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Candida is the most prevalent fungal bloodstream infection (BSI) with a high mortality rate among hospitalized patients. Another concern facing physicians is rising global incidence of drug-resistant Candida. This study aimed to characterize the prevalence, antifungal susceptibility, biofilm formation, and virulence genes (HWP1, ALS1, SAP2) of different Candida spp. isolated from patients with candidemia. 52 isolates of Candida spp. were identified from blood cultures by chromogenic Candida agar and confirmed by the VITEK 2 system. Isolates were tested for antifungal susceptibility by disk diffusion and VITEK 2 system. Biofilm formation and investigated genes were detected by the Congo red method and conventional PCR, respectively. Candida spp. caused 2.3% of detected BSIs, of which 32.7% were caused by Candida albicans (C. albicans) and 67.3% by non-albicans Candida (NAC), with the predominance of C. tropicalis (25%), followed by C. parapsilosis (17.3%), and C. krusei (13.5%). The susceptibility rates to fluconazole, voriconazole, caspofungin, micafungin, amphotericin B, and flucytosine were 64.7%, 76.5%, 100.0%, 100%, 100.0%, and 100.0% in C. albicans, while 53.6%, 71.4%, 91.4%, 91.4%, 94.3%, and 94.3% in NAC, respectively. Biofilm production, HWP1, ALS1, and SAP2 were detected in 70.6%, 82.4%, 76.5%, and 52.9% of C. albicans and 74.3%, 85.7%, 80.0%, and 48.6% of NAC, respectively. There is remarkable shift to NAC BSIs and high azole resistance. Antifungal stewardship and analysis of risk factors associated with this shift are needed. [ABSTRACT FROM AUTHOR]

Cryptococcus neoformans (C. neoformans) is a pathogenic fungus that can cause life-threatening meningitis, particularly in individuals with compromised immune systems. The current standard treatment involves the combination of amphotericin B and azole drugs, but this regimen often leads to inevitable toxicity in patients. Therefore, there is an urgent need to develop new antifungal drugs with improved safety profiles. We screened antimicrobial peptides from the hemolymph transcriptome of Blaps rhynchopetera (B. rhynchopetera), a folk Chinese medicine. We found an antimicrobial peptide named blap-6 that exhibited potent activity against bacteria and fungi. Blap-6 is composed of 17 amino acids (KRCRFRIYRWGFPRRRF), and it has excellent antifungal activity against C. neoformans, with a minimum inhibitory concentration (MIC) of 0.81 μM. Blap-6 exhibits strong antifungal kinetic characteristics. Mechanistic studies revealed that blap-6 exerts its antifungal activity by penetrating and disrupting the integrity of the fungal cell membrane. In addition to its direct antifungal effect, blap-6 showed strong biofilm inhibition and scavenging activity. Notably, the peptide exhibited low hemolytic and cytotoxicity to human cells and may be a potential candidate antimicrobial drug for fungal infection caused by C. neoformans. [ABSTRACT FROM AUTHOR]

PURPOSE: The purpose of this study was to determine the role of transcutaneous retrobulbar amphotericin B (TRAMB) injection in COVID-19-related rhino-orbital-cerebral mucormycosis (ROCM). MATERIALS AND METHODS: This prospective interventional case series included 7 eyes of 7 patients diagnosed with COVID-19 ROCM presenting from May to September 2021 at a tertiary care center in North India. Active or recovered cases of COVID-19 with clinical features suggestive of ROCM and early orbital involvement were included. Following functional endoscopic sinus surgery, patients were given TRAMB 3.5 mg/ml in single ocular quadrant depending upon the muscle involved on contrast-enhanced magnetic resonance imaging (MRI). Patients were followed up for a period of 12 weeks. RESULTS: All patients were diabetic and COVID-19 reverse transcription-polymerase chain reaction positive. The mean age of patients was 48.4 years ± 11 years, out of which 5 patients were male and 2 were female. The left eye was involved in 57.14% of cases whereas 42.85% of cases had right eye involvement. Presenting complaints were drooping of the upper lid (57.14%; n = 4), proptosis (28.57%; n = 2), facial pain and swelling (85.71%; n = 6), and nasal block (57.14%; n = 4). Stagewise distribution was 3a in four patients (57.14%), 3b in two patients (28.57%), and 4a in one patient. TRAMB injections (median - 3) were given, and improvement was seen in all patients in terms of ocular movements, ptosis, proptosis, and muscle enhancement on MRI scan. Three patients had an increase in intraocular pressure and inflammation which settled within a week with favorable anatomical and functional outcomes. CONCLUSION: Transcutaneous retrobulbar amphotericin B should be considered an adjunctive treatment modality for ROCM patients with limited orbital disease to preserve ocular function. [ABSTRACT FROM AUTHOR]

Invasive fungal infections in humans caused by several Candida species, increased considerably in immunocompromised or critically ill patients, resulting in substantial morbidity and mortality. Candida albicans is the most prevalent species, although the frequency of these organisms varies greatly according to geographic region. Infections with C. albicans and non‐albicans Candida species have become more common, especially in the past 20 years, as a result of aging, immunosuppressive medication use, endocrine disorders, malnourishment, extended use of medical equipment, and an increase in immunogenic diseases. Despite C. albicans being the species most frequently associated with human infections, C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei also have been identified. Several antifungal drugs with different modes of action are approved for use in clinical settings to treat fungal infections. However, due to the common eukaryotic structure of humans and fungi, only a limited number of antifungal drugs are available for therapeutic use. Furthermore, drug resistance in Candida species has emerged as a result of the growing use of currently available antifungal drugs against fungal infections. Amphotericin B (AmB), a polyene class of antifungal drugs, is mainly used for the treatment of serious systemic fungal infections. AmB interacts with fungal plasma membrane ergosterol, triggering cellular ion leakage via pore formation, or extracting the ergosterol from the plasma membrane inducing cellular death. AmB resistance is primarily caused by changes in the content or structure of ergosterol. This review summarizes the antifungal drug resistance exhibited by Candida species, with a special focus on AmB. [ABSTRACT FROM AUTHOR]

Background: Fungal keratitis is a severe eye infection that can result in blindness and visual impairment, particularly in developing countries. Fusarium spp. are the primary causative agents of this condition. Diagnosis of Fusarium keratitis (FK) is challenging, and delayed treatment can lead to serious complications. However, there is limited epidemiological data on FK, especially in tropical areas. Objectives: This study aimed to describe the clinical, laboratorial and epidemiological characteristics of FK in a tropical semi‐arid region of Brazil. Patients/Methods: Adult patients with laboratory‐confirmed FK diagnosed between October 2019 and March 2022 were evaluated. Fusarium isolates were characterized at molecular level and evaluated regarding antifungal susceptibility. Results: A total of 226 clinical samples from patients suspected of keratitis were evaluated; fungal growth was detected in 50 samples (22.12%); out of which 42 were suggestive of Fusarium spp. (84%). Molecular analysis of a randomly selected set of 27 isolates identified F. solani species complex (n = 14); F. fujikuroi sensu lato (n = 6) and F. dimerum sensu lato (n = 7); a total of 10 haplotypes were identified among the strains. All but one Fusarium strains were inhibited by amphotericin B, natamycin and fluconazole. Most patients were male (71.42%; 30 out of 42), aged from 27 to 73 years old. Trauma was the most important risk factor for FK (40.47%; 17 out of 42). Patients were treated with antifungals, corticoids and antibiotics; keratoplasty and eye enucleation were also performed. Conclusions: The study provided insights into the characteristics of FK in tropical regions and emphasized the importance of enhanced surveillance and management strategies. [ABSTRACT FROM AUTHOR]

Amphotericin B (AmB) is a broad-spectrum therapeutic and effective drug, but it has serious side effects of toxicity and solubility. Therefore, reducing its toxicity should be considered in therapeutic applications. Nanotechnology has paved the way to improve drug delivery systems and reduce toxicity. The present study, for the first time, comprehensively reviews the studies from 2011 to 2023 on reducing the in vitro toxicity of AmB. The findings showed that loading AmB with micellar structures, nanostructured lipid carriers, liposomes, emulsions, poly lactide-co-glycolide acid, chitosan, dendrimers, and other polymeric nanoparticles increases the biocompatibility and efficacy of the drug and significantly reduces toxicity. In addition, modified carbon nanoparticles (including graphene, carbon nanotubes, and carbon dots) with positively charged amine groups, PEI, and other components showed favorable drug delivery properties. Uncoated and coated magnetic nanoparticles and silver NPs-AmB composites had less cytotoxicity and more antifungal activity than free AmB. Citrate-reduced GNPs and lipoic acid-functionalized GNPs were also effective nanocarriers to reduce AmB cytotoxicity and improve anti-leishmania efficacy. In addition, zinc oxide-NPs and PEGylated zinc oxide-NPs showed favorable antifungal activity and negligible toxicity. According to a review study, carbon-based nanoparticles, metal nanoparticles, and especially polymer nanoparticles caused some reduction in the toxicity and improved solubility of AmB in water. Overall, considering the discussed nanocarriers, further research on the application of nanotechnology as a cost-effective candidate to improve the efficiency and reduce the cytotoxicity of AmB is recommended. [ABSTRACT FROM AUTHOR]

