Currently, the first-line drugs for invasive fungal infections (IFI), such as amphotericin B, fluconazole and itraconazole, have drawbacks including poor water solubility, low bioavailability, and severe side effects. Using drug delivery systems is a promising strategy to improve the efficacy and safety of traditional antifungal therapy. Synthetic and biomimetic carriers have greatly facilitated the development of targeted delivery systems for antifungal drugs. Synthetic carrier drug delivery systems, such as liposomes, nanoparticles, polymer micelles, and microspheres, can improve the physicochemical properties of antifungal drugs, prolong their circulation time, enhance targeting capabilities, and reduce toxic side effects. Cell membrane biomimetic drug delivery systems, such as macrophage or red blood cell membrane-coated drug delivery systems, retain the membrane structure of somatic cells and confer various biological functions and specific targeting abilities to the loaded antifungal drugs, exhibiting better biocompatibility and lower toxicity. This article reviews the development of antifungal drug delivery systems and their application in the treatment of IFI, and also discusses the prospects of novel biomimetic carriers in antifungal drug delivery.
Antifungal Agents/therapeutic use* ; Drug Delivery Systems ; Amphotericin B/therapeutic use* ; Liposomes/chemistry* ; Nanoparticles ; Drug Carriers

Objective:b> To investigate the clinical manifestations, treatments, and prognosis of pediatric patients with Talaromyces marneffei infection. Methods:b> In this retrospective study, 7 children diagnosed with Talaromyces marneffei infection in Shenzhen Children's Hospital from July 2017 to October 2021 were recruited. The clinical features, radiology, pathogen detection, immunological evaluation, treatments, and prognosis were analyzed. Results:b> In 7 cases, 5 were male, 2 were females. The age was from 0.75 to 8.75 years. The main clinical manifestations were fever in 7 cases, cough in 6 cases, malnutrition in 4 cases, papules in 2 cases and medical history of recurrent infection in 3 cases. Physical examination showed that all 7 patients had hepatosplenomegaly, 4 had superficial lymphadenopathy. Laboratory examination showed that 6 cases had decreased hemoglobin and 3 cases had decreased platelet. Chest CT showed that 4 cases had patchy shadows, pleural effusion, mediastinal or axillary lymph node enlargement, 3 had nodular shadows and 2 had cavities. The positive ratio of Talaromyces marneffei culture was 2/2 with tissue samples, 4/5 with bone marrow. The positive ratio was 3/4 by metagenomic next generation sequencing. The fungus was detected in 3 cases by smear microscopy of bone marrow and (or) peripheral blood. All patients were negative for human immunodeficiency virus by the immune function assay. However, 5 cases were confirmed as primary immunodeficiency disease, including 2 cases with high IgM syndrome, 2 with STAT1 gene variation, and the last with severe combined immunodeficiency (IL2RG gene variation). Exclude 1 case which gave up treatment due to acute intracranial infection, and the other patients received effective treatments along with amphotericin B, voriconazole, and itraconazole alone or in combination. Two cases relapsed after medication withdrawal, but 1 case got complete rehabilitation after hematopoietic stem cell transplantation. Conclusions:b> The clinical manifestations involve multisystem, the common charateristics are fever and cough. The chest CT imaging manifestations are diverse, it should be considered in differentiating tuberculosis. The amphotericin B, voriconazole and itraconazole are effective, but it will easily relapse when withdrawing those antifungal agents.
Amphotericin B/therapeutic use* ; Antifungal Agents/therapeutic use* ; Child ; Child, Preschool ; Cough ; Female ; Fever ; Humans ; Infant ; Itraconazole/therapeutic use* ; Male ; Mycoses ; Retrospective Studies ; Talaromyces ; Voriconazole

