[Central nervous system infections and targeted therapies: what to consider]. / Infections du système nerveux central et thérapies ciblées : à quoi faut-il penser ?

The development of targeted therapies has revolutionized the approach to immunosuppression in several medical specialties. While the prescriber of these therapies is familiar with these agents, both the general internist and the infectious disease specialist must deal with the consequences of these products. Encephalitis, for which prompt and appropriate management is paramount, is a challenge in the patient undergoing immunomodulatory therapies because of its atypical presentation, the involvement of particular germs and the potential brain toxicity of some immunomodulatory treatments. This article outlines the mechanisms of action of some targeted therapies and reviews the associated brain infections.

Le développement des thérapies ciblées a révolutionné l'approche de l'immunosuppression dans plusieurs spécialités médicales. Si le prescripteur de ces thérapies est familiarisé avec ces agents, l'interniste généraliste et l'infectiologue doivent tous deux faire face aux conséquences de ces produits. Les encéphalites, dont la prise en charge rapide et adéquate est primordiale, représentent un défi chez le patient soumis aux thérapies immunomodulatrices, en raison de leur présentation atypique, de l'implication de germes particuliers et de la toxicité cérébrale potentielle de certains traitements immunomodulateurs. Cet article expose les mécanismes d'action de certaines thérapies ciblées et passe en revue les infections de l'encéphale qui y sont associées.

Frequency and causes of antifungal treatment changes in allogeneic haematopoïetic cell transplant recipients with invasive mould infections.

BACKGROUND: Antifungal treatment duration and changes for invasive mould infections (IMI) have been poorly described. METHODS: We performed a 10-year cohort study of adult (≥18-year-old) allogeneic haematopoietic cell transplant recipients with proven/probable IMI to describe the duration and changes of antifungal treatment. All-cause-12-week mortality was described. RESULTS: Sixty-one patients with 66 IMI were identified. Overall treatment duration was 157 days (IQR: 14-675) and 213 (IQR: 90-675) days for patients still alive by Day 84 post-IMI diagnosis. There was at least one treatment change in 57/66 (86.4%) cases: median 2, (IQR: 0-6, range:0-8). There were 179 antifungal treatment changes due to 193 reasons: clinical efficacy (104/193, 53.9%), toxicity (55/193, 28.5%), toxicity or drug interactions resolution (15/193, 7.8%) and logistical reasons (11/193, 5.7%) and 15/193 (7.8%) changes due to unknown reasons. Clinical efficacy reasons included lack of improvement (34/104, 32.7%), targeted treatment (30/104, 28.8%), subtherapeutic drug levels (14/104, 13.5%) and other (26/104, 25%). Toxicity reasons included hepatotoxicity, nephrotoxicity, drug interactions, neurotoxicity and other in 24 (43.6%), 12 (21.8%), 12 (21.8%), 4 (7.4%) and 3 (5.5%) cases respectively. All-cause 12-week mortality was 31% (19/61), higher in patients whose antifungal treatment (logrank 0.04) or appropriate antifungal treatment (logrank 0.01) was started >7 days post-IMI diagnosis. All-cause 1-year mortality was higher in patients with ≥2 changes of treatment during the first 6 weeks post-IMI diagnosis (logrank 0.008) with an OR: 4.00 (p = .04). CONCLUSIONS: Patients with IMI require long treatment courses with multiple changes for variable reasons and potential effects on clinical outcomes, demonstrating the need more effective and safer treatment options. Early initiation of appropriate antifungal treatment is associated with improved outcomes.

Trends of the Epidemiology of Candidemia in Switzerland: A 15-Year FUNGINOS Survey.

