Background: Visceral Leishmaniasis (VL), a severe systemic parasitic disease caused by Leishmania species, can be complicated by secondary Hemophagocytic Lymphohistiocytosis (HLH). HLH is a life-threatening hyperinflammatory syndrome characterized by excessive immune activation that results in multiorgan dysfunction. The co-occurrence of VL and HLH in adults is a rare but critical diagnostic and therapeutic challenge, often leading to fatal outcomes if treatment is delayed. Case Presentation: We present two cases of adult males (60 and 72 years old) from Greece, an endemic area for L. infantum, who presented with prolonged fever, pancytopenia, hepatosplenomegaly, and impaired liver function. Both patients exhibited extremely elevated ferritin (all > 2000 ng/mL and one > 20,000 ng/mL) and hypertriglyceridemia, fulfilling key laboratory criteria for HLH. Diagnosis was confirmed by the visualization of Leishmania amastigotes in bone marrow aspirates, which also demonstrated features of hemophagocytosis. Case 1, critically ill with acute kidney injury and coagulopathy, required combined treatment with liposomal Amphotericin B and immunoglobulin therapy for HLH. Case 2, who showed rapid and “spectacular improvement” solely after receiving liposomal Amphotericin B, did not require HLH-specific immunosuppression. Conclusions: VL-associated HLH should be considered in adult patients presenting with complex systemic inflammation, fever, and cytopenias, particularly in endemic settings. Our cases illustrate that the prompt initiation of anti-leishmanial therapy with liposomal Amphotericin B can be sufficient to reverse the HLH syndrome by eliminating the infectious trigger. However, intensive immunomodulation may be necessary in patients presenting with critical multi-organ failure.

Skin pharmacokinetics and pharmacodynamics in patients with post-kala-azar dermal leishmaniasis.

Pharmacokinetic Equivalence of AmphosomTM, a Newly Developed Liposomal Amphotericin B, to AmbisomeⓇ.

Cutaneous diseases in returning travelers encompass a wide spectrum of etiologies and often pose diagnostic challenges. We present the cases of a 50-year-old man and a 57-year-old woman who presented with a 3-month history of erythematous, ulcerated plaques with well-defined elevated borders and a necrotic center on the lower limbs that began 3 weeks after returning from vacation in Costa Rica. Cutaneous biopsy revealed epidermal ulceration and extensive caseating granulomas throughout the full thickness of the dermis. Giemsa staining revealed no amastigotes. Microbiological examinations identified Leishmania braziliensis and excluded mycobacteria and fungi. The diagnosis of cutaneous leishmaniasis was established. Owing to clinical severity and antimonial unavailability, the man was treated with liposomal amphotericin B. The woman underwent surgical excision of the single lesion, along with oral fluconazole. Complete resolution was documented in both patients. These cases, which posed diagnostic and therapeutic challenges, highlight that cutaneous leishmaniasis, in all its versatile and often perplexing presentations, is a parasitic infection that should always be considered in dermatologic patients returning from vacation in endemic countries.

