Triazole Therapy Research Articles

Outcomes in hematopoetic cell transplantation in the setting of mold infections in patients with chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a disorder of immunity characterized by phagocyte dysfunction. Mold infections in patients with CGD are often severe and disseminated. We present patient characteristics, microbiological data, and outcomes for 26 patients with CGD who received hematopoietic cell transplantation (HCT) or gene therapy-modified cells (GT) between 2008 and 2019, with proven fungal infection either before or during their transplant. All patients engrafted, and all but one GT recipient had neutrophil recovery and evidence of functional correction. Eighteen patients (69%) are currently alive and 19 patients (73% of total, 90% of patients with repeat imaging performed) had evidence of radiographic improvement. With 3 exceptions, deaths were not principally related to the fungal infection and duration of antecedent infection did not correlate with death. Aspergillus species accounted for the majority of disease (50%), followed by Phellinus species (18%). Osteomyelitis and disseminated disease were common, as only 11 patients (42%) had disease restricted to pneumonia. Triazole therapy was used in all 26 patients, with combination therapy used in 25 (96%). HCT or gene therapy, with appropriate antifungal therapy, are viable therapies for refractory fungal infections in patients with CGD.

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

Successful Treatment of Paecilomyces variotii Pneumonia and Lupus Nephritis With Posaconazole-Cyclophosphamide Co-administration Without Drug Interaction–Induced Toxicity

Abstract Paecilomyces variotii is an opportunistic mold that causes pulmonary infections in immunosuppressed humans that are often treated with triazole therapy. Lupus nephritis is a major cause of progressive kidney disease in patients with systemic lupus erythematosus, often requiring cyclophosphamide-based therapies. Triazole-cyclophosphamide co-administration is challenging as triazoles increase cyclophosphamide concentrations, which can worsen cyclophosphamide toxicity. We describe herein a patient with Paecilomyces variotii pneumonia and concomitant lupus nephritis who was successfully treated with posaconazole and echinocandin-bridged interruptions to allow for cyclophosphamide therapy. This regimen was well-tolerated without cyclophosphamide toxicity and achieved improvements in both fungal pneumonia and renal function.

Cerebral phaeohyphomycosis at a tertiary healthcare center in Saudi Arabia

To report cases of cerebral phaeohyphomycosis at a tertiary hospital in Riyadh, Saudi Arabia. Phaeohyphomycetes are a widely distributed group of fungi whose cell walls contain 1,8 dihydroxynaphthalene-melanin. Cerebral infections caused by these fungi are uncommon and primarily associated with neurotrophic phaeohyphomycetes. In January of 2020 we looked back to identify cases of culture-positive cerebral phaeohyphomycosis from our medical records at King Faisal Specialist Hospital and Research Center in Riyadh, Saudi Arabia. Data on demographics, potential risk factors, clinical presentation, treatment, and outcomes were analyzed. Twelve cases of cerebral phaeohyphomycosis were identified, of which 4 were caused by Rhinocladiella mackenziei and the other 8 were caused by various phaeohyphomycetes. There were 2 cases caused by Neoscytalidium dimidiatum, and one case each caused by the following: Acrophialophora fusispora, Chaetomium atrobrunneum, Exophiala dermatitidis, Exerohilum rostratum, Fonsecaea pedrosoi, and Cladophialophora bantiana. Most patients (10 of 12) had underlying immunosuppression. R. mackenziei caused a brain-only infection manifesting as abscess formation. Four patients survived for more than a year after therapy. Surgical evacuation and triazole therapy with posaconazole or itraconazole, alone or in combination with other antifungal agents, were associated with success. Cerebral phaeohyphomycosis is an uncommon fungal infection that primarily affects immunocompromised patients and is associated with poor prognosis. R. mackenziei is the most prevalent fungus in our facility and has been linked to a universal mortality.

