Multi-organ involvement caused by Scedosporium apiospermum infection after near drowning: a case report and literature review.

BACKGROUND: Scedosporium apiospermum (S. apiospermum) is a rare fungal pathogen that causes disseminated infections. It rarely affects immunocompetent individuals and has a poor prognosis. CASE PRESENTATION: A 37-year-old woman presented with multiple lesions in the lungs, brain, and eyes, shortly after near drowning in a car accident. The primary symptoms were chest tightness, limb weakness, headache, and poor vision in the left eye. S. apiospermum infection was confirmed by metagenomic next-generation sequencing (mNGS) of intracranial abscess drainage fluid, although intracranial metastases were initially considered. After systemic treatment with voriconazole, her symptoms improved significantly; however, she lost vision in her left eye due to delayed diagnosis. CONCLUSION: While S. apiospermum infection is rare, it should be considered even in immunocompetent patients. Prompt diagnosis and treatment are essential. Voriconazole may be an effective treatment option.

Periprosthetic bacterial and fugal infection after total knee arthroplasty with one-stage debridement: a case report.

BACKGROUND: Periprosthetic infection is a serious complication after arthroplasty and is characterized by a long duration, recurrence, and a low cure rate. Although fungal infections are infrequent, they are often catastrophic, with an insidious onset, a long duration, atypical clinical symptoms, and imaging features in the early stage. They are easily misdiagnosed, or the diagnosis is missed, resulting in wrong treatment approaches. CASE PRESENTATION: This paper reports a case involving a 62-year-old female patient of Korean ethnicity with a periprosthetic infection after knee arthroplasty who underwent joint debridement. A preoperative metagenomic next-generation sequencing of joint aspirate revealed Staphylococcus epidermidis. However, postsurgical tissue cultures confirmed the fungal infection. The patient received oral voriconazole and intra-articular injection of voriconazole for antifungal treatment. Since bacterial infection could not be ruled out, we also prescribed levofloxacin. No infection recurrence was observed after more than 22 months of follow-up. In the treatment of this patient, successful short-term follow-up was achieved, but long-term efficacy still cannot be determined. CONCLUSIONS: In addition to the case study, we provide an analysis of the diagnosis and treatment of fungal infection after arthroplasty, especially the efficacy of debridement, antibiotics, and implant retention for a short-term outcome.

An immunocompetent host with blood-disseminated Aspergillus versicolor spondylitis: a case report and literature review.

Blood-disseminated Aspergillus spondylitis in immunocompetent individuals is rare. The clinical, imaging, and pathological manifestations of this condition are not specific. Therefore, this disease is prone to misdiagnosis and a missed diagnosis. Systemic antifungal therapy is the main treatment for Aspergillus spondylitis. We report a case of blood-disseminated Aspergillus versicolor spondylitis in a patient with normal immune function. The first antifungal treatment lasted for 4 months, but Aspergillus spondylitis recurred a few months later. A second antifungal treatment course was initiated for at least 1 year, and follow-up has been ongoing. Currently, there has been no recurrence.

Pathogenic Aspergillus Strains Identification and Antifungal Susceptibility Analysis of 452 Cases with Otomycosis in Jingzhou, China.

OBJECTIVE: To study the distribution of pathogenic Aspergillus strains of otomycosis in central China and the identification of their antifungal sensitivity. METHODS: We collected external ear canal secretions clinically diagnosed as otomycosis from April 2020 to January 2023 from the Department of Otolaryngology-Head and Neck Surgery in central China. The pathogenic Aspergillus strains were identified through morphological examination and sequencing. The antifungal sensitivity was performed using the broth microdilution method described in the Clinical Laboratory Standard Institute document M38-A3. RESULTS: In the 452 clinical strains isolated from the external ear canal, 284 were identified as Aspergillus terreus (62.83%), 92 as Aspergillus flavus (20.35%), 55 as Aspergillus niger (12.17%). In antifungal susceptibility tests the MIC of Aspergillus strains to bifonazole and clotrimazole was high,all the MIC90 is > 16 ug/mL. However, most Aspergillus isolates show moderate greatly against terbinafine, itraconazole and voriconazole. CONCLUSION: A. terreus is the most common pathogenic Aspergillus strain in otomycosis in central China. The selected topical antifungal drugs were bifonazole and clotrimazole; the drug resistance rate was approximately 30%. If the infection is persistent and requires systemic treatment, terbinafine and itraconazole can be used. The resistance of Aspergillus in otomycosis to voriconazole should be screened to avoid the systemic spread of infection in immunocompromised people and poor compliance with treatment. However, the pan-azole-resistant strain of Aspergillus should be monitored, particularly in high-risk patients with otomycosis.

