Posaconazole Treatment Research Articles

Trichophyton indotineae extensive tinea: Successful posaconazole treatment in four cases from Spain.

Trichophyton indotineae extensive tinea: Successful posaconazole treatment in four cases from Spain.

Management of disseminated histoplasmosis in a high-complexity clinic in Cali, Colombia.

Histoplasmosis presents a substantial clinical challenge globally, with a particular prevalence in South America, especially among patients with concurrent Human Immunodeficiency Virus (HIV) infection. Despite itraconazole's established efficacy, investigating alternative therapeutic approaches remains imperative. This is the largest study in our region to date, assessing the effectiveness of the less explored posaconazole treatment. This observational study, conducted at Fundación Valle del Lili (FVL) from 2016 to 2022, encompassed adults with disseminated histoplasmosis. Patients (n=31) were treated with liposomal amphotericin B as an initial treatment, followed by consolidation treatment with posaconazole or itraconazole. Patients with single-organ cases, those lacking microbiological diagnosis, those who received initial treatment with antifungals other than liposomal Amphotericin B and those with<6 months follow-up were excluded (Figure 1). Analyses considered population characteristics, treatments, and outcomes. Patients (average age: 45.6; 58.1% female) had common comorbidities (HIV 38.7%, solid organ transplantation 29% and oncologic disease 12.9%). Lungs (48.4%) and lymph nodes (16.1%) were commonly affected. Biopsy (64.5%) was the primary diagnostic method. Initial treatment with liposomal amphotericin B (100%) was given for 14 days on average. Follow-up indicated 71% completion with 19.4% requiring treatment modifications. Notably, 70.9% completed a posaconazole consolidation regimen over 350 days on average. Drug interactions during consolidation (80.6%) were common. No relapses occurred, and three deaths unrelated to histoplasmosis were reported. Traditionally, itraconazole has been the prevalent initial treatment; however, in our cohort, 55.9% of patients received posaconazole as the primary option. Encouragingly, posaconazole showed favorable tolerance and infection resolution, suggesting its potential as an effective and well-tolerated alternative for consolidation treatment. This finding prompts further exploration of posaconazole, potentially leading to more effective patient care and better outcomes.

Acquired Triazole Resistance Alters Pathogenicity-Associated Features in Candida auris in an Isolate-Dependent Manner.

Fluconazole resistance is commonly encountered in Candida auris, and the yeast frequently displays resistance to other standard drugs, which severely limits the number of effective therapeutic agents against this emerging pathogen. In this study, we aimed to investigate the effect of acquired azole resistance on the viability, stress response, and virulence of this species. Fluconazole-, posaconazole-, and voriconazole- resistant strains were generated from two susceptible C. auris clinical isolates (0381, 0387) and compared under various conditions. Several evolved strains became pan-azole-resistant, as well as echinocandin-cross-resistant. While being pan-azole-resistant, the 0381-derived posaconazole-evolved strain colonized brain tissue more efficiently than any other strain, suggesting that fitness cost is not necessarily a consequence of resistance development in C. auris. All 0387-derived evolved strains carried a loss of function mutation (R160S) in BCY1, an inhibitor of the PKA pathway. Sequencing data also revealed that posaconazole treatment can result in ERG3 mutation in C. auris. Despite using the same mechanisms to generate the evolved strains, both genotype and phenotype analysis highlighted that the development of resistance was unique for each strain. Our data suggest that C. auris triazole resistance development is a highly complex process, initiated by several pleiotropic factors.

Antifungal Therapeutic Drug Monitoring Practices: Results of an Emerging Infections Network Survey.

In a survey of 523 infectious disease specialists, a moderate to high percentage reported using any antifungal therapeutic drug monitoring (TDM) during itraconazole (72%), posaconazole (72%), and voriconazole (90%) treatment, and a low to moderate percentage reported using any antifungal TDM during prophylaxis (32%, 55%, and 65%, respectively). Long turnaround times for send-out TDM testing and logistical difficulties were frequent barriers.

Cutaneous mucormycosis involving a colostomy site.

