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Ribeiro FDC, Kemmerich KK, Gonçale JC, Junqueira JC, Mannan M, Nabeela S, Colombo AL, Uppuluri P. Candida albicans Recovered From Persistent Candidemia Exhibits Enhanced Virulence Traits. J Infect Dis 2025; 231:e803-e812. [PMID: 39693248 DOI: 10.1093/infdis/jiae631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 10/04/2024] [Accepted: 12/17/2024] [Indexed: 12/20/2024] Open
Abstract
Candida albicans catheter-related candidemia is largely driven by microbial adhesion and biofilm formation on central venous catheters. Cells that disperse from these biofilms can enter the bloodstream, spread to distant organs, and sustain the cycle of infection. In this study, we investigated the virulence potential of C. albicans isolates obtained from the blood of catheterized patients experiencing persistent candidemia, comparing them to isolates that were cleared from the bloodstream early in the infection. Our results show that isolates persisting in the bloodstream for 4 days or longer, despite antifungal treatment, exhibited enhanced adherence, filamentation, and biofilm formation in vitro, along with increased expression of key virulence-related genes. Notably, cells dispersed from second-generation biofilms formed by these persistent isolates displayed even more pronounced pathogenic characteristics, including improved immune evasion. Furthermore, in vivo experiments using Galleria mellonella revealed that persistent isolates were significantly more virulent than their nonpersistent counterparts.
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Affiliation(s)
- Felipe de Camargo Ribeiro
- Department of Medicine, Division of Infectious Diseases, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Karoline Kristina Kemmerich
- Department of Medicine, Division of Infectious Diseases, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Juliana Caparroz Gonçale
- Department of Biosciences and Oral Diagnosis, Institute of Science and Technology, São Paulo State University, São José dos Campos, São Paulo, Brazil
| | - Juliana Campos Junqueira
- Department of Biosciences and Oral Diagnosis, Institute of Science and Technology, São Paulo State University, São José dos Campos, São Paulo, Brazil
| | - Mohammad Mannan
- Division of Infection and Immunity, The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles Medical Center, Torrance, California, USA
| | - Sunna Nabeela
- Division of Infection and Immunity, The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles Medical Center, Torrance, California, USA
| | - Arnaldo Lopes Colombo
- Department of Medicine, Division of Infectious Diseases, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
- The Antimicrobial Resistance Institute of São Paulo, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Priya Uppuluri
- Division of Infection and Immunity, The Lundquist Institute for Biomedical Innovation at Harbor-University of California Los Angeles Medical Center, Torrance, California, USA
- David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
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2
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Walker LW, Nowalk AJ. Clinical and Microbiologic Outcomes of Antifungal Lock-based Catheter Salvage in Pediatric Candidal CLABSI. Pediatr Infect Dis J 2025:00006454-990000000-01281. [PMID: 40208923 DOI: 10.1097/inf.0000000000004820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/12/2025]
Abstract
We report a retrospective review of pediatric candidal central line-associated bloodstream infections (N = 145) with antifungal lock therapy-based catheter salvage. Rates of recurrence (6%) and mortality (5%) were low at 28 days. At 1 year, earlier catheter removal was associated with lower recurrence rates (21% vs. 45%, P = 0.005), but no significant difference in mortality (13% vs. 5%).
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Affiliation(s)
- Lorne W Walker
- From the Division of Pediatric Infectious Diseases
- Department of Medical Informatics and Epidemiology, Oregon Health and Sciences University, Portland, Oregon
| | - Andrew J Nowalk
- Division of Pediatric Infectious Diseases, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
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3
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Weerdenburg H, Walker H, Haeusler GM, Cole T, Curtis N, Duffull S, Gwee A. Relationship between posaconazole concentrations and clinical outcomes in paediatric cancer and haematopoietic stem cell transplant recipients. J Antimicrob Chemother 2025; 80:897-907. [PMID: 40037294 PMCID: PMC11962376 DOI: 10.1093/jac/dkae473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 12/12/2024] [Indexed: 03/06/2025] Open
Abstract
BACKGROUND Posaconazole is used to prevent and treat invasive fungal infections (IFIs) in immunocompromised children, including those undergoing cancer treatment or HSCT. Despite differences in pharmacokinetics and IFI epidemiology between children and adults, therapeutic targets established in adult studies are often applied to children. OBJECTIVES This systematic review evaluated the correlation between serum posaconazole concentrations and clinical outcomes of IFI prophylaxis and treatment in children with malignancies or HSCT recipients. METHODS Four databases (Cochrane, Embase, MEDLINE and PubMed) were searched for studies involving children (≤18 years old) receiving cancer treatment or HSCT that reported posaconazole serum concentrations and treatment outcomes. Animal studies, those primarily in adult (>18 years old) populations, non-malignant conditions (excluding HSCT), case reports, letters, editorials, conference abstracts and narrative reviews were excluded. Bias was assessed using the Newcastle-Ottawa scale. RESULTS Nineteen studies were included: 12 reported outcomes of posaconazole prophylaxis; two of treatment; and five of both. For prophylaxis, breakthrough IFIs occurred in 1%-12% of children. All but one occurred with serum concentrations of ≤0.7 mg/L. For treatment, no clear association was observed between a trough concentration of >1.0 mg/L and treatment efficacy, with poor outcomes reported for serum concentrations ranging between 0.2 and 4.8 mg/L. Overall, quality of evidence was poor (medium to high risk of bias for 18 papers, low risk for 1 paper) and there was variation in IFI definitions across studies. CONCLUSIONS This review supports current recommendations for posaconazole prophylaxis in paediatric oncology and HSCT recipients. The absence of a clear correlation found between serum trough concentrations and treatment efficacy highlights the need for further studies to determine optimal therapeutic targets for treatment.
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Affiliation(s)
- Heather Weerdenburg
- Department of Pharmacy, Children’s Cancer Centre, General Medicine and Allergy and Immunology, Royal Children’s Hospital, Parkville, Australia
- Antimicrobials, Clinical Paediatrics, and Infectious Diseases Groups, Murdoch Children’s Research Institute, Parkville, Australia
- Department of Paediatrics, The University of Melbourne, Parkville, Australia
| | - Hannah Walker
- Department of Pharmacy, Children’s Cancer Centre, General Medicine and Allergy and Immunology, Royal Children’s Hospital, Parkville, Australia
- Antimicrobials, Clinical Paediatrics, and Infectious Diseases Groups, Murdoch Children’s Research Institute, Parkville, Australia
- Department of Paediatrics, The University of Melbourne, Parkville, Australia
| | - Gabrielle M Haeusler
- Department of Pharmacy, Children’s Cancer Centre, General Medicine and Allergy and Immunology, Royal Children’s Hospital, Parkville, Australia
- Antimicrobials, Clinical Paediatrics, and Infectious Diseases Groups, Murdoch Children’s Research Institute, Parkville, Australia
- Department of Paediatrics, The University of Melbourne, Parkville, Australia
- Department of Infectious Diseases, Peter MacCallum Cancer Centre, Parkville, Australia
- Sir Peter MacCallum Department of Oncology, NHMRC National Centre for Infections in Cancer, University of Melbourne, Melbourne, Australia
- The Victorian Paediatric Integrated Cancer Service, Victoria State Government, Melbourne, Australia
| | - Theresa Cole
- Department of Pharmacy, Children’s Cancer Centre, General Medicine and Allergy and Immunology, Royal Children’s Hospital, Parkville, Australia
- Department of Paediatrics, The University of Melbourne, Parkville, Australia
| | - Nigel Curtis
- Department of Pharmacy, Children’s Cancer Centre, General Medicine and Allergy and Immunology, Royal Children’s Hospital, Parkville, Australia
- Antimicrobials, Clinical Paediatrics, and Infectious Diseases Groups, Murdoch Children’s Research Institute, Parkville, Australia
- Department of Paediatrics, The University of Melbourne, Parkville, Australia
| | | | - Amanda Gwee
- Department of Pharmacy, Children’s Cancer Centre, General Medicine and Allergy and Immunology, Royal Children’s Hospital, Parkville, Australia
- Antimicrobials, Clinical Paediatrics, and Infectious Diseases Groups, Murdoch Children’s Research Institute, Parkville, Australia
- Department of Paediatrics, The University of Melbourne, Parkville, Australia
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4
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Schroeder JA, Wilson CM, Pappas PG. Invasive Candidiasis. Infect Dis Clin North Am 2025; 39:93-119. [PMID: 39706747 DOI: 10.1016/j.idc.2024.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2024]
Abstract
Invasive candidiasis (IC) is a term that refers to a group of infectious syndromes caused by a variety of Candida species, 6 of which cause the vast majority of cases globally. Candidemia is probably the most commonly recognized syndrome associated with IC; however, Candida species can cause invasive infection of any organ, especially visceral organs, vasculature, bones and joints, eyes, and central nervous system. The optimal use of these newer diagnostics coupled with a thoughtful clinical assessment of at-risk patients and the judicious use of effective antifungal therapy is a key to achieving good antifungal stewardship and improved patient outcomes.
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Affiliation(s)
- Julia A Schroeder
- The University of Alabama at Birmingham, 1900 University Boulevard, 223 THT, Birmingham, AL 35294, USA
| | - Cameron M Wilson
- The University of Alabama at Birmingham, 1900 University Boulevard, 223 THT, Birmingham, AL 35294, USA
| | - Peter G Pappas
- The University of Alabama at Birmingham, 1900 University Boulevard, 223 THT, Birmingham, AL 35294, USA.
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ElFeky DS, El-Wakil DM, Mwafy MM, Atia MMA, Gohar NM. Comparative evaluation of antifungal susceptibility testing methods of invasive Candida species and detection of FKS genes mutations in caspofungin intermediate and resistant isolates. BMC Infect Dis 2025; 25:114. [PMID: 39856577 PMCID: PMC11760087 DOI: 10.1186/s12879-024-10435-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 12/31/2024] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND Fungal invasive infections caused by Candida species pose a substantial public health risk with limited therapeutic options. Antifungal susceptibility testing (AFST) is necessary to optimize the therapy. The study aimed to compare different AFST methods of Candida spp. and detect FKS gene mutations among caspofungin-intermediate and resistant isolates. METHODS A total of 60 non-replicative invasive Candida isolates recovered from various clinical samples were included. In-vitro AFST was carried out using the ATB FUNGUS 3, Vitek-2 AST-YS08, and E-test. Hotspot (HS) regions of FKS genes were sequenced for caspofungin-intermediate and resistant isolates. RESULTS Candida albicans (58.3%) was the most predominant spp., followed by C. glabrata (28.3%). Based on the clinical breakpoints (CBPs), fluconazole resistance was found in C. albicans (45.7%), C. tropicalis (25%), and the C. parapsilosis isolate, while 35.3% of C. glabrata were susceptible dose-dependent (SDD). None of C. albicans, C. tropicalis, or C. parapsilosis isolates were resistant to voriconazole. Using the epidemiological cut-off values (ECVs) for amphotericin B, 6.7% of isolates were non-wild type (non-WT), including C. guilliermondii (50%), C. tropicalis (25%), and C. glabrata (11.8%), while all C. albicans, C. parapsilosis, and C. kefyr isolates were classified as wild-type (WT). ATB FUNGUS 3 and Vitek-2 had the highest categorical agreement (CA) (83.1%) for amphotericin B, while a lower concordance was detected with voriconazole (23.2%) and fluconazole (52.2%). For caspofungin, Vitek-2 and E-test had a CA of 89.8%. Eleven isolates (10 C. glabrata and one C. parapsilosis) exhibited resistance or intermediate susceptibility to caspofungin (MICs: 0.25‒>32 µg/ml). Molecular characterization of the FKS gene demonstrated that FKS1 mutations V47I, V52K, V56T, D57S, L62F, I71Y, I71Q in the HS1 region, and G7S, P11H mutations in the HS2 region were associated with increased caspofungin MIC values (16 µg/ml). Mutations at the HS1 of the FKS2 gene; K33V, W35K, and W35V; were associated with the highest caspofungin MICs of > 32 µg/ml. CONCLUSIONS ATB FUNGUS 3 demonstrated acceptable performance for AFST, however, azole activity against Candida spp. should be interpreted carefully. Novel mutations within HS regions of FKS genes elucidated different levels of caspofungin resistance in C. glabrata and C. parapsilosis isolates.
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Affiliation(s)
- Dalia Saad ElFeky
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Cairo University, Al-Saray Street, Al-Manial, Cairo, 11562, Egypt
| | - Doaa Mahdy El-Wakil
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Cairo University, Al-Saray Street, Al-Manial, Cairo, 11562, Egypt.
| | - Mai M Mwafy
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Mohamed M A Atia
- Genome Mapping Department, Agricultural Genetic Engineering Research Institute (AGERI), Agricultural Research Center (ARC), Giza, Egypt.
| | - Noha Mahmoud Gohar
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Cairo University, Al-Saray Street, Al-Manial, Cairo, 11562, Egypt
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Chiusaroli L, Cozzolino C, Cocchio S, Saia M, Giaquinto C, Donà D, Baldo V. Epidemiological Analysis of Fungal Infection Disease in Pediatric Population: Focus on Hospitalization from 2007 to 2022 in Veneto Region in Italy. Pathogens 2025; 14:93. [PMID: 39861054 PMCID: PMC11768092 DOI: 10.3390/pathogens14010093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2024] [Revised: 01/15/2025] [Accepted: 01/16/2025] [Indexed: 01/27/2025] Open
Abstract
Fungal infections (FIs) are widespread globally, affecting both immunocompromised and immunocompetent children, with varying clinical implications based on age and comorbidities. In immunocompromised children, particularly those with hematologic oncological conditions, FI leads to substantially longer hospital stays and increased in-hospital mortality, with reported rates ranging from 15% to 20%. Our study aims to analyze the epidemiological trends of fungal infections in the pediatric population within a specific region of Italy. We extracted ICD-9 codes related to fungal infections from hospital discharge records (HDRs) in the pediatric population of Veneto, located in the north-east of Italy, between 2007 and 2022. We included all children admitted to the hospital with a primary or secondary diagnosis during admission for other reasons. Data were stratified based on age, year, ward of admission, and type of diagnosis. Patients older than eighteen and HDRs related to a second admission within thirty days from the previous admission were excluded. A total of 1433 diagnoses were analyzed during the period, with 241 (16.8%) as main diagnoses and 1192 (83.2%) as secondary diagnoses. The overall hospitalization rate was 1084 cases/100,000 (1.69 cases/100,000 as primary diagnosis and 8.95 cases/100,000 as secondary). The hospitalization rate stratified for age was 11,055 cases/100,000 among infants younger than 1 year, 8.48 cases/100,000 among those aged 1-4 years, and 4.4 cases/100,000 among children older than 5. The more frequent infection was Candida spp. (62.8%), followed by Aspergillus spp. (14.6%) and skin mycosis (9.5%). Overall, the pediatric in-hospital case fatality rate due to FI was 2.09%. Our study elucidated the overall experience of fungal infections in the pediatric population of the Veneto region in Italy. Specifically, we underscored a relatively stable hospitalization rate for fungal diseases and a noteworthy mortality rate.
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Affiliation(s)
- Lorenzo Chiusaroli
- Division of Pediatric Infectious Diseases, Department for Women’s and Children’s Health, University of Padua, 35126 Padua, Italy; (C.G.); (D.D.)
| | - Claudia Cozzolino
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, 35126 Padua, Italy; (C.C.); (S.C.); (V.B.)
| | - Silvia Cocchio
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, 35126 Padua, Italy; (C.C.); (S.C.); (V.B.)
- Preventive Medicine and Risk Assessment Unit, Hospital-University of Padua, 35126 Padua, Italy
| | - Mario Saia
- Azienda Zero of Veneto Region, 35131 Padua, Italy;
| | - Carlo Giaquinto
- Division of Pediatric Infectious Diseases, Department for Women’s and Children’s Health, University of Padua, 35126 Padua, Italy; (C.G.); (D.D.)
| | - Daniele Donà
- Division of Pediatric Infectious Diseases, Department for Women’s and Children’s Health, University of Padua, 35126 Padua, Italy; (C.G.); (D.D.)
| | - Vincenzo Baldo
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, 35126 Padua, Italy; (C.C.); (S.C.); (V.B.)
