Version May 2024
INTRODUCTION — Invasive fungal infections are common in selected hematopoietic cell transplant (HCT) recipients, such as allogeneic HCT recipients during the pre-engraftment period and in those with severe graft-versus-host disease and cause substantial morbidity and mortality.
Interest in antifungal prophylaxis for high-risk HCT recipients has been prompted by the rising incidence of life-threatening invasive fungal infections in such patients, the difficulty in establishing the diagnosis early in the course of infection, and the recognition that treatment outcomes are poor if initiation of therapy is delayed.
The epidemiology and prophylaxis of invasive fungal infections in HCT recipients will be discussed here. The epidemiology and prophylaxis of invasive fungal infections in patients with hematologic malignancies is reviewed elsewhere. (See "Prophylaxis of invasive fungal infections in adults with hematologic malignancies".)
Other important issues related to infections in HCT recipients are discussed separately:
●(See "Evaluation for infection before hematopoietic cell transplantation".)
●(See "Overview of infections following hematopoietic cell transplantation".)
●(See "Overview of neutropenic fever syndromes".)
●(See "Diagnostic approach to the adult cancer patient with neutropenic fever".)
●(See "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults".)
●(See "Prevention of infections in hematopoietic cell transplant recipients".)
●(See "Management of candidemia and invasive candidiasis in adults".)
●(See "Treatment and prevention of invasive aspergillosis".)
●(See "Mucormycosis (zygomycosis)".)
●(See "Treatment and prevention of Fusarium infection".)
EPIDEMIOLOGY — Both yeasts and molds cause serious invasive fungal infections in HCT recipients (figure 1). Prior to the routine use of antifungal prophylaxis, Candida spp accounted for the majority of fungal infections that occurred during the pre-engraftment period of HCT, followed by Aspergillus spp. More recently, Aspergillus has surpassed Candida as a cause of invasive fungal infections in HCT recipients, associated with the use of effective antifungal prophylaxis targeting Candida spp [1]. Both pathogens are associated with substantial risk for mortality.
Candida infection — Candida is the most important yeast pathogen in HCT recipients, accounting for most invasive yeast infections [1-3]. Meta-analyses and randomized trials have determined that the threshold incidence of Candida infection for which fluconazole prophylaxis appears to be efficacious is 6 to 10 percent [4-7]. Infection rates at or above this threshold are seen primarily during the pre-engraftment phase in allogeneic HCT recipients receiving myeloablative conditioning regimens and in some autologous HCT recipients who are not given prophylactic hematopoietic growth factors or who are at risk for severe oral and/or gastrointestinal mucositis (which is a risk factor for candidemia) [8].
Although Candida is ordinarily a harmless colonizer of mucosal surfaces and skin, breeches in skin or mucosal integrity can lead to invasion of deep tissues and hematogenous dissemination. The portal of entry for this commensal organism is thought to be primarily the gastrointestinal tract in this patient population, with translocation occurring as a result of mucosal injury from cytotoxic chemotherapy and total body irradiation given in the pretransplant conditioning regimen.
Candidemia is the most frequent clinical manifestation of invasive candidiasis. Candida is also a common fungal cause of central venous catheter infections. Less commonly, Candida causes disseminated candidiasis, including chronic disseminated candidiasis (hepatosplenic candidiasis). HCT recipients are at highest risk for invasive candidiasis during the pre-engraftment period (figure 1). Prior to the routine use of antifungal prophylaxis, the rate of invasive Candida infections was approximately 16 to 18 percent [9,10]. (See "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults" and "Chronic disseminated candidiasis (hepatosplenic candidiasis)".)
Although C. albicans accounts for about one-half of invasive Candida infections, HCT recipients are also at increased risk for infections caused by non-albicans Candida species (eg, C. glabrata, C. tropicalis) compared with other types of patients [11]. (See "Candidemia in adults: Epidemiology, microbiology, and pathogenesis", section on 'Prevalence of Candida species'.)
Aspergillus infection — Aspergillus is the most common mold pathogen, occurring most commonly during the post-engraftment period in patients with severe graft-versus-host disease [12-15]. Among allogeneic HCT recipients, the incidence of invasive aspergillosis ranges from 4 to 24 percent, with most studies reporting rates between 8 and 15 percent; in contrast, the incidence of invasive aspergillosis is only 1 to 2 percent among autologous HCT recipients [16].
The usual portal of entry of this airborne organism is inhalation into the sinuses and respiratory tract. The most frequent manifestation of invasive aspergillosis is pneumonia. Pulmonary infiltrates due to Aspergillus typically consist of one or more nodules with or without surrounding ground-glass opacities (the halo sign), cavities, air-crescent signs, or focal airspace consolidation. Other manifestations include sinusitis, localized skin ulcers, subcutaneous nodules, cerebral infarction, and/or fulminant disseminated disease.
A. fumigatus is the most common Aspergillus species to cause disease, but several other Aspergillus species also cause invasive disease. (See "Epidemiology and clinical manifestations of invasive aspergillosis".)
Other fungal infections — The agents of mucormycosis are the second most common cause of mold infections in HCT recipients [17,18] but are infrequent overall at most centers [19,20]. Mucormycosis can cause life-threatening rhino-orbital, pulmonary, cerebral, and/or disseminated infection [21]. (See "Mucormycosis (zygomycosis)", section on 'Risk factors'.)
Fusarium spp and Scedosporium spp have also been reported in HCT recipients. (See "Mycology, pathogenesis, and epidemiology of Fusarium infection" and "Epidemiology, clinical manifestations, and diagnosis of Scedosporium and Lomentospora infections".)
