Treatment Of Invasive Fungal Infections Research Articles

Establishing an Efficient Genetic Manipulation System for Sulfated Echinocandin Producing Fungus Coleophoma empetri.

Micafungin is an important echinocandin antifungal agent for the treatment of invasive fungal infections. In industry, micafungin is derived from the natural product FR901379, which is a non-ribosomal cyclic hexapeptide produced by the filamentous fungus Coleophoma empetri. The difficulty of genetic manipulation in C. empetri restricts the clarification of FR901379 biosynthetic mechanism. In this work, we developed an efficient genetic manipulation system in the industrial FR901379-producing strain C. empetri MEFC009. Firstly, a convenient protoplast-mediated transformation (PMT) method was developed. Secondly, with this transformation method, the essential genetic elements were verified. Selectable markers hph, neo, and nat can be used for the transformation, and promotors Ppgk, PgpdA, and PgpdAt are functional in C. empetri MEFC009. Thirdly, the frequency of homologous recombination was improved from 4 to 100% by deleting the ku80 gene, resulting in an excellent chassis cell for gene-targeting. Additionally, the advantage of this genetic manipulation system was demonstrated in the identification of the polyketide synthase (PKS) responsible for the biosynthesis of dihydroxynapthalene (DHN)-melanin. This genetic manipulation system will be a useful platform for the research of FR901379 and further genome mining of secondary metabolites in C. empetri.

Impact of CYP2C19 Genotype on Voriconazole Exposure and Effect of Voriconazole on the Activity of CYP3A in Patients with Hematological Malignancies

Voriconazole (VRC) is a first-line drug for the treatment of invasive fungal infections (IFIs) and an inhibitor of CYP3A activity.The aims of this study is to investigate the influence of related factors on the plasma concentration of voriconazole and the effect of voriconazole on the activity of CYP3A in patients with hematological malignancies. A total of 89 patients received an initial dose of 6 mg/kg followed by 4 mg/kg every 12 h were included in the study. Blood samples were collected before and 2 h after administration for subsequent testing and for the extraction of DNA samples. Voriconazole and voriconazole N-oxide in the plasma were detected by LC-MS/MS. The effect of voriconazole on CYP3A activity was evaluated by the ratio of the endogenous biomarkers 6β-hydroxycortisol and cortisol. During the study period, the overall incidence of adverse reactions was 33.6% (with no deaths). The metabolite type of CYP2C19 and combined use of CYP2C19 enzyme inhibitors both had a significant impact on voriconazole exposure. Voriconazole has a long-lasting and potent inhibitory effect on CYP3A activity. The exposure of CYP3A substrate in combination with metabolic enzyme inhibitors voriconazole could increase. Therefore, the combination uses with voriconazole need to be considered carefully and assessed adequately.

Real-world assessment of the effectiveness of posaconazole for the prophylaxis and treatment of invasive fungal infections in hematological patients: A retrospective observational study.

The aim of the study was to analyze the efficacy of posaconazole for the prophylaxis and treatment of invasive fungal diseases (IFDs) in patients with hematological malignancies.In this retrospective observational multi-center study, 762 patients from 25 Chinese hematological centers were enrolled. Inclusion criteria were patients with hematological malignancy or they had undergone hematopoietic stem cell transplantation and received at least 1 dose of posaconazole. The primary endpoints were the observation of breakthrough rates and the clinical efficacy of posaconazole prophylaxis. The secondary endpoint was the efficacy of posaconazole for the treatment of IFDs.Of the 762 enrolled patients, 456 (59.8%) were prescribed posaconazole prophylactically while 243 (31.9%) received posaconazole as an IFD treatment (12 proven, 61 probable, 109 possible, and 61 unclassified IFD cases) for ≥7 days. The overall IFD breakthrough rate (probable cases) for the ≥4 days prophylactic treatment (n = 445) group was 1.6% (95% Cl: 0.6%–3.2%), with breakthrough rates of 2.6% for acute myeloid leukemia/myelodysplastic syndrome patients undergoing chemotherapy and 2.2% for hematopoietic stem cell transplantation patients. For primary antifungal prophylaxis, the breakthrough rate was 1.9% and for secondary antifungal prophylaxis 0%. The overall effective IFD remission rate of patients treated for ≥7 days with posaconazole was 56.0% and the effective remission rate of proven/probable/possible IFD cases was 59.3%. The effective remission rate of posaconazole as salvage therapy was 50% (95% CI: 32.4%–67.6%) including 75% (CI: 19.4%–99.4%) for Aspergillus infections.The present retrospective study confirmed posaconazole as IFD prophylaxis and medication for hematological malignancy patients undergoing various treatments in China.

