Initial Antifungal Treatment Research Articles

Pharmacies Counselling of Patients in the Era of Antifungal Resistance.

Tinea pedis is one of the most prevalent superficial fungal infections. Initial antifungal treatment is often acquired over-the-counter (OTC) without previous consultation with a physician. Lately, increasing antifungal terbinafine resistance has been documented in Denmark and globally and it is therefore of interest to assess how Danish pharmacies advise customers with tinea pedis. One hundred Danish pharmacies were randomly selected and an employee interviewed from each. A structured question guide was followed, with the possibility to add further comments. Interviews of 94 pharmacies were conducted. Six pharmacies never replied. Terbinafine as standard dose or cutaneous solution terbinafine one time application (Lamisil Once (R)) were recommended by 99% of the pharmacy employees as first-line treatment. The customer was advised to seek medical attention when tinea pedis was recurring (93%), or when treatment duration was > 2 weeks (77%). The majority (88%) of the pharmacy employees had no knowledge about antifungal resistance. Only few pharmacy employees were aware of the current problem of antifungal resistance and the majority advised costumers to initiate treatment using OTC topical terbinafine. The problem of emerging antifungal resistance requires attention in order to provide customers with tinea pedis effective treatment and prevent further societal spread of resistance to antifungals.

Severe fusarium oxysporum keratomycosis: About 2 Cases

Fungal keratitis is a destructive ocular infection, representing a serious diagnostic and therapeutic problem, difficult to treat and with poor results. It can cause irreversible damage. Keratomycoses are rare and may be under-diagnosed. Direct microscopic examination and culture are essential for early specific diagnosis and must be taken into consideration to establish the most effective treatment and avoid serious complications. The pathogenesis of this infection is based on three factors: colonization, tissue damage and immunosuppression. We report 2 cases of Fusarium oxysporum keratomycosis treated with amphotericin B. The diagnosis of corneal abscess was made after ophthalmological examination in 2 adult males with no previous ophthalmological history, referred to the Omar Drissi hospital in Fez for decreased visual acuity, photophobia, redness and intense pain in the right/left eye. Corneal scrapings were taken for microbiological analysis, and after initial mycological results, local and systemic antifungal treatment was initiated with amphotericin B and natamycin eye drops. The evolution was marked by a corneal perforation with a tenon patch graft for the first patient, and healing for the 2nd

1702. Disseminated Candidiasis after Candidemia: Epidemiology, Diagnostic Evaluation, and Risk Factors

Abstract Background In patients with candidemia, evaluation for disseminated disease with ophthalmological exam and diagnostic imaging is recommended but not standardized. This study sought to describe practice patterns in the diagnostic evaluation for disseminated disease after candidemia and identify risk factors associated with disseminated candidiasis to improve local management. Methods A retrospective study of all episodes of candidemia diagnosed in patients < 25 years from 2013-2022 at Cincinnati Children’s Hospital Medical Center reported clinical characteristics, microbiology data, and diagnostic testing for dissemination. Disseminated candidiasis was defined as an ophthalmologic exam, echocardiogram or other imaging findings consistent with candidiasis or growth of Candida spp. from a sterile site besides blood. Mixed-effects logistic regression was performed to identify risk factors for disseminated disease. Results 144 episodes of candidemia occurred in 124 patients , with C. albicans (35%) the most commonly identified species (Figure 1). 107/144 (74.3%) episodes underwent evaluation for disseminated candidiasis, with dissemination in 27/107 (25.2%). Of patients with only 1 positive culture, 5/34 (14.7%) had disseminated candidiasis compared to 22/73 (30.1%) with more than 1 positive culture (Figure 2). Ophthalmologic exams and echocardiograms were done in < 70% of workups (Figure 3). History of prematurity (aOR 17.5, 95%CI 3.1-100.4) and solid organ transplantation (aOR 5.3, 95%CI 1.1-24.6) were associated with disseminated candidiasis when controlling for age, sex, underlying disease, and initial antifungal treatment. Each additional day of candidemia significantly increased the odds of dissemination (aOR 1.5, 95%CI 1.2-1.9). Conclusion In this single-center study, most patients with candidemia underwent diagnostic evaluation, though the extent varied. Disseminated disease was common. Prematurity and history of solid organ transplantation were independent risk factors for dissemination as was each additional day of candidemia. Patients with any candidemia should undergo evaluation for dissemination. Multicenter studies are needed to determine the optimal diagnostic evaluation in these high-risk patient groups. Disclosures Grant C. Paulsen, MD, Moderna: Grant/Research Support|Pfizer: Grant/Research Support Lara A. Danziger-Isakov, MD, MPH, Aicuris: Contracted Clinical Research|Ansun Biopharma: Contracted Clinical Research|Astellas: Contracted Clinical Research|GSK: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Contracted Clinical Research|Pfizer: Contracted Clinical Research|Roche Diagnostics: Advisor/Consultant|Takeda: Advisor/Consultant|Takeda: Contracted Clinical Research William R. Otto, MD, MSCE, Moderna: Grant/Research Support

