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To describe reasons for initiation and evolution under isavuconazole (ISZ), a 2-year prospective and observational study was performed. Anonymized data collected during the first 3 months of treatment were indications of treatment, efficacy, overall survival (OS), evolution of toxicity markers, and ISZ trough levels. Fifty-one (26 invasive aspergillosis, 16 prophylaxis, and 9 mucormycosis) patients started on isavuconazole. Isavuconazole was initiated upfront in 12/51 cases, especially to avoid toxicities from other antifungals. As second-line therapy (39/51 patients), isavuconazole was mostly initiated after toxicities of the previous treatments (66.7%; 26/39 cases). An improvement in toxicity markers was reported in most patients. However, five patients experienced adverse events. The mean ISZ trough levels measured from 179 samples collected in 37 patients was 3.33 ± 1.64 mg/l. The mean ISZ through levels was significantly lower (P = .003) in alloHSCT recipients (3.10 ± 1.45 mg/l) than in other patients (3.76 ± 1.88 mg/l) but still within the expected range of efficacy. After 12 weeks, the OS was 69.2% (n = 18/26) in the invasive aspergillosis intention-to-treat (ITT) group and 44.4% (n = 4/9) in the mucormycosis ITT group. After 2 years, the OS was respectively 46.2% (n = 12/26) and 33.3% (n = 3/9) in these two groups.

Serum (1→3)-β-D-glucan (BDG), an pan fungal antigen, is detected in some invasive fungal diseases (IFDs). We compared two commercial kits, the Fungitell assay (FA) (colorimetric) and the Wako assay (WA) (turbidimetric) over a 4-month period to prospectively test 171 patients who mainly had hematological conditions (62%) and experienced episodes (n = 175) of suspected invasive fungal infection. Twenty-three episodes due to BDG-producing fungi were diagnosed (pneumocystosis, n = 12; invasive aspergillosis, n = 5; candidemia, n = 3; invasive fusariosis, n = 2; hepato-splenic candidiasis, n = 1). Both assays provided similar areas under the curves (AUC = 0.9). Using the optimized positivity thresholds (≥120 pg/ml for FA and ≥ 4 pg/ml for WA), the sensitivity and specificity were 81.8% (CI95: 61.5–92.7), 94.8% (90.1–97.3) for FA and 81.8% (61.5–92.7), 95.4% (90.9–97.8) for WA. Negative predictive value was 97.3% (93.3–99.0) for both tests. If the manufacturer's positivity threshold (≥11 pg/ml) was applied, the WA sensitivity decreased to 50%. Among 71 patients with bacterial infections, 21.1% were FA-positive and 5.6% were WA-positive (p < 10−2). The WA performed similarly as compared to the FA with an optimized cutoff value. The WA is a single sample test that is clinically relevant when a prompt therapeutic decision is required. Lay Summary Serum (1→3)-β-D-glucan testing is dominated by two kits including Fungitell colorimetric assay (FA) and the Wako turbidimetric assay (WA). We compared them prospectively and observed that they both perform similarly when selecting their optimal threshold (≥120 pg/ml for FA and ≥ 4 pg/ml for WA).

Black aspergilli of the section Nigri are rarely differentiated at the species level when originating from human specimens. We wondered whether some cryptic species could be more frequently observed in some clinical entities. We analyzed the 198 black isolates consecutively collected from the external ear canal (EEC; n = 66), respiratory specimens (n = 99), and environment (n = 33). DNA was extracted and species identification was performed upon the partial calmodulin gene. We identified by decreasing frequency: Aspergillus welwitschiae (35.3%), Aspergillus tubingensis (34.3%), Aspergillus niger (17.2%), Aspergillus luchuensis (4%), Aspergillus aff. welwitschiae (3%), Aspergillus neoniger (2%), Aspergillus piperis (1.5%), Aspergillus japonicus (1.0%), Aspergillus vadensis (0.5%), and two Aspergillus tubingensis clade (1%). The distribution of the three main cryptic species was different between EEC and respiratory samples (P Lay summary We analyzed 198 black aspergilli isolates collected from different samples type to determine their species identification. We observe a different distribution of species between ear canal and respiratory samples (P

Introduction Le cytomegalovirus (CMV) est un pathogene opportuniste majeur en cas de greffe de cellules souches hematopoietiques (GCSH). Les resistances ainsi que les toxicites observees avec les traitements conventionnels ont rendu necessaire le developpement de nouveaux traitements. Le letermovir est un antiviral qui inhibe le complexe terminase de l’ADN du CMV, permettant ainsi d’eviter les toxicites renales et medullaires respectivement observees avec le foscavir et le ganciclovir. L’objectif de ce travail est d’evaluer, au sein d’un centre de reference en GCSH, l’efficacite en vie reelle du letermovir dans la prophylaxie de la reactivation du CMV apres allogreffe. Materiels et methodes Etude observationnelle monocentrique conduite chez des patients allogreffes traites par letermovir. Periode d’etude: novembre 2019 a octobre 2020. Seuls les patients ayant acheve leur cycle de letermovir ont ete inclus. Le critere pour juger de l’efficacite du letermovir est la presence ou non d’une reactivation significative du CMV (charge virale > 3 log). Resultats Durant la periode etudiee, 30 patients ont ete traites par letermovir. La mediane d’âge etait de 42,5 ± 14 ans [17;72] et le sexe ratio etait de 1,3 (17 F et 13 H). Les principales indications de la GCSH allogenique etaient: leucemie aigue myeloblastique (n = 12), myelodysplasie (n = 6), myelofibrose (n = 3) et drepanocytose (n = 3). Les statuts serologiques du donneur et du receveur vis-a-vis du CMV etaient: R+/D- (n = 11) et R+/D+ (n = 19). Le donneur etait apparente au receveur dans 16 cas sur 30 (6 greffes geno-identiques et 10 haplo-identiques). Parmi les patients traites, 25 l’ont ete en prophylaxie primaire et 5 en prophylaxie secondaire. La mediane du delai d’instauration du letermovir apres la GCSH etait de 5 jours [−7 ;100] en prophylaxie primaire et de 80 jours [5 ;118] en prophylaxie secondaire. Le traitement s’est poursuivi en prophylaxie primaire et secondaire respectivement durant 164,5 jours [34 ;237] et 114 jours [54 ;311]. Seulement 2 cas de reactivation ont ete observes (1 en prophylaxie primaire et 1 en prophylaxie secondaire). Dans un cas le donneur n’etait pas apparente au receveur et dans l’autre, il s’agissait d’une greffe intrafamiliale haplo-identique. Une de ces reactivations etait precedee d’une GVH, diagnostiquee chez 21 patients au total. Les raisons d’arret du letermovir etaient: fin de traitement programmee (n = 22), deces (n = 3), progression de la maladie sous-jacente (n = 2), echec (n = 2), effet indesirable (cytopenies, n = 1). Conclusion L’effet protecteur du letermovir vis-a-vis du CMV est confirme (28/30) ainsi que son excellente tolerance. La mediane d’instauration du letermovir post-allogreffe observee en prophylaxie primaire est compatible avec les preconisations de la Haute Autorite de sante. Ces resultats tres satisfaisants s’accompagnent d’une montee en charge des prescriptions de letermovir au sein du service de greffe de moelle de notre centre.

