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Nature Communications Jun 2024During pulmonary mucormycosis, inhaled sporangiospores adhere to, germinate, and invade airway epithelial cells to establish infection. We provide evidence that HIF1α...
During pulmonary mucormycosis, inhaled sporangiospores adhere to, germinate, and invade airway epithelial cells to establish infection. We provide evidence that HIF1α plays dual roles in airway epithelial cells during Mucorales infection. We observed an increase in HIF1α protein accumulation and increased expression of many known HIF1α-responsive genes during in vitro infection, indicating that HIF1α signaling is activated by Mucorales infection. Inhibition of HIF1α signaling led to a substantial decrease in the ability of R. delemar to invade cultured airway epithelial cells. Transcriptome analysis revealed that R. delemar infection induces the expression of many pro-inflammatory genes whose expression was significantly reduced by HIF1α inhibition. Importantly, pharmacological inhibition of HIF1α increased survival in a mouse model of pulmonary mucormycosis without reducing fungal burden. These results suggest that HIF1α plays two opposing roles during mucormycosis: one that facilitates the ability of Mucorales to invade the host cells and one that facilitates the ability of the host to mount an innate immune response.
Topics: Mucormycosis; Animals; Hypoxia-Inducible Factor 1, alpha Subunit; Mucorales; Humans; Epithelial Cells; Mice; Signal Transduction; Mice, Inbred C57BL; Disease Models, Animal; Lung; Female; Gene Expression Profiling
PubMed: 38902255
DOI: 10.1038/s41467-024-49637-8 -
BMC Infectious Diseases Jun 2024BACKGROUND PAECILOMYCES: and Penicillium are considered as rare opportunistic pathogens in immunocompromised hosts, and pneumonia caused by Paecilomyces and Penicillium...
BACKGROUND PAECILOMYCES: and Penicillium are considered as rare opportunistic pathogens in immunocompromised hosts, and pneumonia caused by Paecilomyces and Penicillium is rare. In this study, we present first case of severe pneumonia with pleural effusion caused by co-infection of Paecilomyces variotii (P. variotii) and Penicillium oxalicum (P. oxalicum) in a 66-year-old female with poorly controlled type 2 diabetes. CASE PRESENTATION: A 56-year-old woman patient presented to hospital for nausea, poor appetite, and vomiting for one day. On the second day of admission, blood culture and renal puncture fluid culture grew multidrug-resistant Escherichia coli (imipenem/cilastatin sensitive), and she received combination therapy with imipenem/cilastatin (1 g, every 8 h) and vancomycin (0.5 g, every 12 h). On the fourth day, she developed symptoms of respiratory failure. Pulmonary computed tomography (CT) showed an increase in pneumonia compared to before, with minor pleural effusion on both sides. Two fungi were isolated repeatedly from BALF culture, which were confirmed as P. variotii and P. oxalicum by Internal transcribed spacer (ITS) sequencing. Her pleural effusion was completely absorbed, pneumonia symptoms have significantly improved and discharged with receiving liposomal amphotericin B treatment for four weeks. CONCLUSIONS: It is worth noting that clinicians and laboratory personnel should not simply consider Paecilomyces and Penicillium species as contaminants, especially in immunocompromised patients. Early fungal identification and antifungal drug sensitivity are crucial for clinical drug selection and patient prognosis.
Topics: Humans; Female; Penicillium; Pleural Effusion; Middle Aged; Aged; Diabetes Mellitus, Type 2; Coinfection; Paecilomyces; Pneumonia; Mycoses; Immunocompromised Host; Anti-Bacterial Agents; Antifungal Agents
PubMed: 38898444
DOI: 10.1186/s12879-024-09496-6 -
Revista Da Sociedade Brasileira de... 2024
Topics: Humans; Mucormycosis; Lung Diseases, Fungal; Male; Middle Aged; Tomography, X-Ray Computed
PubMed: 38896656
DOI: 10.1590/0037-8682-0168-2024 -
Frontiers in Cellular and Infection... 2024
Topics: Fungi; Bacteria; Humans; Molecular Diagnostic Techniques; Mycoses; Bacterial Infections
PubMed: 38895733
DOI: 10.3389/fcimb.2024.1430630 -
International Journal of Molecular... Jun 2024Eumycetoma is a neglected tropical disease (NTD) characterized by subcutaneous lesions and the formation of grains. Attempts to treat eumycetoma involve a combination of...
