ANTIFON-CLIC®, a new clinical decision support system for the treatment of invasive aspergillosis: is it clinically relevant?

BACKGROUND: Invasive aspergillosis (IA) is increasing especially in new groups of patients. Despite advances in management, morbidity and mortality related to IA remain high. Thus, Clinical Decision Support System (CDSS) dedicated to IA are needed to promote the optimal antifungal for each group of patients. PATIENTS AND METHODS: This was a retrospective multicenter cohort study involving intensive care units and medical units. Adult patients who received caspofungin, isavuconazole, itraconazole, liposomal amphotericin B, posaconazole, or voriconazole, for the treatment of IA were eligible for enrollment. The primary objective was the concordance between the clinician's prescription and the prescription recommended by the CDSS. The secondary objective was the concordance according to different hospitals, departments, and indications. RESULTS: Eighty-eight patients (n=88) from three medical hospitals were included. The overall concordance was 97% (85/88) including 100% (41/41) for center A, 92% (23/25) for center B, and 95% (21/22) for center C. There was no significant difference in concordance among the hospitals (P=0.973), the departments (P=1.000), and the indications (P=0.799). The concordance was 70% (7/10) for isavuconazole due to its use as an empirical treatment and 100% (78/78) for the other antifungals. DISCUSSION: The concordance rate was high whatever the hospital, the department, and the indication. The only discrepancy was attributed to the use of isavuconazole as an empirical treatment which is a therapeutic option not included in the CDSS. CONCLUSIONS: This new CDSS dedicated to IA is meeting the clinical practice. Its implementation in routine will help to support antifungal stewardship.

Suboptimal exposure to fluconazole in critically ill patients: Pharmacokinetic analysis and determinants.

OBJECTIVES: This study aims at evaluating fluconazole exposure in critically ill patients and identifying variables associated with the latter. PATIENTS AND METHODS: This was a 2-year (2018-2019) retrospective multicenter cohort study. Adult patients > 18 years-old with at least one fluconazole concentration measurement during their ICU stay were included. RESULTS: Twenty patients were included. Only 11 patients had a fluconazole trough concentration (Cmin) within the target range (≥15 mg/L). According to bivariable analysis, SOFA score, GGT, fluconazole clearance, Ke, and Vd, were independently associated with a decrease in fluconazole Cmin. The median loading dose required to achieve the Cmin target appeared to be greater in patients with higher SOFA or GGT level and in patients undergoing renal replacement therapy. CONCLUSIONS: This study supports recommendation for routine fluconazole therapeutic drug monitoring in ICU patients so as to avoid underexposure, especially if SOFA score is ≥ 7 and/or GGT is ≥ 100 U/L.

Thesaurus for off-label indications for systemic antifungal agents.

OBJECTIVES: Following the removal of temporary treatment protocol procedures, we developed a thesaurus for off-label indications for systemic antifungals at our facility to update clinical practices and to control off-label prescriptions. MATERIALS AND METHODS: Clinical practice guidelines and literature data were analyzed. This work was part of an antifungal stewardship program. RESULTS: Off-label wording (prophylaxis, preemptive, empirical, curative) and corresponding antifungals and references were validated by the multidisciplinary group for antifungal agents under the aegis of the Commission for the use of drugs and sterile medical devices and of the anti-infective committee. CONCLUSION: Considering the complexity of invasive fungal infection management, this thesaurus needs to be shared and used as a helping tool to review off-label situations.

Prospective survey of azole drug resistance among environmental and clinical isolates of Aspergillus fumigatus in a French University hospital during major demolition works.

OBJECTIVES: Recent studies have reported the emerging worldwide problem of azole drug resistance of A. fumigatus isolates. The aim of this study was to evaluate the antifungal susceptibilities of A. fumigatus isolates recovered from air and clinical samples collected in a French University hospital (Lyon), which underwent major deconstruction works over a one year-period. METHODS: A daily surveillance of fungal contamination was implemented during 11-months. Environmental survey was realized by air samplings, outdoor and indoor, with an automatic agar sampler. In parallel, surveillance of IA infection cases was conducted by epidemiological investigation. Environmental and clinical isolates of A. fumigatus were identified by conventional methods and ß-tubulin sequencing. Susceptibility testing of A. fumigatus isolates against Itraconazole (ITZ), Voriconazole (VCZ) was performed using Etest method. RESULTS: A total of 3885 air samples (1744 outdoor samples and 2141 indoor samples) were collected. From the 3073 identified colonies of A. fumigatus, 400 A. fumigatus isolates were tested for their susceptibility to ITZ and VCZ, including 388 isolates coming from the environment (indoor n:157, outdoor n:231) and 12 isolates coming from clinical samples. All the 400 isolates were susceptible to azoles (≤1µg/mL). CONCLUSIONS: No environmental reservoir of A. fumigatus azole resistant strains was found in our hospital which was undergoing major demolition works. Further studies with larger number of A. fumigatus clinical isolates and environmental isolates from agricultural areas and healthcare establishments are needed to better appreciate the occurrence and prevalence of azole resistance.

