Antifungal prophylaxis in haematology patients

REVIEW Antifungal prophylaxis in haematology patients R. de la Ca´mara Hospital de la Princesa, Haematology Department, Madrid, Spain

ABSTRACT Invasive fungal infections (IFIs) are now the main cause of death from infection in cases of allogeneic stem-cell transplantation and an important cause of morbidity and mortality in patients with haematological malignancies undergoing chemotherapy. Their prevention is one of the major objectives of anti-infective support programmes for onco-haematology patients. Fluconazole is safe and effective as prophylaxis for Candida infections in allogeneic stem-cell transplant (SCT) patients, although for nonSCT onco-haematology patients, its role has not been established, in spite of its very frequent use in clinical practice. After more than 10 years of massive use of fluconazole prophylaxis, there are several controversies in relation to its use. The emergence of resistant pathogens, the shift in the epidemiology of the main fungal pathogens, interactions among antifungal and non-antifungal drugs, organ toxicities and cost are some of the problematic issues, and similar problems should be expected with new drugs. Nowadays, the main IFI organisms in onco-haematology patients and the cause of the majority of fungal-related deaths are not Candida but Aspergillus species. Consequently, interest in fungal prophylaxis has moved from prevention of Candida infections to prevention of infections caused by Aspergillus, against which fluconazole has no activity. Itraconazole, administered as an oral solution or intravenously, but not as capsules, is an effective chemoprophylaxis for Aspergillus if the patient can tolerate the drug. New drugs, new prophylactic strategies and new forms of drug administration are under study and are reviewed in this article. Keywords Acute leukaemia, antifungal chemoprophylaxis, Aspergillus, Candida, invasive fungal infection, myelosuppressive chemotherapy, neutropenia, stem-cell transplantation Clin Microbiol Infect 2006; 12 (suppl 7) : 65–76

INTRODUCTION Invasive fungal infections (IFIs) are now the main cause of death from infection in cases of allogeneic stem-cell transplantation, and this represents a major change in the context of transplant mortality. At the end of the 1980s, cytomegalovirus (CMV) was the main cause of death from infection; as many as 20% of patients died because of CMV disease. The development of effective prevention, based on either prophylactic or pre-emptive therapy, dramatically reduced CMV-associated mortality and elevated IFI to first place among deadly infectious diseases. IFIs are also an important cause of morbidity and Corresponding author and reprint requests: R. de la Ca´mara, Hospital de la Princesa, Haematology Department, C ⁄ Diego de Leo´n no. 62, Madrid 28006, Spain E-mail: [email protected]

mortality in patients with haematological malignancies, mainly acute leukaemia and myelodysplastic syndromes, who are undergoing chemotherapy. The high rate of mortality (50– 90%) associated with these infections has remained essentially unchanged for the last 30 years, particularly for mould infections [1–3]. Not surprisingly, but quite disappointingly, the proportion of patients without a clinical diagnosis of invasive aspergillosis but with evidence of disease at autopsy (68%) has remained unchanged for 40 years (1953–1992) [4,5]. It is very difficult, or impossible, to cure what we do not suspect exists. Nowadays, mortality due to IFI, even with the new antifungal agents, is unacceptably high. Voriconazole, one of the great advances in the antifungal armamentarium and now the front-line treatment of choice for invasive aspergillosis, has little more than a 50% chance of overall success [6], a response rate that decreases

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to 32% for allogeneic stem-cell transplant (SCT) patients. Clearly, therefore, there is room for improvement. The prevention of IFI has been a major objective in the supportive care of cancer and SCT patients, and has been approached in different ways historically. In the 1970s, strict infection control and protective environment interventions were the backbone of the anti-infective prevention strategy. In the 1980s, empirical antifungal therapy for persistent febrile neutropenic patients, an early form of antifungal therapy, became very popular after the publication of the study by Pizzo et al. [7], and now it is considered standard practice [8]. In the early 1990s, the introduction of fluconazole [9] marked the beginning of a new era in the prevention of IFI. The great majority of IFIs in onco-haematology and SCT patients are due to Candida spp. and Aspergillus spp., so they have been the main targets of all preventive measures. This article reviews the subject of chemoprophylaxis with systemic antifungal agents in patients with haematological malignancies and in SCT patients. GENERAL CONSIDERATIONS Non-absorbed oral agents, e.g., clotrimazole, miconazole, amphotericin B and nystatin, which may reduce superficial mycoses but not IFI [10–12], are not discussed further. Nonetheless, prophylaxis of superficial candidiasis may be justified, because colonisation of two independent anatomical regions is a documented risk-factor for invasive candidiasis in onco-haematology patients. There are four basic aspects to be considered in relation to antifungal prophylaxis (Table 1). Selection of the patient population that should receive prophylaxis Only patients with high (or at least moderate) risk of acquiring an IFI should receive chemoprophylaxis. Patients clearly at high risk are those who receive an allogeneic SCT, and patients with acute leukaemias receiving myelosuppressive chemotherapy. Patients at low risk of IFI, e.g., those with lymphoma receiving conventional chemotherapy, should not receive antifungal prophylaxis [8,13,14]. The definition of the population at high risk of IFI is out of the scope of this review; however, several risk-assessment schemes are

Table 1. Basic aspects of antifungal prophylaxis 1. Patient selection: only patients at high risk of IFI 2. The fungus itself: knowledge of its epidemiology 3. The antifungal: Considerations: spectrum of activity, efficacy, route of administration, tolerance, drug interactions and cost Appropriate dosage: basic for efficacy: Fluconazole: 400 mg ⁄ day Itraconazole: 400 mg ⁄ day of oral solution or 200 mg ⁄ day intravenously 4. Administration (when and how long) Easy to determine in pure myelosuppressive therapy More difficult to determine in immunosuppressive therapies (allogeneic SCT) IFI, invasive fungal infection; SCT, stem-cell transplant.