612. Coccidioidal Pulmonary Cavitation: A New Age

Abstract Background The majority of literature on cavitary pulmonary coccidioidomycosis is from four decades ago which was prior to the advent of triazoles and focused on surgical treatment. This observational study is a comprehensive retrospective study of pulmonary cavitary coccidioidomycosis from patients at Valley Fever Institute at Kern Medical over the last 12 years. This observational study aims to explore the spectrum of coccidioidal cavities and the evaluation and management of those cavities. Methods IRB approved, retrospective review of electronic medical records of the Valley Fever Institute database was conducted. Demographics, comorbidities, types, and the number of cavities, complications, and medical and surgical treatment were gathered and compared to the literature. PubMed and Google Scholar were searched for cavitary pulmonary coccidioidomycosis Results Of the initially 276 identified patients, 137 met the inclusion criteria. This study found 52 (37.2%) patients with hemoptysis. One case (0.7%) required radiologic intervention to occlude the bleeding vessel, and one (0.7%) case of hemorrhage required right upper lobe lobectomy. Nine (6.6%) cases exhibited a ruptured cavity. Eight of those cases had initial chest tube placement, of which three (3/8, 37.5%) did not require surgical intervention. Seven of 137 (5.1%) cases presented with a pleural effusion not associated with a cavity rupture. Five (3.7%) were due to primary coccidioidomycosis. Three of the coccidioidal effusions required therapeutic thoracentesis, and none required a chest tube or surgery. The mean duration of the initial antifungal treatment was found to be 563 days (n=80). In 35% (28/ 80) of them, a triazole was switched to another triazole for variable reasons, including treatment failure or side effects. Conclusion Coccidioidal pulmonary cavitation remains a complex disease to evaluate and treat. This study's ethnic demographic differed from other cohorts. It also contradicts the notion that pulmonary coccidioidal cavitary disease and dissemination infrequently manifest in the same patient. In the present age of triazole therapy, indications and the need for surgery continue to decline. Further investigation needs to be conducted to evaluate medical therapy’s efficacy and long-term outcomes. Disclosures Rupam Sharma, PGY-1/MD, Astellas: Grant/Research Support George R. Thompson, III, MD, Astellas: Advisor/Consultant|Astellas: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|Mayne: Advisor/Consultant|Mayne: Grant/Research Support|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Mundipharma: Advisor/Consultant|Mundipharma: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support

Efficacy and Safety of Isavuconazole in the Treatment of Invasive Fungal Disease in Patients with Hematological Disorders

Objective: Invasive fungal disease (IFD) poses a significant threat to patients suffering from hematological disorders with high morbidity and mortality. isavuconazole has shown promising efficacy and safety in treating IFD caused by various pathogens including but not limited to Aspergillus and Mucor species in the previous studies. Thus, this retrospective single-arm case analysis study was conducted to evaluate the efficacy and safety of isavuconazole in patients with hematological disorders. Method: This study included 12 patients diagnosed with IFD (including proven/probable/possible IFD) between August 2022 and March 2023 who underwent isavuconazole treatment for a minimum duration of 7 days. Only patients who received itraconazole monotherapy were involved, with 4 of whom taking initial treatment while 8 receiving isavuconazole as salvage therapy. Results: Among the 12 patients included in this study, 7 were diagnosed with invasive aspergillosis and 5 were diagnosed with invasive mucormycosis. The median duration of isavuconazole treatment was 43.5 (11-86) days. At the conclusion of the treatment, the overall response (OR) rate for all patients was 67% (8/12), with a complete response rate of 42% (5/12) and a partial response rate of 25% (3/12). Among patients receiving initial treatment, 75% (3/4) patients achieved OR, while 62.5% (5/8) patients approached OR among those receiving salvage therapy. Importantly, only 1 patient experienced an increase in transaminases without demand to discontinuing isavuconazole treatment. Besides, no patients withdraw isavuconazole therapy due to other adverse reactions. Conclusions: The study results demonstrate that isavuconazole exhibits both effect and safety in the treatment of invasive fungal disease in patients with hematological disorders. Furthermore, there are indications that initial antifungal treatment with itraconazole may yield higher response rates.

The management and outcome of cryptococcosis in patients with different immune statuses and treatment protocols: A multicenter real-world study in Jiangsu Province - China.