- Preventive Medicine and Risk Assessment Unit, Hospital-University of Padua, 35126 Padua, Italy
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Ikeda K, Ifuku T, Matsumoto Y, Haraguchi M, Fukumoto Y, Tsuchiya K. The combined use of the Charlson Comorbidity Index and National Early Warning Score 2 helps predict the prognosis of candidemia. J Infect Chemother 2025; 31:102507. [PMID: 39214386 DOI: 10.1016/j.jiac.2024.08.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 08/22/2024] [Accepted: 08/28/2024] [Indexed: 09/04/2024]
Abstract
BACKGROUND The National Early Warning Score 2 (NEWS2) standardizes assessment and response to acute illnesses using vital signs. Whether NEWS2 is useful in predicting the prognosis of candidemia remains to be determined. METHODS Our study, conducted as a rigorous and retrospective analysis, examined patients with candidemia who were hospitalized between January 2014 and December 2023. We assessed candidemia severity using the Pitt Bacteremia Score (PBS) and NEWS2, while the Charlson Comorbidity Index (CCI) was used to assess underlying medical conditions. The endpoint was all-cause mortality within 30 days of candidemia onset, ensuring comprehensive evaluation of the patient's prognosis. RESULTS Overall, 93 patients with candidemia were included. The 30-day all-cause mortality rate was 29.0 %. The area under the receiver operating characteristic curve (AUC) for CCI, PBS, and NEWS2 were 0.87 (95 % confidence interval [CI]: 0.80-0.95), 0.75 (95 % CI: 0.66-0.85), and 0.92 (95 % CI: 0.87-0.97), respectively, for predicting the 30-day mortality in patients with candidemia. The AUC values for CCI combined with PBS and NEWS2 were 0.89 (95 % CI: 0.83-0.96) and 0.96 (95 % CI: 0.93-1.00) for predicting the 30-day mortality in candidemia. Among the items that were significant in the univariate analysis, multivariate analysis showed that the combination of NEWS2 ≥ 10 and CCI ≥4 was the helpful prognostic factor for 30-day mortality. CONCLUSIONS The combination of NEWS2 ≥ 10 and CCI ≥4 scores may be useful in predicting the risk of 30-day mortality in patients with candidemia.
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Affiliation(s)
- Kenichi Ikeda
- Division of Internal Medicine, Kagoshima City Hospital, Kagoshima, Japan.
| | - Tassei Ifuku
- Department of Emergency Medicine, Kagoshima City Hospital, Kagoshima, Japan
| | - Yuta Matsumoto
- Department of Clinical Laboratory, Kagoshima City Hospital, Kagoshima, Japan
| | - Masaomi Haraguchi
- Department of Clinical Laboratory, Kagoshima City Hospital, Kagoshima, Japan
| | - Yusuke Fukumoto
- Department of Pharmacy, Kagoshima City Hospital, Kagoshima, Japan
| | - Kayoko Tsuchiya
- Division of Infection Control, Kagoshima City Hospital, Kagoshima, Japan
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Said AM, Afridi F, Redell MS, Vrana C, O'Farrell C, Scheurer ME, Dailey Garnes NJ, Gramatges MM, Dutta A. Invasive Candidiasis in Pediatric Hematologic Malignancy: Increased Risk of Dissemination With Candida tropicalis. Pediatr Infect Dis J 2025; 44:58-63. [PMID: 39383401 DOI: 10.1097/inf.0000000000004502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/11/2024]
Abstract
BACKGROUND Candida species are the most common cause of invasive fungal disease, and children with hematologic malignancy are at increased risk. Non- albicans Candida (NAC) now account for more than half of all invasive candidiasis (IC) and carry a worse prognosis. We aimed to compare the epidemiology, risk factors, organ dissemination, biomarkers and outcomes in IC based on the species implicated and evaluate trends in antifungal resistance over time. METHODS Patients 0-18 years of age with hematologic malignancy and IC at 2 centers were included. Fifty-three patients from 2011 to 2022 were identified. Information related to demographics, host and risk factors, Candida species and antifungal susceptibilities, treatment and outcomes was collected via retrospective chart review. Data were analyzed at the species level. RESULTS The incidence rate of IC was 29 per 1000 patients with leukemia and lymphoma. The median time to infection from diagnosis of malignancy was 38 days. Candida tropicalis (n = 17; 30%) was the most identified species followed by Candida albicans (n = 14; 25%). Patients with C. tropicalis infection were more likely to have dissemination to the eyes ( P = 0.035), spleen ( P = 0.001) and skin ( P = 0.003) than patients with C. albicans or other NAC. Of the 34 patients who underwent dilated retinal examination, 24% (n = 8) had evidence of intraocular candidiasis. Seven of the 8 patients with intraocular disease had prolonged candidemia (3 or more days; P = 0.003). The 12-week crude mortality rate was 16.9%. CONCLUSIONS NAC, specifically C. tropicalis , accounted for most of the IC in children with hematological malignancies. Screening for intraocular candidiasis continues to play an important role in patients with IC, and future studies are needed to determine if screening can be limited to patients with select risk factors.
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Affiliation(s)
- Amira M Said
- From the Department of Pediatrics, Section of Pediatric Infectious Diseases, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas
| | - Faraz Afridi
- Department of Infectious Diseases, Infection Control and Employee Health, Division of Internal Medicine, The University of Texas MD Anderson Cancer, Houston, Texas
| | - Michele S Redell
- Department of Pediatrics, Cancer and Hematology Center, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas
| | - Chelsea Vrana
- Department of Pediatrics, Cancer and Hematology Center, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas
| | - Candelaria O'Farrell
- Department of Pediatrics, Cancer and Hematology Center, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas
| | - Michael E Scheurer
- Department of Pediatrics, Cancer and Hematology Center, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas
| | - Natalie J Dailey Garnes
- Department of Infectious Diseases, Infection Control and Employee Health, Division of Internal Medicine, The University of Texas MD Anderson Cancer, Houston, Texas
| | - Maria Monica Gramatges
- Department of Pediatrics, Cancer and Hematology Center, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas
| | - Ankhi Dutta
- From the Department of Pediatrics, Section of Pediatric Infectious Diseases, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas
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9
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Thompson Iii GR, Chastain DB, Ferraz C, Alhayek S, Salinas JL, Sillau S, Stenehjem EA, Henao-Martínez AF. Mortality patterns in candidemia: Insights from a multispecies analysis using a global research network. Med Mycol 2024; 63:myae122. [PMID: 39694690 DOI: 10.1093/mmy/myae122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 12/06/2024] [Accepted: 12/17/2024] [Indexed: 12/20/2024] Open
Abstract
Understanding the impact of different Candida species on patient outcomes is crucial for effective management and treatment strategies. This study aims to comprehensively analyze the association between Candida species and mortality in documented candidemia. We queried TriNetX, a global research network database, to identify patients diagnosed with candidemia through polymerase chain reaction from 2020 to 2023. The primary outcome was mortality in candidemia patients, categorized by Candida species at 90 days and 1 year. The time to death was assessed using Kaplan-Meier plots. Cox proportional hazard (PH) models were also used for comparative analysis, unadjusted and adjusted for demographic and comorbidity covariates. We captured 1234 candidemia episodes during the study period. The 90-day and 1-year mortality rates for the various Candida species were as follows: C. tropicalis (33.9% and 35.6%), C. glabrata (28.3% and 34%), multispecies (27.7% and 36.4%), C. parapsilosis (25.8% and 31.8%), C. krusei (21.4% and 28.6%), C. albicans (21.1% and 23.9%), and C. auris (13.3% and 15.9%). The unadjusted Kaplan-Meier Survival analysis showed that multispecies candidemia, followed by C. tropicalis, had the lowest survival. The adjusted multivariable Cox PH model found that C.albicans, C. glabrata, C. parapsilosis, C. tropicalis, and multispecies candidemia had significantly higher mortality rates than C. auris. Age and a higher Charlson comorbidity index value emerged as independent predictors of increased mortality. Among patients with candidemia, we found an overall 1-year mortality of 28%. Multispecies candidemia, C. tropicalis, older age, and a higher comorbidity burden were associated with the highest mortality rates.
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Affiliation(s)
| | - Daniel B Chastain
- Department of Clinical and Administrative Pharmacy, UGA College of Pharmacy, Albany, Georgia, USA
| | - Carolina Ferraz
- Department of Medicine, Division of Infectious Diseases, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Soubhi Alhayek
- University of California-Davis Medical Center, Sacramento, California, USA
| | - Jorge L Salinas
- Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, California, USA
| | - Stefan Sillau
- Department of Neurology and Biostatistics, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Edward A Stenehjem
- Department of Medicine, Division of Infectious Diseases, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Andrés F Henao-Martínez
- Department of Medicine, Division of Infectious Diseases, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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10
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Chorafa E, Iosifidis E, Oletto A, Warris A, Castagnola E, Bruggemann R, Groll AH, Lehrnbecher T, Ferreras Antolin L, Mesini A, Agakidou E, Controzzi T, De Luca M, Dimitriou G, Emonts M, Esposito S, Fernàndez-Polo A, Ghimenton-Walters E, Gkentzi D, Grasa C, Hatzidaki E, Jõgi P, Kildonaviciute K, Kontou A, Leibold-Aguinarte A, Manzanares A, Mendoza-Palomar N, Metsvaht T, Noni M, Paulus S, Perrone S, Rincón-López E, Romani L, Sánchez L, Cetin BS, Spoulou V, Strenger V, Vergadi E, Villaverde S, Vuerich M, Zamora-Flores E, Roilides E. Antifungal Drug Usage in European Neonatal Units: A Multicenter Weekly Point Prevalence Study. Pediatr Infect Dis J 2024; 43:1047-1048. [PMID: 38917027 DOI: 10.1097/inf.0000000000004445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/27/2024]
Abstract
BACKGROUND Data on antifungal prescribing in neonatal patients are limited to either single-center or single-country studies or to 1-day recording. Therefore, we assessed antifungal longitudinal usage in neonatal units (NUs) within Europe. METHODS CALYPSO, a prospective weekly point prevalence study on antifungal drug usage in NUs in 18 hospitals (8 European countries), was conducted in 2020 during a 12-week period. All patients receiving systemic antifungals were included. Ward demographics were collected at the beginning; ward and patient data including indication, risk factors and antifungal regimen were weekly collected prospectively. RESULTS Among 27 participating NUs, 15 (56%) practiced antifungal prophylaxis for neonates with birth weight <1000 g or <1500 g and additional risk factors. In total, 174 patients received antifungals with a median frequency per week of 10.5% ranging from 6.9% to 12.6%. Indication for antifungal prescribing was prophylaxis in 135/174 (78%) courses and treatment in 22% [39 courses (69% empirical, 10% preemptive, 21% targeted)]. Fluconazole was the most frequent systemic agent used both for prophylaxis (133/135) and treatment (15/39, 39%). Among neonates receiving prophylaxis, the most common risk factors were prematurity (119/135, 88%), mechanical ventilation (109/135, 81%) and central vascular catheters (89/135, 66%). However, gestational age <28 weeks was only recorded in 55/135 (41%) courses and birth weight <1000 g in 48/135 (35%). Most common reason for empirical treatment was late-onset sepsis; all 8 targeted courses were prescribed for invasive candidiasis. CONCLUSION Antifungal usage in European NUs is driven by prophylaxis and empirical treatment with fluconazole being the most prescribed agent for both indications.
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Affiliation(s)
- Elisavet Chorafa
- From the Infectious Diseases Unit, 3rd Department of Pediatrics, Aristotle University School of Medicine, Hippokration Hospital, Thessaloniki, Greece
| | - Elias Iosifidis
- From the Infectious Diseases Unit, 3rd Department of Pediatrics, Aristotle University School of Medicine, Hippokration Hospital, Thessaloniki, Greece
| | | | - Adilia Warris
- Medical Research Council Center for Medical Mycology, University of Exeter, Exeter, United Kingdom
- European Pediatric Mycology Network
| | - Elio Castagnola
- European Pediatric Mycology Network
- Pediatric Infectious Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Roger Bruggemann
- European Pediatric Mycology Network
- Department of Pharmacy, Centre of Expertise in Mycology Radboudumc/Canisius-Wilhelmina Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Andreas H Groll
- European Pediatric Mycology Network
- Infectious Disease Research Program, Center for Bone Marrow Transplantation, Department of Pediatric Hematology/Oncology, University Children's Hospital, Muenster, Germany
| | - Thomas Lehrnbecher
- European Pediatric Mycology Network
- Division of Hematology, Oncology and Hemostaseology, Department of Pediatrics, Goethe University Frankfurt, Frankfurt/Main, Germany
| | - Laura Ferreras Antolin
- Medical Research Council Center for Medical Mycology, University of Exeter, Exeter, United Kingdom
- European Pediatric Mycology Network
- Pediatric Infectious Diseases and Immunology Unit, St George's University Hospitals, NHS Foundation Trust, London, United Kingdom
| | - Alessio Mesini
- European Pediatric Mycology Network
- Pediatric Infectious Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Eleni Agakidou
- 1st Department of Neonatology and Intensive Care Unit, Aristotle University School of Medicine, Hippokration Hospital, Thessaloniki, Greece
| | - Tiziana Controzzi
- Pediatric Department, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
| | - Maia De Luca
- Infectious Disease Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Gabriel Dimitriou
- Department of Pediatrics, University General Hospital of Patras, Medical School, University of Patras, Rio, Greece
| | - Marieke Emonts
- Paediatric Immunology, Infectious Diseases & Allergy Department Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Susanna Esposito
- Pediatric Department, Azienda Ospedaliera-Universitaria di Parma, Parma, Italy
| | - Aurora Fernàndez-Polo
- Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Elisabetta Ghimenton-Walters
- Paediatric Immunology, Infectious Diseases & Allergy Department Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Despoina Gkentzi
- Department of Pediatrics, University General Hospital of Patras, Medical School, University of Patras, Rio, Greece
| | - Carlos Grasa
- Pediatric Department, Hospital Universitario La Paz, IdiPAZ. CIBERINFEC, Madrid, Spain
| | - Eleftheria Hatzidaki
- Pediatric Department, University General Hospital of Heraklion, Medical School, University of Crete, Heraklion, Greece
| | - Piia Jõgi
- Neonatology Department, Tartu University Hospital, Tartu, Estonia
| | | | - Angeliki Kontou
- 1st Department of Neonatology and Intensive Care Unit, Aristotle University School of Medicine, Hippokration Hospital, Thessaloniki, Greece
| | - Alessa Leibold-Aguinarte
- Division of Hematology, Oncology and Hemostaseology, Department of Pediatrics, Goethe University Frankfurt, Frankfurt/Main, Germany
| | | | - Natalia Mendoza-Palomar
- Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Tuuli Metsvaht
- Neonatology Department, Tartu University Hospital, Tartu, Estonia
| | - Maria Noni
- 1st Department of Pediatrics, National and Kapodistrian University of Athens, "Agia Sophia" Children's Hospital, Athens, Greece
| | - Stéphane Paulus
- Pediatric Department, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Serafina Perrone
- Pediatric Department, Azienda Ospedaliera-Universitaria di Parma, Parma, Italy
| | - Elena Rincón-López
- Neonatology Department, Hospital Gregorio Marañón, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
| | - Lorenza Romani
- Infectious Disease Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Laura Sánchez
- Pediatric Department, Hospital Universitario La Paz, IdiPAZ. CIBERINFEC, Madrid, Spain
| | - Benhur Sirvan Cetin
- Department of Pediatric Infectious Diseases, Faculty of Medicine, Erciyes University, Kayseri, Turkey
| | - Vana Spoulou
- 1st Department of Pediatrics, National and Kapodistrian University of Athens, "Agia Sophia" Children's Hospital, Athens, Greece
| | | | - Eleni Vergadi
- Pediatric Department, University General Hospital of Heraklion, Medical School, University of Crete, Heraklion, Greece
| | | | - Marco Vuerich
- Pediatric Department, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
| | | | - Emmanuel Roilides
- From the Infectious Diseases Unit, 3rd Department of Pediatrics, Aristotle University School of Medicine, Hippokration Hospital, Thessaloniki, Greece
- 1st Department of Neonatology and Intensive Care Unit, Aristotle University School of Medicine, Hippokration Hospital, Thessaloniki, Greece
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Arekar T, Katikaneni D, Kasem S, Desai D, Acharya T, Cole A, Khodayari N, Vaulont S, Hube B, Nemeth E, Drakesmith A, Lionakis MS, Mehrad B, Scindia Y. Essential role of Hepcidin in host resistance to disseminated candidiasis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.29.620511. [PMID: 39553949 PMCID: PMC11565830 DOI: 10.1101/2024.10.29.620511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
Candida albicans is a leading cause of life-threatening invasive infections with up to 40% mortality rates in hospitalized individuals despite antifungal therapy. Patients with chronic liver disease are at an increased risk of candidemia, but the mechanisms underlying this susceptibility are incompletely defined. One consequence of chronic liver disease is attenuated ability to produce hepcidin and maintain organismal control of iron homeostasis. To address the biology underlying this critical clinical problem, we demonstrate the mechanistic link between hepcidin insufficiency and candida infection using genetic and inducible hepcidin knockout mice. Hepcidin deficiency led to unrestrained fungal growth and increased transition to the invasive hypha morphology with exposed 1,3, β-glucan that exacerbated kidney injury, independent of the fungal pore-forming toxin candidalysin in immunocompetent mice. Of translational relevance, the therapeutic administration of PR-73, a hepcidin mimetic, improved the outcomes of infection. Thus, we identify hepcidin deficiency as a novel host susceptibility factor against C. albicans and hepcidin mimetics as a potential intervention.