useful for the a priori categorisation of patients according to risk [14,15] and can be used to achieve appropriate risk-based antifungal prophylaxis. The epidemiology of IFI in specific patient populations It is essential to recognise the main fungal pathogens and their incidence in the particular patient population that we manage. Knowledge of the main types of IFI determines the most appropriate drug, based on its spectrum of activity. The incidence of IFI indicates the overall benefit that can be expected; the greater the basal incidence, the greater the probable benefit. Moreover, if the basal incidence is low, it is difficult to prove the benefits of any antifungal prophylaxis, even if they exist. From the experience of more than 50 randomised studies of antifungal prophylaxis, the benefit of prophylaxis is usually demonstrable when the basal IFI incidence is ‡10– 20%; it is difficult, however, to show a benefit when the incidence is between 5% and 10% (this requires studies with a high number of patients); and there is no visible benefit when the incidence is below 5%. Selection of the appropriate antifungal agent and dosage Several characteristics of an antifungal agent have to be taken into consideration: its spectrum of activity, efficacy, route of administration, tolerance, drug interactions and cost. As important as knowledge of the fungal pathogens covered by the drug is knowledge of those not covered. This

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dual consideration has implications for the selection of resistant pathogens according to changes in epidemiology and for the empirical management of the suspected breakthrough infection that may develop during prophylaxis. Good examples of this, although controversial [12,16,17], are the shift to non-albicans species of Candida associated with fluconazole prophylaxis [18–20] and the increase of zygomycosis related to the use of voriconazole [21]. Convenient administration of the drug is an important aspect of all prophylactic regimens. For antifungal prophylaxis, this usually means a drug with both oral and intravenous formulations. At present, only triazoles fulfil this requirement, and that is one of the main reasons for their being first choice for antifungal prophylaxis. Equally important as the selection of the most appropriate antifungal agent is the determination of an adequate dose, as there is a clear dose dependency for efficacy of the two main agents in use, fluconazole and itraconazole (Table 1). For fluconazole, 400 mg ⁄ day is the recommended dose in the main guidelines in use [8,13,22] and in a meta-analysis of 16 trials of prophylactic fluconazole [23]. Nonetheless, some groups prefer a dose of 200 mg ⁄ day, and this is supported by the results of a randomised trial that found no differences in efficacy between dosages of 400 mg and 200 mg per day [24]. For itraconazole, a dose of at least 400 mg ⁄ day of oral solution or 200 mg ⁄ day of intravenous solution is recommended, based on the results of a meta-analysis [25]. Capsules at 400 mg ⁄ day or oral solution at 200 mg ⁄ day proved not to be effective [25]. Drug interactions are an important aspect that should be considered in all patients selected for antifungal prophylaxis, particularly with triazole compounds. Itraconazole [26] and voriconazole [27] have more clinically relevant interactions than fluconazole in combination with other drugs. With appropriate consideration, the management of azoles is easily mastered [28]. Patient co-morbilities, particularly liver and renal dysfunctions, and the safety profile of the antifungal agent are important considerations in the selection of the drug. Clinicians know very well that all formulations of amphotericin B are nephrotoxic, that azoles (particularly those that are broad-spectrum) are associated with hepatotoxicity, and that echinocandins are well-tolerated. Less well known is that liposomal

Antifungal prophylaxis in haematology patients 67

amphotericin B and fluconazole are also associated with hepatotoxicity [29]. Decision of when and for how long antifungal prophylaxis should be administered Although the logical answer, during the period of risk, is obvious, the application in practice is not so easy. The period of risk varies according to the type of pathogen and treatment, among other factors. In acute leukaemias treated with highly myelosuppressive chemotherapy, neutropenia is the major risk-factor for IFI; the period of risk is usually short (3–4 weeks) and coincides with the period of neutropenia. In patients undergoing immunosuppressive therapy in addition to myelosuppression, such as allogeneic SCT, the period of risk is longer (months) than the period of neutropenia, and quantification is much more difficult than the simple counting of neutrophils. SCT patients with graft vs. host disease (GVHD) may experience severe immunosupression for years. Conventional daily antifungal prophylaxis can be administered more or less easily for a period of weeks, but is not practical for many months; thus, alternative approaches are needed for these patients. The time at which antifungal prophylaxis is initiated also has implications for toxicity. It is well-known, from the study of Marr et al. [30], that itraconazole should be administered after the termination of chemotherapy, because of increased liver toxicity when it is given concomitantly with high-dose cyclophosphamide. This toxicity seems to result from an interaction between itraconazole and cyclophosphamide metabolism [31]. A similar effect was described for itraconazole and busulfan [32]. Fluconazole also alters the metabolism of cyclophosphamide [31,33], although no increase in liver toxicity has been reported when it is used concomitantly. As a general principle, these data advise against the concomitant use of antifungal azoles and cytochrome-metabolised cytotoxic agents such as cyclophosphamide. PREVENTION OF YEASTS, MOULDS OR BOTH? As explained in detail in other parts of this supplement, in the last 20 years a marked change has occurred in the epidemiology of IFI in oncohaematology patients [5,34,35]. The main cause of

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IFI in onco-haematology patients and the reason for the majority of fungal-related deaths are not Candida but Aspergillus species. It is important to look at what exactly is meant by ‘prevention of IFI’ in the prophylactic studies, and specifically to look separately for data concerning yeasts and moulds. Fluconazole, a good drug for yeast, is not effective in the prevention of invasive aspergillosis, so when the main IFIs are due to Aspergillus species, the use of fluconazole would be inappropriate. On the other hand, itraconazole, although it is at least as effective as fluconazole in preventing Candida infections [36], is not indicated for preventing only Candida infections, as itraconazole is more toxic and less well-tolerated than fluconazole. CANDIDA PROPHYLAXIS: THE ADVANTAGES Prophylaxis for Candida species is a favourable situation for several reasons (Table 2). Its efficacy in cases of SCT is well-established on the basis of good, randomised placebo-controlled trials [37,38] (Table 3). Fluconazole has been administered until Table 2. Candida prophylaxis: the optimal situation 1. The fungus is susceptible to a broad range of antifungal agents 2. The high-risk period is usually short (weeks) Candida is typically a pathogen of the neutropenic period 3. An antifungal agent of choice exists: fluconazole Convenient administration Well-absorbed and tolerated Few significant drug interactions Inexpensive Very effective (in SCT patients) SCT, stem-cell transplant.

