Endemic mycoses - are we making progress in management?

Purpose of reviewThe endemic fungi are a significant cause of morbidity and mortality in effected patients. The range of endemicity for these are expanding with infections observed outside of traditional locations. Enhanced diagnostic and treatment practices may significantly alter patient outcomes.Recently completed clinical trials have focused on an assessment of improving efficacy while minimizing patient toxicity. Practice changing trials have been completed in histoplasmosis showing the utility of a single up-front liposomal amphotericin B dose followed by standard itraconazole dosing. The recent evaluation of several antifungal options including isauvconazole in the treatment of coccidioidomycosis also show promise for additional therapeutic agents. A recently conducted trial has also shown the superiority of amphotericin B therapy over itraconazole in the treatment of talaromycosis.The increased range of endemic mycoses coupled with the growing immunocompromised patient population mandates continued investigation of improved diagnostic and therapeutic options. Advances in these areas have led to more rapid diagnosis and more efficacious antifungal therapy.Papers of particular interest, published within the annual period of review, have been highlighted as:The endemic mycoses are a diverse group of fungal pathogens that share several key characteristics. Each occupies a specific ecological niche in the environment and is able to cause disease in otherwise healthy hosts. The agents in this review, Blastomyces, Coccidioides, Histoplasma, Sporothrix, and Talaromyces marneffei are each increasingly recognized, and climatic events have been associated with geographic expansion and a higher number of cases per year for many of these organisms. Changes in the in vitro susceptibility profiles of these agents have also been recently reported [1], necessitating the search for alternative or new antifungal agents in an attempt to optimize patient outcomes.Severe disease caused by the endemic mycoses is treated with an amphotericin B formulation (lipid agents are preferred) followed by triazole agents. Each of these agents possess unique pharmacokinetic and toxicity profiles that require a thorough understanding by the prescribing practitioner. The triazoles are teratogens and should not be used in the first trimester, while each also exhibits variable effects on the CYP450 system resulting in potential hepatotoxicity and/or drug-drug interactions. Fluconazole causes dose-dependent alopecia, xerosis, and cheilitis [2]. Itraconazole may cause gastritis, peripheral edema and is a negative inotrope potentially resulting in heart failure. Voriconazole may cause photosensitivity, photopsia, fluorosis, or encephalopathy [3,4], while posaconazole may cause hypertension or electrolyte disturbance [5]. Isavuconazole may similarly cause electrolyte disturbance or infusion reactions. The fungistatic nature of currently available oral antifungals mandates long courses of therapy for most of the endemic mycoses, and these durations allow cumulative toxicities which may contribute to less than desirable treatment tolerability and outcomes. Additionally, the diagnosis is often delayed and only considered after several courses of antibacterial therapy have been (wrongly) prescribed [6,7]. Despite the geographic expansion of these pathogens, they are not required to be reported in most states further complicating our understanding of the burden of these agents. no caption availableThe typical treatments for histoplasmosis treatment have not changed in over two decades, but that stability may be challenged in the coming years. Many persons with mild acute pulmonary disease or evidence of previous or dormant histoplasmosis do not require treatment [8-11]. The standard treatment for moderate to severe acute pulmonary histoplasmosis remains liposomal amphotericin B (LAmb, 3-5 mg/kg/daily intravenously) for 1-2 weeks followed by itraconazole 200 mg three times daily for three days then twice daily for 12 weeks and adjunct corticosteroids are used in some cases [8]. This is primarily based on case reports [8,12]. More mild disease can treated with itraconazole only at the same dose, if necessary [13,14]. Therapeutic drug monitoring is advised due to difficulty with absorption [15]. In severe acute disease, corticosteroids are sometimes used to improve hypoxemia [15].Disseminated histoplasmosis is treated similarly (LAmb followed by itraconazole) but treatment is always required [8]. Johnson et al. conducted a randomized double-blind trial comparing LAmb with amphotericin B deoxycholate (AmBD) and found lower mortality (2% vs. 13%) in those that received liposomal amphotericin B, establishing LAmb as the preferred initial agent [16]. Recently, Pasqualotto et al. conducted an open-label randomized trial and found that among 118 participants, a single dose of LAmb (10 mg/kg) on day 1 appeared to be noninferior to standard LAmb treatment - both arms were followed by standard itraconazole dosing [17]. A larger, phase three trial is planned to confirm these findings and further evaluate efficacy and toxicity. Mild disseminated disease can be treated with itraconazole alone and all disseminated disease requires at least 12 months of itraconazole and ideally documentation of resolution of antigenuria and/or antigenemia (when available) [8,18-20].Histoplasmosis includes a number of other syndromes where the same principles of treatment involving itraconazole for more mild disease requiring treatment and LAmb up-front for more severe (including central nervous system (CNS)) or chronic disease apply [8]. Although often used as 'step-down' therapy for CNS disease, itraconazole's CNS penetration is poor. Thus, an alternative azole could theoretically be preferable, though evidence is limited. The most compelling candidate is isavuconazole which has low in vitro minimum inhibitory concentrations (MICs) in Histoplasma isolates from patients who failed treatment with fluconazole as opposed to voriconazole which had high MICs - both have good CNS penetration [21-26]. In a 2023 systematic review of CNS histoplasmosis, mortality was 12% (9/73) in those treated with itraconazole and 20% (3/15) in those treated with voriconazole [27]. Although the P value for the comparison was 0.43, it's difficult to say whether or not there is a true difference in efficacy based on this data, particularly given the sample size and lack of correction for potential confounders.Posaconazole has low MICs in the same isolates mentioned in relation to isavuconazole above from persons with CNS histoplasmosis and clinical success has been reported, although CNS penetration is low [22,28,29]. Ultimately, evidence is scant and itraconazole is typically used as step-down therapy in most CNS histoplasmosis cases. Of note, super bioavailability (SUBA)-itraconazole is now FDA approved for histoplasmosis but neither formulation is approved for CNS disease where it has not been prospectively studied [30]. Purpose of reviewThe endemic fungi are a significant cause of morbidity and mortality in effected patients. The range of endemicity for these are expanding with infections observed outside of traditional locations. Enhanced diagnostic and treatment practices may significantly alter patient outcomes.Recently completed clinical trials have focused on an assessment of improving efficacy while minimizing patient toxicity. Practice changing trials have been completed in histoplasmosis showing the utility of a single up-front liposomal amphotericin B dose followed by standard itraconazole dosing. The recent evaluation of several antifungal options including isauvconazole in the treatment of coccidioidomycosis also show promise for additional therapeutic agents. A recently conducted trial has also shown the superiority of amphotericin B therapy over itraconazole in the treatment of talaromycosis.The increased range of endemic mycoses coupled with the growing immunocompromised patient population mandates continued investigation of improved diagnostic and therapeutic options. Advances in these areas have led to more rapid diagnosis and more efficacious antifungal therapy.Papers of particular interest, published within the annual period of review, have been highlighted as:The endemic mycoses are a diverse group of fungal pathogens that share several key characteristics. Each occupies a specific ecological niche in the environment and is able to cause disease in otherwise healthy hosts. The agents in this review, Blastomyces, Coccidioides, Histoplasma, Sporothrix, and Talaromyces marneffei are each increasingly recognized, and climatic events have been associated with geographic expansion and a higher number of cases per year for many of these organisms. Changes in the in vitro susceptibility profiles of these agents have also been recently reported [1], necessitating the search for alternative or new antifungal agents in an attempt to optimize patient outcomes.Severe disease caused by the endemic mycoses is treated with an amphotericin B formulation (lipid agents are preferred) followed by triazole agents. Each of these agents possess unique pharmacokinetic and toxicity profiles that require a thorough understanding by the prescribing practitioner. The triazoles are teratogens and should not be used in the first trimester, while each also exhibits variable effects on the CYP450 system resulting in potential hepatotoxicity and/or drug-drug interactions. Fluconazole causes dose-dependent alopecia, xerosis, and cheilitis [2]. Itraconazole may cause gastritis, peripheral