Cryptococcal meningitis (CM) is a significant cause of mortality and morbidity in people with HIV. Standard induction therapy for CM-amphotericin with flucytosine-is associated with significant toxic effects. To assess mortality and CM recurrence outcomes of the AMBITION protocol (single-dose liposomal amphotericin with 2 weeks of fluconazole and flucytosine) for treatment of CM in a high-resource setting. This pre-post cohort study conducted at Los Angeles General Medical Center, a large safety net hospital (80% Medicaid-covered, 5% uninsured), included people with HIV treated for CM with the AMBITION protocol from August 1, 2022, to July 31, 2024, and a control population receiving a guideline-compliant, daily amphotericin-based regimen from August 1, 2020, to July 31, 2022. Exclusion criteria included age less than 18 years, alternative diagnosis, transfer during induction, and death within 48 hours of admission. AMBITION protocol with single infusion of liposomal amphotericin (10 mg/kg) and 14 days of high-dose fluconazole (1200 mg/d) and flucytosine (100 mg/kg/d). The control group was treated with lipid-based amphotericin (3-5 mg/kg/d) and flucytosine (100 mg/kg/d) for 14 days. The primary end point was treatment success, defined as a composite of survival without recurrence or severe adverse events at 90 days. A total of 60 eligible patient episodes were identified during the study period (54 [90.0%] among males; median patient age, 40 [IQR, 34-51] years). In all, 34 patients (56.7%) were treated with the AMBITION protocol, compared with 26 (43.3%) receiving the control regimen. Loss to follow-up by 90 days occurred in 6 patients in the control group (23.1%) and 9 intervention patients (26.5%) (P = .76). Of patients with available data, the composite outcome occurred in 19 of 25 patients receiving the AMBITION protocol (76.0%) compared with 7 of 20 patients in the control group (35.0%) (P = .006). The difference in composite outcome rates was driven by fewer severe adverse events in the AMBITION arm (7 [20.6%] vs 16 [61.5%]; P = .001). Additionally, patients receiving the AMBITION protocol had fewer patient-directed discharges (4 [11.8%] vs 9 [34.6%]; P = .03). In this pre-post study of HIV-associated CM, fewer severe adverse effects were seen in patients receiving the AMBITION protocol compared with a daily amphotericin-based regimen, with no difference in mortality or recurrence. There were also fewer patient-directed discharges, suggesting more patient-centered care. These findings support broader adoption of the AMBITION protocol in high-resource settings.

Intracranial Candida Auris Infection: A Case Report and Scoping Review.

Scedosporium apiospermum is an opportunistic fungal pathogen that causes various infections in immunocompromised patients. Voriconazole is the first-line treatment; however, its clinical use is often challenging due to complex pharmacokinetics and significant interpatient variability, primarily driven by polymorphisms in the CYP450 (CYP2C19) enzymes. These genetic variations affect drug metabolism, resulting in suboptimal drug levels or increased toxicity. We present a case of atraumatic localized Scedosporium apiospermum mycetoma on the back of a patient with a renal transplant. The patient underwent surgical excision and was initiated on voriconazole with a loading dose of 400 mg (6 mg/kg) every 12 h on day one, followed by 200 mg every 12 h (4 mg/kg twice daily). Despite dose adjustments, voriconazole serum levels remained persistently sub-therapeutic. Pharmacokinetic and pharmacogenetic studies were conducted for further evaluation. Pharmacokinetic analysis revealed a shortened voriconazole half-life. Pharmacogenetic testing identified a CYP2C19 *1/*17 genotype, indicating a rapid metaboliser phenotype. This resulted in accelerated drug metabolism, low serum levels and an increased risk of treatment failure and disease progression. Alternative agents to voriconazole, independent of CYP2C19 (isavuconazole, liposomal amphotericin B or posaconazole) were recommended for current and future therapy. Pharmacogenetic and pharmacokinetic testing may play a role in optimizing antifungal therapy. CYP2C19 polymorphisms significantly affect voriconazole metabolism. Patients that are poor metabolisers have greater drug exposure compared with rapid metabolisers. Genotyping may help guide dosage adjustments, predict potential drug interactions and improve treatment efficacy whilst reducing adverse effects. The integration of pharmacogenomic testing, along with therapeutic drug monitoring (TDM), can enhance individualized therapy for both antifungal treatment and prophylaxis in complex clinical scenarios.

Diagnostic and therapeutic capacity for fungal infections in Colombia: An ESCMID-EFISG nationwide multicenter assessment of mycological healthcare.

How to interpret MICs of amphotericin B, echinocandins and flucytosine against Candida auris (Candidozyma auris) according to the newly established European Committee for Antimicrobial Susceptibility Testing (EUCAST) breakpoints.