How urgent is the need for new antifungals?

ABSTRACT Introduction: Invasive fungal infection carries a high morbidity, mortality and economic cost. In recent times, a rising incidence of fungal infection and antifungal resistance is occurring which has prompted the development of novel antifungal agents. Areas covered:In this perspective, the authors describe the current status of registered antifungals and their limitations in the treatment of invasive fungal infection. They also go on to describe the new antifungal agents that are in the clinical stage of development and how they might be best utilized in patient care in the future. Expert opinion: The antifungal drug development pipeline has responded to a growing need for new agents to effectively treat fungal disease without concomitant toxicity or issues with drug tolerance. Olorofim (F901318), ibrexafungerp (SCY-078), fosmanogepix (APX001), rezafungin (CD101), oteseconazole (VT-1161), encochleated amphotericin B (MAT2203), nikkomycin Z (NikZ) and ATI-2307 are all in the clinical stage of development and offer great promise in offering clinicians better agents to treat these difficult infections.

Identification of Thiazoyl Guanidine Derivatives as Novel Antifungal Agents Inhibiting Ergosterol Biosynthesis for Treatment of Invasive Fungal Infections.

Invasive fungal infections (IFIs) are fatal infections, but treatment options are limited. The clinical efficacies of existing drugs are unsatisfactory because of side effects, drug-drug interaction, unfavorable pharmacokinetic profiles, and emerging drug-resistant fungi. Therefore, the development of antifungal drugs with a new mechanism is an urgent issue. Herein, we report novel aryl guanidine antifungal agents, which inhibit a novel target enzyme in the ergosterol biosynthesis pathway. Structure-activity relationship development and property optimization by reducing lipophilicity led to the discovery of 6h, which showed potent antifungal activity against Aspergillus fumigatus in the presence of serum, improved metabolic stability, and PK properties. In the murine systemic A. fumigatus infection model, 6h exhibited antifungal efficacy equivalent to voriconazole (1e). Furthermore, owing to the inhibition of a novel target in the ergosterol biosynthesis pathway, 6h showed antifungal activity against azole-resistant A. fumigatus.

Impact of CYP2C19 Phenotype and Drug-Drug Interactions on Voriconazole Concentration in Pediatric Patients.

Voriconazole (VRC), a first-line agent for the treatment of invasive fungal infections, is mainly metabolized by human cytochrome P450 (CYP) 2C19. In this study, a retrospective analysis was performed to investigate the key factors that influence the plasma trough concentration (Cmin) of VRC, and an appropriate dosing regimen for pediatric patients was drafted subsequently. Overall, factors such as age, CYP2C19 phenotype, and combination medication with proton pump inhibitors accounted for 23.4% of variability in dose-normalized Cmin values of VRC by a multiple linear regression analysis. Dose-normalized Cmin values in the poor metabolizers (PMs) and intermediate metabolizers (IMs) were significantly higher than those in extensive metabolizers (EMs) (P < 0.001). To achieve therapeutic Cmin for CYP2C19 ultrarapid metabolizers (UMs) or EMs, patients aged no more than 12 and more than 12 years required doses of 6.53 ± 2.08 and 3.95 ± 0.85 mg/kg of body weight twice daily (P = 0.007). For CYP2C19 PMs or IMs, patients aged under 12 and over 12 years required doses of 5.75 ± 1.73 and 4.23 ± 0.76 mg/kg twice daily, respectively (P = 0.019). Furthermore, coadministration of rifamycin sodium or omeprazole exhibited significant effects on VRC Cmin. Taken together, it is necessary to pay attention to the impact of CYP2C19 phenotype and drug-drug interactions to achieve optimal therapy.