edema and is a negative inotrope potentially resulting in heart failure. Voriconazole may cause photosensitivity, photopsia, fluorosis, or encephalopathy [3,4], while posaconazole may cause hypertension or electrolyte disturbance [5]. Isavuconazole may similarly cause electrolyte disturbance or infusion reactions. The fungistatic nature of currently available oral antifungals mandates long courses of therapy for most of the endemic mycoses, and these durations allow cumulative toxicities which may contribute to less than desirable treatment tolerability and outcomes. Additionally, the diagnosis is often delayed and only considered after several courses of antibacterial therapy have been (wrongly) prescribed [6,7]. Despite the geographic expansion of these pathogens, they are not required to be reported in most states further complicating our understanding of the burden of these agents. no caption availableThe typical treatments for histoplasmosis treatment have not changed in over two decades, but that stability may be challenged in the coming years. Many persons with mild acute pulmonary disease or evidence of previous or dormant histoplasmosis do not require treatment [8-11]. The standard treatment for moderate to severe acute pulmonary histoplasmosis remains liposomal amphotericin B (LAmb, 3-5 mg/kg/daily intravenously) for 1-2 weeks followed by itraconazole 200 mg three times daily for three days then twice daily for 12 weeks and adjunct corticosteroids are used in some cases [8]. This is primarily based on case reports [8,12]. More mild disease can treated with itraconazole only at the same dose, if necessary [13,14]. Therapeutic drug monitoring is advised due to difficulty with absorption [15]. In severe acute disease, corticosteroids are sometimes used to improve hypoxemia [15].Disseminated histoplasmosis is treated similarly (LAmb followed by itraconazole) but treatment is always required [8]. Johnson et al. conducted a randomized double-blind trial comparing LAmb with amphotericin B deoxycholate (AmBD) and found lower mortality (2% vs. 13%) in those that received liposomal amphotericin B, establishing LAmb as the preferred initial agent [16]. Recently, Pasqualotto et al. conducted an open-label randomized trial and found that among 118 participants, a single dose of LAmb (10 mg/kg) on day 1 appeared to be noninferior to standard LAmb treatment - both arms were followed by standard itraconazole dosing [17]. A larger, phase three trial is planned to confirm these findings and further evaluate efficacy and toxicity. Mild disseminated disease can be treated with itraconazole alone and all disseminated disease requires at least 12 months of itraconazole and ideally documentation of resolution of antigenuria and/or antigenemia (when available) [8,18-20].Histoplasmosis includes a number of other syndromes where the same principles of treatment involving itraconazole for more mild disease requiring treatment and LAmb up-front for more severe (including central nervous system (CNS)) or chronic disease apply [8]. Although often used as 'step-down' therapy for CNS disease, itraconazole's CNS penetration is poor. Thus, an alternative azole could theoretically be preferable, though evidence is limited. The most compelling candidate is isavuconazole which has low in vitro minimum inhibitory concentrations (MICs) in Histoplasma isolates from patients who failed treatment with fluconazole as opposed to voriconazole which had high MICs - both have good CNS penetration [21-26]. In a 2023 systematic review of CNS histoplasmosis, mortality was 12% (9/73) in those treated with itraconazole and 20% (3/15) in those treated with voriconazole [27]. Although the P value for the comparison was 0.43, it's difficult to say whether or not there is a true difference in efficacy based on this data, particularly given the sample size and lack of correction for potential confounders.Posaconazole has low MICs in the same isolates mentioned in relation to isavuconazole above from persons with CNS histoplasmosis and clinical success has been reported, although CNS penetration is low [22,28,29]. Ultimately, evidence is scant and itraconazole is typically used as step-down therapy in most CNS histoplasmosis cases. Of note, super bioavailability (SUBA)-itraconazole is now FDA approved for histoplasmosis but neither formulation is approved for CNS disease where it has not been prospectively studied [30]. Purpose of reviewThe endemic fungi are a significant cause of morbidity and mortality in effected patients. The range of endemicity for these are expanding with infections observed outside of traditional locations. Enhanced diagnostic and treatment practices may significantly alter patient outcomes.Recently completed clinical trials have focused on an assessment of improving efficacy while minimizing patient toxicity. Practice changing trials have been completed in histoplasmosis showing the utility of a single up-front liposomal amphotericin B dose followed by standard itraconazole dosing. The recent evaluation of several antifungal options including isauvconazole in the treatment of coccidioidomycosis also show promise for additional therapeutic agents. A recently conducted trial has also shown the superiority of amphotericin B therapy over itraconazole in the treatment of talaromycosis.The increased range of endemic mycoses coupled with the growing immunocompromised patient population mandates continued investigation of improved diagnostic and therapeutic options. Advances in these areas have led to more rapid diagnosis and more efficacious antifungal therapy.Papers of particular interest, published within the annual period of review, have been highlighted as:The endemic mycoses are a diverse group of fungal pathogens that share several key characteristics. Each occupies a specific ecological niche in the environment and is able to cause disease in otherwise healthy hosts. The agents in this review, Blastomyces, Coccidioides, Histoplasma, Sporothrix, and Talaromyces marneffei are each increasingly recognized, and climatic events have been associated with geographic expansion and a higher number of cases per year for many of these organisms. Changes in the in vitro susceptibility profiles of these agents have also been recently reported [1], necessitating the search for alternative or new antifungal agents in an attempt to optimize patient outcomes.Severe disease caused by the endemic mycoses is treated with an amphotericin B formulation (lipid agents are preferred) followed by triazole agents. Each of these agents possess unique pharmacokinetic and toxicity profiles that require a thorough understanding by the prescribing practitioner. The triazoles are teratogens and should not be used in the first trimester, while each also exhibits variable effects on the CYP450 system resulting in potential hepatotoxicity and/or drug-drug interactions. Fluconazole causes dose-dependent alopecia, xerosis, and cheilitis [2]. Itraconazole may cause gastritis, peripheral edema and is a negative inotrope potentially resulting in heart failure. Voriconazole may cause photosensitivity, photopsia, fluorosis, or encephalopathy [3,4], while posaconazole may cause hypertension or electrolyte disturbance [5]. Isavuconazole may similarly cause electrolyte disturbance or infusion reactions. The fungistatic nature of currently available oral antifungals mandates long courses of therapy for most of the endemic mycoses, and these durations allow cumulative toxicities which may contribute to less than desirable treatment tolerability and outcomes. Additionally, the diagnosis is often delayed and only considered after several courses of antibacterial therapy have been (wrongly) prescribed [6,7]. Despite the geographic expansion of these pathogens, they are not required to be reported in most states further complicating our understanding of the burden of these agents. no caption availableThe typical treatments for histoplasmosis treatment have not changed in over two decades, but that stability may be challenged in the coming years. Many persons with mild acute pulmonary disease or evidence of previous or dormant histoplasmosis do not require treatment [8-11]. The standard treatment for moderate to severe acute pulmonary histoplasmosis remains liposomal amphotericin B (LAmb, 3-5 mg/kg/daily intravenously) for 1-2 weeks followed by itraconazole 200 mg three times daily for three days then twice daily for 12 weeks and adjunct corticosteroids are used in some cases [8]. This is primarily based on case reports [8,12]. More mild disease can treated with itraconazole only at the same dose, if necessary [13,14]. Therapeutic drug monitoring is advised due to difficulty with absorption [15]. In severe acute disease, corticosteroids are sometimes used to improve hypoxemia [15].Disseminated histoplasmosis is treated similarly (LAmb followed by itraconazole) but treatment is always required [8]. Johnson et al. conducted a randomized double-blind trial comparing LAmb with amphotericin B deoxycholate (AmBD) and found lower mortality (2% vs. 13%) in those that received liposomal amphotericin B, establishing LAmb as the preferred initial agent [16]. Recently, Pasqualotto et al. conducted an open-label randomized trial and found that among 118 participants, a single dose of LAmb (10 mg/kg) on day 1 appeared to be noninferior to standard LAmb treatment - both arms were followed by standard itraconazole dosing [17]. A larger, phase three trial is planned to confirm these findings and further evaluate efficacy and toxicity. Mild disseminated disease can be treated with itraconazole alone and all disseminated