Blood Res 2022; 57(S1): S101-S111  https://doi.org/10.5045/br.2022.2022036
Advances in prophylaxis and treatment of invasive fungal infections: perspectives on hematologic diseases
Hyojin Ahn1, Raeseok Lee1,2, Sung-Yeon Cho1,2, Dong-Gun Lee1,2
1Division of Infectious Diseases, Department of Internal Medicine, 2Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea
Correspondence to: Dong-Gun Lee, M.D., Ph.D.
Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea
E-mail: symonlee@catholic.ac.kr
Received: February 6, 2022; Revised: April 21, 2022; Accepted: April 22, 2022; Published online: April 30, 2022.
© The Korean Journal of Hematology. All rights reserved.

cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Invasive fungal infections (IFIs) are common causes of mortality and morbidity in patients with hematologic diseases. Delayed initiation of antifungal treatment is related to mortality. Aspergillus sp. is the leading cause of IFI followed by Candida sp. Diagnosis is often challenging owing to variable conditions related to underlying diseases. Clinical suspect and prompt management is important. Imaging, biopsy, and non-culture-based tests must be considered together. New diagnostic procedures have been improved, including antigen-based assays and molecular detection of fungal DNA. Among hematologic diseases, patients with acute myeloid leukemia, myelodysplastic syndrome, recipients of hematopoietic stem cell transplantation are at high risk for IFIs. Antifungal prophylaxis is recommended for these high-risk patients. There are continuous attempts to achieve ideal management of IFIs. Scoring system for quality control has been developed with important recommendations of current guidelines. Higher adherence to guidelines is related to decreased mortality in IFIs.
Keywords: Hematologic diseases, Invasive fungal infections, Diagnosis, Treatment, Quality control
INTRODUCTION

Fungal species are widely distributed in the environment and can cause opportunistic infections in immunocompromised hosts such as those with hematologic diseases. They can be classified according to their histologic forms: yeast (Candida sp.), mold (Aspergillus, Rhizopus), and dimorphic fungus. Clinical presentation of patients with fungal infections may range from mucocutaneous to deep organ infections [1, 2].

Recently, the incidence of invasive fungal infections (IFIs) has risen substantially and became a major problem in hospitals because of increased immunosuppressive therapy, organ and hematopoietic stem cell transplantation (HSCT), cytotoxic chemotherapy, invasive procedures and indwelling catheter [3, 4]. Patients with hematologic malignancies are at high risk of developing IFIs, which have high mortality and morbidity. Moreover, these group of patients are more exposed to antifungal agents which has contributed to diverse epidemiology and antifungal resistance [5-7].

Definitions for IFIs have been proposed (proven, probable, possible) to have a standard, shared definition, which may aid in communication between researchers, and ultimately improve diagnosis and management in clinical practice. Proven IFI is defined by the detection of fungus by histology or sterile tissue culture. Probable or possible IFI is defined depending on the setting or population, with respect to three elements: host factors, clinical features, and mycologic evidence [8].

IFIs caused by rare fungi are also increasing [9-11]. However, this article focused on IFIs, specifically invasive candidiasis, aspergillosis, and mucormycosis in patients with hematologic diseases. Furthermore, we also aimed to discuss the recent epidemiology, diagnosis, treatment, prophylaxis, and quality control in IFIs.

CANDIDIASIS

Candida species are commonly part of the normal flora, but they can cause a variety of opportunistic infections. Candidiasis is a broad term which refers to any infection caused by Candida sp. Invasive candidiasis refers to candidemia and deep-seated infection with or without candidemia. Examples of deep-seated infections include intra-abdominal abscess, peritonitis, osteomyelitis, brain abscess, endophthalmitis, and endocarditis.

Epidemiology

In patients with hematologic diseases, candidemia is the most common form of invasive candidiasis and is associated with high mortality rates up to 40% [12]. Neutropenia (neutrophil count <500 cells/mL) is a common risk factor and is usually related to cytotoxic chemotherapy or HSCT, use of broad-spectrum antibiotics gastrointestinal mucosal dysfunction, and indwelling vascular catheters [13]. Acute disseminated candidiasis or hepatosplenic candidiasis might also be seen in patients with prolonged neutropenia. Evidence of defining neutropenia as neutrophil count of less than 500 cells/mL followed previous study result [14].

At least 15 distinct Candida sp. can cause human diseases, but majority of invasive infections are caused by 5 species (Candida albicans, Candida tropicalis, Candida glabrata, Candida krusei and Candida parapsilosis). There is geographical, center-to-center variability in the prevalence of Candida species. Patient’s predisposing factors and previous antifungal use also have a considerable influence on the distribution of Candida species. Candidiasis control should therefore include monitoring the epidemiology of Candida species and resistance to various antifungal agents [15, 16].

Traditionally, C. albicans has been the most common species but through the decades, non-albicans species have been increasing in proportion. We compared the epidemiology of candidemia from previous studies (Table 1). C. glabrata was the most common species among non-albicans species in Korea, similar in the United States [16-19]. C. tropicalis disputed this place in Asia-pacific region [20]. C. tropicalis followed C. glabrata in Korea.

Table 1

Changes of species distribution in the case of candidemia.

PathogensSeoul St. Mary’s Hospital
(adult hematology unit only)
KoreaUnited StatesAsiaEuropea)
Study period2011–20212011–20162017–2021201320212012201920162011
References[16][17][18][19][20][114]
TotalN=153 (%)N=84 (%)N=69 (%)N=3,564 (%)N=829 (%)N=2,329 (%)N=3,354 (%)N=861 (%)N=750 (%)
Candida albicans38 (24.8)27 (32.1)11 (15.9)1,354 (38.0)353 (42.6)877 (37.7)1,307 (39.0)309 (35.9)(55.2)
Non-C. albicans115 (75.1)57 (67.9)58 (84.1)2,210 (62.0)476 (57.4)1,452 (62.3)2,047 (61.0)552 (64.1)(44.8)
Candida tropicalis55 (35.9)30 (35.7)25 (36.2)557 (15.6)156 (18.8)241 (10.3)292 (8.7)264 (30.7)(7.3)
Candida glabrata25 (16.3)8 (9.5)17 (24.6)589 (16.5)159 (19.2)670 (28.8)949 (28.3)116 (13.5)(15.7)
Candida krusei16 (10.5)10 (11.9)6 (8.7)20 (0.6)15 (1.8)32 (1.4)72 (2.1)6 (0.7)(2.5)
Candida parapsilosis9 (5.9)4 (4.8)5 (7.2)844 (23.7)112 (13.5)389 (16.7)496 (14.8)135 (15.7)(13.7)
Candida lusitaniae4 (2.6)2 (2.4)2 (2.9)26 (0.7)9 (1.1)34 (1.5)66 (2.0)1 (0.1)(1.2)
Candida auris1 (0.1)
Others6 (3.9)3 (3.6)3 (4.3)174 (4.9)24 (2.9)86 (3.7)172 (5.1)30 (3.5)(2.6)

a)Without exact number of cases, only percentage.