Development of a Simple and Robust Whole Blood Assay with Dual Co-Stimulation to Quantify the Release of T-Cellular Signature Cytokines in Response to Aspergillus fumigatus Antigens.

Deeper understanding of mold-induced cytokine signatures could promote advances in the diagnosis and treatment of invasive mycoses and mold-associated hypersensitivity syndromes. Currently, most T-cellular immunoassays in medical mycology require the isolation of mononuclear cells and have limited robustness and practicability, hampering their broader applicability in clinical practice. Therefore, we developed a simple, cost-efficient whole blood (WB) assay with dual α-CD28 and α-CD49d co-stimulation to quantify cytokine secretion in response to Aspergillus fumigatus antigens. Dual co-stimulation strongly enhanced A. fumigatus-induced release of T-cellular signature cytokines detectable by enzyme-linked immunosorbent assay (ELISA) or a multiplex cytokine assay. Furthermore, T-cell-dependent activation and cytokine response of innate immune cells was captured by the assay. The protocol consistently showed little technical variation and high robustness to pre-analytic delays of up to 8 h. Stimulation with an A. fumigatus lysate elicited at least 7-fold greater median concentrations of key T-helper cell signature cytokines, including IL-17 and the type 2 T-helper cell cytokines IL-4 and IL-5 in WB samples from patients with Aspergillus-associated lung pathologies versus patients with non-mold-related lung diseases, suggesting high discriminatory power of the assay. These results position WB-ELISA with dual co-stimulation as a simple, accurate, and robust immunoassay for translational applications, encouraging further evaluation as a platform to monitor host immunity to opportunistic pathogens.

La infección fúngica en el paciente pediátrico inmunodeprimido

In recent years, immunodeficiency condition has experienced a rise among children, who are at risk of invasive fungal infections (IFI) due to their health condition. Cancer, non-malignant hematological diseases, as primary immunodeficiencies, hematopoietic stem cell transplantation (HSCT), extreme prematurity, or critically ill condition in Pediatric Intensive Care Unit (PICU) are some immunosuppressive situations in children. The use of oncologic therapies, including immunotherapy and monoclonal antibodies, for the treatment of the aforementioned health conditions has led to an increase in morbidity and mortality rates of IFI in children.The underlying diseases and their management, comorbidities, the diagnostic tests used (both molecular and imaging), as well as the treatment used can be significantly different between adult patients and children admitted to PICU or with cancer. In pediatrics, the treatment of IFI is based primarily on pharmacokinetic studies performed in adults. In higher risk patients prophylaxis should be considered and, in the case of an IFI diagnosis, an antifungal treatment should be administered as early as possible, supported by the reversion of the immune dysfunction and surgery when appropriate.

AmBisome, tres retos: infección por Candida auris, infección del sistema nervioso central e infección asociada a biopelículas

The treatment of invasive fungal infections remains a challenge, both for the diagnosis and for the need of providing the appropriate antifungal therapy. Candida auris is a pathogenic yeast that is responsible for hospital outbreaks, especially in intensive care units; it is characterized by a high resistance to the antifungal agents and can become multidrug-resistant. At present, the recommended antifungal agents for the invasive infections with this pathogen are echinocandins, always after carrying out an antifungal susceptibility testing. In case of no clinical response or persistent candidemia, the addition of liposomal amphotericin B or isavuconazole may be considered. Both fungal infection of the central nervous system and that associated with biomedical devices remain rare entities affecting mainly immunocompromised patients. However, an increase in their incidence in recent years, along with high morbidity and mortality, has been shown. The treatment of these infections is conditioned by the limited knowledge of the pharmacokinetic properties of antifungals. A better understanding of the pharmacokinetic and pharmacodynamic parameters of the different antifungals is essential to determine the efficacy of the antifungal agents in the treatment of these infections.