disease requires at least 12 months of itraconazole and ideally documentation of resolution of antigenuria and/or antigenemia (when available) [8,18-20].Histoplasmosis includes a number of other syndromes where the same principles of treatment involving itraconazole for more mild disease requiring treatment and LAmb up-front for more severe (including central nervous system (CNS)) or chronic disease apply [8]. Although often used as 'step-down' therapy for CNS disease, itraconazole's CNS penetration is poor. Thus, an alternative azole could theoretically be preferable, though evidence is limited. The most compelling candidate is isavuconazole which has low in vitro minimum inhibitory concentrations (MICs) in Histoplasma isolates from patients who failed treatment with fluconazole as opposed to voriconazole which had high MICs - both have good CNS penetration [21-26]. In a 2023 systematic review of CNS histoplasmosis, mortality was 12% (9/73) in those treated with itraconazole and 20% (3/15) in those treated with voriconazole [27]. Although the P value for the comparison was 0.43, it's difficult to say whether or not there is a true difference in efficacy based on this data, particularly given the sample size and lack of correction for potential confounders.Posaconazole has low MICs in the same isolates mentioned in relation to isavuconazole above from persons with CNS histoplasmosis and clinical success has been reported, although CNS penetration is low [22,28,29]. Ultimately, evidence is scant and itraconazole is typically used as step-down therapy in most CNS histoplasmosis cases. Of note, super bioavailability (SUBA)-itraconazole is now FDA approved for histoplasmosis but neither formulation is approved for CNS disease where it has not been prospectively studied [30]. Purpose of reviewThe endemic fungi are a significant cause of morbidity and mortality in effected patients. The range of endemicity for these are expanding with infections observed outside of traditional locations. Enhanced diagnostic and treatment practices may significantly alter patient outcomes.Recently completed clinical trials have focused on an assessment of improving efficacy while minimizing patient toxicity. Practice changing trials have been completed in histoplasmosis showing the utility of a single up-front liposomal amphotericin B dose followed by standard itraconazole dosing. The recent evaluation of several antifungal options including isauvconazole in the treatment of coccidioidomycosis also show promise for additional therapeutic agents. A recently conducted trial has also shown the superiority of amphotericin B therapy over itraconazole in the treatment of talaromycosis.The increased range of endemic mycoses coupled with the growing immunocompromised patient population mandates continued investigation of improved diagnostic and therapeutic options. Advances in these areas have led to more rapid diagnosis and more efficacious antifungal therapy.Papers of particular interest, published within the annual period of review, have been highlighted as:The endemic mycoses are a diverse group of fungal pathogens that share several key characteristics. Each occupies a specific ecological niche in the environment and is able to cause disease in otherwise healthy hosts. The agents in this review, Blastomyces, Coccidioides, Histoplasma, Sporothrix, and Talaromyces marneffei are each increasingly recognized, and climatic events have been associated with geographic expansion and a higher number of cases per year for many of these organisms. Changes in the in vitro susceptibility profiles of these agents have also been recently reported [1], necessitating the search for alternative or new antifungal agents in an attempt to optimize patient outcomes.Severe disease caused by the endemic mycoses is treated with an amphotericin B formulation (lipid agents are preferred) followed by triazole agents. Each of these agents possess unique pharmacokinetic and toxicity profiles that require a thorough understanding by the prescribing practitioner. The triazoles are teratogens and should not be used in the first trimester, while each also exhibits variable effects on the CYP450 system resulting in potential hepatotoxicity and/or drug-drug interactions. Fluconazole causes dose-dependent alopecia, xerosis, and cheilitis [2]. Itraconazole may cause gastritis, peripheral edema and is a negative inotrope potentially resulting in heart failure. Voriconazole may cause photosensitivity, photopsia, fluorosis, or encephalopathy [3,4], while posaconazole may cause hypertension or electrolyte disturbance [5]. Isavuconazole may similarly cause electrolyte disturbance or infusion reactions. The fungistatic nature of currently available oral antifungals mandates long courses of therapy for most of the endemic mycoses, and these durations allow cumulative toxicities which may contribute to less than desirable treatment tolerability and outcomes. Additionally, the diagnosis is often delayed and only considered after several courses of antibacterial therapy have been (wrongly) prescribed [6,7]. Despite the geographic expansion of these pathogens, they are not required to be reported in most states further complicating our understanding of the burden of these agents. no caption availableThe typical treatments for histoplasmosis treatment have not changed in over two decades, but that stability may be challenged in the coming years. Many persons with mild acute pulmonary disease or evidence of previous or dormant histoplasmosis do not require treatment [8-11]. The standard treatment for moderate to severe acute pulmonary histoplasmosis remains liposomal amphotericin B (LAmb, 3-5 mg/kg/daily intravenously) for 1-2 weeks followed by itraconazole 200 mg three times daily for three days then twice daily for 12 weeks and adjunct corticosteroids are used in some cases [8]. This is primarily based on case reports [8,12]. More mild disease can treated with itraconazole only at the same dose, if necessary [13,14]. Therapeutic drug monitoring is advised due to difficulty with absorption [15]. In severe acute disease, corticosteroids are sometimes used to improve hypoxemia [15].Disseminated histoplasmosis is treated similarly (LAmb followed by itraconazole) but treatment is always required [8]. Johnson et al. conducted a randomized double-blind trial comparing LAmb with amphotericin B deoxycholate (AmBD) and found lower mortality (2% vs. 13%) in those that received liposomal amphotericin B, establishing LAmb as the preferred initial agent [16]. Recently, Pasqualotto et al. conducted an open-label randomized trial and found that among 118 participants, a single dose of LAmb (10 mg/kg) on day 1 appeared to be noninferior to standard LAmb treatment - both arms were followed by standard itraconazole dosing [17]. A larger, phase three trial is planned to confirm these findings and further evaluate efficacy and toxicity. Mild disseminated disease can be treated with itraconazole alone and all disseminated disease requires at least 12 months of itraconazole and ideally documentation of resolution of antigenuria and/or antigenemia (when available) [8,18-20].Histoplasmosis includes a number of other syndromes where the same principles of treatment involving itraconazole for more mild disease requiring treatment and LAmb up-front for more severe (including central nervous system (CNS)) or chronic disease apply [8]. Although often used as 'step-down' therapy for CNS disease, itraconazole's CNS penetration is poor. Thus, an alternative azole could theoretically be preferable, though evidence is limited. The most compelling candidate is isavuconazole which has low in vitro minimum inhibitory concentrations (MICs) in Histoplasma isolates from patients who failed treatment with fluconazole as opposed to voriconazole which had high MICs - both have good CNS penetration [21-26]. In a 2023 systematic review of CNS histoplasmosis, mortality was 12% (9/73) in those treated with itraconazole and 20% (3/15) in those treated with voriconazole [27]. Although the P value for the comparison was 0.43, it's difficult to say whether or not there is a true difference in efficacy based on this data, particularly given the sample size and lack of correction for potential confounders.Posaconazole has low MICs in the same isolates mentioned in relation to isavuconazole above from persons with CNS histoplasmosis and clinical success has been reported, although CNS penetration is low [22,28,29]. Ultimately, evidence is scant and itraconazole is typically used as step-down therapy in most CNS histoplasmosis cases. Of note, super bioavailability (SUBA)-itraconazole is now FDA approved for histoplasmosis but neither formulation is approved for CNS disease where it has not been prospectively studied [30]. Purpose of reviewThe endemic fungi are a significant cause of morbidity and mortality in effected patients. The range of endemicity for these are expanding with infections observed outside of traditional locations. Enhanced diagnostic and treatment practices may significantly alter patient outcomes.Recently completed clinical trials have focused on an assessment of improving efficacy while minimizing patient toxicity. Practice changing trials have been completed in histoplasmosis showing the utility of a single up-front liposomal amphotericin B dose followed by standard itraconazole dosing. The recent evaluation of several antifungal options including isauvconazole in the treatment of coccidioidomycosis also show promise for additional therapeutic agents. A recently conducted trial has also shown the superiority of amphotericin B therapy