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12
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Aziz HSA, Ismail DK, Mohammed NSA, Elgendy MO, Bassiouny DM. Distribution and antifungal susceptibility profiles of Candida species isolated from candidemia patients admitted to Egyptian tertiary hospitals: a cross-sectional study. BMC Infect Dis 2024; 24:1177. [PMID: 39425018 PMCID: PMC11487776 DOI: 10.1186/s12879-024-10007-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 09/27/2024] [Indexed: 10/21/2024] Open
Abstract
BACKGROUND Candidemia is a widespread threat that can lead to significant complications in healthcare settings. OBJECTIVES Our study aimed to identify isolates of Candida isolated from blood culture bottles of patients with candidemia and assess their antifungal susceptibility profiles. METHODS We conducted a cross-sectional study at Cairo University tertiary care hospitals over 16 months including 90 patients. Candida isolates were collected from blood culture bottles, and identified using MALDI-TOF MS technology of VITEK MS PRIME (bioMérieux) with the corresponding database VITEK IVD Database 3.2. followed by antifungal susceptibility testing using VITEK 2 Compact system. RESULTS Candida albicans was the most common species isolated from both pediatric and adult patients with percentages of 47.3% and 36.4% respectively, followed by Candida parapsilosis with percentages of 32.6% and 25.0% respectively. Voriconazole showed the highest antifungal activity at 90.9% of isolates in adults and 95.7% in pediatrics, followed by caspofungin and micafungin. The mean hospital stays for adults ranged from 8 to 30 days and from 10 to 42 days in the pediatric group. CONCLUSIONS C. albicans remains the predominant species isolated from both pediatric and adult candidemia patients, despite a notable increase in other species. C. tropicalis and C. parapsilosis are considered the most common non-albicans Candida (NAC) species. The rise in Candida species other than albicans highlights the urgent need for effective antifungal stewardship programs. Voriconazole exhibited the higher antifungal activity followed by caspofungin and micafungin.
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Affiliation(s)
- Heba Sherif Abdel Aziz
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt.
| | - Dalia Kadry Ismail
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | | | - Marwa O Elgendy
- Clinical Pharmacy Department, Faculty of Medicine, Beni-Suef University Hospitals, Beni-Suef University, Beni-Suef, Egypt
- Clinical Pharmacy Department, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt
| | - Dina M Bassiouny
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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Villanueva-Cotrina F, Bejar V, Guevara J, Cajamarca I, Medina C, Mujica L, Lescano AG. Biofilm formation and increased mortality among cancer patients with candidemia in a Peruvian reference center. BMC Infect Dis 2024; 24:1145. [PMID: 39395965 PMCID: PMC11470705 DOI: 10.1186/s12879-024-10044-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Accepted: 10/02/2024] [Indexed: 10/14/2024] Open
Abstract
BACKGROUND Candidemia is an invasive mycosis with an increasing global incidence and high mortality rates in cancer patients. The production of biofilms by some strains of Candida constitutes a mechanism that limits the action of antifungal agents; however, there is limited and conflicting evidence about its role in the risk of death. This study aimed to determine whether biofilm formation is associated with mortality in cancer patients with candidemia. METHODS This retrospective cohort study included patients treated at Peru's oncologic reference center between June 2015 and October 2017. Data were collected by monitoring patients for 30 days from the diagnosis of candidemia until the date of death or hospital discharge. Statistical analyses evaluated the association between biofilm production determined by XTT reduction and mortality, adjusting for demographic, clinical, and microbiological factors assessed by the hospital routinary activities. Survival analysis and bivariate and multivariate Cox regression were used, estimating the hazard ratio (HR) as a measure of association with a significance level of p < 0.05. RESULTS A total of 140 patients with candidemia were included in the study. The high mortality observed on the first day of post-diagnosis follow-up (81.0%) among 21 patients who were not treated with either antifungal or antimicrobial drugs led to stratification of the analyses according to whether they received treatment. In untreated patients, there was a mortality gradient in patients infected with non-biofilm-forming strains vs. low/medium and high-level biofilm-forming strains (25.0%, 66.7% and 82.3%, respectively, p = 0.049). In treated patients, a high level of biofilm formation was associated with increased mortality (HR, 3.92; 95% p = 0.022), and this association persisted after adjusting for age, comorbidities, and hospital emergency admission (HR, 6.59; CI: 1.87-23.24, p = 0.003). CONCLUSIONS The association between candidemia with in vitro biofilm formation and an increased risk of death consistently observed both in patients with and without treatment, provides another level of evidence for a possible causal association. The presence of comorbidities and the origin of the hospital emergency, which reflect the fragile clinical condition of the patients, and increasing age above 15 years were associated with a higher risk of death.
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Affiliation(s)
- Freddy Villanueva-Cotrina
- Department of Pathology, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru.
- Mycology Laboratory, Instituto de Medicina Tropical Daniel Alcides Carrion - Universidad Nacional Mayor de San Marcos, Lima, Peru.
- Emerge, Emerging Diseases and Climate Change Research Unit, School of Public Health and Administration, Universidad Peruana Cayetano Heredia, Lima, Peru.
- Instituto de Medicina Regional - Universidad Nacional del Nordeste. CONICET, Chaco, Argentina.
| | - Vilma Bejar
- Mycology Laboratory, Instituto de Medicina Tropical Daniel Alcides Carrion - Universidad Nacional Mayor de San Marcos, Lima, Peru
| | - José Guevara
- Mycology Laboratory, Instituto de Medicina Tropical Daniel Alcides Carrion - Universidad Nacional Mayor de San Marcos, Lima, Peru
| | - Ines Cajamarca
- Department of Pathology, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru
| | - Cyntia Medina
- Mycology Laboratory, Instituto de Medicina Tropical Daniel Alcides Carrion - Universidad Nacional Mayor de San Marcos, Lima, Peru
| | - Luis Mujica
- Mycology Laboratory, Instituto de Medicina Tropical Daniel Alcides Carrion - Universidad Nacional Mayor de San Marcos, Lima, Peru
| | - Andres G Lescano
- Emerge, Emerging Diseases and Climate Change Research Unit, School of Public Health and Administration, Universidad Peruana Cayetano Heredia, Lima, Peru
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Long Y, Xu J, Hu Z, Fan XY, Wang H. Antifungal activity of Cinnamaldehyde derivatives against fluconazole-resistant Candida albicans. Microb Pathog 2024; 195:106877. [PMID: 39173853 DOI: 10.1016/j.micpath.2024.106877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 07/05/2024] [Accepted: 08/20/2024] [Indexed: 08/24/2024]
Abstract
BACKGROUND Candida albicans is an opportunistic pathogen commonly found in human mucous membranes. In light of the escalating challenge posed by antibiotic resistance of C. albicans strains worldwide, it is an urgently necessary to explore alternative therapeutic options. OBJECTIVE This study aims to assess the efficacy of two Cinnamaldehyde derivatives, 2-Cl Cinnamaldehyde (2-Cl CA) and 4-Cl Cinnamaldehyde (4-Cl CA), against C. albicans through both in vitro experiments and in vivo murine models and to evaluate their potential as new drug candidates for treating C. albicans. METHODS AND RESULTS The minimum inhibitory concentrations (MICs) of Cinnamaldehyde 2-Cl and 4-Cl benzene ring derivatives against C. albicans were 25 μg/mL. Time-killing experiments revealed that both Cinnamaldehyde derivatives exhibited fungicidal activity against C. albicans at concentrations of 5 MIC and 10 MIC. In the checkerboard experiment, 4-Cl CA did not show any antagonistic effect when combined with first-line antifungal drugs. Instead, it exhibited additive effects in combination with nystatin. Both 2-Cl and 4-Cl CA demonstrated inhibitory activity against C. albicans biofilm formation, especially at 8 MIC and 16 MIC concentrations. In C. albicans biofilm eradication experiments, although high drug concentrations of 2-Cl and 4-Cl CA were unable to eradicate the biofilm completely, they were still effective in killing C. albicans cells within the biofilm. Moreover, sub-inhibitory concentrations of 4-Cl CA (ranging from 5 to 20 μg/mL) significantly inhibited cell aggregation and hyphal formation. Furthermore, 4-Cl CA effectively inhibited intracellular C. albicans infection in macrophages. Lastly, the effectiveness of 4-Cl CA was evaluated in a mouse model of hematogenous disseminated candidiasis caused by C. albicans, which revealed that 4-Cl CA significantly reduced fungal burden and improved mouse survival compared to the untreated controls. CONCLUSION The 4-Cl CA exhibited inhibitory effects against C. albicans through both in vivo and in vitro models, demonstrating its therapeutic potential as a promising new drug candidate for treating drug-resistant candidiasis albicans.
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Affiliation(s)
- Yujiao Long
- Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, Three Gorges University, Yichang, 443002, China; Shanghai Institute of Infectious Diseases and Biosecurity & Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China
| | - Jinchuan Xu
- Shanghai Institute of Infectious Diseases and Biosecurity & Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China
| | - Zhidong Hu
- Shanghai Institute of Infectious Diseases and Biosecurity & Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China
| | - Xiao-Yong Fan
- Shanghai Institute of Infectious Diseases and Biosecurity & Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China.
| | - Hui Wang
- Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, Three Gorges University, Yichang, 443002, China.
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15
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Long B, Lacy AJ, Koyfman A, Liang SY. Candida auris: A focused review for emergency clinicians. Am J Emerg Med 2024; 84:162-167. [PMID: 39137491 DOI: 10.1016/j.ajem.2024.07.062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 07/25/2024] [Accepted: 07/28/2024] [Indexed: 08/15/2024] Open
Abstract
INTRODUCTION Candida auris is an emerging pathogen and human health threat. However, diagnosis and treatment of fungal infection due to C. auris are challenging. OBJECTIVE This narrative review provides a focused overview of C. auris for the emergency clinician. DISCUSSION C. auris was first identified in 2009 and is currently present on all continents except Antarctica. C. auris possesses multiple genetic factors resulting in antimicrobial resistance, increased virulence and survival within the host, and environmental adaptation. It is readily transmitted from person to person and from the environment to a person, resulting in colonization. Infection may develop days to months following colonization, most commonly in those with immunocompromised state, significant comorbidities or other underlying conditions, healthcare exposure, and recent antimicrobial therapy. Candidemia, device infection (e.g., central venous catheter), soft tissue or wound infection, burn infection, osteomyelitis, myocarditis, meningitis, and urinary tract infection have been associated with C. auris. Samples should be obtained from the suspected site of infection for microbiological culture. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with reference databases to differentiate C. auris from other species is optimal for diagnosis, though other molecular testing methods are available. Treatment is challenging due to antifungal resistance, with over 90% resistant to fluconazole. Echinocandins are most commonly used as the first line therapy. Prevention of colonization and infection are vital and include screening in high-risk populations and strict adherence to infection prevention practices with contact precautions and hand hygiene, as well as appropriate decontamination of patient areas. CONCLUSION An understanding of C. auris can assist emergency clinicians in the care of infected or colonized patients.
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Affiliation(s)
- Brit Long
- SAUSHEC, Emergency Medicine, Brooke Army Medical Center, Fort Sam Houston, TX, United States.
| | - Aaron J Lacy
- Division of Emergency Medicine Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, United States
| | - Alex Koyfman
- Department of Emergency Medicine, UT Southwester, Dallas, TX, United States
| | - Stephen Y Liang
- Divisions of Emergency Medicine and Infectious Diseases, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO, United States.
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Sharifzadeh A, Fasaei BN, Asadi S, Fatemi N, Houshmandzad M, Ghaffari MH. Evaluation of antifungal and apoptotic effects of linalool, citral, and carvacrol separately and in combination with nystatin against clinical isolates of Pichia kudriavzevii. BMC Microbiol 2024; 24:333. [PMID: 39251899 PMCID: PMC11386228 DOI: 10.1186/s12866-024-03487-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 09/02/2024] [Indexed: 09/11/2024] Open
Abstract
Pichia kudriavzevii (formerly Candida krusei) poses a significant threat to immunocompromised patients due to its inherent resistance to various antifungal drugs. This study explored the anticandidal potential of citral, linalool, and carvacrol in combination with nystatin against P. kudriavzevii strains.Using the microdilution method following CLSI guidelines, Minimum Inhibitory Concentrations (MICs) and fungicidal concentrations (MFCs) were determined. Citral exhibited MIC values ranging from 50 to 100 µg/ml, averaging 70.24 ± 16.99 µg/ml, while carvacrol had MIC values of 50 to 100 µg/ml, averaging 86.90 ± 16.99 µg/ml. Linalool demonstrated weaker antifungal activity, with MIC values between 100 and 200 µg/ml, averaging 150 ± 38.73 µg/ml. The study assessed the synergistic effectsof these phenols with nystatin through fractional inhibitory concentration indices (FICIS). In addition, flow cytometry was employed to assess apoptosis induction in P. kudriavzevii cells.Carvacrol displayed a remarkable synergistic effect in combination with nystatin against all 21 isolates tested. Conversely, linalool showed synergy in 17 isolates, while citral exhibited synergy in only 2 isolates. These findings highlight distinct patterns of synergy between the different compounds and nystatin against P. kudriavzevii. Also, Carvacrol emerged as the most potent inducer of apoptosis across all P. kudriavzevii strains, followed by citral and linalool. This suggests that carvacrol not only possesses a stronger antifungal effect but also has a more pronounced ability to trigger programmed cell death in P. kudriavzevii. In conclusion, the study supports the potential of carvacrol, citral and linalool, as anticandidal agents, suggesting their supplementation with nystatin for treating P. kudriavzevii infections.
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Affiliation(s)
- Aghil Sharifzadeh
- Department of Microbiology and Immunology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
| | - Bahar Nayeri Fasaei
- Department of Microbiology and Immunology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Sepideh Asadi
- Department of Microbiology and Immunology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Narges Fatemi
- DVM, Student of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mahdi Houshmandzad
- Department of Microbiology and Immunology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Mohammad Hosein Ghaffari
- DVM, Student of Veterinary Medicine, Science and Research Branch, Islamic Azad University, Tehran, Iran
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17
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Meng Q, Chen B, Xu Y, Zhang Q, Ding R, Ma Z, Jin Z, Gao S, Qu F. A machine learning model for early candidemia prediction in the intensive care unit: Clinical application. PLoS One 2024; 19:e0309748. [PMID: 39250466 PMCID: PMC11383240 DOI: 10.1371/journal.pone.0309748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 08/17/2024] [Indexed: 09/11/2024] Open
Abstract
Candidemia often poses a diagnostic challenge due to the lack of specific clinical features, and delayed antifungal therapy can significantly increase mortality rates, particularly in the intensive care unit (ICU). This study aims to develop a machine learning predictive model for early candidemia diagnosis in ICU patients, leveraging their clinical information and findings. We conducted this study with a cohort of 334 patients admitted to the ICU unit at Ji Ning NO.1 people's hospital in China from Jan. 2015 to Dec. 2022. To ensure the model's reliability, we validated this model with an external group consisting of 77 patients from other sources. The candidemia to bacteremia ratio is 1:1. We collected relevant clinical procedures and eighteen key examinations or tests features to support the recursive feature elimination (RFE) algorithm. These features included total bilirubin, age, platelet count, hemoglobin, CVC, lymphocyte, Duration of stay in ICU and so on. To construct the candidemia diagnosis model, we employed random forest (RF) algorithm alongside other machine learning methods and conducted internal and external validation with training and testing sets allocated in a 7:3 ratio. The RF model demonstrated the highest area under the receiver operating characteristic (AUC) with values of 0.87 and 0.83 for internal and external validation, respectively. To evaluate the importance of features in predicting candidemia, Shapley additive explanation (SHAP) values were calculated and results revealed that total bilirubin and age were the most important factors in the prediction model. This advancement in candidemia prediction holds significant promise for early intervention and improved patient outcomes in the ICU setting, where timely diagnosis is of paramount crucial.