Given reports showing a high prevalence of azole resistance in Aspergillus fumigatus, alternatives to azole therapy are discussed when a threshold of 10% of azole-resistant environmental isolates is reached. This raises the issue of calculation of this threshold, either on the prevalence of azole-resistant isolates as a whole or on the prevalence of azole-resistant cases in populations at risk of invasive aspergillosis (IA). For isolate evaluation, there are high disparities in routine microbiological procedures for the isolation of A. fumigatus and azole resistance detection. There are also huge differences between the microbiological work-up for diagnosing IA. Some centres rely on galactomannan detection alone without actively trying to culture appropriate samples, which affects reliability of the figures on the prevalence of resistance and thus the threshold of resistance. Moreover, reports from the laboratory could mix up figures from completely different patient populations: frequent azole-resistant isolates from pneumology patients and rare azole-resistant isolates from haematology patients. Therefore, to sum isolates from different specimens and different wards can lead to erroneous calculations for the restricted populations at risk of developing IA. In conclusion, assessing the incidence of azole resistance in A. fumigatus should be based on harmonized consensual microbiological methods and reports should be restricted to IA episodes in identified populations at risk of IA when the issue is to define an operational threshold for modifying recommendations.

Introduction Les erreurs d’administration du chlorure de potassium (KCl) injectable font partie de la liste etablie par l’ANSM des « never events ». Dans notre CHU, seules les ampoules de solution hypertonique a 10 % (1 g/10 mL) sont disponibles au livret therapeutique. Suite aux recommandations de l’ANSM et a un avis favorable de la COMEDIMS AP–HP, les solutions pretes a l’emploi de KCl de 1000 mL et de 500 mL a une concentration standard de 3 g/L ont ete referencees par notre centrale d’achat. Avant de mettre a disposition les solutions pretes a l’emploi de KCl dans nos services de soins, un etat des lieux de l’utilisation des ampoules de solution hypertonique de KCl a ete realise pour evaluer les habitudes de prescription et definir les unites ou le remplacement pourra etre effectue tout en evitant la coexistence des deux presentations. Materiels et methode Une enquete sur les prescriptions de KCl injectable dans les services consommateurs a ete realisee sur une semaine par la pharmacie. Les items etudies sont : la dose de KCl, la nature et le volume du solvant, l’unite de prescription, la concentration, le debit et le melange avec d’autres electrolytes dans la poche de perfusion. Les doses et les concentrations prescrites ont ete analysees pour determiner les cas pour lesquels les solutions pretes a l’emploi peuvent etre proposees. Resultats et discussion L’enquete a ete realisee dans 23 services. Au total, 260 lignes de prescription ont ete analysees dont 204 prescriptions avec du KCl dilue et 56 prescriptions avec du KCl concentre. Le KCl concentre est majoritairement utilise par les soins intensifs. Seulement 62,3 % des prescriptions sont conformes. Les principales non-conformites sont l’unite de prescription en « ampoules » et la concentration finale superieure a 4 g/L. Les proportions des prescriptions conformes pour ces deux parametres sont respectivement de 83,2 % et de 78,6 %. Dans les services hors soins intensifs, les poches pretes a l’emploi pourraient etre proposees pour 33 % des lignes selon la dose prescrite et pour seulement 5 % des lignes selon la concentration prescrite. D’autres electrolytes sont melanges au KCl pour 77,5 % des poches de perfusion. Conclusion Les solutions pretes a l’emploi ne seront pas mises a disposition des soins intensifs afin d’eviter la coexistence des deux presentations. Pour les autres services, seule une faible proportion des prescriptions semble eligible. Les recommandations n’autorisent pas l’ajout d’autres medicaments dans les solutions pretes a l’emploi. Or, dans la majorite des prescriptions d’autres electrolytes sont melanges au KCl. Une concertation avec les equipes medicales et paramedicales est necessaire afin de determiner l’utilite du referencement des solutions pretes a l’emploi. Au regard de l’heterogeneite des pratiques, leur harmonisation est necessaire, que cette nouvelle presentation soit referencee ou non.