over itraconazole in the treatment of talaromycosis.The increased range of endemic mycoses coupled with the growing immunocompromised patient population mandates continued investigation of improved diagnostic and therapeutic options. Advances in these areas have led to more rapid diagnosis and more efficacious antifungal therapy.Papers of particular interest, published within the annual period of review, have been highlighted as:The endemic mycoses are a diverse group of fungal pathogens that share several key characteristics. Each occupies a specific ecological niche in the environment and is able to cause disease in otherwise healthy hosts. The agents in this review, Blastomyces, Coccidioides, Histoplasma, Sporothrix, and Talaromyces marneffei are each increasingly recognized, and climatic events have been associated with geographic expansion and a higher number of cases per year for many of these organisms. Changes in the in vitro susceptibility profiles of these agents have also been recently reported [1], necessitating the search for alternative or new antifungal agents in an attempt to optimize patient outcomes.Severe disease caused by the endemic mycoses is treated with an amphotericin B formulation (lipid agents are preferred) followed by triazole agents. Each of these agents possess unique pharmacokinetic and toxicity profiles that require a thorough understanding by the prescribing practitioner. The triazoles are teratogens and should not be used in the first trimester, while each also exhibits variable effects on the CYP450 system resulting in potential hepatotoxicity and/or drug-drug interactions. Fluconazole causes dose-dependent alopecia, xerosis, and cheilitis [2]. Itraconazole may cause gastritis, peripheral edema and is a negative inotrope potentially resulting in heart failure. Voriconazole may cause photosensitivity, photopsia, fluorosis, or encephalopathy [3,4], while posaconazole may cause hypertension or electrolyte disturbance [5]. Isavuconazole may similarly cause electrolyte disturbance or infusion reactions. The fungistatic nature of currently available oral antifungals mandates long courses of therapy for most of the endemic mycoses, and these durations allow cumulative toxicities which may contribute to less than desirable treatment tolerability and outcomes. Additionally, the diagnosis is often delayed and only considered after several courses of antibacterial therapy have been (wrongly) prescribed [6,7]. Despite the geographic expansion of these pathogens, they are not required to be reported in most states further complicating our understanding of the burden of these agents. no caption availableThe typical treatments for histoplasmosis treatment have not changed in over two decades, but that stability may be challenged in the coming years. Many persons with mild acute pulmonary disease or evidence of previous or dormant histoplasmosis do not require treatment [8-11]. The standard treatment for moderate to severe acute pulmonary histoplasmosis remains liposomal amphotericin B (LAmb, 3-5 mg/kg/daily intravenously) for 1-2 weeks followed by itraconazole 200 mg three times daily for three days then twice daily for 12 weeks and adjunct corticosteroids are used in some cases [8]. This is primarily based on case reports [8,12]. More mild disease can treated with itraconazole only at the same dose, if necessary [13,14]. Therapeutic drug monitoring is advised due to difficulty with absorption [15]. In severe acute disease, corticosteroids are sometimes used to improve hypoxemia [15].Disseminated histoplasmosis is treated similarly (LAmb followed by itraconazole) but treatment is always required [8]. Johnson et al. conducted a randomized double-blind trial comparing LAmb with amphotericin B deoxycholate (AmBD) and found lower mortality (2% vs. 13%) in those that received liposomal amphotericin B, establishing LAmb as the preferred initial agent [16]. Recently, Pasqualotto et al. conducted an open-label randomized trial and found that among 118 participants, a single dose of LAmb (10 mg/kg) on day 1 appeared to be noninferior to standard LAmb treatment - both arms were followed by standard itraconazole dosing [17]. A larger, phase three trial is planned to confirm these findings and further evaluate efficacy and toxicity. Mild disseminated disease can be treated with itraconazole alone and all disseminated disease requires at least 12 months of itraconazole and ideally documentation of resolution of antigenuria and/or antigenemia (when available) [8,18-20].Histoplasmosis includes a number of other syndromes where the same principles of treatment involving itraconazole for more mild disease requiring treatment and LAmb up-front for more severe (including central nervous system (CNS)) or chronic disease apply [8]. Although often used as 'step-down' therapy for CNS disease, itraconazole's CNS penetration is poor. Thus, an alternative azole could theoretically be preferable, though evidence is limited. The most compelling candidate is isavuconazole which has low in vitro minimum inhibitory concentrations (MICs) in Histoplasma isolates from patients who failed treatment with fluconazole as opposed to voriconazole which had high MICs - both have good CNS penetration [21-26]. In a 2023 systematic review of CNS histoplasmosis, mortality was 12% (9/73) in those treated with itraconazole and 20% (3/15) in those treated with voriconazole [27]. Although the P value for the comparison was 0.43, it's difficult to say whether or not there is a true difference in efficacy based on this data, particularly given the sample size and lack of correction for potential confounders.Posaconazole has low MICs in the same isolates mentioned in relation to isavuconazole above from persons with CNS histoplasmosis and clinical success has been reported, although CNS penetration is low [22,28,29]. Ultimately, evidence is scant and itraconazole is typically used as step-down therapy in most CNS histoplasmosis cases. Of note, super bioavailability (SUBA)-itraconazole is now FDA approved for histoplasmosis but neither formulation is approved for CNS disease where it has not been prospectively studied [30]. Purpose of reviewThe endemic fungi are a significant cause of morbidity and mortality in effected patients. The range of endemicity for these are expanding with infections observed outside of traditional locations. Enhanced diagnostic and treatment practices may significantly alter patient outcomes.Recently completed clinical trials have focused on an assessment of improving efficacy while minimizing patient toxicity. Practice changing trials have been completed in histoplasmosis showing the utility of a single up-front liposomal amphotericin B dose followed by standard itraconazole dosing. The recent evaluation of several antifungal options including isauvconazole in the treatment of coccidioidomycosis also show promise for additional therapeutic agents. A recently conducted trial has also shown the superiority of amphotericin B therapy over itraconazole in the treatment of talaromycosis.The increased range of endemic mycoses coupled with the growing immunocompromised patient population mandates continued investigation of improved diagnostic and therapeutic options. Advances in these areas have led to more rapid diagnosis and more efficacious antifungal therapy.Papers of particular interest, published within the annual period of review, have been highlighted as:The endemic mycoses are a diverse group of fungal pathogens that share several key characteristics. Each occupies a specific ecological niche in the environment and is able to cause disease in otherwise healthy hosts. The agents in this review, Blastomyces, Coccidioides, Histoplasma, Sporothrix, and Talaromyces marneffei are each increasingly recognized, and climatic events have been associated with geographic expansion and a higher number of cases per year for many of these organisms. Changes in the in vitro susceptibility profiles of these agents have also been recently reported [1], necessitating the search for alternative or new antifungal agents in an attempt to optimize patient outcomes.Severe disease caused by the endemic mycoses is treated with an amphotericin B formulation (lipid agents are preferred) followed by triazole agents. Each of these agents possess unique pharmacokinetic and toxicity profiles that require a thorough understanding by the prescribing practitioner. The triazoles are teratogens and should not be used in the first trimester, while each also exhibits variable effects on the CYP450 system resulting in potential hepatotoxicity and/or drug-drug interactions. Fluconazole causes dose-dependent alopecia, xerosis, and cheilitis [2]. Itraconazole may cause gastritis, peripheral edema and is a negative inotrope potentially resulting in heart failure. Voriconazole may cause photosensitivity, photopsia, fluorosis, or encephalopathy [3,4], while posaconazole may cause hypertension or electrolyte disturbance [5]. Isavuconazole may similarly cause electrolyte disturbance or infusion reactions. The fungistatic nature of currently available oral antifungals mandates long courses of therapy for most of the endemic mycoses, and these durations allow cumulative toxicities which may contribute to less than desirable treatment tolerability and outcomes. Additionally, the diagnosis is often delayed and only considered after several courses of antibacterial therapy have been (wrongly) prescribed [6,7]. Despite the geographic expansion of these pathogens, they are not required to be reported in most states further complicating our understanding of the burden of these agents. no