Antifungal Management Research Articles

Diagnosis and management of invasive fungal diseases in non-neutropenic ICU patients, with focus on candidiasis and aspergillosis: a comprehensive review.

Invasive fungal diseases pose a significant threat to non-neutropenic ICU patients, with Candida and Aspergillus infections being the most common. However, diagnosing these infections in the ICU population remains challenging due to overlapping clinical features, poor sensitivity of blood cultures, and invasive sampling requirements. The classical host criteria for defining invasive fungal disease do not fully apply to ICU patients, leading to missed or delayed diagnoses. Recent advancements have improved our understanding of invasive fungal diseases, leading to revised definitions and diagnostic criteria. However, the diagnostic difficulties in ICU patients remain unresolved, highlighting the need for further research and evidence generation. Invasive candidiasis is the most prevalent form of invasive fungal disease in non-neutropenic ICU patients, presenting as candidemia and deep-seated candidiasis. Diagnosis relies on positive blood cultures or histopathology, while non-culture-based techniques such as beta-D-glucan assay and PCR-based tests show promise. Invasive aspergillosis predominantly manifests as invasive pulmonary aspergillosis in ICU patients, often associated with comorbidities and respiratory deterioration in viral pneumonia. Diagnosis remains challenging due to poor sensitivity of blood cultures and difficulties in performing lung biopsies. Various diagnostic criteria have been proposed, including mycological evidence, clinical/radiological factors and expanded list of host factors. Non-culture-based techniques such as galactomannan assay and PCR-based tests can aid in diagnosis. Antifungal management involves tailored therapy based on guidelines and individual patient factors. The complexity of diagnosing and managing invasive fungal diseases in ICU patients underscore the importance of ongoing research and the need for updated diagnostic criteria and treatment approaches. Invasive fungal disease, Invasive fungal infection, Invasive candidiasis, Invasive aspergillosis, Antifungal drugs.

Influence of invasive aspergillosis during acute leukaemia treatment on survival after allogeneic stem cell transplantation: a prospective study of the EBMT Infectious Diseases Working Party

Infections are the main reason for mortality during acute leukaemia treatment and invasive aspergillosis (IA) is a major concern. Allogeneic stem cell transplantation (alloSCT) is a standard therapy and often is the only live-saving procedure in leukaemia patients. The profound immunodeficiency occurring after alloSCT led to high IA-associated mortality in the past. Therefore, patients with IA were historically considered transplant-ineligible. Recently, there has been improvement of anti-fungal management including novel anti-fungal agents. As a result, more leukaemia patients with IA are undergoing alloSCT. Outcome has not been prospectively assessed. We performed a prospective study in acute leukaemia patients undergoing alloSCT to analyse the impact of a prior history of probable or proven IA (pre-SCT IA). The primary endpoint was 1-year non-relapse mortality (NRM). Relapse free survival and overall survival were analysed as secondary endpoints. 1439 patients were included between 2016 and 2021. The incidence of probable or proven pre-SCT IA was 6.0% (n=87). The cumulative incidence of 1-year NRM was 17.3% (95% CI 10.2-26.0) and 11.2% (9.6-13.0) for patients with and without pre-SCT IA. In multivariate analyses the hazard ratio (HR) for 1-year NRM was 2.1 (1.2-3.6; p=0.009) for patients with pre-SCT IA. One-year relapse-free survival was inferior in patients with pre-SCT IA (59.4% [48.3-68.9] vs. 70.4 [67.9-72.8]; multivariate HR 1.5 [1.1-2.1]; p=0.02). Consequently, 1-year overall survival was lower in patients with pre-SCT IA: (68.8% [57.8-77.4] vs. 79.0% [76.7-81.1]; multivariate HR 1.7 [1.1-2.5]; p=0.01). Pre-SCT IA remains to be significantly associated with impaired alloSCT outcome. On the other hand, more than two thirds of patients with pre-SCT IA were alive at one year after alloSCT. IA is not anymore an absolute contraindication for alloSCT because the majority of patients with IA who undergo alloSCT benefit from this procedure. There was no external funding source for this study.

Emergence of Rhino-Orbito-Cerebral Mucormycosis in Peru: Impact of the COVID-19 Pandemic.