Posaconazole (PSC) is currently recommended as primary prophylaxis in neutropenic patients with acute myeloid leukaemia (AML) and in allogenic haematopoietic stem cell transplantation (AHSCT) recipients with graft-versus-host disease (GVHD). Studies focusing on breakthrough invasive fungal disease (IFD) upon PSC prophylaxis show disparate results. In order to evaluate the incidence of IFD in patients on PSC prophylaxis and identify IFD risk factors, we carried out a retrospective study of all consecutive patients on PP from January 2007 to December 2010 in our hospital. Breakthrough IFDs were identified from the database of the central pharmacy and the French administrative database (PMSI), registering final medical diagnoses of hospitalized patients. Medical data were reviewed to study proven or probable IFD, according to EORTC/MSG definition. PSC plasma concentrations (PPC) were also retrieved. Poisson models were used for statistical analysis. Two hundred and seventy-nine patients received PSC prophylaxis for a median duration of 1.4 months (range 0.2–17.9). Proven (n = 6) or probable (n = 3) IFDs were diagnosed in nine cases (3.2%). IFD incidence rate per 100 person-month was 1.65 (95% CI, 0.79–2.97). IFDs were candidaemia (Candida glabrata, n = 2), pulmonary invasive aspergillosis (n = 3), disseminated fusariosis (n = 2) and pulmonary mucormycosis (n = 2). Seven deaths were reported, directly related to IFD in three patients (33.3%). First dosage of PPC under 0.3 mg/L was the single significant risk factor for IFD (RR, 7.77; 95% CI, 1.30–46.5; p 0.025). Breakthrough IFD in patients receiving PSC prophylaxis is rare but associated with a poor outcome. Low PSC plasma concentrations are associated with an increased risk of IFD.

This study was undertaken to examine the performance of the Fungitell β-glucan (BG) assay, to compare it with that of the galactomannan (GM) test for the diagnosis of invasive aspergillosis (IA) in patients with hematological malignancies, and to examine the rates of false-positive BG and GM test results due to β-lactam antibiotics among sera of patients with Gram-positive or Gram-negative bacteremia and selected sera with false-positive results from the GM test. Serum samples from 105 patients with proven ( n = 14) or probable ( n = 91) IA, 97 hematology patients at risk for invasive fungal infections, 50 healthy blood donors, and 60 patients with bacteremia were used to study the sensitivities and specificities of the assays. The GM test was more specific than the BG assay (97% versus 82%, respectively; P = 0.0001) and the BG assay was more sensitive than the GM test (81% versus 49%, respectively; P < 0.0001) for IA diagnosis. The study of 49 separate batches of β-lactam antibiotics showed high and very similar rates of false-positive results for the GM and BG assays (29 and 33%, respectively; P = 0.82) but with an almost complete lack of concordance between the 2 assays. For patients with bacteremia, the rate of false-positive results was much higher with the BG test than with the GM test (37% versus 2%, respectively; P < 0.0001), with no significant difference between Gram-positive and Gram-negative bacteremia. In conclusion, the BG test may be useful for the diagnosis of IA because of its high sensitivity in comparison with the GM test, but the overall benefit of this assay remains limited because of its inadequate specificity and its cost.

Candida glabrata is a major pathogenic yeast in humans that is known to rapidly acquire resistance to triazole and echinocandin antifungal drugs. A mutator genotype (MSH2 polymorphism) inducing a mismatch repair defect has been recently proposed to be responsible for resistance acquisition in C. glabrata clinical isolates. Our objectives were to evaluate the prevalence of antifungal resistance in a large cohort of patients in Saint-Louis hospital, Paris, France, some of whom were pre-exposed to antifungal drugs, as well as to determine whether MSH2 polymorphisms are associated with an increased rate of fluconazole or echinocandin resistance. We collected 268 isolates from 147 patients along with clinical data and previous antifungal exposure. Fluconazole and micafungin minimal inhibition concentrations (MICs) were tested, short tandem repeat genotyping was performed, and the MSH2 gene was sequenced. According to the European Committee on Antimicrobial Susceptibility breakpoints, 15.7% of isolates were resistant to fluconazole (MIC > 32 mg/L) and 0.7% were resistant to micafungin (MIC > 0.03 mg/L). A non-synonymous mutation within MSH2 occurred in 44% of the isolates, and 17% were fluconazole resistant. In comparison, fluconazole resistant isolates with no MSH2 mutation represented 15% (P = 0.65). MSH2 polymorphisms were associated with the short tandem repeat genotype. The rate of echinocandin resistance is low and correlates with prior exposure to echinocandin. The mutator genotype was not associated with enrichment in fluconazole resistance but instead corresponded to rare and specific genotypes.

Introduction L’incidence des infections fongiques invasives (IFI) chez les patients d’hematologie a haut risque sous posaconazole est Une etude retrospective monocentrique de tous les tests GM chez les patients allogreffes de moelle sous prophylaxie par posaconazole ou voriconazole entre le 01/2013 et le 12/2015 a ete conduite afin d’evaluer l’efficience d’une strategie ciblee chez les patients symptomatiques. Materiels et methodes Un test GM (Platelia Aspergillus® par Bio-Rad) etait positif (+) si l’index etait ≥ 0,7 sur un serum ou ≥ 0,5 sur 2 serums consecutifs. Deux episodes de GM + etaient consideres independants s’il y avait un GM negatif entre les 2 episodes, separes d’un intervalle ≥ 15 jours. Les donnees clinicoradiologiques, mycologiques, therapeutiques ainsi que les conclusions du comite de la cellule aspergillaire ont ete collectees. Chaque episode independant a ete classe en aspergillose (AI) possible/probable/prouvee/exclue selon les criteres 2008 EORTC/MSG. La sensibilite (Se) et valeur predictive positive (VPP) du test GM ont ete calculees. Resultats Sur 1358 GM, 279 GM+ ont ete inclus, correspondant a 43 patients, 70 episodes independants. Une AI etait exclue dans 66/70 episodes (94 %). Les 3 patients/4 episodes ou le GM+ correspondait a un vrai+ avaient des symptomes d’IFI. Chez les patients avec des GM negatifs, 5 avaient une AI possible et 1 une AI probable. La Se etait de 40 % (IC : 9 ; 61), avec une VPP de 6 % (IC : 1,5 ; 13,4). Pour les patients avec des GM+ 74 % ont eu un scanner, 12 % une IRM cerebrale et 7 % une fibroscopie bronchique. Conclusion Le test GM a une tres faible VPP chez le patient allogreffe sous prophylaxie primaire par posaconazole ou voriconazole, et entraine des investigations couteuses. Il reste interessant en cas de suspicion clinique d’IFI. Dans cette population, le GM serique ne devrait plus etre utilise en screening systematique mais en test cible chez des patients symptomatiques.