In a single tertiary-care hospital in Korea where all data were collected from adult patients with hematologic diseases, the trend of decreasing C. albicans and increasing non-albicans species was the same. It was notable that C. tropicalis was considerably high in frequency and was already reported in several studies to be the most common non-albicans species causing candidemia in hematology patients [21-24]. C. glabrata recently increased from 9.5% to 24.6%, following the global trend. A main cause of the shift toward non-albicans species could be an increased azole resistance (ex. C. glabrata, C. tropicalis) due to the increased use of prophylactic antifungal agents. Furthermore, there is an increased use of echinocandin in patients with hematologic diseases for prophylaxis and/or empirical use [21] which could lead to epidemiological change.

Uncommon Candida species include C. lusitaniae, C. guilliermondii, and C. auris. Patients with hematologic diseases were at particular risk of C. lusitaniae and C. guillermondii [25]. These species are known to have intrinsic resistance to certain antifungal agent; C. guilliermondii resistant to echinocandins and C. lusitaniae resistant to amphotericin B. Therefore, selecting antifungal agent is challenging and accurate identification of these species is important [26-28]. C. auris, a nosocomial fungus, has become a serious threat for health care facilities around the globe. It can spread readily and has caused numerous healthcare-associated outbreaks. Moreover, most strains are resistant to at least one antifungal agent [29].

Diagnosis

Classic diagnostic methods for candidiasis are microscopy, histopathology and culture [15]. Tissue samples and body fluids from sterile sites must be collected aseptically and transported to the laboratory promptly. If it is candidemia, the preferred diagnostic would be blood culture [30]. Yeast isolation from normally sterile tissues or fluids is usually indicative of deep-seated infection; however, negative results do not exclude candidiasis. Identification of the isolate to species level is mandatory. Microscopy should make use of special stains such as Grocott-Gomori methenamine silver (GMS) and Periodic Acid Schiff (PAS). β-D-glucan (BDG) is a cell wall component of most fungi and is not specific to detect Candida species with high false positive rate. In contrast, BDG has high negative predictive value, suggesting that invasive candidiasis is unlikely when BDG is negative [15]. However, careful interpretation is needed as it may not be reliable in the early course of IFI. Immuno-histochemistry, in situ hybridization, and polymerase chain reaction (PCR) based procedures are evaluated but utility and accuracy has not been warranted yet [31].

For patients with hematologic diseases, the possibility of obtaining samples of deep tissues is not warranted due to the patient’s condition [32]. Therefore, many clinicians also rely on empirical evidence with prior exposure to antibacterial agents, existence of a central venous catheter (CVC), and recent abdominal surgery to establish diagnosis [15]. As the number of fungal infections has increased and as hosts have become more vulnerable, newer diagnostic tests are needed to identify the pathogens more quickly [33].

Breakthrough invasive candidiasis is also a problem in patients with hematologic diseases. Breakthrough infection is defined as an infection occurring in a patient receiving antifungal agents. Azole-resistant Candida sp., especially C. krusei, were major cause of breakthrough infection. Up to 45% had resistance to antifungal agent which the patient was receiving when the breakthrough infection occurred [34-36]. Therefore, changing antifungal agent to different class and testing susceptibility of cultured species are needed.

Chronic disseminated (hepatosplenic) candidiasis (CDC) is a unique clinical manifestation and almost seen in patients with hematologic diseases. CDC usually occur during recovery from neutropenia. Fever, right upper quadrant discomfort, nausea, elevate liver enzymes following recovery from neutropenia implicate CDC [37]. CT, MRI, or ultrasound imaging is helpful and small, peripheral, target-like abscesses are seen in the liver or spleen [31, 38].

Treatment

The mortality rate is closely correlated with delayed initiation of appropriate antifungal treatment. Therefore, prompt treatment is needed to improve prognostic outcomes in patients [39]. In candidemia, echinocandin antifungals are recommended as initial therapy. Transition from an echinocandin to fluconazole, usually within 5–7 days, is suggested in non-neutropenic patients who are clinically stable, have isolates that are susceptible to fluconazole, and have negative repeat blood cultures following treatment [40]. Fluconazole (intravenous or oral) is an acceptable alternative first line therapy if the patient is not critically ill and is unlikely to have a fluconazole-resistant Candida species [31]. However, antifungal resistance is an emerging problem worldwide and hematology patients might already be exposed to antifungal drugs for prophylaxis, complicating the selection of appropriate antifungal therapy [15]. For example, C. glabrata and C. krusei are more likely to have azole resistance and C. parapsilosis is known to have intrinsic resistance to echinocandin but not clinically significant [41].

Follow-up blood cultures should be performed every day or every other day to check when candidemia has been cleared. Recommended duration of therapy for candidemia without obvious metastatic complications is at least 2 weeks after the documented clearance of Candida species from the bloodstream, provided that neutropenia and other symptoms have resolved. For other complications such as endocarditis, surgical intervention and longer treatment are needed. Therefore, work up with transthoracic (TTE) or transesophageal (TEE) echocardiography should be done in patients with candidemia [32]. To check other disseminated focus, all non-neutropenic patients with candidemia should have a dilated ophthalmological examination within the first week after diagnosis to check for endophthalmitis. In neutropenic patients, ophthalmological findings are usually minimal until recovery from neutropenia; therefore, examination could be performed within the first week after recovery from neutropenia [31]. CVCs should be removed as early as possible when the source of candidemia is presumed to be the CVC. In neutropenic patients, sources of candidemia other than a CVC (ex. gastrointestinal tract) predominate. Removal of CVC should be considered on an individual basis [31, 42].

With CDC, therapy should be continued until lesions resolve on repeated imaging. The usual duration is several months and premature discontinuation of antifungal therapy can lead to relapse. If chemotherapy or HSCT is required, it may not be delayed because of the presence of chronic disseminated candidiasis [43].

For oropharyngeal candidiasis in patients with neutropenia, fluconazole 7–14 days is recommended. Chronic suppressive therapy is usually unnecessary. Esophageal candidiasis always requires systemic antifungal therapy. Diagnostic trial of antifungal therapy is available before endoscopic examination and intravenous therapy is recommended if the patient cannot tolerate oral therapy [31].

Echinocandin, a treatment of choice, has so-called sanctuary sites in the body such as eye, kidney, and meninges; therefore, it might be unsuitable for infection in those sites [44]. In addition, there is an increase in the resistance of C. glabrata to echinocandin [45]. In contrast, C. parapsilosis demonstrates innately higher minimum inhibitory concentrations (MICs) to echinocandins. If echinocandin or fluconazole is inadequate, liposomal amphotericin B could be an alternative.

ASPERGILLOSIS

Aspergillosis is the collective term used to describe all disease entities caused by any one of up to 50 pathogenic and allergenic species of Aspergillus. Aspergillus species continue to be an important cause of life-threatening infection in immunocompromised patients.