Introduction Mucormycosis is an invasive fungal infection caused by Mucorales that has been increasingly recognized over the years, particularly during the COVID-19 pandemic.Nevertheless, in Peru, there has been limited research on this disease. This study seeks to provide insights into the demographics, clinical presentations, treatment, and outcomes of patients with mucormycosis, before and during the COVID-19 pandemic. Materials and methods We conducted a retrospective case series by reviewing the medical records of Peruvian patients hospitalized at a referral medical center between 2017 and 2021. The selection criteria included patients aged 18 years or older with clinical features of rhino-orbito-cerebral mucormycosis supported by radiological imaging. We extracted data related to risk factors for mucormycosis infection, clinical presentation, management, and hospitalization. Data analysis was performed using Stata software (StataCorp LLC, College Station, Texas, USA) to compare patient groups before and during the COVID-19 pandemic. Results Nineteen cases met our selection criteria: 11 men and eight women with an average age of 57.6 ± 10.6 years. All 19 patients had type 2 diabetes mellitus as comorbidity, with 13 cases exhibiting uncontrolled diabetes. Six patients presented before the COVID-19 pandemic, while 13 during its course. Within the group of patients diagnosed during the pandemic, nine were diagnosed with SARS-CoV-2 infection. Regarding the site of mucormycosis infection, the paranasal sinuses were predominantly involved. Survival analysis indicated that patients who developed mucormycosis during the COVID-19 pandemic, those with uncontrolled diabetes, or those who did not undergo surgery had lower probabilities of survival. Conclusion Mucormycosis is a rare infection associated with high mortality and morbidity with increased frequency during the COVID-19 pandemic. Early diagnosis, timely administration of antifungal treatment, surgery, and effective management of comorbidities can have life-saving implications. Unfortunately, despite the availability of various diagnostic tests and less toxic antifungal options such as liposomal amphotericin-B, such resources are not accessible in Peru's national hospitals.

705 Evaluation of Invasive Fungal Infections in the Burn ICU

Abstract Introduction Fungal infections are increasingly associated with critical illness, especially in major burn injury. The risk factors of invasive fungal infections include central venous catheter (CVC) placement, mechanical ventilation, broad-spectrum antibiotics, renal replacement therapy (RRT), and total parental nutrition. Critically ill burn patients have additional risk factors including extensive wounds, impaired immune system, and repeated surgical intervention. Despite significant morbidity and mortality caused by invasive fungal infections, efforts to prevent them with antifungal prophylaxis have not improved outcomes. In patients who develop invasive fungal infection, appropriate empiric antifungal therapy is imperative to reduce morbidity and mortality especially in the setting of delayed culture and sensitivity data. The purpose of this study was to characterize risk factors associated with the development of invasive fungal infection, invasive fungal infection organisms and surgical and pharmacological management. Methods A retrospective chart review was completed of adult patients admitted to the burn ICU found to have an invasive fungal infection (defined as at least one positive blood or tissue fungal infection and receipt of systemic antifungal therapy). The primary outcome was to identify common fungal organisms. Secondary outcomes included susceptibility pattern of the organism, location of infection, surgical management including debridement and amputation, pharmacological management, median ICU and hospital length of stay, and in hospital mortality. Results A total of 10 patients of a goal of 100 patients with a median 54% TBSA burns were evaluated at this time. The most common yeast species included candida albicans; mold species included a variety of organisms such as fusarium, zygomycete and paecilomyces. Common risk factors among these patients included CVC access (57%), mechanical ventilation (43%), and RRT (43%). Yeast infections were primarily treated with anidulafungin and fluconazole, while mold infections were managed with systemic amphotericin as backbone in addition to voriconazole or isavuconazole. Patients underwent aggressive surgical debridement for source control. Median ICU stay was 53 days with a median hospital stay of 63 days, and 42% mortality. Conclusions Fungal infections among critically ill burn patients are associated with the high morbidity and mortality rates. Therefore, mitigation of modifiable risk factors is of utmost importance. This retrospective review of common fungal growth in our unit will inform future empiric antifungal management for patients with concern of invasive fungal infections. Applicability of Research to Practice Fungal infections present a clinical challenge for burn practitioners, especially in geographically moist areas. Prevention and informed surgical and pharmacological management are key to overcoming this infectious disease threat.

Report of terbinafine resistant Trichophyton spp. in Italy: Clinical presentations, molecular identification, antifungal susceptibility testing and mutations in the squalene epoxidase gene.

Numerous reports of resistance to terbinafine in Trichophyton spp. from all over the world are arousing justified attention and concern. Point mutations in the gene that encodes the squalene epoxidase (SQLE) enzyme are responsible for these therapeutic resistances. Primary objective of the study was to describe first isolates of Trichophyton spp. resistant to terbinafine among the patients treated between September 2019 and June 2022 at the Dermatology Units of Ospedale Maggiore Policlinico and San Bortolo Hospital. Secondary objective was to study the resistance mechanism. Patients with confirmed Trichophyton spp. infection has been treated with systemic and topical terbinafine. Patients were then re-evaluated 12 weeks after the therapy. Patients with incomplete or absent response to terbinafine underwent a new skin scraping for direct mycological examination, new identification of dermatophyte species from culture and MALDI-TOF, molecular species identification, antifungal susceptibility testing and molecular analysis of SQLE gene. We identified five patients without clinical response to treatment with terbinafine. The DNA sequencing of the ITS region identified one Trichophyton rubrum and four Trichophyton indotineae. The T. rubrum strain showed minimum inhibitory concentration (MIC) (90% growth inhibition) of 4 mg/L for terbinafine. The four T. indotineae strains showed a MICs range of 0.25-4 mg/L for terbinafine. The analysis of the SQLE gene in the T. rubrum strain showed a nucleotide substitution generating a missense mutation (L393F). The SQLE gene sequencing in the T. indotineae strains showed a nucleotide substitution generating a missense mutation (F397L) in two strains, a nucleotide substitution L393S in one strain and a nucleotide substitution F415C in another strain. We report the first cases of terbinafine-resistant Trichophyton isolates in the Italian population. Solid antifungal management programs will be needed to promote more responsible use of antimycotics and preserve their therapeutic efficacy to control antifungal resistance.