Effect of Isavuconazonium Sulfate and Posaconazole Delayed Release Tablets on Tacrolimus Dose-to-Concentration Ratios.

Limited evidence exists on the effect of isavuconazonium sulfate and posaconazole delayed release tablets on tacrolimus dose-to-concentration ratios in lung transplant recipients. The purpose of this evaluation was to assess the impact of novel triazoles on tacrolimus dose-to-concentration ratios. This retrospective review included lung transplant recipient ≥18 years of age from January 1, 2017 to October 1, 2020 who received either posaconazole delayed release tablets or isavuconazonium sulfate for. A paired analysis evaluated outcomes pre-triazole and post-triazole initiation. Forty-one patients met evaluation criteria for inclusion. A total of 34 of 41 patients received posaconazole delayed release tablets. Of these patients, 22 of 34 were transitioned from previous triazole to posaconazole delayed release tablets and experienced a 47% reduction in tacrolimus dose-to-concentration ratio. Twelve patients were newly initiated on posaconazole delayed release tablets and experienced a 50% reduction in tacrolimus dose-to-concentration ratios. Although not statistically significant, a 30% reduction in tacrolimus dose-to-concentration ratio was observed when transitioning to isavuconazonium sulfate from previous triazole therapy. Limited data exists to provide guidance on tacrolimus dose adjustments with initiation and conversion of novel triazoles, however, this evaluation provides more knowledge on the drug interaction with novel triazoles and tacrolimus.

P435 Evaluation of remote triazole capillary blood testing to facilitate remote therapeutic drug monitoring (TDM): A validation study

Poster session 3, September 23, 2022, 12:30 PM - 1:30 PMBackgroundThe advent of COVID-19 has meant that patients with chronic diseases needed to shield, however, investigations were needed to guide continual management of their disease. Remote monitoring options were evaluated to ensure the standard of care is not compromised.Purpose and HypothesisThe aim was to validate remote (return-posted) capillary triazole blood testing and evaluate the potential role of remote TDM in chronic antifungal therapy.Materials and MethodsA single-center prospective cross-sectional study of remote finger prick capillary blood testing compared with gold standard venesection was performed. Remote finger prick capillary blood testing was validated compared to local standard venesection using comparative statistical analysis Comparative statistical analysis: Paired t-test, correlation and Bland-Altman were used to determine if there was agreement or association between the sampling methods.ResultsA total of 66 patients receiving triazole therapy were recruited and 57 pooled pairs of remote capillary and venous triazole concentrations and metabolites were prospectively analyzed, with the rest of the blood samples not being analyzed due to insufficient sample, hemolysis, or undetectable triazole level of <0.2 mg/l. There was a significant difference in the comparison of the two methods of sampling with paired t-test at P <.0001. Bland-Altman analysis yielded wide bias (−49.07%) and wide limits of agreement (−85.5% to −12.64%). On average capillary triazole, concentrations were 37% lower than venous concentrations (Fig. 1). There was however a very strong correlation between capillary and venous tests (Pearson's correlation coefficient r = 0.9219, P <.0001, Fig. 2).ConclusionsRemote capillary triazole sampling does not appear interchangeable with venous sampling, but being strongly correlated and on average 2/3rd of the venous value, could be a predictor of venous triazole level, or be useful for intra-patient longitudinal monitoring. When incorporated into an outpatient clinical pathway it can improve shared decision-making and patient experience. Further research is required to determine appropriate target reference ranges if the new lower capillary levels can be used routinely, especially in the climate of COVID-19 where social distancing measures limit patient access to hospitals and clinics for routine investigations.

