Necrotizing pancreatitis with invasive candidiasis and candidemia due to Candida albicans and pan-echinocandin-resistant Candidaglabrata.

We report on a 64-year-old man with necrotizing pancreatitis related, invasive candidiasis, and candidemia. Despite a multidisciplinary management including antifungal therapy, endoscopic interventions and surgery, the patients' infection progressed and lead to colon perforation, retroperitoneal abscess formation, and polymicrobial bloodstream infections. Resistance to echinocandins in Candida glabrata further complicated the course. This report emphasizes the need for vigilant monitoring and exploring alternative therapeutic approaches for patients in critical conditions.

The Cologne ECMM Excellence Center: A Two-Year Analysis of External Consultation Service for Invasive Fungal Infections.

The European Confederation of Medical Mycology (ECMM), formed due to the surge in invasive fungal infections (IFI), initiated the Excellence Centers program in 2016 to guide stakeholders to leading medical mycology sites. This report focuses on the Cologne ECMM Excellence Center, recognized with Diamond status for active global involvement in 2017. The center offers free consultation via email and phone, responding within 24 h for life-threatening IFI, collecting data on origin, pathogens, infection details, and more. Over two years, 189 requests were received globally, predominantly from Germany (85%), mainly involving Aspergillus spp., Mucorales, and Candida spp. Fungal mixed infections occurred in 4% of cases. The center's service effectively addresses IFI challenges, advocating for a comprehensive study encompassing all ECMM Excellence Centers to enhance global mycological care. Proactive expansion of consultancy platforms is crucial, with future analyses needed to assess expert advice's impact on patient outcomes.

Short report: impact of selective reporting of antibiotic susceptibility testing on antibiotic use in patients with bloodstream infection with Enterococcus faecalis.

INTRODUCTION: Bloodstream infections with Enterococcus faecalis are associated with relevant morbidity and mortality. Targeted antimicrobial therapy is essential. The choice of an adequate treatment may be challenging when susceptibility testing offers different options. Selective reporting of antibiotic susceptibility test results might lead to a more tailored antibiotic therapy and could therefore be an important antimicrobial stewardship program intervention. The aim of this study was to analyse whether the introduction of selective reporting of antibiotic test results leads to a more targeted antibiotic therapy in patients with bloodstream infection with Enterococcus faecalis. METHODS: This study was performed as a retrospective cohort study at the University Hospital Regensburg, Germany. All patients with blood cultures positive for Enterococcus faecalis between March 2003 and March 2022 were analysed. In February 2014 selective reporting of antibiotic susceptibility test results omitting sensitivity results for agents not recommended was introduced. RESULTS: 263 patients with blood cultures positive for Enterococcus faecalis were included. After introduction of selective reporting of antibiotic tests (AI) significantly more patients received ampicillin than before introduction of selective reporting (BI) (9.6% BI vs. 34.6% AI, p < 0.001). CONCLUSION: Selective reporting of antibiotic susceptibility test results led to a significantly higher use of ampicillin.

Galleria mellonella as an alternative in vivo model to study implant-associated fungal infections.

