Invasive Fungal Disease in High-Acuity Hospitals in Latin America: Practical Pathways from Suspicion to Early Targeted Therapy

1. Introduction

Invasive fungal diseases (IFD) have evolved from occasional complications confined to a narrow group of immunocompromised patients into a daily diagnostic and therapeutic challenge in modern high-acuity hospitals worldwide. Their clinical impact is substantial: they are difficult to recognize early, frequently occur in patients with a high burden of underlying disease, and are associated with prolonged hospitalization, increased costs, and significant mortality. Some estimates suggest that severe fungal diseases account for millions of cases worldwide every year, with invasive candidiasis and invasive aspergillosis representing major contributors to the global burden [1]. Candidemia remains particularly lethal; population-level data indicate that approximately one third of patients die during hospitalization, and invasive candidiasis adds measurable hospital days and costs [2]. Invasive aspergillosis is similarly severe in critical care, where delayed antifungal therapy is associated with longer ICU stay, higher costs, and excess mortality [3]. This burden is increasing as susceptible populations expand: transplantation, oncohematology, biologic immunomodulation, prolonged ICU care, severe viral pneumonias, advanced liver disease, and the post-COVID clinical landscape have all increased the number of patients in whom fungal infection must be considered early rather than as a last diagnostic resort.

In Latin America, the problem is not simply a regional version of the epidemiology described in Europe or North America. Opportunistic mycoses typical of tertiary hospitals coexist with endemic dimorphic fungi, including Histoplasma and Paracoccidioides, which remain underdiagnosed and unevenly represented in surveillance systems [4,5]. Histoplasmosis illustrates this gap: in advanced HIV, nonspecific presentation, overlap with tuberculosis, and limited access to antigen testing contribute to diagnostic delay and preventable mortality [6]. At the same time, Candida auris has emerged across multiple Latin American countries, exposing weaknesses in species-level identification, susceptibility testing, infection prevention, and regional coordination [7]. Mucormycosis has also gained visibility after COVID-19, particularly among patients with diabetes, corticosteroid exposure, and severe viral illness [8]. This diversity means that there is no single “Latin American reality”: epidemiology, diagnostic capacity, antifungal access, and referral pathways vary substantially between countries, cities, hospitals, and units.

Structural underdiagnosis is a central feature of this scenario. Blood cultures have limited sensitivity for invasive candidiasis, conventional cultures are slow, histopathology is not always rapidly available, and biomarkers such as galactomannan, beta-D-glucan, fungal PCR, Histoplasma antigen, and therapeutic drug monitoring (TDM) remain inconsistently accessible. A comparative analysis of Brazil and Europe showed marked gaps in access to galactomannan, beta-D-glucan, Aspergillus PCR, MALDI-TOF identification, echinocandins, liposomal amphotericin B (L-AmB), and azole TDM, underscoring that guideline implementation depends on infrastructure as much as on medical knowledge [9]. Thus, guidelines developed in high-resource settings remain essential but do not fully capture the diagnostic constraints, endemic pathogens, antifungal access barriers, and heterogeneous realities of Latin American hospitals.

The high-acuity hospital is the natural setting in which these tensions converge. Intensive care units, oncology and hematology services, transplant programs, major surgery, invasive devices, broad-spectrum antibacterial exposure, renal replacement therapy, parenteral nutrition, and severely immunocompromised hosts concentrate risk in the same physical and organizational space. These institutions also concentrate the opportunity for intervention, because they can connect bedside suspicion, radiology, microbiology, pathology, source control, stewardship, and early antifungal optimization through explicit pathways.

This narrative review responds to a practical gap: the lack of clinically usable pathways adapted to Latin American high-acuity hospitals. Rather than proposing a meta-analysis or a universal algorithm, its objective is to organize the pathway from clinical suspicion to early directed therapy, integrating host risk, syndrome recognition, local epidemiology, diagnostic availability, and antifungal stewardship. In environments where advanced biomarkers may be unavailable or delayed, structured suspicion becomes the first diagnostic tool. The aim is to help clinicians think earlier, sample better, interpret tests in context, and treat decisively when the probability of IFD becomes clinically meaningful.

2. Clinical Suspicion and Host Risk Factors

2.1. The Window of Suspicion

The first step in any pathway for invasive fungal disease is not a laboratory test, but the construction of a “window of suspicion.” This window opens when the trajectory of a vulnerable host becomes discordant with the presumed bacterial, viral, inflammatory, or postoperative explanation. IFD often enters the differential diagnosis late because its manifestations are nonspecific: persistent fever, culture-negative sepsis, respiratory deterioration, organ dysfunction, or radiologic abnormalities that mimic bacterial pneumonia, tuberculosis, embolic disease, malignancy, or inflammation. In the ICU, this ambiguity is intensified by sedation, ventilation, broad-spectrum antibiotics, devices, and overlapping causes of shock. The pathway should therefore define when the clinician must stop asking only “why is the patient not improving?” and start asking “could this be fungal disease?”