The incidence of cryptococcosis is increasing in non-immunocompromised patients. However, the evidence on proper management is inadequate in this population. We conducted this multi-center real-world study in pulmonary cryptococcosis patients with different immune statuses, so as to provide practical evidence for optimized clinical management of cryptococcosis, especially for mild-to-moderate immunodeficient diseases patients. This is a prospective observational study. The clinical data of patients with proven cryptococcosis were collected and analyzed from 7 tertiary teaching hospitals in Jiangsu Province, China from January, 2013 to December, 2018. Proven cases include pulmonary cryptococcosis, cryptococcal meningitis, cryptococcemia and cutaneous cryptococcosis. Patients were followed up over 24 months. According to their immune status, patients with cryptococcosis were divided into three groups, namely immunocompetent group (IC), mild-to-moderate immunodeficient diseases group (MID), severe immunodeficient diseases group (SID). Meanwhile, pulmonary crypotococcosis (PC) and extrapulmonary crypotococcosis (EPC) were also classified and analyzed. 255 proven cases of cryptococcosis were enrolled. Finally, 220 cases completed the follow-up. 143 proven cases (65.0%) were immunocompetent (IC), 41 cases (18.6%) were MID, and 36 cases (16.4%) were SID. 174 cases (79.1%) were PC and 46 cases (20.9%) were EPC. The mortality was significantly higher in SID and MID patients [47.2% (SID) vs. 12.2% (MID) vs. 0.0% (IC), p<0.001]. The mortality was also significantly higher in EPC patients [45.7% vs. 0.6% (PC), p<0.001]. Patients with alternative initial antifungal treatment had higher mortality than patients with guideline recommended initial treatment [23.1% vs. 9.5%, p=0.041]. In MID group, the mortality of receiving alternative initial antifungal treatment was significantly higher than recommended initial treatment [2/3 vs. 3/34(8.8%), p=0.043]. In pulmonary cryptococcosis patients with MID, the mortality was very similar to IC group [0.0% vs. 0.0% (IC)], lower than SID group [0.0% vs. 11.1% (SID), p=0.555]. However, in extrapulmonary cryptococcosis patients with MID, the mortality was significantly higher than that in IC [62.5% vs. 0.0% (IC)], and similar to SID patients [62.5% vs. 59.3% (SID)]. The immune status exert a significant influence on the management and prognosis of cryptococcosis patients. The mortality of cryptococcosis patients with MID is higher than that of immunocompetent patients. For MID patients with pure pulmonary cryptococcosis, it is acceptable to take the treatment recommended as IC patients. For the MID patients with extrapulmonary cryptococcosis, the mortality is high and the initial treatment should follow the regimen for SID patients. Following the recommended treatment regimen in the IDSA guideline can reduce mortality in patients with cryptococcosis. Starting on alternative initial antifungal treatment may bring worse outcomes.

CNS Aspergillosis Following BTK Inhibitors Mimicking Secondary CNS Lymphoma – A Case Series (P14-13.004)

<h3>Objective:</h3> NA <h3>Background:</h3> BTK inhibitors are commonly used in malignant B-cell lymphomas but can be associated with fungal infections, in part driven by altered platelet functions that diminish anti-fungal immune mechanisms. We describe four unique patients treated for B-cell malignancies (B-cell lymphoma, CLL, mantle cell lymphoma, and Waldenstrom’s disease) with progressive neurological deficits initially thought to represent secondary CNS lymphoma but on further diagnostic workup identified as CNS Aspergillosis. <h3>Design/Methods:</h3> Retrospective review of patients managed for B-cell hematological malignancies with BTK inhibitors associated with CNS Aspergillosis. <h3>Results:</h3> Four male patients (age 61–74) were treated with ibrutinib or zanubrutinib at a dose ranging from 160–560 mg daily (range 3–12 months) when developing new neurological symptoms and imaging findings were suggestive of recurrent lymphoma with CNS involvement. However, subsequent brain biopsies revealed invasive cerebral Aspergillosis in all cases with pulmonary involvement in three out of the four cases. Symptom presentation included headache and seizures (n=4), paresthesias (n=1) and expressive aphasia (n=1). Initial anti-fungal treatment consisted of voriconazole at a dose of 200–500 mg twice daily and subsequently posaconazole in three out of four patients. Additionally, three patients underwent surgical resection. Two patients remained stable without fungal disease progression for more than a year. One patient stopped taking voriconazole after 6 months due to side effects (decreased appetite, fatigue, lethargy, weight loss, and night sweats) and was eventually lost to follow-up. One patient had recurrent Aspergillosis and passed away following antifungal treatment for over two years. <h3>Conclusions:</h3> BTK inhibitors can be associated with fungal infections, including CNS involvement. These four cases illustrate the challenge in establishing a correct diagnosis and highlight the importance of considering atypical and fungal infections in individuals treated with BTK inhibitors. <b>Disclosure:</b> Ms. Murthy has nothing to disclose. The institution of Dr. Martinez-Lage has received research support from NIH. Jeremy Abramson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Bristol-Myers Squibb. Jeremy Abramson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Kite Pharma. Dr. Branagan has nothing to disclose. Dr. Ji has nothing to disclose. Yi-Bin Chen, 13609 has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Incyte. Yi-Bin Chen, 13609 has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Daiichi. Yi-Bin Chen, 13609 has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abbvie. Yi-Bin Chen, 13609 has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Equilium. Yi-Bin Chen, 13609 has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Actinium. Yi-Bin Chen, 13609 has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Celularity. Dr. Letourneau has received research support from World Health Information Science Consultants, LLC. Dr. Letourneau has received publishing royalties from a publication relating to health care. Brian Nahed has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Robeaute. Brian Nahed has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BK Ultrasound. Brian Nahed has stock in React Neuro. Brian Nahed has received research support from NIH. Dr. Nelson has nothing to disclose. Dr. Arrillaga-Romany has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Boehringer Ingelheim. The institution of Dr. Arrillaga-Romany has received research support from Astex Pharmaceuticals. The institution of Dr. Arrillaga-Romany has received research support from Gsk. Dr. Wang has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Seattle Genetics. The institution of Dr. Wang has received research support from Merck. Dr. Wang has received publishing royalties from a publication relating to health care. Dr. Dietrich has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amgen. Dr. Dietrich has received publishing royalties from a publication relating to health care.