Cutaneous mucormycosis is a rapidly advancing fungal infection that most commonly occurs due to airborne spread or direct inoculation and requires early detection and prompt treatment for optimal survival. Major risk factors include diabetes, transplantations, malignancies, surgical procedures, and HIV. Diagnostic criteria are based on microscopy and culture. We present an immunocompromised patient with cutaneous mucormycosis that developed in a peristomal ulcer following a hemicolectomy procedure. Histopathologic evaluation was indicative of mucormycosis. Intravenous posaconazole treatment was initiated, but unfortunately, the patient's condition deteriorated and he passed away.

A Physiologically-Based Pharmacokinetic Model of Ruxolitinib and Posaconazole to Predict CYP3A4-Mediated Drug-Drug Interaction Frequently Observed in Graft versus Host Disease Patients.

Ruxolitinib (RUX) is approved for the treatment of steroid-refractory acute and chronic graft versus host disease (GvHD). It is predominantly metabolized via cytochrome P450 (CYP) 3A4. As patients with GvHD have an increased risk of invasive fungal infections, RUX is frequently combined with posaconazole (POS), a strong CYP3A4 inhibitor. Knowledge of RUX exposure under concomitant POS treatment is scarce and recommendations on dose modifications are inconsistent. A physiologically based pharmacokinetic (PBPK) model was developed to investigate the drug-drug interaction (DDI) between POS and RUX. The predicted RUX exposure was compared to observed concentrations in patients with GvHD in the clinical routine. PBPK models for RUX and POS were independently set up using PK-Sim® Version 11. Plasma concentration-time profiles were described successfully and all predicted area under the curve (AUC) values were within 2-fold of the observed values. The increase in RUX exposure was predicted with a DDI ratio of 1.21 (Cmax) and 1.59 (AUC). Standard dosing in patients with GvHD led to higher RUX exposure than expected, suggesting further dose reduction if combined with POS. The developed model can serve as a starting point for further simulations of the implemented DDI and can be extended to further perpetrators of CYP-mediated PK-DDIs or disease-specific physiological changes.

ODP442 Posaconazole-induced Pseudohyperaldosteronism (PIPH) in Patient Treated for Acute Myeloid Leukemia

Abstract Case summary A 62-year-old Caucasian female presented to our institute with mechanical fall complicated by cervical spine fracture. She had known history of essential hypertension and recently diagnosed acute myeloid leukemia with myelodysplasia related changes (AML-MRC). She had undergone induction chemotherapy with combination of daunorubicin and cytarabine, resulting in chemotherapy induced prolonged pancytopenia. She was initially started on primary prophylaxis with fluconazole, but was switched to voriconazole due to persistent neutropenia. Patient then developed bilateral upper and lower extremity erythematous popular rash on voriconazole. Decision at that time was to switch to Posaconazole 300 mg orally daily. Three months after initiating Posaconazole, patient presented with severe hypokalemia (2.1 mmol/L) and hypertension. Previously her blood pressure was under control with amlodipine, lisinopril and nadolol. Hypokalemia persisted despite aggressive oral and intermittent intravenous potassium replacement therapy. No sources of potassium loss were identified on clinical history. She had persistently elevated blood pressure (systolic blood pressure of 150-180 mmHg) despite being on her home anti-hypertensive regimen. Further work up showed undetectable plasma aldosterone of less than 1 ng/dL (normal &amp;lt; 28 ng/dL) and plasma renin activity level was suppressed to 0.14 ng/mL/h (normal 0.25–5.82 ng/mL/h) with concurrent potassium of 2.9 mmol/L (normal 3.5-5.3 mmol/l). Diagnosis of pseudohyperaldosteronism was made at this time. Posaconazole gradually stopped and eplerenone 25 mg daily was commenced to selectively block mineralocorticoids receptors to control blood pressure. Subsequently hypokalemia resolved after stopping posaconazole and blood pressure normalized with her original home anti-hypertensive regimen. Eplerenone was eventually stopped. Her potassium level and blood pressure remained normal 2 weeks after discharge. Discussion Recent studies have shown the presentation of hypokalemia and hypertension in nearly a quarter of patients on Posaconazole. The clinical presentation of hypokalemia and hypertension with apparent mineralocorticoid excess was evident in our patient and was consistent with posaconazole-induced pseudohyperaldosteronism (PIPH). Posaconazole interference with the steroid synthesis pathway has been described in various literature. Both cortisol and aldosterone activate aldosterone receptors. In the case of posaconazole, excess mineralocorticoid effect is due to relative selectivity of posaconazole for 11ΒHSD2 inhibition. 11ΒHSD2 inhibition causes increased serum cortisol level by preventing the conversion to inactive cortisone. The high cortisol level cross-reacts with the mineralocorticoid receptor leading to apparent mineralocorticoid excess with low serum aldosterone level and low plasma renin activity. The degree of pseudohyperaldosterone effect on systolic blood pressure and hypokalemia has been strongly associated with serum posaconazole level in some studies. Our patient had resolution of uncontrolled hypertension and hypokalemia after withholding the posaconazole and short term treatment with selective mineralocorticoid receptor blocker. Conclusion Early diagnosis and to allow for early intervention with cessation of the offending agent or treatment with mineralocorticoid antagonists, such as spironolactone and eplerenone is necessary in PIPH. Presentation: No date and time listed