Table 3. Candida prophylaxis with fluconazole in stem-cell transplant patients Study IFI incidence (%) Goodman et al. [37] Slavin et al. [38] IFI-related mortality (%) Goodman et al. [37] Slavin et al. [38] Overall mortality (%) Goodman et al. [37] Slavin et al. [38] Marr et al. [39]

No. Fluconazole Placebo p

356 300

2.8 7

15.8 18

<0.001 0.004

356 300

0.5 13

5.6 21

0.001 0.005

356 300 300

31 20 55

26 35 73

0.38 0.004 0.0001

IFI, invasive fungal infection.

engraftment [37], or until day +75 after transplant [38]. These studies showed not only a dramatic decrease in the incidence of IFI in SCT patients, but also a significant decrease in fungal-related mortality [37,38] and, with longer periods of fluconazole administration (until day +75), a decrease in overall mortality [38] (Table 3). A long-term follow-up study of the Slavin et al. trial [38] demonstrated that the survival benefit observed at day +110 was maintained at 8 years [39]. This longterm survival benefit was attributed to a reduction in candidiasis-related mortality [39]. It should be noted that the survival advantage associated with fluconazole prophylaxis was significant only in allogeneic SCT recipients and not in cases of autologous SCT [39]. There is no other trial that has shown a survival advantage with antifungal prophylaxis in the autologous setting. The long-term follow-up study of Marr et al. [39] has some inconsistencies with the original study of Slavin et al. [38]. Although both included exactly the same patient population, there was one difference in patient sex, there were eight differences in the type of room used at transplantation and, more important, the data for acute GVHD were significantly different between the studies. In the original trial [38], a higher statistically significant incidence of acute GVHD (grades 2–4) was associated with fluconazole prophylaxis. The authors pointed out in the discussion that the same finding was made previously in the trial of Goodman et al. [37]. However, in the follow-up study [39], although the incidence of acute GVHD (grades 2–4) was higher in the fluconazole arm, the difference was, surprisingly, not statistically significant. Moreover, fluconazole prophylaxis was associated with a statistically significant reduced incidence of severe gut GVHD (grades 3–4). Finally, it is difficult to understand how prophylaxis during the first 75 days can decrease mortality due to invasive candidiasis and related deaths up to 2 years later. Thus, as there is no other study that has reproduced this increase in survival with fluconazole prophylaxis, this aspect of the Slavin et al. study [38], although impressive, should be regarded with caution. CANDIDA PROPHYLAXIS: THE DISADVANTAGES After more than 10 years of widespread fluconazole prophylaxis, with thousands of patients

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enrolled in trials, there are several important controversial issues and clear shortcomings. For non-SCT onco-haematology patients, the prophylactic role of fluconazole has not been established, in spite of its very frequent use in clinical practice. A meta-analysis of 16 trials with 3734 patients failed to show an effect of fluconazole prophylaxis on either fatal fungal infection or systemic fungal infection in non-SCT patients [23]. This may be explained by the lower incidence of IFI in non-SCT patients (0–7.6%) compared with SCT patients (15.8 vs. 17.6%). First of all, even for allogeneic SCT patients, one wonders whether fluconazole prophylaxis is always necessary in spite of its demonstrated efficacy for Candida prevention. The answer will depend on the basal frequency of Candida infections in the patient population, as the benefits of prophylaxis depend on this. A good example is the study reported by Jantunen et al. [40]. In 685 allogeneic SCT patients managed without any systemic antifungal prophylaxis, the incidence of invasive candidiasis was very low (1.3%). This incidence is lower than the combined incidence (2.1%) of patients receiving prophylaxis with fluconazole in the two main randomised studies mentioned earlier [37,38]. So, if the basal incidence is low in the patient population (even allogeneic SCT patients), fluconazole prophylaxis seems not to be necessary. One important shortcoming of fluconazole prophylaxis relates to its limited spectrum of activity. Particularly significant is the lack of activity against Aspergillus, Candida krusei and some strains of Candida glabrata. Although the trials of prophylactic use of fluconazole have not demonstrated an increased incidence of invasive aspergillosis or other moulds, there is some other evidence that supports this case [34,35,41]. In an autopsy-based study of 355 SCT patients, fluconazole prophylaxis proved to be associated with a 60% increase in invasive aspergillosis, according to univariate and multivariate analyses [41]. This is the most direct evidence of the effect of fluconazole prophylaxis in the shift towards aspergillosis as the most frequent cause of IFI. Two studies fixed 1989 as, more or less, the year of the beginning of the shift from Candida to Aspergillus species as the most frequent cause of IFI [34,35], which coincides with the introduction of fluconazole into the market. In a large Japanese study of 594 263 autopsies, the predominant causative agent for severe mycotic

Antifungal prophylaxis in haematology patients 69

infection shifted from Candida to Aspergillus during the period 1989–1994 [34]. One of the possible reasons for the shift could be the introduction of fluconazole into the Japanese market in 1989. A US study of multiple-cause-of-death records from the National Center of Health Statistics from 1980 to 1997 found that a 50% decrease in candidiasis and a 350% increase in aspergillosis had occurred since 1989 [35]. This also coincides temporally with the introduction of fluconazole into the USA in 1990. There are several possible explanations for the association between fluconazole use and increased risk of mould infections [42]. One obviously disturbing possibility is the biological alteration of the offending opportunistic Aspergillus strain following exposure to fluconazole, resulting in an antagonism with subsequently administered amphotericin [43] and even an attenuation of the fungicidal activity of voriconazole [44]. Today, 50% of the infections caused by Candida are due to non-albicans species [45]. Fluconazole has been related to this species shift [18–20], although it has also occurred in patients who did not receive fluconazole prophylaxis [12,46,47]. In a double-blind, controlled, single-centre trial, fluconazole was associated with prolonged severe neutropenia (p 0.01) [48]. This adverse event has not been reported in other trials, so its significance is doubtful. Prophylaxis against one type of pathogen can have a negative impact on other types of pathogens, e.g., the association between a higher incidence of bacteraemia and antifungal prophylaxis, particularly oral triazoles [49,50]. ASPERGILLUS SPP. PROPHYLAXIS Invasive aspergillosis is the main cause of IFIs in onco-haematology and SCT patients, and its prevention is now the main concern. In acute leukaemia patients undergoing chemotherapy and in autologous SCT patients, invasive aspergillosis is a disease of the pre-engraftment phase, since 90% of the patients are neutropenic at diagnosis. However, in allogeneic SCT patients, it is a post-engraftment complication, as only 30% of the patients are neutropenic at diagnosis [51]. The main epidemiological difference in invasive aspergillosis in the allogeneic SCT setting is a shift of presentation to the late phase of the transplant (more than 6 months), which highlights the