Assistant role of manifestations under tracheoscopy in the diagnosis of invasive pulmonary aspergillosis in severe patients

To evaluate the assistant role of manifestations under tracheoscopy in the diagnosis of invasive pulmonary aspergillosis (IPA) in severe patients. A retrospective study was conducted. The patients with suspected IPA admitted to intensive care unit (ICU) of Affiliated Hospital of Binzhou Medical College from January 2015 to December 2019 were enrolled. The diagnosis, clinical diagnosis and suspected diagnosis were made according to the grading criteria of Guidelines for the diagnosis and treatment of invasive fungal infection in severe patients (2007). Those who met the criteria were enrolled in the IPA group, and those who did not meet the criteria or other pathogens were enrolled in the non-IPA group. The general data of the patients were collected, and the changes of tracheal and bronchial mucosa under tracheal microscope before and after treatment were recorded, as well as the results of galactomannan (GM) test and aetiology culture of bronchoalveolar lavage fluid (BALF). The baseline, bronchoscopy and pulmonary CT manifestations and their dynamic changes were compared in each group. A total of 142 patients with suspected IPA were finally enrolled. Among them, 12 were pathologically proven IPA, 77 were probable IPA, 22 were possible IPA, and 31 were undefined IPA. Of the 142 patients, 60 had typical manifestations of mucosal injury under bronchoscopy, including 7 proven IPA patients (58.3%), 52 probable IPA patients (67.5%), and 1 possible IPA patient (4.5%), but none undefined IPA patient. The patients undergoing lung CT scan were 12 proven IPA patients (100%), 73 probable IPA patients (94.8%), and 21 possible IPA patients (95.5%), respectively. Most of the Chest CT showed patchy or strip density increasing and other non-specific manifestations. There were 3 proven IPA patients (25.0%), 7 probable IPA patients (9.0%), and 0 possible IPA patient (0%) who had typical IPA CT manifestations (halo sign and cavity or crescent sign). Among the patients of proven IPA and probable IPA (89 cases), there were a total of 35 cases with endoscopic airway mucosal injury and tracheoscopy reexamination ≥ 3 times. All the 35 patients received anti-aspergillus treatment, among which 16 survived and 19 died. Among the 16 patients who survived, the microscopic appearance of mucosal injury was gradually reduced and the clinical manifestations were gradually improved. Of the 19 patients who died, 16 had deteriorated endoscopic airway mucosal injury. The specific manifestations of severe patients with bronchial mucosal injury are of great significance in the diagnosis of IPA. In the case of severe patients who cannot receive pathological examination or chest CT in time, dynamic observation of the changes of airway mucosal injury is a simple auxiliary method to discover the changes of patients' condition in time, evaluate the effect of antifungal therapy and the prognosis of IPA.

#78: Use of Isavuconazonium for Treatment Of Invasive Fungal Infection in Immunocompromised Pediatric Patients

Abstract Background Isavuconazole (ISZ), dosed as the pre-drug isavuconazonium (ISM), is active against a wide variety of clinically important fungal pathogens. ISM is approved for the treatment of invasive aspergillosis and mucormycosis in adults ≥18 years of age. We present our experience with ISM to treat proven or probable fungal infection in immunocompromised pediatric patients. Methods Retrospective review of patients who received ISM at our institution between April 2016 and April 2019, we abstracted demographic information, primary diagnosis, indication for ISM therapy, ISZ serum concentrations if available, and outcomes. Results Of 14 patients who received ISM, 11 were ≤18 years of age (range 6–18 years). Underlying conditions included leukemia (n = 7), lymphoma (n = 1), post BMT (n = 1), diabetes (n = 1), and cardiac transplant (n = 1). Nine (82%) had proven invasive fungal infection (IFI) with aspergillosis (n = 2), zygomycosis (n = 3), mixed aspergillosis and zygomycosis (n = 2), mixed Rhizopus and Scedosporium (n = 1), and pathology only (n = 1) and 2 had probable IFI. Five of these 11 patients received combination ISM and liposomal amphotericin initially and the other 6 received liposomal amphotericin with or without other azoles prior to changing to ISM monotherapy. This was followed by monotherapy with ISM in 10 patients after a mean of 26 days (range 6–63) and continued dual therapy in the one. ISM dosing was 10 mg/kg q8h on days 1 and 2, followed by q24 thereafter, up to a maximum of 372 mg/dose. There were 19 measured ISZ serum concentrations obtained from 8 patients after &amp;gt;1 week of verified inpatient dosing, ranging from 1.0 to 7.5 mg/L, above the MIC in all cases when known. Three (27%) patients died of underlying non-mycological causes, 1 (9%) died of progressive scedosporiosis, and 7 (64%) improved. ISM was well tolerated with no dose-limiting, drug-related toxicities noted. Conclusions ISM is a well-tolerated therapeutic option in pediatric patients at risk for or with invasive mycosis. Only 1 of our 11 patients died from progressive fungal disease.