Although primary infection and reactivation infection with endemic fungi (histoplasmosis, blastomycosis, and coccidioidomycosis) is uncommon in HCT recipients, these fungi should also be considered in patients with prolonged glucocorticoid use or other immunosuppression who have lived in or traveled to endemic areas. (See "Pathogenesis and clinical features of pulmonary histoplasmosis" and "Mycology, pathogenesis, and epidemiology of blastomycosis" and "Primary pulmonary coccidioidal infection".)
Pneumocystis jirovecii historically has been a frequent cause of pneumonia. With routine anti-Pneumocystis prophylaxis, Pneumocystis pneumonia occurs infrequently today. However, Pneumocystis infections can occasionally occur; the risk is influenced by lapses in adherence to the prophylactic regimen and may be more frequent with certain prophylactic agents. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV".)
RISK FACTORS — Risk factors for invasive fungal infections in HCT recipients are discussed below.
Allogeneic HCT — After allogeneic HCT, there are three periods of elevated risk for invasive fungal infection (figure 1) [14,22,23]:
●During the neutropenic pre-engraftment phase
●During the early post-engraftment period, especially in patients who develop graft-versus-host disease (GVHD) requiring glucocorticoids
●During the late post-engraftment period, in patients who develop severe chronic GVHD that requires prolonged high-dose glucocorticoids or patients who relapse and must undergo reinduction chemotherapy.
Prior to engraftment, most fungal infections are due to Candida spp and the risk for invasive aspergillosis is low, except in patients with prior Aspergillus infections or in patients who have prolonged neutropenia due to delay in or failure of engraftment. Risk factors for invasive candidiasis during the pre-engraftment period include neutropenia, severe mucositis, and central venous catheter use [24]. Risk factors for aspergillosis before engraftment include prior multiple chemotherapy regimens, iron overload from multiple erythrocyte transfusions, prior history of invasive aspergillosis, failure to engraft after transplantation, and delayed engraftment such as is occasionally seen with umbilical cord blood transplantation [14,25]. Patients with advanced or refractory acute myelogenous leukemia are at higher risk of invasive mold infections than other leukemia patients. (See "Prophylaxis of invasive fungal infections in adults with hematologic malignancies", section on 'Acute leukemia'.)
After engraftment, the risk for invasive aspergillosis is much greater. Risk factors for Aspergillus infection after engraftment are GVHD and prolonged courses of glucocorticoids at high doses (>1 mg/kg per day of methylprednisolone or the equivalent dose of another glucocorticoid) [14].
Autologous HCT — The risk for invasive fungal infections is lower in autologous HCT recipients than allogeneic HCT recipients, but invasive fungal infections do occur in such patients. Risk factors for Candida infections in autologous HCT recipients include intensive conditioning regimens that cause substantial mucosal injury (resulting in oral and/or gastrointestinal mucositis), as well as prolonged neutropenia [26]. Autologous HCT recipients at risk for prolonged neutropenia include those who received a suboptimal number of stem cells and those who did not receive myeloid growth factors following transplantation. Autologous HCT recipients are not usually at high risk for invasive aspergillosis or other mold infections, unless they have a prior history of such an infection.
PROPHYLAXIS
Primary prophylaxis — Primary prophylaxis involves the administration of an antimicrobial agent to prevent infection in patients at increased risk who have not previously had the type of infection being targeted. The benefits of primary antifungal prophylaxis have been demonstrated in multiple studies. Much of the emphasis historically has been on the prevention of Candida infections. However, studies of Aspergillus prevention have intensified in recent years.
A 2007 meta-analysis that included 64 randomized trials compared systemic antifungal prophylaxis (eg, fluconazole, itraconazole, posaconazole) with a control arm (placebo, no intervention, or a nonsystemic antifungal agent such as clotrimazole) in cancer patients receiving myelosuppressive chemotherapy (predominantly for acute leukemia) or undergoing HCT [4]. The following findings were observed in HCT recipients:
●In allogeneic HCT recipients, antifungal prophylaxis reduced all-cause mortality (relative risk [RR] 0.62, 95% CI 0.45-0.85), fungal-related mortality (RR 0.52, 95% CI 0.27-0.99), and the incidence of documented invasive fungal infection (RR 0.33, 95% CI 0.18-0.63).
●In autologous HCT recipients, patients who received antifungal prophylaxis with low-dose intravenous (IV) amphotericin B had similar effect estimates as allogeneic HCT patients, but there were only a few studies, and sample sizes were small and lacked the power to reach significance. Changes in practices, including a multitude of new conditioning regimens, routine use of myeloid growth factors, and greater numbers of stem cells in peripheral blood grafts, means that the risk of fungal infections with current autologous transplant regimens is not clear and the efficacy of antifungal prophylaxis in patients receiving these regimens has not been studied sufficiently. Thus, the applicability of findings in prior studies is uncertain.
A 2012 meta-analysis that included 20 randomized trials compared mold-active prophylaxis with fluconazole prophylaxis in HCT recipients (14 trials) or patients with hematologic malignancy receiving chemotherapy (6 trials) with the following results [27]:
●Mold-active prophylaxis reduced the number of proven or probable invasive fungal infections compared with fluconazole prophylaxis (RR 0.71, 95% CI 0.52-0.98).
●Mold-active prophylaxis reduced the risk of invasive aspergillosis compared with fluconazole prophylaxis (RR 0.53, 95% CI 0.37-0.75).
●Mold-active prophylaxis reduced the risk of invasive fungal infection-related mortality compared with fluconazole prophylaxis (RR 0.67, 95% CI 0.47-0.96).
●There was no difference in overall mortality between patients who received mold-active prophylaxis and those who received fluconazole prophylaxis.
