Invasive Fungal Infections

The human microbiota refers to the vast array of individual microbes and their genes that habitually and stably colonize several surfaces and inhabit various cavities. These host-associated microorganisms exist in complex communities adapted to the environmental conditions of each anatomic body part or organ system function. Microbiota transmission starts during birth, with mothers serving as the initial source of the microbiome for their infants. After childhood, the human microbiome is constantly evolving in response to various host factors that become the influencers and major determinants of the human microbiome at any given point in time. These include the individual’s age, nutrition, lifestyle, hormonal changes, inherited genes, underlying disease, and immunologic status, along with the environment in which they live.1 From the substantial number of phyla that exist on earth, our microbiome is comprised of a relatively narrow representative sample of the known realms of cellular life, bacteria, eukarya (ie, fungi), and arachaea. Bacteria account for the greatest proportion, with an estimated population of nearly 100 to 200 trillion individual organisms, more than the ∼75 trillion cells that constitute the human body. As commensals, these microorganisms characteristically derive or provide benefits from their association with the host in what ordinarily is a mutualistic association. The microorganism provides the human with nutrient availability, immune system development, and protective colonization resistance against pathogens. In turn, the microbe receives necessary growth factors along with a means of dispersion and habitat protection. Clinicians are frequently confronted with the task of determining whether the isolation or detection of a regular microbiota constituent, environmental, or zoonotic microbe represents a contaminant, colonizer, or an active infection pathogen. By and large, in the absence of signs or symptoms of active infection, positive cultures represent colonization or contamination and require no further intervention. This is especially true with cultures that were collected from nonsterile sites. From an infectious disease perspective, a pathogen is defined as a microorganism capable of causing disease independent of it being a commensal or noncommensal microbe. However, to be called a pathogen, a microorganism does not always have to cause disease, being that pathogens are not equally virulent. Moreover, the host’s immunologic status plays an important function in assessing the role of a microbe of interest. Different forms of immune compromise predispose to different types of pathogens. Although many of these organisms are predictable commensals acquired from environmental reservoirs such as water and soil, and are generally nonpathogenic in immunocompetent hosts, they may act as opportunistic pathogens in immunocompromised individuals, resulting in clinically significant infections. For example, fungal pathogens often present clinically in a subacute or chronic manner in persons with a disease or treatment-driven, deficient immune response. Invasive fungal infections (IFIs) are a rapidly increasing global health concern and a leading cause of morbidity and mortality, particularly among patients who are immunocompromised. In the most recent reports, the annual incidence is estimated to be 6.5 million IFIs and 3.8 million deaths, of which ∼2.5 million (68%; range: 35 to 90) were deemed directly accountable for the patient’s demise.2 Before the publication of these data, the World Health Organization (WHO) published an inaugural Fungal Priority Pathogens List signaling an appreciation of their growing importance as the population of immunocompromised hosts has steadily increased.3 What previously were labeled opportunistic infections predominantly relegated to patients with hematologic malignancies, HIV/AIDS, or following hematopoietic cell or solid organ transplant, IFIs are now frequently diagnosed in the escalating numbers of patients receiving biological and targeted therapies (eg, BTK inhibitors, CAR-T cells) for immune-mediated and inflammatory conditions. Likewise, the acknowledged expansion in prevalence and epidemiologic shift of IFIs has been affected in part by the recent advances in rapid diagnostic tests including serologic and lateral flow assays, molecular multiplex PCR, and next generation sequencing, each with its own inherent sensitivity and specificity limitations depending on the fungal organism involved.4,5 Over two-thirds of IFIs are caused by invasive candidiasis, many of which are now non-Candida albicans species, followed by cryptococcosis (20%), and aspergillosis (10%).6 However, invasive mold infections including mucormycosis, Scedosporium, and Fusarium spp are being encountered more frequently, a phenomenon likely interrelated to epidemiologic and environmental factors.7 Unfortunately, as is the case with bacterial antimicrobial resistance, antifungal resistance is on the rise. Presently, there are only 4 classes of antifungal agents (azoles, polyenes, echinocandins, and pyrimidine analogs) while treatment of multidrug-resistant C. auris and azole-resistant A. fumigatus is becoming progressively