Triazole antifungal use for prophylaxis and treatment of invasive fungal diseases for patients receiving gilteritinib

Gilteritinib is primarily metabolized via cytochrome P450 (CYP). Therefore, concomitant administration of strong CYP3A4 inducers or inhibitors is not recommended. We evaluated the incidence of gilteritinib-related adverse events (AEs) in 47 patients who received gilteritinib with or without antifungal triazoles which are known inhibitors of CYP3A4. Reasons for coadministration were antifungal prophylaxis or treatment of suspected or confirmed fungal diseases. Gilteritinib-related AEs were similar in the gilteritinib-triazole group compared to the gilteritinib without triazole group (75 % vs. 55.5 %, P = 0.23). Additionally, severity of AEs, gilteritinib dose reductions (15 % vs. 14.8 %) or discontinuation due to AEs (10 % vs. 22.2 %), and 90-day mortality (35 % vs. 11.1 %) were similar in both groups. Thus, concomitant gilteritinib and triazole therapy is feasible and is not associated with clinically meaningful increase in gilteritinib-related AEs.

Enteral Delivery of Posaconazole or Izavuconazole in Patients with Inability to Swallow Tablets Can Achieve Therapeutic Drug Levels: A Single Center Pilot Study

<h3>Purpose</h3> One of the most common challenges facing the transplant population are invasive fungal infections including aspergillosis, mucormycosis, and those due to endemic fungi. Fungal prophylaxis is becoming standard of practice to limit development of invasive fungal infections. Isavuconazole and posaconazole are commonly used antifungal medications as both prophylaxis and treatment. These drugs are approved for oral and intravenous (IV) administration however, use via alternative enteric routes have not been well studied. <h3>Methods</h3> A retrospective chart review was conducted of transplant patients receiving triazole therapy for prophylaxis or treatment over a seven month period. Patients with an inability to swallow oral medications switched during their course of care from IV therapy to non-oral enteric administration of isavuconazole or posaconazole via nasogastric, orogastric, percutaneous endoscopic gastrostomy (PEG), or percutaneous endoscopic gastrojejunostomy (PEG-J) tubes were included in the study. <h3>Results</h3> We identified 17 patients administered isavuconazole or posaconazole via non-oral enteric routes (Table 1). The indication for therapy was primarily for prophylaxis after single or double lung transplantation. The majority (83%) of cases were therapeutic at the time of their first drug level assessment, with a mean level of 2.47 +/- 0.71 for isavuconazole and 0.84 +/- 1.03 for posaconazole. All patients not therapeutic at initial assessment had doses increased and subsequently achieved therapeutic levels. <h3>Conclusion</h3> Our case series shows isavuconazole and posaconazole can be administered via non-oral enteric routes with therapeutic drug monitoring to achieve acceptable serum drug concentrations and avoid prolonged IV therapy in a transplant population. Given the increasing complexity and age of transplant recipients, continued studies are needed to address alternative antifungal dosing regimens.

Fungal bronchitis is a distinct clinical entity which is responsive to antifungal therapy.

Chronic productive cough in the context of exacerbations of airway disease can be associated with positive sputum cultures for fungi, in particular Aspergillus fumigatus and Candida spp., suggesting fungal bronchitis, a condition not widely recognised, as a possible cause for the exacerbation. Our objective was to determine the response to antifungal therapy in patients with suspected fungal bronchitis. Retrospective analysis of data extracted from case records of patients under secondary care respiratory clinics who had been treated with triazole therapy for suspected fungal bronchitis between 2010–2017. Primary outcome was lung function response after 1 month of treatment. Nineteen patients with fungal bronchitis due to A. fumigatus and 12 patients due to Candida spp., were included in the study. Most of the patients, particularly in the Aspergillus group, had allergic fungal airway disease on a background of asthma. All but one of the patients in each group were recorded as showing clinical improvement with antifungal therapy. In the majority of patients this was reflected in an improvement in lung function. Aspergillus group: FEV1 (1.44 ± 0.8 L vs 1.6 ± 0.8 L: p < 0.02), FVC (2.49 ± 1.08 L vs 2.8 ± 1.1 L: p = 0.01), and PEF (260 ± 150L/min vs 297 ± 194ml/min: p < 0.02). Candida group: FEV1 (1.6 ± 0.76 L vs 2.0 ± 0.72 L: p < 0.004), FVC (2.69 ± 0.91 L vs 3.13 ± 0.7 L: p = 0.05), and PEF (271± 139L/min vs 333 ± 156 L/min: p = 0.01). Side effects of treatment were common, but resolved on stopping treatment. This service improvement project supports the idea that fungal bronchitis is a distinct clinical entity which is responsive to treatment. Controlled clinical trials to confirm the clinical impression that this is relatively common and treatable complication of complex airway disease are required.