●Mold-active prophylaxis was associated with an increased risk of adverse events leading to antifungal discontinuation (RR 1.95, 95% CI 1.24-3.07).
It is important to note that most of the apparent benefit to anti-mold prophylaxis was observed in the non-HCT patients and that most large trials of HCT recipients have not shown a convincing benefit for anti-mold prophylaxis over fluconazole.
Approach to primary prophylaxis — The following recommendations represent our approach to antifungal prophylaxis in HCT recipients. These recommendations are generally in keeping with the 2018 American Society of Clinical Oncology and Infectious Diseases Society of America (IDSA) antimicrobial prophylaxis guidelines for patients with cancer-related immunosuppression [8], the 2016 IDSA guidelines for the diagnosis and management of aspergillosis [28], and the 2009 international guidelines for preventing infectious complications in HCT recipients [24].
It should be noted that there is ongoing controversy about the use of antifungal prophylaxis (see "Prophylaxis of invasive fungal infections in adults with hematologic malignancies", section on 'Risk-benefit assessment'). In addition, the need for antifungal prophylaxis depends at least in part upon local rates of resistance as well as the overall risk of invasive fungal infections based upon which HCT regimens are used. As a result, practices regarding antifungal prophylaxis differ widely at various cancer centers, and our approach may be different from the approach recommended at a specific institution.
We favor the following approach to primary antifungal prophylaxis in HCT recipients:
●For recipients of myeloablative allogeneic HCT who do not have one of the indications for mold prophylaxis discussed below, we recommend prophylaxis against Candida infections during the pre-engraftment period with fluconazole (400 mg orally once daily) [24]. A fluconazole dose of 200 mg once daily has also been studied [29], but we prefer the 400 mg daily dose out of a theoretical concern that the lower dose could promote the development of resistance.
●For autologous HCT recipients who receive conditioning regimens that are expected to cause severe mucositis during the pre-engraftment period (eg, cyclophosphamide plus either ablative doses of busulfan or total body irradiation), we suggest prophylaxis against Candida infections with fluconazole (400 mg orally once daily) [8,24].
●For patients who undergo myeloablative allogeneic HCT for acute myelogenous leukemia, we suggest anti-mold prophylaxis [19,21]. When mold prophylaxis is indicated in an HCT recipient, we generally favor voriconazole (200 mg orally twice daily), but posaconazole is an appropriate alternative. When posaconazole is chosen, we prefer the delayed-release tablet (taken with food) rather than the oral suspension. Another alternative for anti-mold prophylaxis if neither voriconazole nor posaconazole can be given is isavuconazole, although it has not been studied for this indication in randomized controlled trials.
Patients who are unable to take medications orally or who are expected not to absorb oral medications can be given IV posaconazole. Posaconazole delayed-release tablets should be given as a loading dose of 300 mg (three 100 mg tablets) every 12 hours on the first day, followed by a maintenance dose of 300 mg (three 100 mg tablets) daily starting on the second day. The IV formulation of posaconazole should be given as a loading dose of 300 mg every 12 hours on the first day, followed by a maintenance dose of 300 mg daily starting on the second day. The dosing of the oral suspension of posaconazole is 200 mg three times daily. The delayed-release tablets, the IV formulation, and the oral suspension should not be used interchangeably due to differences in dosing.
●Given the association between prolonged neutropenia and invasive aspergillosis, we also suggest prophylaxis during the pre-engraftment period with a mold-active agent in the subset of HCT recipients with a lengthy duration of neutropenia immediately prior to HCT (eg, patients with aplastic anemia) and for those who are anticipated to have slow engraftment (>28 days; eg, umbilical cord blood transplant recipients) or who fail to engraft. In such patients, we generally favor voriconazole (200 mg orally twice daily), but posaconazole is an appropriate alternative.
●As there are many potential drug interactions between extended-spectrum triazoles and drugs that may be used concomitantly, drug interactions should be taken into account before starting a triazole. (See 'Drug interactions' below.)
●For allogeneic HCT recipients with GVHD requiring methylprednisolone at a dose of ≥1 mg/kg per day (or the equivalent dose of another glucocorticoid) for longer than three weeks, we recommend anti-mold prophylaxis. We favor voriconazole in such patients, but posaconazole is an appropriate alternative. The same precautions regarding drug interactions that are discussed above must be considered.
Candida infection — Randomized placebo-controlled trials have shown that fluconazole reduces the incidence of invasive Candida infections during the pre-engraftment period following allogeneic HCT [9,10]. In one of these trials, HCT recipients who received fluconazole had a lower risk of invasive fungal infections (3 versus 16 percent) and fungal infection-related mortality (0.6 versus 5.6 percent) but not all-cause mortality [9]. In another trial, HCT recipients who received fluconazole until day 75 following transplantation had a lower risk of invasive fungal infections (7 versus 18 percent) as well as both fungal infection-related mortality (7 versus 13 percent) and all-cause mortality (20 versus 35 percent) [10]. In a follow-up study in which patients were followed for eight years following HCT, a continued mortality benefit was observed in the patients who received fluconazole (23 versus 45 percent) [30]. Fewer patients who received fluconazole died with invasive candidiasis either early (before day 110; 0.7 versus 9 percent) or late (after day 110; 0.8 versus 8 percent).
Meta-analyses and randomized trials have determined that fluconazole is efficacious in preventing Candida infections in high-risk patients [4-7]. Infection rates at or above a threshold of 10 percent are seen primarily in the following groups of HCT recipients during the pre-engraftment phase [8,24]:
●Allogeneic HCT recipients receiving myeloablative conditioning regimens.