#28: Serum Posaconazole Concentrations Among Children, Adolescents, and Young Adults Receiving Delayed-Release Tablet And Intravenous Posaconazole

Abstract Background Posaconazole is a broad-spectrum antifungal used for prophylaxis and treatment of invasive fungal infections. There are limited data on the optimal dosing, safety, and effectiveness of the delayed-released tablets (DRT) and intravenous (IV) formulations in immunocompromised pediatric and adolescent patients. Methods A retrospective chart review was performed to study all immunocompromised patients who received DRT or IV formulations of posaconazole at our institution from January 1, 2014, to July 31, 2019, and had at least one plasma trough concentration. Plasma concentrations ≥0.7 µg /mL were considered therapeutic for prophylaxis, and ≥1.0 µg/mL for treatment. We describe our experience including dosing, plasma trough concentrations, safety, and tolerability. Results We identified 54 patients (28 males/26 females) who received DRT or IV formulations of posaconazole. The median age was 14 years (range 2–21 years). Thirty-one (57%) patients received posaconazole for treatment and 23 (43%) for prophylaxis. The most common underlying condition was hematological malignancies (66%) and 19 patients (35%) had received an allogeneic HSCT and were receiving immunosuppressive therapy. Overall, 36 (67%) patients achieved targeted initial plasma trough concentrations (median 1.3 µg/mL, IQR 0.758–1.760 µg/mL) (Figure). The median daily dose among patients &amp;lt;13 years of age who achieved the targeted initial plasma trough concentrations was 7.3 mg/kg/day (IQR 6.8–11.0) for the DRT formulation and 9.8 mg/kg/day (IQR 7.4–11.7) for the IV formulation. The median daily dose among patients ≥ 13 years of age who achieved the targeted initial plasma trough concentrations was 4.9 mg/kg/day (IQR 4.1–6.5) for the DRT formulation and 5.6 mg/kg/day (IQR 3.9–5.8) for the IV formulation. Concomitant use of H2-receptor blockers (H2RA) and/or proton pump inhibitors (PPI) medications were not associated with failure to achieve target trough levels (P = 0.96). Thirty-six patients (67%) developed transaminitis, mostly grade 1. Conclusions Our results show that DRT and IV formulations are safe and effective in immunocompromised children, adolescents, and young adults. Higher dosing per body weight of DRT and IV posaconazole may be required in patients &amp;lt;13 years of age compared with patients 13 years of age and older to achieve therapeutic plasma concentrations. It appears that neither a PPI nor an H2RA has an effect on the plasma exposure of the DRT.

Isavuconazole in Lung Transplant Recipients: A Retrospective Case Series to Appraise Clinical Efficacy

