Until a few years ago, only fluconazole and itraconazole had been evaluated in randomized, controlled trials for PAP in patients with hematologic disorders [34–42]. In allo-SCT, fluconazole 400 mg once daily reduced the incidence of IFD, overall and attributable mortality, and use of empiric antifungals and was associated with improved long-term survival probably for its potential role in the containment of severe GVHD [34–36]. In autologous SCT, fluconazole showed to reduce attributable mortality, but the impact on reducing overall mortality, IFD, and empiric use of antifungals was less clear [34]. In AML, fluconazole reduced IFD, but no clear impact was documented on overall and attributable mortality and the need for empiric use of antifungals [37, 38].

Itraconazole is an azole with anti-Aspergillus activity and a variable oral absorption. There is a strong link of blood concentrations to drug efficacy and TDM is indicated especially in case of gastrointestinal dysfunction and potentially harmful co-medication. For IFD prophylaxis target trough blood levels should be above 0.5 mg/l [4]. In a meta-analysis, itraconazole showed to be efficacious in reducing IFD, IA, and fungal-related mortality when used in patients with hematologic malignancies [39]. In an open-label trial, itraconazole IV/PO was compared to fluconazole for long-term prophylaxis in allo-SCT. IFD were documented in 9 % of patients treated with itraconazole vs. 25 % of those receiving fluconazole, but overall mortality was similar and gastrointestinal side effects were more frequently documented in the itraconazole group (24 % vs. 9 %) [40]. In another open-label trial, itraconazole was compared to fluconazole in allo-SCT pts. IFD documented while on treatment were 7 % in the itraconazole-treated patients vs. 15 % in those receiving fluconazole, but at the end of follow-up, no difference was noted (13 % vs. 16 %). More patients were discontinued from itraconazole because of toxicity or gastrointestinal intolerance (36 % vs. 16 %) [41]. A further randomized study which compared itraconazole oral solution with fluconazole oral solution as PAP in 494 neutropenic non-transplant patients with hematologic malignancies reported no differences in the efficacy and safety of the two PAP regimens [42]. However, the incidence of IFDs in this study was too low (1.6 % of patients in the itraconazole group and 2 % of patients in the fluconazole group) to detect any significant efficacy difference [42].

Based on these studies, for several years fluconazole and to a less extent itraconazole were the only drugs recommended for primary prophylaxis against Candida infection in neutropenic patients and allogeneic SCT recipients [43, 44]. However, a major limitation of a Candida oriented prophylaxis is the lack of activity against molds, which now represent the most frequent cause of IFDs in such populations. In the past years, the consciousness of the epidemiological impact of IA and less common molds, including zygomycetes, Fusarium species, and Scedosporium species, has increased worldwide. At the same time, new broad-spectrum and well-tolerated antifungal drugs, in particular second-generation triazoles and echinocandins, became available, and prospective, controlled trials have been conducted to investigate their ability to prevent IFDs in high-risk hematologic patients [18, 19, 45–49].

Posaconazole, a second-generation triazole with broad spectrum of activity, including Aspergillus spp. and zygomycetes fungal group, is available in oral formulation only. The pharmacokinetics are characterized by marked interpatient variability mainly due to erratic bioavailability: the absorption of posaconazole is enhanced by co-administration with food, nutritional supplements, and low-pH beverage (cola), while it is reduced with co-administration of omeprazole. TDM is strongly suggested during posaconazole prophylaxis and target trough blood levels should be above 0.5 mg/l [32, 33]. A new tablet oral formulation and an intravenous formulation of posaconazole with less pharmacokinetic problems will soon be available.