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Table 4. Aspergillus prophylaxis: a complicated situation Compared to Candida prophylaxis: 1. The fungus is susceptible to a narrow range of antifungal agents 2. The high-risk period can be very long In allogeneic SCT patients, Aspergillus is a pathogen of the post-engraftment period 3. Antifungal candidates Convenient administration: only itraconazole and voriconazole Frequent drug interactions: azoles > echinocandin > amphotericin B More expensive Less effective

importance of the non-neutropenic immunosuppressed state in the pathogenesis of this disease [52]. Aspergillus prophylaxis is a more difficult task than Candida prophylaxis (Table 4). Itraconazole Two other reviews in this supplement discuss itraconazole, and thus it is not analysed in detail here. There is considerable experience with this drug in antifungal prophylaxis in onco-haematology patients. There are three main studies that support its efficacy in prophylaxis: two randomised blind studies comparing itraconazole with fluconazole [30,53], and one meta-analysis that included 16 randomised studies with a total of 3597 patients [25]. This evidence shows that itraconazole is effective in the overall prevention of IFIs and also invasive aspergillosis. No other marketed antifungal drug has been effective in preventing invasive aspergillosis until now [25]. Nowadays, itraconazole is the better choice for preventing invasive aspergillosis. A basic requirement for the prevention of Aspergillus infections is the use of an appropriate dosage, as noted before. Amphotericin B Conventional intravenous amphotericin B is poorly tolerated and has never been regarded as a good option for prophylaxis. Two randomised double-blind placebo-controlled studies were conducted with an ultra-low dose of conventional amphotericin B (0.1 mg ⁄ kg ⁄ day) [54,55]. One of the studies had too few patients to make it useful for analysis [55] and the other demonstrated no benefit over placebo [54]. Conventional amphotericin B was compared with fluconazole in two

randomised non-blinded trials, which found that amphotericin B was no more effective than fluconazole but clearly more toxic [56,57]. The lipid formulations of amphotericin B are clearly less toxic than conventional amphotericin B but have not shown a significant effect in the prevention of IFI. Two randomised double-blind, placebo-controlled studies with liposomal amphotericin B demonstrated no benefit over placebo [58,59]. An unusually designed study compared liposomal amphotericin B with a combination of fluconazole and an ineffective dose of itraconazole [60]. Liposomal amphotericin B was no more effective than the azole combination, but was more toxic [60]. An open-label randomised trial comparing amphotericin B colloidal dispersion with fluconazole was prematurely stopped because of the severe toxicity associated with amphotericin B infusion [61]. In summary, no published evidence supports the use of conventional or lipid formulations of amphotericin B for fungal prophylaxis. Nonetheless, a meta-analysis that included four placebo-controlled randomised trials concluded that prophylactic intravenous amphotericin B prevents invasive fungal infection, but not invasive aspergillosis, overall mortality or fungalrelated mortality [62]. An unpublished randomised phase III trial compared liposomal amphotericin B (50 mg every other day) with no antifungal prophylaxis, (Penack O, et al. Low dose Liposomal Amphotericin B (L-AmB) as Prophylaxis of Invasive Fungal Infection (IFI) in Patients (pts) with Prolonged Neutropenia (N): Results from a phase-III Trial. 45th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 2005 Washington. 2005: abstract M-975) and found a lower incidence of proven or probable IFI (4.6% vs. 20.2%, p 0.001) and less use of systemic antifungal agents (22% vs. 59%, p 0.001), but no differences in mortality or liver or renal abnormalities associated with liposomal amphotericin B. Both previously mentioned meta-analyses [62] and the unpublished study of Penack et al. leave open the possibility of liposomal amphotericin B for antifungal prophylaxis. Echinocandins Echinocandins are only suitable for short periods of prophylaxis, mainly during neutropenia, as they can only be given intravenously. In their

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favour, these compounds cover Candida and Aspergillus species, the main fungal pathogens in onco-haematology patients; they are well-tolerated and present few significant clinical drug interactions [27]. The prophylactic studies performed with these drugs, until now, have not been very impressive. Caspofungin was compared with intravenous itraconazole in a randomised, open-label study, [63]. Prophylaxis was administered only during neutropenia (median 21 days), in 192 patients receiving induction chemotherapy. There was no difference between groups in the incidence of proven or probable IFI (5.8% in the itraconazole group vs. 6.6% in the caspofungin group), mortality or adverse events. Micafungin was compared with intravenous fluconazole during neutropenia in a randomised, double-blind trial involving 882 SCT patients [64]. There was no difference in the incidence of proven or probable IFI (1.6% vs. 2.4%, p 0.48), invasive aspergillosis (0.2% vs. 1.5%, p 0.07), candidaemia (0.9% vs. 0.4%, p 0.43), mortality (4.2% vs. 5.7%, p 0.32) or adverse events between micafungin and fluconazole, respectively. The only positive effect associated with micafungin prophylaxis was lower use of empirical antifungal therapy (15.1% vs. 21.4%, p 0.02). Second-generation triazoles There is great interest in the employment of voriconazole and posaconazole for antifungal prophylaxis, as they have a broad spectrum of activity and are available in oral formulation. Voriconazole also has an intravenous formulation that makes it suitable for use during periods of gastrointestinal intolerance or mucositis. No data concerning the use of voriconazole in prophylaxis Table 5. Posaconazole prophylaxis vs. fluconazole prophylaxis in allogeneic stem-cell transplant patients with graft vs. host disease undergoing intense immunosuppressive therapy

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are available yet. There is an ongoing randomised, double-blind trial comparing voriconazole with fluconazole for 100 days (or 180 days in high-risk situations) in 600 allogeneic SCT patients [65]. This study will clarify whether there is an increased risk of zygomycosis associated with voriconazole prophylaxis. Recently, an exciting study was communicated in a preliminary form (Ullmann AJ, et al. Posaconazole (POS) vs Fluconazole (FLU) for prophylaxis of Invasive Fungal Infections (IFIs) in Allogenic Hematopoietic Stem Cell Transplant (HSCT) Recipients with Graft-versus-Host Disease (GVHD): Results of a Multicenter Trial. 45th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 2005 Washington. 2005: abstract M-716). This was a randomised, double-blind trial comparing oral posaconazole with fluconazole for prophylaxis in 600 allogeneic SCT patients with GVHD undergoing intensive immunosuppressive therapy. This is one of the populations at highest risk for IFI, so the drugs were tested in a very demanding scenario. Antifungal prophylaxis started when the patient had acute GVHD (grade 2–4) or extensive chronic GVHD and was undergoing intense immunosuppressive therapy for up to 16 weeks. The preliminary data are shown in Table 5 and are quite impressive. Posaconazole appeared to be superior to fluconazole in preventing invasive aspergillosis, and at least as effective in preventing other breakthrough IFIs. Posaconazole tolerance was good and similar to that of fluconazole, an interesting fact, as fluconazole is the least toxic of the available systemic antifungal agents. Pending publication of this trial, posaconazole is moving towards being regarded as a priority choice in cases of high-risk allogeneic SCT.