caption availableThe typical treatments for histoplasmosis treatment have not changed in over two decades, but that stability may be challenged in the coming years. Many persons with mild acute pulmonary disease or evidence of previous or dormant histoplasmosis do not require treatment [8-11]. The standard treatment for moderate to severe acute pulmonary histoplasmosis remains liposomal amphotericin B (LAmb, 3-5 mg/kg/daily intravenously) for 1-2 weeks followed by itraconazole 200 mg three times daily for three days then twice daily for 12 weeks and adjunct corticosteroids are used in some cases [8]. This is primarily based on case reports [8,12]. More mild disease can treated with itraconazole only at the same dose, if necessary [13,14]. Therapeutic drug monitoring is advised due to difficulty with absorption [15]. In severe acute disease, corticosteroids are sometimes used to improve hypoxemia [15].Disseminated histoplasmosis is treated similarly (LAmb followed by itraconazole) but treatment is always required [8]. Johnson et al. conducted a randomized double-blind trial comparing LAmb with amphotericin B deoxycholate (AmBD) and found lower mortality (2% vs. 13%) in those that received liposomal amphotericin B, establishing LAmb as the preferred initial agent [16]. Recently, Pasqualotto et al. conducted an open-label randomized trial and found that among 118 participants, a single dose of LAmb (10 mg/kg) on day 1 appeared to be noninferior to standard LAmb treatment - both arms were followed by standard itraconazole dosing [17]. A larger, phase three trial is planned to confirm these findings and further evaluate efficacy and toxicity. Mild disseminated disease can be treated with itraconazole alone and all disseminated disease requires at least 12 months of itraconazole and ideally documentation of resolution of antigenuria and/or antigenemia (when available) [8,18-20].Histoplasmosis includes a number of other syndromes where the same principles of treatment involving itraconazole for more mild disease requiring treatment and LAmb up-front for more severe (including central nervous system (CNS)) or chronic disease apply [8]. Although often used as 'step-down' therapy for CNS disease, itraconazole's CNS penetration is poor. Thus, an alternative azole could theoretically be preferable, though evidence is limited. The most compelling candidate is isavuconazole which has low in vitro minimum inhibitory concentrations (MICs) in Histoplasma isolates from patients who failed treatment with fluconazole as opposed to voriconazole which had high MICs - both have good CNS penetration [21-26]. In a 2023 systematic review of CNS histoplasmosis, mortality was 12% (9/73) in those treated with itraconazole and 20% (3/15) in those treated with voriconazole [27]. Although the P value for the comparison was 0.43, it's difficult to say whether or not there is a true difference in efficacy based on this data, particularly given the sample size and lack of correction for potential confounders.Posaconazole has low MICs in the same isolates mentioned in relation to isavuconazole above from persons with CNS histoplasmosis and clinical success has been reported, although CNS penetration is low [22,28,29]. Ultimately, evidence is scant and itraconazole is typically used as step-down therapy in most CNS histoplasmosis cases. Of note, super bioavailability (SUBA)-itraconazole is now FDA approved for histoplasmosis but neither formulation is approved for CNS disease where it has not been prospectively studied [30]. Purpose of reviewThe endemic fungi are a significant cause of morbidity and mortality in effected patients. The range of endemicity for these are expanding with infections observed outside of traditional locations. Enhanced diagnostic and treatment practices may significantly alter patient outcomes.Recently completed clinical trials have focused on an assessment of improving efficacy while minimizing patient toxicity. Practice changing trials have been completed in histoplasmosis showing the utility of a single up-front liposomal amphotericin B dose followed by standard itraconazole dosing. The recent evaluation of several antifungal options including isauvconazole in the treatment of coccidioidomycosis also show promise for additional therapeutic agents. A recently conducted trial has also shown the superiority of amphotericin B therapy over itraconazole in the treatment of talaromycosis.The increased range of endemic mycoses coupled with the growing immunocompromised patient population mandates continued investigation of improved diagnostic and therapeutic options. Advances in these areas have led to more rapid diagnosis and more efficacious antifungal therapy.Papers of particular interest, published within the annual period of review, have been highlighted as:The endemic mycoses are a diverse group of fungal pathogens that share several key characteristics. Each occupies a specific ecological niche in the environment and is able to cause disease in otherwise healthy hosts. The agents in this review, Blastomyces, Coccidioides, Histoplasma, Sporothrix, and Talaromyces marneffei are each increasingly recognized, and climatic events have been associated with geographic expansion and a higher number of cases per year for many of these organisms. Changes in the in vitro susceptibility profiles of these agents have also been recently reported [1], necessitating the search for alternative or new antifungal agents in an attempt to optimize patient outcomes.Severe disease caused by the endemic mycoses is treated with an amphotericin B formulation (lipid agents are preferred) followed by triazole agents. Each of these agents possess unique pharmacokinetic and toxicity profiles that require a thorough understanding by the prescribing practitioner. The triazoles are teratogens and should not be used in the first trimester, while each also exhibits variable effects on the CYP450 system resulting in potential hepatotoxicity and/or drug-drug interactions. Fluconazole causes dose-dependent alopecia, xerosis, and cheilitis [2]. Itraconazole may cause gastritis, peripheral edema and is a negative inotrope potentially resulting in heart failure. Voriconazole may cause photosensitivity, photopsia, fluorosis, or encephalopathy [3,4], while posaconazole may cause hypertension or electrolyte disturbance [5]. Isavuconazole may similarly cause electrolyte disturbance or infusion reactions. The fungistatic nature of currently available oral antifungals mandates long courses of therapy for most of the endemic mycoses, and these durations allow cumulative toxicities which may contribute to less than desirable treatment tolerability and outcomes. Additionally, the diagnosis is often delayed and only considered after several courses of antibacterial therapy have been (wrongly) prescribed [6,7]. Despite the geographic expansion of these pathogens, they are not required to be reported in most states further complicating our understanding of the burden of these agents. no caption availableThe typical treatments for histoplasmosis treatment have not changed in over two decades, but that stability may be challenged in the coming years. Many persons with mild acute pulmonary disease or evidence of previous or dormant histoplasmosis do not require treatment [8-11]. The standard treatment for moderate to severe acute pulmonary histoplasmosis remains liposomal amphotericin B (LAmb, 3-5 mg/kg/daily intravenously) for 1-2 weeks followed by itraconazole 200 mg three times daily for three days then twice daily for 12 weeks and adjunct corticosteroids are used in some cases [8]. This is primarily based on case reports [8,12]. More mild disease can treated with itraconazole only at the same dose, if necessary [13,14]. Therapeutic drug monitoring is advised due to difficulty with absorption [15]. In severe acute disease, corticosteroids are sometimes used to improve hypoxemia [15].Disseminated histoplasmosis is treated similarly (LAmb followed by itraconazole) but treatment is always required [8]. Johnson et al. conducted a randomized double-blind trial comparing LAmb with amphotericin B deoxycholate (AmBD) and found lower mortality (2% vs. 13%) in those that received liposomal amphotericin B, establishing LAmb as the preferred initial agent [16]. Recently, Pasqualotto et al. conducted an open-label randomized trial and found that among 118 participants, a single dose of LAmb (10 mg/kg) on day 1 appeared to be noninferior to standard LAmb treatment - both arms were followed by standard itraconazole dosing [17]. A larger, phase three trial is planned to confirm these findings and further evaluate efficacy and toxicity. Mild disseminated disease can be treated with itraconazole alone and all disseminated disease requires at least 12 months of itraconazole and ideally documentation of resolution of antigenuria and/or antigenemia (when available) [8,18-20].Histoplasmosis includes a number of other syndromes where the same principles of treatment involving itraconazole for more mild disease requiring treatment and LAmb up-front for more severe (including central nervous system (CNS)) or chronic disease apply [8]. Although often used as 'step-down' therapy for CNS disease, itraconazole's CNS penetration is poor. Thus, an alternative azole could theoretically be preferable, though evidence is limited. The most compelling candidate is isavuconazole which has low in vitro minimum inhibitory concentrations (MICs) in Histoplasma isolates from patients who failed treatment with fluconazole as opposed to voriconazole which had high MICs - both have good CNS penetration [21-26]. In a 2023 systematic