Two phase III clinical studies indicated that posaconazole at a dose of 200 mg PO TID was at least non-inferior to a standard-of-care azole antifungal agent for preventing IFDs in acute myeloid leukemia and allo-SCT patients [45, 46]. The first study was a multicenter, randomized, open-label trial that compared posaconazole with fluconazole (400 mg/day) or itraconazole (200 mg/bid) for the prophylaxis of IFDs in 602 patients (aged >13 year) at high risk for neutropenia after receiving standard induction chemotherapy for a new diagnosis or first relapse of acute myelogenous leukemia or myelodysplastic syndrome [45]. Study drugs were administered at the start of each cycle of chemotherapy and were continued for a maximum of 12 weeks or until recovery from neutropenia and complete remission or occurrence of an IFD or adverse reaction to study drug. The primary efficacy end point was the incidence of proven or probable IFDs from randomization to the end of the oral treatment phase. Significantly fewer patients in the posaconazole arm compared with the fluconazole/itraconazole arm developed an IFD during the oral treatment phase (2 % vs 8 %, respectively; p = 0.001). While there was only a minor difference in the frequency of infections caused by Candida spp. between groups during the oral treatment phase, significantly fewer patients in the posaconazole group had IA (1 % vs. 7 %, p < 0.001). Survival was significantly longer among recipients of posaconazole than among recipients of fluconazole or itraconazole (p = 0.04). Serious adverse events possibly or probably related to treatment were reported in 6 % and 2 % of patients in the posaconazole and fluconazole or itraconazole group, respectively (P = 0.01).

The second study was a randomized, double-blind, multicenter trial in which posaconazole was compared with fluconazole (400 mg/day) for prophylaxis of IFDs in 600 allogeneic SCT recipients (aged >13 years) with GVHD [46]. Treatment was continued for 112 days or until the occurrence of a proven or probable IFD. The primary efficacy end point was the incidence of proven or probable IFDs during the period from randomization to day 112. The mean duration of posaconazole and fluconazole therapy was 80 days and 77 days, respectively. At the end of the fixed 112-day treatment period, the overall rates of IFD did not differ significantly between the two drugs (5.3 % in posaconazole group vs 9.0 % in fluconazole group; p = 0.07). Although the incidence of infections caused by Candida spp. was similar in both groups (<1 % of patients in either arm), posaconazole was superior to fluconazole in preventing proven or probable IA (2.3 % vs. 7.0 %; p = 0.006). During exposure period, in the posaconazole group, as compared with the fluconazole group, there were fewer breakthrough IFDs (2.4 % vs. 7.6 %, p = 0.004), particularly IA (1.0 % vs. 5.9 %, p = 0.001). Overall mortality was similar in the two groups, but the number of deaths from IFDs was lower in the posaconazole group (1 %, vs. 4 %; p = 0.046). The incidence of treatment-related adverse events was similar in the two groups (36 % in the posaconazole group and 38 % in the fluconazole group), and the rates of treatment-related serious adverse events were 13 % and 10 %, respectively.

Voriconazole, a second-generation triazole with anti-Aspergillus activity, is characterized by a highly variable pharmacokinetic profile (intra- and inter-subjects) either with IV or oral formulation mostly due to differences in the ability to metabolize the drug via the CYP2C19 P450 enzyme. Polymorphisms in the gene encoding this enzyme are common and result in variable rates of voriconazole metabolism. Additional factors that impact voriconazole metabolism are represented by liver disease, age, and co-medications interacting with CYP2C19 and CYP3A. As demonstrated in several studies, a large number of patients receiving voriconazole for therapy or prophylaxis may reach subtherapeutic or too high blood levels; therefore, also for this triazole TDM is strongly suggested in order to obtain plasma through levels ranging from 1 to 6 mg/L [32, 33, 50].