Fungal implant-associated bone infections are rare but difficult to treat and often associated with a poor outcome for patients. Candida species account for approximately 90% of all fungal infections. In vivo biofilm models play a major role to study biofilm development and potential new treatment options; however, there are only a very few in vivo models to study fungi-associated biofilms. Furthermore, mammalian infection models are replaced more and more due to ethical restrictions with other alternative models in basic research. Recently, we developed an insect infection model with Galleria mellonella larvae to study biofilm-associated infections with bacteria. Here, we further expanded the G. mellonella model to study in vivo fungal infections using Candida albicans and Candida krusei. We established a planktonic and biofilm-implant model to test different antifungal medication with amphotericin B, fluconazole, and voriconazole against the two species and assessed the fungal biofilm-load on the implant surface. Planktonic infection with C. albicans and C. krusei showed the killing of the G. mellonella larvae at 5 × 105 colony forming units (CFU). Treatment of larvae with antifungal compounds with amphotericin B and fluconazole showed significant survival improvement against planktonic C. albicans infection, but voriconazole had no effect. Titanium and stainless steel K-wires were preincubated with C. albicans and implanted inside the larvae to induce biofilm infection on the implant surface. The survival analysis revealed significantly reduced survival of the larvae with Candida spp. infection compared to noninfected implants. The treatment with antifungal amphotericin B and fluconazole resulted in a slight and nonsignificant improvement survival of the larvae. The treatment with the antifungal compounds in the biofilm-infection model was not as effective as in the planktonic infection model, which highlights the resistance of fungal biofilms to antifungal compounds like in bacterial biofilms. Scanning electron microscopy (SEM) analysis revealed the formation of a fungal biofilm with hyphae and spores associated with larvae tissue on the implant surface. Thus, our study highlights the use of G. mellonella larvae as alternative in vivo model to study biofilm-associated implant fungal infections and that fungal biofilms exhibit high resistance profiles comparable to bacterial biofilms. The model can be used in the future to test antifungal treatment options for fungal biofilm infections.

Diagnosis and Treatment of Invasive Aspergillosis Caused by Non-fumigatus Aspergillus spp.

With increasing frequency, clinical and laboratory-based mycologists are consulted on invasive fungal diseases caused by rare fungal species. This review aims to give an overview of the management of invasive aspergillosis (IA) caused by non-fumigatus Aspergillus spp.-namely A. flavus, A. terreus, A. niger and A. nidulans-including diagnostic and therapeutic differences and similarities to A. fumigatus. A. flavus is the second most common Aspergillus spp. isolated in patients with IA and the predominant species in subtropical regions. Treatment is complicated by its intrinsic resistance against amphotericin B (AmB) and high minimum inhibitory concentrations (MIC) for voriconazole. A. nidulans has been frequently isolated in patients with long-term immunosuppression, mostly in patients with primary immunodeficiencies such as chronic granulomatous disease. It has been reported to disseminate more often than other Aspergillus spp. Innate resistance against AmB has been suggested but not yet proven, while MICs seem to be elevated. A. niger is more frequently reported in less severe infections such as otomycosis. Triazoles exhibit varying MICs and are therefore not strictly recommended as first-line treatment for IA caused by A. niger, while patient outcome seems to be more favorable when compared to IA due to other Aspergillus species. A. terreus-related infections have been reported increasingly as the cause of acute and chronic aspergillosis. A recent prospective international multicenter surveillance study showed Spain, Austria, and Israel to be the countries with the highest density of A. terreus species complex isolates collected. This species complex seems to cause dissemination more often and is intrinsically resistant to AmB. Non-fumigatus aspergillosis is difficult to manage due to complex patient histories, varying infection sites and potential intrinsic resistances to antifungals. Future investigational efforts should aim at amplifying the knowledge on specific diagnostic measures and their on-site availability, as well as defining optimal treatment strategies and outcomes of non-fumigatus aspergillosis.

Increased zinc levels facilitate phenotypic detection of ceftazidime-avibactam resistance in metallo-ß-lactamase-producing Gram-negative bacteria.

Ceftazidime-avibactam is one of the last resort antimicrobial agents for the treatment of carbapenem-resistant, Gram-negative bacteria. Metallo-ß-lactamase-producing bacteria are considered to be ceftazidime-avibactam resistant. Here, we evaluated a semi-automated antimicrobial susceptibility testing system regarding its capability to detect phenotypic ceftazidime-avibactam resistance in 176 carbapenem-resistant, metallo-ß-lactamase-producing Enterobacterales and Pseudomonas aeruginosa isolates. Nine clinical isolates displayed ceftazidime-avibactam susceptibility in the semi-automated system and six of these isolates were susceptible by broth microdilution, too. In all nine isolates, metallo-ß-lactamase-mediated hydrolytic activity was demonstrated with the EDTA-modified carbapenemase inactivation method. As zinc is known to be an important co-factor for metallo-ß-lactamase activity, test media of the semi-automated antimicrobial susceptibility testing system and broth microdilution were supplemented with zinc. Thereby, the detection of phenotypic resistance was improved in the semi-automated system and in broth microdilution. Currently, ceftazidime-avibactam is not approved as treatment option for infections by metallo-ß-lactamase-producing, Gram-negative bacteria. In infections caused by carbapenem-resistant Gram-negatives, we therefore recommend to rule out the presence of metallo-ß-lactamases with additional methods before initiating ceftazidime-avibactam treatment.