A novel approach to reducing hepatotoxicity related to fungal prophylaxis in pediatric lung transplant recipients.

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.

Diagnosis of pulmonary Scedosporium apiospermum infection from bronchoalveolar lavage fluid by metagenomic next-generation sequencing in an immunocompetent female patient with normal lung structure: a case report and literature review.

BACKGROUND: Scedosporium apiospermum (S. apiospermum) belongs to the asexual form of Pseudallescheria boydii and is widely distributed in various environments. S. apiospermum is the most common cause of pulmonary infection; however, invasive diseases are usually limited to patients with immunodeficiency. CASE PRESENTATION: A 54-year-old Chinese non-smoker female patient with normal lung structure and function was diagnosed with pulmonary S. apiospermum infection by metagenomic next-generation sequencing (mNGS) of bronchoalveolar lavage fluid (BALF). The patient was admitted to the hospital after experiencing intermittent right chest pain for 8 months. Chest computed tomography revealed a thick-walled cavity in the upper lobe of the right lung with mild soft tissue enhancement. S. apiospermum was detected by the mNGS of BALF, and DNA sequencing reads were 426. Following treatment with voriconazole (300 mg q12h d1; 200 mg q12h d2-d20), there was no improvement in chest imaging, and a thoracoscopic right upper lobectomy was performed. Postoperative pathological results observed silver staining and PAS-positive oval spores in the alveolar septum, bronchiolar wall, and alveolar cavity, and fungal infection was considered. The patient's symptoms improved; the patient continued voriconazole for 2 months after surgery. No signs of radiological progression or recurrence were observed at the 10-month postoperative follow-up. CONCLUSION: This case report indicates that S. apiospermum infection can occur in immunocompetent individuals and that the mNGS of BALF can assist in its diagnosis and treatment. Additionally, the combined therapy of antifungal drugs and surgery exhibits a potent effect on the disease.

A systemic infection involved in lung, brain and spine caused by Scedosporium apiospermum species complex after near-drowning: a case report and literature review.

Scedosporium apiospermum species complex are widely distributed fungi that can be found in a variety of polluted environments, including soil, sewage, and decaying vegetation. Those opportunistic pathogens with strong potential of invasion commonly affect immunosuppressed populations However, few cases of scedosporiosis are reported in immunocompetent individuals, who might be misdiagnosed, leading to a high mortality rate. Here, we reported an immunocompetent case of systemtic infection involved in lung, brain and spine, caused by S. apiospermum species complex (S. apiospermum and S. boydii). The patient was an elderly male with persistent fever and systemtic infection after near-drowning. In the two tertiary hospitals he visited, definite diagnosis was extremely difficult. After being admitted to our hospital, he was misdiagnosed as tuberculosis infection, before diagnosis of S. apiospermum species complex infection by the metagenomic next-generation sequencing. His symptoms were alleviated after voriconazole treatment. In the present case, the details associated with its course were reported and published studies on Scedosporium spp. infection were also reviewed, for a better understanding of this disease and reducing the misdiagnosis rate.

Fluconazole-resistant Candida parapsilosis genotypes from hospitals located in five Spanish cities and one in Italy: Description of azole-resistance profiles associated with the Y132F ERG11p substitution.