Two controlled studies of PAP with voriconazole have been conducted in allo-SCT patients [18, 19]. In the first study of primary prophylaxis, voriconazole was compared to fluconazole (295 patients vs 305 patients) in a randomized, double blind trial [18]. This study was characterized by a predefined, structured fungal screening program in order to obtain early diagnosis and therapy of fungal infections and to minimize morbidity and mortality. Patients undergoing myeloablative allo-SCT were randomized before transplant to receive study drugs for 100 days or for 180 days in higher risk patients. The primary end point was freedom from IFD or death (fungal-free survival, FFS) at 180 days. Despite trends to fewer IFDs (7.3 % vs. 11.2 %, p = 0.12), Aspergillus infections (9 vs. 17, p = 0.09), and less frequent empiric antifungal therapy (24.1 % vs. 30.2 %, p = 0.11) with voriconazole, FFS rates at 180 days were similar (75 % with fluconazole vs. 78 % with voriconazole, p = 0.49). Relapse-free and overall survival and the incidence of severe adverse events were also similar. This study demonstrates comparable efficacy of fluconazole or voriconazole prophylaxis in allo-SCT patients; however, a careful interpretation of the results is required. The study population considered in this trial was at lower risk of IFD as compared to a real-life allo-SCT population. Indeed, about 90 % of patients had a standard disease risk status, over half of transplants were matched related, the HLA match was 6/6 in 96 % of cases, half of patients did not develop acute or chronic GVHD, and the incidence of disease relapse/progression was only about 10 %. One would be interested to evaluate voriconazole’s performance in a higher risk population. This consideration is even more valid when looking at the results among patients with acute myeloid leukemia, a population at higher risk for IFD and with a poorer fungal-free survival. Interestingly, in this patient population voriconazole reduced IFDs (8.5 % vs 21 %; p = 0.04) and improved FFS (78 % vs 61 %; p = 0.04) compared to fluconazole [51].

The second study of primary prophylaxis compared voriconazole (200 mg b.i.d.) versus itraconazole (200 mg b.i.d.) in 489 patients receiving allogeneic HSCT for at least 100 days and up to 180 days from conditioning [19]. The primary objective was assessed on a composite end point, including survival at 180 days after transplant, no proven or probable breakthrough IFD, and no discontinuation of the study drug for more than 14 days during the 100-day prophylactic period. The voriconazole arm met the criteria for superiority in the primary end point when compared with the itraconazole arm (49.1 versus 34.5 %, p = 0.0004). The median duration of voriconazole prophylaxis was longer (97 days) than that of itraconazole (68 days), likely because of significantly more gastrointestinal adverse events (nausea, vomiting, and diarrhea) in the itraconazole group. However, the main concern with this study was the low rate of proven or probable IFDs (three in the voriconazole arm and six in the itraconazole arm).

In a randomized, double-blind trial, micafungin, 50 mg/day iv, was compared to fluconazole 400 mg/day in 882 SCT patients during the neutropenic phase [47]. Treatment success was 80 % for micafungin-treated group (340/425) vs. 73.5 % for the fluconazole-receiving patients (336/457) (p = 0.03). Aspergillosis was documented respectively in 1 vs. 7 cases. Empiric antifungal therapy was needed in 15 % vs. 21 % of the patient population. An increase in C. albicans colonization in micafungin arm was also documented. Criticisms were based on few pts, not exclusively high-risk and few proven IFD.

Caspofungin, 50 mg i.v. daily, was compared to IV itraconazole 200 mg as prophylactic antifungal therapy in 192 neutropenic patients with hematologic malignancies. No difference was documented between the treatment groups for success of prophylaxis (52 % vs. 51 %), proven or probable IFD (7 vs. 5), use of systemic antifungals for pneumonia or FUO (37 % vs. 34 %), fungal deaths: (4 vs 2) and tolerability [48].

Aerosolized liposomal amphotericin B, 10 mg twice weekly, was tested in a single center, double-blind, placebo-controlled trial in 271 patients with hematologic malignancies with neutropenia following chemotherapy or SCT. Both groups received fluconazole. Less proven/probable invasive pulmonary aspergillosis were documented in patients receiving aerosolized liposomal amphotericin B [49].

Based on the above studies, international guidelines on PAP have been updated. European and American guidelines have been summarized in Tables 16.1 and 16.2, respectively [15, 20, 21, 52].