S2.2c Talaromycosis in HIV-negative patients: challenges and counter-measures

S2.2 Histoplasmosis and talaromycosis, September 21, 2022, 3:00 PM - 4:30 PM Talaromycosis is an infection caused by the thermally dimorphic fungus Talaromyces marneffei (T. marneffei). It is endemic in tropical countries of Asia and Southeast Asia and has recently been recognized far beyond the traditional endemic areas. Talaromycosis was thought to be exclusively associated with HIV infection. However, an increasing number of T. marneffei infections have been reported in non-HIV-infected patients. Although the incidence of talaromycosis in non-HIV-infected patients is ˂ 10%, the atypical presentation of this disease can lead to misdiagnosis, inappropriate treatment, and poor outcomes, in addition to tremendous burden and suffering for patients and their families. Screening for immunodeficiencies in patients with talaromycosis is crucial in clinically suspicious cases. Our cohort studies identified three major immunodeficiencies in non-HIV patients with talaromycosis: (1) 85.9% anti-interferon-γ autoantibodies, (2) primary immunodeficiency disorders, and (3) tumors. In disseminated talaromycosis, most patients present with fever, anemia, weight loss, respiratory symptoms, hepatosplenomegaly, lymphadenopathy, and osteolytic destruction and are often misdiagnosed as tuberculosis and other diseases. Localized talaromycosis, on the other hand, is usually manifested by ulcers or masses in the mouth, throat, and external genitalia. Although antigen screening is an effective approach for diagnosing talaromycosis in patients with advanced HIV disease, pathogen-based detection is still limited by atypical clinical presentation. Direct microscopic examination, mycological culture, and histopathology are the standard traditional diagnostic methods used to isolate T. marneffei from clinical specimens, however, due to time-consuming, it might lead to delay diagnosis. Metagenomic next-generation sequencing (mNGS) technology has shown promising results as a rapid, convenient method for detecting T. marneffei from various types of specimens, leading to correct diagnosis and appropriate treatment. Based on our current retrospective study, mNGS has been shown to be equivalent and possibly superior to conventional fungal culture in terms of speed and specificity in the diagnosis of talaromycosis. In terms of final clinical diagnosis, mNGS showed a high sensitivity of 97.22% compared with conventional culture (61.11%). Correction of underlying immunodeficiencies and early use of antifungal agents are important treatment strategies for talaromycosis. Currently, there is no optimal therapeutic regimen for the treatment of talaromycosis in this specific group of patients. Amphotericin B is the first line to initial antifungal treatment, other antifungal agents such as voriconazole have shown good efficacy against talaromycosis. We investigated the efficacy of voriconazole in the treatment of talaromycosis using population pharmacokinetics. C-reactive protein (CRP) was found to significantly affect voriconazole plasma concentrations. Optimization of initial dosing based on CRP levels may be useful to guide voriconazole dosing in clinical practice. The mortality rate in non-HIV talaromycosis is higher than in the HIV population, which may be due to the nonspecific and complex clinical manifestations. Failure to initiate antifungal treatment in a timely manner often results in poor prognosis and even death. The course of treatment is protracted, unclear, and depends on the immune status of the patient. Diagnosis and treatment of talaromycosis remain a challenge. Optimization of diagnostic tools and treatment regimens to ensure early detection and prompt antifungal treatment should be considered.

Treatment Practices for Adults With Candidemia at 9 Active Surveillance Sites-United States, 2017-2018.

Candidemia is a common opportunistic infection causing substantial morbidity and mortality. Because of an increasing proportion of non-albicans Candida species and rising antifungal drug resistance, the Infectious Diseases Society of America (IDSA) changed treatment guidelines in 2016 to recommend echinocandins over fluconazole as first-line treatment for adults with candidemia. We describe candidemia treatment practices and adherence to the updated guidelines. During 2017-2018, the Emerging Infections Program conducted active population-based candidemia surveillance at 9 US sites using a standardized case definition. We assessed factors associated with initial antifungal treatment for the first candidemia case among adults using multivariable logistic regression models. To identify instances of potentially inappropriate treatment, we compared the first antifungal drug received with species and antifungal susceptibility testing (AFST) results from initial blood cultures. Among 1835 patients who received antifungal treatment, 1258 (68.6%) received an echinocandin and 543 (29.6%) received fluconazole as initial treatment. Cirrhosis (adjusted odds ratio = 2.06; 95% confidence interval, 1.29-3.29) was the only underlying medical condition significantly associated with initial receipt of an echinocandin (versus fluconazole). More than one-half (n = 304, 56.0%) of patients initially treated with fluconazole grew a non-albicans species. Among 265 patients initially treated with fluconazole and with fluconazole AFST results, 28 (10.6%) had a fluconazole-resistant isolate. A substantial proportion of patients with candidemia were initially treated with fluconazole, resulting in potentially inappropriate treatment for those involving non-albicans or fluconazole-resistant species. Reasons for nonadherence to IDSA guidelines should be evaluated, and clinician education is needed.

