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Prophylaxis of invasive fungal infections in adults with hematologic malignancies

Prophylaxis of invasive fungal infections in adults with hematologic malignancies
Literature review current through: Jan 2024.
This topic last updated: Nov 08, 2022.

INTRODUCTION — Invasive fungal infections are common in high-risk patients with hematologic malignancies, such as patients with acute leukemia receiving induction chemotherapy, and cause substantial morbidity and mortality. The risk for invasive fungal infections increases with the duration and severity of neutropenia, prolonged antibiotic use, and number of chemotherapy cycles.

Interest in antifungal prophylaxis for high-risk patients receiving chemotherapy has been prompted by the rising incidence of life-threatening invasive fungal infections among cancer patients [1], 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 patients with hematologic malignancies will be discussed here. The epidemiology and prophylaxis of invasive fungal infections in hematopoietic cell transplant recipients are reviewed elsewhere. (See "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients".)

Other important issues related to infections in patients with hematologic malignancies are discussed separately:

(See "Overview of neutropenic fever syndromes".)

(See "Diagnostic approach to the adult cancer patient with neutropenic fever".)

(See "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)".)

(See "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults".)

(See "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications", section on 'Initial regimen'.)

(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 patients with hematologic malignancies. Prior to the routine use of antifungal prophylaxis, Candida spp accounted for the majority of fungal infections that occurred during neutropenia, followed by Aspergillus spp [2-4]. More recently, Aspergillus has surpassed Candida as a cause of invasive fungal infections in patients with hematologic malignancies, likely due to the use of antifungal prophylaxis targeting Candida spp [5-7]. Both pathogens are associated with substantial risk for mortality.

In an autopsy study of patients who died after prolonged neutropenic fever between 1966 and 1975, rising rates of fungal infection were noted [2]. Over half of the patients in this early series had Candida infections, which may have been effectively prevented with antifungal prophylaxis. For example, in one trial, fungal infections were documented in only 1 percent of patients receiving fluconazole prophylaxis who had persistent fevers despite receiving broad-spectrum antibiotics [8].

Candida infection — Candida is the most important yeast pathogen, accounting for most invasive yeast infections [9,10]. The incidence of invasive candidiasis in patients with hematologic malignancies has varied widely in different studies, likely due to differences in the underlying disease (eg, newly diagnosed, in remission, relapsed, or refractory to treatment), the duration of neutropenia, and the types of chemotherapy regimens used [11]. Rates of invasive Candida infection in patients with hematologic malignancies not receiving antifungal prophylaxis have ranged from 8 to 24 percent [12-17].

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. Candidemia is the most frequent clinical manifestation of invasive candidiasis. Candida is also a common fungal cause of central venous catheter-associated infections. Less commonly, Candida causes disseminated candidiasis, including chronic disseminated candidiasis (hepatosplenic candidiasis). (See "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults" and "Chronic disseminated candidiasis (hepatosplenic candidiasis)".)

Patients with acute leukemia are at highest risk for invasive candidiasis during the period of neutropenia that follows induction chemotherapy. Although Candida albicans accounts for about half of invasive Candida infections, patients with hematologic malignancies and hematopoietic cell transplant 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 [18]. (See "Candidemia in adults: Epidemiology, microbiology, and pathogenesis", section on 'Prevalence of Candida species'.)

Aspergillus infection — Aspergillus is the most common mold pathogen in patients with hematologic malignancies [5]. In patients with acute myelogenous leukemia (AML), the incidence of invasive aspergillosis has ranged from 2 to 28 percent, with most studies reporting rates between 5 and 10 percent [11]. In such patients, the risk varies according to the disease status; patients with relapsed or refractory AML receiving salvage chemotherapy are at the greatest risk, whereas newly diagnosed patients receiving induction chemotherapy are at lower risk. AML patients in remission who are receiving consolidation chemotherapy are at the lowest risk.

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 patients with hematologic malignancies [19,20] but are infrequent overall at most centers. 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 patients with hematologic malignancies. (See "Mycology, pathogenesis, and epidemiology of Fusarium infection" and "Epidemiology, clinical manifestations, and diagnosis of Scedosporium and Lomentospora infections".)