Epidemiology

In patients with hematologic diseases, Aspergillus-related infection is the most common IFI, followed by Candida infections [46]. Incidence rates vary according to local epidemiology and many other factors, including environmental control. Aspergillus fumigatus complex is the most common species, followed by A. flavus, A. niger, and A. terrus [47]. Invasive aspergillosis (IA) is a severe IFI, which manifests mostly as invasive pulmonary aspergillosis (IPA). A. fumigatus is responsible for most cases of IA but more commonly colonizes the respiratory tract. In contrast, A. flavus and A. niger often colonize burn wounds, and A. terreus causes only invasive disease, and usually has a poor prognosis [1, 48-50]. Some species are known to have variable susceptibility to antifungal agents. A. terreus is infrequently susceptible to amphotericin B, whereas A. calidoustus and A. lentulus are resistant to multiple antifungal agents, including amphotericin B and voriconazole [50]. Azole resistance in A. fumigatus is also increasing [51], thus raising a problem.

Diagnosis

Diagnosis of IA remains difficult in many reasons. Both microscopy and culture should be attempted and tissue invasion by hyphae would provide a definitive diagnosis of IA. However, examinations such as tissue sampling may be difficult in hematology patients because of neutropenia and thrombocytopenia and yield of culture is frequently suboptimal [52]. Therefore, non-invasive diagnostic tests including non-culture-based tests have gained interest for improving diagnostic accuracy.

A high level of suspicion with meticulous physical examination is important since an immunocompromised patient may be relatively asymptomatic, interrupting early diagnosis [50]. The most prevalent but unspecific sign of IPA reported in approximately 100% of patients is persistent fever despite treatment with broad-spectrum antibiotics [53]. Imaging is a critical component in the diagnosis, and CT scan is recommended whenever there is clinical suspicion or when the patients present with 72–96 hours of persistent neutropenic fever to find IPA or sinusitis regardless of simple chest radiograph results [54]. Routine contrast imaging is not recommended but could be considered if vessel involvement is suspected. Typical findings of IPA include consolidation with surrounding ground-glass opacity (halo sign) or cavitation [55]. Lung ultrasound (US) imaging has been considered as an alternative modality to diagnose invasive fungal pneumonia, including US-guided transthoracic needle aspiration. Considering it is a rapid, bedside, non-invasive technique, lung US could have a significant role but more study is required for expected accuracy [56-58].

Bronchoscopy with bronchoalveolar lavage (BAL) is recommended in patients in the suspicion of IPA. It seems to be a valuable diagnostic tool with high yield and low complication rate even in neutropenic patients with hematologic diseases. Therefore, regarding the diagnostic delay and impact on mortality, bronchoscopy with BAL should be considered if possible [59-61]. Routine fungal culture, cytology, and non-culture-based methods should be performed. Galactomannan (GM) detection is more sensitive than culture in the diagnosis of IA. Additionally, BAL fluid GM is more sensitive compared to serum GM in terms of diagnostic performance [62]. Serum assays for BDG with comparison to GM suggest higher sensitivity but are not a specific marker for Aspergillus and may produce frequent false positive results. Nucleic acid testing in clinical specimens such as PCR has become available and promising but still controversial due to the lack of conclusive validation [8]. Its negative predictive value is high but positive predictive value is low, therefore, conjunction with other diagnostic tests and clinical context is needed [63, 64]. If imaging findings implicate fungal infection with or without positive biomarkers (ex. GM, PCR), probable/possible IFI could be considered. As pulmonary infection is the most frequent form of IFIs in patients with hematologic diseases, we depicted the diagnostic process of invasive fungal pneumonia as an example (Fig. 1).

Figure 1. Diagnosis of fungal pneumonia in patients with hematologic diseases. a)Evidence of neutrophil count (<500 cells/mL) followed the guideline [14].
Abbreviations: ANC, absolute neutrophil count; BAL, broncho- alveolar lavage; BDG, (1→3) beta- D-glucan; CT, computed tomo-graphy; GM, galactomannan; PCR, polymerase chain reaction.

Treatment

For suspected IA, current guideline recommends voriconazole or isavuconazole as the treatment of choice. Isavuconazole is a mold-active triazole antifungal agent and is also susceptible to other molds including mucormycosis. Therefore, isavuconazole could be considered when coinfection of IA with other molds cannot be excluded [65]. If contraindicated or not tolerated, liposomal amphotericin B may be considered as an alternative. Amphotericin B deoxycholate is no longer a primary option but can be used in limited settings when no other antifungal agents are available [66]. Itraconazole should not be used as first line therapy although it is a potential option due to drug-drug interactions. Echinocandin also is not recommended because outcomes were not favorable with monotherapy [67]. Treatment should be continued for a minimum of 6–12 weeks, largely dependent on the degree and duration of immunosuppression, sites of infection, and evidence of disease improvement. Higher GM level is known as a risk factor related to mortality and follow up can be used to monitor disease progression or therapeutic response [68].

When persistent fever exists but no infiltrate seen in chest imaging, possible focus other than the lung should be considered. If there are no suspected focus and biologic markers such as GM, and PCR is negative, no empirical treatment would be required. However, in patients under mold-active prophylaxis, therapeutic drug monitoring (TDM) for prophylactic azoles such as posaconazole and voriconazole should be done and breakthrough IA should be considered [69]. Triazole is not recommended for empiric therapy of breakthrough infection during triazole prophylaxis and a different class of mold-active antifungal agent is required. When fever of unknown origin persists in patients without mold-active prophylaxis, empiric antifungal therapy with triazole might be considered [14, 70].

Reducing the dose or cessation of immunosuppressive agents could be a component of aspergillosis treatment. Colony-stimulating factors in neutropenic patients may also be considered. Granulocyte transfusion can be considered if the patient is unlikely to respond to standard therapy and if the anticipated duration of neutropenia is more than one week [71]. Surgery should be considered in localized disease [ex. invasive fungal sinusitis, endocarditis, osteomyelitis, focal invasion of central nervous system (CNS)]. IA is not an absolute contraindication to additional chemotherapy or stem cell transplantation. Decision must consider the risk of progressive aspergillosis during anti-neoplastic therapy versus the risk of clinical deterioration due to the aggravation of underlying hematologic diseases during delayed treatment [72, 73].

Voriconazole undergoes extensive hepatic metabolism and share metabolic pathways with many drugs. Therefore, TDM and drug interaction (ex. cyclosporin, tacrolimus, sirolimus and other CYP3A4 substrates) must be monitored for optimized therapeutic efficacy and to avoid potential toxicities. Genetic polymorphisms in CYP2C19 also contribute to serum drug levels. Common side effects include photopsia, photosensitivity, CNS disturbance, and prolonged QT interval. Amphotericin B deoxycholate, which is no longer used as primary IA treatment has many side effects including infusion-related toxicity and renal toxicity. However, some centers in Korea still use amphotericin B deoxycholate as the first line of treatment due to insurance and economic issues [73, 74].

MUCORMYCOSIS

Mucormycosis represents a group of life-threatening infections caused by fungi of the order Mucorales. Mucorales are ubiquitous environmental fungi and cause infection in patients with diabetes mellitus, solid organ transplantation or HSCT, prolonged neutropenia, or malignancy [1]. Suspected mucormycosis requires rapid diagnostic and therapeutic intervention including medical, surgical, radiological, and laboratory team to increase survival because of its rapidly progressive and destructive nature [75]. All-cause mortality rates range from 40–80% and poorest prognosis is observed in patients with hematologic diseases and HSCT recipients [76].