Clinical Characteristics, Histopathology, and Treatment Outcomes of Pythium Keratitis: A Retrospective Cohort Study.

PurposeTo identify factors associated with the prognosis in Pythium keratitis.Patients and MethodsThe medical records of 25 patients (26 eyes) diagnosed with Pythium keratitis at a referral institution were reviewed. The demographic and clinical characteristics, treatment, microbiological diagnosis, histopathological features, and outcomes were recorded. The histopathological specimens were reviewed. The patients were divided into a globe removal group and a globe salvage group. Univariate analysis was used to identify factors associated with poor outcomes.ResultsFifteen eyes (57.7%) were removed. Patients in the globe removal group were on average 16.4 years older (95% CI 6.98 to 25.88) than those in the globe salvage group, received the first medication (either topical antifungals or antibiotics) later than one day after the onset of symptoms (RR = 2.75, 95% CI 1.18 to 6.42), and had a maximal diameter of the infiltration area ≥6 mm (RR = 3.14, 95% CI 1.17 to 8.45). The globe removal group showed satellite, multifocal, or total corneal infiltration patterns (RR = 2.82, 95% CI 1.03 to 7.74) and a hypopyon (RR = 3.43, 95% CI 1.26 to 9.35) as risk factors. The histopathological examination showed a higher density of Pythium in the globe removal group than the globe salvage group (median 376 (interquartile range 323, 620) versus 107 (interquartile range 16, 260) hyphae per high power field; P = 0.035).ConclusionThe risk of globe removal in patients with Pythium keratitis increased with age, delayed initial topical antifungal or antibiotic treatment, advanced disease at presentation, and dense Pythium hyphae infiltration of the cornea. Early recognition and treatment are critical to successfully eradicate the infection.

Combination of Sequential Organ Failure Assessment (SOFA) score and Charlson Comorbidity Index (CCI) could predict the severity and prognosis of candidemia more accurately than the Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) score

BackgroundCandidemia has emerged as an important nosocomial infection, with a mortality rate of 30–50%. It is the fourth most common nosocomial bloodstream infection (BSI) in the United States and the seventh most common nosocomial BSI in Europe and Japan. The aim of this study was to assess the performance of the Sequential Organ Failure Assessment (SOFA) score for determining the severity and prognosis of candidemia.MethodsWe performed a retrospective study of patients admitted to hospital with candidemia between September 2014 and May 2018. The severity of candidemia was evaluated using the SOFA score and the Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) score. Patients’ underlying diseases were assessed by the Charlson Comorbidity Index (CCI).ResultsOf 70 patients enrolled, 41 (59%) were males, and 29 (41%) were females. Their median age was 73 years (range: 36–93 years). The most common infection site was catheter-related bloodstream infection (n=36, 51%).The 30-day, and in-hospital mortality rates were 36 and 43%, respectively.Univariate analysis showed that SOFA score ≥5, APACHE II score ≥13, initial antifungal treatment with echinocandin, albumin < 2.3, C-reactive protein > 6, disturbance of consciousness, and CCI ≥3 were related with 30-day mortality. Of these 7, multivariate analysis showed that the combination of SOFA score ≥5 and CCI ≥3 was the best independent prognostic indicator for 30-day and in-hospital mortality.ConclusionsThe combined SOFA score and CCI was a better predictor of the 30-day mortality and in-hospital mortality than the APACHE II score alone.

Adherence to National Consensus Guidelines and Association with Clinical Outcomes in Patients with Candidemia.

Background:National consensus guidelines outline recommendations for best practices in treating patients with candidemia. This study evaluated the impact of receiving care adherent to the best practice recommendations on clinical outcomes in patients with candidemia.Methods:This retrospective, multicenter study included patients with candidemia from 2010 to 2015 at 9 hospitals. The primary outcome was the composite of 30-day in-hospital mortality and 90-day candidemia recurrence. Outcomes were compared between those receiving and not receiving care adherent to the guideline recommendations. Inverse probability weights with regression adjustment were utilized to determine the average treatment effect of adherent care on the composite outcomeResults:295 patients were included with 14.2% meeting criteria for the composite outcome (11.9% mortality and 2.4% recurrence). The average treatment effect of adherent care was not significant (P = .75). However, receiving appropriate initial antifungal treatment and central venous catheter removal were both associated with the composite (average treatment effect of −17.5%, P = .011 and −8.8%, P = .013, respectively). In patients with a source of infection other than the central line, central venous catheter removal was not associated with the composite (P = .95). The most common reason for failure to receive appropriate initial antifungal treatment was omission of the loading dose.Conclusions:Central venous catheter removal and appropriate initial antifungal treatment were associated with a lower incidence of the composite of mortality and recurrence. Additional studies are needed to determine the optimal duration of therapy following candidemia clearance.