Objective:b> To investigate the clinical features, diagnosis,treatment and prognosis of children with acute lymphoblastic leukemia complicated with mucormycosis, and to improve the understanding of the disease. Methods:b> The clinical data of 3 children with acute lymphoblastic leukemia (ALL) complicated with mucormycosis treated at the First Affiliated Hospital of Zhengzhou University between October 2020 and January 2021 were analyzed retrospectively. Literature search and review covered the China national knowledge infrastructure, Wanfang database and Pubmed using the keywords of "acute lymphoblastic leukemia" and "mucormycosis" up to June 2021. Results:b> Case 1, a 12-year-old boy, was diagnosed with ALL, developed fever and chest pain during induction therapy. The Metagenomic next-generation sequencing (mNGS) testing of alveolar perfusion fluid suggested infection with Rhizopus oryzae. Amphotericin B combined with posaconazole was applied and amphotericin B was removed after improvement. Bone destruction was indicated by CT. Amphotericin B was applied again. Case 2, a 4-year-old boy, with a history of pallor and tetter, was diagnosed with ALL. He developed cough and fever during induction therapy. mNGS of blood suggested infection with Rhizomucor pusillus. Amphotericin B combined with voriconazole was applied, but the situation was not significantly improved. The disseminated infection occurred. Amphotericin B combined with posaconazole was applied and vacuum sealing drainage was performed. Case 3, a 2-year-old girl, was diagnosed with ALL, developed fever and cough during induction therapy. Rhizomucor pusillus was indicated by mNGS. Amphotericin B combined with posaconazole was used, and posaconazole was stopped after improvement. Follow-up until June 2021, the condition of the 3 children improved. There was no recurrent Mucor infection, and the primary hematopathy was in complete remission. According to the literature, 7 reports were found in Chinese journals, while 17 reports were found in English literature, 25 cases have been reported. Among a total of 28 children, 11 cases rhino-orbito-cerebral mucormycosis, four pulmonary mucormycosis, 2 cutaneous mucormycosis, 2 gastrointestinal mucormycosis and 9 disseminated mucormycosis. There were 17 cases developed infection during induction chemotherapy, 8 cases during maintenance therapy, 3 cases after hematopoietic stem cell transplantation. Voriconazole was used in 15 cases; 19 cases were treated with combined surgery, 7 cases were treated with drugs only, 2 cases were untreated; 21 cases showed improvement after treatment. Death occurred in seven cases. Conclusions:b> ALL complicated with mucormycosis often occurs in the stage of induction therapy. The clinical features lacked specificity, mNGS can help find the pathogen and provide evidence for diagnosis. Surgical treatment also could be combined when necessary, which is helpful to improve the prognosis.
Amphotericin B/therapeutic use* ; Antifungal Agents/therapeutic use* ; Child ; Child, Preschool ; Female ; Humans ; Male ; Mucormycosis/drug therapy* ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy* ; Retrospective Studies

We report a case of mucormycosis induced by Cunninghamella spp. infection in a ten-year-old girl with acute lymphoblastic leukemia, who developed fever and respiratory symptoms after chemotherapy and was diagnosed with invasive fungal disease. Peripheral blood DNA sequences were analyzed using metagenomic next-generation sequencing (mNGS), and by comparison with the Pathogens Metagenomics Database (PMDB), we identified Cunninghamella spp. with sequence number 514 as the pathogen. The patient was treated with amphotericin B combined with posaconazole and showed a favorable response. We searched Pubmed, Embase, CNKI, and Wanfang database for reports of cases of Cunninghamella spp. infection in children and retrieved 22 reported cases (including 12 males) with a median age of 13.5 (3-18) years. In these 22 cases, hematological malignancy was the most common underlying condition (19/22), and most of patients experienced an acute onset and rapid progression with respiratory symptoms (14/20) and fever (16/20) as the most common symptoms. CT imaging often showed unilateral lesions with varying imaging findings, including pulmonary nodules or masses, infiltrative changes, and pleural effusion. Definite diagnoses were established in 18 of the cases, and 4 had probable diagnoses; the lungs and skin were the most frequent organs compromised by the infection. A definite diagnosis of Cunninghamella spp. infection still relied on histopathological examination and fungal culture, but the molecular techniques including PCR and mNGS had shown potentials in the diagnosis. Almost all the cases received antifungal treatment after diagnosis (21/22), and 13 patients also underwent surgeries. Death occurred in 9 (42%) of the cases at a median of 19 (4-54) days after onset of the signs or symptoms. The patients receiving antifungal therapy combined with surgery had a high survival rate (9/13, 69%) than those with antifungal therapy alone (3/8, 37%). Invasive fungal disease is a common complication in immunoco-mpromised patients, but Cunninghamella spp. infection is rare and has a high mortality rate. In cases highly suspected of this disease, active diagnosis and early treatment are critical to improve the survival outcomes of the patients.
Adolescent ; Amphotericin B/therapeutic use* ; Antifungal Agents/therapeutic use* ; Child ; Cunninghamella ; Female ; Humans ; Male ; Mucormycosis/etiology*