BACKGROUND: Fluconazole-resistant Candida parapsilosis is a matter of concern. OBJECTIVES: To describe fluconazole-resistant C. parapsilosis genotypes circulating across hospitals in Spain and Rome and to study their azole-resistance profile associated with ERG11p substitutions. PATIENTS/METHODS: We selected fluconazole-resistant C. parapsilosis isolates (n = 528 from 2019 to 2023; MIC ≥8 mg/L according to EUCAST) from patients admitted to 13 hospitals located in five Spanish cities and Rome. Additionally, we tested voriconazole, posaconazole, isavuconazole, amphotericin B, micafungin, anidulafungin and ibrexafungerp susceptibility. RESULTS: Of the 53 genotypes found, 49 harboured the Y132F substitution, five of which were dominating city-specific genotypes involving almost half the isolates. Another genotype involved isolates harbouring the G458S substitution. Finally, we found two genotypes with the wild-type ERG11 gene sequence and one with the R398I substitution. All isolates were fully susceptible/wild-type to amphotericin B, anidulafungin, micafungin and ibrexafungerp. The azole-resistance patterns found were: voriconazole-resistant (74.1%) or voriconazole-intermediate (25.2%), posaconazole-resistant (10%) and isavuconazole non-wild-type (47.5%). Fluconazole-resistant and voriconazole non-wild-type isolates were likely to harbour substitution Y132F if posaconazole was wild type; however, if posaconazole was non-wild type, substitution G458S was indicated if isavuconazole MIC was >0.125 mg/L or substitution Y132F if isavuconazole MIC was ≤0.125 mg/L. CONCLUSIONS: We detected a recent clonal spread of fluconazole-resistant C. parapsilosis across some cities in Spain, mostly driven by dominating city-specific genotypes, which involved a large number of isolates harbouring the Y132F ERG11p substitution. Isolates harbouring substitution Y132F can be suspected because they are non-susceptible to voriconazole and rarely posaconazole-resistant.

Novel automated antifungal susceptibility testing system for yeasts based on dual-detection algorithm of turbidimetry and colorimetry.

Introduction. The increasing prevalence and growing resistance of fungi present a significant peril to public health. There are only four classes of antifungal medicines available today, and few candidates are in clinical trials.Hypothesis/Gap Statement. Rapid and sensitive diagnostic techniques are lacking for most fungal pathogens, and those that do exist are expensive or hard to obtain.Aim. This study aimed to evaluate the feasibility of a novel automated antifungal susceptibility testing system, Fungus AST, in comparison to the broth microdilution method (BMD) recommended by the Clinical and Laboratory Standards Institute (CLSI).Methodology. A total of 101 clinical Candida spp. isolates were collected from the Zengcheng Branch of Nanfang Hospital and subjected to antifungal susceptibility testing. Antifungal susceptibility was assessed using the Fungus AST method and the BMD.Results. In this study, we introduce a novel automated antifungal susceptibility testing system, Fungus AST, which detects the turbidity and/or colour intensity of microdilution wells using a four-wavelength detection technology in real time and is designed to match the growth characteristics of strains over time. Based on our analysis, all reportable ranges of Fungus AST were suitable for clinical fungal isolates in PR China. Within ±twofold dilutions, reproducibility was 100 %. Considering the BMD as a referenced method, ten antifungal agents (anidulafungin, caspofungin, micafungin, fluconazole, voriconazole, posaconazole, itraconazole, amphotericin B, 5-flucytosine and nystatin) showed an essential agreement of >95 %. The category agreement of five antifungal agents (anidulafungin, caspofungin, micafungin, fluconazole and voriconazole) was excellent at >90 %. One Candida albicans isolate and voriconazole showed a major error (ME) (1.7 %), and no other ME or very ME agents were found.Conclusion. Given the above, it can be argued that the utilization of Fungus AST is a discretionary automated approach. More improvements are needed in Fungus AST compared to the BMD system for a wider range of clinical isolates, including different types of fungi.

[Clinical features and risk factors for invasive fungal sinusitis after allogeneic hematopoietic stem cell transplantation].