Introduction L’Isavuconazole (ISZ) est indique dans la prise en charge de l’aspergillose invasive en premiere intention et de la mucormycose en deuxieme intention. Le profil de tolerance de l’ISZ, en particulier hepatique, participe a l’augmentation des prescriptions au sein de notre hopital. L’objectif principal de l’etude etait de determiner le profil des patients traites par ISZ dans notre hopital. Les objectifs secondaires etaient de caracteriser les prescriptions d’ISZ et d’evaluer la tolerance de ce medicament. Materiels et methodes Les 45 patients (pts), dont 35 avaient une pathologie hematologique sous-jacente, traites par ISZ dans notre hopital entre 2016 et 2018, ont retrospectivement ete inclus dans l’etude. Les donnees cliniques issues des dossiers pts, la tracabilite de dispensations d’anti-infectieux et les donnees de suivi therapeutique ont ete recueillies. Resultats Chez les 23 (sur 45) pts allogreffes, l’ISZ a ete prescrit 9 fois pour traiter une aspergillose, 3 fois une mucormycose et 11 fois en prophylaxie d’une infection fongique invasive, indication hors-AMM. Dans ce contexte, l’ISZ a ete prescrit 6 fois apres un effet indesirable (EI) hepatique ou neurologique induit par un autre azole, 3 fois lors d’une reaction du greffon contre l’hote (GVH) hepatique et 2 fois en prevention d’interactions medicamenteuses. Un episode de GVH a concerne 18 des 23 pts allogreffes. La concentration residuelle d’ISZ (cISZ) moyenne etait significativement (S) inferieure (p Chez les 22 pts non allogreffes, l’ISZ a majoritairement ete prescrit suite a l’inefficacite d’un autre antifongique dans le traitement d’une mucormycose (n = 10), d’une aspergillose (n = 7), d’une candidemie (n = 3) et en prophylaxie (n = 2). Chez 33 pts (96 dosages) ayant beneficie d’un dosage plasmatique, la cISZ mediane etait de 3,2 mg/L [0,6 ; 10 mg/L] en accord avec les donnees de la litterature (2 a 6 mg/L). La cISZ moyenne n’etait pas S differente entre la population d’allogreffes (3,6 mg/L) et de non allogreffes (3,8 mg/L). Prescrit chez 23 pts en raison de la toxicite d’un autre azole, dont 2 associes a une GVH hepatique, l’ISZ n’a pas permis une amelioration du bilan hepatique chez 7 pts. Le traitement a ete maintenu chez les 16 autres pts. Conclusion En prophylaxie, l’ISZ a essentiellement ete prescrit chez les allogreffes. Mieux tolere deux fois sur trois sur le plan hepatique, ce medicament a ete prescrit dans la moitie des cas apres une atteinte hepatique provoquee par un autre azole. Necessitant une investigation plus approfondie, cette strategie therapeutique fait l’objet d’une etude prospective au sein de notre hopital pour evaluer l’efficacite et la tolerance de l’ISZ en vie reelle.

Introduction Ceftolozane/Tazobactam (C/T) et Ceftazidime/Avibactam (C/A) sont deux nouveaux antibiotiques (ATB) ayant une activite sur certaines bacteries multiresistantes (BMR). L’objectif de ce travail est de decrire leur utilisation en pratique clinique dans notre centre hospitalier. Materiels et methodes Etude retrospective (2016–09/2018) portant sur l’ensemble des patients (P) traites par C/T et/ou C/A en hospitalisation, inclus a partir du fichier de suivi des dispensations d’ATB controles. Ont ete analyses les donnees cliniques, l’indication, la documentation des infections traitees, les interventions de l’Equipe Mobile d’Infectiologie (EMI), la duree de traitement et la mortalite a 30 jours (j). Resultats Le C/T a ete prescrit 48 fois chez 39 P dont 69 % (33/48) de P immunodeprimes ; les pathologies sous-jacentes etaient : grands brules (33 %), hemopathies malignes (21 %), cancers solides (13 %), autres (33 %). Les principaux sites d’infection etaient : poumons (40 %), peau et tissus mous (31 %), dont 52 % avec bacteriemie secondaire. L’infection etait documentee dans 63 % (30/48) des cas : Pseudomonas aeruginosa sensible au C/T etait retrouve dans 97 % (29/30) des cas (1 antibiogramme Non Renseigne = NR). Le C/T ne constituait pas une strategie d’epargne des carbapenemes dans 97 % (28/29 ; 1 NR) des cas. La prescription n’etait pas documentee dans 37 % (18/48) des cas : patients ayant deja ete traites par C/T (7/18), colonises a Pseudomonas multiresistant (6/18), ayant une infection a Pseudomonas multiresistant avec un relai pour C/A (3/18) et NR (2/18). La duree mediane de traitement etait de 6j [1–26] et 63 % (30/48) des prescriptions avaient recu l’avis de l’EMI. La mortalite a 30j etait de 41 % (16/39), liee en partie a l’infection dans 87 % (13/15 ; 1 NR) des cas. Le C/A a ete prescrit 44 fois chez 35 P dont 89 % (39/44) de P immunodeprimes ; les pathologies sous-jacentes etaient : hemopathies malignes (39 %), grands brules (23 %), greffes renaux (14 %), cancers solides (7 %), autres (18 %). Les principaux sites infectieux etaient : poumons (36 %), peau et tissus mous (23 %), reins (16 %), infections sur materiel (16 %), dont 48 % avec bacteriemie secondaire. L’infection etait documentee dans 80 % (35/44) des cas a germes C/A sensible (1 NR) : 27 Pseudomonas dont 25 aeruginosa, 10 enterobacteries, 1 Acinetobacter baumanii et 1 Stenotrophomonas maltophilia, Le C/A ne constituait pas une strategie d’epargne des carbapenemes dans 91 % (30/33 ; 2 NR) des cas. La duree mediane de traitement etait de 7j [1–83] et 55 % (24/44) des prescriptions avaient recu l’avis de l’EMI. La mortalite a 30j etait de 23 % (8/35), liee en partie a l’infection dans 100 % (8/8) des cas. Conclusion En accord avec nos recommandations locales, ces resultats mettent en avant une prescription majoritairement documentee a BMR chez des P deja fragilises. Ces 2 ATB ne rentrent pas, a l’heure actuelle, dans une strategie d’epargne de prescription de carbapenemes.