OBJECTIVES
Eumycetoma is a neglected tropical disease (NTD) characterized by subcutaneous lesions and the formation of grains. Attempts to treat eumycetoma involve a combination of antifungal treatment and surgery, although the outcome is frequently disappointing. Therefore, there is a need to identify novel antifungal drugs to treat eumycetoma. In this respect, Medicines for Malaria Venture (MMV) has assembled libraries of compounds for researchers to use in drug discovery research against NTD. Therefore, we screened two MMVOpen compound libraries to identify novel leads for eumycetoma.
METHODS
A total of 400 compounds from the COVID Box and the Global Health Priority Box were screened in vitro at 100 µM and 25 µM against the most common causative agents of eumycetoma, namely and and the resulting IC and MIC values were obtained. Compounds with an IC < 8 µM were identified for possible in vivo efficacy studies using an grain model in larvae.
RESULTS
Out of the 400 compounds, 22 were able to inhibit both and growth at 100 µM and 25 µM, with compounds MMV1593278, MMV020335, and MMV1804559 being selected for in vivo testing. Of these three, only the pyrazolopyrimidine derivative MMV1804559 was able to prolong the survival of -infected larvae. Furthermore, the grains in MMV1804559-treated larvae were significantly smaller compared to the PBS-treated group.
CONCLUSION
MMV1804559 shows promising in vitro and in vivo activity against .
Topics: Madurella; Mycetoma; Antifungal Agents; Animals; Microbial Sensitivity Tests; Larva; Humans
PubMed: 38892422
DOI: 10.3390/ijms25116227 -
International Journal of Molecular... May 2024Human mycoses cover a diverse field of fungal diseases from skin disorders to systemic invasive infections and pose an increasing global health problem based on... (Review)
Review
Human mycoses cover a diverse field of fungal diseases from skin disorders to systemic invasive infections and pose an increasing global health problem based on ineffective treatment options, the hampered development of new efficient drugs, and the emergence of resistant fungal strains. Niclosamide is currently applied for the treatment of worm infections. Its mechanisms of action, which include the suppression of mitochondrial oxidative phosphorylation (also known as mitochondrial uncoupling), among others, has led to a repurposing of this promising anthelmintic drug for the therapy of further human diseases such as cancer, diabetes, and microbial infections. Given the urgent need to develop new drugs against fungal infections, the considerable antifungal properties of niclosamide are highlighted in this review. Its chemical and pharmacological properties relevant for drug development are also briefly mentioned, and the described mitochondria-targeting mechanisms of action add to the current arsenal of approved antifungal drugs. In addition, the activities of further salicylanilide-based niclosamide analogs against fungal pathogens, including agents applied in veterinary medicine for many years, are described and discussed for their feasibility as new antifungals for humans. Preliminary structure-activity relationships are determined and discussed. Various salicylanilide derivatives with antifungal activities showed increased oral bioavailabilities when compared with niclosamide. The simple synthesis of salicylanilide-based drugs also vouchsafes a broad and cost-effective availability for poorer patient groups. Pertinent literature is covered until 2024.
Topics: Niclosamide; Salicylanilides; Antifungal Agents; Humans; Animals; Structure-Activity Relationship; Fungi; Mycoses; Mitochondria
PubMed: 38892165
DOI: 10.3390/ijms25115977 -
BMC Pulmonary Medicine Jun 2024Persistent inflammatory damage and suppressed immune function play a crucial role in the pathogenesis and progression of the pneumocystis jirovecii pneumonia (PjP).... (Observational Study)
Observational Study
Persistent inflammatory damage and suppressed immune function play a crucial role in the pathogenesis and progression of the pneumocystis jirovecii pneumonia (PjP). Therefore, we aimed to investigate the correlation between the combined immune and inflammatory indicator: the neutrophil-to-lymphocyte ratio (NLR) and prognosis of non-human immunodeficiency virus (non-HIV) PjP.In the retrospective analysis conducted in ICUs at Beijing Chao-Yang Hospital, we examined data from 157 patients diagnosed with non-HIV PjP. Our findings reveal a concerning hospital mortality rate of 43.3%, with the 28-day mortality rate reaching 47.8%.Through multivariable logistic and Cox regression analyses, we established a significant association between elevated NLR levels and hospital mortality (adjusted odd ratio, 1.025; 95% CI, 1.008-1.043; p = 0.004) or 28-day mortality (adjusted hazard ratio, 1.026; 95% CI, 1.008-1.045; p = 0.005). Specifically, patients with an NLR exceeding 20.3 demonstrated markedly lower overall survival rates, underscoring the biomarker's predictive value for both hospital and 28-day mortality.In conclusion, non-HIV PjP patients in the ICU still have a high rate of mortality and a poor short-term prognosis after discharge. A high level of NLR was associated with an increased risk of hospital mortality and 28-day mortality.