Pneumocystis pneumonia (PCP) is an occasional fungal pathogen that occurs in patients with hematologic malignancies, as discussed separately. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV".)

Although primary infection and reactivation infection with endemic fungi (histoplasmosis, blastomycosis, and coccidioidomycosis) is uncommon in patients with hematologic malignancies, 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".)

RISK FACTORS

Acute leukemia — In patients with hematologic malignancies, the incidence of fungal infection (especially those caused by Candida or Aspergillus spp) rises after patients have experienced more than seven days of persistent fever and neutropenia [22]. The major risk factor for invasive candidiasis is receiving an intensive induction regimen for acute leukemia that causes severe oral and/or gastrointestinal mucosal injury. Other contributory risk factors are use of broad-spectrum antibiotics and presence of a central venous catheter.

Risk factors for invasive aspergillosis in patients with hematologic malignancies are advanced or refractory acute myelogenous leukemia or high-risk myelodysplastic syndrome, the need to administer multiple chemotherapy regimens to attempt to achieve remission, iron overload from multiple erythrocyte transfusions, chronic neutropenia before initiation of chemotherapy, and prior aspergillosis during previous treatment [22-26].

Other patients at risk — Hematopoietic cell transplantation, particularly allogeneic HCT, confers substantial risk for invasive fungal infections. This is discussed in detail separately. (See "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients", section on 'Risk factors'.)

Compared with patients with acute leukemia and HCT recipients, the risk for invasive fungal infections is lower in patients with chronic leukemias, lymphoma, and multiple myeloma, but invasive fungal infections do occur in such patients [27].

Ibrutinib, a Bruton tyrosine kinase inhibitor that causes hypogammaglobulinemia and inhibits B cell signaling, has been associated with invasive fungal infections, such as Aspergillus and Cryptococcus infections. Most of these cases have occurred in patients with chronic lymphocytic leukemia. (See "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Bruton tyrosine kinase inhibitors'.)

Therapies that suppress T cell immunity also increase susceptibility to invasive fungal infections, including Candida and Aspergillus infections. Such regimens include intensive glucocorticoid therapy, use of antithymocyte globulin, alemtuzumab, purine analogs (eg, fludarabine, cladribine, pentostatin), and patients receiving chimeric antigen receptor-T cell therapies. (See "Glucocorticoid effects on the immune system", section on 'Infection risk' and "Risk of infections in patients with chronic lymphocytic leukemia".)

PROPHYLAXIS

Primary prophylaxis — Primary prophylaxis involves the administration of an antimicrobial agent to prevent infection in patients at increased risk and who have not previously had the type of infection being targeted. The benefits of primary antifungal prophylaxis have been observed 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 hematopoietic cell transplantation (HCT) [28]. In patients with acute leukemia, antifungal prophylaxis was associated with significant reductions in fungal-related mortality (relative risk [RR] 0.66, 95% CI 0.44-1.00) and documented invasive fungal infections (RR 0.69, 95% CI 0.53-0.90). However, antifungal prophylaxis was associated with only a nonsignificant trend toward a reduction in all-cause mortality (RR 0.88, 95% CI 0.74-1.06).

A 2012 meta-analysis that included 20 randomized trials compared mold-active prophylaxis with fluconazole prophylaxis in patients with hematologic malignancy receiving chemotherapy (6 trials) or HCT recipients (14 trials) with the following results [29]:

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).

Approach to primary prophylaxis — The following recommendations represent our approach to antifungal prophylaxis in patients with hematologic malignancies. 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 [30] and the 2016 IDSA guidelines for the diagnosis and management of aspergillosis [31].

It should be noted that there is ongoing controversy about the use of antifungal prophylaxis (see 'Risk-benefit assessment' below). 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 antineoplastic 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 patients with acute leukemia [30]:

For patients with acute leukemia undergoing initial-induction or salvage-induction chemotherapy who are expected to develop severe oral and/or gastrointestinal mucositis, we recommend prophylaxis against Candida infections. We prefer fluconazole (400 mg orally once daily). A fluconazole dose of 200 mg once daily has also been studied [32], but we favor the 400 mg daily dose out of a theoretical concern that the lower dose could promote the development of resistance. Alternative agents include itraconazole, voriconazole, posaconazole, micafungin, caspofungin, and anidulafungin. (See 'Candida infection' below.)