The present case describes a 42-year-old previously healthy male who presented with two weeks of dull epigastric pain, nausea, and melena. On examination, he was pale but haemodynamically stable. Laboratory evaluation revealed iron deficiency anaemia, while other haematological, renal, and liver parameters were within normal limits. Upper gastrointestinal endoscopy demonstrated two large antral ulcers with irregular margins, necrotic bases, and surrounding mucosal oedema. Histopathology confirmed gastric mucormycosis, showing broad aseptate fungal hyphae with right-angle branching, highlighted by Periodic Acid-Schiff (PAS) and Grocott’s Methenamine Silver (GMS) staining. The patient was treated with intravenous liposomal amphotericin B (5 mg/kg/day) for 21 days, followed by oral posaconazole (300 mg daily) for six weeks. Clinical improvement occurred within 10 days. Followup endoscopy at three months showed complete ulcer healing, and at six months, the patient remained asymptomatic with no evidence of recurrence. The present case emphasises that gastric mucormycosis, although rare, can occur in immunocompetent individuals. Early endoscopic biopsy and prompt initiation of antifungal therapy are crucial, and selected cases may achieve successful outcomes with medical management alone, without surgical intervention.

Primary cutaneous aspergillosis is a rare fungal infection in extremely preterm neonates. We report a male infant born at 25+5 weeks' gestation who developed necrotic lesions at the site of an umbilical catheter covered with an occlusive dressing. Culture confirmed Aspergillus fumigatus, and systemic liposomal amphotericin B combined with local enzymatic debridement and a non-adherent silicone wound contact layer was initiated after receipt of the culture result. The lesions resolved completely, leaving only a fine residual scar without functional impairment.This case emphasises the importance of early recognition, culture-based diagnosis and timely antifungal therapy in preterm neonates with catheter-related skin lesions, even when standard antifungal prophylaxis has been administered.

Cryptococcosis in kidney transplant recipients: Pathogenesis, clinical challenges, and evolving therapeutic strategies.

A 56-year old immuno-competent male from a non-endemic region in India presented with progressive weight loss, hoarseness of voice and widespread cutaneous lesions, including leonine facies, genital nodules and diffuse scaling. Magnetic resonance imaging of the neck revealed oedematous thickening of the false vocal cords, epiglottis and aryepiglottic folds, suggesting laryngeal involvement. All routine investigations were normal. Urine Histoplasma antigen levels were markedly elevated. Skin biopsy revealed granulomatous inflammation with intracellular yeast-like organisms, and polymerase chain reaction confirmed Histoplasma capsulatum DNA. A diagnosis of disseminated histoplasmosis with probable laryngeal involvement was made. The patient responded well to liposomal amphotericin B followed by itraconazole for 12 months. Although histoplasmosis commonly affects immunocompromised individuals, its rising incidence in immuno-competent patients from non-endemic regions necessitates greater clinical vigilance and emphasises the role of dermatological assessment and targeted fungal testing in systemic mycoses.

Candidemia is a leading cause of invasive fungal infections, with an increased incidence of non-Candida species and resistance. However, pediatric epidemiologic data remain limited. Multicenter retrospective study analyzing epidemiologic and clinical variables in neonates and children (≤14 years) with candidemia identified by positive blood cultures across 6 tertiary hospitals in southern Spain (2010-2020). A total of 286 cases were identified. Sixty-one percent of patients were admitted to intensive care units. The incidence rates in the neonatal and pediatric intensive care units were 3.2/1000 and 2.5/1000 admissions, respectively. Prematurity was the most common underlying condition (29.4%), followed by onco-hematologic conditions (20.6%) and congenital heart diseases (15%), with 81% of them infected during the perioperative cardiac surgery. Candida parapsilosis was the most prevalent species (46.5%), with fluconazole resistance <1% but echinocandin resistance 8.4-28.6%. Candida albicans (33.6%) remained highly susceptible to all antifungals. Ninety-five percent of the Candida species were susceptible to fluconazole. Empirical treatment included liposomal amphotericin B (57.6%), fluconazole (30.3%) and echinocandins (7.4%), and targeted therapy with fluconazole was prescribed in only 30% of the cases. Recurrence occurred in 17.2% of cases, more frequently with C. parapsilosis (P = 0.025), parenteral nutrition (P = 0.004) and congenital heart disease (P < 0.001). Mortality was 22.3%, associated with recurrent candidemia (P = 0.009), thrombocytopenia (P = 0.037) and absence of antifungal prophylaxis (P = 0.035). High incidence of C. parapsilosis with the greatest recurrence risk was observed in Southern Spain, with a high overall mortality. Low fluconazole resistance supports the need to optimize targeted therapy and enhance the importance of antimicrobial stewardship programs.