BACKGROUND: The increasing incidence of candidemia and emergence of drug-resistant Candida species are major concerns worldwide. Long-term surveillance studies are needed. METHODS: The Fungal Infection Network of Switzerland (FUNGINOS) conducted a 15-year (2004-2018), nationwide, epidemiological study of candidemia. Hospital-based incidence of candidemia, Candida species distribution, antifungal susceptibility, and consumption were stratified in 3 periods (2004-2008, 2009-2013, 2014-2018). Population-based incidence over the period 2009-2018 derived from the Swiss Antibiotic Resistance Surveillance System (ANRESIS). RESULTS: A total of 2273 Candida blood isolates were studied. Population and hospital-based annual incidence of candidemia increased from 2.96 to 4.20/100 000 inhabitants (P = .022) and 0.86 to 0.99/10 000 patient-days (P = .124), respectively. The proportion of Candida albicans decreased significantly from 60% to 53% (P = .0023), whereas Candida glabrata increased from 18% to 27% (P < .0001). Other non-albicans Candida species remained stable. Candida glabrata bloodstream infections occurred predominantly in the age group 18-40 and above 65 years. A higher proportional increase of C glabrata was recorded in wards (18% to 29%, P < .0001) versus intensive care units (19% to 24%, P = .22). According to Clinical and Laboratory Standards Institute, nonsusceptibility to fluconazole in C albicans was observed in 1% of isolates, and anidulafungin and micafungin nonsusceptibility was observed in 2% of C albicans and C glabrata. Fluconazole consumption, the most frequently used antifungal, remained stable, whereas use of mold-active triazoles and echinocandins increased significantly in the last decade (P < .0001). CONCLUSIONS: Over the 15-year period, the incidence of candidemia increased. A species shift toward C glabrata was recently observed, concurring with increased consumption of mold-active triazoles.

Transcriptomic Signature Differences Between SARS-CoV-2 and Influenza Virus Infected Patients.

The reason why most individuals with COVID-19 have relatively limited symptoms while other develop respiratory distress with life-threatening complications remains unknown. Increasing evidence suggests that COVID-19 associated adverse outcomes mainly rely on dysregulated immunity. Here, we compared transcriptomic profiles of blood cells from 103 patients with different severity levels of COVID-19 with that of 27 healthy and 22 influenza-infected individuals. Data provided a complete overview of SARS-CoV-2-induced immune signature, including a dramatic defect in IFN responses, a reduction of toxicity-related molecules in NK cells, an increased degranulation of neutrophils, a dysregulation of T cells, a dramatic increase in B cell function and immunoglobulin production, as well as an important over-expression of genes involved in metabolism and cell cycle in patients infected with SARS-CoV-2 compared to those infected with influenza viruses. These features also differed according to COVID-19 severity. Overall and specific gene expression patterns across groups can be visualized on an interactive website (https://bix.unil.ch/covid/). Collectively, these transcriptomic host responses to SARS-CoV-2 infection are discussed in the context of current studies, thereby improving our understanding of COVID-19 pathogenesis and shaping the severity level of COVID-19.

Invasive Aspergillosis Due to Aspergillus Section Usti: A Multicenter Retrospective Study.

BACKGROUND: Aspergillus spp. of section Usti (A. ustus) represent a rare cause of invasive aspergillosis (IA). This multicenter study describes the epidemiology and outcome of A. ustus infections. METHODS: Patients with A. ustus isolated from any clinical specimen were retrospectively identified in 22 hospitals from 8 countries. When available, isolates were sent for species identification (BenA/CaM sequencing) and antifungal susceptibility testing. Additional cases were identified by review of the literature. Cases were classified as proven/probable IA or no infection, according to standard international criteria. RESULTS: Clinical report forms were obtained for 90 patients, of whom 27 had proven/probable IA. An additional 45 cases were identified from literature review for a total of 72 cases of proven/probable IA. Hematopoietic cell and solid-organ transplant recipients accounted for 47% and 33% cases, respectively. Only 8% patients were neutropenic at time of diagnosis. Ongoing antimold prophylaxis was present in 47% of cases. Pulmonary IA represented 67% of cases. Primary or secondary extrapulmonary sites of infection were observed in 46% of cases, with skin being affected in 28% of cases. Multiple antifungal drugs were used (consecutively or in combination) in 67% of cases. The 24-week mortality rate was 58%. A. calidoustus was the most frequent causal agent. Minimal inhibitory concentrations encompassing 90% isolates (MIC90) were 1, 8, >16, and 4 µg/mL for amphotericin B, voriconazole, posaconazole, and isavuconazole, respectively. CONCLUSIONS: Aspergillus ustus IA mainly occurred in nonneutropenic transplant patients and was frequently associated with extrapulmonary sites of infection. Mortality rate was high and optimal antifungal therapy remains to be defined.