For selected patients who are expected to experience prolonged severe neutropenia (absolute neutrophil count [ANC] <500 cells/microL for >7 days) due to intensive chemotherapy for acute myelogenous leukemia (AML) or advanced myelodysplastic syndrome (MDS), we suggest prophylaxis against invasive mold infections and Candida spp with posaconazole or voriconazole rather than targeted anti-Candida prophylaxis with fluconazole [30,31]. Patients undergoing induction therapy typically require one or two cycles of intensive chemotherapy, and clearance of leukemia is evaluated with a repeat bone marrow biopsy performed two weeks after the start of chemotherapy, which determines the need for a second course of chemotherapy. A threshold risk for invasive mold infection of >6 percent (which is the estimated risk in those who require two cycles of chemotherapy) is generally considered as sufficient to justify anti-mold prophylaxis. Since the need for a second course of therapy is not known until two weeks after treatment starts and the risk of mold infections is very low during that interval, we typically start with fluconazole, and, if a second course of chemotherapy is needed, switch to voriconazole or posaconazole. An alternative for patients who cannot receive voriconazole or posaconazole is isavuconazole, although it has not been studied for prophylaxis in randomized controlled trials. (See 'Aspergillus infection' below.)

We prefer the delayed-release posaconazole tablet (taken with food) over the oral suspension because it has more reliable oral absorption and achieves higher blood levels. Patients who are unable to take medications orally or who are expected not to absorb oral medications should be given intravenous (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.

The dosing of voriconazole is 200 mg orally twice daily.

Antifungal prophylaxis is not recommended for patients in whom the anticipated duration of severe neutropenia is ≤7 days.

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, therapeutic drug monitoring of mold-active azoles should be done where possible [31]. Serum trough drug levels for the mold-active azoles antifungal agents as well as for potentially interacting drugs, such as the calcineurin inhibitors and other CYP3A4 substrates, is advised. (See "Pharmacology of azoles", section on 'Serum drug concentration monitoring'.)

Candida infection — In the 2007 meta-analysis described above, antifungal prophylaxis resulted in a significant reduction in invasive Candida infections in patients with acute leukemia and HCT recipients (RR 0.31, 95% CI 0.23-0.41) [28]. In a subgroup analysis of patients with acute leukemia, the reduction in invasive Candida infections remained statistically significant.

Meta-analyses and randomized trials have determined that fluconazole is efficacious in preventing Candida infections in high-risk patients [12,28,33,34]. Infection rates at or above a threshold of 10 percent are seen primarily in patients undergoing intensive induction chemotherapy for AML with severe oral and/or gastrointestinal mucositis [30].

Choice of agent — 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 [30].

When Candida prophylaxis is indicated, we favor fluconazole. Fluconazole has the advantage of being available as both oral and intravenous formulations, excellent tolerability, inexpensive generic formulations, and less severe interactions with concomitant medications compared with the extended-spectrum azoles.

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.

Fluconazole 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) have a broader spectrum of activity than fluconazole, with most common Candida species being susceptible, and an excellent safety record. The drawbacks of this antifungal class are its availability only as an IV formulation and its high cost. (See "Pharmacology of echinocandins and other glucan synthesis inhibitors".)

VoriconazoleVoriconazole has both oral and IV formulations but has been noted to cause transient visual disturbances (that are not permanent or serious) and photosensitivity and may cause more hepatotoxicity than fluconazole. 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 'Drug interactions' below.)

PosaconazolePosaconazole was previously available only as an oral suspension. In 2013, delayed-release tablets became available and, in 2014, an IV formulation became available. It has been evaluated primarily for its anti-mold activity, but in trials low rates of Candida infections were noted, and posaconazole is therefore an option for prevention of yeast infections [23]. We prefer the oral delayed-release tablet over the oral suspension because it has more reliable oral absorption and achieves higher blood levels [35,36]. A drawback is its potential interactions with certain chemotherapy agents. (See "Pharmacology of azoles".)

