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Activation of hypoxia inducible factor 1 is a general phenomenon in infections with human pathogens
(2010)
Background: Hypoxia inducible factor (HIF)-1 is the key transcriptional factor involved in the adaptation process of cells and organisms to hypoxia. Recent findings suggest that HIF-1 plays also a crucial role in inflammatory and infectious diseases. Methodology/Principal Findings: Using patient skin biopsies, cell culture and murine infection models, HIF-1 activation was determined by immunohistochemistry, immunoblotting and reporter gene assays and was linked to cellular oxygen consumption. The course of a S. aureus peritonitis was determined upon pharmacological HIF-1 inhibition. Activation of HIF-1 was detectable (i) in all ex vivo in biopsies of patients suffering from skin infections, (ii) in vitro using cell culture infection models and (iii) in vivo using murine intravenous and peritoneal S. aureus infection models. HIF-1 activation by human pathogens was induced by oxygen-dependent mechanisms. Small colony variants (SCVs) of S. aureus known to cause chronic infections did not result in cellular hypoxia nor in HIF-1 activation. Pharmaceutical inhibition of HIF-1 activation resulted in increased survival rates of mice suffering from a S. aureus peritonitis. Conclusions/Significance: Activation of HIF-1 is a general phenomenon in infections with human pathogenic bacteria, viruses, fungi and protozoa. HIF-1-regulated pathways might be an attractive target to modulate the course of life-threatening infections.
Adhesion and host cell modulation: critical pathogenicity determinants of Bartonella henselae
(2011)
Bartonella henselae, the agent of cat scratch disease and the vasculoproliferative disorders bacillary angiomatosis and peliosis hepatis, contains to date two groups of described pathogenicity factors: adhesins and type IV secretion systems. Bartonella adhesin A (BadA), the Trw system and possibly filamentous hemagglutinin act as promiscous or specific adhesins, whereas the virulence locus (Vir)B/VirD4 type IV secretion system modulates a variety of host cell functions. BadA mediates bacterial adherence to endothelial cells and extracellular matrix proteins and triggers the induction of angiogenic gene programming. The VirB/VirD4 type IV secretion system is responsible for, e.g., inhibition of host cell apoptosis, bacterial persistence in erythrocytes, and endothelial sprouting. The Trw-conjugation system of Bartonella spp. mediates host-specific adherence to erythrocytes. Filamentous hemagglutinins represent additional potential pathogenicity factors which are not yet characterized. The exact molecular functions of these pathogenicity factors and their contribution to an orchestral interplay need to be analyzed to understand B. henselae pathogenicity in detail.
Adhesion of human pathogenic bacteria to endothelial cells is facilitated by fibronectin interaction
(2023)
Human pathogenic bacteria circulating in the bloodstream need to find a way to interact with endothelial cells (ECs) lining the blood vessels to infect and colonise the host. The extracellular matrix (ECM) of ECs might represent an attractive initial target for bacterial interaction, as many bacterial adhesins have reported affinities to ECM proteins, in particular to fibronectin (Fn). Here, we analysed the general role of EC-expressed Fn for bacterial adhesion. For this, we evaluated the expression levels of ECM coding genes in different ECs, revealing that Fn is the highest expressed gene and thereby, it is highly abundant in the ECM environment of ECs. The role of Fn as a mediator in bacterial cell-host adhesion was evaluated in adhesion assays of Acinetobacter baumannii, Bartonella henselae, Borrelia burgdorferi, and Staphylococcus aureus to ECs. The assays demonstrated that bacteria colocalised with Fn fibres, as observed by confocal laser scanning microscopy. Fn removal from the ECM environment (FN1 knockout ECs) diminished bacterial adherence to ECs in both static and dynamic adhesion assays to varying extents, as evaluated via absolute quantification using qPCR. Interactions between adhesins and Fn might represent the crucial step for the adhesion of human-pathogenic Gram-negative and Gram-positive bacteria targeting the ECs as a niche of infection.
Infectious diseases remain a remarkable health threat for humans and animals. In the past, the epidemiology, etiology and pathology of infectious agents affecting humans and animals have mostly been investigated in separate studies. However, it is evident, that combined approaches are needed to understand geographical distribution, transmission and infection biology of “zoonotic agents”. The genus Bartonella represents a congenial example of the synergistic benefits that can arise from such combined approaches: Bartonella spp. infect a broad variety of animals, are linked with a constantly increasing number of human diseases and are transmitted via arthropod vectors. As a result, the genus Bartonella is predestined to play a pivotal role in establishing a One Health concept combining veterinary and human medicine.
Background: The federal state of Hesse, Germany, introduced a laboratory-based reporting scheme for carbapenem-resistant organisms (CROs).