●Some autologous HCT recipients who are not given prophylactic hematopoietic growth factors or who are at risk for severe oral and/or gastrointestinal mucositis (which is a risk factor for candidemia) – The transplant regimens best known to cause substantial mucosal injury are cyclophosphamide plus either ablative doses of busulfan or total body irradiation. There is a growing list of transplant preparative regimens with varying degree of intensity that have been insufficiently studied with respect to their effects on mucosal integrity, and thus the risk of Candida infection is not well characterized in patients receiving these regimens.
Choice of agent — When Candida prophylaxis is indicated, we favor fluconazole. Fluconazole has the advantage of being available as oral and IV formulations, excellent tolerability, inexpensive generic formulations, and less severe interactions with concomitant medications compared with the extended-spectrum azoles. Although fluconazole has been studied most rigorously for Candida prophylaxis, other agents have also been evaluated and are considered acceptable alternatives, including itraconazole, voriconazole, posaconazole, micafungin, caspofungin, and anidulafungin [8].
Fluconazole has several important drawbacks, including the following:
●Its spectrum of activity against Candida spp is narrower than the echinocandins.
●Breakthrough infections with fluconazole-resistant Candida species, especially C. krusei and C. glabrata, have been reported.
●It has no activity against Aspergillus or other molds in comparison with the other acceptable agents, which have at least some activity against Aspergillus spp.
Alternative agents have the following benefits and drawbacks:
●Echinocandins – The echinocandins (caspofungin, micafungin, anidulafungin, and rezafungin) have a broader spectrum of activity than fluconazole, with most common Candida species being susceptible, and an excellent safety record. Drawbacks are their availability only as intravenous formulations and high cost. There has been a growing concern about the emergence of echinocandin resistance among Candida spp (see "Pharmacology of echinocandins and other glucan synthesis inhibitors") [31]. Rezafungin has been approved for the treatment of candidemia and systemic candidiasis [32]. A prophylaxis trial is underway in allogeneic HCT recipients.
●Voriconazole – Voriconazole has both oral and IV formulations but has been noted to cause transient visual disturbances (that are not permanent or serious), perhaps more liver toxicity than fluconazole, and some variability in blood levels in allogeneic HCT recipients. A major drawback is its potential interactions with certain chemotherapy agents. (See "Pharmacology of azoles", section on 'Voriconazole' and "Pharmacology of azoles", section on 'Voriconazole' and "Pharmacology of azoles", section on 'Drug interactions'.)
●Posaconazole – Posaconazole was previously available only as an oral suspension. In 2013, delayed-release tablets became available and, in 2014, an IV formulation became available. Posaconazole has been evaluated primarily for its anti-mold activity, but in trials low rates of Candida infections were noted, and it is therefore an option for prevention of yeast infections [33]. We prefer the delayed-release tablet over the oral suspension because it has more reliable oral absorption and achieves higher blood levels [34,35]. A drawback is its potential interactions with certain chemotherapy agents. (See "Pharmacology of azoles", section on 'Posaconazole' and "Pharmacology of azoles", section on 'Posaconazole' and "Pharmacology of azoles", section on 'Drug interactions'.)
●Itraconazole – Itraconazole is available as an oral formulation. The IV formulation has been withdrawn in the United States but remains available in some countries. The oral formulation is poorly tolerated and has variable bioavailability. Another major drawback is its potential interactions with certain chemotherapy agents. Itraconazole is used rarely given these limitations. (See "Pharmacology of azoles", section on 'Drug interactions'.)
●Isavuconazole – Isavuconazole is available in intravenous and oral formulations. It is indicated for the treatment of invasive aspergillosis and invasive mucormycosis. Its safety profile has encouraged investigators to use this agent, off-label, as prophylaxis [36]. A retrospective study suggested higher rates of breakthrough invasive fungal infections in HCT and hematologic malignancy patients with isavuconazole prophylaxis compared with voriconazole or posaconazole prophylaxis [37]. However, a recent multicenter prospective observational registry study examined breakthrough invasive fungal infections (bIFI) among high-risk patients receiving mold-active prophylaxis with posaconazole, voriconazole, isavuconazole, or multiple sequenced mold-active triazoles. Haematological malignancy was the underlying diagnosis in the majority (76.5 percent) of enrollees. bIFI were observed in 11 of 221 (5 percent) isavuconazole recipients, 20 of 374 (5.3 percent) posaconazole recipients, 9 of 226 (4 percent) voriconazole recipients, and 33 of 209 (15.8 percent) multiple-sequenced mold-active triazoles. Discontinuation of mold-active triazoles due to adverse drug reactions occurred in 5 of 245 (2 percent) of isavuconazole recipients, in 30 of 368 (8.2 percent) of posaconazole recipients, and in 27of 267 (10.1 percent) voriconazole recipients, 64 of 262 (24.4 percent) multiple sequenced mold-active triazole recipients. These real-world observations suggest that isavuconazole may be as effective and safe as posaconazole or voriconazole for mold-active anti-fungal prophylaxis.
Each of the agents used for antifungal prophylaxis is associated with some risk of hepatotoxicity, but azoles are likely to confer the highest risk. For patients with significant hepatic dysfunction (eg, hepatic sinusoidal obstruction syndrome [veno-occlusive disease]), we favor an echinocandin over an azole.
Aspergillus (and other mold) infection — The need for Aspergillus prophylaxis varies according to the underlying disease and its therapy. Several trials suggest that the risk-benefit ratio favors prophylaxis when the rate of invasive aspergillosis is at least 6 percent [33,38]. A meta-analysis that compared mold-active prophylaxis with fluconazole prophylaxis is discussed above [27]. (See 'Primary prophylaxis' above.)