ItraconazoleItraconazole is available as an oral formulation; the intravenous formulation has been withdrawn in the United States but remains available in some countries. The oral formulation is relatively 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 'Itraconazole' and 'Drug interactions' below.)

Aspergillus infection — The need for Aspergillus prophylaxis for high-risk neutropenic patients 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 [23,37]. Aspergillus prophylaxis has been demonstrated to be beneficial in patients with AML or MDS receiving induction chemotherapy [23].

The efficacy of antifungal agents with activity against Aspergillus spp and other molds (eg, voriconazole, posaconazole, isavuconazole, and amphotericin B formulations) has been evaluated in various studies. A meta-analysis that compared mold-active prophylaxis with fluconazole prophylaxis is discussed above [29]. (See 'Primary prophylaxis' above.)

All of the agents with activity against molds also have activity against Candida spp. We prefer either posaconazole or voriconazole for anti-mold prophylaxis in this patient population.

Posaconazole — Posaconazole is an extended-spectrum triazole with activity against Aspergillus spp and the agents of mucormycosis. Posaconazole was compared with the standard azole used at participating centers (fluconazole or itraconazole) in a multicenter randomized open-label trial of 602 patients 13 years of age or older with prolonged neutropenia due to chemotherapy for AML or advanced MDS [23]. Prophylaxis was given with each cycle of chemotherapy until recovery from neutropenia and complete remission, occurrence of an invasive fungal infection, or for up to 12 weeks, whichever came first.

Posaconazole prophylaxis was associated with a significant reduction in proven or probable invasive fungal infections (2 versus 8 percent) that was due entirely to a reduction in invasive aspergillosis [23]. Posaconazole was also associated with a significant reduction in all-cause mortality (16 versus 22 percent). However, serious adverse events attributable to the drug were significantly more common with posaconazole (6 versus 2 percent), although the rate of toxicity of all causes was similar between the two groups [23]. It is not known whether the adverse events that were attributable to the study drug were more common in patients who received chemotherapy concomitantly with posaconazole.

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.)

It is important to note that the absorption of the oral suspension of posaconazole is greatly improved by concomitant food (especially high-fat food); if the patient is not eating, absorption is greatly impeded and it is unlikely that blood posaconazole levels will be adequate. For this reason, we prefer the delayed-release tablet due to its more reliable oral absorption [35,36,38,39]. The delayed-release formulation should be taken with food. Patients who are unable to take medications orally or who are expected not to absorb oral medications should be given IV posaconazole. (See "Pharmacology of azoles", section on 'Posaconazole'.)

Voriconazole — Voriconazole has activity against Aspergillus spp but not against the agents of mucormycosis. Although voriconazole is used in some centers, there are no large randomized trials evaluating the possible benefit of this agent for prophylaxis in patients with AML or MDS receiving induction chemotherapy. However, a large randomized trial was performed during the pre- and postengraftment period in HCT recipients, many of whom had AML [40]. Among patients who received voriconazole compared with those who received 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 analysis of HCT recipients with AML, those who received voriconazole had significantly improved fungal-free survival (78 versus 61 percent) and significantly fewer invasive fungal infections (9 versus 21 percent), but no difference in overall survival (81 versus 72 percent) compared with those who received fluconazole. (See "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients", section on 'Prophylaxis during the pre-engraftment period'.)

Voriconazole has been best evaluated for the treatment of invasive aspergillosis; it is the preferred agent for treatment. (See "Treatment and prevention of invasive aspergillosis".)

Itraconazole — Itraconazole has activity against Aspergillus spp. Two meta-analyses concluded that itraconazole was effective for preventing invasive fungal infections [41,42], but one found that the protective effect from prophylaxis was limited to trials using itraconazole oral solution (at a dose of 200 mg twice daily), a preparation that is poorly tolerated [42]. Itraconazole's absorption is greatly affected by the formulation (oral solution greater than oral capsule), gastric acidity, and concomitant food intake.

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.)