Objective: To analyze the clinical characteristics and outcomes of patients with invasive fungal sinusitis (invasive fungal rhinosinusitis, IFR) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and explored the risk factors for IFR after allo-HSCT. Methods: Nineteen patients with IFR after allo-HSCT at Peking University People's Hospital from January 2012 to December 2021 were selected as the study group, and 95 patients without IFR after allo-HSCT during this period were randomly selected as the control group (1:5 ratio) . Results: Nineteen patients, including 10 males and 9 females, had IFR after allo-HSCT. The median age was 36 (10-59) years. The median IFR onset time was 68 (9-880) days after allo-HSCT. There were seven patients with acute myeloid leukemia, five with acute lymphoblastic leukemia, two with myelodysplastic syndrome, two with chronic myeloid leukemia, one with acute mixed-cell leukemia, one with multiple myeloma, and one with T-lymphoblastic lymph node tumor. There were 13 confirmed cases and 6 clinically diagnosed cases. The responsible fungus was Mucor in two cases, Rhizopus in four, Aspergillus in four, and Candida in three. Five patients received combined treatment comprising amphotericin B and posaconazole, one patient received combined treatment comprising voriconazole and posaconazole, nine patients received voriconazole, and four patients received amphotericin B. In addition to antifungal treatment, 10 patients underwent surgery. After antifungal treatment and surgery, 15 patients achieved a response, including 13 patients with a complete response and 2 patients with a partial response. Multivariate analysis revealed that neutropenia before transplantation (P=0.021) , hemorrhagic cystitis after transplantation (P=0.012) , delayed platelet engraftment (P=0.008) , and lower transplant mononuclear cell count (P=0.012) were independent risk factors for IFR after allo-HSCT. The 5-year overall survival rates in the IFR and control groups after transplantation were 29.00%±0.12% and 91.00%±0.03%, respectively (P<0.01) . Conclusion: Although IFR is rare, it is associated with poor outcomes in patients undergoing allo-HSCT. The combination of antifungal treatment and surgery might be effective.

Economic and budgetary impact evaluation of isavuconazole (Cresemba®) versus voriconazole (Vfend®) for the treatment of patients with possible invasive aspergillosis from the perspective of the Brazilian supplementary health system.

OBJECTIVES: This study aims to evaluate the cost-utility and the budgetary impact of isavuconazole compared to voriconazole in patients with suspected invasive aspergillosis (IA) from the perspective of the Brazilian supplementary health system (SHS). METHODS: In this model, a decision tree was developed and included patients with possible IA. Efficacy parameters were extracted from the clinical studies. Drug acquisition, hospitalization costs and adverse events were also collected. Alternative 3- and 10-year time horizon scenarios were used. In addition, deterministic and probabilistic sensitivity analyses were simulated. A budget impact analysis of isavuconazole versus voriconazole was performed, assuming a time horizon of 5 years. In addition, sensitivity analyses were conducted to assess the robustness of the model. Results are reported in Brazilian Real (BRL), year values 2022. RESULTS: The economic analysis of the base case showed that isavuconazole is associated with a saving of 95,174.00 BRL per patient compared to voriconazole. All other simulated scenarios showed that isavuconazole is dominant versus comparators when considering a willingness to pay 40,688.00 BRL/Quality-Adjusted Life Years (QALY). The results were considered robust by the sensitivity analyses. The budget impact analysis showed that the incorporation of isavuconazole generates savings to the SHS, compared to voriconazole, of approximately 20.5 million BRL in the first year. This reaches about 54 million BRL in the fifth incorporation year, considering the market penetration of 20% in the first year, and 50% in the fifth year. CONCLUSION: Compared with voriconazole, isavuconazole is regarded as a dominant treatment strategy for patients with suspected IA and generates savings for the SHS.

Evolutionary trends in antifungal resistance: a meta-analysis.