Saksenaea vasiformis is a rare, opportunistic Mucorales fungus capable of causing rapidly progressive cutaneous and subcutaneous infections, including necrotising fasciitis. Early diagnosis is challenging due to its poor sporulation on routine media and often subtle initial clinical features. We describe a case of a soft-tissue infection in a co-morbid 75-year-old man from rural Australia with limited healthcare engagement. Despite broad-spectrum antibacterial therapy, operative intervention and negative-pressure wound-therapy, the wound continued to deteriorate. Eventually, sequencing of the internal transcribed spacer region confirmed S. vasiformis. The patient was commenced on liposomal amphotericin B followed by prolonged oral itraconazole due to underlying renal impairment and geographic barriers to ongoing inpatient care. This case underscores the need for early suspicion of atypical fungal pathogens in necrotic soft-tissue infections unresponsive to antibacterial therapy and highlights the importance of prompt surgical management, infectious diseases input, specialised fungal diagnostics and tailored antifungal treatment.

Parathyridaria percutanea is a rare melanized fungus causing subcutaneous phaeohyphomycosis, previously reported only in renal transplant recipients. We report the first fatal case in a liver transplant (LT) recipient. A 58-year-old Somali woman developed a right foot fungating mass 10 months post-LT during intensive immunosuppression for multiple episodes of T-cell-mediated and antibody-mediated rejection (high-dose corticosteroids, antithymocyte globulin, plasmapheresis). Cultures of drainage and subsequent operative deep-tissue cultures grew Enterococcus faecalis and Finegoldia species, together with a non-sporulating filamentous mould. Despite empiric antifungals, infection progressed proximally in sporotrichoid pattern. Molecular identification using DNA sequencing of ITS and D1/D2 regions identified P. percutanea after three weeks. Treatment with liposomal amphotericin B/voriconazole was complicated by acute kidney injury requiring amphotericin discontinuation. Despite antifungal therapy and surgical debridement, the patient developed progressive encephalopathy and allograft dysfunction, resulting in death. This first fatal P. percutanea infection following LT highlights the importance of early molecular diagnostics for non-sporulating filamentous fungi in immunocompromised hosts and management challenges under intensive immunosuppression. Not applicable.

Filamentous soil moulds such as Saksenaea and Fusarium are angioinvasive fungi responsible for severe disseminated infections. Saksenaea causes zygomycosis, with disseminated cases having over ninety percent mortality. Fusarium, a hyphomycetes mould, can also cause disseminated infections in immunocompromised individuals, with high mortality. We describe the case of a normally healthy 20-year-old male who survived major traumatic injuries resulting from an aviation incident. He subsequently developed disseminated cutaneous zygomycetes (Saksenaea) and Fusarium infection with associated immunosuppression, multiorgan dysfunction and sepsis. Treatment strategies included repeated and extensive surgical debridement (inferior orbital region to carotid sheath in the neck, to a depth of buccal mucosa and zygomatic bone in the cheek), antifungal agents including intravenous (IV) liposomal amphotericin B and voriconazole, and IV immunoglobulin and granulocyte colony stimulating factor. Despite maximal medical and surgical treatment, disease control was not achieved. After multi-specialty consensus that current management had failed to control the disease process, hyperbaric oxygen treatment (HBOT) was added to standard therapy on an experimental basis based on several case reports, pathophysiological rationale, and institutional experience with angioinvasive Mucor. The patient was on venovenous extracorporeal membrane oxygenation for all HBOT sessions; details are reported separately. Thirteen treatment sessions (243 kPa [2.4 atmospheres absolute], 95 min) were successfully delivered. Local and systemic disease control was achieved within several days of commencing HBOT, and after a prolonged period of rehabilitation and reconstruction, the patient was discharged home. We conclude that HBOT may have an important role in the management of angioinvasive fungal disease.

