In Vitro Antifungal Activity of Ibrexafungerp (SCY-078) Against Contemporary Blood Isolates From Medically Relevant Species of Candida: A European Study

BackgroundIbrexafungerp (SCY-078) is the newest oral and intravenous antifungal drug with broad activity, currently undergoing clinical trials for invasive candidiasis. ObjectiveThe aim of this study was to assess the in vitro activity of ibrexafungerp and comparators against a collection of 434 European blood isolates of Candida. MethodsIbrexafungerp, caspofungin, fluconazole, and micafungin minimum inhibitory concentrations (MICs) were collected from 12 European laboratories for 434 blood isolates, including 163 Candida albicans, 108 Candida parapsilosis, 60 Candida glabrata, 40 Candida tropicalis, 29 Candida krusei, 20 Candida orthopsilosis, 6 Candida guilliermondii, 2 Candida famata, 2 Candida lusitaniae, and 1 isolate each of Candida bracarensis, Candida catenulata, Candida dubliniensis, and Candida kefyr. MICs were determined by the EUCAST broth microdilution method, and isolates were classified according to recommended clinical breakpoints and epidemiological cutoffs. Additionally, 22 Candida auris from different clinical specimens were evaluated. ResultsIbrexafungerp MICs ranged from 0.016 to >= 8 mg/L. The lowest ibrexafungerp MICs were observed for C. albicans (geometric MIC 0.062 mg/L, MIC range 0.016-0.5 mg/L) and the highest ibrexafungerp MICs were observed for C. tropicalis (geometric MIC 0.517 mg/L, MIC range 0.06->= 8 mg/L). Modal MICs/MIC(50)s (mg/L) against Candida spp. were 0.125/0.06 for C. albicans, 0.5/0.5 for C. parapsilosis, 0.25/0.25 for C. glabrata, 0.5/0.5 for C. tropicalis, 1/1 for C. krusei, 4/2 for C. orthopsilosis, and 0.5/0.5 for C. auris. Ibrexafungerp showed activity against fluconazole- and echinocandin-resistant isolates. If adopting wild-type upper limits, a non-wild-type phenotype for ibrexafungerp was only observed for 16/434 (3.7%) isolates: 11 (4.6%) C. parapsilosis, 4 (5%) C. glabrata, and 1 (2.5%) C. tropicalis. ConclusionIbrexafungerp showed a potent in vitro activity against Candida.This study received funding from SCYNEXIS. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of the article, or the decision to submit it for publication. CM-A is a recipient of a grant from Fundació n ONCE (Oportunidad al Talento). EE, AG, NJ, CM-A, and GQ have received grant support from Consejerı́a de Educación, Universidades e Investigación del Gobierno Vasco (GIC15 IT-990-16), Fondo de Investigación Sanitaria del Gobierno de España (FIS PI11/00203), and UPV/EHU (UFI 11/25). All authors declare no other competing interests

Failure of Vitek2 to reliably detect vanB-mediated vancomycin resistance in Enterococcus faecium

Objectives: The increasing prevalence of VRE necessitates their reliable detection, especially for Low-Level resistance mediated by vanB in Enterococcus faecium. In this prospective study we analysed if vanB-mediated vancomycin resistance can be reliably detected by Vitek2. Methods: One thousand, three hundred and forty-four enterococcal isolates from routine clinical specimens were tested by Vitek2 (bioMerieux, Nurtingen, Germany). Additionally, a bacterial suspension (with a turbidity equivalent to that of a 0.5 McFarland standard) was inoculated on chromlD VRE screening agar (bioMerieux) and incubated for 48 h. If vancomycin tested susceptible by Vitek2 but growth was detected on the screening agar, PCR for vanA/vanB was performed (GeneXpert vanA/B test, Cepheid, Frankfurt, Germany). For isolates that tested susceptible to vancomycin by Vitek2 but were vanA/B positive, MICs were determined before and after cultivation in broth with increasing concentrations of vancomycin. Results: One hundred and fifty-six out of 491 E. faecium were VRE and were predominantly vanB positive (81.0%). Of these, Vitek2 did not identify 14 as VRE (sensitivity 91.0%). By broth microdilution 9/14 isolates demonstrated high MICs (>= 32 mg/L) and 5/14 showed Low vancomycin MICs, which did not increase despite vancomycin exposure. Three of the 14 isolates demonstrated growth on chromlD VRE; after vancomycin exposure seven additional isolates were able to grow on chromlD VRE. Conclusions: Vitek2 fails to detect vanB-mediated vancomycin resistance consistently, especially, but not Limited to, Low-Level resistance. As this may Lead to treatment failure and further dissemination of vanB VRE, additional methods (e.g. culture on VRE screening agar or PCR) are necessary to reliably identify vanB-positive enterococci in clinical routine