Characteristics, comorbidities, 30-day outcome and in-hospital mortality of patients hospitalised with COVID-19 in a Swiss area - a retrospective cohort study.

BACKGROUND: Since its first description in December 2019, coronavirus disease 19 (COVID-19) has spread worldwide. There is limited information about presenting characteristics and outcomes of Swiss patients requiring hospitalisation. Furthermore, outcomes 30 days after onset of symptoms and after hospital discharge have not been described. AIMS: To describe the clinical characteristics, outcomes 30 days after onset of symptoms and in-hospital mortality of a cohort of patients hospitalised for COVID-19 in a Swiss area. METHODS: In this retrospective cohort study, we included all inpatients hospitalised with microbiologically confirmed COVID-19 between 1 March and 12 April 2020 in the public hospital network of a Swiss area (Fribourg). Demographic data, comorbidities and outcomes were recorded. Rate of potential hospital-acquired infection, outcomes 30 days after onset of symptoms and in-hospital mortality are reported. RESULTS: One hundred ninety-six patients were included in the study. In our population, 119 (61%) were male and the median age was 70 years. Forty-nine patients (25%) were admitted to the intensive care unit (ICU). The rate of potential hospital-acquired infection was 7%. Overall, 30 days after onset of symptoms 117 patients (60%) had returned home, 23 patients (12%) were in a rehabilitation facility, 18 patients (9%) in a medical ward, 6 patients (3%) in ICU and 32 (16%) patients had died. Among patients who returned home within 30 days, 73 patients (63%) reported persistent symptoms. The overall in-hospital mortality was 17%. CONCLUSION: We report the first cohort of Swiss patients hospitalised with COVID-19. Thirty days after onset of the symptoms, 60% had returned home. Among them, 63% still presented symptoms. Studies with longer follow-up are needed to document long-term outcomes in patients hospitalised with COVID-19.

Clinical Relevance and Characteristics of Aspergillus calidoustus and Other Aspergillus Species of Section Usti.

The Aspergilli of section Usti (group ustus) are represented by over 20 species, of which Aspergillus calidoustus is the most relevant human pathogen. Invasive aspergillosis (IA) caused by these fungi is rare but could represent an emerging issue among the expanding population of patients with long-term immunosuppression receiving antifungal prophylaxis. Clinicians should be aware of this unusual type of IA, which often exhibits distinct clinical features, such as an insidious and prolonged course and a high occurrence of extra-pulmonary manifestations, such as skin/soft tissue or brain lesions. Moreover, these Aspergillus spp. pose a therapeutic challenge because of their decreased susceptibility to azole drugs. In this review, we outline the microbiological and clinical characteristics of IA due to Aspergillus spp. of section Usti and discuss the therapeutic options.

Herpes simplex encephalitis in adult patients with MASP-2 deficiency.

We report here two cases of Herpes simplex virus encephalitis (HSE) in adult patients with very rare, previously uncharacterized, non synonymous heterozygous G634R and R203W substitution in mannan-binding lectin serine protease 2 (MASP2), a gene encoding a key protease of the lectin pathway of the complement system. None of the 2 patients had variants in genes involved in the TLR3-interferon signaling pathway. Both MASP2 variants induced functional defects in vitro, including a reduced (R203W) or abolished (G634R) protein secretion, a lost capability to cleave MASP-2 precursor into its active form (G634R) and an in vivo reduced antiviral activity (G634R). In a murine model of HSE, animals deficient in mannose binding lectins (MBL, the main pattern recognition molecule associated with MASP-2) had a decreased survival rate and an increased brain burden of HSV-1 compared to WT C57BL/6J mice. Altogether, these data suggest that MASP-2 deficiency can increase susceptibility to adult HSE.

[Pulmonary Aspergillosis in immunocompetent patient]. / Aspergillose pulmonaire chez le patient immunocompétent.