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Affiliation(s)
- Qiang Meng
- Jining No. 1 People's Hospital Affiliated to Shandong First Medical University, Jining, Shandong, China
| | - Bowang Chen
- Jining No. 1 People's Hospital Affiliated to Shandong First Medical University, Jining, Shandong, China
| | - Yingyuan Xu
- Pulmonary and Critical Care Medicine, Tengzhou Central People's Hospital, Tengzhou City, Shandong Province, People's Republic of China
| | - Qiang Zhang
- Pulmonary and Critical Care Medicine, Tengzhou Central People's Hospital, Tengzhou City, Shandong Province, People's Republic of China
| | - Ranran Ding
- Jining No. 1 People's Hospital Affiliated to Shandong First Medical University, Jining, Shandong, China
| | - Zhen Ma
- Jining No. 1 People's Hospital Affiliated to Shandong First Medical University, Jining, Shandong, China
| | - Zhi Jin
- Jining No. 1 People's Hospital Affiliated to Shandong First Medical University, Jining, Shandong, China
| | - Shuhong Gao
- Jining No. 1 People's Hospital Affiliated to Shandong First Medical University, Jining, Shandong, China
| | - Feng Qu
- Jining No. 1 People's Hospital Affiliated to Shandong First Medical University, Jining, Shandong, China
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Chen L, Xie Z, Jian J. Epidemiology and Risk Factors of Candidemia a 8-Year Retrospective Study from a Teaching Hospital in China. Infect Drug Resist 2024; 17:3415-3423. [PMID: 39131515 PMCID: PMC11317046 DOI: 10.2147/idr.s471171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Accepted: 07/31/2024] [Indexed: 08/13/2024] Open
Abstract
Purpose We investigated the Epidemiology, risk factors and outcomes of Candida bloodstream infection. Methods The electronic laboratory records data of patients with candidemia (2015-2022) were collected. We used univariate and multivariate logistic regression to determine the risk factors of candidemia. Results Of the 134 patients with candidemia, the most prevalent species were Candida albicans (37.2%), followed by Candida glabrata (27.7%), Candida parapsilosis (18.9%), and others. The mean annual incidence was 0.33/1000 admissions. The overall resistance rate of Candida spp. against fluconazole and voriconazole were 4.9% (7/142) and 5.9% (6/101), while Candida tropicalis showed high resistance to fluconazole (38.8%) and voriconazole (27.8%). The 30-day mortality rate was 32.8%. On multivariate analysis, age ≥ 65 (odds ratio [OR] = 3.874, 95% confidence interval [CI]: 1.146, 13.092; P = 0.029), high Acute Physiology and Chronic Health Evaluation II (APACHE II) score (OR = 12.384, 95% CI: 2.963, 51.762; P = 0.001), shock (OR = 3.428, 95% CI: 1.097, 10.719; P = 0.034), initial antifungal therapy (OR = 0.057, 95% CI: 0.011, 0.306; P = 0.001) and White blood cells (OR = 1.129, 95% CI: 1.016, 1.255; P = 0.024) were the independent risk factors with mortality within 30 day in patients with candidemia. Conclusion The incidence rate and the mortality rate of candidemia are high, and lower azole susceptibility was found in Candida tropicalis. Age≥65 years, Shock, high APACHE II score, Antifungal therapy and White blood cells count were independently associated with 30-day mortality.
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Affiliation(s)
- Liang Chen
- Clinical Laboratory Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, People’s Republic of China
| | - Zeqiang Xie
- Clinical Laboratory Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, People’s Republic of China
| | - Jiyong Jian
- Clinical Laboratory Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, People’s Republic of China
- Beijing Key Laboratory of Urinary Cellular Molecular Diagnostics, Beijing, People’s Republic of China
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19
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Belgacem S, Chebil W, Ben Salem S, Babba O, Mastouri M, Babba H. Identification and antifungal susceptibility profile of uncommon yeast species at Fattouma Bourguiba University Hospital in Tunisia. Med Mycol 2024; 62:myae070. [PMID: 38986508 DOI: 10.1093/mmy/myae070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 06/18/2024] [Accepted: 07/08/2024] [Indexed: 07/12/2024] Open
Abstract
Despite the severe impact of uncommon yeast fungal infections and the pressing need for more research on the topic, there are still few studies available on the identification, epidemiology, and susceptibility profile of those pathogens. The aims of the current study were to define the profile of uncommon yeast species at Fattouma Bourguiba University Hospital using phenotypic, molecular, and proteomic methods and to study their antifungal susceptibility profile. Pre-identified uncommon yeast species were collected from 2018 to 2021. These isolates were further identified using phenotypic methods (ID32C® system and Vitek2® YST), matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS), and sequencing. The antifungal susceptibility profile was studied using the reference CLSI broth microdilution method. In total, 30 strains were collected during the study period. Referring to the sequencing, the most isolated uncommon species were Saprochaete capitata, Candida lusitaniae, Candida kefyr, Candida inconspicua, and Candida guilliermondii. A total of 90% of isolates were correctly identified by MALDI-TOF MS compared to 76.7% and 63.3% by ID32® C and VITEK® 2 YST, respectively. The isolated species showed variable responses to antifungals. Candida guilliermondii showed increased azole minimum inhibitory concentrations. Misidentification of uncommon yeast species was common using commercial phenotypic methods. The high percentage of concordance of MALDI-TOF results with sequencing highlights its high performance and usefulness as a routine diagnosis tool.
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Affiliation(s)
- Sameh Belgacem
- Unit of Parasitology-Mycology, Laboratory of Microbiology, Fattouma Bourguiba University Hospital, Monastir, Tunisia
- Laboratory of Medical and Molecular Parasitology-Mycology (LR12ES08), Department of Clinical Biology B, Faculty of Pharmacy, University of Monastir, Monastir, Tunisia
| | - Wissal Chebil
- Laboratory of Medical and Molecular Parasitology-Mycology (LR12ES08), Department of Clinical Biology B, Faculty of Pharmacy, University of Monastir, Monastir, Tunisia
| | - Safa Ben Salem
- Unit of Parasitology-Mycology, Laboratory of Microbiology, Fattouma Bourguiba University Hospital, Monastir, Tunisia
| | - Oussama Babba
- Laboratory of Medical and Molecular Parasitology-Mycology (LR12ES08), Department of Clinical Biology B, Faculty of Pharmacy, University of Monastir, Monastir, Tunisia
| | - Maha Mastouri
- Unit of Parasitology-Mycology, Laboratory of Microbiology, Fattouma Bourguiba University Hospital, Monastir, Tunisia
| | - Hamouda Babba
- Laboratory of Medical and Molecular Parasitology-Mycology (LR12ES08), Department of Clinical Biology B, Faculty of Pharmacy, University of Monastir, Monastir, Tunisia
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20
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Reitler P, Regan J, DeJarnette C, Srivastava A, Carnahan J, Tucker KM, Meibohm B, Peters BM, Palmer GE. The atypical antipsychotic aripiprazole alters the outcome of disseminated Candida albicans infections. Infect Immun 2024; 92:e0007224. [PMID: 38899880 PMCID: PMC11238555 DOI: 10.1128/iai.00072-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 04/29/2024] [Indexed: 06/21/2024] Open
Abstract
Invasive fungal infections impose an enormous clinical, social, and economic burden on humankind. One of the most common species responsible for invasive fungal infections is Candida albicans. More than 30% of patients with disseminated candidiasis fail therapy with existing antifungal drugs, including the widely used azole class. We previously identified a collection of 13 medications that antagonize the activity of the azoles on C. albicans. Although gain-of-function mutations responsible for antifungal resistance are often associated with reduced fitness and virulence, it is currently unknown how exposure to azole antagonistic drugs impacts C. albicans physiology, fitness, or virulence. In this study, we examined how exposure to seven azole antagonists affects C. albicans phenotype and capacity to cause disease. Most of the azole antagonists appear to have little impact on fungal growth, morphology, stress tolerance, or gene transcription. However, aripiprazole had a modest impact on C. albicans hyphal growth and increased cell wall chitin content. It also aggravated the disseminated C. albicans infections in mice. This effect was abrogated in immunosuppressed mice, indicating that it is at least in part dependent upon host immune responses. Collectively, these data provide proof of principle that unanticipated drug-fungus interactions have the potential to influence the incidence and outcomes of invasive fungal disease.
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Affiliation(s)
- Parker Reitler
- Integrated Program in Biomedical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Jessica Regan
- Pharmaceutical Sciences Program, College of Graduate Health Sciences, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
| | - Christian DeJarnette
- Department of Clinical Pharmacy and Translational Science, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
| | - Ashish Srivastava
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Jen Carnahan
- Department of Clinical Pharmacy and Translational Science, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
| | - Katie M. Tucker
- Department of Clinical Pharmacy and Translational Science, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
| | - Bernd Meibohm
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Brian M. Peters
- Department of Clinical Pharmacy and Translational Science, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
- Department of Microbiology, Immunology, and Biochemistry, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Glen E. Palmer
- Department of Clinical Pharmacy and Translational Science, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
- Department of Microbiology, Immunology, and Biochemistry, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
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Basuli F, Shi J, Shah S, Lai J, Hammoud DA, Swenson RE. Fully Automated Cassette-Based Synthesis of 2-Deoxy-2-[ 18F]Fluorocellobiose Using Trasis AllInOne Module. J Labelled Comp Radiopharm 2024; 67:308-313. [PMID: 38982015 DOI: 10.1002/jlcr.4116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 06/14/2024] [Accepted: 06/21/2024] [Indexed: 07/11/2024]
Abstract
Due to the continuous rise in global incidence and severity of invasive fungal infections (IFIs), particularly among immunocompromised and immunodeficient patients, there is an urgent demand for swift and accurate fungal pathogen diagnosis. Therefore, the need for fungal-specific positron emission tomography (PET) imaging agents that can detect the infection in the early stages is increasing. Cellobiose, a disaccharide, is readily metabolized by fungal pathogens such as Aspergillus species. Recently, our group reported fluorine-18 labeled cellobiose, 2-deoxy-2-[18F]fluorocellobiose ([18F]FCB), for specific imaging of Aspergillus infection. The positive imaging findings with very low background signal on delayed imaging make this ligand a promising fungal-specific imaging ligand. Inspired by this result, the decision was made to automate the radiolabeling procedure for better reproducibility and to facilitate clinical translation. A Trasis AllInOne (Trasis AIO) automated module was used for this purpose. The reagent vials contain commercially available 2-deoxy-2-[18F]fluoroglucose ([18F]FDG), glucose-1-phosphate, and enzyme (cellobiose phosphorylase). A Sep-Pak cartridge was used to purify the tracer. The overall radiochemical yield was 50%-70% (n = 6, decay corrected) in 75-min synthesis time with a radiochemical purity of > 98%. This is a highly reliable protocol to produce current good manufacturing practice (cGMP)-compliant [18F]FCB for clinical PET imaging.
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Affiliation(s)
- Falguni Basuli
- Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Rockville, Maryland, USA
| | - Jianfeng Shi
- Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Rockville, Maryland, USA
| | - Swati Shah
- Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center (CC), National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Jianhao Lai
- Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center (CC), National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Dima A Hammoud
- Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center (CC), National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Rolf E Swenson
- Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Rockville, Maryland, USA
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22
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Hon KLE, Chan VPY, Leung AKC, Leung KKY, Hui WF. Invasive fungal infections in critically ill children: epidemiology, risk factors and antifungal drugs. Drugs Context 2024; 13:2023-9-2. [PMID: 38915918 PMCID: PMC11195526 DOI: 10.7573/dic.2023-9-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 02/20/2024] [Indexed: 06/26/2024] Open
Abstract
Background Invasive fungal infections (IFIs) are important infectious complications amongst critically ill children. The most common fungal infections are due to Candida species. Aspergillus, Zygomycetes and Fusarium are also emerging because of the empirical use of antifungal drugs. This updated review discusses the epidemiology of IFIs as well as antifungal drugs, dosing and potential adverse effects in critically ill children. Methods A PubMed search was conducted with Clinical Queries using the key terms "antifungal", "children", "critical care" AND "paediatric intensive care unit" OR "PICU". The search strategy included clinical trials, randomized controlled trials, meta-analyses, observational studies and reviews and was limited to the English literature in paediatrics. Results Candida and Aspergillus spp. are the most prevalent fungi in paediatric IFIs, causing invasive candidiasis infections (ICIs) and invasive aspergillosis infections (IAIs), respectively. These IFIs are associated with high morbidity, mortality and healthcare costs. Candida albicans is the principal Candida spp. associated with paediatric ICIs. The risks and epidemiology for IFIs vary if considering previously healthy children treated in the paediatric intensive care unit or children with leukaemia, malignancy or a severe haematological disease. The mortality rate for IAIs in children is 2.5-3.5-fold higher than for ICIs. Four major classes of antifungals for critically ill children are azoles, polyenes, antifungal antimetabolites and echinocandins. Conclusions Antifungal agents are highly efficacious. For successful treatment outcomes, it is crucial to determine the optimal dosage, monitor pharmacokinetics parameters and adverse effects, and individualized therapeutic monitoring. Despite potent antifungal medications, ICIs and IAIs continue to be serious infections with high mortality rates. Pre-emptive therapy has been used for IAIs. Most guidelines recommend voriconazole as initial therapy of invasive aspergillosis in most patients, with consideration of combination therapy with voriconazole plus an echinocandin in selected patients with severe disease. The challenge is to identify critically ill patients at high risks of ICIs for targeted prophylaxis. Intravenous/per os fluconazole is first-line pre-emptive treatment for Candida spp. whereas intravenous micafungin or intravenous liposomal amphotericin B is alternative pre-emptive treatment.This article is part of the Challenges and strategies in the management of invasive fungal infections Special Issue: https://www.drugsincontext.com/special_issues/challenges-and-strategies-in-the-management-of-invasive-fungal-infections.
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Affiliation(s)
- Kam Lun Ellis Hon
- Department of Paediatrics and Adolescent Medicine,
Hong Kong Children’s Hospital,
Hong Kong,
China
- Department of Paediatrics, CUHKMC, The Chinese University of
Hong Kong,
Hong Kong,
China
| | - Vivian PY Chan
- Department of Pharmacy,
Hong Kong Children’s Hospital,
Hong Kong,
China
| | - Alexander KC Leung
- Department of Pediatrics, The University of Calgary, and The Alberta Children’s Hospital, Calgary, Alberta,
Canada
| | - Karen Ka Yan Leung
- Department of Paediatrics and Adolescent Medicine,
Hong Kong Children’s Hospital,
Hong Kong,
China
| | - Wun Fung Hui
- Department of Paediatrics and Adolescent Medicine,
Hong Kong Children’s Hospital,
Hong Kong,
China
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23
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Murphy CR, Teoh Z, Whitehurst D, Brammer C, Perkins K, Paulsen G, Miller-Handley H, Danziger-Isakov L, Otto WR. Disseminated Disease After Candidemia in Children and Young Adults: Epidemiology, Diagnostic Evaluation and Risk Factors. Pediatr Infect Dis J 2024; 43:328-332. [PMID: 38091489 DOI: 10.1097/inf.0000000000004212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/09/2024]
Abstract
BACKGROUND Treatment of candidemia may be complicated by hematogenous dissemination. Limited data exist to guide decision-making regarding the evaluation for disseminated disease. We sought to describe the epidemiology of invasive disease after candidemia, report the diagnostic evaluations performed and identify risk factors for disseminated disease. METHODS We performed a retrospective single-center study of candidemia from January 1, 2012 to December 31, 2022. Disseminated candidiasis was defined as radiologic findings consistent with end-organ disease, abnormal ophthalmologic exam or growth of Candida spp. from a sterile site after an episode of candidemia. A multilevel regression model was used to identify risk factors for dissemination. RESULTS The cohort included 124 patients with 144 episodes of candidemia. Twelve patients died before an evaluation for dissemination occurred. Only 107/132 patients underwent evaluation for dissemination. Tests obtained included abdominal imaging (93/132), echocardiography (91/132), neuroimaging (45/132) and chest imaging (38/132). A retinal examination was performed in 90/132 patients. Overall, 27/107 patients (25%) had disseminated disease. Frequently identified sites of dissemination were lungs and abdominal organs. Regression modeling identified prematurity [adjusted odds ratio (aOR): 11.88; 95% confidence interval (CI): 1.72-81.90] and mitochondrial and genetic disease (aOR: 5.66; 95% CI: 1.06-30.17) as risk factors for disseminated candidiasis. Each additional day of candidemia increased the odds of dissemination (aOR: 1.36; 95% CI: 1.12-1.66). DISCUSSION In a heterogeneous cohort of patients, disseminated candidiasis was common. Evaluation for disseminated disease was variable. Those with persistent candidemia had significantly increased risk of dissemination and should undergo a standardized evaluation for disseminated disease.