P172 First report of Aspergillus tamarii producing influenza associated invasive pulmonary Aspergillosis

Poster session 2, September 22, 2022, 12:30 PM - 1:30 PM ObjectiveMultiple infections can occur after 2009, pandemic influenza, including fungal and bacterial infections, but data from India are limited. To our knowledge, this is the first reported case of influenza-associated invasive pulmonary aspergillosis (IAPA), caused by Aspergillus tamarii, after infection with pandemic (H1N1) 2009 which was preceded by COVID-19, 20 months before.Methods and ResultsA 33-year-old male, known asthmatic, had been hospitalized elsewhere in August 2020 with COVID-19 pneumonia for 50 days and had been on mechanical ventilation for 37 days. He had no residual respiratory symptoms 3 months after recovery from COVID-19. He was admitted to Jupiter Hospital in April 2022 with fever, cough, and dyspnea for 8 days, which developed after a cold bath in a temple. HRCT (chest) showed ground glass opacities (GGOs), crazy paving, nodules, and traction bronchiectasis. Review of previous HRCT showed that only GGOs were present (Fig. 1).At admission, the nasopharyngeal swab was positive for pandemic (H1N1) 2009 in the filmarray respiratory panel and no other pathogen was detected. He was treated with oseltamivir. Expectorated sputum examination showed a heavy load of thin septate hyphae, with acute angle branching, resembling Aspergilllus species (Fig. 2). Serum galactomannan was positive (1.8). Based on these features he was diagnosed as a case of probable IAPA and initiated posaconazole (PCZ) treatment. Sputum fungal culture was positive and was identified by MALDI TOF MS as A. tamarii. A. tamarii has been rarely encountered as a human pathogen. Case reports of its involvement in eyelid infection, keratitis, invasive sinonasal infection, and onychomycosis exist. Sensititre MICs were 0.0625 mcg/ml, 0.125 mcg/ml, 0.0625 mcg/ml, and 0.125 mcg/mL for itraconazole, voriconazole, PCZ, and for isavuconazole (ISVCZ) respectively.The usually obtained PCZ trough level with standard dose is 1.2 mg/l which generates AUC of 200R. The usually obtained ISVC) trough level with standard dose is 3 mg/l which generates AUC of 100R. The PKPD index, AUC/MIC of 100, is needed with both these azoles for a therapeutic effectR. Therefore, it would be possible to treat this infection with any of these azoles.PCZ was continued in view of the easy availability of therapeutic drug monitoring (TDM) to assure adequate drug exposure, lower cost, and clinical improvement which had already occurred.ConclusionAn infection due to a rare Aspergillus species needs correct identification, MIC determination, and PKPD consideration for appropriate drug selection and management.