Total IFI (at 16 weeks) primary endpoint Total IFI (at 24 weeks) Invasive aspergillosis (at 16 weeks) Breakthrough IFI Overall mortality IFI-related mortality Discontinuation due to adverse events

Posaconazole

Fluconazole

OR

p

5%

9%

0.56

0.07

7% 2%

14% 7%

0.43 0.31

0.003 0.006

2% 25% 1% 33%

8% 28 4% 33%

0.30

0.004 NS 0.046 NS

IFI, invasive fungal infection; NS, not significant.

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OTHER FORMS OF ANTIFUNGAL PROPHYLAXIS New forms of prophylaxis Time-targeting vs. risk-targeting strategies Traditionally, antifungal prophylaxis in oncohaematology patients has been what we could call a ‘time-targeting’ strategy. It is given during a fixed period, starting at a fixed time, focusing on covering the neutropenic period. This strategy covers reasonably well a patient population in which IFI is mainly associated with neutropenia, e.g., acute leukaemias or myelodysplastic syndromes treated with intensive myelosuppressive therapy and the majority of cases of autologous SCT. In allogeneic SCT patients, one of the groups at highest risk for IFI, the majority of IFIs occur outside the period of neutropenia, highlighting the importance of the non-neutropenic immunosuppressed state in the pathogenesis of IFI. Except for Candida and Scedosporium species, more than 70% of the main IFIs occur after day 40 [66]. Prophylaxis targeting the period of GVHD resulted in very positive results in a recent trial (Ulmann Aj, et al. 45th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 2005 Washington. 2005: abstract M-716) and in another small study [67]. Reasonably, this ‘risk-targeting’ strategy could be complemented with a traditional ‘time-targeting’ strategy, during the neutropenic period, to achieve optimal antifungal coverage in high-risk patients. Prophylactic aerosolised amphotericin B inhalation Because invasive aspergillosis is usually acquired by inhalation of Aspergillus conidia and the lungs are the primary site of infection, the use of prophylactic amphotericin B inhalation is appealing. Although use of prophylactic conventional amphotericin B inhalation was associated with

benefit in some uncontrolled single-arm studies [68–71], it was found not to be effective in a large multicentre randomised trial in neutropenic patients [72]. Based on the result of this trial, the use of nebulised amphotericin B deoxycholate was abandoned in neutropenic patients. In recent aerosol studies, lipid formulations of amphotericin B proved to be safe and better tolerated than amphotericin B deoxycholate in lung transplant patients [73,74]. No amphotericin B can be detected in serum after aerosol administration of conventional or lipid formulations [73,75]. An advantage of the lipid formulation over conventional amphotericin B is the much longer persistence in bronchoalveolar fluid. In a recent study communicated in a preliminary form (Monforte V, et al. Pharmokinetics and Efficacy of Nebulized Ambisome (n-Amb) in lung transplantation (Lt). 44th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Washington. 2004: abstract M-1042), significant concentrations of amphotericin B (6.6 mg ⁄ L) were detected 14 days after a nebulised dose of liposomal amphotericin B. This offers the possibility of a very convenient form of administration (once-weekly) for longterm prophylaxis in onco-haematology patients. The preliminary data concerning this approach were reported recently (Ruiz I, et al. Safety and Tolerability of Nebulized Liposomal Amphotericin B in Hematologic patients. 45th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 2005 Washington. 2005: abstract M-977) . High-dose intermittent liposomal amphotericin B An interesting pharmacokinetic study (Gubbins PO, McConnell SA, Amsden JR, Anaissie E. Comparison of Liposomal Amphotericin B Plasma and Tissue Concentrations following a single

Avoiding

What do we achieve?

Antibacterial chemoprophylaxis Ganciclovir prophylaxis Graft T-cell depletion

Decrease in invasive candidiasis [76–78] Decrease in global IFI (16% to 6%) [79] Decrease in fatal aspergillosis (16% to 6%] [80] Decrease in invasive aspergillosis (HR 2.1) [52] Decrease in invasive aspergillosis (HR 7) [52]

Respiratory virus infections CMV disease

Table 6. Other prophylactic measures

IFI, invasive fungal infection; CMV, cytomegalovirus; HR, hazard ratio.

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Table 7. Antifungal prophylaxis in onco-haematology patients Indication based on clinical studies

Comments

Narrow: Candida

No activity against moulds

Itraconazole

AI: for allogeneic SCT CI: for the rest of patients BI

Broad: yeast and moulds

Voriconazole Posaconazole

No data available A ⁄ B? I for high-risk allogeneic SCT

No data available Broad: yeast and moulds

Conventional amphotericin Liposomal amphotericin ABCD Echinocandins

DI

Decreased incidence of invasive aspergillosis Studies ongoing Decreased incidence of invasive aspergillosis (unpublished data) No better than fluconazole but more toxic No benefit over placebo and expensive Toxic and expensive No better than fluconazole but more expensive

Drug

Graded recommendation

Fluconazole

CI

Narrowa: Candida

DI CI

Narrowa: Candida

a

The spectrum of activity of the antifungal agent is broad but it was classified as narrow according to the clinical efficacy in trials. ABCD, amphotericin B colloidal dispersion.