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Affiliation(s)
- Catherine R Murphy
- From the Department of Pediatrics, University of Cincinnati
- Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Zheyi Teoh
- From the Department of Pediatrics, University of Cincinnati
- Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | | | - Caitlin Brammer
- Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Kerrigan Perkins
- Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Grant Paulsen
- From the Department of Pediatrics, University of Cincinnati
- Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Hilary Miller-Handley
- From the Department of Pediatrics, University of Cincinnati
- Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Lara Danziger-Isakov
- From the Department of Pediatrics, University of Cincinnati
- Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - William R Otto
- From the Department of Pediatrics, University of Cincinnati
- Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
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24
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Reitler P, Regan J, DeJarnette C, Srivastava A, Carnahan J, Tucker KM, Meibohm B, Peters BM, Palmer GE. The atypical antipsychotic aripiprazole alters the outcome of disseminated Candida albicans infections. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.13.580133. [PMID: 38405954 PMCID: PMC10888916 DOI: 10.1101/2024.02.13.580133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/27/2024]
Abstract
Invasive fungal infections (IFIs) impose an enormous clinical, social, and economic burden on humankind. For many IFIs, ≥ 30% of patients fail therapy with existing antifungal drugs, including the widely used azole class. We previously identified a collection of 13 approved medications that antagonize azole activity. While gain-of-function mutants resulting in antifungal resistance are often associated with reduced fitness and virulence, it is currently unknown how exposure to azole antagonistic drugs impact C. albicans physiology, fitness, or virulence. In this study, we examined how exposure to azole antagonists affected C. albicans phenotype and capacity to cause disease. We discovered that most of the azole antagonists had little impact on fungal growth, morphology, stress tolerance, or gene transcription. However, aripiprazole had a modest impact on C. albicans hyphal growth and increased cell wall chitin content. It also worsened the outcome of disseminated infections in mice at human equivalent concentrations. This effect was abrogated in immunosuppressed mice, indicating an additional impact of aripiprazole on host immunity. Collectively, these data provide proof-of-principle that unanticipated drug-fungus interactions have the potential to influence the incidence and outcomes of invasive fungal disease.
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Affiliation(s)
- Parker Reitler
- Integrated Program in Biomedical Sciences, College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Jessica Regan
- Pharmaceutical Sciences Program, College of Graduate Health Sciences, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
| | - Christian DeJarnette
- Department of Clinical Pharmacy and Translational Science, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
| | - Ashish Srivastava
- Department of Pharmaceutical Sciences College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
| | - Jen Carnahan
- Department of Clinical Pharmacy and Translational Science, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
| | - Katie M. Tucker
- Department of Clinical Pharmacy and Translational Science, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
| | - Bernd Meibohm
- Department of Pharmaceutical Sciences College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
| | - Brian M Peters
- Department of Clinical Pharmacy and Translational Science, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
- Department of Microbiology, Immunology, and Biochemistry, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Glen E. Palmer
- Department of Clinical Pharmacy and Translational Science, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
- Department of Microbiology, Immunology, and Biochemistry, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA
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25
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Zhao G, Li Y, Chen T, Liu F, Zheng Y, Liu B, Zhao W, Qi X, Sun W, Gao C. TRIM26 alleviates fatal immunopathology by regulating inflammatory neutrophil infiltration during Candida infection. PLoS Pathog 2024; 20:e1011902. [PMID: 38166150 PMCID: PMC10786383 DOI: 10.1371/journal.ppat.1011902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 01/12/2024] [Accepted: 12/14/2023] [Indexed: 01/04/2024] Open
Abstract
Fungal infections have emerged as a major concern among immunocompromised patients, causing approximately 2 million deaths each year worldwide. However, the regulatory mechanisms underlying antifungal immunity remain elusive and require further investigation. The E3 ligase Trim26 belongs to the tripartite motif (Trim) protein family, which is involved in various biological processes, including cell proliferation, antiviral innate immunity, and inflammatory responses. Herein, we report that Trim26 exerts protective antifungal immune functions after fungal infection. Trim26-deficient mice are more susceptible to fungemia than their wild-type counterparts. Mechanistically, Trim26 restricts inflammatory neutrophils infiltration and limits proinflammatory cytokine production, which can attenuate kidney fungal load and renal damage during Candida infection. Trim26-deficient neutrophils showed higher proinflammatory cytokine expression and impaired fungicidal activity. We further demonstrated that excessive neutrophils infiltration in the kidney was because of the increased production of chemokines CXCL1 and CXCL2, which are mainly synthesized in the macrophages or dendritic cells of Trim26-deficient mice after Candida albicans infections. Together, our study findings unraveled the vital role of Trim26 in regulating antifungal immunity through the regulation of inflammatory neutrophils infiltration and proinflammatory cytokine and chemokine expression during candidiasis.
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Affiliation(s)
- Guimin Zhao
- Key Laboratory of Infection and Immunity of Shandong Province & Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, Shandong, P.R. China
- Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, P.R. China
| | - Yanqi Li
- Key Laboratory of Infection and Immunity of Shandong Province & Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, Shandong, P.R. China
- Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, P.R. China
| | - Tian Chen
- Key Laboratory of Infection and Immunity of Shandong Province & Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, Shandong, P.R. China
- Department of Pathogenic Biology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, P. R. China
| | - Feng Liu
- Key Laboratory of Infection and Immunity of Shandong Province & Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, Shandong, P.R. China
- Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, P.R. China
| | - Yi Zheng
- Key Laboratory of Infection and Immunity of Shandong Province & Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, Shandong, P.R. China
- Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, P.R. China
| | - Bingyu Liu
- Key Laboratory of Infection and Immunity of Shandong Province & Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, Shandong, P.R. China
- Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, P.R. China
| | - Wei Zhao
- Key Laboratory of Infection and Immunity of Shandong Province & Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, Shandong, P.R. China
- Department of Pathogenic Biology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, P. R. China
| | - Xiaopeng Qi
- Advanced Medical Research Institute, Shandong University, Jinan, Shandong, P. R. China
| | - Wanwei Sun
- Key Laboratory of Infection and Immunity of Shandong Province & Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, Shandong, P.R. China
- Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, P.R. China
| | - Chengjiang Gao
- Key Laboratory of Infection and Immunity of Shandong Province & Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan, Shandong, P.R. China
- Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, P.R. China
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Higgins CJ, Kite KA, Klein N, Super M, McCurdy MT, Hargrave D. A novel diagnostic method for a rare fungus: FcMBL facilitates Wickerhamomyces anomalus identification in an immunocompromised neonate. Med Mycol Case Rep 2023; 42:100614. [PMID: 38022892 PMCID: PMC10630647 DOI: 10.1016/j.mmcr.2023.100614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 10/11/2023] [Accepted: 10/19/2023] [Indexed: 12/01/2023] Open
Abstract
Fungemia negatively impacts patient outcomes, current diagnostics lack sensitivity to identify emerging rare mycoses, and fungal infections are increasing in prevalence, variety, and resistance. We report a case of Wickerhamomyces anomalus in an immunocompromised neonate in which FcMBL bead-based matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) resulted in species identification roughly 30 hours before standard pathogen identification methods. Deploying FcMBL bead-based MALDI-TOF MS may improve the speed and accuracy of identification, and therefore treatment, of rare pathogens.
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Affiliation(s)
- Conor J. Higgins
- The Robert Larner, M.D. College of Medicine at the University of Vermont, Burlington, VT, USA
| | - Kerry-Anne Kite
- Great Ormond Street Institute of Child Health, London, United Kingdom
- Great Ormond Street Hospital, London, United Kingdom
| | - Nigel Klein
- Great Ormond Street Institute of Child Health, London, United Kingdom
- Great Ormond Street Hospital, London, United Kingdom
| | - Michael Super
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
| | - Michael T. McCurdy
- University of Maryland School of Medicine, Baltimore, MD, USA
- BOA Biomedical Inc., Cambridge, MA, USA
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27
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Freitas CG, Felipe MS. Candida albicans and Antifungal Peptides. Infect Dis Ther 2023; 12:2631-2648. [PMID: 37940816 PMCID: PMC10746669 DOI: 10.1007/s40121-023-00889-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 10/23/2023] [Indexed: 11/10/2023] Open
Abstract
Candida albicans, a ubiquitous opportunistic fungal pathogen, plays a pivotal role in human health and disease. As a commensal organism, it normally resides harmlessly within the human microbiota. However, under certain conditions, C. albicans can transition into a pathogenic state, leading to various infections collectively known as candidiasis. With the increasing prevalence of immunocompromised individuals and the widespread use of invasive medical procedures, candidiasis has become a significant public health concern. The emergence of drug-resistant strains further complicates treatment options, highlighting the urgent need for alternative therapeutic strategies. Antifungal peptides (AFPs) have gained considerable attention as potential candidates for combating Candida spp. infections. These naturally occurring peptides possess broad-spectrum antimicrobial activity, including specific efficacy against C. albicans. AFPs exhibit several advantageous properties, such as rapid killing kinetics, low propensity for resistance development, and diverse mechanisms of action, making them promising alternatives to conventional antifungal agents. In recent years, extensive research has focused on discovering and developing novel AFPs with improved efficacy and selectivity against Candida species. Advances in biotechnology and synthetic peptide design have enabled the modification and optimization of natural peptides, enhancing their stability, bioavailability, and therapeutic potential. Nevertheless, several challenges must be addressed before AFPs can be widely implemented in clinical practice. These include optimizing peptide stability, enhancing delivery methods, overcoming potential toxicity concerns, and conducting comprehensive preclinical and clinical studies. This commentary presents a short overview of candidemia and AFP; articles and reviews published in the last 10 years were searched on The National Library of Medicine (National Center for Biotechnology Information-NIH-PubMed). The terms used were C. albicans infections, antimicrobial peptides, antifungal peptides, antifungal peptides mechanisms of action, candidemia treatments and guidelines, synthetic peptides and their challenges, and antimicrobial peptides in clinical trials as the main ones. Older publications were cited if they brought some relevant concept or helped to bring a perspective into our narrative. Articles older than 20 years and those that appeared in PubMed but did not match our goal to bring updated information about using antifungal peptides as an alternative to C. albicans infections were not considered.
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Affiliation(s)
- Camila G Freitas
- Higher Education Course in Food Technology, Instituto Federal de Brasília (IFB), Brasília, DF, Brazil
- Genomic Sciences and Biotechnology Graduate Program, Universidade Católica de Brasília (UCB), Brasília, DF, Brazil
| | - Maria Sueli Felipe
- Genomic Sciences and Biotechnology Graduate Program, Universidade Católica de Brasília (UCB), Brasília, DF, Brazil.
- Universidade de Brasília (UNB), Brasília, DF, Brazil.
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Arafa SH, Elbanna K, Osman GEH, Abulreesh HH. Candida diagnostic techniques: a review. JOURNAL OF UMM AL-QURA UNIVERSITY FOR APPLIED SCIENCES 2023; 9:360-377. [DOI: 10.1007/s43994-023-00049-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 04/27/2023] [Indexed: 01/03/2025]
Abstract
AbstractFungal infections (mycoses) represent a major health issue in humans. They have emerged as a global concern for medical professionals by causing high morbidity and mortality. Fungal infections approximately impact one billion individuals per annum and account for 1.6 million deaths. The diagnosis of Candida infections is a challenging task. Laboratory-based Candida species identification techniques (molecular, commercial, and conventional) have been reviewed and summarized. This review aims to discuss the mycoses history, taxonomy, pathogenicity, and virulence characteristics.
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Ramírez JD, Wang CY, Bolton D, Liggayu B, Schaefer S, Patel G, Javaid W, Cordon-Cardo C, Firpo-Betancourt A, Sordillo EM, Paniz-Mondolfi A. Molecular Detection of Candida auris Using DiaSorin Molecular Simplexa ® Detection Kit: A Diagnostic Performance Evaluation. J Fungi (Basel) 2023; 9:849. [PMID: 37623620 PMCID: PMC10455898 DOI: 10.3390/jof9080849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/04/2023] [Accepted: 08/09/2023] [Indexed: 08/26/2023] Open
Abstract
Candida auris is a globally emerging fungal pathogen that is associated with healthcare-related infections. The accurate and rapid detection of C. auris is crucial for effective infection prevention, control, and patient management. This study aimed to validate the analytical and diagnostic performance of the DiaSorin Molecular C. auris Detection Kit. The analytical specificity, sensitivity, and reproducibility of the assay were evaluated. The limit of detection (LOD) was determined to be 266 CFU/µL using the ZeptoMetrix Candida auris Z485 strain and standard calibration curves. The assay demonstrated high analytical specificity and showed no amplification against a diverse panel of bacteria and fungi. Clinical validation was conducted using deidentified residual axillary/groin surveillance culture specimens from C. auris culture-positive and culture-negative patients. The DiaSorin Molecular Detection Kit exhibited 100% agreement in sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) when compared to cultures coupled with MALDI-TOF identification. Intra- and inter-reproducibility testing demonstrated consistent and reliable diagnostic performance. This validated assay offers rapid and accurate detection of C. auris, facilitating timely implementation of infection control measures and appropriate patient care. The DiaSorin Molecular C. auris Detection Kit has the potential to aid in controlling the outbreaks caused by this emerging fungal pathogen. Providing a reliable diagnostic tool can contribute to the effective management and containment of C. auris infections in healthcare settings and ultimately improve patient outcomes.
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Affiliation(s)
- Juan David Ramírez
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (C.Y.W.); (D.B.); (B.L.); (C.C.-C.); (A.F.-B.); (E.M.S.)
- Centro de Investigaciones en Microbiología y Biotecnología-CIMBIUR (UR), Facultad de Ciencias Naturales, Universidad del Rosario, Bogotá 200433, Colombia
| | - Chin Yi Wang
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (C.Y.W.); (D.B.); (B.L.); (C.C.-C.); (A.F.-B.); (E.M.S.)
| | - Deandra Bolton
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (C.Y.W.); (D.B.); (B.L.); (C.C.-C.); (A.F.-B.); (E.M.S.)
| | - Bernadette Liggayu
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (C.Y.W.); (D.B.); (B.L.); (C.C.-C.); (A.F.-B.); (E.M.S.)
| | - Sarah Schaefer
- Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (S.S.); (G.P.); (W.J.)
| | - Gopi Patel
- Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (S.S.); (G.P.); (W.J.)
| | - Waleed Javaid
- Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (S.S.); (G.P.); (W.J.)
| | - Carlos Cordon-Cardo
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (C.Y.W.); (D.B.); (B.L.); (C.C.-C.); (A.F.-B.); (E.M.S.)
| | - Adolfo Firpo-Betancourt
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (C.Y.W.); (D.B.); (B.L.); (C.C.-C.); (A.F.-B.); (E.M.S.)
| | - Emilia Mia Sordillo
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (C.Y.W.); (D.B.); (B.L.); (C.C.-C.); (A.F.-B.); (E.M.S.)
| | - Alberto Paniz-Mondolfi
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; (C.Y.W.); (D.B.); (B.L.); (C.C.-C.); (A.F.-B.); (E.M.S.)