A number of agents are now available for empirical antifungal treatment (EAFT) of patients with persistent fever and neutropenia. We carried out a study of efficacy of antifungal drugs to prevent breakthrough invasive aspergillosis by reviewing the medical records of all consecutive patients who received EAFT from November 2005 to February 2006. Patients’ characteristics and the type, dose and duration of antifungal therapy were recorded. Breakthrough invasive fungal infections were documented according to the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) definition. Fifty-six episodes of persistent fever with neutropenia requiring EAFT were recorded among 49 patients. All patients received high-dose chemotherapy for acute myeloid leukaemia (51%), acute lymphoid leukaemia (12%), lymphoma (14%) or other haematologic conditions (22%). Fourteen (29%) and five (10%) patients were allogeneic and autologous haematopoietic stem cell transplant recipients, respectively. Caspofungin was prescribed initially in 40 episodes (71%), amphotericin B (AmB) desoxycholate and liposomal AmB being prescribed in six (10%) and ten (18%) episodes, respectively. Six patients were switched from liposomal AmB to caspofungin because of adverse events. The median duration of antifungal therapy was 9 days. During follow-up, six patients (12%) were diagnosed with invasive aspergillosis after a median of 8 days (range 3–16 days) of EAFT. Invasive aspergillosis breakthrough occurred in 6/46 (13%) caspofungin recipients and in 0/16 (0%) AmB recipients (OR 3.1, p 0.32). The observed high rate of invasive aspergillosis among caspofungin recipients requires further evaluation.

Introduction Le dossier pharmaceutique (DP), mis en place en 2007, est un dossier electronique present sur la carte vitale, recensant, pour chaque beneficiaire de l’assurance maladie qui le souhaite, tous les medicaments delivres au cours des 4 derniers mois. D’abord reserve aux pharmaciens d’officine, son utilisation a ete etendue aux medecins et pharmaciens exercant dans les etablissements de sante. Afin de connaitre l’interet potentiel de la consultation du DP, nous avons voulu evaluer la place du DP parmi les autres sources disponibles sur les traitements medicamenteux a l’accueil de patients consultant dans un service d’urgences. Materiels et methode Etude prospective monocentrique realisee sur 3 mois, d’octobre a decembre 2016 a l’accueil du service des urgences de l’hopital Saint-Louis (AP–HP). Critere principal : pourcentage de presence d’un DP accessible et renseigne a l’accueil des urgences parmi d’autres sources comme une ordonnance ou un courrier medical precisant les traitements, ou un dossier informatise disponible a l’hopital (compte rendu d’hospitalisation [CRH]) avec traitement cite datant de moins d’1 an. Criteres secondaires : pourcentage de DP renseigne comme seule source d’information disponible et pourcentage de medicaments consideres comme a risque (anticoagulant/antiagregant plaquettaire, antibiotiques, antidiabetique) presents dans le DP lorsqu’il represente la seule source disponible. Resultats et discussion Sur les 260 patients inclus, 80 % d’entre eux avaient une carte vitale dont 63,5 % avec un DP renseigne. Une ordonnance/courrier ou un CRH informatif etaient disponibles dans 27 % des cas chacun. Dans 96 cas (37 %), il n’existait qu’une seule source disponible. Cette source unique etait le DP dans 72 % des cas, le CRH dans 16 % des cas et une ordonnance/courrier dans 12 % des cas. Quand le DP est la seule source disponible, 49 % d’entre eux contient au moins un medicament considere a risque (26 patients avaient un antibiotique, 6 un antidiabetique et 9 un anticoagulant/antiagregant plaquettaire). Conclusion Dans cette etude, le DP est la source documentaire de traitements medicamenteux la plus frequemment accessible a l’accueil des patients aux urgences et parfois la seule source documentaire accessible. La consultation du DP nous semble utile dans le cadre de la conciliation medicamenteuse dans un contexte d’urgence ou le patient peut-etre ininterrogeable. Des travaux complementaires sont necessaires pour evaluer l’impact du DP sur la prise en charge medicale des patients.

To the Editor: First-line antifungal therapy for invasive aspergillosis (IA) is voriconazole, which is challenged by the emergence of azole resistance (1). A recent article reported a 3.2% prevalence of Aspergillus fumigatus isolates that are resistant to azole from 3,788 isolates screened in Europe (2). Of the 1,911 patients from whom the isolates were collected, IA developed in 10 (3 proven, 1 probable, 6 possible). Prevalence of azole-resistant A. fumigatus disease among patient populations at risk of IA was unavailable. As described (3), we screened every A. fumigatus isolate recovered from respiratory specimens from patients with probable or proven IA in our hospital in Paris, France, during January 2012–December 2014. Every isolate recovered from 2% malt extract agar plates or Sabouraud dextrose agar slants (Bio-Rad, Marnes-la-Coquette, France) was incubated at 30°C and tested as individual isolates or multiple ones from a single sample by using itraconazole, voriconazole, and posaconazole Etest strips (bioMerieux, Marcy l’Etoile, France). Resistance was assessed for MICs >2.0 µg/µL for voriconazole and itraconazole and >0.25 µg/µL for posaconazole by using European Committee on Antimicrobial Susceptibility Testing clinical breakpoints for fungi (http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/AFST/Antifungal_breakpoints_v_7.0.pdf). Every 4 months, a local multidisciplinary medical team classified each IA case by using the 2008 criteria established by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (4). For 148 patients (127 with hematologic malignancies and 21 with other conditions), the team recorded 152 episodes: 9 proven and 143 probable IA episodes. Possible IA was not analyzed because of a lack of microbiologic criteria. For 51 probable IA episodes, galactomannan positivity in blood or bronchoalveolar lavage fluid samples was the only microbiologic criterion used for classification. Cultures of respiratory samples (i.e., bronchoalveolar lavage fluid, tracheal aspirate, and sputum) or biopsies were positive for 99 episodes: 68 with A. fumigatus isolates and 31 with other Aspergillus spp. isolates. Among the 68 A. fumigatus isolates, 1 (1.5%) associated with probable IA was resistant to azoles (5). The isolate harbored the TR34/L98H mutation (5), leading to a rate of IA caused by azole-resistant A. fumigatus of 0.7% (1/152) for total episodes recorded and 1% (1/99) for culture-positive episodes only. Nineteen (36%) of 53 culture-negative patients and 35 (37%) of 95 culture-positive patients died. Azole resistance of A. fumigatus warrants specific surveillance in hospitals treating immunocompromised patients. Prevalence of resistant isolates can differ by hospital location and underlying disease (e.g., immunodeficiency vs. chronic lung diseases). When focusing on patients with probable or proven IA, we did not observe an emergence of azole-resistant A. fumigatus isolates during 2006–2009 (3) and 2012–2014 in France. Consequently, our center does not question the use of voriconazole as first-line treatment or of posaconazole as prophylaxis.