A 21-YEAR-OLD MALE WITH A DEADLY COUGH

SESSION TITLE: Medical Student/Resident Critical Care Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Coccidioidomycosis, commonly known as Valley Fever, is caused by Coccidioides immitis/posadasii species endemic to the Southwestern United States. Infection most commonly is asymptomatic, but rarely (1-4.7%) disseminated disease can occur, with mortality as high as 70%. The use of extracorporeal membrane oxygenation (ECMO) has rarely been reported, and never with a duration exceeding 90 days. CASE PRESENTATION: A 21-year-old African American male without significant past medical history, presented with one week history of dyspnea, back pain, and 10 lb weight loss. Chest X-ray showed diffuse bilateral interstitial infiltrates, and the patient was treated for community acquired pneumonia. However, the patient clinically deteriorated. Whole body CT revealed lytic bone lesions (multiple vertebrae, sacral, left scapula, and ribs) with diffuse pulmonary ground-glass and nodular opacities. A rib biopsy diagnosed disseminated coccidioidomycosis. Antifungal therapy was initiated, but the patient continued to worsen and developed acute respiratory distress syndrome (ARDS). He was failing conventional ventilator strategies and was eventually stabilized on ECMO. The patient underwent multiple surgeries to achieve source control. The patient was able to overcome the infectious process, with eventual lung recovery. He was decannulated after 90 days of ECMO and was discharged on life-long triazole therapy. He is currently finishing is college degree. DISCUSSION: Disseminated endemic fungal diseases, although rare, can be devastating. Despite antifungal therapy, our patient failed to improve. This was likely due to the severity of dissemination, particularly his osseous lesions. Surgical debridement is recommended for osseous lesions as antifungal therapy alone is likely to fail. Due to the severity of respiratory involvement, our patient also had to be supported on ECMO, which required continuous systemic anticoagulation to avoid circuit thrombosis. However, he had multiple spinal lesions that required debridement. Need for neurosurgery has previously been considered a relative contraindication to ECMO, however with careful management of anticoagulation these procedures can be done safely with minimal complications. Our patient underwent multiple neurosurgical procedures while on ECMO without significant hemorrhagic complications. CONCLUSIONS: There is a paucity evidence in the literature regarding the use of ECMO as salvage therapy for disseminated endemic fungal infections. Furthermore, surgical intervention has been considered a relative contraindication to ECMO, particularly neurosurgical intervention. Our case shows that not only can ECMO be used as a salvage therapy for ARDS due to disseminated coccidioidomycosis, but surgical interventions with high hemorrhagic risks can be performed with deliberate and strategic anticoagulation planning. Reference #1: Galgiani, J. N. Coccidioidomycosis. West J Med. 1993; 159:153-171. Reference #2: Studemeister, A., Studemeister, L. Brun, F. The role of extracorporeal membrane oxygenation in severe pulmonary coccidioidomycosis. Heart Lung. 2018; 47(3), 261–263. Reference #3: Combes, A., Hajage, D., Capellier, G., et al. Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome. N Engl J Med. 2018; 378:1965–1975. DISCLOSURES: No relevant relationships by Andrew Berglund, source=Web Response No relevant relationships by Thomas Lee, source=Web Response no disclosure on file for Phillip Mason; No relevant relationships by Michael Moulton, source=Web Response No relevant relationships by Whittney Warren, source=Web Response No relevant relationships by Joseph Yabes, source=Web Response