Six different syndromes are grouped according to the anatomic predilection: sinusitis (rhino-orbital or rhinocerebral), pulmonary, cutaneous, gastrointestinal, disseminated, and other. Disseminated mucormycosis, usually as pulmonary mucormycosis typically develops in hematology patients with profound neutropenia [76, 77] and graft-versus-host diseases after allogeneic HSCT [78, 79]. Similar to IA, persistent fever without suspected symptoms is seen in most patients [75]. Rhino-orbito-cerebral mucormycosis typically develops in patients with diabetes mellitus, but can also be seen in patients with hematologic diseases [80].

Epidemiology

In the mid-20th century, diabetes mellitus used to be a major risk factor for mucormycosis. However, in recent years, underlying malignancy emerged as another important risk factor due to the increasing number of patients undergoing chemotherapy, immunotherapy, or HSCT [81, 82]. The most frequently reported pathogens are Rhizopus spp., Mucor spp., Cunninghamella, Lichtheimia spp. and Rhizomucor spp. Incidence rates vary by region or center, indicating geographical variation.

Diagnosis

The diagnosis of mucormycosis depends on the availability of imaging techniques, trained personnel, and mycological and histological investigations. In patients with hematologic diseases and suspected pulmonary mucormycosis, chest CT scan is recommended. Typical finding includes ground glass opacity surrounded by a ring of consolidation (reversed halo sign).

If mucormycosis is a potential diagnosis, biopsy is strongly recommended. It is usually suspected based on the results of direct microscopy. However, diagnosis with histomorphological basis is challenging because misidentification of Mucorales as Aspergillus species is common [83]. Culture of specimen is also strongly recommended for species identification and antifungal susceptibility testing. Frankly, identification of causative Mucorales does not obviously guide the choice of antifungal treatment because treatment should be started before the report. However, clinical course may be different depending on the species, leading to a better epidemiologic understanding. Immunohistochemistry with monoclonal antibodies or PCR could also be done, although still not widely available [75]. BDG is usually negative in patients with mucormycosis, as these fungi do not produce BDG [84]. However, about one-third of patients with pulmonary mucormycosis had concomitant opportunistic fungal infection according to previous study [85]. Cases of mixed fungal infection have also been reported [86]. Therefore, BDG, GM is recommended in suspected mucormycosis to support differential diagnosis or mixed IFI [75].

Treatment

Suspected and confirmed mucormycosis are medical and surgical emergencies and require rapid management. Breakthrough mucormycosis during mold-active prophylaxis is also possible [87, 88] and must be considered. Early complete surgical debridement with clean margins is strongly recommended for disease control, histopathology, and microbiologic diagnosis [89, 90]. In neutropenic patients, immediate surgery may be required; however, some still prefer surgical resection after the resolution of neutropenia and thrombocytopenia in IA [91].

For first line antifungal therapy, liposomal amphotericin B with dose of 5–10 mg/kg/day is recommended. When CNS involvement is suspected, dose of 10 mg/kg/day is needed [92]. Increased dose tends to have an increased response rate, but doses higher than 10 mg/kg/day did not result in higher blood concentrations and instead increased the creatinine level [93, 94]. Amphotericin B deoxycholate has been the drug of choice for decades but its use is limited due to toxicity. It is only recommended when there is no other option. Isavuconazole has similar efficacy with liposomal amphotericin B and could be used as first line treatment for mucormycosis [95]. Posaconazole is recommended as an alternative therapy if first line medication has side effect or is ineffective [75]. Two oral forms (tablet and syrup) are available. Posaconazole syrup is influenced by food and concomitant use of other drugs such as proton pump inhibitors. Therefore, TDM must be monitored for optimal blood trough levels [96, 97].

The duration of therapy in mucormycosis is unknown. In general, weeks to months of therapy are usually given. If the underlying immune defect (ex. neutropenia or use of immunosuppressants) is resolved, therapy can be continued until there is resolution of signs and symptoms or radiographic improvement. There is moderate support for intravenous treatment until stable disease is achieved. The decision to switch to oral monotherapy with isavuconazole or posaconazole depends on the patient’s response to therapy and severity of the illness [75, 98].

ANTIFUNGAL PROPHYLAXIS AGAINST INVASIVE FUNGAL INFECTIONS

Despite improvements in diagnosis and treatment, IFI-associated mortality remains high and thus, antifungal prophylaxis represents an important strategy in patients at high risk for IFI [99].

Patients with neutropenia lasting less than 7 days are at low risk and do not require antifungal prophylaxis. Antifungal prophylaxis is strongly recommended in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) who are in remission or undergoing induction chemotherapy as they are expected to have neutropenia for more than 7 days. Allogeneic HSCT recipients with risk factors such as GVHD are also recommended to have antifungal prophylaxis depending on the local incidence and epidemiology. Fluconazole was often used [100], but protection against non-albicans Candida species and mold was not warranted. Therefore, guidelines strongly suggest posaconazole as an antifungal prophylaxis for these groups [99, 101-103]. Echinocandin is susceptible in azole resistant Candida and Aspergillus and can be used as prophylaxis in both autologous and allogeneic HSCT patients [104].

Voriconazole is only used as secondary prophylaxis during HSCT in patients with a previous history of IA in Korea. Aerosolized liposomal amphotericin B inhalation was found to be effective in reducing IPA and may be considered as an option in the future, considering the increasing azole resistance [105]. New chemotherapy drugs (ex. venetoclax) with drug interaction to triazoles are continuously developed, and strategies might be delicately managed considering the risk factors [106]. An example of antifungal prophylaxis strategy in our hospital regarding guidelines mentioned above is shown in Table 2.

Table 2

Antifungal prophylaxis for patients with hematologic diseases in Seoul St. Mary’s Hospital (last revised January 2022).

Type of patientsPrimaryAlternative
AML Induction/reinduction chemotherapya)Posaconazole (T)Posaconazole (S)
Fluconazole
HMA/Venetoclasa)
- Secondary/refractory AMLPosaconazole (T)Posaconazole (S)
- Relapsed AML (only in 1st and 2nd cycle)Posaconazole (T)Fluconazole
- OtherwiseFluconazole
Other chemotherapy (neutropenia >7 days)a)Fluconazole
Auto-HSCTa),c)MicafunginFluconazole
Itraconazole
Allo-HSCT (pre-engraftment)a),c)MicafunginItraconazole (S)
Allo-HSCT (in the presence of GVHD)b)Posaconazole (T)Posaconazole (S)
Fluconazole

a)Start from absolute neutrophil count ≤1,000 until resolution of neutropenia. b)Until at least 75 days from start or resolution of significant GVHD. c)Voriconazole is only used as secondary prophylaxis in patients with previous proven or probable IPA history.