Wound-invasive fungal diseases (WIFDs), especially mucormycosis, have emerged as life-threatening infections during recent military combat operations. Many combat-relevant fungal pathogens are refractory to current antifungal therapy. Therefore, animal models of WIFDs are urgently needed to investigate new therapeutic solutions. Our study establishes combat-relevant murine models of wound mucormycosis using Rhizopus arrhizus and Lichtheimia corymbifera, two Mucorales species that cause wound mucormycosis worldwide. These models recapitulate the characteristics of combat-related wounds from explosions, including blast overpressure exposure, full-thickness skin injury, fascial damage, and muscle crush. The independent inoculation of both pathogens caused sustained infections and enlarged wounds. Histopathological analysis confirmed the presence of necrosis and fungal hyphae in the wound bed and adjacent muscle tissue. Semi-quantification of fungal burden by colony-forming units corroborated the infection. Treatment with liposomal amphotericin B, 30 mg/kg, effectively controlled R. arrhizus growth and significantly reduced residual fungal burden in infected wounds (p < 0.001). This study establishes the first combat-relevant murine model of wound mucormycosis, paving the way for developing and evaluating novel antifungal therapies against combat-associated WIFDs. [ABSTRACT FROM AUTHOR]

Fungal infections cause 1.7 million deaths annually, which can be attributed not only to fungus-specific factors, such as antifungal resistance and biofilm formation, but also to drug-related challenges. In this study, the potential of Amphotericin (AmB) loaded polymeric nanoparticles (AmB-NPs) combined with murine monoclonal antibodies (mAbs) (i.e., CC5 and DD11) was investigated as a strategy to overcome these challenges. To achieve this goal, AmB-NPs were prepared by nanoprecipitation using different polymers (polycaprolactone (PCL) and poly(D,L-lactide) (PLA)), followed by comprehensive characterization of their physicochemical properties and in vitro biological performance. The results revealed that AmB-loaded NPs exhibited no cytotoxicity toward mammalian cells (baby hamster kidney cells—BHK and human monocyte cells—THP-1). Conversely, both AmB-NPs demonstrated a cytotoxic effect against C. albicans, C. neoformans, and H. capsulatum throughout the entire evaluated range (from 10 µg/mL to 0.1 µg/mL), with a significant MIC of up to 0.031 µg/mL. Moreover, the combination of AmB-NPs with mAbs markedly intensified antifungal activity, resulting in a synergistic effect that was two to four times greater than that of AmB-NPs alone. These findings suggest that the combination of AmB-NPs with mAbs could be a promising new treatment for fungal infections that is potentially more effective and less toxic than current antifungal treatments. [ABSTRACT FROM AUTHOR]

Purpose: This study investigates how surfactants affect the in-vitro anti-infective efficacy of micafungin, caspofungin, anidulafungin, and amphotericin B in treating pulmonary mycoses. Methods: MIC values for antifungal agents were determined against Candida krusei (now Pichia kudriavzevii) ATCC 6258, Candida albicans ATCC 90028, and 18 clinical isolates using the broth microdilution method in RPMI medium, following EUCAST recommendations. MIC assays included testing with and without Curosurf® surfactant at 1 mg/mL for C. krusei ATCC 6258 and all C. krusei isolates. Subsequent Time-kill studies in Sabouraud broth involved testing both C. albicans ATCC 90028 and C. krusei ATCC 6258 strains at concentrations equal their respective MIC values, with and without surfactant, using all four antifungals. CFU/mL were assessed at multiple time points up to 24 h. TKCs with different surfactant concentrations for C. krusei ATCC 6258 and mini-TKCs at various concentrations relative to the MIC of C. krusei isolates and the reference strain were conducted with micafungin, anidulafungin, and caspofungin. Results: MIC results showed that 1 µg/mL surfactant reduced killing of micafungin and anidulafungin against C. krusei, while caspofungin was unaffected. Amphotericin B's MIC decreased by half. TKCs demonstrated significant effects of surfactant on micafungin and anidulafungin against C. krusei, with complete abolition of anidulafungin's activity against C. albicans. Conclusion: This in-vitro study highlights the concentration-dependent inhibitory effect of surfactant on antifungal activity against C. krusei and, to some extent, C. albicans, necessitating further clinical validation for invasive lung mycoses treatment. [ABSTRACT FROM AUTHOR]

Background: The threat of antibiotic resistance of fungal pathogens and the high toxicity of the most effective drugs, polyene macrolides, force us to look for new ways to develop innovative antifungal formulations. Objective: The aim of this study was to determine how the sterol, phospholipid, and flavonoid composition of liposomal forms of polyene antibiotics, and in particular, amphotericin B (AmB), affects their ability to increase the permeability of lipid bilayers that mimic the membranes of mammalian and fungal cells. Methods: To monitor the membrane permeability induced by various polyene-based lipid formulations, a calcein leakage assay and the electrophysiological technique based on planar lipid bilayers were used. Key results: The replacement of cholesterol with its biosynthetic precursor, 7-dehydrocholesterol, led to a decrease in the ability of AmB-loaded liposomes to permeabilize lipid bilayers mimicking mammalian cell membranes. The inclusion of plant flavonoid phloretin in AmB-loaded liposomes increased the ability of the formulation to disengage a fluorescent marker from lipid vesicles mimicking the membranes of target fungi. I–V characteristics of the fungal-like lipid bilayers treated with the AmB phytosomes were symmetric, demonstrating the functioning of double-length AmB pores and assuming a decrease in the antibiotic threshold concentration. Conclusions and Perspectives: The therapeutic window of polyene lipid formulations might be expanded by varying their sterol composition. Polyene-loaded phytosomes might be considered as the prototypes for innovative lipid antibiotic formulations. [ABSTRACT FROM AUTHOR]

Background: Pediatric lung transplant patients are at risk for developing invasive fungal infections post‐transplant. No consensus exists on optimal antifungal regimens and voriconazole, a common first‐line agent, has been shown to cause hepatotoxicity. We describe a single‐center experience utilizing a novel antifungal regimen of intravenous micafungin and nebulized amphotericin B immediately post‐transplant with conversion to an azole at the time of hospital discharge and compare it to a historical cohort of patients who received voriconazole monotherapy throughout their immediate post‐operative course. Methods: This is a retrospective review of patients in the age 0–18 who received a lung transplant from June 2016–May 2021. Data points collected included: demographic data, transplant date and discharge date, Aspergillus colonization, type of lung transplant, hospitalization and level of care information, induction and antifungal medication regimen; AST, ALT, GGT, bilirubin, and direct bilirubin at various timepoints; and respiratory and blood culture results. The two patient groups were compared by assessment of changes in LFTs and culture results. Results: Forty‐two patients were included in the analysis, with 24 patients receiving micafungin and nebulized amphotericin and 18 patients receiving voriconazole. All patients in both groups experienced a post‐operative elevation in at least one transaminase or bilirubin. More patients in the micafungin/amphotericin group had resolution of all abnormal LFTs by 1 month post‐transplant (p =.036). Additionally, patients in the micafungin/amphotericin group experienced faster normalization of their LFTs compared with the voriconazole group (p <.001). Ten patients in the micafungin/amphotericin group and five patients in the voriconazole group were found to have fungal growth on culture post‐transplant, but this difference was not found to be statistically significant (p =.507). Conclusions: An antifungal regimen of micafungin and nebulized amphotericin B liposomal may be useful at decreasing the duration of elevated liver enzymes in pediatric patients in the immediate post‐lung transplant period when compared with voriconazole monotherapy. Larger prospective studies looking at antifungal regimens in pediatric patients post‐lung transplant are warranted. [ABSTRACT FROM AUTHOR]

The treatment for visceral leishmaniasis (VL) causes toxicity in patients, entails high cost and/or leads to the emergence of resistant strains. No human vaccine exists, and diagnosis presents problems related to the sensitivity or specificity of the tests. Here, we tested two phage clones, B1 and D11, which were shown to be protective against Leishmania infantum infection in a murine model as immunotherapeutics to treat mice infected with this parasite species. The phages were used alone or with amphotericin B (AmpB), while other mice received saline, AmpB, a wild‐type phage (WTP) or WTP/AmpB. Results showed that the B1/AmpB and D11/AmpB combinations induced polarised Th1‐type cellular and humoral responses, which were primed by high levels of parasite‐specific IFN‐γ, IL‐12, TNF‐α, nitrite and IgG2a antibodies, which reflected in significant reductions in the parasite load in distinct organs of the animals when analyses were performed 1 and 30 days after the treatments. Reduced organic toxicity was also found in these animals, as compared with the controls. In conclusion, preliminary data suggest the potential of the B1/AmpB and D11/AmpB combinations as immunotherapeutics against L. infantum infection. [ABSTRACT FROM AUTHOR]