Invasive Candida parapsilosis Bloodstream Infections in Children: The Antifungal Susceptibility, Clinical Characteristics and Impacts on Outcomes

Background: Candida parapsilosis is the most common non-albicans candida species that causes invasive candidiasis, but little is known about its impacts on the outcomes of pediatric patients. We aimed to characterize the clinical characteristics, risk factors and outcomes of C. parapsilosis bloodstream infections (BSIs) in children. Methods: All pediatric patients with Candida parapsilosis BSIs between 2005 and 2020 from a medical center in Taiwan were enrolled and analyzed. The antifungal susceptibility, clinical manifestations, management and outcomes were investigated. Cases of Candida parapsilosis BSIs were compared between patients with C. albicans BSIs and other Candida spp. BSIs. Results: During the study period, 95 episodes (26.0% of total cases) of Candida parapsilosis BSIs were identified and analyzed. No significant difference was found between pediatric patients with C. parapsilosis BSIs and those with C. albicans BSIs in terms of patients’ demographics, most chronic comorbidities or risk factors. Pediatric patients with C. parapsilosis BSIs were significantly more likely to have previous azole exposure and be on total parenteral nutrition than those with C. albicans BSIs (17.9 vs. 7.6% and 76.8 vs. 63.7%, p = 0.015 and 0.029, respectively). The duration of C. parapsilosis candidemia was relatively longer, and therefore patients often required a longer duration of antifungal treatment when compared with those of C. albicans candidemia, although the candidemia-attributable mortality rates were comparable. Of the C. parapsilosis isolates, 93.7% were susceptible to all antifungal agents, and delayed appropriate antifungal treatment was an independent factor in treatment failure. Conclusions: Pediatric patients with C. parapsilosis BSIs were more likely to have previous azole exposure and be on total parenteral nutrition, and the clinical significances included a longer duration of candidemia and patients often required a longer duration of antifungal treatment.

Non-Aspergillus Hyaline Molds: A Host-Based Perspective of Emerging Pathogenic Fungi Causing Sinopulmonary Diseases.

The incidence of invasive sino-pulmonary diseases due to non-Aspergillus hyaline molds is increasing due to an enlarging and evolving population of immunosuppressed hosts as well as improvements in the capabilities of molecular-based diagnostics. Herein, we review the following opportunistic pathogens known to cause sinopulmonary disease, the most common manifestation of hyalohyphomycosis: Fusarium spp., Scedosporium spp., Lomentospora prolificans, Scopulariopsis spp., Trichoderma spp., Acremonium spp., Paecilomyces variotii, Purpureocillium lilacinum, Rasamsonia argillacea species complex, Arthrographis kalrae, and Penicillium species. To facilitate an understanding of the epidemiology and clinical features of sino-pulmonary hyalohyphomycoses in the context of host immune impairment, we utilized a host-based approach encompassing the following underlying conditions: neutropenia, hematologic malignancy, hematopoietic and solid organ transplantation, chronic granulomatous disease, acquired immunodeficiency syndrome, cystic fibrosis, and healthy individuals who sustain burns, trauma, or iatrogenic exposures. We further summarize the pre-clinical and clinical data informing antifungal management for each pathogen and consider the role of adjunctive surgery and/or immunomodulatory treatments to optimize patient outcome.

Candida bloodstream infection among children hospitalised in three public-sector hospitals in the Metro West region of Cape Town, South Africa