Abbreviations: AML, acute myeloid leukemia; GVHD, graft versus host disease; HMA, hypomethylating agent; HSCT, hematopoietic stem cell transplantation; S, Syrup; T, Tablet.



In addition to medical prophylaxis, environmental protection should be supervised. High risk patients should be placed in a protected environment to reduce mold exposure. High-efficiency particulate air (HEPA) filtration and maintenance of positive pressure room are examples. If protected environment is not available, a private room could be alternative. Reasonable precautions include avoidance of gardening, and not allowing plants or cut flowers to patient’s room [107]. Health care workers can also play a key role in transmission [108]. Therefore, regular surveillance of IFI cases and education of workers are needed [48].

QUALITY CONTROL OF THE CLINICAL MANAGEMENT

There are guidelines recommended for the ideal managements of IFIs but following these guidelines may be challenging. To highlight the strongest recommendations and measure guideline adherence, the ECMM QUALity of Clinical management score (EQUAL score) was designed. Factors include diagnostic and follow-up procedures, and treatment parameters with different scores. Total score is measured by summing each item. Simplified figure cards for each disease showing items and weights are released for free so anyone can use. Physicians might get important recommendations concisely without reading complicated guidelines entirely. Whether a high score correlates with an outcome remains to be explored; however, these efforts might facilitate antifungal stewardship [109-111]. Previous studies reported that greater guideline adherence with a higher EQUAL Candida score was associated with survival among patients with candidemia [112, 113].

CONCLUSION

IFIs are related to high mortality and morbidity in patients with hematologic diseases and HSCT recipients. Diagnosis and treatment are complicated due to different epidemiology, risk factors, and immune status of the patients. There is a need to analyze the epidemiology regularly and be aware of risk factors to efficiently apply prophylactic antifungal agents. Various tests are mandatory to diagnose and treat IFIs as accurately as possible and further studies are required to improve the prognosis of IFIs in the future.

Authors’ Disclosures of Potential Conflicts of Interest

No potential conflicts of interest relevant to this article were reported.