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Biswas B, Sharma AK, Seema K, Kumar A, Boipai M, Kumar M. Emerging threat of candida resistance among neonates at a teaching institute of Jharkhand. J Family Med Prim Care 2023; 12:946-952. [PMID: 37448944 PMCID: PMC10336938 DOI: 10.4103/jfmpc.jfmpc_2104_22] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 12/14/2022] [Accepted: 01/16/2023] [Indexed: 07/18/2023] Open
Abstract
Purpose In the past few decades, candidemia has escalated to worrisome levels, leading to substantial morbidity and mortality in neonates. The rise in anti-fungal drug resistance demands prompt diagnosis and treatment. This study aimed to determine the speciation and susceptibility pattern of Candida species recovered from special care new-born units and identify risk factors for developing candidemia in neonates. Method A total of 580 blood samples from clinically suspected septicemic neonates were collected and subjected to culture. Cultures positive for yeasts were sub-cultured on Sabouraud dextrose agar. Identification of a suspected purified colony of Candida was confirmed to the species level by both conventional and automated techniques matrix-assisted laser desorption and ionization time-of-flight mass spectrometry. Anti-fungal susceptibility of isolates was performed by an automated method (VITEK 2 system) using VITEK 2 cards. Multi-variate logistic regression analysis was used to identify risk factors associated with candidemia. Result A total of 56 (9.66%) isolates of Candida species were recovered from 580 blood cultures. Non-albicans Candida species predominated with 82.14% of cases, whereas 17.86% of cases were caused by Candida albicans. Candida tropicalis (46.42%) was the most common isolate recovered, followed by Candida albicans (17.8%). Risk factor analyses identified a very low birth weight [odds ratio (OR) =4.05, 95% confidence interval (CI) =2.03-8.08] and prolonged antibiotic therapy (OR = 3.79, 95% CI = 1.7-8.7) among others as significant predictors of candidemia. All the Candida isolates showed 100% sensitivity to voriconazole and micafungin, whereas the overall sensitivities for fluconazole, amphotericin B, caspofungin, and flucytosine were 85.71%, 96.43%, 96.43%, and 91.07%, respectively. Conclusion Candidemia is a life-threatening condition in neonates. Identification of Candida species and routine anti-fungal susceptibility is a must to select a suitable and effective anti-fungal therapy to revoke emerging resistance to anti-fungals.
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Affiliation(s)
- Binita Biswas
- Junior Resident, Department of Microbiology, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India
| | - Ashok Kumar Sharma
- Associate Professor, Department of Microbiology, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India
| | - Kumari Seema
- Assistant Professor, Department of Microbiology, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India
| | - Abhay Kumar
- Assistant Professor, Department of Microbiology, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India
| | - Manju Boipai
- Assistant Professor, Department of Microbiology, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India
| | - Manoj Kumar
- Professor, Department of Microbiology, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand, India
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Kahan Y, Tope SG, Ovadia A, Shpring A, Shatzman-Steuerman R, Sherman G, Barkai G, Mandelberg A, Armoni-Domany K, Tasher D. Risk Factors and Characteristics of Candidemia After Cardiac Surgery in Pediatric Patients in Central Israel. Pediatr Infect Dis J 2023; 42:368-373. [PMID: 36854105 DOI: 10.1097/inf.0000000000003847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/02/2023]
Abstract
BACKGROUND Candidemia is a serious complication in pediatric patients with congenital heart defects (CHD) after cardiac surgery. Information about the epidemiology, clinical characteristics and risk factors for candidemia in this vulnerable population remains limited. METHODS This retrospective case-control study was conducted in 2 pediatric intensive care units between 2004 and 2019. All patients <18 years old who developed candidemia following cardiac surgery were included. Each case was matched with 2 control patients based on age and date of surgery. Multivariable logistic regression analysis was conducted to determine the risk factors for postoperative candidemia. RESULTS Thirty-five candidemia cases were identified and matched to 70 control cases. The incidence of candidemia was 6.3 episodes per 1000 admissions. The median age for candidemia cases was 4 months. The attributable mortality was 28.5%. The predominant (54%) pathogens isolated were non- albicans Candida species, of which C. parapsilosis isolates demonstrated high resistance to fluconazole (70%). Independent risk factors associated with candidemia included cumulative antibiotic exposure for ≥4 days [OR: -4.3; 95% confidence interval (CI): 1.3-14.6; P = 0.02], the need for total parenteral nutrition or peritoneal dialysis (OR: -6.1; 95% CI: 2-18.8; P = 0.001), male sex (OR: 6.2; 95% CI: 1.9-20.3; P = 0.002) and delayed sternal closure≥2 days (OR: -3.2; 95% CI: 1-11.2; P = 0.05). CONCLUSIONS Postoperative candidemia in children with CHD is an uncommon but severe complication. Our study revealed an unexpectedly high frequency of fluconazole-resistant C. parapsilosis as the main cause of non- albicans candidemia. In addition to confirming previously recognized risk factors, our results reveal new potential risk factors such as delayed sternal closure and male sex.
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Affiliation(s)
- Yaara Kahan
- Pediatric Infectious Diseases Unit, Edith Wolfson Medical Center, Holon, Israel
- Pediatric Infectious Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel
| | - Samantha G Tope
- Pediatric Infectious Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel
| | - Adi Ovadia
- Pediatric Infectious Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel
- Department of Pediatrics, Edith Wolfson Medical Center, Holon, Israel
| | - Adi Shpring
- Pediatric Infectious Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel
- Department of Pediatrics, Edith Wolfson Medical Center, Holon, Israel
| | - Rachel Shatzman-Steuerman
- Pediatric Infectious Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel
| | - Gilad Sherman
- Pediatric Infectious Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel
| | - Galia Barkai
- Pediatric Infectious Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel
| | - Avigdor Mandelberg
- Pediatric Infectious Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel
- Department of Pediatrics, Edith Wolfson Medical Center, Holon, Israel
| | - Keren Armoni-Domany
- Pediatric Infectious Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel
- Department of Pediatrics, Edith Wolfson Medical Center, Holon, Israel
| | - Diana Tasher
- Pediatric Infectious Diseases Unit, Edith Wolfson Medical Center, Holon, Israel
- Pediatric Infectious Disease Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel
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Liu SH, Mitchell H, Nasser Al-Rawahi G. Epidemiology and associated risk factors for candidemia in a Canadian tertiary paediatric hospital: An 11-year review. JOURNAL OF THE ASSOCIATION OF MEDICAL MICROBIOLOGY AND INFECTIOUS DISEASE CANADA 2023; 8:29-39. [PMID: 37008577 PMCID: PMC10052903 DOI: 10.3138/jammi-2022-0021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 09/12/2022] [Accepted: 09/14/2022] [Indexed: 03/30/2023]
Abstract
Background: Candidemia represents a significant cause of morbidity and mortality in children. We examined the epidemiology and associated risk factors of candidemia at a Canadian tertiary care paediatric hospital over an 11-year period. Methods: A retrospective chart review was conducted on children with positive blood culture for Candida species between January 1, 2007 and December 31, 2018. Patient demographics, previously described candidemia risk factors, Candida species, follow-up investigations, interventions, and outcome data were included in the analysis. Results: Sixty-one candidemia episodes were reported with an overall incidence rate of 5.1 cases per 10,000 patient admissions. Of the 66 species identified, the most common was Candida albicans (53%, 35), followed by Candida parapsilosis (18%, 12), and Candida glabrata (8%, 5). Mixed candidemia was noted in 8% (5/61) of episodes. The most common risk factors included presence of central venous catheter (95%, 58/61) and receipt of antibiotics in the last 30 days (92%, 56/61). Majority of patients received abdominal imaging (89%, 54/61), ophthalmology consult (84%, 51/61), and echocardiogram (70%, 43/61), regardless of age. Line removal was performed in 81% (47/58) of cases. Evidence of disseminated fungal disease on abdominal imaging was observed in 11% (6/54) of patients, all in non-neonates but with risk factors including immunosuppression and gastrointestinal abnormalities. The overall 30-day case fatality rate was 8% (5/61). Conclusions: C. albicans was the most commonly isolated species. Disseminated candidiasis was demonstrated mainly on abdominal imaging in patients with relevant risk factors, including immunosuppression and gastrointestinal abnormalities.
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Affiliation(s)
- Suefay Harumi Liu
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Hana Mitchell
- Department of Pediatrics, Division of Infectious Diseases, BC Children's Hospital and BC Women's Hospital & Health Centre, Vancouver, British Columbia, Canada
| | - Ghada Nasser Al-Rawahi
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
- Correspondence: Ghada N Al-Rawahi, Department of Pathology and Laboratory Medicine, University of British Columbia, G105-Koerner Pavilion, 2211 Wesbrook Mall UBC Hospital, Vancouver, British Columbia V6T 2B5 Canada. Telephone: +968-72758585. E-mail:
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Incidence, susceptibility and outcomes of candidemia in adults living in Calgary, Alberta, Canada (2010-2018). BMC Infect Dis 2023; 23:100. [PMID: 36803357 PMCID: PMC9940426 DOI: 10.1186/s12879-023-08050-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 02/02/2023] [Indexed: 02/22/2023] Open
Abstract
BACKGROUND Candidemia is increasing in frequency and is associated with high mortality. We sought to determine the burden of illness, the population it affects and its resistance profile in our region. METHODS The Calgary Zone (CZ) provides all care for residents of Calgary and surrounding communities (~ 1.69 million) via five tertiary hospitals each served by a common single laboratory for acute care microbiology. All adult patients in the CZ with at least one Candida spp.-positive blood culture between January 1, 2010, and December 31, 2018, were identified using microbiological data from Calgary Lab Services, the laboratory that processes > 95% of all blood culture samples in the CZ, were reviewed for the study. RESULTS The overall annual incidence of candidemia among individuals living in the CZ was 3.8 per 100,000 persons (Median age 61 years (IQR 48-72) and 221/455 (47.4%) were female). C. albicans was the most common species (50.6%), followed by C. glabrata, (24.0%). No other species accounted for more than 7% of cases. Overall mortality at 30, 90, and 365 days was 32.2, 40.1, and 48.1% respectively. Mortality rate did not differ by Candida species. Of individuals who developed candidemia, more than 50% died within the next year. No new resistance pattern has emerged in the most common Candida species in Calgary, Alberta. CONCLUSIONS In Calgary, Alberta, the incidence of candidemia has not increased in the last decade. C. albicans was the most common species and it remains susceptible to fluconazole.
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Xu J, Luo Y, Wang J, Tu W, Yi X, Xu X, Song Y, Tang Y, Hua X, Yu Y, Yin H, Yang Q, Huang WE. Artificial intelligence-aided rapid and accurate identification of clinical fungal infections by single-cell Raman spectroscopy. Front Microbiol 2023; 14:1125676. [PMID: 37032865 PMCID: PMC10073597 DOI: 10.3389/fmicb.2023.1125676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 02/27/2023] [Indexed: 04/11/2023] Open
Abstract
Integrating artificial intelligence and new diagnostic platforms into routine clinical microbiology laboratory procedures has grown increasingly intriguing, holding promises of reducing turnaround time and cost and maximizing efficiency. At least one billion people are suffering from fungal infections, leading to over 1.6 million mortality every year. Despite the increasing demand for fungal diagnosis, current approaches suffer from manual bias, long cultivation time (from days to months), and low sensitivity (only 50% produce positive fungal cultures). Delayed and inaccurate treatments consequently lead to higher hospital costs, mobility and mortality rates. Here, we developed single-cell Raman spectroscopy and artificial intelligence to achieve rapid identification of infectious fungi. The classification between fungi and bacteria infections was initially achieved with 100% sensitivity and specificity using single-cell Raman spectra (SCRS). Then, we constructed a Raman dataset from clinical fungal isolates obtained from 94 patients, consisting of 115,129 SCRS. By training a classification model with an optimized clinical feedback loop, just 5 cells per patient (acquisition time 2 s per cell) made the most accurate classification. This protocol has achieved 100% accuracies for fungal identification at the species level. This protocol was transformed to assessing clinical samples of urinary tract infection, obtaining the correct diagnosis from raw sample-to-result within 1 h.
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Affiliation(s)
- Jiabao Xu
- Department of Engineering Science, University of Oxford, Oxford, United Kingdom
| | - Yanjun Luo
- Shanghai Hesen Biotech Co., Shanghai, China
| | - Jingkai Wang
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Weiming Tu
- Department of Engineering Science, University of Oxford, Oxford, United Kingdom
| | - Xiaofei Yi
- Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China
- National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Xiaogang Xu
- Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China
- National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Yizhi Song
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Yuguo Tang
- Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Xiaoting Hua
- Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yunsong Yu
- Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Huabing Yin
- James Watt School of Engineering, University of Glasgow, Glasgow, United Kingdom
| | - Qiwen Yang
- Department of Clinical Laboratory, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Qiwen Yang,
| | - Wei E. Huang
- Department of Engineering Science, University of Oxford, Oxford, United Kingdom
- Wei E. Huang,
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Khan P, Datta A, Basu M, Chatterjee A, Banerjee B, Mitra AK. Lantibiotics in antifungal therapy: a futuristic approach. LANTIBIOTICS AS ALTERNATIVE THERAPEUTICS 2023:205-220. [DOI: 10.1016/b978-0-323-99141-4.00018-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Population Pharmacokinetic Model and Optimal Sampling Strategies for Micafungin in Critically Ill Patients Diagnosed with Invasive Candidiasis. Antimicrob Agents Chemother 2022; 66:e0111322. [PMID: 36377940 PMCID: PMC9765295 DOI: 10.1128/aac.01113-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Candida bloodstream infections are associated with high attributable mortality, where early initiation of adequate antifungal therapy is important to increase survival in critically ill patients. The exposure variability of micafungin, a first-line agent used for the treatment of invasive candidiasis, in critically ill patients is significant, potentially resulting in underexposure in a substantial portion of these patients. The objective of this study was to develop a population pharmacokinetic model including appropriate sampling strategies for assessing micafungin drug exposure in critically ill patients to support adequate area under the concentration-time curve (AUC) determination. A two-compartment pharmacokinetic model was developed using data from intensive care unit (ICU) patients (n = 19), with the following parameters: total body clearance (CL), volume of distribution of the central compartment (V1), inter-compartmental clearance (CL12), and volume of distribution of the peripheral compartment (V2). The final model was evaluated with bootstrap analysis and the goodness-of-fit plots for the population and individual predicted micafungin plasma concentrations. Optimal sampling strategies (with sampling every hour, 24 h per day) were developed with 1- and 2-point sampling schemes. Final model parameters (±SD) were: CL = 1.03 (0.37) (L/h/1.85 m2), V1 = 0.17 (0.07) (L/kg LBMc), CL12 = 1.80 (4.07) (L/h/1.85 m2), and V2 = 0.12 (0.06) (L/kg LBMc). Sampling strategies with acceptable accuracy and precision were developed to determine the micafungin AUC. The developed model with optimal sampling procedures provides the opportunity to achieve quick optimization of the micafungin exposure from a single blood sample using Bayesian software and may be helpful in guiding early dose decision-making.
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Gebretekle GB, Fentie AM, Gebremariam GT, Ali EE, Erku DA, Alemayehu T, Abebe W, Sander B. Cost-utility analysis of caspofungin and fluconazole for primary treatment of invasive candidiasis and candidemia in Ethiopia. BMC Health Serv Res 2022; 22:1302. [PMID: 36309674 PMCID: PMC9618213 DOI: 10.1186/s12913-022-08662-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 08/22/2022] [Accepted: 09/30/2022] [Indexed: 11/17/2022] Open
Abstract
Background Invasive candidiasis and/or candidemia (IC/C) is a common fungal infection leading to significant health and economic losses worldwide. Caspofungin was shown to be more effective than fluconazole in treating inpatients with IC/C. However, cost-effectiveness of caspofungin for treating IC/C in Ethiopia remains unknown. We aimed to assess the cost-utility of caspofungin compared to fluconazole-initiated therapies as primary treatment of IC/C in Ethiopia. Methods A Markov cohort model was developed to compare the cost-utility of caspofungin versus fluconazole antifungal agents as first-line treatment for adult inpatients with IC/C from the Ethiopian health system perspective. Treatment outcome was categorized as either a clinical success or failure, with clinical failure being switched to a different antifungal medication. Liposomal amphotericin B (L-AmB) was used as a rescue agent for patients who had failed caspofungin treatment, while caspofungin or L-AmB were used for patients who had failed fluconazole treatment. Primary outcomes were expected quality-adjusted life years (QALYs), costs (US$2021), and the incremental cost-utility ratio (ICUR). These QALYs and costs were discounted at 3% annually. Cost data was obtained from Addis Ababa hospitals while locally unavailable data were derived from the literature. Cost-effectiveness was assessed against the recommended threshold of 50% of Ethiopia’s gross domestic product/capita (i.e.,US$476). Deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of the findings. Results In the base-case analysis, treatment of IC/C with caspofungin as first-line treatment resulted in better health outcomes (12.86 QALYs) but higher costs (US$7,714) compared to fluconazole-initiated treatment followed by caspofungin (12.30 QALYs; US$3,217) or L-AmB (10.92 QALYs; US$2,781) as second-line treatment. Caspofungin as primary treatment for IC/C was not cost-effective when compared to fluconazole-initiated therapies. Fluconazole-initiated treatment followed by caspofungin was cost-effective for the treatment of IC/C compared to fluconazole with L-AmB as second-line treatment, at US$316/QALY gained. Our findings were sensitive to medication costs, drug effectiveness, infection recurrence, and infection-related mortality rates. At a cost-effectiveness threshold of US$476/QALY, treating IC/C patient with fluconazole-initiated treatment followed by caspofungin was more likely to be cost-effective in 67.2% of simulations. Conclusion Our study showed that the use of caspofungin as primary treatment for IC/C in Ethiopia was not cost-effective when compared with fluconazole-initiated treatment alternatives. The findings supported the use of fluconazole-initiated therapy with caspofungin as a second-line treatment for patients with IC/C in Ethiopia.
