Klebsiella pneumoniae and Escherichia coli : multidrug-resistance and different aspects of invasive infections

Klebsiella pneumoniae and Escherichia coli are pathogens belonging to the Enterobacteriaceae family. They can cause infections ranging from uncomplicated urinary tract infection to severe bloodstream infection (BSI). The prevalence of extended spectrum β- lactamase-producing Enterobacteriaceae (EPE) is increasing worldwide and carbapenemases (CPE), a subgroup of EPE where antibiotic treatment is very limited, is a major threat to patients.The aims of this thesis were to get expanded molecular and epidemiological knowledge about K. pneumoniae, its association to morbidity and mortality in BSI (II, III), to increase sensitivity in detection of carbapenemase-producers (I), to determine risk to acquire fecal colonization with EPE during traveling, and to characterize colonizing EPE in terms of virulence factors and phylogroups (IV). In paper I methods for antimicrobial susceptibility testing were evaluated for detection of K. pneumoniae carbapenemase (KPC)- and Verona integron-encoded metallo-- lactamase (VIM)-producing K. pneumoniae in order to define appropriate screening breakpoints. Strains (n=51) were tested against different carbapenems using disk diffusion, gradient test, and automated susceptibility testing. Results were interpreted with the European (EUCAST) and American (CLSI) antimicrobial susceptibility testing breakpoints. We found that clinical breakpoints cannot be used for carbapenemase screening. Meropenem was the most suited carbapenem to use for screening purposes. A breakpoint of 0.5 mg/L detected all isolates with an at the same time good separation from the wild type population. In paper II and III a cohort of patients with BSI caused by K. pneumoniae was evaluated retrospectively and compared with BSI caused by E. coli. Data on risk factors, prognostic factors and mortality was retrieved from 1251 medical charts (III). The late mortality (within 90 days) was significantly higher among patients with BSI caused by K. pneumoniae and could be explained by higher comorbidity. Contrary to European trends our study showed low antibiotic resistance among K. pneumoniae isolates supporting the hypothesis of absence of successful multidrug-resistant K. pneumoniae clones in the Stockholm area. For a subset of the patients (n=139) molecular analysis was performed on the K. pneumoniae isolates (II). Based on multilocus sequence typing, the isolates could be separated in three phylogenetic clades: KpI (n=96), KpII (n=9) and KpIII, also known as K. variicola (n=34). Patients infected with strains belonging to K. variicola had higher 30 days mortality (29.4 %), also when adjusting for age and comorbidity (OR for KpIII = 3.0 (95% CI: 1.1-8.4) compared to KpI). Only three of the isolates causing mortality within 30 days belonged to any of the virulent serotypes, had a mucoid phenotype, or harbored virulence genes. Hence, the increased mortality could not be related to any known strain factor. In general, a high level of comorbidity was observed in the K. pneumoniae cohort. Paper IV was a prospective study. Fecal samples and survey data were collected from 188 Swedes traveling to four regions of high EPE prevalence, and molecular characterization was performed on EPE. Colonization incidence varied by visited region; the Indian subcontinent 49%, northern Africa 44%, Southeast Asia 19% and Turkey 10%. Few strains harbored virulence factors connected to uropathogenicity, and most E. coli strains belonged to phylogroup A, rarely associated with extraintestinal infections. No clinical infections were seen in follow-up. No CPE was found, but one strain contained the plasmid- mediated colistin resistance gene, mcr-1. Independent risk factors for EPE acquisition were travelers ́ diarrhea and use of antibiotics during travel. EPE acquired during travel have seemingly low pathogenicity as indicated by the low frequency of virulence factors and phylogroups associated with extraintestinal infections. In summary this thesis provides new knowledge about K. pneumoniae BSI in a clinical and a molecular perspective. It also adds to the knowledge about molecular features of EPE colonizing the intestine, and appropriate breakpoints to use in detection of CPE