Amphotericin B — Amphotericin B formulations have activity against Aspergillus spp and the agents of mucormycosis as well as Candida spp, but they are generally not used for antifungal prophylaxis due to their adverse effects and insufficient evidence regarding their efficacy. Amphotericin B deoxycholate given parenterally has been plagued by infusional toxicities and nephrotoxicity, and its efficacy as prophylaxis is not well established. Some studies in patients with hematologic malignancies have suggested a benefit of the prophylactic use of lipid formulations of amphotericin B given parenterally [13,43,44], whereas others have not [45-47]. Unfortunately, several trials were underpowered to provide definitive answers. The possible efficacy of lipid formulations of amphotericin B for antifungal prophylaxis has been insufficiently studied to date. Although the lipid formulations of amphotericin B are less toxic than amphotericin B deoxycholate, adverse effects are still substantial [44,46,47]. (See "Pharmacology of amphotericin B", section on 'Safety and efficacy'.)

The efficacy of aerosolized liposomal amphotericin B in preventing invasive pulmonary aspergillosis was evaluated in a randomized placebo-controlled trial of 271 patients with hematologic malignancies (during 407 neutropenic episodes) who were expected to be neutropenic for at least 10 days [48]. All patients received prophylaxis to prevent Candida infection. In the intent-to-treat analysis, aerosolized amphotericin B was associated with a significant reduction in the rate of invasive aspergillosis compared with placebo (4.3 versus 13.6 percent; odds ratio 0.26, 95% CI 0.09-0.72). No survival benefit was observed, but this study was probably underpowered to detect such an effect. There was a significantly greater incidence of adverse events, primarily cough, preventing adherence to the drug administration in a sizable proportion of patients.

Aerosolized amphotericin B has not been directly compared with systemic antifungal prophylaxis. Thus, additional studies are needed before this therapy can be recommended for patients who require antifungal prophylaxis. It is also important to note that droplet size is crucial to ensure delivery of the drug to the lower respiratory tract and may vary from one delivery device to another.

Amphotericin B or nystatin given as an oral suspension or lozenge has had some benefit in reducing superficial infections (mostly Candida) in some (but not all) studies, but, overall, has not had a consistent benefit in reducing colonization and, more importantly, systemic or invasive infections [49,50]. This is not surprising since the usual portals of entry for Aspergillus spp and other molds are the sinuses and respiratory tract.

Isavuconazole — Isavuconazole has excellent anti-mold activity, has been found to be effective in treatment of both aspergillosis and mucormycosis, and has shown protective effects against mucormycosis in mice [51]. In a small phase II trial in patients with acute myelogenous leukemia undergoing induction therapy, isavuconazole prophylaxis was found to be well tolerated and reliably achieved trough serum concentrations of >1 micrograms/mL, but reductions in some antileukemic agents were required due to avoid deleterious drug-drug interactions [52]. However, in one retrospective review of 145 patients with hematologic malignancies and HCT recipients, an increase in invasive fungal infections was observed when isavuconazole was used for primary prophylaxis compared with either voriconazole or posaconazole [53]. Nine invasive fungal infections occurred in patients receiving isavuconazole prophylaxis compared with three patients receiving posaconazole and one patient receiving voriconazole. Most infections were due to molds (eg, Aspergillus, Fusarium, Rhizopus spp) and occurred primarily in neutropenic patients undergoing chemotherapy for AML. Breakthrough infections have also been reported with isavuconazole prophylaxis in case series; however, the patient populations studied are often heavily treated, which may enhance the likelihood of this outcome [54].

Risk-benefit assessment — Although antifungal prophylaxis has been proven to be efficacious in selected high-risk patients with hematologic malignancies, 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. The level of immunosuppression is higher after induction chemotherapy for acute leukemia compared with other settings, such as following consolidation chemotherapy. Important comorbidities include older age, the presence or absence of 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 [11].

Secondary prophylaxis — Patients who have a history of a prior invasive fungal infection, especially Aspergillus infections, are at high risk for recurrence of infection with further antileukemic therapy. This has been best studied in patients with prior Aspergillus infection. Continued treatment after initial control (so-called secondary prophylaxis) can prevent reactivation of infection in most patients and permit further antileukemic therapy [31,55,56].