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Invasive fungal infections in a paediatric intensive care unit in a low-to middle-income country. Afr J Thorac Crit Care Med 2022; 28:10.7196/AJTCCM.2022.v28i3.200. [PMID: 36285010 PMCID: PMC9583846 DOI: 10.7196/ajtccm.2022.v28i3.200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/08/2022] [Indexed: 11/06/2022] Open
Abstract
Background
Paediatric intensive care units (PICUs) are high-risk settings for healthcare-associated infections. Invasive fungal infection
(IFI) is one of the common causes of healthcare-associated infections.
Objectives
To describe the prevalence and short-term outcomes of children with IFI, and to offer a basis for the efficient prevention and
treatment of IFI.
Methods
A retrospective study was conducted in children under the age of 12 years over a two-year period. Participants were categorised
according to pre-defined microbiology criteria into IFI if they had a positive culture from blood or other sterile sites. Data collected included
demographics, invasive procedures, length of stay and mortality.
Results
One thousand and forty-two children were admitted during the study period. Of the total, 56.8% (n=592) were male. Median
length of stay was 18 days (mean±SE 18.6±8.9). IFI was identified in 35 cases per 1 000 admissions, with 77.7% of these infants under
the age of one year. The mean length of stay was 18.6 days compared with 7.5 days for children with bacterial infections. The in-hospital
mortality for invasive fungal infection was 36% compared with 16% for all admissions. Findings confirmed that colonisation was more
prevalent than IFI.
Conclusion
IFIs are common among infants, and these patients have a higher mortality rate and prolonged hospital stay. Therefore we
recommend early diagnosis and timely treatment with high-performance antifungal drugs to improve the prognosis in children with IFI.
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Matzko ME, Sephton-Clark PCS, Young EL, Jhaveri TA, Martinsen MA, Mojica E, Boykin R, Pierce VM, Cuomo CA, Bhattacharyya RP. A novel rRNA hybridization-based approach to rapid, accurate Candida identification directly from blood culture. Med Mycol 2022; 60:6674770. [PMID: 36002024 PMCID: PMC9989835 DOI: 10.1093/mmy/myac065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 08/03/2022] [Accepted: 08/22/2022] [Indexed: 01/24/2023] Open
Abstract
Invasive fungal infections are increasingly common and carry high morbidity and mortality, yet fungal diagnostics lag behind bacterial diagnostics in rapidly identifying the causal pathogen. We previously devised a fluorescent hybridization-based assay to identify bacteria within hours directly from blood culture bottles without subculture, called phylogeny-informed rRNA-based strain identification (Phirst-ID). Here, we adapt this approach to unambiguously identify 11 common pathogenic Candida species, including C. auris, with 100% accuracy from laboratory culture (33 of 33 strains in a reference panel, plus 33 of 33 additional isolates tested in a validation panel). In a pilot study on 62 consecutive positive clinical blood cultures from two hospitals that showed yeast on Gram stain, Candida Phirst-ID matched the clinical laboratory result for 58 of 59 specimens represented in the 11-species reference panel, without misclassifying the 3 off-panel species. It also detected mixed Candida species in 2 of these 62 specimens, including the one discordant classification, that were not identified by standard clinical microbiology workflows; in each case the presence of both species was validated by both clinical and experimental data. Finally, in three specimens that grew both bacteria and yeast, we paired our prior bacterial probeset with this new Candida probeset to detect both pathogen types using Phirst-ID. This simple, robust assay can provide accurate Candida identification within hours directly from blood culture bottles, and the conceptual approach holds promise for pan-microbial identification in a single workflow. LAY SUMMARY Candida bloodstream infections cause considerable morbidity and mortality, yet slow diagnostics delay recognition, worsening patient outcomes. We develop and validate a novel molecular approach to accurately identify Candida species directly from blood culture one day faster than standard workflows.
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Affiliation(s)
- Michelle E Matzko
- Infectious Diseases Division, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Poppy C S Sephton-Clark
- Infectious Disease and Microbiome Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Eleanor L Young
- Infectious Disease and Microbiome Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Tulip A Jhaveri
- Microbiology Laboratory, Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Melanie A Martinsen
- Infectious Disease and Microbiome Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Evan Mojica
- Microbiology Laboratory, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Rich Boykin
- NanoString Technologies, Inc., Seattle, WA 98109, USA
| | - Virginia M Pierce
- Microbiology Laboratory, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Christina A Cuomo
- Infectious Disease and Microbiome Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Roby P Bhattacharyya
- Infectious Diseases Division, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.,Infectious Disease and Microbiome Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
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Co CM, Mulgaonkar A, Zhou N, Harris S, Öz OK, Tang L, Sun X. PET Imaging of Active Invasive Fungal Infections with d-[5- 11C]-Glutamine. ACS Infect Dis 2022; 8:1663-1673. [PMID: 35869564 DOI: 10.1021/acsinfecdis.2c00249] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The increasing prevalence and severity of invasive fungal infections (IFIs), especially in immunocompromised populations, has amplified the need for rapid diagnosis of fungal pathogens. Radiotracers derived from d-amino acids (DAAs) show promise as bacterial-specific positron emission tomography (PET) imaging agents due to their preferential consumption by bacteria and largely nonutilization by hosts. Unlike mammals, fungi can utilize external DAAs including d-glutamine for their growth by rapidly upregulating DAA oxidases. Additionally, glutamine is essential for fungal nitrogen assimilation, survival, and virulence. We previously validated d-[5-11C]-glutamine (d-[5-11C]-Gln) as an efficient radiotracer targeting live bacterial soft-tissue infections. Here, we further expanded this investigation to evaluate its translational potential for PET imaging of IFIs in immunocompetent mouse models subcutaneously (SubQ) and intramuscularly (IM) infected with Candida albicans (C. albicans), using its l-isomer counterpart (l-[5-11C]-Gln) as a control. Comparative studies between pathogens showed significantly (p < 0.05) higher uptake in fungi (C. albicans and C. tropicalis) versus tested bacterial species for d-[5-11C]-Gln, suggesting that it could potentially serve as a more sensitive radiotracer for detection of fungal infections. Additionally, comparative PET imaging studies in immunocompetent infected mice demonstrated significantly higher infection-to-background ratios for d- versus l-[5-11C]-Gln in both SubQ (ratio = 1.97, p = 0.043) and IM (ratio = 1.97, p = 0.028) infections. Fungal infection imaging specificity was confirmed with no significant difference observed between localized inflammation sites versus untreated muscle background (heat-killed injection site/untreated muscle: ∼1.1). Taken together, this work demonstrates the translational potential of d-[5-11C]-Gln for noninvasive PET imaging of IFIs.
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Affiliation(s)
- Cynthia M Co
- Department of Bioengineering, University of Texas at Arlington, Arlington, Texas 76019, United States
| | - Aditi Mulgaonkar
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Ning Zhou
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Shelby Harris
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Orhan K Öz
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Liping Tang
- Department of Bioengineering, University of Texas at Arlington, Arlington, Texas 76019, United States
| | - Xiankai Sun
- Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
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Impact of Gamma Irradiation on the Properties of Magnesium-Doped Hydroxyapatite in Chitosan Matrix. MATERIALS 2022; 15:ma15155372. [PMID: 35955308 PMCID: PMC9369862 DOI: 10.3390/ma15155372] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/29/2022] [Accepted: 08/02/2022] [Indexed: 12/14/2022]
Abstract
This is the first report regarding the effect of gamma irradiation on chitosan-coated magnesium-doped hydroxyapatite (xMg = 0.1; 10 MgHApCh) layers prepared by the spin-coating process. The stability of the resulting 10 MgHApCh gel suspension used to obtain the layers has been shown by ultrasound measurements. The presence of magnesium and the effect of the irradiation process on the studied samples were shown by X-ray photoelectron spectroscopy (XPS). The XPS results obtained for irradiated 10 MgHApCh layers suggested that the magnesium and calcium contained in the surface layer are from tricalcium phosphate (TCP; Ca3(PO4)2) and hydroxyapatite (HAp). The XPS analysis has also highlighted that the amount of TCP in the surface layer increased with the irradiation dose. The energy-dispersive X-ray spectroscopy (EDX) evaluation showed that the calcium decreases with the increase in the irradiation dose. In addition, a decrease in crystallinity and crystallite size was highlighted after irradiation. By atomic force microscopy (AFM) we have obtained images suggesting a good homogeneity of the surface of the non-irradiated and irradiated layers. The AFM results were also sustained by the scanning electron microscopy (SEM) images obtained for the studied samples. The effect of gamma-ray doses on the Fourier transform infrared spectroscopy (ATR-FTIR) spectra of 10 MgHApCh composite layers was also evaluated. The in vitro antifungal assays proved that 10 MgHApCh composite layers presented a strong antifungal effect, correlated with the irradiation dose and incubation time. The study of the stability of the 10 MgHApCh gel allowed us to achieve uniform and homogeneous layers that could be used in different biomedical applications.
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Kakehi A, Hagiya H, Iio K, Nakano Y, Ihoriya H, Taira Y, Nakamoto K, Hasegawa K, Higashikage A, Otsuka F. Candida dubliniensis fungemia in a patient with severe COVID-19: A case report. J Infect Chemother 2022; 28:1433-1435. [PMID: 35863730 PMCID: PMC9293379 DOI: 10.1016/j.jiac.2022.07.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 06/27/2022] [Accepted: 07/12/2022] [Indexed: 10/30/2022]
Abstract
Candida dubliniensis phenotypically mimics Candida albicans in its microbiological features; thus, its clinical characteristics have yet to be fully elucidated. Here we report the case of a 68-year-old Japanese man who developed C. dubliniensis fungemia during treatment for severe coronavirus disease 2019 (COVID-19). The patient was intubated and received a combination of immunosuppressants, including high-dose methylprednisolone and two doses of tocilizumab, as well as remdesivir, intravenous heparin, and ceftriaxone. A blood culture on admission day 11 revealed Candida species, which was confirmed as C. dubliniensis by mass spectrometry. An additional sequencing analysis of the 26S rDNA and ITS regions confirmed that the organism was 100% identical to the reference strain of C. dubliniensis (ATCC MYA-646). Considering the simultaneous isolation of C. dubliniensis from a sputum sample, the lower respiratory tract could be an entry point for candidemia. Although treatment with micafungin successfully eradicated the C. dubliniensis fungemia, the patient died of COVID-19 progression. In this case, aggressive immunosuppressive therapy could have caused the C. dubliniensis fungemia. Due to insufficient clinical reports on C. dubliniensis infection based on definitive diagnosis, the whole picture of the cryptic organism is still unknown. Further accumulation of clinical and microbiological data of the pathogen is needed to elucidate their clinical significance.
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Affiliation(s)
- Ayaka Kakehi
- Microbiology Division, Clinical Laboratory, Okayama University Hospital, Okayama, 700-8558, Japan
| | - Hideharu Hagiya
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
| | - Koji Iio
- Microbiology Division, Clinical Laboratory, Okayama University Hospital, Okayama, 700-8558, Japan
| | - Yasuhiro Nakano
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan
| | - Hiromi Ihoriya
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan
| | - Yuki Taira
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan
| | - Kenta Nakamoto
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan
| | - Kou Hasegawa
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan
| | - Akihito Higashikage
- Microbiology Division, Clinical Laboratory, Okayama University Hospital, Okayama, 700-8558, Japan
| | - Fumio Otsuka
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan
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Cavassin FB, Baú-Carneiro JL, de Araújo Motta F, Ville APM, Staszczak L, de Queiroz-Telles F. Amphotericin B in Pediatrics: Analysis by Age Stratification Suggests a Greater Chance of Adverse Events from 13 Months of Age Onwards. Paediatr Drugs 2022; 24:513-528. [PMID: 35849282 DOI: 10.1007/s40272-022-00523-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/21/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND AND OBJECTIVE Amphotericin B deoxycholate (AMB-D) remains an antifungal agent with great therapeutic value in pediatric patients. The currrent consensus is that its use in neonates is safer than in older children. However, childhood presents different periods of development that deserve to be evaluated more precisely. Our goal was to assess the usage profile of AMB-D in stratified pediatric age groups, adapted according to the National Institute of Child Health and Human Development classification. METHODS This retrospective cross-sectional observational study was conducted at a Brazilian tertiary children's hospital between January 2014 and December 2019. Data of patients who received at least two doses of intravenous AMB-D while hospitalized were extracted from electronic health files. Information on patient demographics, underlying diseases and comorbidities, laboratory examinations, fungal infection diagnosis, and AMB-D use were gathered following specific criteria. Nonparametric tests were applied, such as the chi-square test to compare proportions and Fisher's exact test to assess the association between categorical variables or contingency tables. RESULTS One hundred and twenty-seven (127) medical records were stratified as preterm neonatal (birth <37 weeks postmenstrual age), term neonatal (birth-27 days), infants (28 days-12 months), toddlers (13 months-2 years), early childhood (3-5 years), middle childhood (6-11 years), and early adolescence (12-18 years). The criteria for the indication of AMB-D followed empirical use as the main indication (n = 74; 58.26%), proven and probable fungal infection (n = 39; 30.71%), and medical suspicion (n = 14; 11.02%). Candida spp. was the main etiologic agent isolated in cultures, with the highest frequency of C. albicans (n = 18; 40%), followed by Candida parapsilosis (n = 14; 31.11%), and Candida tropicalis (n = 6; 13.33%). Very few acute infusion-related adverse effects were observed during the administration of AMB-D in pediatric patients. We found an unfavorable impact of AMB-D use in patients from 13 months of age onwards suggesting this group as a turning point for a greater chance of adverse events, and not soon after the neonatal period. CONCLUSIONS Clinical or observational studies based on age stratification are essential to accurately elucidate whether potentially toxic drugs can be used safely in the pediatric population. Our search for a turning point was shown to contribute to the accuracy of the study, as it provided data on the impact of D-AMB in specific pediatric age groups.
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Affiliation(s)
- Francelise Bridi Cavassin
- Postgraduate Program in Internal Medicine and Health Sciences, Federal University of Paraná (UFPR), 181, General Carneiro Street, Curitiba, Brazil.
| | | | | | | | | | - Flávio de Queiroz-Telles
- Department of Public Health, Hospital de Clínicas, Federal University of Paraná (HC-UFPR), Curitiba, Brazil
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Early Empirical Anidulafungin Reduces the Prevalence of Invasive Candidiasis in Critically Ill Patients: A Case-control Study. J Crit Care Med (Targu Mures) 2022; 8:89-99. [PMID: 35950155 PMCID: PMC9097641 DOI: 10.2478/jccm-2022-0006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 04/06/2022] [Indexed: 11/21/2022] Open
Abstract
Introduction Invasive candidiasis (IC) in critically ill patients is a serious infection with high rate of mortality. As an empirical therapy, like antibiotics, the use of antifungals is not common in intensive care units (ICUs) worldwide. The empirical use of echinocandins including anidulafungin is a recent trend. Aim of the study The objective of this study was to assess the impact of empirical anidulafungin in the development of invasive candidiasis in critically ill patients in ICU. Methods This retrospective case-control study was conducted on 149 patients with sepsis with/without septic shock and bacterial pneumonia. All the patients were divided into two groups. The ‘control group’ termed as ‘NEAT group’ received no empirical anidulafungin therapy and the ‘treated group’ termed as ‘EAT group’ received empirical anidulafungin therapy in early hospitalization hours. Results Seventy-two and 77 patients were divided into the control and the treated group, respectively. Patients in EAT group showed less incidences of IC (5.19%) than that of the NEAT group (29.17%) (p = 0.001). Here, the relative risk (RR) was 0.175 (95% CI, 0.064-0.493) and the risk difference (RD) rate was 24% (95% CI, 12.36%-35.58%). The 30-day all-cause mortality rate in NEAT group was higher (19.44%) than that of in EAT group (10.39%) (p = 0.04). Within the first 10-ICU-day, patients in the EAT group left ICU in higher rate (62.34%) than that in the NEAT group (54.17%). Conclusion Early empirical anidulafungin within 6 h of ICU admission reduced the risk of invasive candidiasis, 30-day all-cause mortality rate and increased ICU leaving rate within 10-day of ICU admission in critically ill patients.