Aspergillus prophylaxis with posaconazole has been demonstrated to be beneficial in patients with severe graft-versus-host disease (GVHD) following HCT [38].
Allogeneic HCT recipients — As noted above, fluconazole is effective at reducing rates of invasive Candida infection in allogeneic HCT recipients, but it lacks anti-mold activity. Agents with anti-mold activity include voriconazole, posaconazole, isavuconazole, and amphotericin B; all of these agents also have activity against Candida spp. During the pre-engraftment period, Candida is the fungal pathogen of greatest concern in the majority of patients, and fluconazole is therefore adequate for prophylaxis early after HCT in most patients. However, allogeneic HCT recipients are also at some risk for mold infections during the pre-engraftment period and are at the highest risk during the post-engraftment phase in the setting of severe GVHD. The use of antifungal agents with activity against Aspergillus and other molds has been evaluated in various studies of HCT recipients, both during the pre-engraftment period and later in patients with severe GVHD.
Prophylaxis during the pre-engraftment period — Itraconazole and voriconazole prophylaxis have been studied most extensively in allogeneic HCT recipients during the pre-engraftment period and, compared with fluconazole, appear to modestly reduce the incidence of invasive fungal infections without conferring a survival benefit. Relevant findings from trials include the following:
●Voriconazole was compared with fluconazole (with both agents being given until day 100 after HCT) in a randomized double-blind trial conducted in 600 allogeneic HCT recipients [19]. Among patients who received voriconazole versus fluconazole, fungal-free survival (the primary endpoint, defined as freedom from an invasive fungal infection or death at 180 days) was similar (78 versus 75 percent). There were trends toward fewer invasive fungal infections (7 versus 11 percent), Aspergillus infections (9 versus 17), and less frequent use of empiric antifungal therapy (24 versus 30 percent) in patients who received voriconazole compared with those who received fluconazole. In a post-hoc subgroup analysis of HCT recipients who were transplanted for acute myelogenous leukemia, those who received voriconazole had significantly improved fungal-free survival (78 versus 61 percent) and fewer invasive fungal infections (8.5 versus 21 percent), but no difference in overall survival (81 versus 72 percent) compared with those who received fluconazole.
●Similar results were observed in a randomized open-label trial comparing voriconazole with itraconazole in 489 patients undergoing allogeneic HCT [39]. In patients who received voriconazole versus itraconazole, there were no differences in the incidence of proven or probable invasive fungal infections (1.3 versus 2.1 percent) or survival to day 180 (82 versus 81 percent). There were fewer interruptions of study drug with voriconazole. Gastrointestinal adverse effects were more common with itraconazole, but there were more adverse visual and hepatic effects with voriconazole.
●Itraconazole has been compared with fluconazole in randomized trials using the IV formulation and the oral suspension [40,41]. One small trial found fewer fungal infections but no survival benefit [40], whereas another trial showed a trend toward inferior survival and was stopped prematurely due to greater toxicity associated with concomitant administration of itraconazole and cyclophosphamide compared with fluconazole and cyclophosphamide and considerable intolerance of itraconazole [41]. (See "Prophylaxis of invasive fungal infections in adults with hematologic malignancies", section on 'Drug interactions'.)
●Low-dose IV amphotericin B deoxycholate has been evaluated for the prophylaxis of invasive fungal infections in patients undergoing HCT, with conflicting results [42]. The toxicities of amphotericin B deoxycholate make it unsuitable for use after HCT. Several trials have evaluated lipid formulations of amphotericin B, which are less toxic than amphotericin B deoxycholate, but the efficacy results have been mixed [43-46]. (See "Pharmacology of amphotericin B", section on 'Safety and efficacy'.)
●Posaconazole and isavuconazole have not been well studied during the pre-engraftment period of HCT [37,47,48]. However, one retrospective review of 145 patients with hematologic malignancies and HCT recipients suggests that isavuconazole may be less effective than both voriconazole and posaconazole [37].
Prophylaxis in patients with GVHD — Posaconazole has been evaluated in the post-engraftment period in patients with graft-versus-host disease (GVHD) requiring high-dose glucocorticoid therapy [38]. In a randomized double-blind trial, 600 allogeneic HCT patients with GVHD were assigned to posaconazole (200 mg three times daily of the oral suspension) or fluconazole (400 mg once daily) for prophylaxis of invasive fungal infections [38]. Patients were eligible for the trial if they had grade II to IV acute GVHD or if they had chronic extensive GVHD or if they were being treated with intensive immunosuppressive therapy (≥1 mg/kg per day of methylprednisolone or the equivalent dose of another glucocorticoid; or antithymocyte globulin; or a combination of two or more immunosuppressive agents) (see "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease"). At the end of the 112-day treatment period, posaconazole was associated with a trend toward fewer proven and probable invasive fungal infections (5.3 versus 9.0 percent; odds ratio [OR] 0.56, 95% CI 0.30-1.07) and a significant reduction in proven or probable invasive aspergillosis (2.3 versus 7.0 percent; OR 0.31, 95% CI 0.13-0.75), which accounted for the majority of infections.
Although there were no significant differences in the overall incidence of invasive fungal infections between the patients receiving posaconazole or fluconazole, significantly fewer patients receiving posaconazole developed breakthrough invasive fungal infections (2.4 versus 7.6 percent), particularly invasive aspergillosis (1.0 versus 5.9 percent) [38]. Mortality from invasive fungal infections was also significantly lower in the posaconazole group (1 versus 4 percent). Treatment-related adverse events were similar in both groups. Some patients (7 percent in the posaconazole group, 10 percent in the fluconazole group) had positive galactomannan assays before enrollment into the trial and thus may have had incipient Aspergillus infections. This raises the possibility that some patients were receiving treatment for established infections rather than prophylaxis and suggests that the putative benefit of posaconazole as prophylaxis is less than suggested in the report.