Læreres erfaringer med fysisk aktivitet som virkemiddel i den tilpassede opplæringen for elever med ADHD diagnose

Masteroppgave i tilpassa opplæring - Nord universitet, 201

Acquisition of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE) carriage after exposure to systemic antimicrobials during travel: systematic review and meta-analysis

BACKGROUND: International travel is an important risk factor for colonization with extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-PE). Antimicrobial use during travel likely amplifies this risk, yet to what extent, and whether it varies by antimicrobial class, has not been established. METHODS: We conducted a systematic review that included prospective cohorts reporting both receipt of systemic antimicrobials and acquired ESBL-PE isolated from stool or rectum during international travel. We performed a random effects meta-analysis to estimate odds of acquiring ESBL-PE due to antimicrobials during travel, overall and by antimicrobial class. RESULTS: Fifteen studies were included. The study population was mainly female travellers from high income countries recruited primarily from travel clinics. Participants travelled most frequently to Asia and Africa with 10% reporting antimicrobial use during travel. The combined odds ratio (OR) for ESBL-PE acquisition during travel was 2.37 for antimicrobial use overall (95% confidence interval [CI], 1.69 to 3.33), but there was substantial heterogeneity between studies. Fluoroquinolones were the antibiotic class associated with the highest combined OR of ESBL-PE acquisition, compared to no antimicrobial use (OR 4.68, 95% CI, 2.34 to 9.37). CONCLUSIONS: The risk of ESBL-PE colonization during travel is increased substantially with exposure to antimicrobials, especially fluoroquinolones. While a small proportion of colonized individuals will develop a resistant infection, there remains the potential for onward spread among returning travellers. Public health efforts to decrease inappropriate antimicrobial usage during travel are warranted

Screening for multi-drug-resistant Gram-negative bacteria: what is effective and justifiable?

Effectiveness is a key criterion in assessing the justification of antibiotic resistance interventions. Depending on an intervention's effectiveness, burdens and costs will be more or less justified, which is especially important for large scale population-level interventions with high running costs and pronounced risks to individuals in terms of wellbeing, integrity and autonomy. In this paper, we assess the case of routine hospital screening for multi-drug-resistant Gram-negative bacteria (MDRGN) from this perspective. Utilizing a comparison to screening programs for Methicillin-Resistant Staphylococcus aureus (MRSA) we argue that current screening programmes for MDRGN in low endemic settings should be reconsidered, as its effectiveness is in doubt, while general downsides to screening programs remain. To accomplish justifiable antibiotic stewardship, MDRGN screening should not be viewed as a separate measure, but rather as part of a comprehensive approach. The program should be redesigned to focus on those at risk of developing symptomatic infections with MDRGN rather than merely detecting those colonised

Rhenium and yttrium ions as antimicrobial agents against multidrug resistant Klebsiella pneumoniae and Acinetobacter baumannii biofilms

© 2019 The Authors. Letters in Applied Microbiology published by John Wiley & Sons Ltd on behalf of Society for Applied Microbiology. Antimicrobial resistance presents major global concerns to patient health. In this study, metal ions of molybdenum, rhenium, yttrium and thallium were tested against bacteria in planktonic and biofilm form using one strain of Klebsiella pneumoniae and Acinetobacter baumannii. The antimicrobial efficacy of the metal ions was evaluated against the planktonic bacterial strains using minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations, whilst the efficacy of the metal ions against biofilms was tested using a crystal violet biofilm assay. Live Dead staining was used to visualize the antimicrobial activity elicited by the metal ions on the bacterial cell. The results showed that higher concentrations of the metals were required to inhibit the growth of biofilms (72·9 mg l −1 to 416·7 mg l −1 ), in comparison to their planktonic counterparts. MICs of the metal ions (<46·9 mg l −1 ) (planktonic cells) did not affect biofilm formation. Overall, rhenium and yttrium were effective antimicrobial agents. Molybdenum demonstrated the greatest level of biotoxicity. When taking into account these results and the known toxicity of thallium, it is possible that rhenium or yttrium ions could be developed as effective biocidal formulations in order to prevent transmission in healthcare environments. Significance and Impact of the Study: The metal ions, molybdenum, rhenium, thallium and yttrium were tested against both Klebsiella pneumoniae and Acinetobacter baumannii in planktonic and biofilm forms. This research demonstrated that all the metal ions may be effective antimicrobial agents. However, molybdenum induced high levels of cytotoxicity, whilst, there was no significant difference in the toxicity of the other metal ions tested. When considering the results for the antimicrobial efficacy and biotoxicity of the metal ions, in conjunction with the known toxicity of thallium in certain chemical compositions, it was concluded that overall rhenium or yttrium ions may be effective antimicrobial agents, one potential application may be utilizing these metal ions in hospital surface cleaning formulations