A systematic review of interventions and performance measures for antifungal stewardship programmes.

Objectives: Antifungal resistance is a significant and emerging threat. Stewardship programmes (SPs) have been proposed as an opportunity to optimize antifungal use. While examples of antifungal SP implementation have been recently described, there is yet to be an overview of interventions and their impacts on performance measures. Methods: We systematically reviewed published articles using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses check-list 2009. MEDLINE was searched using the term 'antifungal stewardship' on 15 February 2017. Eligible studies were those that described an antifungal SP and included an intervention and an evaluation of performance measures. Results: A total of 97 studies were identified and 14 were included. Only five studies reported an antifungal stewardship team composed of all the recommended members. The main intervention was the formulation of recommendations to change treatment (12 of 14). The main performance measure collected was antifungal consumption (10 of 14), followed by antifungal expenditure (7 of 14), adherence to therapeutic advice (4 of 14) and impact on mortality (4 of 14). Antifungal consumption was reduced by 11.8% to 71% and antifungal expenditure by as much as 50%. Adherence to therapeutic advice ranged from 40% to 88%, whereas antifungal SPs had no impact on mortality. Conclusions: All antifungal SPs had an impact, in particular on antifungal consumption and antifungal expenditure. Active intervention including a review of prescriptions seems to have more impact than implementation of treatment guidelines only. According to available published studies, antifungal consumption appears to be the most achievable performance measure to evaluate the impact of an antifungal SP.

Combined medico-surgical strategy for invasive sino-orbito-cerebral breakthrough fungal infection with Hormographiella aspergillata in an acute leukaemia patient.

Hormographiella aspergillata is a rare causative agent of invasive filamentous breakthrough infection, mostly arising after echinocandin exposure. We report a neutropenic patient who developed a severe sino-orbito-cerebral H. aspergillata infection while receiving empirical caspofungin, successfully controlled by an aggressive strategy associating surgical debridement and combined high-dose regimen of antifungal drugs.

[Cerebral aspergillosis and liver transplantation: about one case]. / Aspergillose cérébrale et transplantation hépatique: discussion autour d'un cas.

Cerebral invasive aspergillosis is a rare but serious infection. Mortality is still high despite appropriate treatment. We report the case of a patient with liver transplantation in the context of alcoholic cirrhosis and transplanted back seven years later consequently to an ischemic cholangitis. Following an acquired active viral infection by HCV and treated by antiviral combination therapy the patient presented six months after this second operation a cerebral aspergillosis of tumour-like presentation. It rapidly evolved to an unfavourable outcome with intracranial hypertension state. If the therapeutic management is well established, the diagnosis is difficult. This observation allows us to discuss the various diagnostic criteria of cerebral aspergillosis.

A multicenter, randomized, open-label, controlled study comparing the efficacy, safety and cost-effectiveness of a sequential therapy with RV4104A ointment, ciclopiroxolamine cream and ciclopirox film-forming solution with amorolfine nail lacquer alone in dermatophytic onychomycosis.

BACKGROUND: The efficacy of topical antifungals is controversial. OBJECTIVE: To compare the efficacy and safety of a sequential(SEQ) treatment with chemical nail avulsion and topical antifungals to amorolfine nail lacquer in dermatophytic onychomycosis. METHODS: This was a randomized,parallel-group, controlled study comparing a 36-week SEQ treatment with chemical nail avulsion with RV4104A ointment(class I medical device containing 40% urea) followed by ciclopirox cream for 8 weeks and ciclopirox nail lacquer for 25 weeks (SEQ group) to amorolfine nail lacquer for 36 weeks (AMO group). Patients had to have a big toenail onychomycosis,sparing the matrix. The primary efficacy criterion was complete cure at week 48. A cost-effectiveness analysis was performed. RESULTS: A total of 142 patients were randomized. The complete cure rate at week 48 was significantly higher in the SEQ group than in the AMO group (36.6 vs. 12.7%, p = 0.001). Clinical cure at week 48 was observed in 53.5% of patients in the SEQ group versus 17% in the AMO group (p < 0.01). The cost of cure per patient was 50% lower with SEQ treatment (EUR 33) compared with amorolfine(EUR 76). CONCLUSION: A treatment of onychomycosis comprising chemical avulsion of the pathological nail, ciclopirox cream and nail lacquer is significantly more effective than amorolfine nail lacquer.