References
  1. Edwards JE Jr. Diagnosis and treatment of fungal infections. In: Jameson JL, Fauci A, Kasper D, Hauser S, Longo D, Loscalzo J, eds. Harrison's principles of internal medicine. 20th ed. New York, NY:. McGraw-Hill Education,:1515-38.
  2. Cho SY, Lee HJ, Lee DG. Infectious complications after hematopoietic stem cell transplantation: current status and future perspectives in Korea. Korean J Intern Med 2018;33:256-76.
    Pubmed PMC CrossRef
  3. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003;348:1546-54.
    Pubmed CrossRef
  4. Verduyn Lunel FM, Meis JF, Voss A. Nosocomial fungal infections: candidemia. Diagn Microbiol Infect Dis 1999;34:213-20.
    Pubmed CrossRef
  5. Shin JH, Won EJ, Kim SH, et al. A multicenter study of antifungal use and species distribution and antifungal susceptibilities of candida isolates in South Korea. J Mycol Infect 2020;25:10-6.
    CrossRef
  6. Lee R, Cho SY, Lee DG. Fundamentals of mycology for infection control and prevention. Korean J healthc assoc Infect Control Prev 2020;25:86-99.
    CrossRef
  7. Eren E, Alp E, Cevahir F, et al. The outcome of fungal pneumonia with hematological cancer. Infect Chemother 2020;52:530-8.
    Pubmed PMC CrossRef
  8. Donnelly JP, Chen SC, Kauffman CA, et al. Revision and update of the consensus definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin Infect Dis 2020;71:1367-76.
    Pubmed PMC CrossRef
  9. Sprute R, Cornely OA, Chen SC, Seidel D, Schuetz AN, Zhang SX. All you need to know and more about the diagnosis and management of rare yeast infections. mBio 2021;12:e0159421.
    Pubmed PMC CrossRef
  10. Kim H, Yi Y, Cho SY, et al. Pneumonia due to Schizophyllum commune in a patient with acute myeloid leukemia: case report and literature review. Infect Chemother 2022;54:195-201.
    Pubmed PMC CrossRef
  11. Hong SI, Suh YS, Kim HO, Bae IG, Shin JH, Cho OH. Successful treatment of catheter related blood stream infection by Millerozyma farinosa with micafungin: a case report. Infect Chemother 2018;50:362-6.
    Pubmed PMC CrossRef
  12. Sipsas NV, Lewis RE, Tarrand J, et al. Candidemia in patients with hematologic malignancies in the era of new antifungal agents (2001?2007): stable incidence but changing epidemiology of a still frequently lethal infection. Cancer 2009;115:4745-52.
    Pubmed CrossRef
  13. Raad I, Hanna H, Boktour M, et al. Management of central venous catheters in patients with cancer and candidemia. Clin Infect Dis 2004;38:1119-27.
    Pubmed CrossRef
  14. Lee DG, Kim SH, Kim SY, et al. Evidence-based guidelines for empirical therapy of neutropenic fever in Korea. Infect Chemother 2011;43:285-321.
    Pubmed PMC CrossRef
  15. Pappas PG, Lionakis MS, Arendrup MC, Ostrosky-Zeichner L, Kullberg BJ. Invasive candidiasis. Nat Rev Dis Primers 2018;4:18026.
    Pubmed CrossRef
  16. Won EJ, Shin JH, Lee WK, et al. Distribution of yeast and mold species isolated from clinical specimens at 12 hospitals in Korea during 2011. Ann Clin Microbiol 2013;16:92-100.
    CrossRef
  17. Kwon YJ, Won EJ, Jeong SH, et al. Dynamics and predictors of mortality due to candidemia caused by different Candida species: comparison of intensive care unit-associated candidemia (ICUAC) and Non-ICUAC. J Fungi (Basel) 2021;7:597.
    Pubmed PMC CrossRef
  18. Cleveland AA, Farley MM, Harrison LH, et al. Changes in incidence and antifungal drug resistance in candidemia: results from population-based laboratory surveillance in Atlanta and Baltimore, 2008-2011. Clin Infect Dis 2012;55:1352-61.
    Pubmed PMC CrossRef
  19. Toda M, Williams SR, Berkow EL, et al. Population-based active surveillance for culture-confirmed candidemia - four sites, United States, 2012-2016. MMWR Surveill Summ 2019;68:1-15.
    Pubmed PMC CrossRef
  20. Tan TY, Hsu LY, Alejandria MM, et al. Antifungal susceptibility of invasive Candida bloodstream isolates from the Asia-Pacific region. Med Mycol 2016;54:471-7.
    Pubmed CrossRef
  21. Chen XC, Xu J, Wu DP. Clinical characteristics and outcomes of breakthrough candidemia in 71 hematologic malignancy patients and/or allogeneic hematopoietic stem cell transplant recipients: a single-center retrospective study from China, 2011-2018. Clin Infect Dis 2020;71(Suppl 4):S394-9.
    Pubmed CrossRef
  22. Wu PF, Liu WL, Hsieh MH, et al. Epidemiology and antifungal susceptibility of candidemia isolates of non-albicans Candida species from cancer patients: non-albicans candidemia in cancer patients. Emerg Microbes Infect 2017;6:e87.
    Pubmed PMC CrossRef
  23. Bassetti M, Merelli M, Righi E, et al. Epidemiology, species distribution, antifungal susceptibility, and outcome of candidemia across five sites in Italy and Spain. J Clin Microbiol 2013;51:4167-72.
    Pubmed PMC CrossRef
  24. Komshian SV, Uwaydah AK, Sobel JD, Crane LR. Fungemia caused by Candida species and Torulopsis glabrata in the hospitalized patient: frequency, characteristics, and evaluation of factors influencing outcome. Rev Infect Dis 1989;11:379-90.
    Pubmed CrossRef
  25. Chen SC, Marriott D, Playford EG, et al. Candidaemia with uncommon Candida species: predisposing factors, outcome, antifungal susceptibility, and implications for management. Clin Microbiol Infect 2009;15:662-9.
    Pubmed CrossRef
  26. Kim TH, Kweon OJ, Kim HR, Lee MK. Identification of uncommon Candida species using commercial identification systems. J Microbiol Biotechnol 2016;26:2206-13.
    Pubmed CrossRef
  27. Girmenia C, Pizzarelli G, Cristini F, et al. Candida guilliermondii fungemia in patients with hematologic malignancies. J Clin Microbiol 2006;44:2458-64.
    Pubmed PMC CrossRef
  28. Atkinson BJ, Lewis RE, Kontoyiannis DP. Candida lusitaniae fungemia in cancer patients: risk factors for amphotericin B failure and outcome. Med Mycol 2008;46:541-6.
    Pubmed CrossRef
  29. Lockhart SR, Etienne KA, Vallabhaneni S, et al. Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses. Clin Infect Dis 2017;64:134-40.
    Pubmed PMC CrossRef
  30. Jensen HE, Salonen J, Ekfors TO. The use of immuno-histochemistry to improve sensitivity and specificity in the diagnosis of systemic mycoses in patients with haematological malignancies. J Pathol 1997;181:100-5.
    Pubmed CrossRef
  31. Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 2016;62:e1-50.
    Pubmed PMC CrossRef
  32. Cuenca-Estrella M, Verweij PE, Arendrup MC, et al. ESCMID* guideline for the diagnosis and management of Candida diseases 2012: diagnostic procedures. Clin Microbiol Infect 2012;18:9-18.
    Pubmed CrossRef
  33. Alexander BD, Pfaller MA. Contemporary tools for the diagnosis and management of invasive mycoses. Clin Infect Dis 2006;43(Suppl 1):S15-27.
    CrossRef
  34. Uzun O, Ascioglu S, Anaissie EJ, Rex JH. Risk factors and predictors of outcome in patients with cancer and breakthrough candidemia. Clin Infect Dis 2001;32:1713-7.
    Pubmed CrossRef
  35. Kim SH, Choi JK, Cho SY, et al. Risk factors and clinical outcomes of breakthrough yeast bloodstream infections in patients with hematological malignancies in the era of newer antifungal agents. Med Mycol 2018;56:197-206.
    Pubmed PMC CrossRef
  36. Puig-Asensio M, Ruiz-Camps I, Fern?ndez-Ruiz M, et al. Epidemiology and outcome of candidaemia in patients with oncological and haematological malignancies: results from a population-based surveillance in Spain. Clin Microbiol Infect 2015;21:491, e1-10.
    Pubmed CrossRef
  37. Kontoyiannis DP, Luna MA, Samuels BI, Bodey GP. Hepatosplenic candidiasis. A manifestation of chronic disseminated candidiasis. Infect Dis Clin North Am 2000;14:721-39.