La mucormycose est une infection fongique rare et grave, survenant majoritairement sur des terrains immunodéprimés, diabétiques, des polytraumatismes ou des brûlures. Les traitements de références actuels reposent sur des parages chirurgicaux carcinologiques itératifs, un traitement systémique par amphotéricine B liposomale et en deuxième ligne par du Posaconazole ou Isavuconazole. Le cas d'une patiente de 37 ans sans antécédents, ayant présenté une mucormycose disséminée, avec perte de substance cutanée estimée à 25 % et délabrement majeur de la paroi thoracique est rapporté. En plus du traitement de référence, des instillations locales d'amphotéricine B en utilisant le système VAC Veraflow® ont été réalisées. Nous pensons que les instillations locales d'amphotéricine B par VAC pourrait permettre d'améliorer le pronostic fonctionnel des patients présentant une atteinte cutanée. Mucormycosis is a rare and serious fungal infection, occurring mainly in immunocompromised, diabetic, polytrauma or burn patients. Current standard treatments include iterative carcinological surgical trimming, systemic treatment with liposomal amphotericin B and second-line Posaconazole or Isavuconazole. We report the case of a 37-year-old female patient with no previous medical history who developed a disseminated mucormycosis, with an estimated 25 % loss of skin substance and major decay of the chest wall. In addition to standard treatment, local instillations of amphotericin B using the VAC Veraflow® system were performed. We believe that local instillations of amphotericin B by VAC could improve the functional prognosis of patients with skin involvement. [ABSTRACT FROM AUTHOR]

Background: Liposomal amphotericin B (LAMB) is a crucial agent in the treatment of invasive fungal diseases caused by a wide variety of yeasts and molds. In the presence of an infection caused by a fungal agent resistant to alternative antifungal drugs, desensitization may be the only option to continue treatment. However, there is insufficient information and consensus with regard to amphotericin B desensitization protocols in the pediatric age group. Objective: We present our experience with five cases of patients in whom successful desensitization protocols were applied with LAMB, along with a review of the literature on pediatric cases. We also provide a sample desensitization protocol that we successfully applied. Methods: Pediatric patients who continued their treatment with the successful rapid desensitization protocol conducted at the Paediatric Allergy and Immunology Clinic of the Ministry of Health Ankara City Hospital between September 2019 and September 2023 were examined. Desensitization protocols were applied based on Castells’ desensitization protocol. Results: Five patients ages between 5 and 12 years were referred to us due to the development of anaphylaxis during their treatment with LAMB. Anaphylaxis is diagnosed clinically, according to the European Academy of Allergy and Clinical Immunology guidelines: anaphylaxis (2021 update). A 16-step desensitization protocol was prepared by using LAMB solutions at four different dilutions (0.001, 0.01, 0.1, and 1 mg/mL). Each solution consisted of four steps, with a 15-minute infusion for each step. The patients were premedicated with 1 mg/kg/dose methylprednisolone and an antihistamine. Conclusion: The data we present on the successful application of a sample protocol to five cases, particularly in a pediatric setting, are noteworthy valuable contributions to the field, which demonstrates the feasibility and success of rapid desensitization with LAMB in pediatric patients. This can provide important insights and potentially serve as a reference for medical professionals working with similar cases in the future. [ABSTRACT FROM AUTHOR]

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Purpose: Azole resistance in Aspergillus fumigatus poses a significant challenge in the management of invasive aspergillosis. This study aimed to investigate the antifungal susceptibility and cyp51A mutation profiles of A. fumigatus isolates in Malaysia. Patients and Methods: Sixty clinical A. fumigatus isolates were collected and subjected to antifungal susceptibility testing (AFST) and molecular analysis. The antifungal susceptibility testing was performed according to CLSI M38 guideline. The geometric mean (GM) minimum inhibitory concentration (MIC), MIC50/MIC90 for voriconazole, itraconazole, posaconazole, amphotericin B, and isavuconazole against A. fumigatus in non-invasive cases and invasive cases were calculated. In addition, the presence of cyp51A mutations was also identified. Results: The present study revealed an overall resistance rate of 6.7% among the isolates. In non-invasive cases, isavuconazole and posaconazole demonstrated the lowest GM MIC of 0.08 μg/mL. Following them were itraconazole, voriconazole, and amphotericin B with concentrations of 0.15μg/mL, 0.16μg/mL and 0.90μg/mL, respectively. Similarly, in invasive cases, isavuconazole and posaconazole exhibited the lowest GM MIC of 0.09μg/mL. Following them were itraconazole, voriconazole, and amphotericin B with concentrations of 0.14μg/mL, 0.17μg/mL and 0.80μg/mL, respectively. Genotypic analysis revealed various cyp51A mutations, including F46Y, M172V, N248K, R34L, V244A, V244S, and E427K. However, not all mutations corresponded to antifungal resistance. Conclusion: The majority of clinical Aspergillus fumigatus isolates demonstrated susceptibility to the antifungal agents tested, with isavuconazole and posaconazole demonstrating the lowest MIC values. However, cyp51A mutations were discovered without a consistent correlation to antifungal resistance, emphasising the need for additional research. [ABSTRACT FROM AUTHOR]

Infection caused by the Humicola sp is extremely rare. We report the first case of fungal keratitis caused by Humicola pulvericola (H. pulvericola) in a 63-year-old man with a history of exposed to hot oil two weeks ago who developed keratitis. Direct examination of confocal microscopy and corneal scrapings showed fungal hyphae and isolates were identified by morphology and by sequencing the internal transcribed spacer region of ribosomal DNA. The in vitro antifungal susceptibilities of the case strain were tested for five antifungal agents. The results showed that the infectious agent was resistant towards fluconazole, caspofungin and amphotericin B; itraconazole and voriconazole were highly effective against H. pulvericola. He was diagnosed with H. pulvericola keratitis and treated with oral itraconazole and natamycin eyedrops. After one month of treatment, the lesion gradually improved, with the best-corrected visual acuity improving to 0.8. [ABSTRACT FROM AUTHOR]

Infections caused by Candida species, especially Candida albicans, threaten the public health and create economic burden. Shortage of antifungals and emergence of drug resistance call for new antifungal therapies while natural products were attractive sources for developing new drugs. In our study, fangchinoline, a bis‐benzylisoquinoline alkaloid from Chinese herb Stephania tetrandra S. Moore, exerted antifungal effects on planktonic growth of several Candida species including C. albicans, with MIC no more than 50 μg/mL. In addition, results from microscopic, MTT and XTT reduction assays showed that fangchinoline had inhibitory activities against the multiple virulence factors of C. albicans, such as adhesion, hyphal growth and biofilm formation. Furthermore, this compound could also suppress the metabolic activity of preformed C. albicans biofilms. PI staining, followed by confocal laser scanning microscope (CLSM) analysis showed that fangchinoline can elevate permeability of cell membrane. DCFH‐DA staining suggested its anti‐Candida mechanism also involved overproduction of intracellular ROS, which was further confirmed by N‐acetyl‐cysteine rescue tests. Moreover, fangchinoline showed synergy with three antifungal drugs (amphotericin B, fluconazole and caspofungin), further indicating its potential use in treating C. albicans infections. Therefore, these results indicated that fangchinoline could be a potential candidate for developing anti‐Candida therapies. [ABSTRACT FROM AUTHOR]

Rhodotorula mucilaginosa fungemia is rare and highly resistant to antifungal therapy. We herein report a case involving a 31-year-old male admitted after a high-velocity road traffic accident. He sustained a grade IV liver injury with right hepatic vein thrombosis, which necessitated an urgent laparotomy. Post-operatively, repeated imaging of the abdomen revealed the presence of a biloma. Percutaneous subdiaphragmatic drainage was carried out but appeared ineffective, prompting a second surgery for an urgent hemi-hepatectomy. The patient was then nursed in the intensive care unit (ICU); however, during his stay in the ICU, he became more sepsis, which was evident by worsening ventilatory support and a rise in septic parameters from the biochemistry parameters. Despite intravenous piperacillin–tazobactam and fluconazole, his septic parameters did not improve and a full septic workup was conducted and was found to be positive for Rhodotorula mucilaginosa from the blood cultures. After discussion with the infectious disease physicians and clinical microbiologists, it was decided to initiate a course of intravenous meropenem and amphotericin B based on minimum inhibitory concentration (MIC) values, considering the patient's extended ICU stay and catheter use. Eventually, after successfully weaning off mechanical ventilation, the patient was discharged from ICU care. This case underscores the necessity of individualized approaches, combining timely imaging, appropriate drainage techniques, and tailored treatments to optimize outcomes for such intricate post-traumatic complications. [ABSTRACT FROM AUTHOR]