BACKGROUND: Candida auris was first isolated from the ears of Japanese and Korean patients. However, the prevalence of yeast isolates from ear cultures and their antifungal susceptibility profiles in these nations remain unclear.METHODS: We assessed yeast isolates recovered from ear cultures from a university hospital in Korea over a 4-year period from January 2014 to December 2017. Species identification was performed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and/or sequence analysis. Antifungal minimal inhibitory concentrations (MICs) were determined using the broth microdilution method of the Clinical and Laboratory Standards Institute.RESULTS: Among 81 non-duplicate isolates from ear cultures, Cadida parapsilosis was the most frequently detected yeast species (34.6%), followed by C. auris (28.4%), Candida metapsilosis (9.9%), Candida orthopsilosis (8.6%), Candida albicans (7.4%), and others (11.1%). The MICs of the isolates were 0.125 to > 64 µg/mL, ≤0.03 to 4 µg/mL, 0.25 to 1 µg/mL, 0.125 to 1 µg/mL, and ≤0.03 to 2 µg/mL for fluconazole, voriconazole, amphotericin B, caspofungin, and micafungin, respectively. Of the 81 isolates, 44.4% (36/81) showed decreased susceptibility to fluconazole (MIC ≥4 µg/mL). Of the 23 C. auris isolates, 19 (82.6%) had a fluconazole MIC of ≥32 µg/mL. None of the isolates showed resistance to amphotericin B or echinocandins. Most of these patients suffered from chronic otitis media (84%).CONCLUSION: Candida parapsilosis complex and C. auris were the yeast species identified most frequently from ear cultures and they exhibited a high rate of fluconazole non-susceptibility, particularly C. auris.
Amphotericin B ; Asian Continental Ancestry Group ; Candida ; Candida albicans ; Ear ; Echinocandins ; Fluconazole ; Humans ; Korea ; Mass Spectrometry ; Methods ; Otitis Media ; Prevalence ; Sequence Analysis ; Voriconazole ; Yeasts

