Candida species are the fourth most common cause of bloodstream infection in hospitalized patients in the United States and carry a crude mortality of approximately 30 to 40% for candidemia despite therapy. The transition of first-line treatment from fluconazole to echinocandins over the past two decades reflects accumulating evidence of superior outcomes, the rising prevalence of fluconazole-resistant Candida glabrata, and the emergence of multidrug-resistant Candida auris as a global healthcare threat.
Invasive Candidiasis and Candidemia. The 2016 Infectious Diseases Society of America (IDSA) guidelines recommend an echinocandin as the preferred initial therapy for most adults with candidemia and invasive candidiasis, regardless of species. The three licensed echinocandins (caspofungin, micafungin, and anidulafungin) have demonstrated equivalent efficacy in randomized controlled trials and differ primarily in their dose adjustment requirements, interaction profiles, and indications rather than antifungal activity. The rationale for echinocandin preference over fluconazole as empirical therapy is threefold: echinocandins are fungicidal against Candida where fluconazole is only fungistatic; echinocandins retain activity against fluconazole-resistant Candida glabrata and intrinsically fluconazole-resistant Candida krusei; and meta-analyses of randomized trials show reduced mortality with echinocandin initial therapy. Fluconazole remains appropriate for less severely ill patients with no prior azole exposure and no clinical features suggesting azole-resistant species.1
Step-Down to Oral Therapy. A defining feature of modern candidemia management is the transition from intravenous (IV) echinocandin to oral fluconazole once clinical stability is achieved and susceptibility data are available. This step-down strategy reduces treatment cost, enables outpatient completion, and avoids prolonged IV access. The criteria for step-down include: documented clinical improvement with defervescence and hemodynamic stability, a fluconazole-susceptible isolate on culture and susceptibility testing, negative follow-up blood cultures, absence of deep-seated infection requiring prolonged IV therapy (endocarditis, osteomyelitis, central nervous system (CNS) involvement), resolution of neutropenia if present, and ability to tolerate oral medication. The recommended total duration of therapy for uncomplicated candidemia is 14 days from the date of the last positive blood culture, with central venous catheter removal performed whenever feasible and clinically safe. Oral voriconazole is an alternative step-down option for Candida krusei infections where fluconazole resistance precludes its use.12
Candida auris and Emerging Resistance. Candida auris is a globally emergent, often multidrug-resistant yeast first described in 2009 that poses a distinct healthcare challenge because of its propensity for nosocomial spread, its resistance to standard decontamination procedures, and its high rates of resistance to fluconazole and, in some clades, to amphotericin B (AmB). Echinocandins are the preferred agents for C. auris infections pending formal susceptibility results, as the majority of current isolates retain echinocandin susceptibility. However, echinocandin resistance in C. auris caused by FKS (glucan synthase subunit) mutations is documented and emerging, and susceptibility testing of all C. auris isolates before definitive therapy is essential. Patients with C. auris candidemia who fail echinocandin therapy and have pan-resistant isolates may require experimental or combination regimens; this situation mandates early consultation with infectious disease specialists and reference mycology laboratories.2
Mucocutaneous Candidiasis. Oropharyngeal candidiasis (OPC) and esophageal candidiasis are the most common forms of mucocutaneous Candida infection and occur most frequently in patients with HIV (human immunodeficiency virus) infection, hematologic malignancy, solid organ transplant recipients, and patients receiving inhaled or systemic corticosteroids. For OPC in patients able to tolerate oral medication, fluconazole 100 mg once daily for 7 to 14 days is the preferred treatment and is superior to topical agents (clotrimazole troches, nystatin suspension) in immunocompromised patients. Esophageal candidiasis requires systemic therapy and fluconazole 200 to 400 mg (3 to 6 mg/kg) once daily for 14 to 21 days is the first-line regimen; IV formulations are used when the patient cannot swallow. Recurrent OPC in HIV-positive patients reflects underlying immunosuppression and ideally is addressed by optimizing antiretroviral therapy (ART) rather than chronic antifungal suppression, which risks azole resistance.1
Empiric: echinocandin (all patients except lowest-risk/no prior azoles). De-escalation to oral fluconazole: when clinically stable, susceptible isolate, negative follow-up cultures, able to take oral meds. Duration: 14 days from last positive culture. Central catheter removal whenever feasible. C. auris: echinocandin preferred; susceptibility testing mandatory; FKS resistance emerging. Source control is as important as antifungal selection.