Amphotericin B (AmB)–induced acute kidney injury (AKI) is a common health problem having an undesirable impact on its urgent therapeutic utility for fatal systemic fungal infections. Tadalafil (TAD), a phosphodiesterase-5 (PDE-5) inhibitor, has been observed to have a wide range of pharmacological actions, including nephroprotection. The study's objective was to examine the possible underlying protective mechanism of TAD against AmB-induced nephrotoxicity. Experimentally, animals were divided randomly into four groups: control, TAD (5 mg/kg/day; p.o.), AmB (18.5 mg/kg/day; i.p.), and TAD+AmB groups. Sera and tissue samples were processed for biochemical, molecular, and histological analyses. The biochemical investigations showed that TAD significantly ameliorated the increase of kidney function biomarkers (creatinine, urea, CysC, KIM-1) in serum, renal nitric oxide (NO), lipid peroxidation (MDA), and inflammatory cytokines (TNF-α, IL-6) in AmB-treated rats. Meanwhile, TAD significantly retarded AmB-induced decrease in serum magnesium, sodium, potassium, and renal glutathione content. Molecular analysis revealed that TAD reduced AmB-induced imbalance in the protein expression of eNOS/iNOS, which explains its regulatory effect on renal NO content. These results were also supported by the down-regulation of nuclear NF-κB p65 and cleaved caspase-3 protein expressions, as well as the improvement of histological features by TAD in AmB-treated rats. Therefore, it can be suggested that TAD could be a promising candidate for renoprotection against AmB-induced AKI. That could be partly attributed to its regulatory effect on renal eNOS/iNOS balance and NO, the inhibition of NF-κB p65 nuclear translocation, its downstream inflammatory cytokines and iNOS, and ultimately the inhibition of caspase-3-induced renal apoptosis. [ABSTRACT FROM AUTHOR]

This study aims to report the efficacy of a combined intrastromal injection in optimizing the outcome of severe mycotic keratitis. Herein, we report a case series of 20 consecutive patients with positive fungal cultures not responding to topical antifungal treatment. Patients received cycles of intrastromal injections of voriconazole (50 µg/0.1 mL) and amphotericin B (2.5 µg/0.1 mL); all patients continued their topical antifungal therapy. The organisms isolated were Fusarium (n = 5), Aspergillus (n = 4), Candida (n = 4), Rhodotorula (n = 2), Penicillium (n = 2), Alternaria (n = 1), Bipolaris (n = 1), and Curvularia (n = 1). The size of the infiltrate varied from 6.5 to 1.5 mm. At presentation, the best corrected visual acuity (BCVA, namely, the best visual acuity achieved with glasses, if needed) was less than 20/400 in all patients, improving to better than 20/400 in eleven patients. Seven patients required surgical intervention; four of them underwent penetrating keratoplasty (PK) à chaud one month after the first intrastromal injection. Patients who underwent surgery achieved a BCVA of 20/40 or better. Combined intrastromal injections before therapeutic penetrating keratoplasty (TPK) effectively reduced ulcer size and graft diameter, preventing infection recurrence. Our results highlight the efficacy of combined intrastromal injections in optimizing outcomes for severe mycotic keratitis undergoing TPK. [ABSTRACT FROM AUTHOR]

Visceral leishmaniasis (VL) is an infectious disease caused by Leishmania infantum. Clinically, VL evolves with systemic impairment, immunosuppression and hyperactivation with hypergammaglobulinemia. Although renal involvement has been recognized, a dearth of understanding about the underlying mechanisms driving acute kidney injury (AKI) in VL remains. We aimed to evaluate the involvement of immunoglobulins (Igs) and immune complexes (CIC) in the occurrence of AKI in VL patients. Fourteen VL patients were evaluated between early treatment and 12 months post-treatment (mpt). Anti-Leishmania Igs, CIC, cystatin C, C3a and C5a were assessed and correlated with AKI markers. Interestingly, high levels of CIC were observed in VL patients up to 6 mpt. Concomitantly, twelve patients met the criteria for AKI, while high levels of cystatin C were observed up to 6 mpt. Plasmatic cystatin C was positively correlated with CIC and Igs. Moreover, C5a was correlated with cystatin C, CIC and Igs. We did not identify any correlation between amphotericin B use and kidney function markers in VL patients, although this association needs to be further explored in subsequent studies. Our data reinforce the presence of an important renal function impairment during VL, suggesting the involvement of Igs, CIC, and C5a in this clinical condition. [ABSTRACT FROM AUTHOR]

Background: Currently available treatment options are mostly effective in achieving long-term cure in visceral leishmaniasis (VL) patients. However, there have been reports of recurrence of this illness in both immunosuppressed and immunocompetent patients. Case presentation: We report the first case of recurrent VL relapse in a 19-year-old immunocompetent female with functional hypopituitarism (hypogonadotropic hypogonadism with central hypothyroidism) from Bangladesh, who has been treated three times previously with optimal dosage and duration- liposomal amphotericin B (LAmB) alone and in combination with miltefosine. We treated the patient successfully with a modified treatment regimen of 10 mg/kg body weight LAmB for two consecutive days along with oral miltefosine for seven days as loading dose. For secondary prophylaxis, the patient received 3 mg/kg body weight LAmB along with oral miltefosine for seven days monthly for five doses followed by hormonal replacement. The patient remained relapse free after 12 months of her treatment completion. Conclusion: In the absence of protective vaccines against Leishmania species and standard treatment regimen, this modified treatment regimen could help the management of recurrent relapse cases. Author summary: Visceral leishmaniasis is a globally recognized neglected tropical disease, and Bangladesh is a major contributor of the global burden of this illness. In this article, we present a case on a 19-year-old immunocompetent female with pubertal delay, who has been diagnosed as a case of visceral leishmaniasis for 11 years and presented to us with recurrent relapses despite being treated with standard treatment regimens. The patient also developed functional hypopituitarism due to this chronic illness, which hindered her personal, familial, as well as social life. In scarcity of evidence of a standard treatment regimen for recurrent relapse cases, we treated her with high dose liposomal amphotericin B and miltefosine, along with secondary prophylaxis combining these two drugs with excellent result. Her pubertal delay was also addressed with utmost importance to re-establish her social confidence. This article could encourage physicians to outline an effective regimen to deal with these difficult-to-treat cases. [ABSTRACT FROM AUTHOR]

Background: In recent years, the prevalence of respiratory fungal diseases has increased. Polyene antifungal drugs play a pivotal role in the treatment of these conditions, with amphotericin B (AmB) being the most representative drug. This study aimed to evaluate the efficacy and safety of topical administration of AmB in the treatment of respiratory fungal infections. Methods: We conducted a retrospective study on hospitalized patients treated with topical administered AmB for respiratory fungal infections from January 2014 to June 2023. Results: Data from 36 patients with invasive pulmonary fungal infections treated with topical administration of AmB were collected and analyzed. Nebulization was administered to 27 patients. After the treatment, 17 patients evidenced improved conditions, whereas 10 patients did not respond and died in the hospital. One patient experienced an irritating cough as an adverse reaction. Seven patients underwent tracheoscopic instillation, and two received intrapleural irrigation; they achieved good clinical therapeutic efficacy without adverse effects. Conclusion: The combined application of systemic antifungal treatment and topical administration of AmB yielded good therapeutic efficacy and was well-tolerated by the patients. Close monitoring of routine blood tests, liver and kidney function, and levels of electrolytes, troponin, and B-type natriuretic peptide supported this conclusion. [ABSTRACT FROM AUTHOR]