BackgroundCandida bloodstream infection (BSI) causes appreciable mortality in neonates and children. There are few studies describing the epidemiology of Candida BSI in children living in sub-Saharan Africa.MethodsA retrospective descriptive study was conducted at three public sector hospitals in Cape Town, South Africa. Demographic and clinical details, antifungal management and patient outcome data were obtained by medical record review. Candida species distribution and antifungal susceptibility testing results were obtained from the National Health Laboratory Service database.ResultsOf the 97 Candida BSI episodes identified during a five-year period, 48/97 (49%) were Candida albicans (C. albicans), and 49/97 (51%) were non-C. albicans species. The overall incidence risk was 0.8 Candida BSI episodes per 1000 admissions at Red Cross War Memorial Children’s Hospital. Of the 77/97 (79%) Candida BSI episodes with available clinical information, the median age (interquartile range) at the time of BSI was 7 (1–25) months, 36/77 (47%) were associated with moderate or severe underweight-for-age and vasopressor therapy was administered to 22/77 (29%) study participants. Most of the Candida BSI episodes were healthcare-associated infections, 63/77 (82%). Fluconazole resistance was documented among 17%, 0% and 0% of C. parapsilosis, C. tropicalis and C. albicans isolates, respectively. All Candida isolates tested were susceptible to amphotericin B and the echinocandins. The mortality rate within 30 days of Candida BSI diagnosis was 13/75 (17%). On multivariable analysis, factors associated with mortality within 30 days of Candida BSI diagnosis included vasopressor therapy requirement during Candida BSI, adjusted Odds ratio (aOR) 53 (95% confidence interval 2–1029); hepatic dysfunction, aOR 13 (95% CI 1–146); and concomitant bacterial BSI, aOR 10 (95% CI 2–60).ConclusionThe study adds to the limited number of studies describing paediatric Candida BSI in sub-Saharan Africa. Non-C. Albicans BSI episodes occurred more frequently than C. albicans episodes, and vasopressor therapy requirement, hepatic dysfunction and concomitant bacterial BSI were associated with an increase in 30-day mortality.

85. Plasma Cell Free Deoxyribonucleic Acid (cfDNA) Fungal Polymerase Chain Reaction (PCR): a Non-Invasive Diagnostic for Invasive Fungal Disease Evaluation in At-Risk Pediatric Oncology and Stem Cell Transplant Patients

Abstract Background Molecular diagnostics appear promising for early, non-invasive detection of invasive fungal disease (IFD) in immunocompromised patients. Our clinical lab developed and validated cell free DNA (cfDNA) fungal polymerase chain reaction (PCR) assays (Table 1), which have been in clinical use since November 2020 and were recently included in an institutional pediatric clinical care pathway for prolonged febrile neutropenia. We aimed to evaluate the performance of these plasma cfDNA fungal PCR assays in pediatric oncology and hematopoietic stem cell transplant (HSCT) patients with clinical concern for IFD. Methods We initiated an observational study of inpatient oncology and HSCT patients who had plasma mold panel (+/- Candida panel) cfDNA fungal PCR obtained as part of an IFD evaluation at our freestanding quaternary care children’s hospital. The primary outcome was IFD clinical diagnosis (proven, probable, possible, unlikely) as per EORTC/MSG† definitions within one month of the cfDNA fungal PCR, which was assigned independently by two physicians, with a third physician utilized in cases of discrepancy. Patient demographics, hospital course, imaging results, and clinical laboratory data were abstracted and maintained in an encrypted REDCap© database. Results In a preliminary analysis of October 2021-March 2022 data, there were 21 IFD evaluations for 18 patients (Table 2). Most oncology evaluations were for prolonged febrile neutropenia, while many HSCT were non-neutropenic, but on enhanced immunosuppression with new clinical concerns (e.g., respiratory symptoms, persistent fever). Plasma cfDNA detected a mold or yeast consistent with the clinical presentation in 100% of the five proven/probable cases (Figures 1 & 2). All 14 possible IFD cases had a negative cfDNA fungal PCR. Proven cases are designated with blue icon, while the probable case is orange. All five cases were in oncology patients who did not have history of hematopoietic stem cell transplant. Cell free DNA (cfDNA) fungal polymerase chain reaction (PCR) results include the organism identified, followed by the cycle threshold (Ct) in parenthesis. Maximum Ct for the assay is 45. Abbreviations: AG: Aspergillus galactomannan index (Ref <0.5); ALL: acute lymphoblastic leukemia. BAL: bronchoalveolar lavage; 1,3-BDG: 1,3-beta-D-glucan (Ref <60 pg/ml); cfDNA: cell free deoxyribonucleic acid; CNS: central nervous system; EORTC/MSG: European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group & the National Institute of Allergy & Infectious Diseases Mycoses Study Group; L-AmB: liposomal amphotericin B; SARS-CoV-2: severe acute respiratory syndrome associated with coronavirus 2. Conclusion Upfront plasma cfDNA fungal PCR successfully detected a relevant mold or yeast with short turnaround time in 100% of cases that were later classified as proven/probable. This appears promising for early, noninvasive diagnosis that enables prompt optimization of antifungal and surgical management, particularly for mucormycosis cases. Additional data may permit consideration of Mucorales agents PCR as a new EORTC/MSG mycologic criteria. Disclosures Lauren E. Kushner, MD, Roman: Client of my husband's business..