P317 Phaeohyphomycosis caused by Phialophora verrucosa in a patient with CARD9 mutations

Poster session 2, September 22, 2022, 12:30 PM - 1:30 PMObjectivesTo study an intractable case of phaeohyphomycosis caused by Phialophora verrucosa and the underlying genetic and immunological mechanisms.MethodsClinical and laboratory findings of the patient were studied. The patient's DNA was sequenced for CARD9. Innate and adaptive immunological responses of patient-derived PBMCs were evaluated with ELISA and flow cytometry.ResultsA 29-year-old Chinese male, born to nonconsanguineous parents, developed an enlarging plaque on his right anterior tibia at 25 years and underwent a 15-month treatment of oral itraconazole at the local hospital. Upon discontinuation of the medication, the plaque spread over his face, upper limbs, and back. Physical examination indicated dark brown verrucous plaques and nodules with surface ulcers and scabs on his right leg, upper limbs, and face. Skin biopsy revealed pigmented yeast cells with budding and yeast cell chain in the dermis. Based on tissue culture, we identified P. verrucosa as the causative pathogen, which was further validated by ITS, BT, and TEF gene sequencing. Thus, subcutaneous phaeohyphomycosis was diagnosed, and itraconazole combined with amphotericin B was prescribed. The lesions improved only marginally. We, therefore, gave him oral posaconazole instead, based on in vitro antifungal susceptibility results. After 1 month of posaconazole treatment, the serum BG assay value decreased and the lesions improved markedly.Based on previous reports linking CARD9 deficiency to phaeohyphomycosis, as well as early onset and recalcitrance characters, Sanger sequencing was performed in this patient and identified two compound heterozygous mutations in exon 6 (R373P) and exon 8 (D274GfsX60) of CARD9. We then evaluated the functional effect of the CARD9 mutations by assessing the stimuli-dependent release of proinflammatory cytokines and helper T cell differentiation. Cytokine production was markedly impaired in PBMCs post 24 h of stimulation with LPS, curdlan, TDB, mannan, MDP, β‐glucan, and various fungal ligands. Moreover, the patient showed a significant absence in Th22 and Th17 cell proportions, as well as lower IL-17A and IL-22 production after six days of co-incubation with the stimuli mentioned above.ConclusionOur report highlighted that otherwise healthy patients diagnosed with early-onset, unexplained, and recalcitrant phaeohyphomycosis should be analyzed for CARD9 mutations and immune deficiency. Furthermore, posaconazole may be an alternative worth trying after the failure of other antifungals due to its ideal results achieved in our case.

Effect of posaconazole on the concentration of intravenous and oral cyclosporine in patients undergoing hematopoietic stem cell transplantation.

This study aimed to investigate the interactions between posaconazole (POS) and intravenously/orally administered cyclosporine A (CsA) in allogeneic hematopoietic stem cell transplant (HSCT) recipients. We included 118 allogeneic HSCT patients who received CsA and POS simultaneously between January 2017 and June 2020 in this study. The ratio of CsA blood concentration (ng/mL) to dosage (mg/day) (C/D) before and after POS initiation was compared. After the initiation of POS, the level of CsA increased 1 to 2 times in 66% (78/118) of patients compared to those without POS. However, the CsA C/D ratio increased by more than threefold in 6% (7/118) of patients after POS initiation, with an increase of more than fourfold in two patients. The median C/D ratio of CsA increased from 0.89 to 1.23 (P < 0.001) and 0.78 to 1.22 (P < 0.001) after POS initiation when CsA was administered intravenously and orally, respectively. In patients who received POS at the time of transition from intravenous to oral CsA, the value increased from 1.01 to 1.38 (P = 0.001). The route of administration had no significant effect on the change in the CsA C/D ratio (P = 0.615). Additionally, we observed the time required for the C/D ratio to reach a plateau after POS initiation was similar on days 13, 8, and 15 under various scenarios. POS treatment increased blood CsA levels. A large variability was found in the fold-change in the CsA C/D ratio. Therefore, CsA doses should be adjusted by closely monitoring the blood levels of CsA after POS initiation.