Performance of two MALDI-TOF MS systems for the identification of yeasts isolated from bloodstream infections and cerebrospinal fluids using a time-saving direct transfer protocol

The rapid and correct identification of pathogens is of paramount importance for the treatment of patients with invasive infections. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) can speed up the identification of bacteria and fungi and has quickly been embraced by medical microbiology laboratories worldwide. Different MALDI-TOF systems have been compared in studies focussing on identification rates of different pathogens. Another aspect that has not been systematically assessed is the performance in daily routine and handling, which is important especially for microbiology routine laboratories. We compared two widespread commercial systems, Microflex LT Biotyper (Bruker) and VitekMS (bioM,rieux), for the identification of 210 relevant clinical yeasts under routine conditions, using a time-saving direct transfer protocol. We assessed the need for an additional extraction step, the threshold for species identification and the duration of measurements with the two systems. The tested yeasts included 34 Candida albicans isolates, 144 non-albicans Candida spp. and 32 yeasts of different genera. The results of the two MS systems were compared with that of biochemical identification and, in case of discrepancies, DNA sequencing of the internal transcribed spacer or the large subunit of ribosomal DNA. Both systems correctly identified 96.2 % of isolates [202/210, non-significant (n.s.)]. Misidentifications were observed for VitekMS only (n = 5, no major errors, n.s.). VitekMS was the slower system (19.8 vs. 8.0 min for 10 samples, p = 0.002) but had the advantage of a more effective direct transfer protocol with less need for an additional extraction step

Comparison of Phenotypic Tests and an Immunochromatographic Assay and Development of a New Algorithm for Detection of OXA-48-like Carbapenemases

OXA-48 is the most prevalent carbapenemase in Enterobacteriaceae in Europe and the Middle East, but it is frequently missed because many isolates display low MICs for carbapenems. Furthermore, in contrast to metallo-beta-lactamases or Klebsiella pneumoniae carbapenemases (KPC), no specific inhibitor is available for the phenotypic detection of OXA-48. Molecular detection of blaOXA-48 is the gold standard but is not available in many laboratories. A few phenotypic assays have been described but have not been independently evaluated. The aim of this study was the systematic comparison of phenotypic tests and an immunochromatographic assay (ICT) for the detection of OXA-48/OXA-48-like carbapenemases and the development of an algorithm for reliable phenotypic detection of OXA-48. Four phenotypic tests (temocillin disk test, faropenem disk test, OXA-48 disk test, and high-inoculum [HI] OXA-48 disk test) and a new ICT (OXA-48 K-SeT) were compared by using a set of 166 Enterobacteriaceae isolates, including isolates producing OXA-48/OXA-48-like carbapenemases (n = 84) or Ambler class A and B carbapenemases (n = 41) and carbapenemase-negative isolates (n = 41). The sensitivity and specificity for the different assays were 100% and 43.9% for temocillin, 57.1% and 98.8% for faropenem, 53.6% and 100% for the OXA-48 disk test, 98.8% and 97.6% for the HI OXA-48 disk test, and 100% and 100% for the ICT, respectively. The ICT displayed the highest sensitivity and specificity and was the most rapid assay, but it is more costly than phenotypic assays. Based on these results, a new algorithm incorporating temocillin, faropenem, and ICT which allows cost-effective detection of OXA-48 with 100% sensitivity and specificity was developed

Surgical Implications for Diagnosis and Treatment of Intestinal Aspergillosis in Pediatric Patients with ALL