Screening for triazole resistance in clinically significant Aspergillus species; report from Pakistan

BackgroundBurden of aspergillosis is reported to be significant from developing countries including those in South Asia. The estimated burden in Pakistan is also high on the background of tuberculosis and chronic lung diseases. There is concern for management of aspergillosis with the emergence of azole resistant Aspergillus species in neighbouring countries in Central and South Asia.Hence the aim of this study was to screen significant Aspergillus species isolates at the Microbiology Section of Aga Khan Clinical Laboratories, Pakistan, for triazole resistance.MethodsA descriptive cross-sectional study, conducted at the Aga Khan University Laboratories, Karachi, from September 2016–May 2019. One hundred and fourteen, clinically significant Aspergillus isolates [A. fumigatus (38; 33.3%), A. flavus (64; 56.1%), A. niger (9; 7.9%) A. terreus (3; 2.6%)] were included. The clinical spectrum ranged from invasive aspergillosis (IA) (n = 25; 21.9%), chronic pulmonary aspergillosis (CPA) (n = 58; 50.9%), allergic bronchopulmonary aspergillosis (ABPA) (n = 4; 3.5%), severe asthma with fungal sensitization (SAFS) (n = 4; 3.5%), saprophytic tracheobronchial aspergillosis (n = 23; 20.2%). Screening for triazole resistance was performed by antifungal agar screening method. The minimum inhibitory concentration (MIC) of 41 representative isolates were tested and interpreted according to the Clinical and Laboratory Standards Institute broth microdilution method.ResultsAll the isolates were triazole-susceptible on agar screening. MICs of three azole antifungals for 41 tested isolates were found to be ≤1 ml/L; all isolates tested were categorized as triazole-susceptible, including 4 isolates from patients previously on triazole therapy for more than 2 weeks. The minimum inhibitory concentration required to inhibit the growth of 90% organisms (MIC90) of itraconazole, voriconazole and posaconazole of the representative Aspergillus isolates was 1 mg/L, 1 mg/L and 0.5 mg/L, respectively.ConclusionTriazole resistance could not be detected amongst clinical Aspergillus isolates from the South of Pakistan. However, environmental strains remain to be tested for a holistic assessment of the situation. This study will set precedence for future periodic antifungal resistance surveillance in our region on Aspergillus isolates.

Central Nervous System Infections Due to Coccidioidomycosis.

Coccidioidomycosis is a common infection in the western and southwestern United States as well as parts of Mexico and Central and South America and is due to the soil-dwelling fungi Coccidioides. Central nervous system (CNS) infection is an uncommon manifestation that is nearly always fatal if untreated. The presentation is subtle, commonly with headache and decreased mentation. The diagnosis should be considered in patients with these symptoms in association with a positive serum coccidioidal antibody test. The diagnosis can only be established by analysis of cerebrospinal fluid (CSF), which typically demonstrates a lymphocytic pleocytosis, hypoglycorrhachia, elevated protein, and positive CSF coccidioidal antibody. Cultures are infrequently positive but a proprietary coccidioidal antigen test has reasonable sensitivity. Current therapy usually begins with fluconazole at 800 mg daily but other triazole antifungals also have efficacy and are often used if fluconazole fails. Triazole therapy should be lifelong. Intrathecal amphotericin B, the original treatment, is now reserved for those in whom triazoles have failed. There are several distinct complications of CNS coccidioidal infection, the most common of which is hydrocephalus. This is nearly always communicating and requires mechanical shunting in addition to antifungal therapy. Other complications include cerebral vasculitis, brain abscess, and arachnoiditis. Management of these is difficult and not well established.