review of CNS histoplasmosis, mortality was 12% (9/73) in those treated with itraconazole and 20% (3/15) in those treated with voriconazole [27]. Although the P value for the comparison was 0.43, it's difficult to say whether or not there is a true difference in efficacy based on this data, particularly given the sample size and lack of correction for potential confounders.Posaconazole has low MICs in the same isolates mentioned in relation to isavuconazole above from persons with CNS histoplasmosis and clinical success has been reported, although CNS penetration is low [22,28,29]. Ultimately, evidence is scant and itraconazole is typically used as step-down therapy in most CNS histoplasmosis cases. Of note, super bioavailability (SUBA)-itraconazole is now FDA approved for histoplasmosis but neither formulation is approved for CNS disease where it has not been prospectively studied [30]. Purpose of reviewThe endemic fungi are a significant cause of morbidity and mortality in effected patients. The range of endemicity for these are expanding with infections observed outside of traditional locations. Enhanced diagnostic and treatment practices may significantly alter patient outcomes.Recently completed clinical trials have focused on an assessment of improving efficacy while minimizing patient toxicity. Practice changing trials have been completed in histoplasmosis showing the utility of a single up-front liposomal amphotericin B dose followed by standard itraconazole dosing. The recent evaluation of several antifungal options including isauvconazole in the treatment of coccidioidomycosis also show promise for additional therapeutic agents. A recently conducted trial has also shown the superiority of amphotericin B therapy over itraconazole in the treatment of talaromycosis.The increased range of endemic mycoses coupled with the growing immunocompromised patient population mandates continued investigation of improved diagnostic and therapeutic options. Advances in these areas have led to more rapid diagnosis and more efficacious antifungal therapy.Papers of particular interest, published within the annual period of review, have been highlighted as:The endemic mycoses are a diverse group of fungal pathogens that share several key characteristics. Each occupies a specific ecological niche in the environment and is able to cause disease in otherwise healthy hosts. The agents in this review, Blastomyces, Coccidioides, Histoplasma, Sporothrix, and Talaromyces marneffei are each increasingly recognized, and climatic events have been associated with geographic expansion and a higher number of cases per year for many of these organisms. Changes in the in vitro susceptibility profiles of these agents have also been recently reported [1], necessitating the search for alternative or new antifungal agents in an attempt to optimize patient outcomes.Severe disease caused by the endemic mycoses is treated with an amphotericin B formulation (lipid agents are preferred) followed by triazole agents. Each of these agents possess unique pharmacokinetic and toxicity profiles that require a thorough understanding by the prescribing practitioner. The triazoles are teratogens and should not be used in the first trimester, while each also exhibits variable effects on the CYP450 system resulting in potential hepatotoxicity and/or drug-drug interactions. Fluconazole causes dose-dependent alopecia, xerosis, and cheilitis [2]. Itraconazole may cause gastritis, peripheral edema and is a negative inotrope potentially resulting in heart failure. Voriconazole may cause photosensitivity, photopsia, fluorosis, or encephalopathy [3,4], while posaconazole may cause hypertension or electrolyte disturbance [5]. Isavuconazole may similarly cause electrolyte disturbance or infusion reactions. The fungistatic nature of currently available oral antifungals mandates long courses of therapy for most of the endemic mycoses, and these durations allow cumulative toxicities which may contribute to less than desirable treatment tolerability and outcomes. Additionally, the diagnosis is often delayed and only considered after several courses of antibacterial therapy have been (wrongly) prescribed [6,7]. Despite the geographic expansion of these pathogens, they are not required to be reported in most states further complicating our understanding of the burden of these agents. no caption availableThe typical treatments for histoplasmosis treatment have not changed in over two decades, but that stability may be challenged in the coming years. Many persons with mild acute pulmonary disease or evidence of previous or dormant histoplasmosis do not require treatment [8-11]. The standard treatment for moderate to severe acute pulmonary histoplasmosis remains liposomal amphotericin B (LAmb, 3-5 mg/kg/daily intravenously) for 1-2 weeks followed by itraconazole 200 mg three times daily for three days then twice daily for 12 weeks and adjunct corticosteroids are used in some cases [8]. This is primarily based on case reports [8,12]. More mild disease can treated with itraconazole only at the same dose, if necessary [13,14]. Therapeutic drug monitoring is advised due to difficulty with absorption [15]. In severe acute disease, corticosteroids are sometimes used to improve hypoxemia [15].Disseminated histoplasmosis is treated similarly (LAmb followed by itraconazole) but treatment is always required [8]. Johnson et al. conducted a randomized double-blind trial comparing LAmb with amphotericin B deoxycholate (AmBD) and found lower mortality (2% vs. 13%) in those that received liposomal amphotericin B, establishing LAmb as the preferred initial agent [16]. Recently, Pasqualotto et al. conducted an open-label randomized trial and found that among 118 participants, a single dose of LAmb (10 mg/kg) on day 1 appeared to be noninferior to standard LAmb treatment - both arms were followed by standard itraconazole dosing [17]. A larger, phase three trial is planned to confirm these findings and further evaluate efficacy and toxicity. Mild disseminated disease can be treated with itraconazole alone and all disseminated disease requires at least 12 months of itraconazole and ideally documentation of resolution of antigenuria and/or antigenemia (when available) [8,18-20].Histoplasmosis includes a number of other syndromes where the same principles of treatment involving itraconazole for more mild disease requiring treatment and LAmb up-front for more severe (including central nervous system (CNS)) or chronic disease apply [8]. Although often used as 'step-down' therapy for CNS disease, itraconazole's CNS penetration is poor. Thus, an alternative azole could theoretically be preferable, though evidence is limited. The most compelling candidate is isavuconazole which has low in vitro minimum inhibitory concentrations (MICs) in Histoplasma isolates from patients who failed treatment with fluconazole as opposed to voriconazole which had high MICs - both have good CNS penetration [21-26]. In a 2023 systematic review of CNS histoplasmosis, mortality was 12% (9/73) in those treated with itraconazole and 20% (3/15) in those treated with voriconazole [27]. Although the P value for the comparison was 0.43, it's difficult to say whether or not there is a true difference in efficacy based on this data, particularly given the sample size and lack of correction for potential confounders.Posaconazole has low MICs in the same isolates mentioned in relation to isavuconazole above from persons with CNS histoplasmosis and clinical success has been reported, although CNS penetration is low [22,28,29]. Ultimately, evidence is scant and itraconazole is typically used as step-down therapy in most CNS histoplasmosis cases. Of note, super bioavailability (SUBA)-itraconazole is now FDA approved for histoplasmosis but neither formulation is approved for CNS disease where it has not been prospectively studied [30]. Purpose of reviewThe endemic fungi are a significant cause of morbidity and mortality in effected patients. The range of endemicity for these are expanding with infections observed outside of traditional locations. Enhanced diagnostic and treatment practices may significantly alter patient outcomes.Recently completed clinical trials have focused on an assessment of improving efficacy while minimizing patient toxicity. Practice changing trials have been completed in histoplasmosis showing the utility of a single up-front liposomal amphotericin B dose followed by standard itraconazole dosing. The recent evaluation of several antifungal options including isauvconazole in the treatment of coccidioidomycosis also show promise for additional therapeutic agents. A recently conducted trial has also shown the superiority of amphotericin B therapy over itraconazole in the treatment of talaromycosis.The increased range of endemic mycoses coupled with the growing immunocompromised patient population mandates continued investigation of improved diagnostic and therapeutic options. Advances in these areas have led to more rapid diagnosis and more efficacious antifungal therapy.Papers of particular interest, published within the annual period of review, have been highlighted as:The endemic mycoses are a diverse group of fungal pathogens that share several key characteristics. Each occupies a specific ecological niche in the environment and is able to cause disease in otherwise healthy hosts. The agents in this review, Blastomyces, Coccidioides, Histoplasma, Sporothrix, and Talaromyces marneffei are each increasingly recognized, and climatic events have been associated with geographic expansion and a higher number of cases per year for