Invasive pulmonary aspergillosis (IPA) is the most common life-threatening mold infection in immunocompromised patients and carries a mortality of 30 to 50% even with appropriate antifungal therapy. The fungal pathogen is almost always Aspergillus fumigatus, though other species including Aspergillus flavus, Aspergillus terreus (which is intrinsically amphotericin B-resistant), and Aspergillus niger contribute. Rapid diagnosis and prompt initiation of effective antifungal therapy are the most important determinants of outcome.
Diagnosis and Biomarkers. The diagnosis of IPA relies on a combination of clinical features, radiological findings, and mycological evidence. The characteristic computed tomography (CT) findings include nodules with a halo sign (representing hemorrhagic infarction surrounding a fungal nodule) in early-stage neutropenic IPA, and consolidation, wedge-shaped infarcts, and air-crescent signs in later stages or in non-neutropenic hosts. Serum galactomannan (GM) is the most validated biomarker for IPA in neutropenic patients and hematopoietic stem cell transplant (HSCT) recipients; an optical density index (ODI) of 0.5 or above on two consecutive samples, or above 1.0 on a single sample, is considered positive using the Platelia Aspergillus enzyme-linked immunosorbent assay (ELISA) in most guidelines. Beta-d-glucan (BDG) is a non-specific marker of invasive fungal infection (elevated in Candida, Aspergillus, and Pneumocystis but not in Mucorales); its combination with galactomannan increases sensitivity. Bronchoalveolar lavage (BAL) galactomannan has higher sensitivity than serum in non-neutropenic patients. Aspergillus polymerase chain reaction (PCR) testing from blood and BAL adds incremental diagnostic value but is not yet universally standardized.3
First-Line Therapy. Voriconazole is the most extensively studied first-line agent for IPA, established by the landmark randomized trial by Herbrecht et al. (2002), which demonstrated superior survival and response rates compared to amphotericin B deoxycholate. Voriconazole is administered as a 6 mg/kg intravenous (IV) loading dose every 12 hours for two doses on Day 1, followed by 4 mg/kg IV every 12 hours, with transition to oral voriconazole 200 to 300 mg every 12 hours when clinically appropriate. Therapeutic drug monitoring (TDM) with a target trough of 1.0 to 5.5 mg/L is mandatory given the extensive pharmacokinetic variability driven by CYP2C19 (cytochrome P450 2C19) genotype. Isavuconazole is an approved alternative to voriconazole for IPA, demonstrated non-inferior to voriconazole in the SECURE (Safety and Efficacy of Isavuconazole vs. Voriconazole) trial, with a simpler interaction profile, better tolerability (less hepatotoxicity and visual adverse effects), and once-daily dosing after loading. Current IDSA (Infectious Diseases Society of America) guidelines list both voriconazole and isavuconazole as first-line agents, with the choice guided by patient-specific factors including comedications, hepatic function, and CYP2C19 status.34
Salvage Therapy and Combination Regimens. Patients with IPA who fail primary therapy or have disease progression despite adequate voriconazole or isavuconazole exposure present a major clinical challenge. Salvage options include: liposomal amphotericin B (L-AmB) at 3 to 5 mg/kg/day; posaconazole (particularly the delayed-release (DR) tablet or IV formulation to ensure adequate exposure); micafungin; and combination antifungal regimens. The evidence base for combination therapy in IPA is incomplete. The COMBISTRAT (Combination Antifungal Therapy for Invasive Aspergillosis) pilot study and a larger multicenter observational study by Marr et al. (2015) suggested potential benefit of voriconazole plus anidulafungin in patients with galactomannan-positive IPA. Current IDSA guidelines consider combination therapy an option for selected patients with severe disease but do not make it a universal recommendation. Aspergillus terreus infections should not be treated with amphotericin B because of intrinsic resistance; voriconazole or isavuconazole is required.348
First-line: voriconazole or isavuconazole (equivalent efficacy; prefer isavuconazole when drug interactions or visual side effects are concerns). Voriconazole TDM mandatory: target trough 1.0–5.5 mg/L. A. terreus: intrinsically AmB-resistant; must use triazole. Prophylaxis in high-risk patients (AML induction, HSCT): posaconazole DR tablet is preferred. Galactomannan monitoring during therapy: rising values suggest treatment failure or reinfection. Duration: minimum 6–12 weeks; guided by immunosuppression status and radiological response.