1156. Clinical and epidemiological features and outcomes of Blastomycosis in a tertiary hospital in Kentucky

BackgroundBlastomycosis is an endemic dimorphic fungal infection caused by Blastomyces dermatitidis. The risk factors associated with severe presentation are not well defined.MethodsRetrospective study of patients treated for blastomycosis at the University of Kentucky Hospital from 2004-2019. Statistical analyses were performed with STATA version 12.0 (College Station, Texas). Logistic regression was used to identify variables associated with severe infections.ResultsAmong 82 patients, median age was 48 years old (range: 16 - 89); 66 (80.5%) were male and 71 (92.2%) were white, 25/77 (32.4%) were obese, 24 (29.2%) were diabetic, 21 (25.6%) had COPD, 26 (31.7%) had at least one immunosuppressive condition. The median duration of illness was 86 (3-365) days. 37 (45.1%) had cough and 35 (42.6%) had dyspnea 19 (23.1%) patients were treated in the ICU, 42 (51.3%) in non-ICU inpatient wards, and 21 (25.6%) in an outpatient setting. Cultures were obtained in 69 cases, 59 (85.5%) reported as positive, KOH stain positive in 30/61 (49.1%). Histopathology was positive in 48/66 (72.7%) samples. Urine Histoplasma or Blastomyces antigen was positive in 41/58 (70.6%), and Serum Histoplasma or Blastomyces antigen was positive in 22/34 (64.7%). Among 64 (78.0%) patients with pulmonary blastomycosis, acute and chronic pneumonia were 16 (25.0%) and 12 (18.7%) cases respectively, and nodular lung lesions were reported in 36 (56.2%). Initial antifungal treatment was amphotericin B liposomal in 38/80 (47.5%), overall mortality was 11 (13.4%). A multivariable analysis was performed to find predictors of severe blastomycosis infection, no association was seen with factors as male sex (IRR 1.96; 95%CI 0.84 – 4.55), and was confirmed that significant independent associated risk factors for severe infection were age older than 50 (IRR 3.5; 95%CI 1.42-8.83), obesity (IRR 3.1; 95% CI 1.41-6.87), diabetes (IRR 2.5; 95% CI 1.16-5.50), leukocytosis (IRR 1.03; 95%CI 1.00-1.07) and anemia (IRR 3.0; 95% CI 1.55-5.85).ConclusionPulmonary Blastomycosis is the most common presentation. Culture and histopathology are more sensitive than antigen assay. Independent factors associated to severe disease were older age, obesity, diabetes, and anemia at admission.Disclosures All Authors: No reported disclosures

Mucormycosis in Hematopoietic Cell Transplant Recipients and in Patients With Hematological Malignancies in the Era of New Antifungal Agents.

BackgroundThe survival benefit of combination antifungal therapy for invasive mucormycosis (IM) in patients with hematologic malignancy (HM) and hematopoietic cell transplant (HCT) is not well defined.MethodsThis multicenter, retrospective study included HM and HCT recipients with proven or probable IM between January 1, 2007 and December 31, 2017 from 10 transplant centers across North America.ResultsSixty-four patients with proven (n = 47) or probable (n = 17) IM defined by 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) consensus definitions were included. Thirty-nine (61%) were HCT recipients (95% allogeneic). Sites of infection included rhino-orbital-cerebral (33), pulmonary (30%), disseminated (19%), gastrointestinal (3%), and cutaneous (3%). Surgical debridement was performed in 66%. Initial antifungal treatment consisted of the following: lipid formulation of amphotericin B (AmB) alone (44%), AmB + posaconazole (25%), AmB + echinocandin (13%), AmB + isavuconazole (8%), posaconazole alone (5%), and isavuconazole alone (3%). All-cause mortality at 30 days and 1 year were 38% and 66%, respectively. Initial treatment with AmB plus posaconazole or isavuconazole (n = 28) was associated with a trend toward lower treatment failure compared with AmB (n = 21) (42% vs 64%, P = .136).ConclusionsLong-term survival with IM among HM and HCT populations remains poor. However, initial use of AmB + azole in conjunction with surgery may result in less treatment failure. More evidence from prospective controlled studies is needed to confirm this observation.