Posaconazole inhibits multiple steps of the alphavirus replication cycle

Repurposing drugs is a promising strategy to identify therapeutic interventions against novel and re-emerging viruses. Posaconazole is an antifungal drug used to treat invasive aspergillosis and candidiasis. Recently, posaconazole and its structural analog, itraconazole were shown to inhibit replication of multiple viruses by modifying intracellular cholesterol homeostasis. Here, we show that posaconazole inhibits replication of the alphaviruses Semliki Forest virus (SFV), Sindbis virus and chikungunya virus with EC50 values ranging from 1.4 μM to 9.5 μM. Posaconazole treatment led to a significant reduction of virus entry in an assay using a temperature-sensitive SFV mutant, but time-of-addition and RNA transfection assays indicated that posaconazole also inhibits post-entry stages of the viral replication cycle. Virus replication in the presence of posaconazole was partially rescued by the addition of exogenous cholesterol. A transferrin uptake assay revealed that posaconazole considerably slowed down cellular endocytosis. A single point mutation in the SFV E2 glycoprotein, H255R, provided partial resistance to posaconazole as well as to methyl-β-cyclodextrin, corroborating the effect of posaconazole on cholesterol and viral entry. Our results indicate that posaconazole inhibits multiple steps of the alphavirus replication cycle and broaden the spectrum of viruses that can be targeted in vitro by posaconazole, which could be further explored as a therapeutic agent against emerging viruses.

Comparison of Antifungal Prophylaxis Drugs in Patients With Hematological Disease or Undergoing Hematopoietic Stem Cell Transplantation

Several antifungal drugs are available for antifungal prophylaxis in patients with hematological disease or who are undergoing hematopoietic stem cell transplantation (HSCT). To summarize the evidence on the efficacy and adverse effects of antifungal agents using an integrated comparison. Medline, EMBASE, and the Cochrane Central Register of Controlled Clinical Trials were searched to collect all relevant evidence published in randomized clinical trials that assessed antifungal prophylaxis in patients with hematological disease. Sources were search from inception up to October 2019. Studies that compared any antifungal agent with a placebo, no antifungal agent, or another antifungal agent among patients with hematological disease or undergoing HSCT were included. Of 39 709 studies identified, 69 met the criteria for inclusion. The outcome from each study was estimated using the relative risk (RR) with 95% CIs. The Mantel-Haenszel random-effects model was used. The reliability and validity of the networks were estimated by addressing inconsistencies in the evidence from comparative studies of different treatments. Data were analyzed from December 2019 to February 2020. Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses for Network Meta-analysis (PRISMA-NMA) guideline. The primary outcomes were invasive fungal infections (IFIs) and mortality. The secondary outcomes were fungal infections, proven IFIs, invasive candidiasis, invasive aspergillosis, fungi-related death, and withdrawal owing to adverse effects of the drug. We identified 69 randomized clinical trials that reported comparisons of 12 treatments with at total of 14 789 patients. Posaconazole was the treatment associated with the best probability of success against IFIs (surface under the cumulative ranking curve, 86.7%; mean rank, 2.5). Posaconazole treatment was associated with a significant reduction in IFIs (RR, 0.57; 95% CI, 0.42-0.79) and invasive aspergillosis (RR, 0.36; 95% CI, 0.15-0.85) compared with placebo. Voriconazole was associated with a significant reduction in invasive candidiasis (RR, 0.15; 95% CI, 0.09-0.26) compared with placebo. However, posaconazole was associated with a higher incidence of withdrawal because of the adverse effects of the drug (surface under the cumulative ranking curve, 17.5%; mean rank, 9.2). In subgroup analyses considering efficacy and tolerance, voriconazole might be the best choice for patients undergoing HSCT, especially allogenic HSCT; however, posaconazole was ranked as the best choice for patients with acute myeloid leukemia or myelodysplastic syndrome. These findings suggest that voriconazole may be the best prophylaxis option for patients undergoing HSCT, and posaconazole may be the best prophylaxis option for patients with acute myeloid leukemia or myelodysplastic syndrome.