Cryptococcal meningitis is caused predominantly by Cryptococcus neoformans (var. grubii and var. neoformans) in HIV (human immunodeficiency virus)-positive individuals and by Cryptococcus gattii in immunocompetent hosts, particularly in regions where this species is endemic. It remains a leading cause of meningitis-related mortality in sub-Saharan Africa and Southeast Asia and accounts for an estimated 15 to 20% of AIDS (acquired immunodeficiency syndrome)-related deaths globally. The three-phase treatment strategy (induction, consolidation, maintenance) is distinct from virtually every other infectious disease paradigm and reflects the dual need to sterilize the cerebrospinal fluid (CSF) rapidly while preventing relapse in a persistently immunocompromised host.
Induction Therapy. The goal of induction therapy is rapid clearance of Cryptococcus from the CSF, quantified by early fungicidal activity (EFA) and time to CSF sterilization (negative culture at lumbar puncture (LP) performed during therapy). The preferred induction regimen is amphotericin B (preferably liposomal: L-AmB 3 to 4 mg/kg/day; or amphotericin B deoxycholate 0.7 to 1.0 mg/kg/day if L-AmB is unavailable) combined with flucytosine (5-FC) 25 mg/kg orally or IV every 6 hours for a minimum of 2 weeks. This combination is the most fungicidal regimen available and achieves faster CSF sterilization than amphotericin B monotherapy or fluconazole-based regimens. The 2022 World Health Organization (WHO) guidelines recommend amphotericin B plus 5-FC as the preferred induction regimen wherever both are available, based on evidence from multiple randomized trials including the ACTA (Advancing Cryptococcal Meningitis Treatment for Africa) trial. Where IV amphotericin B is unavailable, the ACTA trial demonstrated that oral fluconazole 1200 mg/day plus 5-FC 25 mg/kg four times daily for 2 weeks is a viable alternative, superior to fluconazole monotherapy.6
Consolidation and Maintenance. Following successful induction (defined as clinical improvement and preferably a negative CSF culture), consolidation therapy consists of fluconazole 400 mg orally once daily for 8 weeks. The mechanism is consolidation of CSF sterilization begun during induction and prevention of early relapse. Maintenance (suppressive) therapy is required in HIV-positive patients to prevent late relapse: fluconazole 200 mg orally once daily, continued until the patient has received effective ART (antiretroviral therapy) for at least 1 year and has sustained CD4 (cluster of differentiation 4) counts above 100 cells/mm³ with undetectable viral load. Discontinuation of maintenance therapy below these thresholds carries significant relapse risk because the immune response to Cryptococcus is CD4-dependent. In HIV-negative patients with non-immunocompromising conditions, the decision to continue maintenance therapy is guided by the degree and reversibility of the underlying immunosuppression.56
Intracranial Pressure Management. Elevated intracranial pressure (ICP) is a frequent and potentially fatal complication of cryptococcal meningitis, arising because Cryptococcus polysaccharide capsule and yeast cells obstruct CSF outflow through the arachnoid villi. Management of elevated ICP is as critical as antifungal therapy in reducing early mortality. Serial therapeutic lumbar punctures (LPs) are the standard approach: if opening pressure exceeds 25 cm H₂O (water), CSF should be drained to achieve a closing pressure below 20 cm H₂O or a reduction of 50% from opening pressure at each procedure. Daily LPs may be required in the first 2 weeks of therapy. Corticosteroids have not been shown to reduce ICP in cryptococcal meningitis and are associated with harm (increased mortality) in this context based on evidence from randomized trials, contrasting their role in bacterial meningitis.5
Immune Reconstitution Inflammatory Syndrome. Immune reconstitution inflammatory syndrome (IRIS) in the context of cryptococcal meningitis is a paradoxical worsening of inflammatory symptoms occurring after ART initiation in HIV-positive patients, as recovering immune function mounts an exuberant response to residual Cryptococcus antigens. Unmasking IRIS presents as new meningitis in patients starting ART who had subclinical infection; paradoxical IRIS presents as clinical deterioration in patients already being treated for cryptococcal meningitis after ART is initiated. The timing of ART initiation after cryptococcal meningitis diagnosis is therefore critical: evidence from the COAT (Cryptococcal Optimal ART Timing) trial demonstrated that immediate ART initiation (within 1 to 2 weeks) is associated with significantly higher mortality compared to deferring ART for 5 weeks after antifungal induction; this is one of the few clinical contexts in HIV management where delayed ART initiation is the standard of care.5