Background: With the current treatment options for visceral leishmaniasis (VL), recrudescence of the parasite is seen in a proportion of patients. Understanding parasite dynamics is crucial to improving treatment efficacy and predicting patient relapse in cases of VL. This study aimed to characterize the kinetics of circulating Leishmania parasites in the blood, during and after different antileishmanial therapies, and to find predictors for clinical relapse of disease. Methods: Data from three clinical trials, in which Eastern African VL patients received various antileishmanial regimens, were combined in this study. Leishmania kinetoplast DNA was quantified in whole blood with real-time quantitative PCR (qPCR) before, during, and up to six months after treatment. An integrated population pharmacokinetic-pharmacodynamic model was developed using non-linear mixed effects modelling. Results: Parasite proliferation was best described by an exponential growth model, with an in vivo parasite doubling time of 7.8 days (RSE 12%). Parasite killing by fexinidazole, liposomal amphotericin B, sodium stibogluconate, and miltefosine was best described by linear models directly relating drug concentrations to the parasite elimination rate. After treatment, parasite growth was assumed to be suppressed by the host immune system, described by an Emax model driven by the time after treatment. No predictors for the high variability in onset and magnitude of the immune response could be identified. Model-based individual predictions of blood parasite load on Day 28 and Day 56 after start of treatment were predictive for clinical relapse of disease. Conclusion: This semi-mechanistic pharmacokinetic-pharmacodynamic model adequately captured the blood parasite dynamics during and after treatment, and revealed that high blood parasite loads on Day 28 and Day 56 after start of treatment are an early indication for VL relapse, which could be a useful biomarker to assess treatment efficacy of a treatment regimen in a clinical trial setting. Author summary: After primary treatment of visceral leishmaniasis (VL), relapse of disease occurs in a proportion of patients. Understanding parasite dynamics is crucial to improving treatment efficacy and predicting disease relapse at an early stage. Leishmania kinetoplast DNA loads in blood from East African VL patients from three clinical trials, treated with five different treatment regimens, were used to develop a semi-mechanistic model to integrate in vivo parasite replication in the host, parasite clearance by different VL drug regimens, and suppression of parasite regrowth by the host immune system after treatment. This model deepened our understanding of the parasite-drug-host interaction and described the in vivo parasite growth rate in human for the first time. Moreover, the model revealed that high blood parasite loads on Day 28 and Day 56 after start of treatment are an early indication for VL relapse, which could serve as a biomarker to predict long-term clinical outcome, an important new tool for optimizing future VL treatment regimens. [ABSTRACT FROM AUTHOR]

Background: Cutaneous leishmaniasis (CL) is characterized by potentially disfiguring skin ulcers carrying significant social stigma. To mitigate systemic drug exposure and reduce the toxicity from available treatments, studies addressing new local therapeutic strategies using available medications are coming up. This review systematically compiles preclinical and clinical data on the efficacy of amphotericin B (AmB) administered locally for cutaneous leishmaniasis. Methodology: Structured searches were conducted in major databases. Clinical studies reporting cure rates and preclinical studies presenting any efficacy outcome were included. Exclusion criteria comprised nonoriginal studies, in vitro investigations, studies with fewer than 10 treated patients, and those evaluating AmB in combination with other antileishmanial drug components. Principal findings: A total of 21 studies were identified, encompassing 16 preclinical and five clinical studies. Preclinical assessments generally involved the topical use of commercial AmB formulations, often in conjunction with carriers or controlled release systems. However, the variation in the treatment schedules hindered direct comparisons. In clinical studies, topical AmB achieved a pooled cure rate of 45.6% [CI: 27.5–64.8%; I2 = 79.7; p = 0.002), while intralesional (IL) administration resulted in a 69.8% cure rate [CI: 52.3–82.9%; I2 = 63.9; p = 0.06). In the direct comparison available, no significant difference was noted between AmB-IL and meglumine antimoniate-IL administration (OR:1.7; CI:0.34–9.15, I2 = 79.1; p = 0.00), however a very low certainty of evidence was verified. Conclusions: Different AmB formulations and administration routes have been explored in preclinical and clinical studies. Developing therapeutic technologies is evident. Current findings might be interpreted as a favorable proof of concept for the local AmB administration which makes this intervention eligible to be explored in future well-designed studies towards less toxic treatments for leishmaniasis. Author summary: Cutaneous leishmaniasis (CL) is a neglected disease recognized for causing ulcers distributed throughout the body; such ulcers can be disfiguring and may intrinsically attract a social stigma. Furthermore, the currently available therapeutic arsenal is admittedly limited and associated with significant toxicity. Long therapeutic regimens and parenteral administration have been considered in recent years as a strategy to be replaced. In this scenario, the search for new treatment alternatives for CL is considered a priority by the World Health Organization, which has been expanding its treatment recommendations with alternatives for local use. In this study, we performed an extensive literature search to gather evidence on the efficacy of amphotericin B (AmB) in local administration for the treatment of CL in preclinical or clinical studies. In total, 21 studies, 16 preclinical studies and five clinical studies were identified. The global cure rate for clinical studies addressing intralesional infiltration and topical application was estimated at 56.9% (CI: 41.1–71.4%). High heterogeneity in the design, groups, and route of administration of AmB among studies was observed, requiring caution in interpreting and extrapolating of this pooled rate. In summary, the results show that local routes of administration of AmB are a promising strategy and need to be evaluated in studies with adequate design, enabling the expansion of therapeutic alternatives for the treatment of CL. [ABSTRACT FROM AUTHOR]

Background: The emergence of the pathogenic yeast Candida auris is of global concern due to its ability to cause hospital outbreaks and develop resistance against all antifungal drug classes. Based on published data for baker's yeast Saccharomyces cerevisiae, sphingolipid biosynthesis, which is essential for maintaining membrane fluidity and formation of lipid rafts, could offer a target for additive treatment. Methods: We analysed the susceptibility of C. auris to myriocin, which is an inhibitor of the de novo synthesis of sphingolipids in eukaryotic cells in comparison to other Candida species. In addition, we combined sublethal concentrations of myriocin with the antifungal drugs amphotericin B and fluconazole in E‐tests. Consequently, the combinatory effects of myriocin and amphotericin B were examined in broth microdilution assays. Results: Myriocin‐mediated inhibition of the sphingolipid biosynthesis affected the growth of C. auris. Sublethal myriocin concentrations increased fungal susceptibility to amphotericin B. Isolates which are phenotypically resistant (≥2 mg/L) to amphotericin B became susceptible in presence of myriocin. However, addition of myriocin had only limited effects onto the susceptibility of C. auris against fluconazole. Conclusions: Our results show that inhibition of de novo sphingolipid biosynthesis increases the susceptibility of C. auris to amphotericin B. This may potentially enhance antifungal treatment options fighting this often resistant yeast pathogen. [ABSTRACT FROM AUTHOR]

Background: Recurrent vulvovaginal candidiasis (RVVC) is an important and underestimated fungal infection. Objective: We aimed to determine the fungicidal and proliferative capacities of neutrophils and peripheral blood mononuclear cells (PBMCs), respectively and the clinical and microbiological characteristics of a cohort of Colombian patients diagnosed with RVVC. Methods: A cross‐sectional study was conducted. A total of 66 women were included (40 diagnosed with RVVC and 26 healthy women [HW]). Demographic and clinical data were recorded. Vaginal fluid samples were obtained for isolation, identification and antifungal susceptibility testing of Candida species using selective culture media and the Vitek 2.0® system. Blood samples were also obtained to evaluate cell subpopulations; furthermore, neutrophils and PBMCs were isolated to determine their fungicidal and proliferative capacities, respectively. Results: The median age was 29 (IQR: 34–23) for RVVC and 24 (IQR: 30–23) for HW. Only two species of the genus Candida were identified: Candida albicans (92.5%) and Candida lusitaniae (7.5%). Resistance to fluconazole, voriconazole, flucytosine and amphotericin B was observed on six C. albicans isolates and one C. lusitaniae isolate. Only the family history of vulvovaginal candidiasis was associated with RVVC occurrence. The RVVC group exhibited a significantly higher number of neutrophils but with lower fungicidal activity in comparison to HW; likewise, PBMCs from RVVC patients presented a lower proliferation index when stimulated with C. albicans. Conclusion: Contrary to what has been reported worldwide, in Colombian patients with RVVC, C. albicans was the main isolated species without increased antifungal resistance. The diminished fungicidal and proliferative capacities of neutrophils and PBMCs, respectively, could suggest a possible alteration in the innate and adaptive immune responses. [ABSTRACT FROM AUTHOR]

Amphotericin B (AmB) has long stood as a cornerstone in the treatment of invasive fungal infections (IFIs), especially among immunocompromised patients. However, the landscape of antifungal therapy is evolving. New antifungal agents, boasting novel mechanisms of action and better safety profiles, are entering the scene, presenting alternatives to AmB's traditional dominance. This shift, prompted by an increase in the incidence of IFIs, the growing demographic of immunocompromised individuals, and changing patterns of fungal resistance, underscores the continuous need for effective treatments. Despite these challenges, AmB's broad efficacy and low resistance rates maintain its essential status in antifungal therapy. Innovations in AmB formulations, such as lipid complexes and liposomal delivery systems, have significantly mitigated its notorious nephrotoxicity and infusion-related reactions, thereby enhancing its clinical utility. Moreover, AmB's efficacy in treating severe and rare fungal infections and its pivotal role as prophylaxis in high-risk settings highlight its value and ongoing relevance. This review examines AmB's standing amidst the ever-changing antifungal landscape, focusing on its enduring significance in current clinical practice and exploring its potential future therapeutic adaptations. [ABSTRACT FROM AUTHOR]