Because of the uncertainty of the benefit of anti-mold prophylaxis in this situation, practices vary considerably from center to center. Some centers give no anti-mold prophylaxis or give fluconazole prophylaxis while maintaining vigilance for Aspergillus infections with laboratory screening (eg, Aspergillus galactomannan antigen, beta-D-glucan) and/or early diagnostic tests for patients with suggestive findings (eg, Aspergillus galactomannan antigen, beta-D-glucan, computed tomography [CT] scans). Other centers use posaconazole or voriconazole prophylaxis in all patients with GVHD requiring high-dose glucocorticoid therapy. Still other centers give anti-mold prophylaxis with either voriconazole or posaconazole in patients who require doses of methylprednisolone of at least 1 mg/kg per day (or the equivalent dose of another glucocorticoid) for longer than three weeks, drawing on the observation that those patients who require prolonged high-dose glucocorticoids are at greatest risk [23]. Itraconazole is limited by poor tolerability and unreliable absorption [28]. We use voriconazole prophylaxis for patients with GVHD requiring methylprednisolone of at least 1 mg/kg per day (or the equivalent dose of another glucocorticoid) for longer than three weeks. Patients requiring high doses of glucocorticoids are generally those with more severe (grade II to IV) GVHD.
Autologous HCT recipients — Autologous HCT recipients do not require primary prophylaxis against Aspergillus spp and other molds, given the low rate of such infections in these patients. (See 'Aspergillus infection' above.)
Choice of agent — Current data are insufficient to conclusively determine which mold-active drug is optimal for prophylaxis. The choice of the initial antifungal agent may vary based on an institution's experience (ie, epidemiology and susceptibility patterns), risk for specific mold infections (eg, Aspergillus versus the agents of mucormycosis), and patient category (acute myelogenous leukemia [AML] induction therapy versus HCT). In general, most experts prefer voriconazole if Aspergillus is the most likely pathogen for which one has concern (eg, prior infection with Aspergillus, epidemiology at that center, patient population). Voriconazole has been studied more extensively after HCT, whereas posaconazole has been studied more extensively in AML patients receiving induction therapy. Some experts recommend either voriconazole or posaconazole based on the published literature. But, as mentioned above, there are specific strengths and drawbacks to each agent (see 'Choice of agent' above). When the decision is made that anti-mold prophylaxis is justified in an HCT recipient, we generally recommend voriconazole.
In patients at increased risk for mucormycosis, posaconazole should be given since voriconazole has no activity against the agents of mucormycosis. However, it is important to note that, at most centers, aspergillosis accounts for the majority of invasive mold infections. As an example, in a multicenter surveillance study of HCT recipients in the United States, 363 invasive mold infections were detected within the first year following HCT; aspergillosis was diagnosed in 66 percent of cases whereas mucormycosis was diagnosed in 12 percent [1]. Among HCT recipients, the reported incidence of mucormycosis has ranged from 0.1 to 2 percent, with the highest incidence in patients with GVHD [49].
When posaconazole is given, we prefer the delayed-release tablet (taken with food) over the oral suspension due to its better absorption [34,35]. This is especially important for patients who cannot eat a full meal; the delayed-release tablets result in higher plasma drug concentrations than the oral suspension regardless of food intake [50]. Patients who are unable to take medications orally or who are expected not to absorb oral medications should be given IV posaconazole.
Another alternative for patients who cannot receive voriconazole or posaconazole is isavuconazole, although it has not been studied for prophylaxis in randomized controlled trials.
As there are many potential drug interactions between the extended-spectrum triazoles and drugs that may be used concomitantly, drug interactions should be taken into account before starting a triazole. (See 'Drug interactions' below.)
Because of inter-patient variability in drug levels of the mold-active azoles, therapeutic drug monitoring should be done when possible [28]. Serum trough drug levels for the mold-active azoles as well as for potentially interacting drugs, such as the calcineurin inhibitors and other CYP3A4 substrates, are advised. (See "Pharmacology of azoles", section on 'Serum drug concentration monitoring'.)
Risk-benefit assessment — Although antifungal prophylaxis has been proven to be efficacious in allogeneic HCT recipients, issues surrounding overuse of antifungal agents (eg, resistance, toxicity, and cost) and the heterogeneity of risk and the overall relatively low incidence of invasive fungal infections in these patients have tempered enthusiasm for universal prophylaxis. The risk-benefit analysis must include an assessment of the relative level of immunosuppression and comorbidities to identify individuals at increased risk for invasive fungal infections. The level of immunosuppression is higher following allogeneic HCT compared with other settings, such as following consolidation chemotherapy for leukemia. Important comorbidities include older age, mucositis, poorly controlled diabetes, smoking history, iron overload from transfusions, and recurrent use of antibacterial agents.
Factors that support the use of antifungal prophylaxis in high-risk patients include the substantial morbidity and mortality of invasive fungal infections and the difficulty in obtaining a timely diagnosis due to the limitations of available diagnostic tests [16].
Secondary prophylaxis — Patients who have a history of a prior invasive fungal infection, especially Aspergillus infection, are at high risk for recurrence of infection following HCT. This has been best studied in patients with prior Aspergillus infection. In the past, prior mold infection was deemed a contraindication for HCT due to the high risk of recurrent infection and death. However, more recently, it has been shown that continued treatment after initial control (so-called secondary prophylaxis) can prevent reactivation of infection in most patients and permit HCT [51,52].