    Pubmed CrossRef
  38. Chen CY, Cheng A, Tien FM, et al. Chronic disseminated candidiasis manifesting as hepatosplenic abscesses among patients with hematological malignancies. BMC Infect Dis 2019;19:635.
    Pubmed PMC CrossRef
  39. Morrell M, Fraser VJ, Kollef MH. Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother 2005;49:3640-5.
    Pubmed PMC CrossRef
  40. Rex JH, Pappas PG, Karchmer AW, et al. A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects. Clin Infect Dis 2003;36:1221-8.
    Pubmed CrossRef
  41. McCarty TP, Pappas PG. Invasive candidiasis. Infect Dis Clin North Am 2016;30:103-24.
    Pubmed CrossRef
  42. Nucci M, Anaissie E. Revisiting the source of candidemia: skin or gut? Clin Infect Dis 2001;33:1959-67.
    Pubmed CrossRef
  43. Poon LM, Chia HY, Tan LK, Liu TC, Koh LP. Successful intensive chemotherapy followed by autologous hematopoietic cell transplantation in a patient with acute myeloid leukemia and hepatosplenic candidiasis: case report and review of literature. Transpl Infect Dis 2009;11:160-6.
    Pubmed CrossRef
  44. Denning DW. Echinocandin antifungal drugs. Lancet 2003;362:1142-51.
    Pubmed CrossRef
  45. Arendrup MC, Perlin DS. Echinocandin resistance: an emerging clinical problem? Curr Opin Infect Dis 2014;27:484-92.
    Pubmed PMC CrossRef
  46. Hsu LY, Lee DG, Yeh SP, et al. Epidemiology of invasive fungal diseases among patients with haematological disorders in the Asia-Pacific: a prospective observational study. Clin Microbiol Infect 2015;21:594, e7-11.
    Pubmed CrossRef
  47. Cadena J, Thompson GR 3rd, Patterson TF. Invasive aspergillosis: current strategies for diagnosis and management. Infect Dis Clin North Am 2016;30:125-42.
    Pubmed CrossRef
  48. Patterson TF, Thompson GR 3rd, Denning DW, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 2016;63:e1-60.
    Pubmed PMC CrossRef
  49. Bassetti M, Azoulay E, Kullberg BJ, et al. EORTC/MSGERC definitions of invasive fungal diseases: summary of activities of the Intensive Care Unit Working Group. Clin Infect Dis 2021;72(Suppl 2):S121-7.
    Pubmed CrossRef
  50. Thompson GR 3rd, Young JH. Aspergillus infections. N Engl J Med 2021;385:1496-509.
    Pubmed CrossRef
  51. Vermeulen E, Lagrou K, Verweij PE. Azole resistance in Aspergillus fumigatus: a growing public health concern. Curr Opin Infect Dis 2013;26:493-500.
    Pubmed CrossRef
  52. Prattes J, Flick H, Pr?ller F, et al. Novel tests for diagnosis of invasive aspergillosis in patients with underlying respiratory diseases. Am J Respir Crit Care Med 2014;190:922-9.
    Pubmed CrossRef
  53. Gerson SL, Talbot GH, Lusk E, Hurwitz S, Strom BL, Cassileth PA. Invasive pulmonary aspergillosis in adult acute leukemia: clinical clues to its diagnosis. J Clin Oncol 1985;3:1109-16.
    Pubmed CrossRef
  54. Greene RE, Schlamm HT, Oestmann JW, et al. Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign. Clin Infect Dis 2007;44:373-9.
    Pubmed CrossRef
  55. Caillot D, Couaillier JF, Bernard A, et al. Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia. J Clin Oncol 2001;19:253-9.
    Pubmed CrossRef
  56. Raffaella G, Lorenzo L, Elisabetta X, et al. Lung ultrasound to evaluate invasive fungal diseases after allogeneic hematopoietic stem cell transplantation. Infect Chemother 2019;51:386-92.
    Pubmed PMC CrossRef
  57. Keng LT, Lee CF. Ultrasound-guided transthoracic needle aspiration to diagnose invasive pulmonary aspergillosis. Am J Respir Crit Care Med 2020;201:1451-2.
    Pubmed PMC CrossRef
  58. Grabala J, Grabala M, Onichimowski D, Grabala P. Possibilities of using ultrasound for diagnosis of invasive pulmonary mucormycosis - a case study. Polish Annals of Medicine 2017;24:224-7.
    PMC CrossRef
  59. Hummel M, Rudert S, Hof H, Hehlmann R, Buchheidt D. Diagnostic yield of bronchoscopy with bronchoalveolar lavage in febrile patients with hematologic malignancies and pulmonary infiltrates. Ann Hematol 2008;87:291-7.
    Pubmed CrossRef
  60. Peikert T, Rana S, Edell ES. Safety, diagnostic yield, and therapeutic implications of flexible bronchoscopy in patients with febrile neutropenia and pulmonary infiltrates. Mayo Clin Proc 2005;80:1414-20.
    Pubmed CrossRef
  61. Gupta V, Rajagopalan N, Patil M, Shivaprasad C. Aspergillus and mucormycosis presenting with normal chest X-ray in an immunocompromised host. BMJ Case Rep 2014;2014:bcr2014204022.
    Pubmed PMC CrossRef
  62. Heng SC, Morrissey O, Chen SC, et al. Utility of bronchoalveolar lavage fluid galactomannan alone or in combination with PCR for the diagnosis of invasive aspergillosis in adult hematology patients: a systematic review and meta-analysis. Crit Rev Microbiol 2015;41:124-34.
    Pubmed CrossRef
  63. Imbert S, Gauthier L, Joly I, et al. Aspergillus PCR in serum for the diagnosis, follow-up and prognosis of invasive aspergillosis in neutropenic and nonneutropenic patients. Clin Microbiol Infect 2016;22:562, e1-8.
    Pubmed PMC CrossRef
  64. Cruciani M, Mengoli C, Loeffler J, et al. Polymerase chain reaction blood tests for the diagnosis of invasive aspergillosis in immunocompromised people. Cochrane Database Syst Rev:CD009551.
    Pubmed CrossRef
  65. Marty FM, Cornely OA, Mullane KM, et al. Isavuconazole for treatment of invasive fungal diseases caused by more than one fungal species. Mycoses 2018;61:485-97.
    Pubmed CrossRef
  66. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408-15.
    Pubmed CrossRef
  67. Cornely OA, Vehreschild JJ, Vehreschild MJ, et al. Phase II dose escalation study of caspofungin for invasive aspergillosis. Antimicrob Agents Chemother 2011;55:5798-803.
    Pubmed PMC CrossRef
  68. Kim SH, Moon SM, Han SH, et al. Epidemiology and clinical outcomes of invasive pulmonary aspergillosis: a nationwide multicenter study in Korea. Infect Chemother 2012;44:282-8.
    CrossRef
  69. Lerolle N, Raffoux E, Socie G, et al. Breakthrough invasive fungal disease in patients receiving posaconazole primary prophylaxis: a 4-year study. Clin Microbiol Infect 2014;20:O952-9.
    Pubmed CrossRef
  70. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis 2011;52:e56-93.
    Pubmed CrossRef
  71. Cornely OA, Arikan-Akdagli S, Dannaoui E, et al. ESCMID and ECMM joint clinical guidelines for the diagnosis and management of mucormycosis 2013. Clin Microbiol Infect 2014;20(Suppl 3):5-26.
    Pubmed CrossRef
  72. El-Cheikh J, Castagna L, Wang L, et al. Impact of prior invasive aspergillosis on outcome in patients receiving reduced-intensity conditioning allogeneic hematopoietic stem cell transplant. Leuk Lymphoma 2010;51:1705-10.
    Pubmed CrossRef
  73. Lee DG. Epidemiology and clinical characteristics of invasive pulmonary aspergillosis in Korea: tasks for the future. Infect Chemother 2012;44:328-30.
    CrossRef
  74. Cho SH, Kim CW, Nam MS. Pharmacokinetics and safety of two voriconazole formulations after intravenous infusion in healthy Korean volunteers. Infect Chemother 2020;52:204-11.
    Pubmed PMC CrossRef
  75. Cornely OA, Alastruey-Izquierdo A, Arenz D, et al. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Lancet Infect Dis 2019;19:e405-21.
    Pubmed PMC CrossRef
  76. Roden MM, Zaoutis TE, Buchanan WL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis 2005;41:634-53.
    Pubmed CrossRef
  77. Park JW, Chung JS, Lee S, Shin HJ. Neutropenic enterocolitis due to mucormycosis in a patient with myelodysplastic syndrome. Infect Chemother 2020;52:98-104.
    Pubmed PMC CrossRef