German Multicenter Study Analyzing Antimicrobial Activity of Ceftazidime-Avibactam of Clinical Meropenem-Resistant Pseudomonas aeruginosa Isolates Using a Commercially Available Broth Microdilution Assay.

Multidrug resistance is an emerging healthcare issue, especially concerning Pseudomonas aeruginosa. In this multicenter study, P. aeruginosa isolates with resistance against meropenem detected by routine methods were collected and tested for carbapenemase production and susceptibility against ceftazidime-avibactam. Meropenem-resistant isolates of P. aeruginosa from various clinical materials were collected at 11 tertiary care hospitals in Germany from 2017−2019. Minimum inhibitory concentrations (MICs) were determined via microdilution plates (MICRONAUT-S) of ceftazidime-avibactam and meropenem at each center. Detection of the presence of carbapenemases was performed by PCR or immunochromatography. For meropenem-resistant isolates (n = 448), the MIC range of ceftazidime-avibactam was 0.25−128 mg/L, MIC90 was 128 mg/L and MIC50 was 16 mg/L. According to EUCAST clinical breakpoints, 213 of all meropenem-resistant P. aeruginosa isolates were categorized as susceptible (47.5%) to ceftazidime-avibactam. Metallo-ß-lactamases (MBL) could be detected in 122 isolates (27.3%). The MIC range of ceftazidime-avibactam in MBL-positive isolates was 4−128 mg/L, MIC90 was >128 mg/L and MIC50 was 32 mg/L. There was strong variation in the prevalence of MBL-positive isolates among centers. Our in vitro results support ceftazidime-avibactam as a treatment option against infections caused by meropenem-resistant, MBL-negative P. aeruginosa.

[Current practice of empiric antibiotic treatment for spondylodiscitis]. / Aktuelle Praxis der empirischen Antibiotikatherapie bei Spondylodiszitis.

BACKGROUND AND RESEARCH QUESTION: In pyogenic spondylodiscitis, infections with coagulase-negative staphylococci must be given increasing importance. Empirical antibiosis is particularly necessary in patients with severe or progressive neurological deficits or hemodynamic instability, as well as in the case of culture-negative spondylodiscitis. It is unclear whether uniform empirical antibiosis standards adapted to the resistance profiles exist in Germany. STUDY DESIGN AND METHODS: A survey on the empirical antibiotic therapy for pyogenic spondylodiscitis was conducted at German university and Berufsgenossenschaft clinics, each in the departments of orthopedics and trauma surgery. The survey results were applied to the resistance profiles of pathogens in 45 spondylodiscitis patients treated in our department between 2013 and 2020. Thus, the potential susceptibility and resistance rates were calculated for the indicated antibiotic therapies. RESULTS: Of the 71 clinics queried, a total of 44 (62.0%) responded. Sixteen different antibiotic therapies were reported as standard regimes. Among these, 14 different combination therapies were reported. The most commonly reported empirical antibiotics, namely amoxicillin/clavulanic acid or ampicillin/sulbactam (29.5%) and cephalosporins (18.2%) showed high potential resistance rates of 20.0% and 35.6%, respectively, in relation to the previously published resistance profile. The highest potential susceptibility rates were achieved with a combination of vancomycin + ampicillin/sulbactam (91.1% sensitive pathogens), vancomycin + piperacillin/tazobactam (91.1% sensitive pathogens), and ampicillin/sulbactam + teicoplanin (95.6% sensitive pathogens). One out of these combinations was reported as standard regime by three clinics (6.8%). CONCLUSION: The nationwide survey of empiric antibiotic treatment for pyogenic spondylodiscitis revealed a large heterogeneity in the standard of care. A combination of a broad-spectrum-ß-lactam antibiotic with an additional glycopeptide antibiotic may be justified.