more problematic.8 However, novel antifungals, including 2 new classes, are currently in development in phase II or phase III studies, the results of which, along with the practical availability of those proven to be beneficial, will determine the future of IFI treatment and outcome.9 In this edition of Infectious Diseases in Clinical Practice, Andreadakis et al present the results of their retrospective study of invasive Fusariosis in immunocompromised cancer patients diagnosed in a large tertiary cancer center over a 27-year period.10 The analysis of the clinical characteristics, imaging findings, antifungal susceptibility, treatment, and outcome adds much to what is generally known regarding human infection with Fusarium species, fungal organisms that commonly reside in soil and are frequently pathogenic to plants. The authors selected 85 patients with proven hematologic malignancy and cultured-confirmed Fusarium species isolated from a sterile site, which was specified as blood or sterile tissue biopsy, as well as nonsterile sites such as a bronchoalveolar lavage (BAL) or sinus tissue in the setting of additional clinical and radiographic findings. Although included as a variable in the study, neutropenia absolute neutrophil count (ANC): <500 was not one of the inclusive criteria. The authors performed antifungal susceptibility testing according to the guidelines of the Clinical and Laboratory Standards Institute (CLSI), determining the minimum inhibitory concentrations (MICs) for amphotericin B, voriconazole, posaconazole, and isavuconazole. Pulmonary and sinus computed tomography (CT) findings were evaluated, with imaging characteristics interpreted in correlation with clinical features. Sinus mucosal thickening was frequently reported and, therefore, considered a variable and nonspecific radiographic finding. All patients in the study cohort received empiric antifungal therapy with amphotericin B, voriconazole, or a combination of both upon clinical suspicion of invasive fungal infection (IF), pending antifungal susceptibility testing. Antifungal therapy was subsequently adjusted based on susceptibility results when available. In cases of refractory fusariosis considered resistant to conventional therapy, the investigational antifungal agent fosmanogepix (APX001) was administered under compassionate use. Out of 85 patients with IF, 48 (56.5%) underwent susceptibility testing. From this group, 36 out of 48 (75%) were resistant to amphotericin B MIC, 47 (97.9%), had resistance to voriconazole, and all (100%) had resistance to posaconazole. Amphotericin B resistance was associated with prior antifungal therapy exposure (P = 0.049). Otherwise, there was no significant association between amphotericin B resistance and patient clinical characteristics. It is worth noting that empiric therapy was continued without modification in 58.8% of the patients and modified upon susceptibility results in 41.2% of the patients. There was no statistically significant difference between these two strategies (P = 0.826). Radiographic findings were significant for a high incidence of pulmonary nodules in 62.8% of the patients, as well as sinus mucosal thickening in 58.5%. Incidence of sinus mucosal thickening was associated with decreased survival (P = 0.047). There was no statistically significant difference in mortality or amphotericin B resistance associated with pulmonary nodules. The authors concluded that in-hospital mortality was 58.8% (50/85), with 41.2% (35/85) surviving to hospital discharge. Out of all other hematologic malignancies, acute myeloid leukemia (AML) was associated with lower mortality (P = 0.027). Interestingly, the study concluded that duration of neutropenia did not statistically impact clinical outcomes (P = 0.244), prompting the authors to hypothesize that host immune factors and neutrophil recovery may play a larger role in patient survival than antifungal therapeutic agent choice. Overall, the findings of this retrospective cohort study highlight the clinical implications, therapeutic challenges and impact on mortality of invasive fusariosis in a high-risk patient population. At the same time, the study acknowledges important limitations, including its single-center design and the restricted susceptibility data set (48/85). The continuation of empiric antifungal therapy and variable treatment strategies may have also influenced the treatment outcomes. Despite these limitations, this study introduces important considerations when treating patients with hematologic malignancies and stresses the need for early involvement of infectious/transplant disease specialists in the care of this patient population group. In the era of escalating multidrug resistance, antifungal therapy must be guided by a judicious and individualized approach that integrates patient-specific factors, prior antifungal exposure, and early susceptibility testing. Such strategies are essential to optimize antifungal selection while mitigating the emergence of resistance. Moving forward, well-designed multicenter prospective studies, robust antifungal stewardship programs, and the development of novel antifungal agents will be pivotal in addressing this growing threat for our most susceptible patients.