large (15 mg/kg) Dose or daily 1 mg/kg Dosing. 44th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Washington. 2004: abstract A-33) communicated in a preliminary form compared plasma and tissue concentrations following a large single dose (15 mg ⁄ kg) or a low daily dose of 1 mg ⁄ kg for 15 days in 11 SCT patients. For tissue sampling, a mucosal biopsy specimen was obtained on days 7 and 15 of treatment. There were no differences in tissue concentrations and creatinine in the singlelarge-dose vs. daily low-dose groups. At day 15 post-treatment, the mean concentrations in tissue were 12.1 mg ⁄ kg and 16.6 mg ⁄ kg, respectively. These results suggest a practical long-term regimen for intravenous prophylaxis. Clinical studies are needed, as there is no available information concerning the efficacy and safety of this approach in a large number of patients. OTHER PROPHYLACTIC MEASURES Other measures have a significant impact on the risk of IFI, even greater than antifungal prophylaxis (Table 6). Some of these measures include chemoprophylaxis for other types of pathogens, or the indirect effect of some viruses (e.g., CMV, respiratory virus), showing how interrelated and complex the infectious complications of oncohaematology patients can be. When thinking about administering chemoprophylaxis for a

specific pathogen, the possibility of inducing a change, not always in a good direction, in other apparently unrelated pathogens must be remembered. CONCLUSIONS The prevention of IFIs is one of the major objectives of the anti-infective support of oncohaematology patients. Graded recommendations, based on the criteria of the CDC [13], are shown in Table 7. Fluconazole proved, more than a decade ago, to be safe and effective as prophylaxis for Candida infections in allogeneic SCT patients. However, after more than 10 years of its widespread use, there have been, until now, controversies in relation to the best means of antifungal prophylaxis. The interest in fungal prophylaxis has moved from Candida to Aspergillus prevention, where fluconazole has no activity. Itraconazole, in oral solution or intravenous form, is the drug with most published evidence of efficacy. New drugs such as the secondgeneration triazoles, particularly voriconazole and posaconazole, new prophylactic strategies (‘risk-targeting’ instead of ‘time-targeting’), and new forms of antifungal delivery, e.g., inhalation and high-dose intermittent intravenous administration, are some of the promising possible solutions for improved prevention of IFI in the coming years.

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REFERENCES 1. Roden MM, Zaoutis TE, Buchanan WL et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis 2005; 41: 634–653. 2. Denning DW. Antifungal and surgical treatment of invasive aspergillosis: review of 2121 published cases. Rev Infect Dis 1997; 12: 1147–1201. 3. Lin S, Schranz J, Teutsch S. Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis 2001; 32: 358–366. 4. Young RC, Bennett JE, Vogel CL, Carbone PP, Devita VT. Aspergillosis. The spectrum of the disease in 98 patients. Medicine (Baltimore) 1970; 49: 147–173. 5. Groll AH, Shah PM, Mentzel C, Schneider M, Just-Nuebling G, Huebner K. Trends in the postmortem epidemiology of invasive fungal infections at a university hospital. J Infect 1996; 33: 23–32. 6. Herbrecht R, Denning DW, Patterson TF et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002; 347: 408–415. 7. Pizzo PA, Robichaud KJ, Gill FA, Witebsky FG. Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. Am J Med 1982; 72: 101–111. 8. Hughes WT, Armstrong D, Bodey GP et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 2002; 34: 730–751. 9. Maertens JA. History of the development of azole derivatives. Clin Microbiol Infect 2004; 10 (suppl 1): 1–10. 10. Gotzsche PC, Johansen HK. Nystatin prophylaxis and treatment in severely immunodepressed patients. Cochrane Database Syst Rev 2002; 2: CD002033. 11. Cornely OA, Ullmann AJ, Karthaus M. Evidence-based assessment of primary antifungal prophylaxis in patients with hematologic malignancies. Blood 2003; 101: 3365– 3372. 12. Hamza NS, Ghannoum MA, Lazarus HM. Choices aplenty: antifungal prophylaxis in hematopoietic stem cell transplant recipients. Bone Marrow Transplant 2004; 34: 377–389. 13. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Recommendations of CDC, the Infectious Disease Society of America, and the American Society of Blood and Marrow Transplantation. MMWR 2000; 49 (RR-10): 1–125. 14. Prentice HG, Kibbler CC, Prentice AG. Towards a targeted, risk-based, antifungal strategy in neutropenic patients. Br J Haematol 2000; 110: 273–284. 15. Mclintock LA, Jordanides NE, Allan EK et al. The use of a risk group stratification in the management of invasive fungal infection: a prospective validation. Br J Haematol 2004; 124: 403–404. 16. Kauffman CA. Zygomycosis: reemergence of an old pathogen. Clin Infect Dis 2004; 39: 588–590. 17. Garbino J, Kolarova L, Rohner P, Lew D, Pichna P, Pittet D. Secular trends of candidemia over 12 years in adult patients at a tertiary care hospital. Medicine (Baltimore) 2002; 81: 425–433. 18. Abi-Said D, Anaissie E, Uzun O, Raad I, Pinzcowski H, Vartivarian S. The epidemiology of hematogenous candidiasis caused by different Candida species. Clin Infect Dis 1997; 24: 1122–1128.