Host risk factors can be organized into four practical categories. The first is classic immunosuppression. Prolonged neutropenia remains a major risk factor for mold disease and is incorporated into international definitions when neutrophil counts fall below 500 cells/µL for more than 10 days [10]. Allogeneic hematopoietic stem cell transplantation (HSCT), solid organ transplantation (SOT), hematologic malignancy, graft-versus-host disease (GVHD), sustained corticosteroids, and T-cell or B-cell immunosuppressants are also core host factors; the EORTC/MSGERC threshold for corticosteroids is at least 0.3 mg/kg/day prednisone equivalent for three or more weeks [10]. Biologic agents and targeted immunomodulators add further complexity, including anti-TNF, IL-17 pathway inhibitors, and JAK inhibitors.

The second category is ICU-acquired vulnerability. Many critically ill patients who develop IFD do not meet classical definitions designed for neutropenic or transplant populations. Mechanical ventilation, central venous catheters, parenteral nutrition, renal replacement therapy, broad-spectrum antibacterials, abdominal surgery, pancreatitis, anastomotic leak, and shock create a risk ecology in which Candida and Aspergillus may become clinically relevant without traditional immunosuppression. FUNDICU was developed because non-neutropenic ICU patients often fall outside classical frameworks, particularly in severe influenza, COVID-19, cirrhosis, COPD, solid tumors, and uncontrolled HIV [11]. For Candida, the IDSA guideline recommends considering empiric antifungal therapy in critically ill patients with risk factors and no other fever source, especially in septic shock [12].

The third category is underlying disease that points toward specific fungal syndromes. Diabetes mellitus, especially when uncontrolled or accompanied by ketoacidosis, should raise concern for mucormycosis in compatible rhino-orbital, cerebral, pulmonary, or cutaneous disease. Cirrhosis increases susceptibility to candidemia through immune dysfunction, gastrointestinal translocation, invasive care, and frequent hospitalization. Advanced HIV remains a central risk factor for cryptococcosis and disseminated histoplasmosis in Latin America, where histoplasmosis is often misdiagnosed as tuberculosis [6]. Severe COPD, structural lung disease, lung cancer, and corticosteroids should increase suspicion for aspergillosis when deterioration is unexplained.

The fourth category includes emerging and contextual risks. Severe COVID-19 introduced ICU fungal syndromes such as COVID-19-associated pulmonary aspergillosis (CAPA) and mucormycosis. CAPA is difficult to diagnose because many patients lack classic host factors, imaging may be nonspecific, bronchoscopy may be delayed, and serum galactomannan has limited sensitivity [13]. Prior echinocandin exposure, recurrent healthcare contact, prolonged hospitalization, and local outbreaks should raise concern for Candida auris, for which rapid species-level identification remains limited in the region [7]. Colombian surveillance has shown ongoing transmission with clinically relevant azole and amphotericin B resistance [14].

Clinical alarm signs should be interpreted as syndrome-host combinations rather than isolated findings. Persistent fever despite broad-spectrum antibiotics is the classic trigger, but the more useful signal is the pattern: fever without bacterial source in a colonized ICU patient; recurrent fever after severe COVID-19; progressive pulmonary infiltrates during corticosteroids; septic shock after abdominal surgery with negative bacterial cultures; or neurological symptoms in advanced HIV or transplant recipients. Nodules, cavitation, the halo sign, airway lesions, or progressive ground-glass abnormalities should prompt consideration of invasive mold disease. The IDSA aspergillosis guideline recommends chest CT whenever invasive pulmonary aspergillosis (IA) is suspected and supports bronchoalveolar lavage (BAL) when feasible [15].

Skin, mucosal, neurological, and rhino-orbital findings can shorten the pathway. Disseminated skin lesions in advanced HIV should prompt evaluation for histoplasmosis and other disseminated mycoses. Headache, altered mental status, cranial nerve abnormalities, or meningeal symptoms should trigger urgent cryptococcal evaluation in advanced HIV. Facial pain, orbital swelling, black eschar, palatal necrosis, or rapidly progressive necrosis in a patient with diabetes, COVID-19, or corticosteroid exposure should be treated as possible mucormycosis. Section 2.2 through 2.5 detail these risk factors, syndromes, and alarm findings organized by pathogen (Figure 1).

2.2. Pathogen-Specific Risk Factors

Early identification of IFD requires integrating host factors, immunosuppression intensity, clinical syndrome, and diagnostic tools (Table 1).

Candidemia and invasive candidiasis are frequent in the ICU and are driven by cumulative risk from antibiotic exposure, central venous catheters, and high-risk abdominal surgery (Table 1; see also Section 5.1 for detailed odds ratios).

Invasive aspergillosis is associated with profound (<500 cells/µL) and prolonged (>10 days) neutropenia, allogeneic transplantation, GVHD, and corticosteroids (≥0.3 mg/kg/day for ≥3 weeks). It should also be considered in critically ill patients with epithelial injury caused by influenza or SARS-CoV-2 (IAPA/CAPA), especially in the setting of mechanical ventilation, COPD, or cirrhosis (Table 1; see also Tables 3 and 4 and Section 5.2 for host-risk stratification).

Mucormycosis: diabetic ketoacidosis remains one of the dominant triggers, particularly in rhino-orbito-cerebral disease, alongside classic hematologic and post-COVID corticosteroid-related pathways (Table 1).

Cryptococcosis reflects profoundly impaired cell-mediated immunity; the main global risk factor is advanced HIV infection (CD4+ <100/µL), followed by solid organ transplantation, hematologic malignancies, and anti-CD20 therapies (Table 1).