OBJECTIVE: To investigate the clinical characteristics, prevention and treatment of invasive fungal disease (IFD). METHODS: The clinical data of 164 patients who met the diagnostic criteria of IFD in our center from January 2012 to January 2015 were retrospectively analyzed. The incidence, clinical characteristics, related factors, treatment methods and prognosis were analyzed. RESULTS: Among 1289 cases of blood diseases, 164 cases suffered from IFD with inciduce of 12.7%. The main infection sites were as followed: lung, blood and gastrointestinal tract, with incidence of 84.2%, 5.5% and 3% respectively. The funge was found in 35 cases by detection; among fungi, the detected rate of candida albicans. aspergillus and candida glabrata was more high with 51.5%, 20% and 14.3% respectively. Among 164 childen with blood deseases complicated by IFD, 36 cases gained complete remission, 97 cases gained partial remission, 10 cases were stable, 11 cases were progressive and 10 cases died, the overall effective rate reached 81.1%. The univariate analysis showed that the gramulopenia, granulocyte recovery, long-term use of corticosteroid and immuno-suppressive agents, as well as different grades of diagnosis were significant factors affecting the efficacy of antifungal therapy for blood disease children with IFD, the multivariate analysis further showed that the granulocyte recovery and diagnosis grades were independent prognostic factors affecting the therapeutic efficacy for IFD children. The overall survival rate of IFD children with 12 weeks of antifungal treatnment was 81.7%, out of which the survival rate of IFD children at 12 weeks of treatment with itraconazole, voriconazole, amphotericin B and caspofungin was 81.4%, 80%, 69.4% and 97.1% respectively, there were significant differences in survival rate between each other by long rank test. In addition of caspofungin, the other 3 kinds of drugs had toxic side effects of different degrees, but IFD children could tolerated these effects after symptomatic treatment. CONCLUSION The incidence of IFD in children with blood deseases in our hospital is 12.7%, the lung is most common infective site, moreover patogens of IFD mainly is candida. The promotion of granulocyte recovery and early stratified diagnosis can contribule to the treatment of IFD. For the IFD children with better economic condition, the caspofungin is a potent antifungal agent with high efficacy, low toxicity and better prognosis.
Amphotericin B ; Antifungal Agents ; Child ; Hematologic Diseases ; etiology ; Humans ; Invasive Fungal Infections ; complications ; Retrospective Studies

Primary amebic encephalitis (PAM) is a devastating central nervous system infection caused by Naegleria fowleri, a free-living amoeba, which can survive in soil and warm fresh water. Here, a 43-year-old healthy male was exposed to warm freshwater 5 days before the symptom onset. He rapidly developed severe cerebral edema before the diagnosis of PAM and was treated with intravenous conventional amphotericin B while died of terminal cerebral hernia finally. Comparing the patients with PAM who has similar clinical symptoms to those with other common types of meningoencephalitis, this infection is probably curable if treated early and aggressively. PAM should be considered in the differential diagnosis of purulent meningoencephalitis, especially in patients with recent freshwater-related activities during the hot season.
Adult ; Amoeba ; Amphotericin B ; Brain Edema ; Central Nervous System Infections ; Central Nervous System Protozoal Infections ; Diagnosis ; Diagnosis, Differential ; Encephalitis ; Encephalocele ; Fresh Water ; Humans ; Male ; Meningoencephalitis ; Naegleria fowleri ; Seasons ; Soil

BACKGROUND: Amphotericin B is used in pediatrics for severe fungal infections despite its known nephrotoxic side effects. Tubular injury and renal vasoconstriction range from 15-58% with exact risk factors that predispose children to developing these complications still undefined. OBJECTIVES: To determine the risk factors for nephrotoxicity with deoxycholate Amphotericin B treatment among children 6 months-18 years old at the Philippine Children‘s Medical Center from 2006-2017 METHODS: This is a retrospective case-control study of 150 patients. Cases had decrease in eGFR by at least 25% and/or developed hypokalemia after at least one dose of Amphotericin. Those who did not develop nephrotoxicity were considered controls. Risk factors evaluated were age, sex, nutritional status, underlying medical condition, cumulative dose, concomitant use of nephrotoxic drugs used, treatment with diuretics and intravenous hydration. Results were analyzed using univariate and multivariate regression models. RESULTS: Using logistic regression, underlying malignancy had the highest odds ratio of 33.1 and nutritional status of z score=0 showed the lowest at 0.158. Duration of treatment >14 days had 1.75 times chance of developing nephrotoxicity while total cumulative dose >7.1 mg/kg had 1.5 times more chance of developing nephrotoxicity. Subjects given diuretics had 5.5 times more odds, while those not given concomitant nephrotoxic medications were 5.33% less likely to develop renal toxicity. CONCLUSION: Risk factors for nephrotoxicity were malignancy as an underlying medical condition, duration of amphotericin treatment of >14 days, cumulative dose >7.1 mg/kg and diuretic use. Normal nutritional status and no other concomitant nephrotoxic medication use had lesser odds of developing nephrotoxicity. RECOMMENDATIONS Clinicians should consider these risk factors, institute measures to monitor occurrence of nephrotoxicity and the need for alternative fungal therapy in these children. With identification of the population at risk, prospective research on determining the specific onset of renal effects and possible intervention is recommended.
Amphotericin B