Extrapulmonary infections by Coccidioides spp., though rare, can occur via dissemination, affecting singular or multiple sites, including the skin and musculoskeletal system. Skeletal involvement often manifests as osteomyelitis, particularly in the axial skeleton. The present systematic review evaluates all documented cases of skeletal coccidioidomycosis to assess the diagnostic and treatment strategies alongside the outcomes, drawing insights from an analysis of 163 verified cases. A systematic review following PRISMA guidelines identified all studies reporting skeletal infections by Coccidioides spp. up to 2023 from the PubMed and Scopus databases. Eligible studies evaluated osteoarticular infections from Coccidioides spp. Data extraction included demographics, microbiological data, diagnostic methods, and treatment outcomes. Of the 501 initially identified records, a total of 163 patients from 69 studies met the inclusion criteria. Most cases were from the USA, predominantly males, while the median age of the population was 36 years. Diabetes mellitus was the common comorbidity (14.7%). C. immitis was the most prevalent pathogen. The spine and hand were common sites of infection (17.5% and 15.1%, respectively). Osteomyelitis by Coccidioides spp. was diagnosed, in most cases, by positive cultures (n = 68; 41.7%), while, in 49 (30.9%), both the histological examination and cultures yielded the fungus. Surgical debridement was performed in 80.9% of cases. A total of 118 (72.3%) patients were treated with monotherapy, while combination therapy with two or more antifungal agents was reported in 45 (17.7%). Amphotericin B (either liposomal or deoxycholate) was the most commonly given agent as monotherapy in 51 (31.2%) patients, while 30 (18.4%) patients received itraconazole as monotherapy. The rate of infection's resolution was higher in patients undergoing surgical debridement (79.5%), compared to those treated only with antifungal agents (51.6%, p = 0.003). Treatment outcomes showed complete resolution in 74.2% of patients, with a mortality rate of 9.2%. Coccidioidal osseous infections present diagnostic and therapeutic challenges. Surgical intervention is often necessary, complementing antifungal therapy. Vigilance for Coccidioides spp. infections, especially in regions with endemicity, is crucial, particularly when bacterial cultures yield negative results. [ABSTRACT FROM AUTHOR]

The Candida auris species is a multidrug-resistant yeast capable of causing systemic and lethal infections. Its virulence and increase in outbreaks are a global concern, especially in hospitals where outbreaks are more recurrent. In many cases, monotherapy is not effective, and drug combinations are opted for. However, resistance to antifungals has increased over the years. In view of this, nanoemulsions (NEs) may represent a nanotechnology strategy in the development of new therapeutic alternatives. Therefore, this study developed a co-encapsulated nanoemulsion with amphotericin B (AmB) and micafungin (MICA) (NEMA) for the control of infections caused by C. auris. NEs were developed in previous studies. Briefly, the NEs were composed of a mixture of 10% sunflower oil and cholesterol as the oil phase (5:1), 10% Polyoxyethylene (20) cetyl ether (Brij® 58) and soy phosphatidylcholine as surfactant/co-surfactant (2:1), and 80% PBS as the aqueous phase. The in vivo assay used BALB/c mice weighing between 25 and 28 g that were immunosuppressed (CEUA/FCF/CAr n° 29/2021) and infected with Candida auris CDC B11903. The in vivo results show the surprising potentiate of the antifungal activity of the co-encapsulated drugs in NE, preventing yeast from causing infection in the lung and thymus. Biochemical assays showed a higher concentration of liver and kidney enzymes under treatment with AmB and MICAmB. In conclusion, this combination of drugs to combat the infection caused by C. auris can be considered an efficient therapeutic option, and nanoemulsions contribute to therapeutic potentiate, proving to be a promising new alternative. [ABSTRACT FROM AUTHOR]

Background and aim: Patients with end-stage liver disease (ESLD) are susceptible to invasive pulmonary aspergillosis (IPA). This study aimed to investigate the risk factors affecting the occurrence and short-term prognosis of ESLD complicated by IPA. Methods: This retrospective case–control study included 110 patients with ESLD. Of them, 27 ESLD-IPA received antifungal therapy with amphotericin B (AmB); 27 AmB-free-treated ESLD-IPA patients were enrolled through 1:1 propensity score matching. Fifty-six ESLD patients with other comorbid pulmonary infections were enrolled as controls. The basic features of groups were compared, while the possible risk factors affecting the occurrence and short-term outcomes of IPA were analyzed. Results: Data analysis revealed invasive procedures, glucocorticoid exposure, and broad-spectrum antibiotic use were independent risk factors for IPA. The 54 patients with ESLD-IPA exhibited an overall treatment effectiveness and 28-d mortality rate of 50.00% and 20.37%, respectively, in whom patients treated with AmB-containing showed higher treatment efficacy than patients treated with AmB-free antifungal regimens (66.7% vs. 33.3%, respectively, χ2 = 6.000, P = 0.014). Multivariate logistic regression analysis revealed that the treatment regimen was the only predictor affecting patient outcomes, with AmB-containing regimens were 4.893 times more effective than AmB-free regimens (95% CI, 1.367–17.515; P = 0.015). The only independent predictors affecting the 28-d mortality rate were neutrophil-to-lymphocyte ratio and IPA diagnosis (OR = 1.140 and 10.037, P = 0.046 and 0.025, respectively). Conclusions: Glucocorticoid exposure, invasive procedures, and broad-spectrum antibiotic exposure increased the risk of IPA in ESLD patients. AmB alone or combined with other antifungals may serve as an economical, safe, and effective treatment option for ESLD-IPA. [ABSTRACT FROM AUTHOR]

Liposomal amphotericin B (Ambisome®) is the gold standard for the treatment and prevention of fungal infections both in the adult and pediatric populations. The lyophilized dosage form has to be reconstituted and diluted by hospital staff, but its management can be challenging due to the spontaneous tendency of amphotericin B to form aggregates with different biological activity. In this study, the colloidal stability of the liposomes and the chemical stability of amphotericin B were investigated over time at storage conditions. Three liposomal formulations of amphotericin B at 4.0 mg/mL, 2.0 mg/mL, and 0.2 mg/mL were prepared and assayed for changes regarding the dimensional distribution, zeta potential, drug aggregation state, and onset of by-products. Our analyses highlighted that the most diluted formulation, kept at room temperature, showed the greatest changes in the aggregation state of the drug and accordingly the highest cytotoxicity. These findings are clinically relevant since the lower dosages are addressed to the more vulnerable patients. Therefore, the centralization of the dilution of AmBisome® at the pharmacy is of fundamental importance for assuring patient safety, and at the same time for reducing medication waste, as we demonstrated using the cost-saving analysis of drug expense per therapy carried out at the G. Gaslini children hospital. [ABSTRACT FROM AUTHOR]

The objective of this work was to evaluate the combination of synthetic peptides based on the γ-core motif of defensin PvD1 with amphotericin B (AmB) at different concentrations against Candida albicans. We applied the checkerboard assay using different concentrations of the commercial drug AmB and the synthetic peptides γ31-45PvD1++ and γ33-41PvD1++ against C. albicans, aiming to find combinations with synergistic interactions. Between these two interactions involving γ31-45PvD1++ and AmB, an additive effect was observed. One such interaction occurred at concentrations of 0.009 μMof peptide γ31-45PvD1++ and 13.23 μMof AmB and another condition of 0.019 μM of peptide γ31-45PvD1++ and 6.61 μM of AmB. The other two concentrations of the interaction showed a synergistic effect in the combination of synthetic peptide γ31-45PvD1++ and AmB, where the concentrations were 1.40 μM peptide γ31-45PvD1++ and 0.004 μM AmB and 0.70 μM γ31-45PvD1++ peptide and 0.002 μM AmB. We proceeded with analysis of the mechanism of action involving synergistic effects. This examination unveiled a range of impactful outcomes, including the impairment of mitochondrial functionality, compromise of cell wall integrity, DNA degradation, and a consequential decline in cell viability. We also observed that both synergistic combinations were capable of causing damage to the plasma membrane and cell wall, causing leakage of intracellular components. This discovery demonstrates for the first time that the synergistic combinations found between the synthetic peptide γ31-45PvD1++ and AmB have an antifungal effect against C. albicans, acting on the integrity of the plasma membrane and cell wall. [ABSTRACT FROM AUTHOR]