Risk of Skin Cancers with Long-Term Itraconazole in Lung Transplant Recipients

Purpose The objective of this study was to determine if long term itraconazole use, as antifungal prophylaxis, in lung transplant recipients is an independent risk factor for skin cancer. Methods We retrospectively reviewed patients who received a lung transplant at Mayo Clinic Rochester from 2002 to 2010. The antifungal prophylaxis protocol at our institution is triazole therapy, itraconazole or voriconazole, for a minimum of 3 years. Patients who died within 6 months of initial transplant were excluded. Characteristics to help assess independent risk for the development of cutaneous cancers and type of antifungal prophylaxis were noted. Patients who were exposed to both voriconazole and more than 6 months of itraconazole were analyzed separately. Results We identified 102 patients who underwent lung transplant at Mayo Clinic from 2002 to 2010; 11 patients died within 6 months of transplant and were excluded. Of the remaining 91 patients, 44 received only itraconazole prophylaxis, 10 received only voriconazole prophylaxis, and 37 received both itraconazole and voriconazole. No statistically significant difference between the baseline characteristics of the 3 groups was observed with the exception of race. There was a lower proportion of Caucasians in the voriconazole only group compared with the itraconazole only and combined itraconazole/voriconazole groups (p=0.02). Out of the 91 patients included in the study, 40 (44.0%) were diagnosed with skin cancer post-transplant, and 5 (12.5%) developed aggressive, metastatic cutaneous squamous cell carcinoma. Follow-up time was similar between patients who developed skin cancer (93.0 ± 45.0 months) and those who did not (62.0 ± 49.0 months, p=0.23). No significant difference was found in incidence of skin cancer or rate of metastatic squamous cell carcinoma between patients in the three groups (p=0.65) Duration of itraconazole was greater in patients who developed skin cancer [median 62.5 months (22.7, 87.5) vs 32.0 (18.0, 64.8), p=0.07] despite similar follow-up time. Absolute exposure (i.e. exposed to itraconazole or not) did not appear to correlate with the development of skin cancer post-transplant. Conclusion Prolonged itraconazole exposure when used as a prophylactic agent in lung transplant recipients appears to correlate with the development of skin cancers but further studies are warranted.

Discontinuation of Anti-Fungal Prophylaxis in Lung Transplant Recipients: Why Does It Happen

Purpose The objective of this study was to review the reasons lung transplant recipients discontinue antifungal prophylaxis, as documented by treating physicians. Methods We retrospectively reviewed patients who received a single or double lung transplant at Mayo Clinic Rochester from 2002 to 2010 examining the type of antifungal medication and reasons for discontinuation. Lung transplant recipients at our institution receive triazole therapy, voriconazole or itraconazole, for prevention of invasive fungal infections. Results We identified 102 patients who underwent lung transplant at Mayo Clinic from 2002 to 2010; 11 patients died within 6 months of transplant and were excluded. Of the 91 patients who survived longer than 6 months post lung transplant: 86 received itraconazole, 44 received voriconazole, and 37 received both (Table 1). A significantly higher proportion of patients discontinued voriconazole than itraconazole [31 out of 44 (70.5%) versus 41 out of 86 (47.6%), p=0.01]. Side effects (gastrointestinal intolerance, hepatitis, and fluorosis) were the most common reason for discontinuing voriconazole [20/44 (45.5)] compared to one of the least common reasons itraconazole was discontinued [6/86 (8.4), p Conclusion Itraconazole was discontinued prior to the prophylactic end point significantly less often than voriconazole and appeared to be better tolerated; although, several patients were diagnosed with an invasive fungal infection while on itraconazole prophylaxis.