Induction (2 weeks): L-AmB 3–4 mg/kg/day + 5-FC 25 mg/kg q6h (preferred); or fluconazole 1200 mg/day + 5-FC if IV AmB unavailable. Consolidation (8 weeks): fluconazole 400 mg once daily. Maintenance (until immune recovery): fluconazole 200 mg once daily. ICP management: serial LPs if opening pressure above 25 cm H₂O; drain to below 20 cm H₂O. Corticosteroids: NOT indicated for ICP management in cryptococcal meningitis (increases mortality). ART timing in HIV: defer 5 weeks after antifungal induction (COAT trial evidence).
Mucormycosis (previously called zygomycosis) is a rapidly progressive and often fatal invasive fungal infection caused by members of the order Mucorales, predominantly Rhizopus species, Mucor species, and Lichtheimia (formerly Absidia). It occurs almost exclusively in immunocompromised or metabolically compromised hosts, with uncontrolled diabetic ketoacidosis (DKA) and prolonged high-dose corticosteroid use being among the most common predisposing conditions. The hallmark of mucormycosis pathophysiology is angioinvasion, which leads to vessel thrombosis, tissue ischemia, and the characteristic black necrotic eschar.
Pathophysiology and Risk Factors. Mucorales spores are inhaled or deposited on mucosal surfaces in all individuals, but in immunocompetent hosts phagocytic killing prevents tissue invasion. In susceptible hosts, spores germinate and hyphae invade blood vessel walls, causing endothelial damage, thrombosis, and tissue infarction. The hyphal invasion of blood vessels explains both the characteristic imaging appearance (wedge-shaped infarcts, sinus opacification with bone erosion in rhinocerebral disease) and the poor penetration of antifungal drugs into necrotic tissue where blood flow is absent. Key risk factors include uncontrolled diabetes mellitus (particularly DKA), prolonged high-dose corticosteroids, hematologic malignancy with neutropenia, hematopoietic stem cell or solid organ transplantation, iron overload, and deferoxamine therapy (which provides iron as a growth substrate for Mucorales). Post-COVID-19 mucormycosis was documented in epidemic proportions in India during the 2021 Delta wave, linked to corticosteroid use and underlying diabetes, highlighting how reversible predisposing factors directly influence risk.7
Treatment: Antifungal Agents. Liposomal amphotericin B (L-AmB) at 5 to 10 mg/kg/day is the first-line antifungal agent for mucormycosis. The high dose range (compared to 3 to 4 mg/kg/day for aspergillosis) reflects the need to achieve fungicidal concentrations in tissues with compromised blood flow and the generally lower susceptibility of Mucorales compared to Aspergillus. Isavuconazole is the only licensed azole with established activity against Mucorales and is approved as primary or salvage therapy; it demonstrated non-inferiority to L-AmB in an open-label trial for mucormycosis and mold infections and is an alternative for patients who cannot tolerate or receive AmB. Posaconazole (DR tablet or IV) is used as step-down oral therapy after initial L-AmB induction once clinical stability is achieved, and as salvage therapy. Voriconazole lacks activity against Mucorales and should never be used for mucormycosis; a historical concern exists that Aspergillus prophylaxis with voriconazole may create a Mucorales niche, an observation confirmed in several retrospective series from high-risk hematology populations.7