Endemic mycoses in Latin America are shaped by ecological niches: Histoplasma capsulatum in bird/bat guano and caves, Paracoccidioides spp. in humid agricultural areas of Brazil, Colombia, and Venezuela, and Coccidioides spp. in arid regions of Mexico, Brazil, Argentina, Venezuela, and La Guajira, Colombia. Disseminated histoplasmosis is especially relevant with CD4+ <200/µL (Table 1).

2.3. Special Populations and Risk Stratification

The categories introduced in Section 2.1 (Figure 1) translate into distinct risk profiles across specific patient populations, summarized below.

Hematology-oncology: AML and MDS receiving intensive chemotherapy carry the highest risk (10–25%), driven by >10–14 days of neutropenia and mucosal injury. Relapsed/refractory hemopathies significantly increase mold infection risk (HR 3.43), predominantly Aspergillus spp. and Mucorales. ALL poses an intermediate-high risk (6.5–15%) from induction corticosteroids. Baseline risk in lymphomas, CLL, and multiple myeloma is low (<3%), but increases markedly with targeted therapies: ibrutinib is associated with early aspergillosis with CNS involvement (up to 40%); venetoclax plus hypomethylating agents reach 8–13% IFD rates; alemtuzumab/fludarabine favor Pneumocystis jirovecii, cryptococcosis, and mucormycosis; and CAR-T therapy carries a ~3% incidence, escalating with prolonged neutropenia, lymphopenia, inflammatory toxicity, or corticosteroids.

HSCT: risk concentrates in allogeneic transplants (autologous <3%), peaking with active leukemia, refractory disease, or prior IFD. Pre-engraftment features neutropenia, mucositis, catheters, and candidiasis. Post-engraftment, GVHD (grades II–IV), corticosteroids, and antithymocyte globulin strongly increase Aspergillus spp. and Mucorales risk. Critical risk modifiers include haploidentical transplantation (HR 2.41); specifically in allo-HSCT, acute GVHD (HR 3.23) and chronic GVHD (HR 2.95) independently increase mold infection risk, while CMV disease specifically raises aspergillosis risk (HR 3.23).

SOT follows a classic chronology: within 1 month, Candida spp. predominates from surgical complications. From 1–6 months, Aspergillus spp. and other opportunists rise, driven by immunosuppression, CMV (OR 2.97), and lung-transplant factors. After >6 months, Cryptococcus spp. and endemic mycoses emerge, often reactivated by rejection or intensified immunosuppression.

ICU: two high-risk phenotypes predominate: complicated intra-abdominal infection with candidiasis/candidemia, associated with 40–60% mortality when source control is delayed; and severe viral ARDS complicated by IAPA/CAPA, reported in 10–20% of critically ill influenza or COVID-19 patients, with mortality around 40–60%.

HIV/AIDS: disseminated histoplasmosis requires strong suspicion at CD4+ <200 cells/µL (especially <150 cells/µL) presenting with fever, cytopenias, or respiratory involvement; it frequently mimics tuberculosis, delaying diagnosis. Cryptococcal meningitis remains a lethal threat, classically associated with CD4+ <100 cells/µL.

2.4. Scores and Risk Stratification Tools

Predictive rules complement clinical judgment primarily by excluding disease through their high negative predictive value (NPV), which depends on pretest prevalence; they are not meant to replace bedside decision-making. The Candida Score — severe sepsis, surgery, parenteral nutrition, and multifocal colonization — with a cutoff ≥3 (sensitivity 81%, specificity 74%) was originally designed to guide empirical therapy initiation [16]; however, its low positive predictive value (PPV, ~10–15%) limits this use in practice, and contemporary stewardship-oriented literature therefore groups it with other rules as predominantly useful for excluding low-risk patients rather than triggering treatment [17]. The Ostrosky-Zeichner rule combines central venous catheters or broad-spectrum antibiotics with minor factors (surgery, parenteral nutrition, dialysis, immunosuppression), providing excellent specificity (~83%) and NPV (97–99%), but low sensitivity (~50%) and PPV (~10%) [18]. To overcome low PPV, the Nebraska rule refines selection using abdominal surgery and prior ICU stay (NPV 99.4%) [19]. Coupling these scores with biomarkers (e.g., β-D-glucan) increases specificity and PPV while maintaining NPV >99%, reducing unnecessary echinocandin use.

The classic Pittet colonization index (cutoff ≥0.5) offers strong prediction (sensitivity 100%, NPV 100%, PPV ~66%) but requires impractical serial surveillance cultures and is only useful if surveillance is standardized [20]. The EORTC/MSGERC criteria do not dictate empirical treatment: they classify IFD as proven, probable, or possible for research purposes in classic hosts (hematology-oncology, HSCT, SOT) [10]. In the general ICU, adapted algorithms (AspICU, FUNDICU) that integrate clinical features, biomarkers, and microbiology should be used [11,21]. In Latin America, scores require caution because biomarker access is limited, surveillance is not routine, species distribution differs, endemic mycoses enter the differential diagnosis, and antifungal therapy may be constrained. A regional pathway should use scores as guardrails, not gates. The infectologist's role is to integrate local epidemiology, host phenotype, trajectory, diagnostic feasibility, and therapeutic consequences. The key question is whether the patient's course justifies activating a fungal diagnostic bundle and considering early antifungal therapy while data are pending (Figure 2).