The efficacy of voriconazole in 24 ocular Fusarium infections.

PURPOSE: We examined, retrospectively, the efficacy of voriconazole in Fusarium eye infections. METHODS: Voriconazole-treated patients with proven or probable keratitis or endophthalmitis from the voriconazole database (9 patients) and six French ophthalmology departments (15 patients) were included. Sociodemographic features, predisposing factors, history of corneal trauma, associated ocular conditions, other diseases and prior therapies were analysed. Investigator-determined success was defined as infection resolution with medical treatment. Failure was no response or persistent infection and required surgery. RESULTS: Most patients were Caucasian (83 %) and male (71 %). The infection was keratitis (63 %) or endophthalmitis (37 %) and proven in 23 (96 %). Prior therapy included topical and/or systemic amphotericin (46 %), fluconazole (17 %) or others (33 %), often in combination. Causative fungi were Fusarium solani (14, 58 %), Fusarium moniliforme (1), Fusarium oxysporum (1) and Fusarium spp. (8). Voriconazole was administered systemically, topically and/or by intraocular injection, and 16 patients (67 %) received salvage and eight primary therapy. The overall response was 67 % (73 % keratitis and 56 % endophthalmitis) but seven patients required adjunctive surgery. However, response was 63 % for eight primary therapy patients and 69 % for 16 salvage therapy patients. Response by species was Fusarium solani 64 % (9/14) and all others 80 % (8/10). In 13 patients (77 %), voriconazole was used in combination (response 69 vs. 64 % alone) with topical [amphotericin B 10/24 (42 %), caspofungin 5 (21 %), natamycin 1 (4 %)] and systemic agents [caspofungin 3 (13 %), amphotericin 2 (8 %)]. CONCLUSIONS: Topical and systemic voriconazole appears to be effective alone or in combination with other agents for treating severe Fusarium keratitis or endophthalmitis.

Invasive aspergillosis: an important risk factor on the short- and long-term survival of acute myeloid leukemia (AML) patients.

Invasive aspergillosis (IA) during induction chemotherapy of acute myeloid leukemia (AML) could worsen the prognosis. Our objective was to study how the development of IA during AML interferes with the therapeutic strategy and to evaluate its impact on the short- and long-term survival. Newly diagnosed AML patients between the years 2004 and 2007 were retrospectively analyzed. The outcome was death of the patient. A Cox proportional hazards model with the diagnosis of IA and post-induction response evaluation as the main exposure was fitted. Overall, 262 patients were analyzed and 58 IA were observed. The 2-year survival of patients having had remission of AML was 54% and, for patients with failure of chemotherapy, it was 5% (p < 0.001). The 2-year survival of patients having had IA was 14%, and without IA, it was 32% (p = 0.01). Multivariate analysis showed that IA was associated with a higher risk of death in case of remission compared to no IA (hazard ratio [HR] = 1.66 [1.05-2.65], p = 0.031) and also in case of failure (HR = 6.43, p < 0.001). IA was associated with an increased risk of death for patients if they were either in remission or in failure after induction chemotherapy.

Maxillary sinus fungal infection by Acremonium.

OBJECTIVE: To illustrate by this case report that Acremonium must now be considered as a differential diagnosis in cases of maxillary fungus balls. CASE REPORT: Seventy-seven-year-old woman consulted for persistent pain of the right maxillary sinus, with rhinorrhea and nocturnal coughing. Computed tomography (CT) of the sinuses showed a heterogeneous opacification of the right maxillary sinus with well-defined hyperdense foci suggesting aspergillosis. She underwent a middle meatus antrectomy by an endonasal approach. Six months after the surgery, her symptoms were gone and had not recurred. Mycological examination found Acremonium. DISCUSSION/CONCLUSION: Acremonium is a genus of saprobic fungi that rarely cause disease in humans. Infection with Acremonium has recently been described in immunocompromised patients. We describe the first case of fungal maxillary sinusitis caused by Acremonium in an immunocompetent person. Clinically and radiologically, the initial diagnosis was aspergillosis. Acremonium must be considered together with aspergillosis in all situations of fungus ball chronic sinusitis.