Surgical Debridement and Reversal of Predisposing Factors. Surgical debridement is the cornerstone of mucormycosis management and cannot be replaced by antifungal therapy alone. In rhinocerebral mucormycosis, extensive surgical resection of necrotic tissue from the sinuses, orbit, and surrounding structures is required; delay in surgery is independently associated with mortality. In pulmonary mucormycosis, surgical resection of involved lung parenchyma is performed when anatomically feasible and the patient can tolerate it. Reversal of predisposing factors is equally essential: DKA must be corrected aggressively; corticosteroids should be tapered to the lowest clinically acceptable dose; deferoxamine must be discontinued; and immunosuppression in transplant recipients should be reduced. In neutropenic patients, recovery of neutrophil count (whether spontaneous or myeloid growth factor-assisted) is the most important determinant of antifungal response. The combination of L-AmB plus surgical debridement plus reversal of predisposing factors constitutes the integrated management strategy required for any realistic chance of cure.7
Antifungal: L-AmB 5–10 mg/kg/day (first-line); isavuconazole or posaconazole DR as alternative or step-down. Voriconazole: NEVER use for mucormycosis (no activity). Surgery: mandatory for rhinocerebral and often for pulmonary disease; do not delay. Predisposing factors: correct DKA aggressively; stop deferoxamine; taper corticosteroids; restore neutrophil count. Imaging: CT of sinuses and brain for rhinocerebral disease; chest CT for pulmonary. Duration: typically months; guided by clinical and radiological response plus immune recovery.
The endemic mycoses are invasive fungal infections caused by thermally dimorphic fungi that exist as moulds in the environment and convert to pathogenic yeast or spherule forms at body temperature. Unlike opportunistic fungi such as Candida or Aspergillus, which cause disease primarily in immunocompromised patients, endemic fungi can infect immunocompetent individuals following inhalation of infectious particles in endemic regions, though severe and disseminated disease is far more common in immunocompromised hosts.
Histoplasmosis. Histoplasma capsulatum is endemic in the Ohio and Mississippi River valleys of the United States, parts of Central and South America, and sub-Saharan Africa. Infection occurs through inhalation of microconidia from soil disturbed by activities such as construction, excavation, or spelunking near bird or bat roosts. Most immunocompetent individuals develop asymptomatic or self-limited pulmonary illness; severe pulmonary histoplasmosis, chronic pulmonary histoplasmosis, and disseminated histoplasmosis occur in immunocompromised patients, including those with advanced HIV (human immunodeficiency virus) infection (CD4 (cluster of differentiation 4) count below 150 cells/mm³), solid organ transplant recipients, and patients on tumor necrosis factor (TNF) inhibitors. For mild-to-moderate pulmonary or disseminated histoplasmosis, itraconazole 200 mg three times daily for 3 days (loading) followed by 200 mg twice daily for 6 to 12 weeks is the recommended treatment. Severe or life-threatening histoplasmosis, including diffuse pulmonary infiltrates with respiratory failure and CNS (central nervous system) histoplasmosis, requires L-AmB 3 mg/kg/day induction for 1 to 2 weeks followed by step-down to itraconazole. Urine Histoplasma antigen (MVISTA or IMMY assays) is the most sensitive test for disseminated disease and is used for monitoring treatment response.9
Coccidioidomycosis. Coccidioides immitis and Coccidioides posadasii are endemic in the arid regions of the southwestern United States (particularly the San Joaquin Valley of California, Arizona, New Mexico, and west Texas), northern Mexico, and parts of Central and South America. Primary pulmonary coccidioidomycosis occurs in up to 30% of those exposed and is often self-limited in immunocompetent hosts, manifesting as "valley fever" with fever, cough, and fatigue. Disseminated coccidioidomycosis, most commonly involving the skin, bone, joints, and meninges, occurs in immunocompromised patients and in specific populations including pregnant women, patients with diabetes, and individuals of African or Filipino descent who may have a genetically determined increased susceptibility. Fluconazole 400 to 800 mg once daily is first-line therapy for most forms of non-meningeal coccidioidomycosis in immunocompetent patients given its excellent oral bioavailability and tolerability. Coccidioidal meningitis requires fluconazole 400 to 800 mg once daily indefinitely (lifelong therapy) because relapse rates with discontinuation are very high. L-AmB is used for severe or rapidly progressive disease. Intrathecal (IT) amphotericin B, historically used for meningeal disease, is now reserved for fluconazole-refractory cases given the availability of effective oral therapy.910