For patients with a history of prior invasive aspergillosis undergoing allogeneic or autologous HCT and for patients with a prolonged period of neutropenia immediately prior to HCT, we recommend antifungal prophylaxis with a mold-active agent [53]. The choice of agent depends in part upon the need to avoid drug interactions while chemotherapy is being given. Voriconazole is the first-line agent for Aspergillus spp and has been best studied as secondary prophylaxis, but mold-active azoles are usually not given concomitantly with certain chemotherapy regimens with hepatically metabolized drugs. Of note, this is not a concern for agents such as cytarabine or fludarabine. (See 'Approach to primary prophylaxis' above and 'Drug interactions' below and "Prophylaxis of invasive fungal infections in adults with hematologic malignancies", section on 'Approach to primary prophylaxis'.)
For patients with prior Candida infections, the agent selected for secondary prophylaxis should be based upon the Candida species and which agent was successful in achieving earlier control.
Duration — The duration of antifungal prophylaxis should be individualized based on the patient's clinical status and history of prior fungal infections. The following general principles can be used to help determine the appropriate duration of prophylaxis:
●In allogeneic HCT recipients who do not have GVHD, prophylaxis against Candida spp is continued either until engraftment or for up to 75 days following transplantation, which in one trial was associated with continued benefit after engraftment [10,30].
●The optimal duration of antifungal prophylaxis in allogeneic HCT recipients with GVHD has not been defined [24]. In general, prophylaxis should be continued during the period of peak immunosuppression (eg, glucocorticoid equivalent of ≥1 mg/kg per day of prednisone for more than two weeks or addition of other anti-GVHD therapies for refractory GVHD) [28]. In such patients, we continue anti-mold prophylaxis until substantial doses of immunosuppressants (especially glucocorticoids) are no longer required. As an example, we suggest stopping once the dose of prednisone drops below 20 mg every other day, but the optimal duration has not been formally studied. The use of CD4 counts to guide when to stop antifungal prophylaxis (eg, >200 cells/L) has been found to be useful in some immunocompromised patient groups, but this has not been well studied in HCT patients.
●In patients who have a history of a prior invasive fungal infection who are receiving secondary prophylaxis following HCT, prophylaxis is usually continued until discontinuation of immunosuppressive therapy. In such patients, follow-up imaging (CT scan of the organ involved in prior infection) and fungal markers (eg, Aspergillus galactomannan antigen, beta-D-glucan) are often obtained two to four weeks after antifungal prophylaxis has been discontinued to ensure that reactivation has not occurred.
PRE-EMPTIVE THERAPY — An alternative to anti-mold prophylaxis involves pre-emptive therapy. This approach involves targeted screening of high-risk patients for markers of colonization and/or infection in an attempt to prevent invasive infection. Screening involves checking fungal markers, such as the Aspergillus galactomannan antigen, Aspergillus polymerase chain reaction (if available), and beta-D-glucan, and chest computed tomography scanning. This approach is discussed in detail separately. (See "Treatment and prevention of invasive aspergillosis", section on 'Pre-emptive therapy'.)
BREAKTHROUGH INFECTIONS AND RESISTANCE — Breakthrough fungal infections and resistance are discussed separately. (See "Prophylaxis of invasive fungal infections in adults with hematologic malignancies", section on 'Breakthrough infections and resistance'.)
DRUG INTERACTIONS — There are many potential drug interactions between antifungal agents and drugs that may be used concomitantly [54]. Specific drug interactions unique to patients with hematologic malignancies and HCT recipients are mentioned here. Amphotericin B deoxycholate used in combination with the calcineurin inhibitor class of immunosuppressive drugs (cyclosporine and tacrolimus) used after HCT is associated with a high risk for severe nephrotoxicity [55]. The risk of nephrotoxicity is much lower with the lipid formulations of amphotericin B.
The triazoles are metabolized by the cytochrome P450 isoenzymes, and there are multiple potential drug interactions:
●Itraconazole has been associated with a harmful interaction with cyclophosphamide, resulting in renal and hepatic toxicity [56].
●Itraconazole has a potential negative inotropic effect and should be avoided in patients with prior congestive heart failure and drugs that could be cardiotoxic (eg, anthracyclines or high-dose cyclophosphamide).
●Interactions between the anti-mold azoles and immunosuppressive drugs are substantial; reductions of cyclosporine and tacrolimus doses by approximately 50 percent are important, and monitoring of levels of these drugs is necessary to avoid toxicity. Voriconazole increases sirolimus levels by approximately 10-fold [57,58], and posaconazole increases sirolimus levels by approximately ninefold [50]. The concomitant use of voriconazole or posaconazole with sirolimus is generally avoided. (See "Pharmacology of azoles", section on 'Selected clinical effects'.)
Given the potential for serious drug interactions, concomitant administration of extended-spectrum triazole-based (posaconazole, voriconazole, itraconazole) prophylaxis should be delayed until after completion of the transplant conditioning regimen. In patients receiving posttransplant cyclophosphamide (eg, haploidentical HCT recipients), extended-spectrum azoles should be avoided until completion of cyclophosphamide. An echinocandin can be given safely if a gap in antifungal prophylaxis is inadvisable, such as in patients with prior aspergillosis. Caution is advised for concomitant use of the extended-spectrum triazoles with chemotherapy drugs metabolized by the liver, especially those metabolized by cytochrome P450 isoenzymes.
Although drug-drug interactions related to cytochrome P450 metabolism appear less for isavuconazole than for voriconazole or posaconazole, therapeutic drug monitoring of concomitantly administered drugs metabolized by cytochrome P450 may be prudent.