P417 Evaluation of matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS)-Bruker Biotyper Sirius for identification of invasive molds

Poster session 3, September 23, 2022, 12:30 PM - 1:30 PM ObjectivesSusceptibility to various antifungal drugs varies between different species and subspecies within the same genus. Phenotypic identification of fungi has limitations for species-level identification. Correct identification of species and subspecies in invasive mold infections is important to initiate the appropriate antifungal therapy. Matrix Assisted Laser Desorption Ionization Time-of-Flight mass spectrometry (MALDI-TOF MS) with its proteomic analysis overcomes this limitation and helps in administering the correct anti-fungal therapy. A total of seven mold isolates from invasive fungal infections were evaluated for identification by MALDI-TOF MS and conventional morphological methods.MethodsTotal of seven isolates from invasive mold infections were identified by the conventional method of culturing specimens on Sabouraud's dextrose agar and Potato Dextrose agar with incubation at room temperature and 37°C in Biological oxygen demand (BOD) incubator. Micro-morphological identification of the fungus was done by Lacto Phenol Cotton Blue (LPCB) mount. Same isolates were processed on MALDI-TOF MS Bruker Biotyper Sirius (Bruker Daltonics, Bremen Germany) following recommended extraction protocol using ethanol absolute, acetonitrile, and 70% formic acid.ResultsAs per the below Figure.ConclusionIn four out of seven isolates phenotypic identification upto species level based on LPCB micromorphology was confirmed on MALDI-TOF MS. In the remaining three isolates we could only give a genus level identification based on LPCB mount. These three isolates were further identified upto the level of species after processing on MALDI as Aspergillus tamarii, Phaeoacremonium cinerum, and Fusarium equiseti. All mold isolates were identified with good quality mass spectra. In our experience, mold identification by MALDI-TOF MS using the Bruker Biotyper Sirius platform definitely has an edge over conventional phenotypic methods in species-level differentiation of various molds, impacting targeted antifungal management.

Fungal Keratitis: Clinical Features, Risk Factors, Treatment, and Outcomes.

Fungal keratitis (FK) can be challenging to diagnose and treat. In this retrospective case series, FK cases presenting at the University of Pittsburgh Medical Center, Pennsylvania, USA, from 2015 to 2021 were reviewed for ocular risk factors, clinical presentation, management, and outcomes. Twenty-eight cases of FK were included. The median presenting age was 58.5 (18.5) years, and the median symptom duration prior to presentation was 10 (35.8) days. Predisposing ocular risk factors included contact lens use (67.9%), recent ocular trauma/abrasion (42.9%), and history of ocular surgery (42.9%). The median presenting visual acuity (VA) was 1.35 (1.72) LogMAR. About half presented with a central ulcer (42.9%), large infiltrate (6.7 (6.3) mm2), corneal thinning (50.0%), and hypopyon (32.1%). The majority of isolated fungal species were filamentous (75.0%). Most common antifungal medications included topical voriconazole (71.4%) and natamycin (53.6%) drops and oral voriconazole (64.3%). Surgical management was necessary in 32.1% of cases and enucleation in one case. Defect resolution occurred in 42.5 (47.0) days, and median final VA was 0.5 (1.84) LogMAR. Features associated with poor final visual outcomes included poor initial VA (p < 0.001) and larger defect size (p = 0.002). In conclusion, unlike prior studies in the northeast region of the USA, FK was commonly caused by filamentous fungi, and antifungal management most often consisted of topical and oral voriconazole.

New Developments in Pediatric Antifungal Pharmacology.

New Developments in Pediatric Antifungal Pharmacology.

Screening the Tocriscreen™ bioactive compound library in search for inhibitors of Candida biofilm formation.

Biofilms formed by Candida species present a significant clinical problem due to the ineffectiveness of many conventional antifungal agents, in particular the azole class. We urgently require new and clinically approved antifungal agents quickly for treatment of critically ill patients. To improve efficiency in antifungal drug development, we utilized a library of 1280 biologically active molecules within the Tocriscreen 2.0 Micro library. Candida auris NCPF 8973 and Candida albicans SC5314 were initially screened for biofilm inhibitory activity using metabolic and biomass quantitative assessment methods, followed up by targeted evaluation of five selected hits. The initial screening (80% metabolic inhibition rate) revealed that there was 90 and 87 hits (approx. 7%) for C. albicans and C. auris, respectively. Additionally, all five compounds selected from the initial hits exhibited a biofilm inhibition effect against several key Candida species tested, including C. glabrata and C. krusei. Toyocamycin displayed the most potent activity at concentrations as low as 0.5 μg/mL, though was limited to inhibition. Darapladib demonstrated an efficacy for biofilm inhibition and treatment at a concentration range from 8 to 32 μg/mL and from 16 to 256 μg/mL, respectively. Combinational testing with conventional antifungals against C. albicans strains demonstrated a range of synergies for planktonic cells, and notably an anti‐biofilm synergy for darapladib and caspofungin. Together, these data provide new insights into antifungal management possibilities for Candida biofilms.