Effect of Posaconazole in an in vitro model of cardiac fibrosis induced by Trypanosoma cruzi

Posaconazole (POS) is an inhibitor of ergosterol biosynthesis in clinical use for treating invasive fungal infections. POS has potent and selective anti-Trypanosoma cruzi activity and has been evaluated as a possible treatment for Chagas disease. Microtissues are a 3D culture system that has been shown to reproduce better tissue architecture and functionality than cell cultures in monolayer (2D). It has been used to evaluate chemotropic response as in vitro disease models. We previously developed an in vitro model that reproduces aspects of cardiac fibrosis observed in Chagas cardiomyopathy, using microtissues formed by primary cardiac cells infected by the T. cruzi, here called T. cruzi fibrotic cardiac microtissue (TCFCM). We also showed that the treatment of TCFCM with a TGF-β pathway inhibitor reduces fibrosis. Here, we aimed to evaluate the effect of POS in TCFCM, observing parasite load and molecules involved in fibrosis. To choose the concentration of POS to be used in TCFCM we first performed experiments in a monolayer of primary cardiac cell cultures and, based on the results, TCFCM was treated with 5 nM of POS for 96 h, starting at 144 h post-infection. Our previous studies showed that at this time the TCFCM had established fibrosis, resulting from T. cruzi infection. Treatment with POS of TCFCM reduced 50 % of parasite load as observed by real-time PCR and reduced markedly the fibrosis as observed by western blot and immunofluorescence, associated with a strong reduction in the expression of fibronectin and laminin (45 % and 54 %, respectively). POS treatment also changed the expression of proteins involved in the regulation of extracellular matrix proteins (TGF-β and TIMP-4, increased by 50 % and decreased by 58 %, respectively) in TCFCM. In conclusion, POS presented a potent trypanocidal effect both in 2D and in TCFCM, and the reduction of the parasite load was associated with a reduction of fibrosis in the absence of external immunological effectors.

P315 Impact of posaconazole treatment on exercise capacity in children with Aspergillus lung disease in cystic fibrosis

P315 Impact of posaconazole treatment on exercise capacity in children with Aspergillus lung disease in cystic fibrosis

Galactomannan Is a Biomarker of Fosmanogepix (APX001) Efficacy in Treating Experimental Invasive Pulmonary Aspergillosis.

Galactomannan (GM) detection in biological samples has been shown to predict therapeutic response by azoles and polyenes. In a murine invasive pulmonary aspergillosis model, fosmanogepix or posaconazole treatment resulted in an ∼6- to 7-log reduction in conidial equivalents (CE)/g lung tissue after 96 h versus placebo. Changes in GM levels in BAL fluid and serum mirrored reductions in lung CE, with significant decreases seen after 96 h or 72 h for fosmanogepix or posaconazole, respectively (P < 0.02).

Posaconazole is a novel inhibitor for alphavirus viral entry

Chikungunya virus (CHIKV), a mosquito-borne alphavirus, causes millions of infection globally. Posaconazole (PCZ) is an antifungal drug, which we and others have previously found to inhibit replication of a number of viruses, including dengue virus, a member of the Flaviviridae family. In this study, we analyzed the antiviral activity of PCZ against alphaviruses. We found that PCZ potently inhibits a number of alphaviruses, including Semliki forest virus (SFV), Sindbis virus (SINV) and CHIKV with half maximal effective concentration (EC50) of 2.3 μM, 4.0 μM and 0.8 μM, respectively. Time-of-addition assays indicated that PCZ treatment before and at the time of SFV infection showed potent inhibition, whereas addition of PCZ at later time points post infection showed minor to no inhibition, suggesting inhibition at an early stage of the replication cycle. In accordance, PCZ treatment of a temperature sensitive mutant of SFV that is capable of cell entry and translation, but not RNA replication, resulted in an almost 90% reduction in luciferase activity. To confirm these findings, PCZ resistant mutant virus were generated and we identified mutations in E1 (V148A) and E2 (H255R) viral glycoproteins, of which the E2 mutation confers partial resistance to PCZ when introduced into wild-type SFV. To see whether PCZ alters clathrin-mediated endocytosis, we analyzed the uptake of fluorescence-tagged transferrin and found that PCZ reduced transferrin uptake by 50% compared to DMSO-treated cells. Together, these results establish PCZ as a novel inhibitor of alphaviruses and identify viral entry as its target.