Background The incidence of invasive aspergillosis (IA) in children with hematooncological malignancies is increasing as a result of intensive treatment, immunosuppression, and extended use of broad-spectrum antibiotics. Infection of the GI tract by Aspergillus spp. is a rare and fatal complication, which often requires surgical diagnostic and therapeutic exploration. Objective The aim of this study was to determine the characteristics of symptomatic intestinal aspergillosis, diagnosis, treatment, and outcome of pediatric patientswith an underlying hemato-oncologic disease. Patients andMethods We analyzed 2,307 German patients with acute lymphoblastic leukemia (ALL) from age 1 to 17 years registered in the AIEOP-BFM ALL 2000 study from 2000 to 2006. All reported adverse events were assessed for symptoms of IA and retrospectively reviewed for any sign or proof of intestinal involvement of IA. Results In this cohort, IA was reported in 30 of 2,307 patients while intestinal involvement was documented in five patients. Four of these patients had intestinal symptoms and three patients underwent explorative laparotomy. Among clinical cases with IA, gastrointestinal manifestation of IA mostly occurred in adolescent patients (10-16 years). Symptoms varied from abdominal tenderness and pain to constipation. Intestinal aspergillosis was proven by microbiological and histopathological examination and fungal infection was observed macroscopically in the jejunal lumen during surgery. Despite the extended surgery and antifungal therapy, outcome of disseminated IA with intestinal involvement remains poor. Conclusion Surgeons should be aware of surgical complications of intestinal aspergillosis in children with hematooncological diseases requiring exploration and resection. IA is a rare event and still difficult to diagnose due to unspecific abdominal symptoms. Thus, biopsy sampling is of utmost importance to ensure diagnosis, and resection of necrotic or perforated tissue should be attempted early

Incidence of infections due to third generation cephalosporin-resistant Enterobacteriaceae - a prospective multicentre cohort study in six German university hospitals

BackgroundInfections caused by third generation cephalosporin-resistant Enterobacteriaceae (3GCREB) are an increasing healthcare problem. We aim to describe the 3GCREB infection incidence and compare it to prevalence upon admission. In addition, we aim to describe infections caused by 3GCREB, which are also carbapenem resistant (CRE).MethodsIn 2014-2015, we performed prospective 3GCREB surveillance in clinically relevant patient specimens (screening specimens excluded). Infections counted as hospital-acquired (HAI) when the 3GCREB was detected after the third day following admission, otherwise as community-acquired infection (CAI).ResultsOf 578,420 hospitalized patients under surveillance, 3367 had a 3GCREB infection (0.58%). We observed a similar 3GCREB CAI and HAI incidence (0.28 and 0.31 per 100 patients, respectively). The most frequent pathogen was 3GCR E. coli, in CAI and HAI (0.15 and 0.12 per 100 patients). We observed a CRE CAI incidence of 0.006 and a HAI incidence of 0.008 per 100 patients (0.014 per 1000 patient days).ConclusionsComparing the known 3GCREB admission prevalence of the participating hospitals (9.5%) with the percentage of patients with a 3GCREB infection (0.58%), we conclude the prevalence of 3GCREB in university hospitals to be about 16 times higher than suggested when only patients with 3GCREB infections are considered. Moreover, we find the HAI and CAI incidence caused by CRE in Germany to be relatively low

Invasive Pilzinfektionen - Diagnostik

Invasive Pilzinfektionen sind eine wesentliche Ursache von Morbidität und Letalität bei Patienten mit malignen hämatologischen Systemerkrankungen. Die häufigsten pathogenen Pilze sind Aspergillus- und Candida-Spezies. In zunehmendem Maße werden aber auch andere Pilze wie Zygomyzeten, Trichosporon, Fusarium spp. u. a. gefunden. Die exakte Diagnose einer invasiven Pilzinfektion (Mykose) erfordert eine Kombination diagnostischer Maßnahmen, einschl. konventioneller Pilzkulturen, weiterer mikrobiologischer Tests wie Antikörper/Antigen-Reaktionen und Molekularbiologie, Histopathologie und Bildgebung. Das Risiko invasiver Pilzinfektionen ist am höchsten nach allogener Stammzelltransplantation und bei Patienten mit akuter Leukämie, deutlich niedriger bei Patienten mit soliden Tumoren. Die Leitlinie 'Diagnosis of Invasive Fungal Infections in Haematology and Oncology: 2018 update of the recommendations of the infectious diseases working party of the German society for hematology and medical oncology (AGIHO)' wurde von der Arbeitsgemeinschaft Infektionen der DGHO (AGIHO) erstellt [1]. Grundlagen sind eine systematische Literaturrecherche, die einheitliche Bewertung der Evidenzstärke [2] und ein Konsensfindungsprozess. Dies ist die Kurzfassung dieser Empfehlungen