Introduction Avec 9 services d’hematologie/oncologie et une unite de brules, notre hopital a eu une augmentation des diagnostics de mucormycose invasive, c’est pourquoi une etude epidemiologique de 2006 a 2016 a ete entreprise avec comme objectif d’analyser les facteurs predisposants (FDR), de faire une epidemiologie descriptive des cas et de leur evolution. Materiels et methodes Analyse retrospective des FDR, aspects cliniques, radiologiques, microbiologiques et de la survie de tous les patients avec un diagnostic de mucormycose invasive. Tous les cas ont ete valides par un comite mutidisciplinaire. Resultats Quarante-cinq cas de mucormycose invasive diagnostiques (10 avant 2011, et 35 apres) : 11 chez des brules severes, 27 en hematologie (14 leucemies aigues, 5 lymphomes, 4 myelodysplasies, 3 aplasie medullaire,1 autre) dont 14 allogreffes, 2 avec des cancers solides, 1 transplante renal, 4 avec un diabete seul. Le site de l’infection etait pulmonaire (19 cas, 22 %), sinusien (16 cas, 36 %), cutane (14 cas, 31 %), hepatique (3 cas, 7 %), autre (12 cas, 26 %), dissemine (4 cas, 9 %). L’examen direct montrait des filaments de type mucorales dans 35/42 (83 %) cas, avec une culture positive chez 23/40 (58 %), une PCR quantitative DNA mucorales (qPCR) serique dans 16/18 cas (89 %) et 9/13 biopsies effectuees (69 %). Une infection concommittante etait presente dans 16 (36 %) cas. Une exposition prealable aux antifongiques etait notee pour 27 (60 %) patients. Une chirurgie a ete effectuee dans 26 (58 %) cas, 40 (89 %) ont recu de l’ amphotericine B liposomale (amphB), 22 (49 %) du posaconazole, 7 de la caspofongine (16 %), 1 de l’isavuconazole (2 %), et 7 (16 %) ont eu un allegement du traitement immunosuppresseur. La mortalite a 3 mois etait de 50 %. Concernant les FDR, avoir recu prealablement au diagnostic de mucormycose du voriconazole (HR : 2,4 (1,2–4,6) p : 0,008) ou du fluconazole (HR : 2,5 (1,0–6,2), p : 0,02) etaient associes a un risque accru de mortalite mais pas les autres antifongiques. En traitements curatifs, avoir recu de l’amphB (HR : 0,4 (0,1–0,97), p : 0,04) ou du posaconazole (HR : 0,3 (0,2–0,68), p : 0,002) etaient protecteur mais l’association d’une chirurgie ( p :0,2) ou de caspofongine ( p :0,9) etaient non significatives. Conclusion Notre etude permet d’avoir une analyse epidemiologique recente des mucormycoses invasives et des challenges restant. La mortalite reste elevee chez les patients d’hematologie et les brules. Depuis 2 ans, des outils moleculaires par qPCR ont permis de faire des diagnostics plus rapides, les patients severement brules sont maintenant screenes par qPCR et nous esperons voir prochainement une baisse de la mortalite.

Introduction L’incidence de l‘aspergillose invasive (AI) chez le patient transplante renal (PTR) est plus faible que chez les autres patients transplantes d’organes solides, rendant difficile l’analyse des facteurs de risque et pronostic d’IA dans cette population. Materiels et methodes Une etude monocentrique retrospective cas–temoins entre 2006 et 2016 a ete menee dans le service de transplantation renale (TR) d’un hopital universitaire incluant tous les PTR avec un diagnostic d’IA probable ou prouvee selon les criteres EORTC/MSG 2008. Les temoins transplantes renaux ont ete inclus en fonction de la date de transplantation du cas (immediatement avant ou apres la date de transplantation du cas), avec un ratio 1:3 (39 temoins). Resultats Treize cas ont ete inclus (12 IA probables et 1 prouvees), dont 11 (85 %) survenus > 6 mois apres la TR. L’age median etait de 63 ans, sans ATCD de BPCO connu ni d’infection recente grippale, 3 patients etaient diabetiques (23 %), 10 (77 %) avec une co-infection CMV dans les 6 mois precedent l’IA. L’AI etait d’origine pulmonaire dans 10 (77 %) cas, atteinte bilaterale dans 10 cas (77 %), condensation alveolaire dans 8 cas (62 %), atteinte nodulaire (micro ou macronodules dont 4 avec halo de verre depoli), dans 10 cas (77 %), sinusienne dans 3 cas (23 %), cerebrale 1 cas, disseminee 2 cas (15 %). L’antigene galactomannane etait > 0,5 dans 7 (54 %) cas. En comparaison avec les temoins, les cas etaient + leucopenique (leucocytes 3 au diagnostic d’IA, 12 [92 %] cas vs 1 temoin [3 %]), + lymphopeniques (200/mm 3 versus 640/mm 3 lymphocytes en mediane chez les cas et temoins respectivement [ p : 0,03]), avaient plus de co-infections bacteriennes au diagnostic d’IA (OR : 16 ; IC 95 % : 2,0–132,4 ; p : 0,009), de facon non significative une majoration de la corticotherapie > 0,2 mg/kg dans les 6 mois precedant l’AI (3 [23 %] cas vs 0 temoin). La survie a 3 mois, 1 an et 3 ans apres l’IA etait de 83 % (IC 95 : 0,65–1), 74 % (IC 95 : 0,53–1) et 49 % (IC 95 : 0,21–1) respectivement alors que la survie a 1 an chez les PTR dans les registres nationaux est de 90 %. Conclusion L’IA chez les PTR est associee a un mauvais pronostic avec un taux de mortalite a 1 an de 26 % malgre un traitement par voriconazole chez tous les patients. Les facteurs classiques predisposant d’IA etaient absents chez la majorite des patients, ceux-ci n’avaient pas egalement de pathologie chronique pulmonaire. Une etude plus large serait interessante pour affiner les facteurs de risque d’IA chez le PTR, en recherchant notamment d’autres facteurs lies a l’hote, afin d’ameliorer le depistage et le pronostic.