Purpose Lung transplant patients are at increased susceptibility to fungal infections. Isavuconazole, a triazole anti-fungal with broad-spectrum activity against medically important fungal pathogens, received a marketing authorisation in the U.K. in 2015. The use of isavuconazole has advantages over voriconazole and posaconazole as it presents a more favourable toxicity profile. There is some, but very limited data appraising its clinical effectiveness, but this is predominantly in the context of anti-fungal prophylaxis. This research looks to review the experience of a single centre by reviewing clinical outcome data in lung transplant patients who received isavuconazole as treatment for invasive fungal infections. Methods We performed a single-centre retrospective study to describe the clinical outcome data from patients commenced on treatment with Isavuconazole for invasive fungal infections between October 2016 and December 2019. We assessed outcomes at 3 months and 6 months post-commencement of treatment including patient reported improvement of presenting symptoms, stability or improvement in lung function (FEV1), radiological improvement or histocytoloical resolution on bronchoscopy (including galactomannan and persistent invasion of fungal hyphae/pseudohyphae or features in keeping with fungal infection). Results Fifty patients were treated with isavuconazole during the study period. Eleven patients were excluded from analysis (two due to transfer of care to a different centre and nine due to early treatment cessation). Of the thirty-nine patients, twenty-six were treated for possible and thirteen were treated for proven invasive fungal infection. A range of fungal isolates were encountered. Treatment success was observed in 60% (n=24). Isavuconazole was well tolerated by most patients (n = 37). Conclusion Isavuconazole is well tolerated and appears effective in the management of invasive fungal infection after lung transplantation. The limitations of this study are that it is a single centred, retrospective study, however, is the largest case series to date where clinical effectiveness of Isavuconazole has been appraised.

Comparative metabolomics analysis of amphotericin B high-yield mechanism for metabolic engineering

BackgroundThe polyene macrocyclic compound amphotericin B (AmB) is an important antifungal antibiotic for the clinical treatment of invasive fungal infections. To rationally guide the improvement of AmB production in the main producing strain Streptomyces nodosus, comparative metabolomics analysis was performed to investigate the intracellular metabolic changes in wild-type S. nodosus ZJB20140315 with low-yield AmB production and mutant S. nodosus ZJB2016050 with high-yield AmB production, the latter of which reached industrial criteria on a pilot scale.ResultsTo investigate the relationship of intracellular metabolites, 7758 metabolites were identified in mutant S. nodosus and wildtype S. nodosus via LC–MS. Through analysis of metabolism, the level of 26 key metabolites that involved in carbon metabolism, fatty acids metabolism, amino acids metabolism, purine metabolism, folate biosynthesis and one carbon pool by folate were much higher in mutant S. nodosus. The enrichment of relevant metabolic pathways by gene overexpression strategy confirmed that one carbon pool by folate was the key metabolic pathway. Meanwhile, a recombinant strain with gene metH (methionine synthase) overexpressed showed 5.03 g/L AmB production within 120 h fermentation, which is 26.4% higher than that of the mutant strain.ConclusionsThese results demonstrated that comparative metabolomics analysis was an effective approach for the improvement of AmB production and could be applied for other industrially or clinically important compounds as well.

Mini Review: Biologically Synthesized Nanoparticles as Antifungal Agents

Fungal infections are affecting millions of people in the world every year. Severity of infections range from superficial mycoses to more chronic systemic mycoses. As more fungi species evolve, emergence of drug resistant strains is becoming a serious concern to the public health. There is now less number of effective antifungal drugs available in the market for treatment of invasive fungal infections. In an effort to combat this escalating issue, the use of nanoparticles as antifungal agent has been proposed and explored. Versatility of nanoparticles and its unique physico-chemical properties are proven beneficial for developing new therapeutic methods in treatment of fungal infections. Nanoparticles produced from biological synthesis have attracted keen interests from researchers, as they are more environmentally friendly, sustainable, cost-effective, and biocompatible. This mini review will provide an insight on the current antifungal studies and discuss the theory behind mechanism of actions of nanoparticles.

The application of Voriconazole in 76 patients with cirrhosis at Child-Pugh C stage complicated by invasive fungal infection