19. Hope W, Morton A, Eisen DP. Increase in prevalence of nosocomial non-Candida albicans candidaemia and the association of Candida krusei with fluconazole use. J Hosp Infect 2002; 50: 56–65. 20. Bodey GP, Mardani M, Hanna HA et al. The epidemiology of Candida glabrata and Candida albicans fungemia in immunocompromised patients with cancer. Am J Med 2002; 112: 380–385. 21. Kontoyiannis DP, Lionakis MS, Lewis RE et al. Zygomycosis in a tertiary-care cancer center in the era of Aspergillus-active antifungal therapy: a case-control observational study of 27 recent cases. J Infect Dis 2005; 191: 1350–1359. 22. Kruger WH, Bohlius J, Cornely OA et al. Antimicrobial prophylaxis in allogeneic bone marrow transplantation. Guidelines of the infectious diseases Working Party (AGIHO) of the German society of haematology and oncology. Ann Oncol 2005; 16: 1381–1390. 23. Kanda Y, Yamamoto R, Chizuka A et al. Prophylactic action of oral fluconazole against fungal infection in neutropenic patients. A meta-analysis of 16 randomized, controlled trials. Cancer 2000; 89: 1611–1625. 24. Macmillan ML, Goodman JL, Defor TE, Weisdorf DJ. Fluconazole to prevent yeast infections in bone marrow transplantation patients: a randomized trial of high versus reduced dose, and determination of the value of maintenance therapy. Am J Med 2002; 112: 369–379. 25. Glasmacher A, Prentice A, Gorschluter M et al. Itraconazole prevents invasive fungal infections in neutropenic patients treated for hematologic malignancies: evidence from a meta-analysis of 3,597 patients. J Clin Oncol 2003; 21: 4615–4626. 26. Prentice AG, Glasmacher A. Making sense of itraconazole pharmacokinetics. J Antimicrob Chemother 2005; 56 (suppl 1): i17–i22. 27. Kulemann V, Bauer M, Graninger W, Joukhadar C. Safety and potential of drug interactions of caspofungin and voriconazole in multimorbid patients. Pharmacology 2005; 75: 165–178. 28. Glasmacher A, Prentice AG. Evidence-based review of antifungal prophylaxis in neutropenic patients with haematological malignancies. J Antimicrob Chemother 2005; 56 (suppl 1): i23–i32. 29. Fischer MA, Winkelmayer WC, Rubin RH, Avorn J. The hepatotoxicity of antifungal medications in bone marrow transplant recipients. Clin Infect Dis 2005; 41: 301–307. 30. Marr KA, Crippa F, Leisenring W et al. Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants. Blood 2004; 103: 1527–1533. 31. Marr KA, Leisenring W, Crippa F et al. Cyclophosphamide metabolism is affected by azole antifungals. Blood 2004; 103: 1557–1559. 32. Buggia I, Zecca M, Alessandrino EP et al. Itraconazole can increase systemic exposure to busulfan in patients given bone marrow transplantation. GITMO (Gruppo Italiano Trapianto Midollo Osseo). Anticancer Res 1996; 16: 2083– 2088. 33. Yule SM, Walker D, Cole M et al. The effect of fluconazole on cyclophosphamide metabolism in children. Drug Metab Dispos 1999; 27: 417–421. 34. Yamazaki T, Kume H, Murase S, Yamashita E, Arisawa M. Epidemiology of visceral mycoses: analysis of data in

 2006 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 12 (suppl 7), 65–76

de la Ca´mara

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

annual of the pathological autopsy cases in Japan. J Clin Microbiol 1999; 37: 1732–1738. Mcneil MM, Nash SL, Hajjeh RA et al. Trends in mortality due to invasive mycotic diseases in the United States, 1980–1997. Clin Infect Dis 2001; 33: 641–647. Vardakas KZ, Michalopoulos A, Falagas ME. Fluconazole versus itraconazole for antifungal prophylaxis in neutropenic patients with haematological malignancies: a meta-analysis of randomised-controlled trials. Br J Haematol 2005; 131: 22–28. Goodman JL, Winston DJ, Greenfield RA et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 1992; 326: 845–851. Slavin MA, Osborne B, Adams R et al. Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation—a prospective, randomized, double-blind study. J Infect Dis 1995; 171: 1545–1552. Marr KA, Seidel K, Slavin MA et al. Prolonged fluconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: long-term follow-up of a randomized, placebo-controlled trial. Blood 2000; 96: 2055–2061. Jantunen E, Nihtinen A, Volin L et al. Candidaemia in allogeneic stem cell transplant recipients: low risk without fluconazole prophylaxis. Bone Marrow Transplant 2004; 34: 891–895. van Burik JH, Leisenring W, Myerson D et al. The effect of prophylactic fluconazole on the clinical spectrum of fungal diseases in bone marrow transplant recipients with special attention to hepatic candidiasis. An autopsy study of 355 patients. Medicine (Baltimore) 1998; 77: 246– 254. Singh N. Trends in the epidemiology of opportunistic fungal infections: predisposing factors and the impact of antimicrobial use practices. Clin Infect Dis 2001; 33: 1692– 1696. Kontoyiannis DP. Why prior fluconazole use is associated with an increased risk of invasive mold infections in immunosuppressed hosts: an alternative hypothesis. Clin Infect Dis 2002; 34: 1281–1283. Liu W, Lionakis MS, Lewis RE, Wiederhold N, May GS, Kontoyiannis DP. Attenuation of itraconazole fungicidal activity following preexposure of Aspergillus fumigatus to fluconazole. Antimicrob Agents Chemother 2003; 47: 3592– 3597. Pfaller MA, Diekema DJ. Twelve years of fluconazole in clinical practice: global trends in species distribution and fluconazole susceptibility of bloodstream isolates of Candida. Clin Microbiol Infect 2004; 10 (suppl 1): 11–23. Merz WG, Karp JE, Schron D, Saral R. Increased incidence of fungemia caused by Candida krusei. J Clin Microbiol 1986; 24: 581–584. Laverdiere M, Rotstein C, Bow EJ et al. Impact of fluconazole prophylaxis on fungal colonization and infection rates in neutropenic patients. The Canadian Fluconazole Study. J Antimicrob Chemother 2000; 46: 1001–1008. Schaffner A, Schaffner M. Effect of prophylactic fluconazole on the frequency of fungal infections, amphotericin B use, and health care costs in patients undergoing intensive chemotherapy for hematologic neoplasias. J Infect Dis 1995; 172: 1035–1041.