702. Hepatic Safety Among Patients Treated with Anti-Fungal Triazole Agent Posaconazole: Characterization of Adverse events in a Manufacturer’s Safety Database

BackgroundSecond-generation triazoles including posaconazole are highly efficacious for the prophylaxis and salvage treatment of life-threatening invasive fungal diseases. All triazoles have been associated with hepatic adverse events (AEs), which may affect their clinical use; however, risk factors for those AEs are poorly defined.MethodsReports of hepatobiliary AEs for posaconazole from clinical trials and post-market use in our company’s global safety database were reviewed to characterize concomitant medical conditions and drug exposure.ResultsAs of 2018, 444 cases of hepatic AEs were reported; 139 (31%) led to discontinuation of posaconazole. Most hepatic AEs had a time to onset >20 days (55.5%). The most frequent AEs reported (per Medical Dictionary for Regulatory Activities) were: Hyperbilirubinaemia (17%); Hepatotoxicity (13.5%); Hepatic function abnormal (11.5%); and Hepatocellular injury (11.3%). Most patients were adults (18–64 years old) (65%). Hematological malignancy (128 cases, 29%) and hematopoietic stem cell transplant (91 cases, 20%) were leading concurrent medical conditions. Notably, 75% of the cases reported exposure to other drugs (often multiple ones) with known risks for drug-induced liver injury (DILI, e.g., acetaminophen, cytarabine, cyclosporine). Among 139 cases in which posaconazole treatment was discontinued due to hepatic AEs, 6 of the 20 most frequently used co-medications (used by >4.5% of the cases) were classified by the FDA in its DILIRank as “Most-DILI-Concern” (resulting in drug withdrawal, or prominent labeling for severe DILI risk in boxed warning or warnings and precautions), and 7 were “Less-DILI-concern” drugs (DILI risk language in warnings and precautions or adverse reactions). Similarly, of the top 35 concomitant medications for the entire group, 9 are classified as “Most-DILI-Concern” and 12 are “Less-DILI Concern” drugs.ConclusionThe use of concomitant medications with known risks for hepatic injury appears to be an important contributor to the development of hepatotoxicity in patients treated with posaconazole. Co-administration of these drugs with anti-fungal triazole agents such as posaconazole, when needed, will continue to be carefully monitored.Disclosures All authors: No reported disclosures.

2107. Azole Therapeutic Drug Monitoring (TDM) in a Multiracial Cohort with Varied Pharmacogenetics

BackgroundVoriconazole (VOR) and posaconazole (POS) exhibit wide pharmacokinetic variability. Various factors including race and genetic polymorphisms are at play and this may affect treatment response. We aim to evaluate the utility of VOR/POS TDM among Southeast Asians that are predominantly intermediate/poor VOR metabolizers.MethodsAll adults with VOR/POS TDM performed at our institution from 2015 to 2018 were included. We determined proportion of patients and doses required to achieve TDM targets [(2 – 5.5 mg/L (VOR) or ≥ 0.7 and ≥ 1.0 mg/L (POS prophylaxis and treatment respectively)], and correlate levels with treatment efficacy and safety.ResultsVOR/POS TDM was performed mostly among patients with hematological malignancy or solid-organ transplant (146/174, 83.9%). Less than half (32/70, 45.7%) of patients on VOR achieved target—18 (25.7%) were < 2 mg/L while 20 (28.5%) had levels > 5.5 mg/L. Doses required to achieve TDM target ranged from 1.9–11.4 mg/kg/day. Drug interactions, critically ill state and change in drug formulation were major causes of intra-patient variability. One-fifth (n = 14) experienced transaminitis; corresponding VOR trough levels were 0.5–> 7.5 mg/L. Neurotoxicity was also seen in 3 (4.3%) patients—all 3 had VOR trough ≥ 6.7 mg/L and saw symptom resolution upon dose reduction. There appears to be no association between the achievement of TDM targets and response rates. Majority (81/104, 77.9%) of patients on POS achieved TDM targets. Patients prescribed POS tablet were significantly more likely to attain targets compared with suspension 600 mg/day [19/26 (73.0%) vs. 27/62 (43.5%), P < 0.05] and 800 mg/day [17/26 (65.3%) vs. 4/16 (25.0%), P < 0.05)]. Of 23 with sub-therapeutic levels, 19 (82.6%) responded to dose increase and/or change in acid-reducing agents. Breakthrough infection occurred despite troughs ≥ 0.7 mg/L [5/42 (11.9%) vs. 2/40 (5.0%) when < 0.7 mg/L (P = 0.3)]. Treatment failure was observed in 2 patients (troughs > 1.0 mg/L).ConclusionVOR/POS TDM should be implemented in Southeast Asians due to significant unpredictability in dose exposure and potential to avoid need for switch to alternative anti-fungals due to intolerability. Higher POS trough cutoff may be required for effective anti-fungal prophylaxis.Disclosures All authors: No reported disclosures.