  78. Xhaard A, Lanternier F, Porcher R, et al. Mucormycosis after allogeneic haematopoietic stem cell transplantation: a French Multicentre Cohort Study (2003-2008). Clin Microbiol Infect 2012;18:E396-400.
    Pubmed CrossRef
  79. Farmakiotis D, Kontoyiannis DP. Mucormycoses. Infect Dis Clin North Am 2016;30:143-63.
    Pubmed CrossRef
  80. Hibbett DS, Binder M, Bischoff JF, et al. A higher-level phylogenetic classification of the Fungi. Mycol Res 2007;111:509-47.
    Pubmed CrossRef
  81. Corzo-Le?n DE, Chora-Hern?ndez LD, Rodr?guez-Zulueta AP, Walsh TJ. Diabetes mellitus as the major risk factor for mucormycosis in Mexico: epidemiology, diagnosis, and outcomes of reported cases. Med Mycol 2018;56:29-43.
    Pubmed CrossRef
  82. Cuenca-Estrella M, Bernal-Martinez L, Isla G, Gomez-Lopez A, Alcazar-Fuoli L, Buitrago MJ. Incidence of zygomycosis in transplant recipients. Clin Microbiol Infect 2009;15(Suppl 5):37-40.
    Pubmed CrossRef
  83. Skiada A, Lass-Floerl C, Klimko N, Ibrahim A, Roilides E, Petrikkos G. Challenges in the diagnosis and treatment of mucormycosis. Med Mycol 2018;56(Suppl 1):93-101.
    Pubmed PMC CrossRef
  84. Obayashi T, Yoshida M, Mori T, et al. Plasma (1-->3)- beta-D-glucan measurement in diagnosis of invasive deep mycosis and fungal febrile episodes. Lancet 1995;345:17-20.
    CrossRef
  85. Kontoyiannis DP, Wessel VC, Bodey GP, Rolston KV. Zygomycosis in the 1990s in a tertiary-care cancer center. Clin Infect Dis 2000;30:851-6.
    Pubmed CrossRef
  86. Weng TF, Ho MW, Lin HC, Lu MY, Peng CT, Wu KH. Successful treatment of disseminated mixed invasive fungal infection after hematopoietic stem cell transplantation for severe aplastic anemia. Pediatr Transplant 2012;16:E35-8.
    Pubmed CrossRef
  87. Mousset S, Bug G, Heinz WJ, Tintelnot K, Rickerts V. Breakthrough zygomycosis on posaconazole prophylaxis after allogeneic stem cell transplantation. Transpl Infect Dis 2010;12:261-4.
    Pubmed CrossRef
  88. Kang SH, Kim HS, Bae MN, et al. Fatal breakthrough mucormycosis in an acute myelogenous leukemia patient while on posaconazole prophylaxis. Infect Chemother 2015;47:49-54.
    Pubmed PMC CrossRef
  89. Hong HL, Lee YM, Kim T, et al. Risk factors for mortality in patients with invasive mucormycosis. Infect Chemother 2013;45:292-8.
    Pubmed PMC CrossRef
  90. Lanternier F, Dannaoui E, Morizot G, et al. A global analysis of mucormycosis in France: the RetroZygo Study (2005-2007). Clin Infect Dis 2012;54(Suppl 1):S35-43.
    Pubmed CrossRef
  91. Liss B, Vehreschild JJ, Bangard C, et al. Our 2015 approach to invasive pulmonary aspergillosis. Mycoses 2015;58:375-82.
    Pubmed CrossRef
  92. Ibrahim AS, Gebremariam T, Husseiny MI, et al. Comparison of lipid amphotericin B preparations in treating murine zygomycosis. Antimicrob Agents Chemother 2008;52:1573-6.
    Pubmed PMC CrossRef
  93. Lanternier F, Poiree S, Elie C, et al. Prospective pilot study of high-dose (10 mg/kg/day) liposomal amphotericin B (L-AMB) for the initial treatment of mucormycosis. J Antimicrob Chemother 2015;70:3116-23.
    Pubmed CrossRef
  94. Walsh TJ, Goodman JL, Pappas P, et al. Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi: maximum tolerated dose study. Antimicrob Agents Chemother 2001;45:3487-96.
    Pubmed PMC CrossRef
  95. Marty FM, Ostrosky-Zeichner L, Cornely OA, et al. Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis 2016;16:828-37.
    Pubmed CrossRef
  96. Park WB, Cho JY, Park SI, et al. Effectiveness of increasing the frequency of posaconazole syrup administration to achieve optimal plasma concentrations in patients with haematological malignancy. Int J Antimicrob Agents 2016;48:106-10.
    Pubmed CrossRef
  97. Suh HJ, Kim I, Cho JY, et al. Comparison of plasma concentrations of posaconazole with the oral suspension and tablet in Korean patients with hematologic malignancies. Infect Chemother 2017;49:135-9.
    Pubmed PMC CrossRef
  98. Blyth CC, Gilroy NM, Guy SD, et al. Consensus guidelines for the treatment of invasive mould infections in haematological malignancy and haemopoietic stem cell transplantation, 2014. Intern Med J 2014;44:1333-49.
    Pubmed CrossRef
  99. Mellinghoff SC, Panse J, Alakel N, et al. Primary prophylaxis of invasive fungal infections in patients with haematological malignancies: 2017 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO). Ann Hematol 2018;97:197-207.
    Pubmed PMC CrossRef
  100. Lionakis MS, Lewis RE, Kontoyiannis DP. Breakthrough invasive mold infections in the hematology patient: current concepts and future directions. Clin Infect Dis 2018;67:1621-30.
    Pubmed PMC CrossRef
  101. Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007;356:348-59.
    Pubmed CrossRef
  102. Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 2007;356:335-47.
    Pubmed CrossRef
  103. Maertens JA, Girmenia C, Br?ggemann RJ, et al. European guidelines for primary antifungal prophylaxis in adult haematology patients: summary of the updated recommendations from the European Conference on Infections in Leukaemia. J Antimicrob Chemother 2018;73:3221-30.
    Pubmed CrossRef
  104. Kim SH, Lee DG, Choi SM, et al. Efficacy and safety of micafungin for prophylaxis of invasive fungal infection in hematopoietic stem cell transplantation recipients. Infect Chemother 2010;42:149-55.
    CrossRef
  105. Duckwall MJ, Gales MA, Gales BJ. Inhaled amphotericin B as aspergillosis prophylaxis in hematologic disease: an update. Microbiol Insights 2019;12:1178636119869937.
    Pubmed PMC CrossRef
  106. Lee R, Cho SY, Lee DG, et al. Infections of venetoclax-based chemotherapy in acute myeloid leukemia: rationale for proper antimicrobial prophylaxis. Cancers (Basel) 2021;13:6285.
    Pubmed PMC CrossRef
  107. Nucci M, Anaissie EJ. Prevention of infections in patients with hematological malignancies. Neoplastic Diseases of the Blood:1047-62.
    PMC CrossRef
  108. Parry MF, Grant B, Yukna M, et al. Candida osteomyelitis and diskitis after spinal surgery: an outbreak that implicates artificial nail use. Clin Infect Dis 2001;32:352-7.
    Pubmed CrossRef
  109. Mellinghoff SC, Hoenigl M, Koehler P, et al. EQUAL Candida score: an ECMM score derived from current guidelines to measure QUAlity of clinical candidaemia management. Mycoses 2018;61:326-30.
    Pubmed CrossRef
  110. Cornely OA, Koehler P, Arenz D, Mellinghoff SC. EQUAL aspergillosis score 2018: an ECMM score derived from current guidelines to measure QUALity of the clinical management of invasive pulmonary aspergillosis. Mycoses 2018;61:833-6.
    Pubmed CrossRef
  111. Koehler P, Mellinghoff SC, Stemler J, et al. Quantifying guideline adherence in mucormycosis management using the EQUAL score. Mycoses 2020;63:343-51.
    Pubmed CrossRef
  112. Huang HY, Lu PL, Wang YL, Chen TC, Chang K, Lin SY. Usefulness of EQUAL Candida Score for predicting outcomes in patients with candidaemia: a retrospective cohort study. Clin Microbiol Infect 2020;26:1501-6.
    Pubmed CrossRef
  113. Kim JH, Suh JW, Kim MJ. Epidemiological trends of candidemia and the impact of adherence to the candidemia guideline: six-year single-center experience. J Fungi (Basel) 2021;7:275.
    Pubmed PMC CrossRef
  114. Pfaller MA, Moet GJ, Messer SA, Jones RN, Castanheira M. Candida bloodstream infections: comparison of species distributions and antifungal resistance patterns in community- onset and nosocomial isolates in the SENTRY Antimicrobial Surveillance Program, 2008-2009. Antimicrob Agents Chemother 2011;55:561-6.
    Pubmed PMC CrossRef


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