Blastomycosis. Blastomyces dermatitidis is endemic primarily in the United States and Canada in overlapping regions with Histoplasma, particularly in the Great Lakes region, the Mississippi and Ohio River valleys, and the southeastern United States. Primary pulmonary blastomycosis ranges from asymptomatic to severe pneumonia. Extrapulmonary dissemination involves the skin (verrucous or ulcerative plaques), bone, genitourinary tract, and CNS. Unlike histoplasmosis, blastomycosis does not have a reliable and widely available antigen assay, making diagnosis more dependent on culture and histopathology. Itraconazole 200 mg three times daily for 3 days then 200 mg twice daily for 6 to 12 months is the recommended treatment for mild-to-moderate pulmonary and extrapulmonary blastomycosis. L-AmB induction is required for CNS blastomycosis (fluconazole and itraconazole penetrate the CNS poorly compared to voriconazole; for CNS blastomycosis, voriconazole or fluconazole step-down after L-AmB induction is used based on susceptibility data), and for severely ill patients with respiratory failure. Itraconazole TDM (therapeutic drug monitoring) is advisable for patients with blastomycosis receiving prolonged itraconazole therapy, particularly those not responding as expected, given the variable oral absorption of the capsule formulation.910
Histoplasmosis mild-moderate: itraconazole 200 mg TID × 3 days then 200 mg BID × 6–12 weeks. Histoplasmosis severe: L-AmB 3 mg/kg/day × 1–2 weeks, then itraconazole step-down. Coccidioidomycosis non-meningeal: fluconazole 400–800 mg once daily. Coccidioidal meningitis: fluconazole indefinitely (lifelong). Blastomycosis mild-moderate: itraconazole 200 mg TID × 3 days then 200 mg BID × 6–12 months. All endemic mycoses severe/disseminated/CNS: L-AmB induction before azole step-down. TNF inhibitors: consider prophylaxis or monitoring in endemic areas.
The seven modules of the Chapter 37 antifungal pharmacology series have covered each major class of antifungal agent in the context of its mechanisms, pharmacokinetics, interactions, toxicities, and clinical applications. This final section integrates that pharmacological foundation with the clinical syndrome-based framework from the preceding sections and articulates key antifungal stewardship principles relevant to prescribing practice.
Matching Agent to Pathogen: Core Decision Framework. The central pharmacological principle underlying antifungal selection is that no single agent covers all relevant fungal pathogens at adequate concentrations with acceptable toxicity. The major gaps are: echinocandins lack activity against Cryptococcus, Mucorales, and the endemic dimorphic fungi; polyenes (amphotericin B) are inactive against most dermatophytes and have problematic toxicity for outpatient use; azoles are variably active across pathogens and species-dependent susceptibility must be verified. Matching the correct agent to the confirmed or suspected pathogen requires integration of the patient's exposure history, immune status, geographic background, prior antifungal exposure, and species identification from culture or molecular diagnostics. Empiric therapy must be broad enough to cover the most likely and most dangerous pathogens in a given clinical context; definitive therapy should be narrowed based on species identification and susceptibility data whenever possible.13
Antifungal Stewardship Principles. Antifungal stewardship is the structured application of evidence-based practices to optimize antifungal prescribing, reduce unnecessary use, minimize toxicity and drug interactions, and preserve the effectiveness of the antifungal armamentarium against resistance development. Core stewardship interventions include: species-level identification with susceptibility testing before initiating definitive therapy; TDM (therapeutic drug monitoring) for voriconazole (mandatory), posaconazole suspension (advisable), and flucytosine (mandatory); systematic interaction screening before initiating any azole, particularly in transplant patients; de-escalation from IV to oral therapy and from broad-spectrum to targeted agents once diagnostic clarity is achieved; defined treatment durations based on published guidelines rather than arbitrary or open-ended courses; and prospective audit and feedback by multidisciplinary teams. Overuse of broad-spectrum antifungals, particularly echinocandins for non-candida indications or extended-spectrum azoles for low-risk infections, places selection pressure on fungal populations without clinical benefit.2