Aspergillus is a group of molds which is found everywhere worldwide, exposition of human being is common. Most of immunocompetent people do not develop disease caused by Aspergillus. However, diseases in different forms may occur in certain conditions in immunocompetent patient. These diseases include hypersensitivity reactions, like allergic broncho-pulmonary aspergillosis, or infectious process like chronic pulmonary aspergillosis or invasive pulmonary aspergillosis. This article reviewed the clinical features of these diseases and the current available diagnostic techniques.

Aspergillus englobe un groupe de champignons ubiquitaires auquels l'être humain est quotidiennement exposé. Il est rarement pathogène chez le patient immunocompétent, cependant il peut être responsable de différentes formes de maladies dans certaines conditions. Ces pathologies comprennent des réactions d'hypersensibilité, comme l'aspergillose bronchopulmonaire allergique, ou des processus infectieux comme l'aspergillose pulmonaire chronique et l'aspergillose pulmonaire invasive aiguë. Cet article aborde les situations cliniques lors desquelles ces pathologies doivent être suspectées, tout en décrivant les caractéristiques de ces dernières et les moyens diagnostiques à disposition.

Pott's puffy tumor presenting as a frontal swelling under a Swiss army helmet.

In this report, we describe an uncommon presentation of a Pott's puffy tumor, which is defined as a subperiosteal abscess related to a chronic frontal sinusitis. This condition has become rare in our part of the world because of the widespread use of antibiotics. Clinical history, investigations, and management are presented.

[Vancomycine-resistant enterocci (VRE) : a new reality in our hospitals]. / Entérocoque résistant à la vancomycine (ERV) : une nouvelle réalité dans nos hôpitaux.

Limiting the emergence and spread of multi-resistant bacteria is a global concern and the management of colonized patient represents a real challenge, especially in the hospital setting, where risks of acquisition and transmission are increased. Switzerland is not protected from undesirable trends : for instance, recent outbreaks of vancomycin-resistant enterococci (VRE) have been reported in several hospitals in western Switzerland. Since 2011, more than 250 patients have been tested positive during these outbreak episodes and the molecular analysis of the documented strains shows an unexpected diversity, including both sporadic and epidemic strains. This emerging threat requires strict monitoring, prevention and infection control strategies in our healthcare facilities.

Limiter l'émergence et la diffusion des bactéries multirésistantes (BMR) est une urgence mondiale et la gestion des patients porteurs représente un véritable défi, notamment en milieu hospitalier, où les risques d'acquisition et de transmission de ces germes sont multipliés. La Suisse n'est pas épargnée par ce phénomène. En témoignent les épidémies récentes à entérocoques résistant à la vancomycine (ERV) dans plusieurs hôpitaux de Suisse romande. Depuis 2011, plus de 250 patients ont été dépistés positifs durant ces épisodes et l'analyse moléculaire par séquençage complet de génome montre une diversité inattendue des souches, qu'elles soient sporadiques ou à potentiel épidémique. Cette menace émergente, bien réelle, implique une stratégie de surveillance, prévention et contrôle de l'infection stricte dans nos établissements de soins.

Correction to: Catheter retention as a consequence rather than a cause of unfavorable outcome in candidemia.

In the original publication the members of the FUNGINOS network were provided in such a way that they could not be indexed as collaborators on PubMed.

Fluconazole non-susceptible breakthrough candidemia after prolonged low-dose prophylaxis: a prospective FUNGINOS study.