F-18 fluorodeoxyglucose positron emission tomography/computed tomography image of gastric mucormycosis mimicking advanced gastric cancer: A case report

BACKGROUNDMucormycosis is a very rare fungal infection, and its prognosis is poor. Most common sites of infection are the sinuses, lung, or skin, and gastric involvement is uncommon. The standard antifungal therapy is the treatment of choice for gastric mucormycosis. However, the symptoms of gastric mucormycosis are varied and the early diagnosis is not easy.CASE SUMMARYI report a 53-year-old alcoholic man, who was admitted due to epigastric pain. The upper gastrointestinal endoscopy revealed a huge ulcer lesion in the stomach, which was suspected to be gastric cancer. F-18 fluorodeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) showed diffusely intense FDG uptake at the ulcer lesion of the stomach, and several enlarged hypermetabolic lymph nodes were noted at the left gastric chain. Although, endoscopy and F-18 FDG PET/CT findings suggested advanced gastric cancer with regional lymph node metastases, there was no cancer cells in the biopsy results and multiple fungal hyphae were noted in the periodic acid-Schiff stained image.CONCLUSIONHe was diagnosed with gastric mucormycosis and successfully underwent amphotericin B and posaconazole treatment.

Posaconazole trough concentrations are not influenced by inflammation: A prospective study

During inflammation, several cytochrome P450 enzymes are downregulated. Recently it was shown that voriconazole metabolism is reduced during inflammation. Posaconazole, another triazole with broad-spectrum antifungal activity, is metabolised only to a limited extent by cytochrome P450 enzymes and to a wider extent by phase 2 enzyme systems. The aim of this study was to investigate posaconazole concentrations during inflammation. Patients aged ≥18 years receiving posaconazole prophylaxis or treatment for fungal infections were enrolled in a prospective observational study. Samples for posaconazole and C-reactive protein (CRP) concentrations were collected routinely for each patient. Longitudinal data analysis was performed to analyse the correlation between posaconazole serum trough concentrations and CRP values, corrected for potential factors that could influence the posaconazole concentration. Between August 2015 and June 2017, 64 patients were recruited to this study. Data for 55 patients (511 posaconazole samples) were included in the final analysis. The overall median posaconazole concentration was 1.8 mg/L [interquartile range (IQR) 1-2.9 mg/L, range 0.1-7.94 mg/L] and the overall median CRP concentration was 23.5 mg/L (IQR 5-75 mg/L, range 0-457 mg/L). Longitudinal data analysis showed that only the posaconazole daily dose (in mg/kg body weight) had a significant influence on posaconazole concentration after correction for other factors (P < 0.0001). Posaconazole concentrations were not influenced by CRP concentrations (P = 0.77). Posaconazole concentrations are not influenced by inflammation, reflected by CRP concentration. Therefore, more frequent therapeutic drug monitoring of posaconazole during inflammation or after an infection subsides is not necessary.