For patients with a history of prior invasive aspergillosis receiving myelosuppressive chemotherapy with an anticipated prolonged neutropenic period of at least two weeks, we recommend antifungal prophylaxis with a mold-active agent [57]. 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 containing agents metabolized in the liver. Of note, this is not a concern for agents such as cytarabine or fludarabine. This is discussed in greater detail below. (See 'Drug interactions' below.)

For patients with prior Candida infections, secondary prophylaxis should be selected based on the Candida species and on 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 [57]:

In patients with acute leukemia, primary prophylaxis against molds and/or Candida spp is typically continued until myeloid reconstitution has occurred.

In patients who have a history of a prior invasive fungal infection who are receiving secondary prophylaxis during a period of myelosuppression (eg, during induction chemotherapy in AML patients), prophylaxis is usually continued at least until myeloid reconstitution has occurred. In such patients, follow-up imaging (computed tomography 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. Patients undergoing repeated courses of myelosuppressive chemotherapy should generally continue secondary prophylaxis until completion of the course of chemotherapy.

PRE-EMPTIVE THERAPY — An alternative to antifungal 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 — Broad use of fluconazole prophylaxis has led to increases in Candida species with reduced susceptibility or resistance to fluconazole (eg, C. glabrata, C. krusei) [58,59]. Cross-resistance to any azole may occur in Candida species, especially C. glabrata [60,61]. There has also been growing concern about the emergence of echinocandin resistance among Candida spp [62]. Thus, prophylaxis should be limited to those patients who are at substantial risk for invasive infection, and one should be mindful of the potential for breakthrough Candida infections, especially with C. krusei or C. glabrata. (See "Candidemia in adults: Epidemiology, microbiology, and pathogenesis".)

An increase in mucormycosis has been reported in several retrospective studies of voriconazole prophylaxis in several centers [63-65], but, in prospective epidemiologic studies and in controlled prophylaxis trials, mucormycosis remains infrequent and no clear-cut association has been established between voriconazole prophylaxis and the development of mucormycosis. (See "Mucormycosis (zygomycosis)".)

It is important to note that caspofungin and other echinocandins are not active against Cryptococcus neoformans, Trichosporon, Fusarium, or filamentous molds other than Aspergillus. In addition, some yeasts can demonstrate relative resistance to these drugs (Candida parapsilosis, Candida rugosa, Candida guilliermondii, and non-Candida yeasts). Failure of caspofungin to prevent aspergillosis has also been reported [66]. Moreover, the clinical efficacy of the echinocandins for endemic fungi (Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides spp) has not been demonstrated. In addition, some studies, mostly from one center, suggest an increase in mold infections with echinocandin prophylaxis relative to the mold-active azoles [67]. More data are needed. (See "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated infection in patients without HIV" and "Diagnosis and treatment of disseminated histoplasmosis in patients without HIV" and "Treatment of blastomycosis" and "Primary pulmonary coccidioidal infection" and "Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis".)

For suspected breakthrough mold infection in patients receiving mold-active azoles, a prompt and aggressive approach to establish a specific diagnosis is recommended [31]. Serum trough levels of the prophylactic azole should be obtained if possible. The patient should be changed to another class of anti-mold drug during the evaluation and immunosuppression reduced if feasible. If a breakthrough mold infection is diagnosed, antifungal susceptibility testing should ideally be considered. (See "Antifungal susceptibility testing".)

DRUG INTERACTIONS — There are many potential drug interactions between antifungal agents and drugs that may be used concomitantly [68]. Specific drug interactions unique to patients with hematologic malignancies are mentioned here.

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 [69].

Itraconazole and voriconazole have been associated with severe neurotoxicity with vincristine [70].

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).

In a trial of patients receiving chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome, posaconazole was associated with greater attributable drug toxicity than fluconazole or itraconazole [23]. However, it is not known whether the adverse events were more common in patients who received chemotherapy concomitantly with posaconazole.