Results from a national survey on COVID-19-associated mucormycosis in Germany: 13 patients from six tertiary hospitals.

BACKGROUND: Most COVID-19-associated mucormycosis (CAM) cases are reported from India and neighbouring countries. Anecdotally cases from Europe have been presented. OBJECTIVE: To estimate the disease burden and describe the clinical presentation of CAM in Germany. METHODS: We identified cases through German mycology networks and scientific societies, and collected anonymised clinical information via FungiScope®. RESULTS: We identified 13 CAM cases from six tertiary referral hospitals diagnosed between March 2020 and June 2021. Twelve patients had severe or critical COVID-19, eleven were mechanically ventilated for a median of 8 days (range 1-27 days) before diagnosis of CAM. Eleven patients received systemic corticosteroids. Additional underlying medical conditions were reported for all but one patient, five were immunocompromised because of malignancy or organ transplantation, three were diabetic. Eleven patients developed pneumonia. Mortality was 53.8% with a median time from diagnosis of mucormycosis to death of 9 days (range 0-214 days) despite treatment with liposomal amphotericin B and/or isavuconazole in 10 of 13 cases. CAM prevalence amongst hospitalised COVID-19 patients overall (0.67% and 0.58% in two centres) and those admitted to the intensive care unit (ICU) (1.47%, 1.78% and 0.15% in three centres) was significantly higher compared to non-COVID-19 patients (P < .001 for respective comparisons). CONCLUSION: COVID-19-associated mucormycosis is rare in Germany, mostly reported in patients with comorbidities and impaired immune system and severe COVID-19 treated in the ICU with high mortality compared to mainly rhino-orbito-cerebral CAM in patients with mild COVID-19 in India. Risk for CAM is higher in hospitalised COVID-19 patients than in other patients.

Autopsy findings after long-term treatment of COVID-19 patients with microbiological correlation.

Between April and June 2020, i.e., during the first wave of pandemic coronavirus disease 2019 (COVID-19), 55 patients underwent long-term treatment in the intensive care unit at the University Hospital of Regensburg. Most of them were transferred from smaller hospitals, often due to the need for an extracorporeal membrane oxygenation system. Autopsy was performed in 8/17 COVID-19-proven patients after long-term treatment (mean: 33.6 days). Autopsy revealed that the typical pathological changes occurring during the early stages of the disease (e.g., thrombosis, endothelitis, capillaritis) are less prevalent at this stage, while severe diffuse alveolar damage and especially coinfection with different fungal species were the most conspicuous finding. In addition, signs of macrophage activation syndrome was detected in 7 of 8 patients. Thus, fungal infections were a leading cause of death in our cohort of severely ill patients and may alter clinical management of patients, particularly in long-term periods of treatment.

Dalbavancin as long-term suppressive therapy for patients with Gram-positive bacteremia due to an intravascular source-a series of four cases.

We present four cases with Gram-positive bacteremia (pathogens: MRSA n = 1, Enterococcus spp. n = 3) due to an intravascular source (left ventricular assist device: n = 2, transfemoral aortic valve implantation n = 1, prosthetic aortic valve: n = 1) where no curative treatment was available. These patients received indefinite, chronic suppressive (palliative) therapy with dalbavancin (500 mg weekly or 1000 mg biweekly regimens). Outcomes and clinical characteristics are described; treatment was effective in suppression of bacteremia in all patients over several months (range: 1 to more than 12 months), we observed no relevant side effects.

Candida Endocarditis in Patients with Candidemia: A Single-Center Experience of 14 Cases.