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Li DD, Jawale CV, Zhou C, Lin L, Trevejo-Nunez GJ, Rahman SA, Mullet SJ, Das J, Wendell SG, Delgoffe GM, Lionakis MS, Gaffen SL, Biswas PS. Fungal sensing enhances neutrophil metabolic fitness by regulating antifungal Glut1 activity. Cell Host Microbe 2022; 30:530-544.e6. [PMID: 35316647 PMCID: PMC9026661 DOI: 10.1016/j.chom.2022.02.017] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 12/10/2021] [Accepted: 02/16/2022] [Indexed: 12/30/2022]
Abstract
Combating fungal pathogens poses metabolic challenges for neutrophils, key innate cells in anti-Candida albicans immunity, yet how host-pathogen interactions cause remodeling of the neutrophil metabolism is unclear. We show that neutrophils mediate renal immunity to disseminated candidiasis by upregulating glucose uptake via selective expression of glucose transporter 1 (Glut1). Mechanistically, dectin-1-mediated recognition of β-glucan leads to activation of PKCδ, which triggers phosphorylation, localization, and early glucose transport by a pool of pre-formed Glut1 in neutrophils. These events are followed by increased Glut1 gene transcription, leading to more sustained Glut1 accumulation, which is also dependent on the β-glucan/dectin-1/CARD9 axis. Card9-deficient neutrophils show diminished glucose incorporation in candidiasis. Neutrophil-specific Glut1-ablated mice exhibit increased mortality in candidiasis caused by compromised neutrophil phagocytosis, reactive oxygen species (ROS), and neutrophil extracellular trap (NET) formation. In human neutrophils, β-glucan triggers metabolic remodeling and enhances candidacidal function. Our data show that the host-pathogen interface increases glycolytic activity in neutrophils by regulating Glut1 expression, localization, and function.
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Affiliation(s)
- De-Dong Li
- Division of Rheumatology & Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Chetan V Jawale
- Division of Rheumatology & Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Chunsheng Zhou
- Division of Rheumatology & Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Li Lin
- Division of Rheumatology & Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Giraldina J Trevejo-Nunez
- Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Syed A Rahman
- Center for Systems Immunology, Departments of Immunology and Computational & Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Steven J Mullet
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jishnu Das
- Center for Systems Immunology, Departments of Immunology and Computational & Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Stacy G Wendell
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Greg M Delgoffe
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Michail S Lionakis
- Fungal Pathogenesis Section, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
| | - Sarah L Gaffen
- Division of Rheumatology & Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Partha S Biswas
- Division of Rheumatology & Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
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Changes in the incidence of Candida-related central line-associated bloodstream infections in Pediatric Intensive Care Unit: Could central line bundle have a role? J Mycol Med 2022; 32:101277. [DOI: 10.1016/j.mycmed.2022.101277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 02/18/2022] [Accepted: 04/02/2022] [Indexed: 11/18/2022]
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A Proteomic Landscape of Candida albicans in the Stepwise Evolution to Fluconazole Resistance. Antimicrob Agents Chemother 2022; 66:e0210521. [PMID: 35343782 DOI: 10.1128/aac.02105-21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
As an opportunistic fungal pathogen, Candida albicans is a major cause of superficial and systemic infections in immunocompromised patients. The increasing rate of azole resistance in C. albicans has brought further challenges to clinical therapy. In this study, we collected five isogenic C. albicans strains recovered over discrete intervals from an HIV-infected patient who suffered 2-year recurrent oropharyngeal candidiasis. Azole resistance was known from the clinical history to have developed gradually in this patient, and this was confirmed by MIC assays of each strain. Proteomic techniques can be used to investigate more comprehensively how resistance develops in pathogenic fungi over time. Our study is the first to use tandem mass tag (TMT) labeling combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology to investigate the acquired resistance mechanisms of serial C. albicans isolates at the proteomic level. A total of 4,029 proteins have been identified, of which 3,766 have been quantified. Compared with Ca1, bioinformatics analysis showed that differentially expressed proteins were mainly associated with aspects such as the downregulation of glycolysis/gluconeogenesis, pyruvate metabolism, fatty acid degradation, and oxidative stress response proteins in all four subsequent strains but, remarkably, the activation of amino acid metabolism in Ca8 and Ca14 and increased protection against osmotic stress or excessive copper toxicity, upregulation of respiratory chain activity, and suppression of iron transport in Ca17. By tracing proteomic alterations in this set of isogenic resistance isolates, we acquire mechanistic insight into the steps involved in the acquisition of azole resistance in C. albicans.
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Fisher BT, Boge CLK, Xiao R, Shuster S, Chin-Quee D, Allen J, Shaheen S, Hayden R, Suganda S, Zaoutis TE, Chang YC, Yin DE, Huppler AR, Danziger-Isakov L, Muller WJ, Roilides E, Romero J, Sue PK, Berman D, Wattier RL, Halasa N, Pong A, Maron G, Soler-Palacin P, Hutto SC, Gonzalez BE, Salvatore CM, Rajan S, Green M, Doby Knackstedt E, Hauger SB, Steinbach WJ. Multicenter Prospective Study of Biomarkers for Diagnosis of Invasive Candidiasis in Children and Adolescents. Clin Infect Dis 2022; 75:248-259. [PMID: 35134165 PMCID: PMC9890499 DOI: 10.1093/cid/ciab928] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Diagnosis of invasive candidiasis (IC) relies on insensitive cultures; the relative utility of fungal biomarkers in children is unclear. METHODS This multinational observational cohort study enrolled patients aged >120 days and <18 years with concern for IC from 1 January 2015 to 26 September 2019 at 25 centers. Blood collected at onset of symptoms was tested using T2Candida, Fungitell (1→3)-β-D-glucan, Platelia Candida Antigen (Ag) Plus, and Platelia Candida Antibody (Ab) Plus assays. Operating characteristics were determined for each biomarker, and assays meeting a defined threshold considered in combination. Sterile site cultures were the reference standard. RESULTS Five hundred participants were enrolled at 22 centers in 3 countries, and IC was diagnosed in 13 (2.6%). Thirteen additional blood specimens were collected and successfully spiked with Candida species, to achieve a 5.0% event rate. Valid T2Candida, Fungitell, Platelia Candida Ag Plus, and Platelia Candida Ab Plus assay results were available for 438, 467, 473, and 473 specimens, respectively. Operating characteristics for T2Candida were most optimal for detecting IC due to any Candida species, with results as follows: sensitivity, 80.0% (95% confidence interval, 59.3%-93.2%), specificity 97.1% (95.0%-98.5%), positive predictive value, 62.5% (43.7%-78.9%), and negative predictive value, 98.8% (97.2%-99.6%). Only T2Candida and Platelia Candida Ag Plus assays met the threshold for combination testing. Positive result for either yielded the following results: sensitivity, 86.4% (95% confidence interval, 65.1%- 97.1%); specificity, 94.7% (92.0%-96.7%); positive predictive value, 47.5% (31.5%-63.9%); and negative predictive value, 99.2% (97.7%-99.8%). CONCLUSIONS T2Candida alone or in combination with Platelia Candida Ag Plus may be beneficial for rapid detection of Candida species in children with concern for IC. CLINICAL TRIALS REGISTRATION NCT02220790.
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Affiliation(s)
- Brian T Fisher
- Correspondence: B. T. Fisher, Division of Infectious Diseases, Children’s Hospital of Philadelphia, Roberts Pediatric Research Center, 2716 South St, Room 10-362, Philadelphia, PA 19146 ()
| | - Craig L K Boge
- Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Rui Xiao
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Sydney Shuster
- Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | | | - John Allen
- Duke University, Durham, North Carolina, USA
| | | | - Randall Hayden
- Department of Pathology, St Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Sri Suganda
- Department of Pathology, St Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | - Theoklis E Zaoutis
- Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA,Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | | | - Dwight E Yin
- Children’s Mercy and University of Missouri–Kansas City School of Medicine, Kansas City, Missouri, USA
| | - Anna R Huppler
- Medical College of Wisconsin and Children’s Wisconsin, Milwaukee, Wisconsin, USA
| | | | - William J Muller
- Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Emmanuel Roilides
- Infectious Disease Unit, 3rd Department of Pediatrics, School of Medicine, Aristotle University and Hippokration Hospital, Thessaloniki, Greece
| | - José Romero
- Arkansas Children’s Hospital Research Institute, Little Rock, Arkansas, USA
| | - Paul K Sue
- University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - David Berman
- John Hopkins All Children’s Hospital, St Petersburg, Florida, USA
| | - Rachel L Wattier
- University of California–San Francisco, San Francisco, California, USA
| | - Natasha Halasa
- Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Alice Pong
- University of California San Diego, San Diego, California, USA
| | - Gabriela Maron
- St Jude Children’s Research Hospital, Memphis, Tennessee, USA
| | | | - Susan C Hutto
- University of Alabama, Birmingham, Birmingham, Alabama, USA
| | | | | | - Sujatha Rajan
- Cohen Children’s Medical Center of New York, New Hyde Park, New York, USA
| | - Michael Green
- UPMC Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Shaly NJ, Pervez MM, Huq S, Ahmed D, Ahsan CR, Sarmin M, Afroze F, Nuzhat S, Chisti MJ, Ahmed T. Invasive Fungal Infections in Under-Five Diarrheal Children: Experience from an Urban Diarrheal Disease Hospital. LIFE (BASEL, SWITZERLAND) 2022; 12:life12010094. [PMID: 35054490 PMCID: PMC8777596 DOI: 10.3390/life12010094] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 12/31/2021] [Accepted: 01/05/2022] [Indexed: 11/16/2022]
Abstract
Invasive fungal infections (IFIs) are opportunistic, especially in immunocompromised and hospitalized patients. Children with IFIs are more vulnerable to a fatal outcome. For early diagnosis and treatment, knowledge of the spectrum and frequency of IFIs among children is prerequisite. In this prospective observational study, we enrolled 168 children of 2–59 months old of either sex from March 2018 to December 2019 admitted to the Dhaka hospital, icddr,b. Study participants with suspected IFIs were with or without severe acute malnutrition (SAM) along with sepsis/pneumonia and fulfilled any of the following criteria: (i) failure to respond to injectable antibiotics, (ii) development of a late-onset hospital-acquired infection, (iii) needed ICU care for >7 days, (iv) took steroids/antibiotics for >2 weeks before hospitalization, and (v) developed thrush after taking injectable antibiotics. The comparison group included non-SAM (weight-for-length Z score ≥ −2) children with diarrhea and fever <3 days in the absence of co-morbidity. We performed real-time PCR, ELISA, and blood culture for the detection of fungal pathogen. Study group children with SAM, positive ELISA and PCR considered to have a IFIs. In the study group, 15/138 (10.87%) children had IFIs. Among IFIs, invasive candidiasis, aspergillosis, histoplasmosis detected in 6 (4.53%), 11 (7.97%), and 1 (0.72%) children, respectively, and (3/15 [2.17%]) children had both candidiasis and aspergillosis. Children with IFIs more often encountered septic shock (26.7% vs. 4.9%; p = 0.013) and had a higher death rate (46.7% vs. 8.9%; p < 0.001) than those without IFIs. IFIs were independently associated with female sex (OR = 3.48; 95% CI = 1.05, 11.55; p = 0.042) after adjusting for potential confounders. Our findings thus implicate that, malnourished children with septic shock require targeted screening for the early diagnosis and prompt management of IFIs that may help to reduce IFIs related deaths.
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Affiliation(s)
- Nusrat Jahan Shaly
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Mohakhali, Dhaka 1212, Bangladesh; (N.J.S.); (M.M.P.); (S.H.); (D.A.); (M.S.); (F.A.); (S.N.); (T.A.)
| | - Mohammed Moshtaq Pervez
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Mohakhali, Dhaka 1212, Bangladesh; (N.J.S.); (M.M.P.); (S.H.); (D.A.); (M.S.); (F.A.); (S.N.); (T.A.)
| | - Sayeeda Huq
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Mohakhali, Dhaka 1212, Bangladesh; (N.J.S.); (M.M.P.); (S.H.); (D.A.); (M.S.); (F.A.); (S.N.); (T.A.)
| | - Dilruba Ahmed
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Mohakhali, Dhaka 1212, Bangladesh; (N.J.S.); (M.M.P.); (S.H.); (D.A.); (M.S.); (F.A.); (S.N.); (T.A.)
| | | | - Monira Sarmin
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Mohakhali, Dhaka 1212, Bangladesh; (N.J.S.); (M.M.P.); (S.H.); (D.A.); (M.S.); (F.A.); (S.N.); (T.A.)
| | - Farzana Afroze
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Mohakhali, Dhaka 1212, Bangladesh; (N.J.S.); (M.M.P.); (S.H.); (D.A.); (M.S.); (F.A.); (S.N.); (T.A.)
| | - Sharika Nuzhat
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Mohakhali, Dhaka 1212, Bangladesh; (N.J.S.); (M.M.P.); (S.H.); (D.A.); (M.S.); (F.A.); (S.N.); (T.A.)
| | - Mohammod Jobayer Chisti
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Mohakhali, Dhaka 1212, Bangladesh; (N.J.S.); (M.M.P.); (S.H.); (D.A.); (M.S.); (F.A.); (S.N.); (T.A.)
- Correspondence:
| | - Tahmeed Ahmed
- International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Mohakhali, Dhaka 1212, Bangladesh; (N.J.S.); (M.M.P.); (S.H.); (D.A.); (M.S.); (F.A.); (S.N.); (T.A.)
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Mazi PB, Olsen MA, Stwalley D, Rauseo AM, Ayres C, Powderly WG, Spec A. Attributable Mortality of Candida Bloodstream Infections in the Modern Era: A Propensity Score Analysis. Clin Infect Dis 2022; 75:1031-1036. [PMID: 34989802 DOI: 10.1093/cid/ciac004] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND This study quantifies the mortality attributable to Candida bloodstream infections (BSI) in the modern era of echinocandins. DESIGN We conducted a retrospective cohort study of adult patients admitted to Barnes Jewish Hospital, a 1,368-bed tertiary care academic hospital, in Saint Louis, Missouri from 1/2/2012-4/30/2019. We identified 626 adult patients with Candida BSI that were frequency-matched with 6,269 control patients that had similar Candida BSI risk-factors. The 90-day all-cause mortality attributable to Candida BSI was calculated using three methods-propensity score matching, matching by inverse weighting of propensity score, and stratified analysis by quintile. RESULTS The 90-day crude mortality was 42.4% (269 patients) for Candida BSI cases and 17.1% (1,083 patients) for frequency-matched controls. Following propensity score-matching, the attributable risk difference for 90-day mortality was 28.4% with hazard ratio (HR) of 2.12 (95% CI, 1.98-2.25, p<0.001). In the stratified analysis, the risk for mortality at 90 days was highest in patients in the lowest risk quintile to develop Candida BSI (HR 3.13 (95% CI, 2.33-4.19). Patients in this lowest risk quintile accounted for 81(61%) of the 130 untreated patients with Candida BSI. Sixty nine percent of untreated patients (57/83) died versus 35% of (49/127) of treated patients (p<0.001). CONCLUSIONS Patients with Candida BSI continue to experience high mortality. Mortality attributable to Candida BSI was more pronounced in patients at lowest risk to develop Candida BSI. A higher proportion of these low-risk patients went untreated, experienced higher mortality, and should be the target of aggressive interventions to ensure timely, effective treatment.
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Affiliation(s)
- Patrick B Mazi
- Division of Infectious Diseases, Department of Medicine, Washington University in St Louis School of Medicine, St. Louis, MO, USA
| | - Margaret A Olsen
- Division of Infectious Diseases, Department of Medicine, Washington University in St Louis School of Medicine, St. Louis, MO, USA
| | - Dustin Stwalley
- Division of Infectious Diseases, Department of Medicine, Washington University in St Louis School of Medicine, St. Louis, MO, USA
| | - Adriana M Rauseo
- Division of Infectious Diseases, Department of Medicine, Washington University in St Louis School of Medicine, St. Louis, MO, USA
| | - Chapelle Ayres
- Division of Infectious Diseases, Department of Medicine, Washington University in St Louis School of Medicine, St. Louis, MO, USA
| | - William G Powderly
- Division of Infectious Diseases, Department of Medicine, Washington University in St Louis School of Medicine, St. Louis, MO, USA
| | - Andrej Spec
- Division of Infectious Diseases, Department of Medicine, Washington University in St Louis School of Medicine, St. Louis, MO, USA
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