Method: The results of the first year of mandated reporting of CROs from April 2012 through March 2013 to the Public Health Authority of Frankfurt/Main, responsible for a population of 700,000 inhabitants, are described.
Results: Within a period of 12 months 243 CROs were notified to the health authority. Of these 213 isolates had been reported from 16 of the 17 hospitals in Frankfurt/Main, 6 from ambulatory settings and 24 from clinics outside of Frankfurt/Main. Mean incidence rate per 1,000 patient days in hospitals was 0.138 (range 0.02-0.28).
Conclusion: In Frankfurt/Main almost all hospitals have reported CROs in the study period though the frequency of isolation varies strongly and many facilities only report CROs sporadically. Molecular data indicate a high diversity of different carbapenemases. Autochthonous transmission must be assumed despite the absence of major outbreaks. Rapid and coordinated efforts by clinicians and health departments are crucial to control the spread of CRO infections. The mandatory reporting scheme provides important data to guide the implementation of preventive measures.
Background: Multidrug-resistant Gram-negative bacteria (MRGN) and the infections they cause are a serious threat and a challenge to the healthcare system. This particularly applies to carbapenem-resistant Gram-negative bacteria (CRGN). Currently, the introduction of a nationwide mandatory notification system for CRGN in Germany is under consideration. Against this background, this paper presents an analysis of the mandatory reporting system for CRGN in effect since November 2011 in the federal state of Hesse (Germany).
Materials and methods: All carbapenem-resistant Gram-negative bacteria and the detected carbapenemases reported to the public health department of the city of Frankfurt am Main, Hesse, Germany, on the basis of the mandatory notification system were analyzed.
Results: 827 CRGN cases were reported to the public health department of Frankfurt/Main between April 2012 and December 2015. The following bacterial species were reported: Pseudomonas spp. (n=268), Acinetobacter spp. (n=183), Klebsiella spp. (n=195), Enterobacter spp. (n=77), Escherichia coli (n=75) and others (n=29). Between 2012 and 2015, a reduction of the CRGN reports was noticed, mainly due to changes in the reporting of Pseudomonas spp. Between 2012 and 2015, the total number of notifications decreased slightly, although the number of reported CRGN in screening samples increased, thus giving no indication of a decreased testing frequency. For 10.5% of the patients, the place of residence was not Germany, 18.0% of the patients had previously stayed in hospitals abroad, often in countries with a high CRGN prevalence. CRGN bacteria were reported from all of Frankfurt’s hospitals, and 3.9% were reported from out-patient care facilities. Carbapenemases were detected and reported in 251 CRGN bacteria, including 73 OXA-48, 76 OXA-23, 56 NDM subtypes, and 21 KPC subtypes. There have been no major epidemiological signs of outbreak scenarios.
Discussion: CRGN bacteria are already widespread in patients from hospitals and out-patient care facilities. Clearly, infection control measurements should therefore not only include hospital patients but also those receiving out-patient care. Screening strategies focused on patients from foreign countries with high MRGN prevalence is not sufficient, as only 10.5% of MRGN patients resided in those countries, and only 18% of the patients had been previously treated in a foreign hospital. In a public health context, infection control measures should therefore encompass broader screening strategies.
Objective: This study aims to evaluate catheter management in acute epididymitis (AE) patients requiring inpatient treatment and risk factors predicting severity of disease.
Material and Methods: Patients with diagnosed AE and inpatient treatment between 2004 and 2019 at the University Hospital Frankfurt were analyzed. A risk score, rating severity of AE, including residual urine > 100 ml, fever > 38.0°C, C-reactive protein (CRP) > 5 mg/dl, and white blood count (WBC) > 10/nl was introduced.
Results: Of 334 patients, 107 (32%) received a catheter (transurethral (TC): n = 53, 16%, suprapubic (SPC): n = 54, 16%). Catheter patients were older, exhibited more comorbidities, and had higher CRP and WBC compared with the non-catheter group (NC). Median length of stay (LOS) was longer in the catheter group (7 vs. 6 days, p < 0.001), whereas necessity of abscess surgery and recurrent epididymitis did not differ. No differences in those parameters were recorded between TC and SPC. According to our established risk score, 147 (44%) patients exhibited 0–1 (low-risk) and 187 (56%) 2–4 risk factors (high-risk). In the high-risk group, patients received a catheter significantly more often than with low-risk (TC: 22 vs. 9%; SPC: 19 vs. 12%, both p ≤ 0.01). Catheter or high-risk patients exhibited positive urine cultures more frequently than NC or low-risk patients. LOS was comparable between high-risk patients with catheter and low-risk NC patients.
Conclusion: Patients with AE who received a catheter at admission were older, multimorbid, and exhibited more severe symptoms of disease compared with the NC patients. A protective effect of catheters might be attributable to patients with adverse risk constellations or high burden of comorbidities. The introduced risk score indicates a possibility for risk stratification.