The present paper includes a meta-analysis of literature data on 318 species of fungi belonging to 34 orders in their response to 8 antifungal agents (amphotericin B, caspofungin, fluconazole, itraconazole, ketoconazole, posaconazole, terbinafine, and voriconazole). Main trends of MIC results at the ordinal level were visualized. European Committee on Antimicrobial Susceptibility Testing and Clinical & Laboratory Standards Institute (CLSI) clinical breakpoints were used as the staff gauge to evaluate MIC values ranging from resistance to susceptibility, which were subsequently compared with a phylogenetic tree of the fungal kingdom. Several orders (Hypocreales, Microascales, and Mucorales) invariably showed resistance. Also the basidiomycetous orders Agaricales, Polyporales, Sporidiales, Tremellales, and Trichosporonales showed relatively high degrees of azole multi-resistance, while elsewhere in the fungal kingdom, including orders with numerous pathogenic and opportunistic species, that is, Onygenales, Chaetothyiales, Sordariales, and Malasseziales, in general were susceptible to azoles. In most cases, resistance vs susceptibility was consistently associated with phylogenetic distance, members of the same order showing similar behavior. IMPORTANCE: A kingdom-wide the largest set of published wild-type antifungal data comparison were analyzed. Trends in resistance in taxonomic groups (monophyletic clades) can be compared with the phylogeny of the fungal kingdom, eventual relationships between fungus-drug interaction and evolution can be described.

In vitro interactions of proton pump inhibitors and azoles against pathogenic fungi.

Introduction: Azole resistance has been increasingly reported and become an issue for clinical managements of invasive mycoses. New strategy with combination therapy arises as a valuable and promising alternative option. The aim of the present study is to investigate the in vitro combinational effect of proton pump inhibitors (PPIs) and azoles against pathogenic fungi. Methods: In vitro interactions of PPIs including omeprazole (OME), lansoprazole (LAN), pantoprazole (PAN), and rabeprazole (RAB), and commonly used azoles including itraconazole (ITC), posaconazole (POS), voriconazole (VRC) and fluconazole (FLC), were investigated via broth microdilution chequerboard procedure adapted from the CLSI M27-A3 and M38-A2. A total of 67 clinically isolated strains, namely 27 strains of Aspergillus spp., 16 strains of Candida spp., and 24 strains of dematiaceous fungi, were studied. C. parapsilosis (ATCC 22019) and A. flavus (ATCC 204304) was included to ensure quality control. Results: PPIs individually did not exert any significant antifungal activity. The combination of OME with ITC, POS, or VRC showed synergism against 77.6%, 86.6%, and 4% strains of tested pathogenic fungi, respectively, while synergism of OME/FLC was observed in 50% strains of Candida spp. Synergism between PAN and ITC, POS, or VRC was observed against 47.8%, 77.6% and 1.5% strains of tested fungi, respectively, while synergism of PNA/FLC was observed in 50% strains of Candida spp. Synergism of LAN with ITC, POS, or VRC was observed against 86.6%, 86.6%, and 3% of tested strains, respectively, while synergism of LAN/FLC was observed in 31.3% strains of Candida spp. Synergy of the combination of RAB with ITC, POS, or VRC was observed against 25.4%, 64.2%, and 4.5% of tested strains, respectively, while synergism of RAB/FLC was observed in 12.5% of Candida spp.. Among PPIs, synergism was least observed between RAB and triazoles, while among triazoles, synergism was least observed between VRC and PPIs. Among species, synergy was much more frequently observed in Aspergillus spp. and dematiaceous fungi as compared to Candida spp. Antagonism between PPIs with ITC or VRC was occasionally observed in Aspergillus spp. and dematiaceous fungi. It is notable that PPIs combined with azoles showed synergy against azole resistant A. fumigatus, and resulted in category change of susceptibility of ITC and POS against Candida spp. Discussion: The results suggested that PPIs combined with azoles has the potential to enhance the susceptibilities of azoles against multiple pathogenic fungi and could be a promising strategy to overcome azole resistance issues. However, further investigations are warranted to study the combinational efficacy in more isolates and more species, to investigate the underlying mechanism of interaction and to evaluate the potential for concomitant use of these agents in human.

A systematic review and disability-adjusted life years of Scedosporium/Lomentospora infection in patients after near-drowning.