Introduction L’utilisation du dossier pharmaceutique (DP), cree et deploye en officine depuis 2007, est en experimentation nationale pilotee par le Conseil national de l’Ordre des pharmaciens et la direction generale de l’Offre de soins depuis 2013 dans des services d’anesthesie, de geriatrie et des urgences des hopitaux volontaires. Le service des urgences de notre etablissement participe a cette experimentation. Apres une phase de travail d’amelioration d’accessibilite au logiciel de consultation du DP, puis du positionnement du DP parmi les sources documentaires medicamenteuses pour des patients admis dans l’unite d’hospitalisation des urgences, une etude a ete realisee a l’accueil des urgences. Materiels et methode Enquete prospective menee par un externe en pharmacie entre le 1er avril et le 30 juin 2015 aupres de tous les entrants entre 9 h et 12 h 30, du lundi au vendredi. L’evaluation a porte sur : l’accessibilite du DP via la carte vitale necessaire a la connexion, l’accord du patient pour sa consultation, la presence effective du DP a l’aide du logiciel « Fast.Dossier-Pharmaceutique.fr », la connaissance des patients (pts) de leur DP et le temps necessaire a la consultation. Resultats et discussion Sept cents patients ont ete interroges : 433 (62 %) avaient leur carte vitale ; 426 patients (61 %) ont donne leur accord pour consultation des donnees de la carte vitale, 265 (61 %) avaient un DP ouvert dont 247 (93 %) etaient renseignes. Seuls 47/265 patients (18 %) avaient ete informes de l’ouverture dans une officine de leur propre DP. Le temps median de consultation du DP a ete de 1,7 min. Cette etude met en evidence une meconnaissance generale des patients vis-a-vis du DP et notamment de l’ouverture de celui-ci. Il n’est pas exclu qu’un certain nombre de patients se disant non informes l’aient effectivement ete, puis ont oublie, neanmoins, cela souleve un probleme ethique. A noter, que lorsqu’un DP est ouvert, il est quasi-constamment renseigne. Notre etude n’a pas porte sur l’exhaustivite des donnees contenues dans le DP. Un temps de consultation de moins de 2 min nous parait compatible avec une consultation quasi-systematique du DP et un externe en pharmacie dedie le permet avec la limite d’une presence a mi-temps. Conclusion Ce travail qui a permis d’assurer une information sur le DP sera complete par une analyse de la connaissance des patients de leur(s) traitement(s). Parallelement, l’apport du DP en tant que source d’information a l’admission aux urgences sera examine, dans l’optique d’une optimisation de la prise en charge des patients.

Early evaluation of treatment efficacy in invasive aspergillosis (IA), a leading cause of morbidity and mortality in hematological patients, remains a challenge. We conducted a prospective study to evaluate the performance of different markers in predicting the outcome of patients with IA. Both clinical and biological criteria were assessed 7, 14, 21, and 45 days after inclusion in the study, and mortality was assessed at day 60. The association between baseline data and their evolution and the day 45 response to treatment was analyzed. A total of 57 patients (4 with proven, 44 with probable, and 9 with possible aspergillosis according to the revised EORTC/MSG [European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and National Institute of Allergy and Infectious Diseases Mycoses Study Group] definitions) were included. At day 45, 30 patients (53%) were determined to be responders, 25 (44%) were nonresponders, and 2 were not able to be evaluated. Twenty patients died within the 60 days of follow-up. We found that a poor day 45 outcome was associated with patients who had high baseline serum galactomannan (GM) antigen levels and those receiving steroids at the time of IA. A consistently negative serum GM index was associated with a good outcome, and the day 14 clinical evaluation was predictive of the day 45 outcome. No association was found between Aspergillus antibodies or DNA detection and patients' outcome. We conclude that the GM index value at diagnosis of IA, GM index kinetics, and clinical evaluation at day 14 are good markers for predicting the outcome of patients with IA and should be taken into account for adapting antifungal treatment.

Several reports have described a high rate of false-positive Aspergillus galactomannan (GM) test results for patients treated with piperacillin-tazobactam. In this retrospective study, we first examined the relationships between intravenous administration of three β-lactam antibiotics and the occurrence of false-positive GM test results in hematology patients. We then estimated the kinetics of clearance of GM after the cessation of treatment. Sequential serum samples from 69 patients that had received β-lactams were analyzed by using a Platelia Aspergillus test. A significant association was found between GM positivity (≥0.5) and the administration of β-lactams ( P < 0.0001). The direct role of β-lactams in patients' serum positivity was assessed by testing 39 batches of β-lactams, of which 27 were positive for GM. None of the latter were positive according to a fungus- and Aspergillus -specific PCR. The kinetics of the decrease of GM was analyzed on sequential serum samples obtained after treatment. By use of a nonlinear regression model, the average time to negative antigen was assessed to be 5.5 days (95% confidence interval [CI], 4.1 to [7.0]), with a half-life of elimination of GM of 2.4 days (95% CI, 1.8 to 3.0). This study confirms that the administration of β-lactams containing GM is responsible for false-positive diagnostic results, even up to 5 days after the cessation of treatment.