PURPOSE: To report a case of candida endogenous endophthalmitis in healthy women who had received extraction of wisdom tooth. CASE SUMMARY: A 65-year-old medically healthy woman who had received extraction of wisdom tooth two weeks ago, presented with floater symptoms in her left eye. Best-corrected visual acuity was 20/40 and intraocular pressure was 17 mmHg in her left eye. Inflammatory cells were found in the anterior chamber and vitreous. Fluorescein angiography showed multiple hypofluorescence without vascular leakage. With provisional diagnosis of intermediate uveitis, she was prescribed oral steroid for two weeks. After that, inflammatory cells in anterior chamber was reduced but vitreous imflammatory cell was increased and fundus examination detected newly developed infiltrated lesion at superotemporal area. The patient was presumed to have fungal endophthalmitis and immediate intravitreal voriconazole injection was performed. Three days after intravitreal voriconazole injection, diagnostic vitrectomy and intravitreal voriconazole injection were performed. Vitreous cultures revealed the growth of Candida albicans. Despite the treatment, inflammatory response in anterior chamber and vitreous rapidly increased and visual acuity was decreased to hand movement. We changed anti-fungal agent, voriconazole to Amphotericin B. Additional three-time intravitreal injection was done and therapeutic vitrectomy with oil injection were performed. After treatment, the patient's fundus markedly improved and inflammatory response was decreased. CONCLUSIONS: This case report shows candida endophthalmitis in healthy woman who had received extraction of wisdom tooth. So to diagnose endophthalmitis, patient's medical history should carefully be checked including dental care history who presented with vitreous inflammation and inflammatory infiltrated lesion at fundus.
Aged ; Amphotericin B ; Anterior Chamber ; Candida ; Candida albicans ; Dental Care ; Diagnosis ; Endophthalmitis ; Female ; Fluorescein Angiography ; Hand ; Humans ; Inflammation ; Intraocular Pressure ; Intravitreal Injections ; Molar, Third ; Uveitis, Intermediate ; Visual Acuity ; Vitrectomy ; Voriconazole

PURPOSE: To report a case of rhino-orbito-cerebral aspergillosis successfully treated with a combination of amphotericin B, posaconazole and amphotericin B irrigation. CASE SUMMARY: A 59-year-old male with hypertension, diabetes mellitus and hyperlipidemia was admitted to our neurology department for left facial paresthesia, pain and consulted to ophthalmology for left eyeball pain. His visual acuity was no light perception in the left eye, and fundus examination showed papilledema and a cherry-red spot. Left exophthalmos and complete ptosis with ophthalmoplegia were also observed. Orbital computed tomography revealed left maxillary and ethmoid sinusitis, and nasal endoscopic examination revealed a black eschar adjacent to the middle turbinate. Subsequent biopsy suggested mucormycosis. The patient was immediately treated with a combination of amphotericin B and posaconazole. In addition, left endoscopic sinus surgery was performed and aspergillosis was histopathologically confirmed. The patient underwent amphotericin B irrigation for 5 days after canula insertion up to orbital apex. The patient survived for 18 months and is still alive. CONCLUSIONS: A combination of amphotericin B, posaconazole and amphotericin B irrigation using the canula through the orbital apex may be helpful in treating patients with rhino-orbito-cerebral aspergillosis who refuse orbital exenteration.
Amphotericin B* ; Aspergillosis* ; Biopsy ; Diabetes Mellitus ; Ethmoid Sinus ; Ethmoid Sinusitis ; Exophthalmos ; Humans ; Hyperlipidemias ; Hypertension ; Male ; Middle Aged ; Mucormycosis ; Neurology ; Ophthalmology ; Ophthalmoplegia ; Orbit ; Papilledema ; Paresthesia ; Turbinates ; Visual Acuity