The validation of VIPcheck™ plates to screen Aspergillus fumigatus isolates for phenotypic resistance to triazole antifungal agents in St. James’s Hospital, Dublin

Triazole resistance is an emerging problem in Aspergillus fumigatus (AF) resulting in failure of azole therapy. Triazole resistant AF is acquired through one of two routes – previous exposure to triazole therapy or an environmental source. In vitro antifungal susceptibility testing (AFST) on all AF strains isolated in a microbiology laboratory would be both labour intensive and impractical. A method to screen for triazole resistance would be more favourable. VIPcheck™ plates provide a simple agar based screening method. Each 4-well plate contains a growth control (GC) well and 3 wells containing itraconazole (4 mg l−1), voriconazole (2 mg l−1) and posaconazole (0.5 mg l−1). Briefly, 25 µl of a 0.5-2 McF suspension AF is inoculated into each well and plates are read after 48 h incubation at 37 °C. Any growth in a triazole containing well is suggestive of resistance. Currently in SJH, AFST is carried out using gradient strips (Liofilchem™) and results are interpreted using EUCAST breakpoints. We validated the VIPcheck™ plates with the intention to include this screening method as part of our AFST for AF isolated from clinical samples. A total of 18 isolates (clinical and environmental) of AF were tested using the VIPcheck™ plates (n=2 wild type, n=18 resistant to ≥1 triazole drug as previously determined by AFST and/or molecular methods). The wild type isolates showed growth only in the GC well while the resistant strains all showed growth in one or more of the triazole containing wells. Our results suggest that the VIPcheck™ plate is a reliable screening method for triazole resistance.

393. Isavuconazole in the Treatment of Coccidioidal Meningitis

BackgroundPatients with coccidioidal meningitis require life-long antifungal therapy and cumulative toxicity from these agents may occur. Isavuconazole is the newest triazole antifungal and has demonstrated a lower toxicity profile than voriconazole and may represent a useful therapy in meningitis, although no data regarding efficacy in coccidioidal meningitis has yet been presented.MethodsWe conducted a retrospective analysis of all coccidioidal meningitis patients treated at our centers. Data abstracted included demographic and clinical information, results of laboratory and radiographic studies, serologic results, and outcomes. Responses to therapy were measured using a previously validated scoring system used in clinical trials of coccidioidal meningitis (MSG Coccidioidomycosis Scoring System).ResultsNine patients met criteria for inclusion. Seven of nine were previously treated with voriconazole and transitioned to isavuconazole following: photodermatitis, five patients; transaminitis and photodermatitis one patient; failure of therapy, one patient. Two other patients failed fluconazole therapy and were transitioned to isavuconazole as salvage therapy. All patients transitioned to isavuconazole had a complete response to therapy five patients; or were deemed partial response (stable disease), four patients.ConclusionIsavuconazole therapy resulted in symptomatic and laboratory improvement in five of nine patients. The remaining patients exhibited clinical resolution of symptoms or continued with stable disease following adverse reactions to prior alternative triazole therapy. Isavuconazole may be a useful addition to the therapeutic choices currently available for coccidioidal meningitis.Disclosures All authors: No reported disclosures.