OBJECTIVES: Breakthrough candidemia (BTC) on fluconazole was associated with non-susceptible Candida spp. and increased mortality. This nationwide FUNGINOS study analyzed clinical and mycological BTC characteristics. METHODS: A 3-year prospective study was conducted in 567 consecutive candidemias. Species identification and antifungal susceptibility testing (CLSI) were performed in the FUNGINOS reference laboratory. Data were analyzed according to STROBE criteria. RESULTS: 43/576 (8%) BTC occurred: 37/43 (86%) on fluconazole (28 prophylaxis, median 200 mg/day). 21% BTC vs. 23% non-BTC presented severe sepsis/septic shock. Overall mortality was 34% vs. 32%. BTC was associated with gastrointestinal mucositis (multivariate OR 5.25, 95%CI 2.23-12.40, p < 0.001) and graft-versus-host-disease (6.25, 1.00-38.87, p = 0.05), immunosuppression (2.42, 1.03-5.68, p = 0.043), and parenteral nutrition (2.87, 1.44-5.71, p = 0.003). Non-albicans Candida were isolated in 58% BTC vs. 35% non-BTC (p = 0.005). 63% of 16 BTC occurring after 10-day fluconazole were non-susceptible (Candida glabrata, Candida krusei, Candida norvegensis) vs. 19% of 21 BTC (C. glabrata) following shorter exposure (7.10, 1.60-31.30, p = 0.007). Median fluconazole MIC was 4 mg/l vs. 0.25 mg/l (p < 0.001). Ten-day fluconazole exposure predicted non-susceptible BTC with 73% accuracy. CONCLUSIONS: Outcomes of BTC and non-BTC were similar. Fluconazole non-susceptible BTC occurred in three out of four cases after prolonged low-dose prophylaxis. This implies reassessment of prophylaxis duration and rapid de-escalation of empirical therapy in BTC after short fluconazole exposure.

[Food-borne trematodiases]. / Trématodoses alimentaires.

Food-borne trematodiases (flukes) are transmitted through the consumption of contaminated undercooked aquatic food. Infections are most prevalent in Southeast Asia and Latin America, but might occur anywhere due to food trade, international travel, human migration. Clinical manifestations are hepatobiliary, intestinal, and pleuropulmonary. The worse complication is development of cholangiocarcinoma. Efficacious drug therapy are available, however prevention control measures are essential to avoid transmission. Since 2015, trematodiases are included in the WHO program implemented to fight neglected tropical diseases.

Les trématodoses (ou distomatoses) alimentaires sont des parasitoses transmises par la consommation de poissons, crustacés et mollusques d'eau douce. Les infections sont prévalentes en Asie et en Amérique latine. L'acquisition est liée aux habitudes culinaires impliquant la consommation d'aliments aquatiques insuffisamment ou non cuits. De nos jours, des cas d'infection peuvent se présenter dans des populations issues ou résidant dans des zones non endémiques, en raison de la globalisation du marché, du développement de l'aquaculture, de la migration des populations, et des voyages internationaux. Les manifestations cliniques sont hépatobiliaires, digestives ou pleuropulmonaires. La complication la plus redoutable est l'évolution vers le cholangiocarcinome. Depuis 2015, les trématodoses font partie du plan de lutte de l'OMS contre les maladies négligées tropicales.

Infrarenal Infected Aortic Aneurysm Caused by Streptococcus pyogenes.

Infectious aneurysm is a rare entity associated with significant morbidity and mortality. Current knowledge on pathogenesis, outcome, diagnosis, management, and follow-up remains debatable. We report the case of a patient with Streptococcus pyogenes aneurysm who was successfully treated with a homograft implant and discuss microbiological characteristics, diagnostic methods, and treatment options currently available for this serious disease.

Cytomegalovirus (CMV) DNA Quantitation in Bronchoalveolar Lavage Fluid From Hematopoietic Stem Cell Transplant Recipients With CMV Pneumonia.