Topics: Humans; Pneumonia, Pneumocystis; Retrospective Studies; Male; Female; Middle Aged; Neutrophils; Prognosis; Aged; Hospital Mortality; Pneumocystis carinii; Lymphocytes; China; Logistic Models; Intensive Care Units; Biomarkers; Proportional Hazards Models; Adult
PubMed: 38890590
DOI: 10.1186/s12890-024-03093-8 -
Open Forum Infectious Diseases Jun 2024Several recent randomized trials have been conducted in resource-limited settings for cryptococcal meningitis that have rapidly innovated international guidelines. The...
BACKGROUND
Several recent randomized trials have been conducted in resource-limited settings for cryptococcal meningitis that have rapidly innovated international guidelines. The 2010 Infectious Diseases Society of America (IDSA) cryptococcal meningitis guideline has not been updated with recent trials. The 2022 AMBITION-cm trial found that a single 10-mg/kg dose of liposomal amphotericin B plus daily flucytosine and fluconazole for 2 weeks was noninferior to 1 week of amphotericin B deoxycholate with flucytosine. It is unknown whether physicians in high-resource settings are using this regimen or more traditional regimens.
METHODS
We developed an electronic survey in June 2023 to better understand whether physician members of the IDSA Emerging Infections Network (EIN) and Mycoses Study Group Education and Research Consortium (MSG-ERC) had used the AMBITION-cm induction regimen, would use the regimen in hypothetical clinical scenarios, and what perceived barriers to use existed.
RESULTS
A total of 242 of 561 (43%) physicians responded to the survey, of whom 205 provided care for persons with cryptococcal meningitis in the last year. Overall, 29 (14%) had used the AMBITION-cm regimen, and 176 (86%) had not. In various hypothetical clinical scenarios, only ∼10% of 209 respondents selected the AMBITION-cm regimen as preferred. Perceived barriers to uptake included the applicability of trials performed in low-resource settings to high-resource settings, that the regimen is not recommended in the 2010 IDSA guidelines, and the applicability to persons without HIV.
CONCLUSIONS
Most respondents had not used the single-dose liposomal amphotericin B regimen, but the regimen is being used. Further study of this regimen in other patient populations and settings is necessary.
PubMed: 38887490
DOI: 10.1093/ofid/ofae120 -
Open Forum Infectious Diseases Jun 2024A vaccine for coccidioidomycosis is likely to undergo trials in the near future. In this paper, we raise 4 questions that should be answered before its use and offer our...
A vaccine for coccidioidomycosis is likely to undergo trials in the near future. In this paper, we raise 4 questions that should be answered before its use and offer our solutions to these questions. These include defining the goals of vaccination, determining who should be vaccinated, how to measure vaccine immunity and protection, and how to address vaccine hesitancy and denial.
PubMed: 38887487
DOI: 10.1093/ofid/ofae095 -
Open Forum Infectious Diseases Jun 2024Patients with hematological malignancy are at high risk of invasive fungal infections (IFIs). Diagnosis is challenging, which can lead to overtreatment. Reducing...
BACKGROUND
Patients with hematological malignancy are at high risk of invasive fungal infections (IFIs). Diagnosis is challenging, which can lead to overtreatment. Reducing exposure to inappropriate antifungal prescribing is likely to improve patient safety, but modifying prescribing behavior is difficult. We aimed to describe patterns and drivers of therapeutic antifungal prescribing in a large tertiary hemato-oncology center in the United Kingdom.
METHODS
We studied adults receiving treatment for acute leukemia at our center between 1 April 2019 and 14 October 2022. We developed a reproducible method to analyze routinely collected data on antifungal therapy episodes in a widely used electronic health record system. We report antifungal use in days of therapy stratified by level of diagnostic confidence, as defined by consensus diagnostic guidelines (European Organisation for Research and Treatment of Cancer/Mycoses Study Group).
RESULTS
Two hundred ninety-eight patients were included in the analysis; 21.7% of inpatient antifungal use occurred in cases of proven/probable IFI. Substantial antifungal use occurred in the absence of strong evidence of infection in patients receiving high-intensity first-line chemotherapy or approaching death (81.0% and 77.9%, respectively). Approximately 33% of high-resolution computed tomography (HRCT) reports were indeterminate for IFI. Indeterminate reports were around 8 times more likely to be followed by a new antifungal therapy episode than a negative report.
CONCLUSIONS
Antifungal stewardship remains challenging in the absence of reliable diagnostics, particularly in more unwell patients. The proportion of antifungal therapy given for proven/probable infection is a new metric that will likely be useful to target antifungal stewardship programs. The thoracic HRCT report is an important contributor to diagnostic uncertainty.
PubMed: 38887486
DOI: 10.1093/ofid/ofae094