Objectives: Multidrug-resistant organisms (MDRO) are considered an emerging threat worldwide. Data covering the clinical impact of MDRO colonization in patients with solid malignancies, however, is widely missing. We sought to determine the impact of MDRO colonization in patients who have been diagnosed with Non-small cell lung cancer (NSCLC) who are at known high-risk for invasive infections.
Materials and methods: Patients who were screened for MDRO colonization within a 90-day period after NSCLC diagnosis of all stages were included in this single-center retrospective study.
Results: Two hundred and ninety-five patients were included of whom 24 patients (8.1%) were screened positive for MDRO colonization (MDROpos) at first diagnosis. Enterobacterales were by far the most frequent MDRO detected with a proportion of 79.2% (19/24). MDRO colonization was present across all disease stages and more present in patients with concomitant diabetes mellitus. Median overall survival was significantly inferior in the MDROpos study group with a median OS of 7.8 months (95% CI, 0.0–19.9 months) compared to a median OS of 23.9 months (95% CI, 17.6–30.1 months) in the MDROneg group in univariate (p = 0.036) and multivariate analysis (P = 0.02). Exploratory analyses suggest a higher rate of non-cancer-related-mortality in MDROpos patients compared to MDROneg patients (p = 0.002) with an increased rate of fatal infections in MDROpos patients (p = 0.0002).
Conclusions: MDRO colonization is an independent risk factor for inferior OS in patients diagnosed with NSCLC due to a higher rate of fatal infections. Empirical antibiotic treatment approaches should cover formerly detected MDR commensals in cases of (suspected) invasive infections.
Introduction: The global spread of multidrug-resistant organisms (MDRO) complicates treatment and isolation measures in hospitals and has shown to increase mortality. Patients with disease- or therapy-related immunodeficiency are especially at risk for fatal infections caused by MDRO. The impact of MDRO colonization on the clinical course of AML patients undergoing intensive induction chemotherapy—a potentially curative but highly toxic treatment option—has not been systematically studied.
Materials & methods: 312 AML patients undergoing intensive induction chemotherapy between 2007 and 2015 were examined for MDRO colonization. Patients with evidence for MDRO before or during the hospital stay of induction chemotherapy were defined as colonized, patients who never had a positive swab for MDRO were defined as noncolonized.
Results: Of 312 AML patients 90 were colonized and 130 were noncolonized. Colonized patients suffered from significantly more days with fever, spent more days on the intensive care unit and had a higher median C-reactive protein value during the hospital stay. These findings did not result in a prolonged length of hospital stay or an increased mortality rate for colonized patients. However, in a subgroup analysis, patients colonized with carbapenem-resistant enterobacteriaceae (CRE) had a significantly reduced 60- and 90-day, as well as 1- and 2-year survival rates when compared to noncolonized patients.
Conclusion: Our analysis highlights the importance of intensive MDRO screening especially in patients with febrile neutropenia since persisting fever can be a sign of MDRO-colonization. CRE-colonized patients require special surveillance, since they seem to be at risk for death.
Introduction: MDRO-colonization has been shown to impair survival in patients with hematological malignancies and solid tumors as well as in patients with liver disease. Despite the increasing spread of multidrug-resistant organisms (MDRO), its impact on patients with hepatocellular carcinoma (HCC) has not been studied. We conducted this retrospective study to analyze the impact of MDRO-colonization on overall prognosis in HCC patients.
Materials and methods: All patients with confirmed HCC diagnosed between January 2008 and December 2017 at the University Hospital Frankfurt were included in this study. HCC patients with a positive MDRO screening before or within the first 90 days after diagnosis of HCC were defined as colonized HCC patients, HCC patients with a negative MDRO screening were defined as noncolonized HCC patients.
Results: 59 (6%) colonized and 895 (94%) noncolonized HCC patients were included. Enterobacterales with extended-spectrum β-lactamase-like phenotype with or without resistance to fluoroquinolones (ESBL/ ± FQ) were the most frequently found MDRO with 59%, followed by vancomycin-resistant Enterococcus faecium with 37%. Colonized HCC patients had more severe cirrhosis and more advanced HCC stage compared to noncolonized HCC patients. Colonized HCC patients showed an impaired survival with a median OS of 189 days (6.3 months) compared to a median OS of 1001 days (33.4 months) in noncolonized HCC patients. MDRO-colonization was identified as an independent risk factor associated with survival in multivariate analysis.
Conclusion: MDRO-colonization is an independent risk factor for survival in patients with HCC highlighting the importance of regular MDRO screening, isolation measures as well as interdisciplinary antibiotic steward-ship programs to guide responsible use of antibiotic agents.