Background: Quantitative cytomegalovirus (CMV) DNA-specific polymerase chain reaction (PCR) analysis is widely used as a surveillance method for hematopoietic stem cell transplant (HCT) recipients. However, no CMV DNA threshold exists in bronchoalveolar lavage (BAL) to differentiate pneumonia from pulmonary shedding. Methods: We tested archived BAL fluid samples from 132 HCT recipients with CMV pneumonia and 139 controls (100 patients with non-CMV pneumonia, 18 with idiopathic pneumonia syndrome [IPS], and 21 who were asymptomatic) by quantitative CMV and ß-globin DNA-specific PCR. Results: Patients with CMV pneumonia had higher median viral loads (3.9 log10 IU/mL; interquartile range [IQR], 2.6-6.0 log10 IU/mL) than controls (0 log10 IU/mL [IQR, 0-1.6 log10 IU/mL] for patients with non-CMV pneumonia, 0 log10 IU/mL [IQR, 0-1.6 log10 IU/mL] for patients with IPS, and 1.63 log10 IU/mL [IQR, 0-2.5 log10 IU/mL] for patients who were asymptomatic; P < .001 for all comparisons to patients with CMV pneumonia). Receiver operating characteristic curve analyses and predictive models identified a cutoff CMV DNA level of 500 IU/mL to differentiate between CMV pneumonia and pulmonary shedding, using current CMV pneumonia prevalence figures. However, different levels may be appropriate in settings of very high or low CMV pneumonia prevalence. The presence of pulmonary copathogens, radiographic presentation, or pulmonary hemorrhage did not alter predictive values. Conclusion: CMV DNA load in BAL can be used to differentiate CMV pneumonia from pulmonary shedding.

Cerebral Rhizomucor Infection Treated by Posaconazole Delayed-Release Tablets in an Allogeneic Stem Cell Transplant Recipient.

Mucormycosis (zygomycosis) is an emerging fungal disease in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. A 30-year-old woman diagnosed with acute myelomonocytic leukemia and needing allo-HSCT presented pulmonary and cerebral infection due to Rhizomucor pusillus. This fungal infection was treated with surgical treatment and posaconazole delayed-release tablets. This strategy allowed reaching high drug levels that could not be obtained with the posaconazole solution.

Three-times-weekly, post-dialysis cefepime therapy in patients on maintenance hemodialysis: a retrospective study.

BACKGROUND: In hemodialysis patients, post-dialysis treatment with intravenous antibiotics permits even severe infections to be managed on an outpatient basis. Cefepime is a fourth-generation cephalosporin with a broad spectrum of action in monotherapy. We report on the pharmacokinetics of cefepime in post-dialysis therapy. METHODS: Since June 2012, twelve infections were treated with post-dialysis cefepime in 9 patients on high-flux hemodialysis. The initial post-dialysis dose of cefepime was approximately 15 mg/kg. The following doses were adapted according to the trough serum levels obtained before the subsequent dialysis in order to be above the EUCAST breakpoints for susceptible organisms and above the MIC90. Residual plasma concentrations were determined before (n = 30) and after (n = 17) dialysis by liquid chromatography-mass spectrometry. RESULTS: Overall, the mean ± SD dose of cefepime was 920 ± 270 mg (14.5 ± 5.1 mg/kg), but it was significantly lower before the 48 h interval (775 ± 210 mg or 12.7 ± 4.5 mg/kg) compared to the 72 h interval (1125 ± 225 mg or 17.2 ± 4.9 mg/kg) (p < 0.05). The mean trough pre-dialysis concentrations were 10.7 ± 3.9 mg/l and 11.3 ± 5.6 mg/l at 48 and 72 h, respectively. These levels always largely exceeded the EUCAST susceptibility breakpoints for all the targeted bacteria (>1 mg/l) with the exception of Pseudomonas aeruginosa (>8 mg/l). Cefepime concentrations were higher in anuric patients compared to those with preserved diuresis (15.6 ± 3.5 vs 9.25 ± 3.6 mg/l; p < 0.001) and decreased on average by 81 % during dialysis (from 10.5 ± 3.7 to 1.96 ± 1.2 mg/l; p < 0.001). The clinical outcome of all patients was good. CONCLUSIONS: Outpatient treatment with cefepime administered post-dialysis three-times-weekly was effective and well-tolerated in our patients. According to our data, in patients infected by highly susceptible pathogens a fixed dose of cefepime of 1 g before every 48-h interval and of 1.5 g before every 72-h interval should be recommended, without need of routine monitoring of the cefepime blood levels. In patients having an infection with less susceptibles pathogens as P. aeruginosa, and particularly in those among them exhibiting residual renal function, higher initial doses are necessary (1.5 g before a 48-h interval and 2.0 g before a 72-h interval) with adaption according to the subsequent pre-dialysis trough serum levels.