2.5. Clinical and Radiologic Red Flags

Given delayed microbiological confirmation, red flags must trigger early evaluation and therapy. A key warning sign is persistent fever after 3–7 days of broad-spectrum antibiotics in neutropenic or critically ill patients. Multiple erythematous-violaceous papulonodular skin lesions, often appearing during neutrophil recovery, suggest hematogenous candidiasis. On chest CT, nodules and the halo sign suggest angioinvasive aspergillosis; conversely, a reverse halo, multiple nodules (>10), or pleural effusion point toward pulmonary mucormycosis in diabetic or immunosuppressed patients. In this context, facial pain, proptosis, or periorbital edema require urgent MRI; the black turbinate sign indicates early mucormycosis ischemia. Painful necrotic skin lesions or black eschars suggest angioinvasive mold dissemination. In endemic areas, hilar/mediastinal lymphadenopathy with reticulonodular infiltrates suggests pulmonary histoplasmosis. In advanced HIV infection, fever, cytopenias, hepatosplenomegaly, and progressive lymphadenopathy indicate disseminated disease. Table 1 consolidates host risk factors, clinical/radiological red flags, and first-line diagnostic actions by pathogen for rapid bedside use.

3. Epidemiology

The epidemiology of IFD in Latin America has historically been under-studied compared with North America, Europe, and Asia, and most regional data come from a small number of multicenter, laboratory-based surveillance networks rather than from national notification systems [22]. Despite this gap, the available evidence consistently points to a regional pattern that differs from high-resource settings in incidence, age distribution, and species mix, reinforcing the need for locally adapted pathways rather than direct extrapolation from international guidelines.

Candidemia is the best-characterized syndrome in the region. A 24-month, laboratory-based survey across 21 tertiary hospitals in seven Latin American countries documented an overall incidence of 1.18 cases per 1000 hospital admissions, with substantial variation between countries and the highest rates reported in Colombia; 44.2% of episodes occurred in children, a considerably higher pediatric share than typically reported in North America or Europe [23]. Candida albicans remained the leading agent (37.6%), followed closely by C. parapsilosis (26.5%) and C. tropicalis (17.6%), with marked country-to-country variability in species distribution and, in some countries, a high local prevalence of C. guilliermondii [23]. This species mix is consistent with earlier regional reviews describing a comparatively high burden of non-albicans Candida infection in Latin American hospitals [4].

Invasive aspergillosis is far less systematically documented in the region; most available series originate from single hematology-oncology or transplant centers rather than multicenter surveillance, and Aspergillus is consistently reported as the leading mold pathogen in allogeneic HSCT recipients, with a bimodal risk distribution around engraftment and later immunosuppression [22]. Population-level incidence and mortality estimates for the region remain largely extrapolated from global models rather than measured directly, which is itself a marker of the regional diagnostic gap described in Section 6.

Mucormycosis has historically been considered rare outside of hematologic and diabetic populations, but its regional visibility increased sharply after the COVID-19 pandemic, with case clusters reported across several Latin American countries in patients with diabetes, corticosteroid exposure, and severe viral pneumonia [8].

Cryptococcal disease remains a leading cause of HIV-associated mortality in the region. Global burden-of-disease modelling has estimated more than 5000 incident cases of HIV-associated cryptococcal meningitis annually in Latin America and the Caribbean, with approximately 2400 attributable deaths per year, placing the region among those with a substantial absolute burden outside sub-Saharan Africa [24]. Reported case-fatality rates from Latin American cohorts are correspondingly high, in the order of 30–63% depending on the setting and on access to timely diagnosis and induction therapy.

Among the endemic mycoses, histoplasmosis has emerged as a particularly consequential and under-recognized disease in people with advanced HIV. A modelling study comparing the regional burden of HIV-associated histoplasmosis with that of tuberculosis found the two diseases to be of comparable incidence, with histoplasmosis mortality meeting or exceeding tuberculosis mortality in several Latin American countries, despite receiving a fraction of the diagnostic and programmatic attention [25]. Paracoccidioidomycosis and coccidioidomycosis remain geographically restricted to their respective ecological niches described in Section 2.2, with incidence data that are almost entirely derived from country-level case series rather than systematic surveillance [5].

Finally, the regional emergence of Candida auris (reclassified as Candidozyma auris) since the mid-2010s has added a new, resistance-associated dimension to the region's candidemia burden, with documented in-hospital outbreaks and, in Colombia, genomic surveillance demonstrating ongoing transmission with clinically relevant azole and amphotericin B resistance [7,14]. Taken together, these data support the premise developed throughout this review: Latin American high-acuity hospitals face a fungal disease burden that is at least as high as, and in several syndromes higher than, that described in high-resource settings, while operating with comparatively limited surveillance, diagnostic, and reporting infrastructure to characterize and respond to it (Section 6).

4. Diagnostic Pathway: From Suspicion to Confirmation

The diagnosis of IFD integrates host factors, clinical–radiological findings, and mycological evidence. The EORTC/MSGERC definitions classify disease as proven, probable, or possible (Figure 3). In Latin America, diagnosis must be adapted to available resources without delaying treatment when clinical suspicion is high.