Antifungal prophylaxis in haematology patients 75

49. Viscoli C, Paesmans M, Sanz M et al. Association between antifungal prophylaxis and rate of documented bacteremia in febrile neutropenic cancer patients. Clin Infect Dis 2001; 32: 1532–1537. 50. Castagnola E, Machetti M, Bucci B, Viscoli C. Antifungal prophylaxis with azole derivatives. Clin Microbiol Infect 2004; 10 (suppl 1): 86–95. 51. Wald A, Leisenring W, van Burik JA, Bowden RA. Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis 1997; 175: 1459–1466. 52. Marr KA, Carter RA, Boeckh M, Martin P, Corey L. Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood 2002; 100: 4358–4366. 53. Winston DJ, Maziarz RT, Chandrasekar PH et al. Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients. A multicenter, randomized trial. Ann Intern Med 2003; 138: 705–713. 54. Perfect JR, Klotman ME, Gilbert CC et al. Prophylactic intravenous amphotericin B in neutropenic autologous bone marrow transplant recipients. J Infect Dis 1992; 165: 891–897. 55. Riley DK, Pavia AT, Beatty PG et al. The prophylactic use of low-dose amphotericin B in bone marrow transplant patients. Am J Med 1994; 97: 509–514. 56. Wolff SN, Fay J, Stevens D et al. Fluconazole vs low-dose amphotericin B for the prevention of fungal infections in patients undergoing bone marrow transplantation: a study of the North American Marrow Transplant Group. Bone Marrow Transplant 2000; 25: 853–859. 57. Bodey GP, Anaissie EJ, Elting LS, Estey E, O’Brien S, Kantarjian H. Antifungal prophylaxis during remission induction therapy for acute leukemia fluconazole versus intravenous amphotericin B. Cancer 1994; 73: 2099– 2106. 58. Kelsey SM, Goldman JM, Mccann S et al. Liposomal amphotericin (AmBisome) in the prophylaxis of fungal infections in neutropenic patients: a randomised, doubleblind, placebo-controlled study. Bone Marrow Transplant 1999; 23: 163–168. 59. Tollemar J, Ringden O, Andersson S, Sundberg B, Ljungman P, Tyden G. Randomized double-blind study of liposomal amphotericin B (Ambisome) prophylaxis of invasive fungal infections in bone marrow transplant recipients. Bone Marrow Transplant 1993; 12: 577–582. 60. Mattiuzzi GN, Estey E, Raad I et al. Liposomal amphotericin B versus the combination of fluconazole and itraconazole as prophylaxis for invasive fungal infections during induction chemotherapy for patients with acute myelogenous leukemia and myelodysplastic syndrome. Cancer 2003; 97: 450–456. 61. Timmers GJ, Zweegman S, Simoons-Smit AM, van Loenen AC, Touw D, Huijgens PC. Amphotericin B colloidal dispersion (Amphocil) vs fluconazole for the prevention of fungal infections in neutropenic patients: data of a prematurely stopped clinical trial. Bone Marrow Transplant 2000; 25: 879–884. 62. Bow EJ, Laverdiere M, Lussier N, Rotstein C, Cheang MS, Ioannou S. Antifungal prophylaxis for severely neutropenic chemotherapy recipients: a meta analysis of

 2006 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 12 (suppl 7), 65–76

76 Clinical Microbiology and Infection, Volume 12 Supplement 7, 2006

63.

64.

65.

66.

67.

68.

69.

70.

71.

randomized-controlled clinical trials. Cancer 2002; 94: 3230–3246. Mattiuzzi GN, Alvarado G, Giles FJ et al. Open-label, randomized comparison of itraconazole versus caspofungin for prophylaxis in patients with hematologic malignancies. Antimicrob Agents Chemother 2006; 50: 143– 147. van Burik JA, Ratanatharathorn V et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis 2004; 39: 1407–1416. Wingard JR. Design issues in a prospective randomized double-blinded trial of prophylaxis with fluconazole versus voriconazole after allogeneic hematopoietic cell transplantation. Clin Infect Dis 2004; 39 (suppl 4): S176– S180. Marr KA, Carter RA, Crippa F, Wald A, Corey L. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002; 34: 909–917. Grigg AP, Brown M, Roberts AW, Szer J, Slavin MA. A pilot study of targeted itraconazole prophylaxis in patients with graft-versus-host disease at high risk of invasive mould infections following allogeneic stem cell transplantation. Bone Marrow Transplant 2004; 34: 447– 453. Conneally E, Cafferkey MT, Daly PA, Keane CT, Mccann SR. Nebulized amphotericin B as prophylaxis against invasive aspergillosis in granulocytopenic patients. Bone Marrow Transplant 1990; 5: 403–406. Myers SE, Devine SM, Topper RL et al. A pilot study of prophylactic aerosolized amphotericin B in patients at risk for prolonged neutropenia. Leuk Lymphoma 1992; 8: 229–233. Hertenstein B, Kern WV, Schmeiser T et al. Low incidence of invasive fungal infections after bone marrow transplantation in patients receiving amphotericin B inhalations during neutropenia. Ann Hematol 1994; 68: 21–26. Erjavec Z, Woolthuis GM, de Vries-Hospers HG et al. Tolerance and efficacy of amphotericin B inhalations for prevention of invasive pulmonary aspergillosis in haematological patients. Eur J Clin Microbiol Infect Dis 1997; 16: 364–368.

72. Schwartz S, Behre G, Heinemann V et al. Aerosolized amphotericin B inhalations as prophylaxis of invasive aspergillus infections during prolonged neutropenia: results of a prospective randomized multicenter trial. Blood 1999; 93: 3654–3661. 73. Palmer SM, Drew RH, Whitehouse JD et al. Safety of aerosolized amphotericin B lipid complex in lung transplant recipients. Transplantation 2001; 72: 545–548. 74. Drew RH, Dodds Ashley E, Benjamin DK Jr, Duane Davis R, Palmer SM, Perfect JR. Comparative safety of amphotericin B lipid complex and amphotericin B deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipients. Transplantation 2004; 77: 232– 237. 75. Monforte V, Roman A, Gavalda J et al. Nebulized amphotericin B concentration and distribution in the respiratory tract of lung-transplanted patients. Transplantation 2003; 75: 1571–1574. 76. Wingard JR, Merz WG, Rinaldi MG, Johnson TR, Karp JE, Saral R. Increase in Candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole. N Engl J Med 1991; 325: 1274–1277. 77. Krcmery V Jr, Oravcova E, Spanik S et al. Nosocomial breakthrough fungaemia during antifungal prophylaxis or empirical antifungal therapy in 41 cancer patients receiving antineoplastic chemotherapy: analysis of aetiology risk factors and outcome. J Antimicrob Chemother 1998; 41: 373– 380. 78. Marr KA, Seidel K, White TC, Bowden RA. Candidemia in allogeneic blood and marrow transplant recipients: evolution of risk factors after the adoption of prophylactic fluconazole. J Infect Dis 2000; 181: 309–316. 79. Boeckh M, Gooley TA, Myerson D, Cunningham T, Schoch G, Bowden RA. Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study. Blood 1996; 88: 4063–4071. 80. Wagner JE, Thompson JS, Carter SL, Kernan NA. Effect of graft-versus-host disease prophylaxis on 3-year diseasefree survival in recipients of unrelated donor bone marrow (T-cell Depletion Trial): a multi-centre, randomised phase II–III trial. Lancet 2005; 366: 733–741.

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