A retrospective, single-center analysis of 14 cases of Candida endocarditis (from 355 candidemia cases during the years 2012-2019) revealed a high in-hospital mortality (57.1%), a high proportion of healthcare-associated infections (13/14) and a high treatment preference for echinocandins. Transthoracic echocardiography and 18F-FDG PET/CT had a sensitivity of 54.5% and 57.1%, respectively. Patients were older than previously described and most patients with Candida endocarditis had persistent candidemia for ≥ 3 days despite antifungal therapy.

Child Maltreatment during the COVID-19 Pandemic: Consequences of Parental Job Loss on Psychological and Physical Abuse Towards Children.

BACKGROUND: Job loss resulting from the COVID-19 pandemic presents significant risk for child abuse. Protective factors, such as reframing coping, may mitigate the risk of job loss on child maltreatment. OBJECTIVE: The current study investigated factors associated with child maltreatment during the COVID-19 pandemic, including parental job loss, and whether cognitive reframing moderated associations between job loss and child maltreatment. METHOD: A community sample of 342 parents (62% mothers) of 4- to 10-year-olds (M = 7.38, SD = 2.01; 57.3% male) living in the United States completed online questionnaires regarding experiences with COVID-19, the Parent-Child Conflict Tactics Scale, and the Family Crisis Oriented Personal Evaluation Scales. RESULTS: Two logistic regression analyses evaluated predictors of whether parents psychologically maltreated or physically abused their children during the pandemic controlling for maltreating history, parental depressive symptoms, financial stability, parent age, parent gender, child age, and child gender. Parents who lost their jobs (OR = 4.86, 95% CI [1.19, 19.91], p = .03), were more depressed (OR = 1.05, 95% CI [1.02, 1.08], p < .01), and previously psychologically maltreated their children (OR = 111.94, 95% CI [28.54, 439.01], p < .001) were more likely to psychologically maltreat during the pandemic. Regarding physical abuse, a significant interaction between job loss and reframing coping emerged (OR = 0.76, 95% CI [0.59, 0.99], p = .04). Among parents who lost their jobs, the probability of physical abuse decreased as reframing coping increased. CONCLUSIONS: Job loss during the COVID-19 pandemic is a significant risk factor for child maltreatment. Reframing coping may be an important buffer of this association on physical abuse and presents implications for maltreatment prevention.

Epidemiology of candidemia and impact of infectious disease consultation on survival and care.

BACKGROUND: The aim of this study was to analyse temporal changes in the epidemiology of candidemia assessing patient's characteristics, risk factors, diagnostic management, treatment, and outcome in a tertiary care hospital in South Eastern Germany. METHODS: In this retrospective cohort study patients with blood cultures positive for Candida spp. were identified from the microbiological database in the years 2006-2018. A detailed collection of patients' characteristics was obtained for the time periods 2006-2008 and 2016-2018. Risk factors for survival were analysed in a logistic regression analysis. RESULTS: In the years 2006-2018, a total of 465 episodes of candidemia were identified. An increase in candidemia cases was evident in the period of 2016-2018 compared to 2006-2015 and to 2006-2008 in absolute numbers and adjusted to patient-days. C. albicans was responsible for 62.8% of cases in 2006-2008 and 51.2% of all cases in the years 2016-2018, respectively, whereas there was a significant increase of C. glabrata in the latter period (16.3-31.5%). Overall mortality was not significantly different in the two periods. Infectious diseases consultation led to a lower mortality of patients with candidemia and to a higher adherence to guidelines. In multivariate analysis, only complete change or extraction of intravascular indwelling material and female gender were independent predictors for survival. CONCLUSION: We observed an increase in candidemia rates and rates of non-albicans spp. over time. A complete change of all catheters and/or indwelling devices improved survival. ID consultation led to a better guideline adherence.

Detection of carbapenemase-producing Enterobacterales and the BD Phoenix CPO Detect panel.