Prophylaxis in High-Risk Populations. Primary antifungal prophylaxis is evidence-based in several high-risk populations and represents one of the most impactful interventions for reducing invasive fungal disease incidence. Fluconazole prophylaxis in surgical ICU (intensive care unit) patients and in high-risk liver transplant recipients reduces Candida infections but is not universally recommended in all ICU populations. Posaconazole DR (delayed-release) tablet prophylaxis (300 mg once daily after loading) in patients receiving remission-induction chemotherapy for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), and in allogeneic HSCT (hematopoietic stem cell transplant) recipients with graft-versus-host disease (GVHD) on high-dose steroids, is a category I recommendation in IDSA (Infectious Diseases Society of America) guidelines; the EORTC/IFICG (European Organisation for Research and Treatment of Cancer / Invasive Fungal Infections Cooperative Group) posaconazole trials demonstrated significant reductions in IPA (invasive pulmonary aspergillosis) incidence and all-cause mortality compared to fluconazole or itraconazole. Micafungin 50 mg once daily is the approved prophylactic dose in HSCT recipients. Prophylaxis decisions must balance benefit against toxicity, interactions, and cost, and require re-evaluation when the patient's risk profile changes.34
Integrating the Series: Key Pharmacological Takeaways. The antifungal pharmacology series has demonstrated several overarching themes relevant to clinical practice. First, mechanism dictates spectrum: agents targeting ergosterol (polyenes, azoles) are broadly active but encounter resistance through ergosterol pathway mutations; echinocandins targeting beta-glucan are powerfully active against Candida but have fundamental spectrum gaps; antimetabolites and microtubule disruptors have narrow niches defined by pathogen-specific enzyme expression. Second, pharmacokinetic heterogeneity requires monitoring: voriconazole and posaconazole show up to 10-fold interpatient variability; TDM converts unpredictable dosing into personalized therapy. Third, drug interactions are class-defining: the azole-calcineurin inhibitor interaction is the most important pharmacological interaction in transplant medicine and requires proactive management at every step. Fourth, resistance is growing: FKS (glucan synthase subunit gene) mutations in Candida, azole resistance in Aspergillus fumigatus (driven in part by environmental triazole use in agriculture), and multidrug resistance in C. auris require systematic susceptibility testing and stewardship to preserve therapeutic options.1
Polyenes: ergosterol binding; fungicidal; L-AmB preferred for mucormycosis and severe endemic mycoses; nephrotoxicity dose-limiting. Azoles: CYP51 inhibition; broad spectrum; TDM for voriconazole and posaconazole suspension; major CYP interactions; first-line for IPA (vori/isavu), consolidation for cryptococcosis (fluco), coccidioidomycosis (fluco), endemic mycoses (itra). Echinocandins: glucan synthase inhibition; fungicidal vs. Candida; first-line for candidemia; no CNS/ocular penetration; FKS resistance emerging. Flucytosine: antimetabolite; only in combination; mandatory TDM; AmB+5FC for cryptococcal meningitis. Terbinafine: squalene epoxidase; fungicidal vs. dermatophytes; CYP2D6 inhibitor. Griseofulvin: microtubule inhibitor; dermatophytes only; tinea capitis.
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(4):e1-e50.
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doi:10.1086/649858World Health Organization. Guidelines for Diagnosing, Preventing and Managing Cryptococcal Disease Among Adults, Adolescents and Children Living with HIV. Geneva: WHO; 2022. ISBN 9789240052178.
who.int/publications/i/item/9789240052178Cornely 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(12):e405-e421.
doi:10.1016/S1473-3099(19)30312-3Marr KA, Schlamm HT, Herbrecht R, et al. Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med. 2015;162(2):81-89.
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