Esophageal Parakeratosis: Not All White Plaques Are Candida

Endoscopic appearance and clinical significance of esophageal parakeratosis have not been well described. We report a case of esophageal parakeratosis which presented as whitish plaques mimicking candidiasis. A 67-year-old male presented to our clinic for evaluation of progressive solid food dysphagia of one-month duration. His medical history was significant for active tobacco use, congestive heart failure and coronary artery disease. Physical examination of mouth, oropharynx and head and neck region did not disclose any abnormal findings. Upper endoscopy showed friable mid to distal esophageal mucosa. Biopsies showed severe active fungal esophagitis consistent with candida species. PAS-D stain was also positive for fungal organisms. Patient was prescribed fluconazole 400mg loading dose followed by 200mg daily for 2 weeks. A repeat upper endoscopy in 4 weeks again showed diffuse white plaques in mid and distal esophagus (Figure 1). Mucosal biopsies were obtained and patient was prescribed voriconazole for suspected resistant candida species. Interestingly the microscopic examination showed hyperplastic squamous epithelium with marked parakeratosis. PAS-D stain was negative for fungus. Antifungal treatment was discontinued and a repeat upper endoscopy in 4 weeks showed similar whitish plaques throughout mid to distal esophagus consistent with parakeratosis. Patient's dysphagia resolved after initial antifungal treatment and was discharged from clinic. Endoscopic findings of esophageal parakeratosis have not been well described. It can present as linear plaques, mucosal thickenings with rings and furrows or as a discrete flat elevated lesion. These findings can easily mimic endoscopic appearance of eosinophilic esophagitis, candida esophagitis and even neoplastic lesions like squamous cell cancer or dysplasia. Parakeratosis had been found to be associated with alcoholic cirrhosis, tylosis and zinc deficiency. In one reported case series involving 100 esophagectomies for esophageal cancer, parakeratosis was present in non-cancerous portion of mucosa in 90% of the specimens. However, there are no reports of progression of parakeratosis to dysplasia or cancer. We could not find any recommendations in literature regarding treatment or surveillance of this condition. Our case highlights the importance of considering all the possible differential diagnosis for whitish plaques in esophagus before resorting to prolonged courses of antifungal drugs.1740 Figure 1. Whitish Plaques of parakeratosis

Challenges in the diagnosis and treatment of mucormycosis.

The diagnosis and treatment of mucormycosis are challenging. The incidence of the disease seems to be increasing. Hematological malignancies are the most common underlying disease in countries with high income and uncontrolled diabetes in developing countries. Clinical approach to diagnosis lacks sensitivity and specificity. Radiologically, multiple (≥10) nodules and pleural effusion are reportedly associated with pulmonary mucormycosis. Another finding on computerized tomography (CT) scan, which seems to indicate the presence of mucormycosis, is the reverse halo sign. Microscopy (direct and on histopathology) and culture are the cornerstones of diagnosis. Molecular assays can be used either for detection or identification of mucormycetes, and they can be recommended as valuable add-on tools that complement conventional diagnostic procedures. Successful management of mucormycosis is based on a multimodal approach, including reversal or discontinuation of underlying predisposing factors, early administration of active antifungal agents at optimal doses, complete removal of all infected tissues, and use of various adjunctive therapies. Our armamentarium of antifungals is slightly enriched by the addition of two newer azoles (posaconazole and isavuconazole) to liposomal amphotericin B, which remains the drug of choice for the initial antifungal treatment, according to the recently published guidelines by ECIL-6, as well as those published by ECMM/ESCMID. Despite the efforts for better understanding of the pathogenesis, early diagnosis and aggressive treatment of mucormycosis, the mortality rate of the disease remains high.

Pharmacoeconomic evaluation of micafungin versus caspofungin as definitive therapy for candidaemia and invasive candidiasis (IC) in Turkey

Micafungin was shown to be as efficacious as caspofungin in treating patients with candidaemia and invasive candidiasis (IC). However, it remains unknown if micafungin or caspofungin is a cost-effective definitive therapy for candidaemia and IC in Turkey. The present study aimed to determine the economic impact of using micafungin versus caspofungin for treatment of candidaemia and IC in the Turkish setting. A decision analytic model was constructed and was populated with data (i.e. transition probabilities, duration of initial antifungal treatment, reasons for treatment failure, percentage of patients who stepped down to oral fluconazole, and duration on oral fluconazole) obtained from a published randomised clinical trial. Cost inputs were derived from the latest Turkish resources while data that were not readily available in the literature were estimated by expert panels. One-way sensitivity analyses, threshold analyses, scenario analyses and probabilistic sensitivity analyses were conducted. Caspofungin (€2693) incurred a lower total cost than micafungin (€4422), with a net cost saving of €1729 per treated patient. Drug acquisition cost was the main cost driver for both study arms. The model outcome was robust over wide variations (of ±100.0% from the base case value) for all input parameters except for micafungin drug cost and the duration of initial treatment with micafungin. Caspofungin appears to be a cost-saving option in treating candidaemia and IC from the Turkish hospital perspective.

Fontana-Masson stain in fungal infections

Fontana-Masson (FM) staining is a histopathology technique used to identify dematiaceous fungi. The result often guides initial species identification and antifungal treatment; however, there is evidence that nondematiaceous fungi might react with this stain. Few studies in the current literature address this issue. Our aim was to classify the FM staining patterns of common fungal pathogens for use by pathologists attempting to accurately identify fungi on histopathologic examination. In total, 132 cases of culture proven mycoses were identified. We stained tissue with 2 different FM protocols and recorded the intensity and distribution of results. There was variability in staining, and many nondematiaceous fungi showed positivity, including Zygomycetes, Aspergillus, and Fusarium spp. The study was limited by the number of cases. Of 132 cases identified, 112 cases had adequate tissue left after sectioning deeper into the block. Nondematiaceous fungi frequently stained positive with FM. The course of treatment should not be based on the result of this stain alone. Histopathology should be examined in multiple tissue sections, and therapy should be determined on the basis of clinical context and culture results.