388. New Observations in Coccidioidomycosis Serology

BackgroundCoccidioidomycosis is associated with a broad spectrum of illness severity, ranging from asymptomatic or self-limited pulmonary infection to life-threatening manifestations of disseminated disease. Current understanding of serologic kinetics and serologic features are largely based on serologic studies from the 1950s before antifungals were widely available. The effects of antifungal therapy on serologic characteristics has not previously been evaluated.MethodsWe retrospectively analyzed chart history and complement fixation titer trends of 434 patients classified by infectious disease physicians as having either uncomplicated pulmonary coccidioidomycosis (UPC) (n = 248), chronic pulmonary coccidioidomycosis (CPC) (n = 64), disseminated coccidioidomycosis not including meningitis (DC) (n = 86), or coccidioidal meningitis (CM) (n = 36). All patients received azole antifungal therapy. Serologic kinetics and features were analyzed and compared between groups.ResultsRoughly 94% of UPC, 61% of CPC, 29% of DC, and 56% of CM patients developed maximum complement fixation titers ≤1:32. Surprisingly, 25.4% of UPC, 6.3% of CPC, 2.3% of DC, and 8.3% of CM patients did not develop a detectable complement fixation titer during the study period (at least 3 years after diagnosis for each patient). The median maximum titer was 1:4 (range <1:2 – 1:512) for UPC, 1:24 (range <1:2 – 1:2,048) for CPC, 1:128 (range <1:2 – 1:4,096) for DC, and 1:32 (range <1:2 – 1:4,096) for CM patients. Few significant differences were observed in the mean time to maximum titer (overall mean 31 days, 95% CI 13–50) and serologic resolution rates (average 3–4 months/dilution reduction). However, 9% of UPC, 36% of CPC, 50% of DC, 52% of CM patients exhibited serologic reactivations (defined as ≥2 dilution titer increase >90 days from initial positive serology). Meanwhile, 15% of UPC, 25% of CPC, 31% of DC, and 25% of CM patients exhibited a serofast phenotype despite antifungal therapy.ConclusionOur findings provide an update to serologic studies performed prior to long-term triazole therapy. An understanding of the serologic features and kinetics for patients with varying forms of coccidioidomycosis receiving antifungal therapy is key to clinical evaluation and therapeutic decision making.Disclosures All authors: No reported disclosures.

Micafungin may be safely administered as outpatient parenteral antimicrobial therapy for chronic pulmonary aspergillosis.

Intravenous micafungin has been reported as a treatment alternative in patients with chronic pulmonary aspergillosis (CPA) where long-term oral triazole therapy is unfeasible. We evaluated the safety and efficacy of micafungin administered via the outpatient parenteral antimicrobial therapy (OPAT) service for the treatment of CPA. We included all CPA patients who received micafungin via OPAT between April 2016 and March 2018. Data on adverse events and line-related complications, and Quality of Life (QoL) scores at the start of micafungin course and 3months later were extracted. Improvements in QoL were defined as an improvement of ≥4 points in at least one modality (symptom, impact, activity, total) in the St George's QoL score. A stable QoL score was defined as a change in score of <4 points in either direction whilst deterioration was defined as an increase of ≥4 points. There were 20 OPAT episodes involving 18 patients with a median duration of micafungin therapy of 21 (range: 4-248) days. Improvement or stability in the symptoms, activity, impact and total score was seen in 14 (78%), 12 (67%), 9 (50%) and 9 (50%) of the patients, respectively. However, half of the patients reported deterioration in the impact domain and total scores. By self-assessment, patients who categorised themselves as "poor" were comparable at the start of OPAT and at 3months (43% vs 50%, McNemar's P=0.7). Adverse events attributable to micafungin were recorded in 3 (14.3%) episodes. Micafungin may be safely administered via an OPAT service. Micafungin therapy was associated with an improvement or stability in QoL scores in at least 50% of the patients across the four domains.

Successful long-term terbinafine therapy in an asthmatic patient with Aspergillus sensitization and bronchiectasis

Severe asthma with fungal sensitization (SAFS) is estimated to affect ~25% of patients with poorly controlled asthma. Tri-azole therapy is effective in only 60–80% and side effects are common. We report a 25 years-old woman with severe asthma, Aspergillus sensitization and marked bronchiectasis that developed a rare Achilles-tendinopathy with both itraconazole and voriconazole. She started a trial with terbinafine as salvage therapy that led to a striking improvement and long-term control of her respiratory disease.

Invasive Scedosporium sternal osteomyelitis following lung transplant: Cured

Scedosporium is an important pathogen in cystic fibrosis (CF) and post-transplant but rarely causes invasive infection. Treatment remains challenging, particularly due to inherent resistance to multiple antifungal agents. We present a young man with CF who developed invasive sternal and rib infection 10-months following lung transplant. The infection has been clinically and radiologically cured with extensive surgery and triazole therapy. This case highlights the importance of adjunctive surgery in addition to prolonged triazole treatment to manage invasive Scedosporium infections in immunosuppressed patients.