Antibacterial and Antifungal Management in Relation to the Clinical Characteristics of Elderly Patients with Infective Endocarditis: A Retrospective Analysis.

Infective endocarditis (IE) is increasingly prevalent in the elderly, particularly due to the rising frequency of invasive procedures and intracardiac devices placed on these individuals. Several investigations have highlighted the unique clinical and echocardiographic characteristics, the microorganisms implicated, and the prognosis of IE in the elderly. In addition, the old population seems to be fairly diverse, ranging from healthy individuals with no medical history to patients with many ailments and those who are immobile. Furthermore, the therapy of IE in this group has not been well investigated, and worldwide recommendations do not propose tailoring the treatment approach to the patient’s functional state and comorbid conditions. A multicenter research study was designed as a retrospective study of hospitalized patients with infective endocarditis, aiming to examine the characteristics of elderly patients over 65 years old with infective endocarditis in relation to the antibiotic and antifungal treatments administered, as well as to quantify the incidence of treatment resistance, adverse effects, and mortality in comparison to patients younger than 65. Based on a convenience sampling method, we included in the analysis a total of 78 patients younger than 65 and 131 patients older than 65 years. A total of 140 patients had endocarditis on native valves and 69 patients had endocarditis on prosthetic valves. A significantly higher proportion of elderly patients had signs of heart failure on admission, and the mortality rate was significantly higher in the elderly population. A majority of infections had a vascular cause, followed by dental, maxillo-facial, and ENT interventions. The most common complications of IE were systemic sepsis (48.1% of patients older than 65 years vs. 30.8% in the younger group). The most frequent bacterium involved was Staphylococcus aureus, followed by Streptococcus spp. in a total of more than 50% of all patients. The most commonly used antibiotics were cephalosporins in 33.5% of cases, followed by penicillin in 31.2% and glycopeptides in 28.7%, while Fluconazole was the initial option of treatment for fungal endocarditis in 24.9% of cases. Heart failure at admission (OR = 4.07), the development of septic shock (OR = 6.19), treatment nephrotoxicity (OR = 3.14), severe treatment complications (OR = 4.65), and antibiotic resistance (OR = 3.24) were significant independent risk factors for mortality in the elderly patients. Even though therapeutic management was initiated sooner in the older patients, the associated complications and mortality rate remained significantly greater than those in the patients under 65 years old.

Phaeohyphomycosis caused by Neoscytalidiumdimidiatum in a COVID-19 patient

BackgroundNeoscytalidiumdimidiatum is an opportunistic dematiaceous fungus belonging to the class Dothideomycetes. Case reportWe report a case of N. dimidiatum cerebral phaeohyphomycosis post COVID-19 infection in a 32-year-old male from Iran. The causative agent was identified by cytopathology, routine mycological methods, and DNA sequencing of the internal transcribed spacer (ITS) region of rDNA. Apart from COVID-19 complications and the corticosteroid therapy, no underlying condition was diagnosed. The symptoms suggesting the fungal infection were shown two weeks after being discharged from COVID-19 hospital stay. Magnetic resonance of the brain showed a multi-focal central nervous system infection. The delayed identification of the fungus and, thus, a late starting of the antifungal treatment with amphotericin B, might have affected the patient outcome as he finally died. ConclusionsConsidering the rare incidence of N. dimidiatum infections, this case should aware us about them, leading to a timely antifungal management.

Predictive factors in treatment response of malignant external otitis.

To evaluate the prevalence and impact of various predictive factors including diabetes control in malignant external otitis (MEO) treatment response. In a cross-sectional study on MEO patients, we defined treatment response with three indices; ESR level decrease, hospitalization period, and systemic antifungal drug usage. The impact of diabetes control and other predictive factors on these indices have been evaluated. Overall, 164 patients with a mean age of 67.8 ± 9.7years were included. Cranial nerve involvement was present in 56 patients. Nine patients had immunodeficiency. 19.5% of cases had leukocytosis. Diabetes mellitus was present in 156 patients, suffering for an average of 13.9 ± 8.6years. The overall mean hemoglobin A1C (HbA1c) level was 8.3% (4.4-12.8%), and the mean fasting blood sugar was 146.4mg/dl (63-292mg/dl). 29.3% of patients had good diabetes control before admission (HbA1c < 7%), 54.9% had poor control (7% < HbA1c < 10%) and 15.9% had very poor glycemic control (HbA1c > 10%). The predictive role for the following factors were not statistically significant: age, gender, comorbidities, diabetes, diabetes management method used before and during hospitalization, diabetes duration, leukocytosis, immunodeficiency, fasting blood sugar level, HbA1c level, glycemic control index, and insulin amount. However, CRP level with a mean value of 34.3mg/L showed a significant correlation with ESR decrease, hospitalization period, and antifungal drug usage. CRP level could be used as a predictor for the hospitalization period, the need for systemic antifungal and ESR level decrease. It would be helpful to check the CRP level at the time of diagnosis to predict the hospitalization period and the necessity of systemic antifungal management to adjust the treatment strategy.