Administration of Voriconazole in Disseminated Talaromyces (Penicillium) Marneffei Infection: A Retrospective Study.

Talaromyces (Penicillium) marneffei infection is a fatal disseminated mycosis caused by the dimorphic fungus Talaromyces marneffei; the therapeutic strategies for this infectious disease are limited. The aim of this retrospective study was to evaluate the efficacy and safety of voriconazole for treating patients with disseminated T. marneffei infection with or without HIV infection in a clinical setting. Patients who intravenously received voriconazole (6mg/kg q12h for the first 24h followed by 4mg/kg q12h) as the initial antifungal treatment were enrolled. The duration of the following antifungal treatment varied at the discretion of the investigators according to the patient responses. The primary global response was evaluated at Week 16 or at the end of treatment (EOT). Follow-up evaluations were performed at 6months and 1year after the EOT. Seventeen patients were enrolled in this study, but three were not evaluable because the treatment was prematurely discontinued. Among the remaining fourteen patients, ten patients had complete response and three had partial response at Week 16. Only one patient was determined to have failed response. Follow-up assessments in eleven patients showed that eight patients were cured and the remaining three patients relapsed at 6months after the EOT. These eight patients were assessed 1year later, and none of them had relapsed. No adverse events associated with voriconazole were recorded during the treatment. The results from our study suggest that voriconazole is an effective, well-tolerated therapeutic option for disseminated T. marneffei infection.

Evaluation of PNA-FISH method for direct identification of Candida species in blood culture samples and its potential impact on guidance of antifungal therapy

Early antifungal therapy has a major influence on survival in candidemia. Rapid identification of the species has importance for the treatment, prediction of the species-specific primary resistance and variable antifungal susceptibility. Recently, molecular-based methods attempt to reduce the time between the positive signal of a blood culture and identification of the fungus. PNA-FISH (Peptide nucleic acid fluorescence in situ hybridization) assay distinguishes a number of frequently isolated Candida species in groups following the growth in blood culture. The aim of this study was to investigate the correlation of the species identified by PNA-FISH with conventional identification methods in yeast positive blood cultures and its influence on the selection of antifungal therapy. Specimens of adult patients diagnosed as yeast with Gram stain in signal-positive blood cultures between August to December 2013, were included in the study. The strains were concomitantly cultivated by subculturing from the blood culture bottles onto solid media and identified by conventional methods (germ tube test, ID32C and morphology on cornmeal Tween 80 agar). Rapid species identification was performed by Yeast Traffic Light PNA-FISH, which generates green flourescence for Candida albicans and Candida parapsilosis, yellow for Candida tropicalis, and red for Candida krusei and Candida glabrata. C.tropicalis was identified as a single species whereas the others were identified in pairs. The time points when the yeast positive blood culture bottle was received by the mycology laboratory and reporting of the species identification results by PNA-FISH and the conventional methods were recorded. Seven C.albicans, six C.glabrata, three C.parapsilosis, one C.tropicalis, one C.krusei, one Cryptococcus neoformans, one Saprochaete capitata (Blastoschizomyces capitatus), one C.albicans and Candida dubliniensis, one C.krusei and C.dubliniensis, and one C.glabrata and C.parapsilosis were identified by conventional methods in 23 specimens. Results of PNA-FISH and conventional methods were in full agreement in 19 of the 23 specimens (82.6%). Two specimens were negative by PNA-FISH and yielded S.capitata and C.neoformans which were not included in the test panel. In three specimens that were infected with multiple species, PNA-FISH detected only one of the species. On the other hand and in one specimen, PNA-FISH detected a second species (C.glabrata or C.krusei) that could not be isolated and identified conventionally. Species identification were obtained 72 hours (mean) earlier with PNA-FISH. PNA-FISH provided accurate species identification that were consistent with conventional methods. However and expectedly, it failed to detect species that were not included in the test panel. During the study period, 13 of the 23 patients have passed away. Apart from six patients died prior to blood culture positivity and the one that could not get any antifungal therapy during hospital stay, 16 patients received antifungal treatment. Of sixteen patients who received antifungal therapy, initial antifungal treatment was fluconazole for five and echinocandin for 10 patients. Fluconazole and amphotericin B combination was preferred for one patient. In this study, PNA-FISH result had an influence on the modification of the antifungal treatment of only for one patient in accordance with the clinical findings. We conclude that the utility of PNA-FISH method appeared to be limited in our center since the assay cannot differentiate C.albicans and C.parapsilosis, the two commonly isolated species among our candidemia isolates. However, advantages of the assay might be more pronounced for the centers where C.glabrata is a relatively more frequent species.