4.1. Non-Culture-Based Biomarkers

(1,3)-β-D-glucan (BDG). This is a fungal biomarker detectable in Candida, Aspergillus, and Pneumocystis jirovecii infections (absent in Mucorales and Cryptococcus spp.). Its greatest value is to rule out IFD through its high negative predictive value, which depends on pretest prevalence; it does not confirm the diagnosis on its own, and specificity improves with two positive tests [10,26]. In meta-analyses, sensitivity is 77–80% and specificity 82–85%, with variation according to population and assay [26,27]. False positives are associated with immunoglobulins, albumin, some hemodialysis membranes, and surgical gauze, and sensitivity decreases under antifungal prophylaxis. Manufacturer cutoffs are ≥80 pg/mL for Fungitell® and ≥11 pg/mL for Wako® [28].

Galactomannan (GM). In the Platelia™ assay, the EORTC/MSGERC definitions accept as mycological evidence an optical density index (ODI) ≥1.0 in serum/plasma, BAL, or CSF, or the combination of serum/plasma ≥0.7 and BAL ≥0.8 [10]. Its performance depends on the cutoff and the sample: in serum, at ODI ≥0.5 sensitivity is 78% and specificity 85%, and at ≥1.0 sensitivity falls (71%) but specificity rises (90%) [29]; BAL is more sensitive than serum, performance is higher in neutropenic patients, and decreases with active mold-directed prophylaxis [29,30]. For CAPA, the ECMM/ISHAM criteria accept serum GM ≥0.5 or BAL GM ≥1.0 [13]. Rapid lateral-flow tests (LFA/LFD) are alternatives when ELISA is unavailable, with results not necessarily interchangeable between platforms [31]. Cross-reactivity with other fungi, including Fusarium and Histoplasma, should be considered [32].

Cryptococcus and Histoplasma antigens. The cryptococcal lateral-flow antigen (CrAg-LFA) is the preferred rapid test — with sensitivity and specificity of approximately 95–100% — and can be performed on CSF, serum, plasma, or whole blood [33]; at very high titers, the prozone phenomenon should be excluded [34]. When meningitis is suspected, lumbar puncture remains essential, both for diagnosis and to measure opening pressure [33]. In histoplasmosis, urinary antigen detection — complemented with serum — performs best in disseminated disease, especially in people with HIV, with a pooled sensitivity close to 95% (specificity 97%) that decreases in localized forms [35,36,37].

4.2. PCR and Molecular Platforms

Aspergillus PCR is incorporated into the EORTC/MSGERC definitions: it requires ≥2 consecutive positive samples in serum/plasma/whole blood, ≥2 positive replicates in BAL, or ≥1 positive in blood plus ≥1 in BAL [10,38]. For CAPA, a single positive BAL PCR with Ct <36 may also constitute mycological evidence [13]. A positive respiratory result must be interpreted within the clinical–radiological context, as it does not by itself demonstrate tissue invasion [38]. Some platforms, such as AsperGenius®, additionally detect CYP51A mutations related to azole resistance [39].

Multiplex panels speed up identification but with limited fungal coverage: BioFire BCID2 detects six Candida species — including C. auris — and Cryptococcus neoformans/gattii in approximately 1 hour, although it requires a prior positive blood culture [40]. T2Candida detects five Candida species directly in whole blood by T2 magnetic resonance, without culture; in the DIRECT study it achieved a sensitivity of 91.1% and a specificity of 99.4% — part of the validation was performed with spiked samples [41]. It does not include C. auris nor replace culture for susceptibility, and after T2 Biosystems ceased operations in 2026, it is today mainly a precedent for the feasibility of direct molecular detection from blood [42]. Metagenomics (mNGS) is reserved for complex cases with a negative conventional work-up and remains concentrated in reference centers [43].

4.3. Imaging

When invasive pulmonary aspergillosis is suspected, a chest CT should be requested early, regardless of conventional radiography findings; the halo sign is especially suggestive of angioinvasive aspergillosis in the neutropenic patient [15]. The reversed halo, pleural effusion, and the presence of multiple nodules increase the suspicion of mucormycosis, although none of these findings is specific [44]. In hepatosplenic candidiasis, CT, ultrasound, or MRI show “bull's-eye” hepatosplenic lesions, most evident during recovery from neutropenia [12].

4.4. Culture, Microscopy, and Histopathology

Blood cultures remain the conventional reference method for candidemia, but they have limited sensitivity in invasive candidiasis, especially in deep-seated disease without fungemia [45]. When pulmonary aspergillosis is suspected, BAL should be sent for direct examination, culture, GM, and, when available, PCR; the presence of septate hyphae with acute-angle branching is compatible with Aspergillus, but is not genus-specific [15].

In mucormycosis, tissue biopsy is essential: histopathology typically shows broad, irregular, pauciseptate or aseptate hyphae, with a variable branching pattern — frequently wide-angle — necrosis, and angioinvasion. The branching angle can be distorted in tissue, so the sample should also be sent for culture and molecular identification [46]. In central nervous system cryptococcosis, India ink allows a rapid evaluation but loses sensitivity when the fungal burden is low; CrAg-LFA in CSF is the preferred rapid test and should be complemented with culture when possible [33].

5. Clinical Pathways

5.1. Candidemia

Candidemia is the most frequent form of invasive Candida infection, frequently associated with critically ill patients and/or immunosuppressed hosts such as SOT recipients or those with febrile neutropenia. Diagnosis requires a high index of suspicion, as its clinical presentation is nonspecific and clinicians rely on imperfect methods — blood cultures and serum biomarkers — compounded by the difficulty of interpreting positive or negative results in a population at risk for several concomitant nosocomial infections. For Latin America specifically, a recent expert consensus on the diagnosis of candidemia in critically ill patients was published in 2024 [47].