Access to flucytosine for the treatment of HIV-associated cryptococcal meningitis in Africa

Cryptococcal meningitis, a major cause of meningitis in adults living with HIV infection, accounts for 15% of global HIV-associated mortality. 1 Rajasingham R Smith RM Park BJ et al. Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis. Lancet Infect Dis. 2017; 17: 873-881 Summary Full Text Full Text PDF PubMed Scopus (973) Google Scholar Treatment of cryptococcal meningitis involves three phases: induction, consolidation, and maintenance. The induction phase, which aims at reducing cerebral and meningeal fungal burden crucial for early survival, requires combination antifungal therapy and management of increased cerebrospinal fluid intracranial pressure. WHO in 2018 recommended at induction either 1-week amphotericin B deoxycholate plus flucytosine followed by high-dose fluconazole or 2-week oral fluconazole plus flucytosine. 2 WHOGuidelines for the diagnosis, prevention, and management of cryptococcal disease in HIV-infected adults, adolescents and children. Supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. https://www.who.int/publications/i/item/9789241550277Date: 2018 Date accessed: April 14, 2022 Google Scholar However, in the absence of flucytosine, fluconazole plus amphotericin B deoxycholate could be an alternative. The Advancing Cryptococcal Meningitis treatment for Africa trial on which these recommendations were based showed flucytosine to be a better drug at reducing mortality than is fluconazole in combination with amphotericin B deoxycholate. 3 Molloy SF Kanyama C Heyderman RS et al. Antifungal combinations for treatment of cryptococcal meningitis in Africa. N Engl J Med. 2018; 378: 1004-1017 Crossref PubMed Scopus (176) Google Scholar In a recent trial, a combination of single dose 10 mg/kg liposomal amphotericin B and 2-week flucytosine plus fluconazole showed non-inferiority and tolerance benefits to previously recommended induction therapy. 4 Jarvis JN Lawrence DS Meya DB et al. Single-dose liposomal amphotericin B treatment for cryptococcal meningitis. N Engl J Med. 2022; 386: 1109-1120 Crossref PubMed Scopus (9) Google Scholar These trials and some observational studies 5 Dromer F Mathoulin-Pelissier S Launay O Lortholary O French Cryptococcosis Study GDeterminants of disease presentation and outcome during cryptococcosis: the CryptoA/D study. PLoS Med. 2007; 4: e21 Crossref PubMed Scopus (280) Google Scholar provide data that confirm flucytosine as an important drug combination for inductive treatment of cryptococcal meningitis. However, access to this old, off patent drug is not guaranteed in Africa, South America, and Asia where the burden of cryptococcal meningitis is highest. 6 Loyse A Dromer F Day J Lortholary O Harrison TS Flucytosine and cryptococcosis: time to urgently address the worldwide accessibility of a 50-year-old antifungal. J Antimicrob Chemother. 2013; 68: 2435-2444 Crossref PubMed Scopus (83) Google Scholar In South Africa, a region with a long-standing high burden of cryptococcal meningitis, flucytosine was only registered in December, 2021, by the South African Health Products Regulatory Authority (SAHPRA) despite the application being submitted 2 years previously by Viatris. 7 Application for WHO Model List of Essential Medicines: flucytosine (5FC). http://www.life-worldwide.org/assets/uploads/files/Flucytosine_63_CORE_AC.pdfDate: 2018 Date accessed: April 24, 2022 Google Scholar Outcomes of flucytosine-containing combination treatment for cryptococcal meningitis in a South African national access programme: a cross-sectional observational studyIn-hospital mortality among patients treated with a flucytosine-containing regimen was comparable to reduced mortality reported in patients receiving a flucytosine-containing regimen in a recent multicentre African clinical trial. Flucytosine-based treatment can be delivered in routine care in a middle-income country with a substantial survival benefit. Full-Text PDF

Department of Defense Trauma Registry Infectious Disease Module Impact on Clinical Practice.