The circular on the sterilization and the law of july 1, 1998 enact clearly that the medical devices that support steam sterilization must be sterilized with an organization of sterilization that ensure quality. Endoscope that enter normally sterile tissues should be subjected to a sterilization procedure before each use; if this is not feasible, they should receive high-level disinfection to destroy bacterial spores. The endoscope must be immersed for at least one hour in aqueous solution of 2% glutaraldehyde. This lengthened duration of processing must be integrate in the organization of medical department. The endoscopes not penetrating in a sterile cavity are disinfected with manual processing according to the protocol of the circular of april 1996, or with automated endoscope reprocessing machine. The different types of automated machine used to wash and disinfect endoscope must now answer to criterion concerning their design described in the circular of july 15, 1998. A significant work has to be made in hospitals to conform automated machine and procedure, to control the risk dependent with their use.

To the Editor: The detection of aspergillus galactomannan antigenemia is a method used in the diagnosis of invasive aspergillosis.1,2 Some transient false positive reactions have been reported with the use of enzyme-linked immunosorbent assays in relation to the passage of galactomannan of food origin through the intestinal mucosa or in relation to possible interactions with antibiotics, including piperacillin.3 We report a recent marked increase in the frequency of false positive tests and its relation to the concomitant administration of piperacillin and tazobactam. Between May 1 and July 15, 2003, 931 serum samples were examined for the presence of galactomannan . . .

Background: The detection of Aspergillus galactomannan antigenemia (GM-Ag) is a contributive method in the diagnosis of invasive aspergillosis (IA). Herein, we report 3 cases of false positive GM-Ag in paediatric patients (pts) receiving NP2 Enfants AP-HP® parenteral nutrition (Fresenius, France), and none of them had or developed IA. Methods: In December 2006, the sera of these 3 pts (1 allogeneic transplant recipient and 2 neutropenic acute leukaemia pts) taken before, during, and after cessation of NP2 solution were tested for the presence of GM-Ag using the Platelia® Aspergillus kit. This solution, its 30 components and 8 other commercially available solutions for parenteral nutrition were tested for the presence of GM. Results: GM became detectable within 1 day after IV administration of NP2 with indices up to 9.25, remained positive throughout treatment, and became negative (≤0.5) within 48 hours in 2/3 pts. The NP2 solution and a single one of its components, sodium gluconate (SG), tested positive with GM estimated at 55.4ng/ml. No Aspergillus DNA was detected by real-time PCR. Three NP2 and 6 SG batches from different origins yielded similar results. On the other hand, 6 different batches of calcium gluconate and 8 other commercially available SG-free parenteral nutrition solutions tested negative. Conclusions: These results suggest a strong cross reactivity of Platelia® kit with SG-containing NP2, as recently described with Plasma-Lyte® (Baxter Distribution Centre Europe). We estimate that clinicians and biologists should become aware of this problem which might lead to inappropriate invasive investigations and/or treatments.

International audience; The French National Reference Center for Invasive Mycoses and Antifungals leads an active and sustained nationwide surveillance program on probable and proven invasive fungal diseases (IFDs) to determine their epidemiology in France. Between 2012 and 2018, a total of 10,886 IFDs were recorded. The incidence increased slightly over time (2.16 to 2.36/10,000 hospitalization days, P = 0.0562) in relation with an increase of fungemia incidence (1.03 to 1.19/10,000, P = 0.0023), while that of other IFDs remained stable. The proportion of ≥65-year-old patients increased from 38.4% to 45.3% (P < 0.0001). Yeast fungemia (n = 5,444) was due mainly to Candida albicans (55.6%) with stable proportions of species over time. Echinocandins became the main drug prescribed (46.7% to 61.8%), but global mortality rate remained unchanged (36.3% at 1 month). Pneumocystis jirovecii pneumonia (n = 2,106) was diagnosed mostly in HIV-negative patients (80.7%) with a significantly higher mortality than in HIV-positive patients (21.9% versus 5.4% at 1 month, P < 0.0001). Invasive aspergillosis (n = 1,661) and mucormycosis (n = 314) were diagnosed mostly in hematology (>60% of the cases) with a global mortality rate of 42.5% and 59.3%, respectively, at 3 months and significant changes in diagnosis procedure over time. More concurrent infections were also diagnosed over time (from 5.4% to 9.4% for mold IFDs, P = 0.0115). In conclusion, we observed an aging of patients with IFD with a significant increase in incidence only for yeast fungemia, a trend toward more concurrent infections, which raises diagnostic and therapeutic issues. Overall, global survival associated with IFDs has not improved despite updated guidelines and new diagnostic tools.IMPORTANCE The epidemiology of invasive fungal diseases (IFDs) is hard to delineate given the difficulties in ascertaining the diagnosis that is often based on the confrontation of clinical and microbiological criteria. The present report underlines the interest of active surveillance involving mycologists and clinicians to describe the global incidence and that of the main IFDs. Globally, although the incidence of Pneumocystis pneumonia, invasive aspergillosis, and mucormycosis remained stable over the study period (2012 to 2018), that of yeast fungemia increased slightly. We also show here that IFDs seem to affect older people more frequently. The most worrisome observation is the lack of improvement in the global survival rate associated with IFDs despite the increasing use of more sensitive diagnostic tools, the availability of new antifungal drugs very active in clinical trials, and a still low/marginal rate of acquired in vitro resistance in France. Therefore, other tracks of improvement should be investigated actively.