Mucormycosis is an aggressive, fatal fungal infection. The fungal organisms are ubiquitous and easily affect immunocompromised patients. The main aim of this article is to emphasize over the knowledge of different diagnostic methods (diagnostic nasal endoscopy, ct/ contrast mri pns + orbit + brain, Wet KOH mount), the importance of practising an aggressive surgical resection, medical treatments (liposomal amphotericin B, amphotericin gel, tablet posaconazole, nasal douching, retrorbital amphotericin injection), suction cleaning and regular follow up of the patient after surgical management. This can greatly help in minimizing the recurrence of mucormycosis even in immunocompromised patients in a population. The study performed was a prospective study conducted from April 2021 to July 2021 in which we included 500 patients who presented to the OPD & Department of ENT or Emergency Department of Maharaja Yashwantrao Hospital with complaints suggestive of mucormycosis. The patients who were surgically fit were operated. Out of the 500 patients who were diagnosed with Mucormycosis, from April 2021 to July 2021 complete cure was achieved in 456 patients(91.2%) and only 44 patients (8.8%) have shown recurrence due to various causes (specially those who did not came for regular follow up). Rhinorbital was the most common site to be involved. In the study it was found that most of the patients which showed recurrence were male, post covid and immunocompromised. Diabetes mellitus was found to be most common among immunocompromised patients. The recurrence in patients with mucormycosis can be minimise by educating the masses regarding importance of public and personal hygiene, and multidisciplinary management with regular follow up offers a better approach to treat this life-threatening condition. The study shows the importance of clinical diagnosis, concurrent surgical treatment, medical treatment, post op care, suction cleaning and regular follow up advice. It is necessary us to take the step forward in this regard, so that in the future we will be better prepared for such type of epidemic. [ABSTRACT FROM AUTHOR]

Background and Objectives: Amphotericin B is a broad-spectrum antifungal agent commonly used to treat Candida haemulonii infection. C. haemulonii was isolated from patients reported to be intrinsically resistant to amphotericin B, encoded by the ERG2 and ERG11 genes. However, there have been limited studies concerning amphotericin B-resistant C. haemulonii in Indonesia. The objective of this study is to explore the phenotypic and genotypic characteristics (ERG2 and ERG11) of C. haemulonii isolated from the ICU of a referral hospital in Indonesia. Materials and Methods: Identification and susceptibility tests were conducted using VITEK2. Thereafter, DNA was extracted and amplified using conventional PCR followed by DNA sequencing (Sanger method). Results: The results of the phenotypic susceptibility test showed that all C. haemulonii were resistant to amphotericin B. ERG2 and ERG11 sequences showed the same amino acid sequence and corresponded to references that are resistant to amphotericin B. Conclusion: The resistant properties of C. haemulonii against amphotericin B found in this study require further exploration, including comparing resistant and sensitive C. haemulonii to amphotericin B. In addition, it is necessary to analyze other genes besides ERG2 and ERG11. [ABSTRACT FROM AUTHOR]

Background and Objectives: The presence of fungi in the respiratory tract as mycobiome, particularly Candida species (spp.), remains a serious problem due to increasing numbers of immunocompromised patients. The confirmed reliable existence of these pathogens due to frequent colonization is essential. This investigation aimed to recognize Candida spp. among isolates from bronchoalveolar lavage of immunocompromised and critically ill patients and to evaluate their susceptibility to antimycotic drugs. Materials and Methods: Bronchoalveolar lavage fluid was collected from 161 hospitalized patients presenting with suspected respiratory fungal infection/colonization. The specimens were examined by standard molecular and mycological assays. Candida spp. were recognized with sequence assessment of the D1-D2 section of the large subunit ribosomal DNA. The susceptibility of Candida isolates to common antimycotic drugs was distinguished by standard broth microdilution. Results: Seventy-one clinical isolates of Candida spp. were recognized. Candida albicans was the most frequent, followed by C. glabrata, C. krusei (Pichia kudriavzevii), C. dubliniensis, C. parapsilosis, and C. tropicalis. We found 5.1% of C. albicans isolates and 8% of C. glabrata isolates to show resistance to fluconazole. The whole of the Candida spp. were sensitive to amphotericin B and caspofungin. Conclusion: This study demonstrated that C. albicans and C. glabrata are the most common isolates of bronchoalveolar lavage fluid in patients, and the drug susceptibility screening confirmed that amphotericin B and caspofungin are effective against Candida spp. but some C. glabrata and C. albicans isolates showed resistance to fluconazole. [ABSTRACT FROM AUTHOR]

Candida albicans is a prevalent fungal pathogen that displays antibiotic resistance. The polyene antifungal amphotericin B (AmB) has been the gold standard because of its broad antifungal spectra, and its liposomal formulation, AmBisome, has been used widely and clinically in treating fungal infections. Herein, we explored enhancing the antifungal activity of AmBisome by integrating a small chitin-binding domain (LysM) of chitinase A derived from Pteris ryukyuensis. LysM conjugated with a lipid (LysM–lipid) was initially prepared through microbial transglutaminase (MTG)-mediated peptide tag-specific conjugation of LysM with a lipid–peptide substrate. The AmBisome formulation modified with LysM–lipid conjugates had a size distribution that was comparable to the native liposomes but an increased zeta potential, indicating that LysM–lipid conjugates were anchored to AmBisome. LysM–lipid-modified AmBisome exhibited long-term stability at 4 °C while retaining the capacity to bind chitin. Nevertheless, the antifungal efficacy of LysM–lipid-modified AmBisome against C. albicans was modest. We then redesigned a new LysM–lipid conjugate by introducing a peptide linker containing a thrombin digestion (TD) site at the C-terminus of LysM (LysM–TD linker–lipid), thereby facilitating the liberation of the LysM domain from AmBisome upon the addition of thrombin. This new AmBisome formulation anchored with LysM–TD linker–lipid exhibited superior performance in suppressing C. albicans growth in the presence of thrombin compared with the LysM–lipid formulation. These results provide a platform to design stimuli-responsive AmBisome formulations that respond to external environments and thus advance the treatment of pathogenic fungi infections. [ABSTRACT FROM AUTHOR]

Introduction Therapeutic drug monitoring (TDM) is a tool that supports personalized dosing, but its role for liposomal amphotericin B (L-amb) is unclear. This systematic review assessed the evidence for L-amb TDM in children. Objectives To evaluate the concentration–efficacy relationship, concentration–toxicity relationship and pharmacokinetic/pharmacodynamic (PK/PD) variability of L-amb in children. Methods We systematically reviewed PubMed and Embase databases following PRISMA guidelines. Eligible studies included L-amb PK/PD studies in children aged 0–18 years. Review articles, case series of 600 mg·h/L for nephrotoxicity. L-amb doses of 2.5–10 mg/kg/day were reported to achieve C max/MIC > 25 using an MIC of 1 mg/L. Conclusions While significant PK variability was observed in children, evidence to support routine L-amb TDM was limited. Further studies on efficacy and toxicity benefits are required before routine TDM of L-amb can be recommended. [ABSTRACT FROM AUTHOR]

In recent years, Vancomycin (VCM) dosing design using area under the concentration-time curve (AUC) has been recommended as a measure of efficacy and safety, but there are fewer reports on pediatric patients than on adults. In this study, we evaluated the threshold of AUC for AKI occurrence in pediatric patients and investigated the factors that contribute to the occurrence of AKI. Pediatric patients aged 1–15 years on VCM treatment who underwent TDM at Kagoshima University Hospital from April 2016 to March 2022 were included in the computation of AUC using pediatric population pharmacokinetic parameters. The ROC curve showed that the AUC threshold for the risk of developing AKI was 583.0 μg・h/mL, and the AUC-ROC curve was 0.873 (sensitivity 0.930, specificity 0.750). Univariate analysis showed that factors associated with AKI incidence were the duration of VCM administration, ICU admission, and AUC SS. Concomitant medications identified as risk factors for AKI incidence were tazobactam/piperacillin, liposomal amphotericin B, calcineurin inhibitors, contrast agents, and H 2 -receptor blockers. The multivariate analysis showed that AUC ≧ 583.0 μg・h/mL (odds ratio 20.14, 95% CI 3.52–115.22, p < 0.001) and H 2 -receptor blockers (odds ratio 8.70, 95% confidence interval = 1.38–54.87, p = 0.02) were independent factors for AKI incidence. We showed that in pediatric patients receiving VCM, the risk of AKI increases as AUC increases. The findings imply that concurrent use of VCM and H 2 -receptor blockers may increase the risk of AKI. [ABSTRACT FROM AUTHOR]