Objective: To investigate the safety and efficacy of voriconazole in the patients with cirrhosis at Child-Pugh C stage complicated by invasive fungal infection(IFI). Methods: A retrospective collection of medical records of 76 patients with cirrhosis at Child-Pugh C stage complicated by IFI who were admitted to our hospital, from August 2014 to August 2017 was carried out. All the 76 patients who used voriconazole to treat IFI were divided into recommended dose group for hepatic insufficiency(56 cases) and routine dose group(20cases). The two groups were observed and compared in terms of the voriconazole's plasma concentrations, the outcomes of IFI and the rate of untoward reactions. The liver functional indicators were also compared between before and after treatment each group. We used Student's t test, Z test, chi-square test, or Fisher's exact test, as appropriate, for statistical analysis. Results: Both groups had good performance and low frequencies of side effects in the treatment of IFI, but there were also significant differences in the plasma concentrations of voriconazole and the incidence of untoward reactions between the two groups(P = 0.008 and P = 0.022). There commended dose group for hepatic insufficiency had lower adverse effect rate. The levels of direct bilirubin, alanine aminotransferase and aspartate aminotransferase were significantly lower after treatment of IFI in the recommended dose group for hepatic insufficiency(P < 0.05). Conclusion: In our research, it is relatively safe and effective to use voriconazole to treat IFI in the patients with cirrhosis at Child-Pugh C stage if according to the recommended dose regimen for cirrhosis at Child-Pugh A,B stage.

Strain Distribution and Drug Susceptibility of Invasive Fungal Infection in Clinical Patients With Systemic Internal Diseases.

BackgroundPatients with systemic internal diseases present high risks for invasive fungal infections, which results in increased morbidity and mortality. Identification of high-risk departments and susceptibility systems could help to reduce the infective rate clinically. Correct selection of sensitive anti-fungal drugs not only could improve the cure rate but also could reduce the adverse reactions and complications caused by long-term antifungal drug treatment, which can be especially important in patients with serious systemic diseases. Therefore, the distribution changes of invasive fungal strains in patients with systemic internal diseases and the choice of antifungal drugs in clinical practice should be updated.ObjectiveThis work aimed to investigate the incidence, strain distributions, and drug susceptibility of invasive fungal strains isolated from patients with systemic internal diseases.MethodsSamples were collected from 9,430 patients who were diagnosed with internal diseases in our hospital from January to December 2018. We then cultured and identified the fungal strains using API 20C AUX. We performed drug sensitivity analysis via the ATB Fungus-3 fungal susceptibility strip. Resistance was defined using the revised Clinical Laboratory Standardization Committee of United States breakpoints/epidemiological cutoff values to assign susceptibility or wild-type status to systemic antifungal agents.ResultsA total of 179 patients (49 female, 130 male) with fungal infection were included. The high-incidence departments were determined to be the respiratory department (34.64%), intensive care unit (ICU; 21.79%), and hepatology department (9.50%). The susceptible systems for infection were the respiratory tract (sputum, 68.72%, 123/179; secretion retained in the tracheal catheter, 3.35%, 6/179), urinary tract (urine, 9.50%, 17/179), and gastrointestinal tract (feces, 9.50%, 17/179). The major pathogens were Candida (90.50%), Aspergillus (8.93%), and Cryptococcus neoformans (0.56%). The infective candida subgroups were Candida albicans (70.95%), Candida krusei (6.15%), Candida glabrata (5.59%), Candida parapsilosis (3.91%), and Candida tropicalis (3.91%). The susceptibility of non-Aspergillus fungi for amphotericin B was 100.0%. The susceptibility rates of 5-fluorocytocine (5-FC) and voriconazole were 72.73 and 81.82%, respectively, for C. krusei, 98.43 and 100% for C. albicans, and 100% for both drugs for C. glabrata, C. parapsilosis, and C. tropicalis. The susceptibility rates of fluconazole and itraconazole were 0 and 54.55%, respectively, for C. krusei, 20 and 20% for C. glabrata, and 57.14 and 57.14% for C. tropicalis. The resistance rate of C. tropicalis for both fluconazole and itraconazole was 41.43%.ConclusionPatients in the respiratory department, ICU, and hepatology department presented high rates of invasive fungal infections and should include special attention during clinical treatment. The respiratory tract, urinary tract, and gastrointestinal tract were the susceptible systems. Candida, especially C. albicans, was the main pathogen. From the perspective of drug sensitivity, amphotericin B should be given priority in treating the non-Aspergillus fungi infection in patients with systemic internal diseases, while the susceptibility of invasive fungal strains to azoles was variant. These data might provide clinical evidence for the prevention and treatment of invasive fungal infection in patients with systemic internal diseases.