Suspicion for invasive candidiasis typically arises from fever and/or septic shock in a patient with established risk factors (Table 2) [48].

Several attempts have been made at external validation of clinical scores such as the Candida Score [16] to identify patients who would benefit from earlier antifungal therapy. Nevertheless, its implementation has been hindered by very low PPV and poor generalizability outside the original derivation cohorts [19]. These scores are more useful as a rule-out tool, particularly when paired with available serological markers [49].

Blood cultures remain the cornerstone of candidemia diagnosis in most Latin American countries. At least two sets (four bottles total), drawn sequentially from different sites, are recommended [47], though sensitivity is poor, with historical figures reported between 21–71% [45]. Newer techniques such as T2Candida and Platelia Candida Ag (mannan antigen, MAg) improve on this performance, but neither is routinely available in the region.

Early recognition of candidemia in the region therefore relies mainly on imperfect clinical scores and blood cultures.

5.2. Invasive Aspergillosis

Invasive aspergillosis is largely restricted to severely immunocompromised patients, such as those with SOT and HSCT, but it is also reported in a variety of immunosuppressed patients, such as those with COVID-19, autoimmune disease on DMARDs, cirrhosis, and COPD. Most of the available data regarding clinical presentation, diagnosis, and treatment come from HSCT cohorts, where it is much more prevalent, especially in allogeneic HSCT, where the risk of IA approaches 10%.

Attempts at homogenizing the diagnosis of IA are therefore difficult due to differences in epidemiology, level of immunosuppression, the multiple clinically relevant Aspergillus species, and the differing performance of serum-based diagnostic methods, which may not perform equally across different populations. For Latin America specifically, a companion expert consensus to the candidemia evidence-based clinical standard (EBCS) was published in 2025 on the diagnosis and treatment of invasive lung aspergillosis [50].

Suspicion of IA is first raised in a patient with persistent fever beyond what would be expected despite broad-spectrum antibiotics (febrile neutropenia), or new clinical symptoms or deterioration in patients with established risk factors. Not every type of immunosuppression confers the same risk of developing IA, and although IA can affect any organ, the lungs are the most commonly involved (Table 3 and Table 4) [51,52,53].

Definitive diagnosis of IA requires direct visualization of branching septate hyphae in tissue, although this approach may not be feasible in an already compromised, thrombocytopenic, or coagulopathic patient. Cultures (sputum, BAL) are an unreliable and difficult-to-interpret method, as Aspergillus spp. may be a colonizing organism, especially in lung-transplant patients, among whom cohort data report colonization in up to 30% [54]. Currently, diagnosis depends on a combination of clinical, radiological, and serum-based methods.

A now well-known classification for IA in “classical hosts” was published by the EORTC/MSGERC [55]; originally developed to standardize case definitions for clinical trials and epidemiological research, it is now used at the bedside without external validation in heterogeneous populations. As the lungs are the most commonly involved organ, a high-resolution chest CT is usually the next step, combined with serum biomarkers such as β-D-glucan and galactomannan, and PCR where available.

The performance of serum-based diagnostic methods, as mentioned earlier, is quite variable, and not every population at risk for IA has established performance figures to guide clinical decisions. The most common available methods are the Platelia Aspergillus Ag, Fungitell β-D-glucan, and Aspergillus PCR, with variable availability across Latin America. BDG and galactomannan are commercially available in Chile and Mexico; galactomannan has regulatory approval in Brazil, though BDG use there remains restricted by low availability; BDG has been explicitly reported as unavailable in public hospitals in Buenos Aires, Argentina; and a Honduran capacity survey found antigen testing available in only 2.6% of institutions, with none offering PCR.

Cut-off points for galactomannan and β-D-glucan remain a subject of debate; most data are derived from HSCT/hematologic malignancy cohorts, with less well-described performance in SOT or “non-classical” hosts. We advise the reader to interpret these numbers with caution, as host biology differs and using a single cut-off for every suspected case may result in under- or over-diagnosis. Table 5 reports performance figures across host types to the best of our knowledge [56,57,58,59,60,61,62].

5.3. Antifungal Therapy: From Empirical to Early Targeted Treatment

The choice of empiric antifungal therapy depends mostly on host risk factors for a specific type of fungal infection, available medications, pharmacokinetic/pharmacodynamic (PK/PD) parameters, and safety profile. Just as the performance of serum-based diagnostics does not apply uniformly to all types of patients, the same is true for antifungal therapy. Historically, critically ill patients with risk factors were candidates for empirical antifungal therapy until the EMPIRICUS trial, published in 2016 [63], compared micafungin with placebo in critically ill non-neutropenic patients and found no significant benefit of empirical antifungal therapy over placebo. Nevertheless, ICU patients are a heterogeneous population, and some subsets may benefit from early therapy, such as those with upper GI perforations, new-onset septic shock in a previously stable critically ill patient, or settings where local epidemiology reports invasive candidiasis incidences >5–10%. It is in this situation that the cautious use of the previously mentioned clinical scores is useful to rule out patients who would not benefit from empirical antifungal therapy. Echinocandins such as caspofungin, micafungin, and anidulafungin are guideline-recommended as first-line empirical therapy in this population, though observational data comparing the three agents directly show no clear superiority among them [64,65].