Given the potential for serious drug interactions, concomitant administration of extended-spectrum triazole-based prophylaxis (posaconazole, voriconazole, itraconazole) should be avoided in patients receiving vincristine or high doses of cyclophosphamide. Caution is advised for the concomitant use of the extended-spectrum triazoles with chemotherapy drugs metabolized by the liver, especially those metabolized by cytochrome P450 isoenzymes such as the tyrosine kinase inhibitors (eg, nilotinib). Of note, this is not a concern for agents such as cytarabine or fludarabine.

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.

One tactic advised by some experts is to avoid administration of the extended-spectrum triazoles (posaconazole, voriconazole, itraconazole) approximately one week before (to allow clearance) and during chemotherapy and then resume it after chemotherapy to avoid potential drug interactions; if interruption of antifungal drugs will pose a hazard to the patient, another class of antifungal agent (eg, amphotericin B or an echinocandin) can be given during the chemotherapy. Further study of the drug interactions between the extended-spectrum triazoles and chemotherapy drugs is necessary.

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 (see "Pharmacology of azoles", section on 'Drug interactions'). Details about specific interactions may be obtained by using the drug interactions program included within UpToDate.

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: Neutropenic fever in adults with cancer" and "Society guideline links: Invasive fungal infections".)

SUMMARY AND RECOMMENDATIONS

Risk for invasive fungal infection The risk for invasive fungal infections increases with the duration and severity of neutropenia, prolonged antibiotic use, and number of chemotherapy cycles. (See 'Introduction' above.)

Candida infection Candida is by far the most common fungal pathogen in patients with acute leukemia not receiving antifungal prophylaxis. Invasive candidiasis occurs most often as a result of translocation of colonizing Candida spp across the oral and/or gastrointestinal mucosa in the setting of mucositis from cytotoxic chemotherapy. Candidemia is the most frequent clinical manifestation of invasive candidiasis. Patients with acute leukemia are at highest risk for invasive candidiasis during induction chemotherapy. (See 'Candida infection' above.)

Aspergillus Aspergillus is the most common mold pathogen in patients with acute leukemia. Its most common manifestation is pneumonia; less common manifestations include sinusitis and disseminated infection. (See 'Aspergillus infection' above.)

Antifungal prophylaxis The following recommendations represent our approach to antifungal prophylaxis in patients with hematologic malignancies. 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.)

Although antifungal prophylaxis has been proven to be efficacious in selected high-risk patients with hematologic malignancies, 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.)

For patients with acute leukemia undergoing initial remission-induction or salvage-induction chemotherapy who are expected to develop severe oral and/or gastrointestinal mucositis, we recommend prophylaxis against Candida infections (Grade 1B). We prefer fluconazole (400 mg orally once daily) for anti-Candida prophylaxis. (See 'Approach to primary prophylaxis' above.)

For selected patients who are expected to experience prolonged severe neutropenia (absolute neutrophil count [ANC] <500 cells/microL for >7 days) due to intensive chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome, we recommend prophylaxis against both invasive mold infections and Candida spp rather than targeted anti-Candida prophylaxis with fluconazole (Grade 1B). In such patients, either posaconazole or voriconazole is an appropriate option as there is evidence of efficacy with both agents compared with other antifungal agents; these agents have not been compared directly to one another. When posaconazole is used, we prefer the delayed-release formulation rather than the oral suspension. The dosing of these agents is discussed above. Another alternative for patients who cannot receive posaconazole or voriconazole is isavuconazole, although it has not been studied for prophylaxis. (See 'Approach to primary prophylaxis' above.)

For patients with a history of prior invasive aspergillosis receiving myelosuppressive chemotherapy with an anticipated prolonged neutropenic period of at least two weeks, we recommend secondary antifungal prophylaxis with a mold-active agent (Grade 1B). (See 'Secondary prophylaxis' above.)

Drug interactions – Given the potential for serious drug interactions, concomitant administration of extended-spectrum triazole-based (posaconazole, voriconazole, itraconazole) prophylaxis should be avoided in patients receiving vincristine or high doses of cyclophosphamide. Caution is advised for concomitant use of the extended-spectrum azoles with chemotherapy drugs metabolized by the liver, especially those metabolized by cytochrome P450 isoenzymes and other CYP3A4 substrates. (See '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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Topic 16141 Version 35.0

References

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