Scedosporium/Lomentospora species exist as saprophytic moulds that can potentially lead to serious infections in patients who have experienced near-drowning incidents. Scedosporium species are distributed across different regions of the world while Lomentospora prolificans has quite a restricted geographic distribution. We aimed to systematically review scedosporiosis cases after near-drowning, their clinical manifestations, underlying diseases, treatments, outcomes and its impact through disability-adjusted life years (DALYs). Five available sources were searched from 1 January 2007, to 20 April 2022. Thirty-eight studies, including 41 patients, were evaluated. Mean age was 33.6 ± 18.6 years (range 1-68), and 28 were male (68.3%). Central nervous system (CNS) dissemination predominated (36/41; 87.8%), presenting mainly as multiple brain abscesses (26/41; 63.4%), followed by lung involvement (22/41; 56.4%). Scedosporium apiospermum species complex was the most causative agent (38/41; 92.7%). Overall mortality was 51.2%. Half of the patients (18/37) were cured after receiving proper treatment, and in most cases, voriconazole alone or in combination with surgery or other antifungals caused survival. The mean survival time was 123 ± 27 days. Mean DALYs in 1980-2022 were 46.110 ± 3.318 (39.607-52.612). Time to diagnosis was estimated to be 120 days, and there was no association between time to diagnosis and outcome. Voriconazole is a potentially effective therapy, and combination of surgery and antifungal treatment may lead to more favourable outcome. Advances in early diagnosis and appropriate antifungal therapy may have contributed to reducing its mortality.

Invasive pulmonary and central nervous system aspergillosis in a child: A case report and literature review.

RATIONALE: Children with haematological malignancies have a higher risk of developing aggressive pulmonary aspergillosis and a higher mortality rate. The most common site of extrapulmonary aspergillosis in children is the central nervous system (CNS), and the death rate is higher when CNS is affected. Therefore, early diagnosis and treatment of invasive aspergillosis are essential for reducing mortality. PATIENT CONCERNS: We report a case of an 8-year-old girl with acute lymphoblastic leukaemia who developed invasive pulmonary aspergillosis complicated by CNS aspergillosis. Aspergillus was confirmed by metagenomic sequencing of pathogenic microorganisms. DIAGNOSES: Invasive pulmonary and central nervous system aspergillosis. INTERVENTIONS: The patient was treated with combined systemic antifungal agents (voriconazole and liposomal amphotericin B) and intrathecal injection of amphotericin B. OUTCOMES: The treatment was well tolerated and resulted in remarkable clinical and radiological head improvements. LESSONS: Invasive aspergillosis has a high mortality rate and requires early diagnosis and treatment. Pathogenic microbial metagenomic sequencing is a convenient method to assist in the early diagnosis of aspergillosis. Voriconazole is the drug of choice for the treatment of invasive aspergillosis. When CNS aspergillosis occurs, it can be combined with other systemic antifungal drugs and intrathecal injection of amphotericin B.

Safety, Tolerability, and Pharmacokinetics of Voriconazole for Injection in Two Preparations in Chinese Healthy Adult Volunteers.

Voriconazole is a second-generation, synthetic, triazole antifungal drug based on the structure of fluconazole. We compared the safety, tolerability, and pharmacokinetic characteristics of voriconazole for injection (200 mg) manufactured by at a dose of 6 mg/kg in Chinese healthy adult volunteers. This was a single-center, randomized, open, 2-preparation, single-dose, 2-period, 2-sequence, crossover bioequivalence clinical trial. Twenty-four eligible, healthy, male, and female volunteers were assigned randomly to one of 2 dose-sequence groups (test-reference group or reference-test group) in a 1:1 block. The voriconazole concentration in plasma was determined by protein precipitation and high-performance liquid chromatography-tandem mass spectrometry. The main PK parameters were calculated on the basis of a noncompartmental model. The ratio of the geometric mean of the maximum plasma drug concentration, area under the plasma concentration-time curve from time 0 to the last time of quantifiable concentration, and area under the plasma concentration-time curve from time 0 to infinity of the test preparation, and the reference preparation was 100.4%, 102%, and 102.2%, respectively. The 90% confidence intervals were between 80% and 125%, indicating that the 2 preparations were bioequivalent. The adverse events experienced by healthy adult volunteers were mild. Both preparations had a good safety profile.

Anti-Aspergillus activities of olorofim at sub-MIC levels during early-stage growth.