many of these organisms. Changes in the in vitro susceptibility profiles of these agents have also been recently reported [1], necessitating the search for alternative or new antifungal agents in an attempt to optimize patient outcomes.Severe disease caused by the endemic mycoses is treated with an amphotericin B formulation (lipid agents are preferred) followed by triazole agents. Each of these agents possess unique pharmacokinetic and toxicity profiles that require a thorough understanding by the prescribing practitioner. The triazoles are teratogens and should not be used in the first trimester, while each also exhibits variable effects on the CYP450 system resulting in potential hepatotoxicity and/or drug-drug interactions. Fluconazole causes dose-dependent alopecia, xerosis, and cheilitis [2]. Itraconazole may cause gastritis, peripheral edema and is a negative inotrope potentially resulting in heart failure. Voriconazole may cause photosensitivity, photopsia, fluorosis, or encephalopathy [3,4], while posaconazole may cause hypertension or electrolyte disturbance [5]. Isavuconazole may similarly cause electrolyte disturbance or infusion reactions. The fungistatic nature of currently available oral antifungals mandates long courses of therapy for most of the endemic mycoses, and these durations allow cumulative toxicities which may contribute to less than desirable treatment tolerability and outcomes. Additionally, the diagnosis is often delayed and only considered after several courses of antibacterial therapy have been (wrongly) prescribed [6,7]. Despite the geographic expansion of these pathogens, they are not required to be reported in most states further complicating our understanding of the burden of these agents. no caption availableThe typical treatments for histoplasmosis treatment have not changed in over two decades, but that stability may be challenged in the coming years. Many persons with mild acute pulmonary disease or evidence of previous or dormant histoplasmosis do not require treatment [8-11]. The standard treatment for moderate to severe acute pulmonary histoplasmosis remains liposomal amphotericin B (LAmb, 3-5 mg/kg/daily intravenously) for 1-2 weeks followed by itraconazole 200 mg three times daily for three days then twice daily for 12 weeks and adjunct corticosteroids are used in some cases [8]. This is primarily based on case reports [8,12]. More mild disease can treated with itraconazole only at the same dose, if necessary [13,14]. Therapeutic drug monitoring is advised due to difficulty with absorption [15]. In severe acute disease, corticosteroids are sometimes used to improve hypoxemia [15].Disseminated histoplasmosis is treated similarly (LAmb followed by itraconazole) but treatment is always required [8]. Johnson et al. conducted a randomized double-blind trial comparing LAmb with amphotericin B deoxycholate (AmBD) and found lower mortality (2% vs. 13%) in those that received liposomal amphotericin B, establishing LAmb as the preferred initial agent [16]. Recently, Pasqualotto et al. conducted an open-label randomized trial and found that among 118 participants, a single dose of LAmb (10 mg/kg) on day 1 appeared to be noninferior to standard LAmb treatment - both arms were followed by standard itraconazole dosing [17]. A larger, phase three trial is planned to confirm these findings and further evaluate efficacy and toxicity. Mild disseminated disease can be treated with itraconazole alone and all disseminated disease requires at least 12 months of itraconazole and ideally documentation of resolution of antigenuria and/or antigenemia (when available) [8,18-20].Histoplasmosis includes a number of other syndromes where the same principles of treatment involving itraconazole for more mild disease requiring treatment and LAmb up-front for more severe (including central nervous system (CNS)) or chronic disease apply [8]. Although often used as 'step-down' therapy for CNS disease, itraconazole's CNS penetration is poor. Thus, an alternative azole could theoretically be preferable, though evidence is limited. The most compelling candidate is isavuconazole which has low in vitro minimum inhibitory concentrations (MICs) in Histoplasma isolates from patients who failed treatment with fluconazole as opposed to voriconazole which had high MICs - both have good CNS penetration [21-26]. In a 2023 systematic review of CNS histoplasmosis, mortality was 12% (9/73) in those treated with itraconazole and 20% (3/15) in those treated with voriconazole [27]. Although the P value for the comparison was 0.43, it's difficult to say whether or not there is a true difference in efficacy based on this data, particularly given the sample size and lack of correction for potential confounders.Posaconazole has low MICs in the same isolates mentioned in relation to isavuconazole above from persons with CNS histoplasmosis and clinical success has been reported, although CNS penetration is low [22,28,29]. Ultimately, evidence is scant and itraconazole is typically used as step-down therapy in most CNS histoplasmosis cases. Of note, super bioavailability (SUBA)-itraconazole is now FDA approved for histoplasmosis but neither formulation is approved for CNS disease where it has not been prospectively studied [30]. Purpose of reviewThe endemic fungi are a significant cause of morbidity and mortality in effected patients. The range of endemicity for these are expanding with infections observed outside of traditional locations. Enhanced diagnostic and treatment practices may significantly alter patient outcomes.Recently completed clinical trials have focused on an assessment of improving efficacy while minimizing patient toxicity. Practice changing trials have been completed in histoplasmosis showing the utility of a single up-front liposomal amphotericin B dose followed by standard itraconazole dosing. The recent evaluation of several antifungal options including isauvconazole in the treatment of coccidioidomycosis also show promise for additional therapeutic agents. A recently conducted trial has also shown the superiority of amphotericin B therapy over itraconazole in the treatment of talaromycosis.The increased range of endemic mycoses coupled with the growing immunocompromised patient population mandates continued investigation of improved diagnostic and therapeutic options. Advances in these areas have led to more rapid diagnosis and more efficacious antifungal therapy.Papers of particular interest, published within the annual period of review, have been highlighted as:The endemic mycoses are a diverse group of fungal pathogens that share several key characteristics. Each occupies a specific ecological niche in the environment and is able to cause disease in otherwise healthy hosts. The agents in this review, Blastomyces, Coccidioides, Histoplasma, Sporothrix, and Talaromyces marneffei are each increasingly recognized, and climatic events have been associated with geographic expansion and a higher number of cases per year for many of these organisms. Changes in the in vitro susceptibility profiles of these agents have also been recently reported [1], necessitating the search for alternative or new antifungal agents in an attempt to optimize patient outcomes.Severe disease caused by the endemic mycoses is treated with an amphotericin B formulation (lipid agents are preferred) followed by triazole agents. Each of these agents possess unique pharmacokinetic and toxicity profiles that require a thorough understanding by the prescribing practitioner. The triazoles are teratogens and should not be used in the first trimester, while each also exhibits variable effects on the CYP450 system resulting in potential hepatotoxicity and/or drug-drug interactions. Fluconazole causes dose-dependent alopecia, xerosis, and cheilitis [2]. Itraconazole may cause gastritis, peripheral edema and is a negative inotrope potentially resulting in heart failure. Voriconazole may cause photosensitivity, photopsia, fluorosis, or encephalopathy [3,4], while posaconazole may cause hypertension or electrolyte disturbance [5]. Isavuconazole may similarly cause electrolyte disturbance or infusion reactions. The fungistatic nature of currently available oral antifungals mandates long courses of therapy for most of the endemic mycoses, and these durations allow cumulative toxicities which may contribute to less than desirable treatment tolerability and outcomes. Additionally, the diagnosis is often delayed and only considered after several courses of antibacterial therapy have been (wrongly) prescribed [6,7]. Despite the geographic expansion of these pathogens, they are not required to be reported in most states further complicating our understanding of the burden of these agents. no caption availableThe typical treatments for histoplasmosis treatment have not changed in over two decades, but that stability may be challenged in the coming years. Many persons with mild acute pulmonary disease or evidence of previous or dormant histoplasmosis do not require treatment [8-11]. The standard treatment for moderate to severe acute pulmonary histoplasmosis remains liposomal amphotericin B (LAmb, 3-5 mg/kg/daily intravenously) for 1-2 weeks followed by itraconazole 200 mg three times daily for three days then twice daily for 12 weeks and adjunct corticosteroids are used in some cases [8]. This is primarily based on case reports [8,12]. More mild disease can treated with itraconazole only at the same dose, if necessary [13,14]. Therapeutic drug monitoring is advised due to difficulty with absorption [15]. In severe acute disease, corticosteroids are sometimes used to improve