Ferula latisecta belongs to the Ferula genus and is endemic to Iran. The present study aims to extract the essential oil of F. latisecta oleo-gum-resin for the first time and evaluate its phytochemistry and antimicrobial activity. The essential oil was extracted using a Clevenger-type hydrodistillation apparatus. The essential oil constituents were identified and quantified using GC and GC/MS methods. The antimicrobial activity of the essential oil was assayed against two Gram-negative bacteria, Acinetobacter baumannii and Pseudomonas aeruginosa, a Gram-positive bacterium, Staphylococcus aureus, and a fungal strain, Candida krusei using the broth microdilution method to determine MIC and MBC values. The results showed that the essential oil was rich in β- and α-pinene with 30.72% and 25.07% content, respectively. Additionally, the essential oil contained a significant amount of sulfur-containing compounds (7.49%) such as (E)-sec-butyl propenyl disulfide (4.21%), (Z)-sec-butyl propenyl disulfide (2.34%), and hexamethylene sulfide (0.94%). According to the results, the essential oil exhibited high inhibitory activity against C. krusei fungi, with MIC and MBC values of 2 μg/mL, which were more potent than amphotericin B (MIC: 8 and MBC: 32 μg/mL), as a standard antifungal agent. Additionally, the essential oil showed significant antibacterial activity against A. baumannii, with MIC and MBC values of 32 μg/mL, which were more potent than cefixime. Furthermore, the essential oil exhibited moderate activity against S. aureus with MIC and MBC values of 16 μg/mL. This study introduces a new oleo-gum resin from F. latisecta, with a high content of terpenoids and strong antimicrobial potency. [ABSTRACT FROM AUTHOR]

Background: Candida species, commonly present in the human body, can result in severe infections. Non-albicans Candida (NAC) species, with increasing antifungal resistance, pose a growing concern. Aims and Objectives: This study aims to evaluate candidiasis prevalence and antifungal susceptibility in isolated Candida species among suspected patients at tertiary care hospitals in Butwal, emphasizing early identification and appropriate treatment to avoid unnecessary use of toxic antifungal drugs. Materials and Methods: In a descriptive study on 303 patients with clinical symptoms of Candida infections, specimens underwent direct microscopic examination and culture on Sabouraud dextrose agar. Species identification involved phenotypic methods such as chromogenic character on CHROMagar Candida media, germ tube examination, and microscopic characteristics. Subsequently, isolated species were tested for antifungal susceptibility using the disc diffusion method. Results: Among the 303 samples tested, 80 (26.4%) were positive for candidal infection. NAC species were the most commonly isolated, with Candida albicans and Candida krusei being the most virulent. The isolates exhibited the highest sensitivity to fluconazole (77.5%) followed by itraconazole (75%), whereas amphotericin B showed the lowest effectiveness with 63.75% resistance. Conclusion: The rising prevalence of NAC species, particularly their growing resistance to Amphotericin B, has become a significant concern, as these species are frequently detected in various clinical samples. These findings underscore the importance of diligent monitoring and judicious selection of antifungal agents to ensure effective treatment strategies. [ABSTRACT FROM AUTHOR]

Mucormycosis is a disease with a high percentage of mortality. This opportunistic disease is caused by pathogens of the Zygomicota family of the order Mucorales, which affect considerably, mainly immunocompromised patients. We present the case of a patient approached at the Hospital Central Militar de México, diagnosed with rhino-orbito-cerebral mucormycosis, with histopathological report of non-septated hyaline hyphae of 90 º, referring to the aforementioned diagnosis. A multidisciplinary approach to the pathology was carried out with diagnosis, timely medical and surgical treatment, achieving a favorable evolution and prognosis in a condition whose outcome is usually fatal. [ABSTRACT FROM AUTHOR]

PURPOSE: A sudden surge of Mucormycosis cases during the second wave of Covid 19 was observed in certain parts of India. The reasons for this upsurge remain unknown. However its impact on the overall healthcare system was quite overwhelming. In this context this study was decided to estimate and assess the spectrum of orbital involvement in patients with Mucormycosis, to find its association with coexisting disease entities if any, and at the same time evaluate the therapeutic response to established treatment regimens. MATERIALS AND METHODS: This descriptive longitudinal study was conducted over a period of six months. Patients presenting with symptoms of Mucormycosis were jointly evaluated by a multi speciality team. After confirmation of diagnosis, patients were treated with intravenous Amphotericin B, surgical debridement of affected sinuses and orbital exenteration when indicated. They were followed up for three months after discharge. RESULTS: Forty-three patients were enrolled in this study. Thirty-seven (86.04%) were COVID positive. All of them had history of steroid exposure during COVID treatment. Ninety five percent of study participants had diabetes mellitus. Twenty-seven (62.79%) patients had orbital involvement. Most common clinical presentation was peri-orbital or facial pain and edema. Besides medical treatment, thirty-nine patients (90.69%) required sinus debridement and nine patients (20.9%) required orbital exenteration. Thirteen patients (30.23%) expired during the follow up period. With treatment disease regressed in twenty patients (46.51%). CONCLUSION: Diabetes and use of steroids to prevent anticipated cytokine storm may be the inciting factors for Orbital Mucormycosis in COVID patients. Early diagnosis, treatment and control of risk factors are keys for recovery and survival. [ABSTRACT FROM AUTHOR]

This study aims to investigate the clinical distribution characteristics and drug susceptibility profiles of invasive Candida isolates in a tertiary hospital in Urumqi. Methods: The examination was conducted on samples obtained from patients who were clinically diagnosed with invasive candidiasis in this hospital. A total of 109 strains of Candida strains were identified through the use of internal transcribed spacer (ITS) sequencing and fungal cultivation methods.The clinical distribution of the strains was analyzed. Antifungal drug susceptibility tests were performed using the Sensititre YO10 fungal drug susceptibility plate based on the micro-broth dilution method. Results: Candida albicans had the highest percentage (51.38%) among 109 Candida isolates, followed by C. glabrata (18.35%) and C. tropicalis (15.60%). The isolates were predominantly found in the respiratory department (41.28%), intensive care unit (ICU) (31.19%), and infection department (9.17%).The results of drug susceptibility tests indicated that amphotericin B, 5-fluorocytosine, and echinocandins exhibited good in vitro antifungal activity, with a susceptibility rate of over 96%. However, the azoles demonstrated low antifungal activity, especially posaconazole and voriconazole, which had high resistance rates of 64.71% for C. tropicalis and 70% for C. glabrata, respectively. Conclusion: In our hospital, Candida albicans was identified as the primary causal agent of invasive candidiasis. In terms of in vitro antifungal activity, echinocandins, amphotericin B, and 5-fluorocytosine demonstrated efficacy against invasive Candida infections. However, it was important to note that C. glabrata and C. tropicalis exhibited low susceptibility to azoles. [ABSTRACT FROM AUTHOR]

Purpose: Cladophialophora bantiana is a wonted melanized fungus causing brain abscess. In past many cases were reported from Asia, particularly from India. Of late, there is a rise in cases in places besides Asia and hence a review of the cases is warranted. Methods: We present a case of fatal cerebral phaeohyphomycosis caused by C. bantiana and conduct a systematic review of culture confirmed brain abscess due to C. bantiana reported between 2015 and 2022. Results: Of the 39 cases found, majority (68%) were immunocompromised. The various clinical presentations were headache (53%), hemiparesis (34%), visual disturbance (25%), altered sensorium (18%), aphasia/dysarthria (12%) and seizures (9%). Isolated lesion was observed in 18 (60%) patients. In the sequence of occurrence, the lesions were in frontal (30%), temporal (27%) and parietal (20%) region. There were five cases with coinfections such as concurrent detection of Nocardia pneumonia in two cases, toxoplasma DNA in brain abscess, coexisting pulmonary Cryptococcus neoformans infection and coexisting Candida in a case of brain abscess in one case each. Surgical intervention was performed in 84% cases. Antifungal therapy included voriconazole (80%), liposomal amphotericin B (76%), 5-fluorocytosine (30%), posaconazole (10%), and amphotericin B deoxycholate (6%). The overall mortality was 50% with lower mortality (42%) in regions outside Asia compared to Asia (63.6%) though not statistically significant. Conclusions: C. bantiana brain abscess is an emerging infection worldwide. Next generation sequencing is an upcoming promising diagnostic test. Early complete excision of the lesion with effective antifungals may improve the outcome. [ABSTRACT FROM AUTHOR]

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Pulmonary Mucormycosis is a fatal infectious disease with high mortality rate. The occurrence of Mucormycosis is commonly related to the fungal virulence and the host's immunological defenses against pathogens. Mucormycosis infection and granulation tissue formation occurred in the upper airway was rarely reported. This patient was a 60-year-old male with diabetes mellitus, who was admitted to hospital due to progressive cough, sputum and dyspnea. Highresolution computed tomography (HRCT) and bronchoscopy revealed extensive tracheal mucosal necrosis, granulation tissue proliferation, and severe airway stenosis. The mucosal necrotic tissue was induced by the infection of Rhizopus Oryzae, confirmed by metagenomic next-generation sequencing (mNGS) in tissue biopsy. This patient was treated with the placement of a covered stent and local instillation of amphotericin B via bronchoscope. The tracheal mucosal necrosis was markedly alleviated, the symptoms of cough, shortness of breath, as well as exercise tolerance were significantly improved. The placement of airway stent and transbronchial microtube drip of amphotericin B could conduce to rapidly relieve the severe airway obstruction due to Mucormycosis infection. [ABSTRACT FROM AUTHOR]