The Joint Trauma System (JTS) is a DoD Center of Excellence for Military Health System trauma care delivery and the DoD's reference body for trauma care in accordance with National Defense Authorization Act for Fiscal Year 2017. Through the JTS, evidence-based clinical practice guidelines (CPGs) have been developed and subsequently refined to standardize and improve combat casualty care. Data are amassed through a single, centralized DoD Trauma Registry to support process improvement measures with specialty modules established as the registry evolved. Herein, we review the implementation of the JTS DoD Trauma Registry specialty Infectious Disease Module and the development of infection-related CPGs and summarize published findings on the subsequent impact of the Infectious Disease Module on combat casualty care clinical practice and guidelines. The DoD Trauma Registry Infectious Disease Module was developed in collaboration with the Infectious Disease Clinical Research Program (IDCRP) Trauma Infectious Disease Outcomes Study (TIDOS). Infection-related information (e.g., syndromes, antibiotic management, and microbiology) were collected from military personnel wounded during deployment June 1, 2009 through December 31, 2014 and medevac'd to Landstuhl Regional Medical Center in Germany before transitioning to participating military hospitals in the USA. To support process improvements and reduce variation in practice patterns, data collected through the Infectious Disease Module have been utilized in TIDOS analyses focused on assessing compliance with post-trauma antibiotic prophylaxis recommendations detailed in JTS CPGs. Analyses examined compliance over three time periods: 6 months, one-year, and 5 years. The five-year analysis demonstrated significantly improved adherence to recommendations following the dissemination of the 2011 JTS CPG, particularly with open fractures (34% compliance compared to 73% in 2013-2014). Due to conflicting recommendations regarding use of expanded Gram-negative coverage with open fractures, infectious outcomes among patients with open fractures who received cefazolin or expanded Gram-negative coverage (cefazolin plus fluoroquinolones and/or aminoglycosides) were also examined in a TIDOS analysis. The lack of a difference in the proportion of osteomyelitis (8% in both groups) and the significantly greater recovery of Gram-negative organisms resistant to aminoglycosides or fluoroquinolones among patients who received expanded Gram-negative coverage supported JTS recommendations regarding the use of cefazolin with open fractures. Following recognition of the outbreak of invasive fungal wound infections (IFIs) among blast casualties injured in Afghanistan, the ID Module was refined to capture data (e.g., fungal culture and histopathology findings, wound necrosis, and antifungal management) needed for the TIDOS team to lead the DoD outbreak investigation. These data captured through the Infectious Disease Module provided support for the development of a JTS CPG for the prevention and management of IFIs, which was later refined based on subsequent TIDOS IFI analyses. To improve combat casualty care outcomes and mitigate high-consequence infections in future conflicts, particularly in the event of prolonged field care, expansion, refinement, and a mechanism for sustainability of the DoD Trauma Registry Infectious Disease Module is needed to include real-time surveillance of infectious disease trends and outcomes.

Efficacy and safety of Isavuconazole for the treatment of invasive Aspergillus infection - an update of the literature

ABSTRACT Introduction Invasive aspergillosis is associated with high morbidity and mortality in immunocompromised patients. It is now increasingly reported in critically ill patients, including those with respiratory viral infections, such as influenza and COVID-19. Antifungal management is challenging due to diagnostic delay, adverse drug reactions, drug–drug interactions, narrow therapeutic window, and the emergence of resistance. Isavuconazole is the most recent FDA approved azole for the treatment of invasive aspergillosis, with data continuing to accumulate. Areas covered The authors review the safety and efficacy of isavuconazole in the management of invasive aspergillosis based on the currently available evidence. The authors also report on the structure, mechanism of action, pharmacokinetic properties, in vitro and in vivo studies as well as clinical safety and efficacy reports of isavuconazole since its FDA approval. Expert opinion Isavuconazole is non-inferior to voriconazole and is a safe, effective, and better tolerated option for the treatment of invasive aspergillosis. It offers several advantages over other antifungal agents, including having a better adverse event profile with respect to hepatotoxicity, neuro-visual toxicity, QTc prolongation, as well as a stable pharmacokinetic profile obviating the need for therapeutic drug monitoring. Further studies are needed to evaluate its performance in prophylaxis against invasive aspergillosis as well as in the treatment of aspergillosis in critically ill patients without underlying cancer or transplant.

A Case Report of Aspergillus Fungal Spinal Infection in Immunocompetent Patient and Review of Literature

Background: Spinal aspergillus infection is rare but can cause significant morbidity and mortality. Sometime it may mis-diagnosed as pyogenic or tuberculous infection in immunocompetent patients. Therefore, it causes delay in diagnosis and leads to spinal instability, neurological deficit, and sometimes death. Case Report: Here we discussed a case of 68 years old female patient with severe back pain and difficulty in walking which was gradually increased over the period of time of two months. During this, she was diagnosed as koch’s spine based on MRI report and she had been started on empirical anti-tuberculous medication. But her condition was deteriorated. After that patient underwent surgical management and infected tissue sent for culture and sensitivity and histopathological examination. The report was positive for aspergillus fungal infection. she was started with anti-fungal medication and course of treatment was uneventful. Conclusion: Early diagnosis of spinal fungal infection is often delayed in immunocompetent patients and it lead to delayed in anti-fungal management which lead to increase in morbidity and mortality. Keywords: Aspergillus, Spinal fungal infection, Case Report