Introduction: Treatment options for infections with carbapenem-resistant Enterobacterales are strongly limited. New antimicrobials are not effective against all types of carbapenemases. Therefore, rapid and reliable antimicrobial susceptibility testing and identification of the resistance mechanism are important. Areas covered: We assess several methods to determine carbapenemase production of Enterobacterales in culture and discuss the value of the novel automated BD Phoenix CPO Detect (BDPCPO) panel for the detection and classification of carbapenemases. Expert opinion: The meropenem minimum inhibitory concentration (MIC) range used in the BDPCPO panel includes the EUCAST screening breakpoint for the detection of carbapenemase producers. The phenotypic, inhibitor-based assay for detection of carbapenemase activity in the BDPCPO panel displays high sensitivity for carbapenemase detection while its specificity is modest. Therefore, confirmation testing of positive results is warranted. Nevertheless, implementing the BDPCPO panel has the potential to reduce time-to-result for detection and classification of carbapenemase producers.

HIF1A and NFAT5 coordinate Na+-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting.

Infection and inflammation are able to induce diet-independent Na+-accumulation without commensurate water retention in afflicted tissues, which favors the pro-inflammatory activation of mouse macrophages and augments their antibacterial and antiparasitic activity. While Na+-boosted host defense against the protozoan parasite Leishmania major is mediated by increased expression of the leishmanicidal NOS2 (nitric oxide synthase 2, inducible), the molecular mechanisms underpinning this enhanced antibacterial defense of mouse macrophages with high Na+ (HS) exposure are unknown. Here, we provide evidence that HS-increased antibacterial activity against E. coli was neither dependent on NOS2 nor on the phagocyte oxidase. In contrast, HS-augmented antibacterial defense hinged on HIF1A (hypoxia inducible factor 1, alpha subunit)-dependent increased autophagy, and NFAT5 (nuclear factor of activated T cells 5)-dependent targeting of intracellular E. coli to acidic autolysosomal compartments. Overall, these findings suggest that the autolysosomal compartment is a novel target of Na+-modulated cell autonomous innate immunity. Abbreviations: ACT: actins; AKT: AKT serine/threonine kinase 1; ATG2A: autophagy related 2A; ATG4C: autophagy related 4C, cysteine peptidase; ATG7: autophagy related 7; ATG12: autophagy related 12; BECN1: beclin 1; BMDM: bone marrow-derived macrophages; BNIP3: BCL2/adenovirus E1B interacting protein 3; CFU: colony forming units; CM-H2DCFDA: 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate, acetyl ester; CTSB: cathepsin B; CYBB: cytochrome b-245 beta chain; DAPI: 4,6-diamidino-2-phenylindole; DMOG: dimethyloxallyl glycine; DPI: diphenyleneiodonium chloride; E. coli: Escherichia coli; FDR: false discovery rate; GFP: green fluorescent protein; GSEA: gene set enrichment analysis; GO: gene ontology; HIF1A: hypoxia inducible factor 1, alpha subunit; HUGO: human genome organization; HS: high salt (+ 40 mM of NaCl to standard cell culture conditions); HSP90: heat shock 90 kDa proteins; LDH: lactate dehydrogenase; LPS: lipopolysaccharide; Lyz2/LysM: lysozyme 2; NFAT5/TonEBP: nuclear factor of activated T cells 5; MΦ: macrophages; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFI: mean fluorescence intensity; MIC: minimum inhibitory concentration; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; NaCl: sodium chloride; NES: normalized enrichment score; n.s.: not significant; NO: nitric oxide; NOS2/iNOS: nitric oxide synthase 2, inducible; NS: normal salt; PCR: polymerase chain reaction; PGK1: phosphoglycerate kinase 1; PHOX: phagocyte oxidase; RFP: red fluorescent protein; RNA: ribonucleic acid; ROS: reactive oxygen species; sCFP3A: super cyan fluorescent protein 3A; SBFI: sodium-binding benzofuran isophthalate; SLC2A1/GLUT1: solute carrier family 2 (facilitated glucose transporter), member 1; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like kinase 1; v-ATPase: vacuolar-type H+-ATPase; WT: wild type.