hypoxemia [15].Disseminated histoplasmosis is treated similarly (LAmb followed by itraconazole) but treatment is always required [8]. Johnson et al. conducted a randomized double-blind trial comparing LAmb with amphotericin B deoxycholate (AmBD) and found lower mortality (2% vs. 13%) in those that received liposomal amphotericin B, establishing LAmb as the preferred initial agent [16]. Recently, Pasqualotto et al. conducted an open-label randomized trial and found that among 118 participants, a single dose of LAmb (10 mg/kg) on day 1 appeared to be noninferior to standard LAmb treatment - both arms were followed by standard itraconazole dosing [17]. A larger, phase three trial is planned to confirm these findings and further evaluate efficacy and toxicity. Mild disseminated disease can be treated with itraconazole alone and all disseminated disease requires at least 12 months of itraconazole and ideally documentation of resolution of antigenuria and/or antigenemia (when available) [8,18-20].Histoplasmosis includes a number of other syndromes where the same principles of treatment involving itraconazole for more mild disease requiring treatment and LAmb up-front for more severe (including central nervous system (CNS)) or chronic disease apply [8]. Although often used as 'step-down' therapy for CNS disease, itraconazole's CNS penetration is poor. Thus, an alternative azole could theoretically be preferable, though evidence is limited. The most compelling candidate is isavuconazole which has low in vitro minimum inhibitory concentrations (MICs) in Histoplasma isolates from patients who failed treatment with fluconazole as opposed to voriconazole which had high MICs - both have good CNS penetration [21-26]. In a 2023 systematic review of CNS histoplasmosis, mortality was 12% (9/73) in those treated with itraconazole and 20% (3/15) in those treated with voriconazole [27]. Although the P value for the comparison was 0.43, it's difficult to say whether or not there is a true difference in efficacy based on this data, particularly given the sample size and lack of correction for potential confounders.Posaconazole has low MICs in the same isolates mentioned in relation to isavuconazole above from persons with CNS histoplasmosis and clinical success has been reported, although CNS penetration is low [22,28,29]. Ultimately, evidence is scant and itraconazole is typically used as step-down therapy in most CNS histoplasmosis cases. Of note, super bioavailability (SUBA)-itraconazole is now FDA approved for histoplasmosis but neither formulation is approved for CNS disease where it has not been prospectively studied [30]. Purpose of reviewThe endemic fungi are a significant cause of morbidity and mortality in effected patients. The range of endemicity for these are expanding with infections observed outside of traditional locations. Enhanced diagnostic and treatment practices may significantly alter patient outcomes.Recently completed clinical trials have focused on an assessment of improving efficacy while minimizing patient toxicity. Practice changing trials have been completed in histoplasmosis showing the utility of a single up-front liposomal amphotericin B dose followed by standard itraconazole dosing. The recent evaluation of several antifungal options including isauvconazole in the treatment of coccidioidomycosis also show promise for additional therapeutic agents. A recently conducted trial has also shown the superiority of amphotericin B therapy over itraconazole in the treatment of talaromycosis.The increased range of endemic mycoses coupled with the growing immunocompromised patient population mandates continued investigation of improved diagnostic and therapeutic options. Advances in these areas have led to more rapid diagnosis and more efficacious antifungal therapy.Papers of particular interest, published within the annual period of review, have been highlighted as:The endemic mycoses are a diverse group of fungal pathogens that share several key characteristics. Each occupies a specific ecological niche in the environment and is able to cause disease in otherwise healthy hosts. The agents in this review, Blastomyces, Coccidioides, Histoplasma, Sporothrix, and Talaromyces marneffei are each increasingly recognized, and climatic events have been associated with geographic expansion and a higher number of cases per year for many of these organisms. Changes in the in vitro susceptibility profiles of these agents have also been recently reported [1], necessitating the search for alternative or new antifungal agents in an attempt to optimize patient outcomes.Severe disease caused by the endemic mycoses is treated with an amphotericin B formulation (lipid agents are preferred) followed by triazole agents. Each of these agents possess unique pharmacokinetic and toxicity profiles that require a thorough understanding by the prescribing practitioner. The triazoles are teratogens and should not be used in the first trimester, while each also exhibits variable effects on the CYP450 system resulting in potential hepatotoxicity and/or drug-drug interactions. Fluconazole causes dose-dependent alopecia, xerosis, and cheilitis [2]. Itraconazole may cause gastritis, peripheral edema and is a negative inotrope potentially resulting in heart failure. Voriconazole may cause photosensitivity, photopsia, fluorosis, or encephalopathy [3,4], while posaconazole may cause hypertension or electrolyte disturbance [5]. Isavuconazole may similarly cause electrolyte disturbance or infusion reactions. The fungistatic nature of currently available oral antifungals mandates long courses of therapy for most of the endemic mycoses, and these durations allow cumulative toxicities which may contribute to less than desirable treatment tolerability and outcomes. Additionally, the diagnosis is often delayed and only considered after several courses of antibacterial therapy have been (wrongly) prescribed [6,7]. Despite the geographic expansion of these pathogens, they are not required to be reported in most states further complicating our understanding of the burden of these agents. no caption availableThe typical treatments for histoplasmosis treatment have not changed in over two decades, but that stability may be challenged in the coming years. Many persons with mild acute pulmonary disease or evidence of previous or dormant histoplasmosis do not require treatment [8-11]. The standard treatment for moderate to severe acute pulmonary histoplasmosis remains liposomal amphotericin B (LAmb, 3-5 mg/kg/daily intravenously) for 1-2 weeks followed by itraconazole 200 mg three times daily for three days then twice daily for 12 weeks and adjunct corticosteroids are used in some cases [8]. This is primarily based on case reports [8,12]. More mild disease can treated with itraconazole only at the same dose, if necessary [13,14]. Therapeutic drug monitoring is advised due to difficulty with absorption [15]. In severe acute disease, corticosteroids are sometimes used to improve hypoxemia [15].Disseminated histoplasmosis is treated similarly (LAmb followed by itraconazole) but treatment is always required [8]. Johnson et al. conducted a randomized double-blind trial comparing LAmb with amphotericin B deoxycholate (AmBD) and found lower mortality (2% vs. 13%) in those that received liposomal amphotericin B, establishing LAmb as the preferred initial agent [16]. Recently, Pasqualotto et al. conducted an open-label randomized trial and found that among 118 participants, a single dose of LAmb (10 mg/kg) on day 1 appeared to be noninferior to standard LAmb treatment - both arms were followed by standard itraconazole dosing [17]. A larger, phase three trial is planned to confirm these findings and further evaluate efficacy and toxicity. Mild disseminated disease can be treated with itraconazole alone and all disseminated disease requires at least 12 months of itraconazole and ideally documentation of resolution of antigenuria and/or antigenemia (when available) [8,18-20].Histoplasmosis includes a number of other syndromes where the same principles of treatment involving itraconazole for more mild disease requiring treatment and LAmb up-front for more severe (including central nervous system (CNS)) or chronic disease apply [8]. Although often used as 'step-down' therapy for CNS disease, itraconazole's CNS penetration is poor. Thus, an alternative azole could theoretically be preferable, though evidence is limited. The most compelling candidate is isavuconazole which has low in vitro minimum inhibitory concentrations (MICs) in Histoplasma isolates from patients who failed treatment with fluconazole as opposed to voriconazole which had high MICs - both have good CNS penetration [21-26]. In a 2023 systematic review of CNS histoplasmosis, mortality was 12% (9/73) in those treated with itraconazole and 20% (3/15) in those treated with voriconazole [27]. Although the P value for the comparison was 0.43, it's difficult to say whether or not there is a true difference in efficacy based on this data, particularly given the sample size and lack of correction for potential confounders.Posaconazole has low MICs in the same isolates mentioned in relation to isavuconazole above from persons with CNS histoplasmosis and clinical success has been reported, although CNS penetration is low [22,28,29]. Ultimately, evidence is scant and itraconazole is typically used as step-down therapy in most CNS histoplasmosis cases. Of note, super bioavailability (SUBA)-itraconazole is now FDA approved for histoplasmosis but neither formulation is approved for CNS disease where it has not been prospectively studied [30].