Other populations, such as those with prolonged, profound febrile neutropenia, require a different approach, with more liberal use of empirical antifungals given the high mortality of untreated invasive fungal infections. The distribution of fungal infections in this population tends to be more mold-associated, such as Aspergillus and Mucorales; therefore, mold-active antifungal therapy is preferred in these clinical situations. IDSA recommendations from 2010/2011 [66] recommend empirical antifungal therapy in patients with persistent or recurrent fever after 4–7 days of antibiotics and whose overall expected duration of neutropenia is >7 days. Newer azoles such as voriconazole and isavuconazole have become first-line therapy for suspected IA.

Several mold-active agents are currently available in the region, especially newer triazoles such as posaconazole, voriconazole, and isavuconazole, and polyenes such as amphotericin B and its different formulations. While SOT recipients have their own evidence-based guidelines for the treatment of IA, recommendations are mainly extrapolated from small observational cohorts or the HSCT population, which does not necessarily account for the significant drug–drug interactions encountered with prolonged use of calcineurin inhibitors/mTOR inhibitors in the SOT population.

Two pivotal trials published in the last decade have established voriconazole as the standard of treatment, with posaconazole and isavuconazole as non-inferior second choices for IA. The SECURE trial, published in 2016 [67], was a phase 3 trial comparing voriconazole with isavuconazole in patients with suspected invasive mould disease, stratified by allogeneic HSCT and active malignancy status; notably, SOT recipients were not included. Isavuconazole met the non-inferiority criterion for the 42-day all-cause mortality endpoint, with a better safety profile and fewer treatment discontinuations. A similarly designed phase 3 trial of posaconazole versus voriconazole, published in 2021, again excluded SOT recipients; posaconazole met the non-inferiority criterion for the 42-day all-cause mortality endpoint [68].

Culture-based identification of some fungal organisms is difficult and time-consuming, which limits de-escalation strategies, especially in the treatment of IA; there is no randomized data to guide the duration of IA therapy, and current practice is mainly based on observational studies in heterogeneous populations. Robust data support early de-escalation in candidemia, where yeast readily grow in non-selective media and EUCAST/CLSI breakpoints are available for most clinically relevant yeasts and are frequently included in automated minimum inhibitory concentration (MIC) panels. RCT data published in 2014 [69] support IDSA recommendations for oral step-down to fluconazole or voriconazole after an initial 5 days of IV echinocandin therapy, with similar findings in a more recent observational study supporting less than 5 days of intravenous therapy before de-escalation [70].

As mentioned previously, triazoles have significant drug interactions and safety concerns; most require TDM and frequent follow-up to address adherence and tolerance. It is not uncommon to have to stop azole treatment due to GI intolerance, reducing available options and optimal results. Table 6 reports the general properties of the most commonly used azoles in the region.

There has been increasing interest in antifungal stewardship (AFS) strategies, especially early oral de-escalation and TDM. Efforts have been limited in the region due to the lack of availability of TDM and rapid identification techniques, with a recent paper identifying lack of structure and resources as the main barriers to implementing an effective fungal AFS program [71]. Section 6 expands on these regional antifungal stewardship barriers and opportunities.

5.4. Mucormycosis — Medical-Surgical Emergency

Suspicion: compatible host with necrotizing sinusitis, facial edema, proptosis, nasal/palatal eschar, necrotic skin lesions, or atypical pulmonary imaging (Table 1).

Urgent diagnosis: CT for extension/bone involvement, MRI if rhino-orbito-cerebral disease is suspected, and early biopsy for histopathology/culture.

Initial treatment: L-AmB 5 mg/kg/day, or 10 mg/kg/day with CNS involvement, plus urgent repeated surgical debridement. If unavailable, use amphotericin B lipid complex (ABLC) 5 mg/kg/day; avoid deoxycholate when lipid formulations exist.

Consolidation/alternative: isavuconazole 200 mg every 8 h for 6 doses, then 200 mg/day; or posaconazole 300 mg every 12 h on day 1, then 300 mg/day; duration individualized (Table 6). Control of the predisposing factor is essential: correct ketoacidosis/hyperglycemia, reduce immunosuppression when feasible, and discontinue deferoxamine [46].

5.5. Cryptococcal Meningitis

Suspicion: subacute headache, fever, visual disturbance, altered mental status, or elevated intracranial pressure (ICP) in an immunosuppressed host (Table 1).

Diagnosis: lumbar puncture with opening pressure, CSF India ink stain, CrAg, and culture; manage elevated ICP with serial therapeutic punctures.

Induction: L-AmB 3–4 mg/kg/day + flucytosine 100 mg/kg/day for ≥14 days. In HIV/resource-limited settings: single-dose L-AmB 10 mg/kg + flucytosine + fluconazole 1200 mg/day for 14 days. If L-AmB is unavailable: ABLC or amphotericin B deoxycholate + flucytosine. If flucytosine is unavailable: available amphotericin formulation + fluconazole 1200 mg/day [33,72].

Consolidation/ART: fluconazole 400–800 mg/day for 8 weeks, then 200 mg/day for 12 months or until immune restoration (Table 6). Start antiretroviral therapy (ART) at 2–4 weeks if the patient has improved, ICP is controlled, and cultures are negative; otherwise defer 4–6 weeks [73].