Cutaneous leishmaniasis (CL) is a parasitic disease endemic to the Americas, with a high prevalence in Peru. In resource-limited settings where liposomal amphotericin B is often unavailable, amphotericin B deoxycholate (AmB-d) remains a second-line option. However, data on its safety and effectiveness in children are scarce. This study describes the clinical experience of 20 paediatric patients with CL treated with AmB-d in a referral centre in Peru. We conducted a retrospective descriptive study of patients ≤14 years with confirmed localised CL who had failed parental sodium stibogluconate (Sb5+ IM/IV) treatment and received intravenous AmB-d at Hospital Cayetano Heredia (Peru) between January 2000 and December 2007. Patients received daily treatment until all lesions met the early cure criteria, defined as complete reepithelialization at the time of discharge. We collected demographic, clinical, and laboratory data, including the mean daily dose, cumulative dose, and adverse events (AEs). We included 20 patients with a mean age of 4.9 years (±3.7), and 90% had lesions on the face. Nineteen patients (95%) completed treatment and achieved early clinical cure. Mean cumulative dose was 19.8 mg/kg (±5.7) and mean treatment duration was 28.8 days (±7.1). A total of 63.2% (12/19) of patients achieved clinical cure with a cumulative dose below 20mg/kg, and 84.2% with a dose below 25 mg/kg. Systemic adverse events (AEs), including fever (90%) and anorexia (70%), occurred mainly between the second and third weeks of treatment (83%). Six patients (30%) developed an increase in serum creatinine and nine (45%) developed hypokalemia. Intravenous amphotericin B deoxycholate (AmB-d) is an effective and well-tolerated second-line treatment for paediatric American CL unresponsive to Sb5+ treatment. Despite the need for high cumulative doses, prolonged treatment durations, and frequent AEs, side effects were mild to moderate, transient, and did not lead to treatment discontinuation.

ABSTRACTRhino‐orbital‐cerebral mucormycosis (ROCM) is a rare but highly lethal fungal infection that typically occurs in patients with classical immunosuppressive states. This report presents a case of ROCM in a 27‐year‐old male whose sole systemic risk factor was chronic Hepatitis B (HBV) and Hepatitis D (HDV) coinfection. The patient presented with advanced disease, including nasal necrosis and progressive periorbital swelling. Advanced imaging revealed extensive intraorbital and intracranial invasion with significant mass effect, a finding that rendered the standard‐of‐care surgical debridement prohibitively high risk. A definitive diagnosis was established via histopathology. Consequently, a deliberate decision was made to proceed with exclusive medical management. The patient was treated successfully with high‐dose intravenous liposomal amphotericin B monotherapy, resulting in a favorable clinical outcome. This case establishes chronic viral hepatitis as a significant non‐classical risk factor for ROCM and provides critical evidence that aggressive medical monotherapy can serve as a definitive, life‐saving treatment when the standard bimodal surgical approach is contraindicated.

Cutaneous leishmaniasis (CL) is a protozoan parasitic infection caused by the Leishmania species and transmitted through the bite of infected sandflies. The disease is endemic in tropical, subtropical, and Mediterranean regions, where it presents as localized skin ulcers, often leaving scars that can lead to significant morbidity and social stigma. This review focuses on the etiopathogenesis, epidemiology, clinical features, management strategies, and research gaps in CL. Understanding the complex immune response involved in the pathogenesis of CL, as well as the environmental and socio-economic factors driving its spread, is critical for designing effective control measures. Clinical presentation varies from simple ulcers to more complex forms like mucocutaneous leishmaniasis. Management primarily involves antimicrobial therapy, with treatments such as miltefosine, antimony compounds, and liposomal amphotericin B being the mainstay, although drug resistance is emerging as a significant challenge. Research gaps remain in the development of effective vaccines, better diagnostic tools, and alternative treatments. Addressing these gaps will improve patient health outcomes and facilitate the elimination of CL in endemic regions.