overall mortality. Indeed, only two individual trials, fluconazole in mostly allogeneic HSCT recipients (Slavin et al, 1995) and posaconazole in patients with AML or MDS undergoing induction chemotherapy (Cornely et al, 2007), have had such an impact. The decision to use prophylaxis and which agent to choose is informed by a risk-benefit assessment taking into account the estimated probability of prior IFD based on patient risk factors and the institutional fungal epidemiology, reported reductions in IFD and mortality, available diagnostic tools, risk of breakthrough infections, drug toxicity, drug–drug interactions, and pharmacoeconomics.

As discussed earlier, meta-analyses support the use of prophylaxis for those at highest risk, namely allogeneic HSCT recipients and adults treated for acute leukaemia or MDS, as the incidence of IA in these groups without prophylaxis is likely to exceed 5% in many units. However, de Pauw and Donnelly (2007) have argued that in units like theirs with an incidence of IFD of <5%, antifungal prophylaxis is not justified since the number of patients needing to be treated by prophylaxis to prevent one IFD would be >20 which makes it ‘not effective’.

An alternative strategy in these high-risk populations relies on employing twice-weekly GM screening, and/or other biomarkers, together with early CT scan. Earlier, Maertens et al (2005) conducted a feasibility study of what they termed a preemptive approach, though a more accurate description might be a diagnostic-driven approach (Fig 1). This depends on having a high level of support available locally from laboratory medicine and imaging departments as components of an ‘integrated care plan’ (Barnes et al, 2009). If effective, this alternative approach might reduce costs of antifungals used for empirical therapy, a practice that is still widespread because of the inability to reliably exclude breakthrough IFD in persistently febrile neutropenic patients or because of the lack of suitable isolation facilities. Nevertheless, opinions about the best approach to managing IFD have gradually begun to shift away from empirical therapy towards the diagnostic-driven approach (Maertens et al, 2006; Herbrecht & Berceanu, 2008). However, recent studies comparing these have failed to establish that this alternative strategy has yet come of age (Maertens et al, 2005Cordonnier et al, 2009) and it is clear that biomarkers of IFD need to have more reliable sensitivity, specificity and predictive values.

image

Figure 1.  Management strategies for invasive mould disease. The figure depicts three phases: (1) colonization with a mould just after starting chemotherapy but before the patient becomes neutropenic, (2) infection with the mould has occurred, the patient is neutropenic but disease is not yet manifested and (3) the patient is profoundly neutropenic and mould disease is now established. Administering an antifungal agent during phase 1 would be considered to be prophylaxis, treatment during phase 2 treatment would be diagnostic-driven whereas therapy during phase 3 is directed-therapy for mould disease.

Download figure to PowerPoint

Meta-analyses indicate a high degree of diagnostic utility for the GM test in high-risk patients (Pfeiffer et al, 2006; Leeflang et al, 2008), and the EORTC/MSG definitions have included it in their mycological criteria, together with the less well studied beta-D-glucan assay (Senn et al, 2008). Application of the GM test to bronchoalveolar lavage fluid may additionally enhance its utility (Guo et al, 2010). Fungal polymerase chain reaction (PCR), which also has a long pedigree, has yet to attain the same degree of analytic validity and Aspergillus PCR has a way to go but progress is being made towards establishing a standardized methodology (Mengoli et al, 2009).

The two studies of posaconazole prophylaxis have brought this debate into sharp relief and now set the diagnostic-driven approach as a potential alternative (de Pauw & Donnelly, 2009). For the future, antifungal prophylaxis can be used with a greater confidence that high-risk patients are being protected from breakthrough IFD, but empirical therapy is likely to continue as part of standard care until the diagnostic driven approach is evaluated further to see if becomes the ‘third way’.

References

  1. Top of page
  2. Summary
  3. Historical perspective
  4. Evidence for antifungal prophylaxis: randomized studies
  5. Meta-analyses of antifungal prophylaxis
  6. Recommendations of evidence-based guidelines
  7. Continuing debate and future perspectives
  8. References
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