6. Barriers and Opportunities in Latin America

The management of IFDs in Latin America faces the challenge of controlling potentially lethal endemic mycoses and emerging opportunistic infections within health-care systems marked by unequal resources. Critical social determinants, such as migration, internal displacement, and gaps in access to care, increase the vulnerability of immunosuppressed patients and hinder epidemiologic follow-up. Recognizing these gaps is the first step toward optimizing care (Figure 4).

6.1. Access to Diagnostics

Fungal infections remain a neglected public health problem. A regional survey of 129 centers in 24 countries showed that CrAg was the most available biomarker, with routine use in 75% of institutions, followed by galactomannan in 48% [74]. In contrast, Histoplasma antigen and BDG were reported in only 22% and 17% of institutions, respectively. Furthermore, rapid identification tools such as MALDI-TOF and fungal PCR are each available in less than 20% of institutions, representing a major missed opportunity for early diagnosis and targeted therapy (Figure 4). These data require local interpretation: although some countries have high-acuity centers that meet international standards, diagnostic capacity remains concentrated in referral hubs, generating inequitable access. In most hospitals, limited diagnostic availability perpetuates a model based on clinical suspicion, delayed cultures, and prolonged empirical treatment, with greater exposure to toxicity, costs, and additional ICU days.

6.2. Access to Antifungals

The regional therapeutic arsenal is heterogeneous (Figure 4). L-AmB has irregular availability in public systems, and its high cost limits sustained use, especially for prolonged courses or severe mold disease. Voriconazole is widely available, but its utility is affected by limited TDM, available in fewer than 20% of centers, exposing patients to hepatotoxicity, neurotoxicity, or subtherapeutic concentrations. Echinocandins are usually available in tertiary hospitals, but access is limited outside high-acuity centers. Newer molecules, such as ibrexafungerp, rezafungin, olorofim, or fosmanogepix, still have limited or country-dependent registration and clinical availability.

6.3. Emerging Antifungal Resistance

The region is not immune to the global resistance crisis (Figure 4). The high burden of candidemia in Latin America amplifies the clinical impact of shifts in species distribution and antifungal susceptibility. In-hospital dissemination of multidrug-resistant Candida auris — taxonomically reclassified as Candidozyma auris — has been documented, with severe outbreaks in Colombia, Venezuela, and Brazil [7,75]. In addition, selective pressure from broad azole and echinocandin use has been associated with resistant profiles in prevalent species. Interhospital outbreaks of fluconazole-resistant Candida parapsilosis were reported in Brazil during the COVID-19 era [76], along with growing interest in resistance and virulence mechanisms of Candida glabrata — currently Nakaseomyces glabratus — in Mexico [77]. Among molds, azole resistance in Aspergillus fumigatus, including environmental mutations such as TR34/L98H, represents an emerging regional threat [78].

6.4. Antifungal Stewardship (AFS)

The implementation of antifungal optimization programs in Latin America faces barriers that differ from those in high-income countries, including a critical lack of funding, personnel, information technology, and occasional prescriber opposition (Figure 4). In this context, AFS should be led by multidisciplinary teams, with active participation from infectious diseases, microbiology, pharmacy, and intensive care, adapting strategies to the actual availability of diagnostic tests and drugs [79]. Success metrics should pragmatically focus on reducing unnecessary days of empirical therapy, increasing the proportion of targeted therapy, promoting early oral step-down, and achieving de-escalation to fluconazole when microbiology and susceptibility results allow it. To maximize clinical impact and overcome regional diagnostic limitations, the implementation of clinical care pathways or “treatment bundles,” firmly supported by hospital governance, is strongly recommended as a core strategy [71,80].

6.5. Opportunities

Despite these challenges, clinical mycology in Latin America is growing (Figure 4). There is an urgent need to strengthen medical mycology education from undergraduate training and to promote dissemination of scientific literature in local languages. The consolidation of regional networks, such as the INFOCUS LATAM ISHAM Working Group and PAHO/GAFFI initiatives, offers a strategic platform to generate local data, map local resistance, adapt diagnostic algorithms to available resources, and influence public health policies aimed at improving equitable access to diagnosis and treatment [81].

7. Conclusions

Invasive fungal disease in Latin American high-acuity hospitals cannot be managed by directly transplanting algorithms built for high-resource settings. A workable pathway instead starts from a structured “window of suspicion” built on host risk factors, proceeds through a diagnostic work-up that is explicitly adapted to regional biomarker and molecular-testing availability, and resolves into syndrome-specific clinical pathways for candidemia, invasive aspergillosis, mucormycosis, and cryptococcal meningitis. Across these syndromes, the same principles recur: clinical prediction rules are most useful for ruling out disease rather than triggering therapy; imaging and biomarkers must be interpreted against host biology rather than a single universal cut-off; and early, syndrome-directed antifungal therapy — followed by prompt de-escalation once culture and susceptibility data allow it — offers the best balance between mortality reduction and antifungal stewardship. Persistent gaps in diagnostic access, TDM, and newer antifungal availability remain the principal barriers to implementing these pathways consistently across the region. Strengthening regional networks, mycology training, and locally adapted stewardship programs represents the most realistic route toward earlier, better-targeted antifungal therapy in Latin American high-acuity hospitals.