Olorofim, the first member of the novel class of antifungal drugs, the orotomides, shows promising anti-Aspergillus activity and is currently in phase III clinical development. Using high-throughput microscopy, we monitored olorofim's antifungal potential at sub-minimum inhibitory concentration (MIC) levels with a focus on early-stage growth. Unlike voriconazole, olorofim showed significant growth inhibitory activities against three main pathogenic Aspergillus species, Aspergillus fumigatus, Aspergillus flavus, and Aspergillus niger, at concentrations >100,000-fold below its MIC. IMPORTANCE: Among antifungal compounds in clinical development for systemic disease, the orotomide olorofim is one of only two that target a completely new mechanism of action. Olorofim is highly potent against pathogenic Aspergillus species including cryptic species that frequently show increased resistance to current agents. In this study, our primary focus was on evaluating in detail the inhibitory activity of voriconazole and olorofim against different pathogenic Aspergillus species employing high-throughput microscopy. Compared to standardized, less-sensitive visual assessment-based methods, microscopy-assisted growth monitoring allowed us to detect sub-MIC drug concentration ranges with significant inhibitory activity at early-stage growth. This revealed that olorofim exerts growth inhibition at concentrations that are several magnitudes below those of voriconazole.

Skin Manifestations of Micafungin Breakthrough Disseminated Trichosporonosis in Acute Megakaryoblastic Leukemia.

Disseminated trichosporonosis is a rare fungal infection whose risk factors are hematological malignancies and neutropenia. Recently, breakthrough Trichosporon infections after administration of micafungin, the first-line systemic antifungal agent in compromised hosts, have been widely recognized. A man in his seventies about 1 month into chemotherapy for acute megakaryoblastic leukemia presented with a worsening fever and dyspnea. The patient was being administered with empirical micafungin therapy for suspected candidiasis. As the symptoms progressed, scattered erythema appeared on the trunk, some with a dark red vesicle at the center. Blood cultures identified Trichosporon asahii, as did the specimen of the skin biopsy. On the basis also of the presence of pneumonia on chest computed tomography, we confirmed the diagnosis of disseminated trichosporonosis and changed the antifungal agent from micafungin to voriconazole. Blood culture turned out to be negative 1 month after administrating voriconazole. However, the patient died of the leukemia. Our review of previous reports on cutaneous manifestations of disseminated trichosporonosis revealed that despite their morphological diversity, erythema with a red papule or vesicle at the center, implying necrosis, was also observed in previous cases. Our case report suggests that dermatologists should be aware of skin manifestations of disseminated trichosporonosis after micafungin administration, especially in cases of hematological malignancies.

Fusariosis in burn patients: A systematic review of case reports.

Burns can cause skin damage, facilitating the entry of fungi and other microorganisms into the body, leading to infections. Fusarium is a fungus capable of infecting individuals with burn injuries. Diagnosing and treating Fusarium infections in burn patients can be challenging due to the manifestation of nonspecific symptoms. This study aims to investigate case reports and case series from published literature describing Fusarium infection in burned patients, in order to assess treatment regimens, clinical outcomes, and make recommendations for future management. We conducted searches on Web of Science, PubMed, ScienceDirect, and Medline for all case reports and case series containing keywords 'Burn', 'Burns', 'Burned', 'Fusarium', or 'Fusariosis' in the title or abstract. All burn patients who developed Fusarium fungal infections between January 1974 and March 2023 were included in the study. Demographic and clinical data were analyzed retrospectivity. The final analysis incorporates 24 case reports encompassing a total of 87 burn patients with Fusarium infection. Patient ages ranged from one to 85 years, with the majority being male (53%). The median percentage of burn surface area was 78%, and the skin in the face, upper limbs, and lower limbs were the most commonly infected sites. Fungal infections appeared around 10 days after the burn injury on average. The majority of the patients were identified through culture or histopathology. The Fusarium dimerum species complex, which was found in nine patients, was the most frequently identified Fusarium species complex. Amphotericin B was the most preferred treatment drug, followed by voriconazole, and 62% of patients underwent debridement. In our study, 23 patients (37%) died from fungal infections. Implementing early and effective treatment protocols targeting Fusarium spp. in burn treatment units can significantly reduce mortality rates. It is critical to enhance the understanding of fusariosis epidemiology and emphasize the importance of maintaining a high clinical suspicion for this condition in burn patients.