Combination prophylaxis with fluoroquinolones and triazoles is common, and both classes have the potential to prolong the QTc interval and increase the risk for torsades de pointes. Other examples of important drug interactions between azoles and other drugs are provided in the table (table 1). Drug interactions involving azoles are discussed in greater detail separately. Details about specific interactions may be obtained by using the drug interactions program included within UpToDate.
A discussion of the interactions between antifungal agents and chemotherapy drugs is presented separately. (See "Prophylaxis of invasive fungal infections in adults with hematologic malignancies", section on 'Drug interactions'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Invasive fungal infections".)
SUMMARY AND RECOMMENDATIONS
●Microbiology and timing of fungal infection – Both yeasts and molds cause serious invasive fungal infections in hematopoietic cell transplant (HCT) recipients. Prior to the routine use of antifungal prophylaxis, Candida spp accounted for the majority of fungal infections that occurred during the pre-engraftment period of HCT, followed by Aspergillus spp. HCT recipients are at highest risk for Candida infections during the pre-engraftment period (figure 1). Aspergillus is the most common mold pathogen and the second most common fungal pathogen in HCT recipients, occurring most commonly during the post-engraftment period in patients with severe graft-versus-host disease (GVHD). (See 'Introduction' above and 'Candida infection' above.)
●Approach to prophylaxis – The following recommendations represent our approach to antifungal prophylaxis. It should be noted that there is ongoing controversy about the use of antifungal prophylaxis. As a result, practices regarding antifungal prophylaxis differ widely at various cancer centers, and our approach may be different from the approach recommended at a specific institution. (See 'Approach to primary prophylaxis' above and 'Risk-benefit assessment' above.)
●Risks and benefits – Although antifungal prophylaxis has been proven to be efficacious in selected HCT recipients, issues surrounding overuse of antifungal agents (eg, resistance, toxicity, and cost) and the relatively low incidence of invasive fungal infections in these patients have tempered enthusiasm for universal prophylaxis. The risk-benefit analysis must include an assessment of the relative level of immunosuppression and comorbidities to identify those individuals at increased risk for invasive fungal infections. (See 'Risk-benefit assessment' above.)
●Prophylactic regimens – We provide antifungal prophylaxis to the following groups of HCT recipients:
•Recipients of myeloablative allogeneic HCT who do not have an indication for mold prophylaxis – For these patients, we recommend prophylaxis against Candida infections during the pre-engraftment period rather than no prophylaxis (Grade 1B). In such patients, we use fluconazole (400 mg once daily). (See 'Approach to primary prophylaxis' above.)
•Recipients of autologous HCT who receive conditioning regimens that are expected to cause severe mucositis during the pre-engraftment period (eg, cyclophosphamide plus either ablative doses of busulfan or total body irradiation) – We suggest prophylaxis against Candida infections rather than no prophylaxis for these patients (Grade 2B). In such patients, we use fluconazole (400 mg once daily). (See 'Approach to primary prophylaxis' above.)
•Recipients of myeloablative allogeneic HCT for acute myelogenous leukemia – We suggest anti-mold prophylaxis rather than narrower anti-Candida prophylaxis with fluconazole (Grade 2B). When mold prophylaxis is indicated in an HCT recipient, we generally favor voriconazole (200 mg orally twice daily), but posaconazole is an appropriate alternative. Another alternative for patients who cannot receive voriconazole or posaconazole is isavuconazole, although it has not been prospectively studied for prophylaxis. (See 'Approach to primary prophylaxis' above.)
•Patients who have a lengthy duration of neutropenia immediately prior to HCT (eg, patients with aplastic anemia), are anticipated to have slow engraftment (>28 days; eg, umbilical cord blood transplant recipients), or who fail to engraft – We suggest prophylaxis during the pre-engraftment period for these patients with an agent that has both anti-mold and anti-Candida activity rather than narrower anti-Candida prophylaxis with fluconazole (Grade 2B). In such patients, we generally favor voriconazole (200 mg orally twice daily), but posaconazole is an appropriate alternative. Another alternative for patients who cannot receive voriconazole or posaconazole may be isavuconazole. (See 'Approach to primary prophylaxis' above.)
•Recipients of allogeneic HCT who have GVHD requiring methylprednisolone at a dose of ≥1 mg/kg per day (or the equivalent dose of another glucocorticoid) for longer than three weeks – We recommend anti-mold prophylaxis rather than no antifungal prophylaxis (Grade 1B). We favor voriconazole (200 mg orally twice daily) in such patients, but delayed-release posaconazole is an appropriate alternative. The same precautions regarding drug interactions that are discussed above must be considered. (See 'Approach to primary prophylaxis' above.)
•HCT recipients who have a history of prior invasive aspergillosis – For these patients, we recommend antifungal prophylaxis with a mold-active agent (Grade 1B). (See 'Secondary prophylaxis' above.)
●Drug interactions and timing of prophylaxis – Given the potential for serious drug interactions, administration of extended-spectrum triazole-based (posaconazole, voriconazole, itraconazole) prophylaxis should be delayed until after completion of the transplant conditioning regimen; an echinocandin can be given safely during the conditioning regimen if a gap in antifungal coverage is unadvisable, such as in a patient with prior aspergillosis. Caution is advised for concomitant use of the extended-spectrum triazoles with chemotherapy drugs metabolized by the liver, especially those metabolized by cytochrome P450 isoenzymes. Interactions between the anti-mold azoles and immunosuppressive drugs are substantial; reductions of cyclosporine and tacrolimus doses by 50 percent are important, and monitoring of levels of these drugs is necessary to avoid toxicity. Coadministration with sirolimus should be avoided due to extreme potentiation of sirolimus levels. (See 'Approach to primary prophylaxis' above and 'Drug interactions' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Kieren A Marr, MD, who contributed to an earlier version of this topic review.
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