Review of T-2307, an Investigational Agent That Causes Collapse of Fungal Mitochondrial Membrane Potential.

Invasive infections caused by Candida that are resistant to clinically available antifungals are of increasing concern. Increasing rates of fluconazole resistance in non-albicans Candida species have been documented in multiple countries on several continents. This situation has been further exacerbated over the last several years by Candida auris, as isolates of this emerging pathogen that are often resistant to multiple antifungals. T-2307 is an aromatic diamidine currently in development for the treatment of invasive fungal infections. This agent has been shown to selectively cause the collapse of the mitochondrial membrane potential in yeasts when compared to mammalian cells. In vitro activity has been demonstrated against Candida species, including C. albicans, C. glabrata, and C. auris strains, which are resistant to azole and echinocandin antifungals. Activity has also been reported against Cryptococcus species, and this has translated into in vivo efficacy in experimental models of invasive candidiasis and cryptococcosis. However, little is known regarding the clinical efficacy and safety of this agent, as published data from studies involving humans are not currently available.

Characterisation of a clinical isolated Aspergillus lentulus strain using a Galleria mellonella infection model.

BackgroundIn recent years, the number of invasive aspergillus infection cases caused by Aspergillus lentulus (A. lentulus) has gradually increased and this fungus is usually difficult to distinguish from Aspergillus fumigatus in morphology. All of these presents a great challenge to the treatment of invasive fungal infections caused by A. lentulus. The present study aims to discuss the antifungal resistance, virulence and inflammatory factors’ changes after the infection of larvae of A. lentulus separated from patients with chronic obstructive pulmonary disease (COPD) to reflect the host immune response.MethodsA. lentulus isolated from COPD patients was identified by morphology and molecular biology, and its drug sensitivity was determined in vitro. Then the virulence factors and inflammatory response related factors of A. lentulus were determined by the model of A. lentulus infecting larvae. These were divided into three groups: A. lentulus standard strain, A. lentulus strain isolated from patients; PBS control. The infection model was formed by injecting the suspension of A. lentulus at a concentration of 1×106 CFU into larvae, in order to determine the (1,3)-β-D-glucan and galactomannan levels, and determine the caspase-1 and TNF-α concentration in Galleria mellonella larvae by RT-PCR.ResultsThe results revealed that A. lentulus had good sensitivity to itraconazole, voriconazole and micafungin, while (1,3)-β-D-glucan was negative in the two groups. The level of galactomannan in the two groups was higher than that in the control group, and the difference was statistically significant (P<0.05). However, there was no statistical difference between the standard strain group and patient strain group (P>0.05). After the infection of larvae, caspase-1 and TNF-α in the Galleria mellonella larvae increased in the two groups, and these elevated levels were statistically significant in both groups (P<0.05). However, there was no significant difference between the two groups (P>0.05).ConclusionsThere is no significant difference in virulence factor and host inflammatory response between A. lentulus isolated from COPD patients and standard strains. Galactomannan has more advantages in the early detection of A. lentulus invasive infection. Furthermore, the caspase-1-mediated inflammasome pathway may be involved in the host immune response to A. lentulus.

Sixtyyears of AmphotericinB: An Overview of the Main Antifungal Agent Used to Treat Invasive Fungal Infections.

Introduced in the late 1950s, polyenes represent the oldest family of antifungal drugs. The discovery of amphotericin B and its therapeutic uses is considered one of the most important scientific milestones of the twentieth century . Despite its toxic potential, it remains useful in the treatment of invasive fungal diseases owing to its broad spectrum of activity, low resistance rate, and excellent clinical and pharmacological action. The well-reported and defined toxicity of the conventional drug has meant that much attention has been paid to the development of new products that could minimize this effect. As a result, lipid-based formulations of amphotericin B have emerged and, even keeping the active principle in common, present distinct characteristics that may influence therapeutic results. This study presents an overview of the pharmacological properties of the different formulations for systemic use of amphotericin B available for the treatment of invasive fungal infections, highlighting the characteristics related to their chemical, pharmacokinetic structures, drug–target interactions, stability, and others, and points out the most relevant aspects for clinical practice.