Invasive infection caused by <i>Klebsiella pneumoniae</i> is a disease affecting patients with high comorbidity and associated with high long-term mortality

<div><p><i>Klebsiella pneumoniae</i> (KP) is after <i>Escherichia coli</i> (EC) the most common gram-negative species causing invasive infections. Herein, we analyzed risk factors and prognosis in invasive infections caused by KP versus EC, in an area with low antimicrobial resistance. Moreover, we compared antimicrobial resistance and relative prevalence of KP and EC (KP/EC-ratio) in different European countries, using EARS-Net data. Adult patients admitted to Karolinska University Hospital 2006–2012 with invasive infection caused by KP (n = 599) were matched regarding sex and age with patients infected by EC. The medical records were retrospectively reviewed. Comorbidity was adjusted for with multivariable analysis. European data were retrieved from the EARS-Net database. No differences were observed in 7- and 30-day mortality between the groups. The 90-day mortality was significantly higher in the KP cohort (26% versus 17%, p<0.001), but not after adjusting for comorbidity. Malignancy was seen in 53% of the patients with KP versus 38% with EC, OR 1.86 (1.34–2.58). A significant increase in the rate of ESBL-production was observed in EC, but not in KP. The KP/EC-ratio remained stable. In contrast, European data showed increasing percentages of isolates non-susceptible to third-generation cephalosporins in EC and KP, and increasing KP/EC-ratio. Invasive infection caused by KP is a disease affecting patients with high comorbidity and associated with high 90-d mortality. The stable KP/EC-ratio and low occurrence of antimicrobial resistance in data from Karolinska University Hospital compared to aggregate data from 20 EARS-Net countries could be related to absence of clonal spread of multidrug-resistant KP.</p></div

Associated factors for mortality in the extended <i>K</i>. <i>pneumoniae</i> cohort, factors significant in multivariable analysis.

<p>Associated factors for mortality in the extended <i>K</i>. <i>pneumoniae</i> cohort, factors significant in multivariable analysis.</p

Rates of invasive isolates non-susceptible to third-generation cephalosporins among <i>K</i>. <i>pneumoniae</i> and <i>E</i>. <i>coli</i> 2006–2012, and <i>K</i>. <i>pneumoniae</i> / <i>E</i>. <i>coli</i> (KP/EC) ratio.

<p>A) Karolinska University Hospital. B) Twenty countries within EU/EEA reporting to EARS-Net. Population-weighted data.</p

Clinical characteristics of patients with invasive infection caused by <i>K</i>. <i>pneumoniae</i> versus <i>E</i>. <i>coli</i>, multivariable analysis.

<p>Clinical characteristics of patients with invasive infection caused by <i>K</i>. <i>pneumoniae</i> versus <i>E</i>. <i>coli</i>, multivariable analysis.</p

Invasive infection caused by <i>Klebsiella pneumoniae</i> is a disease affecting patients with high comorbidity and associated with high long-term mortality - Fig 3

<p><b>The percentages of <i>E</i>. <i>coli</i> (3A) and <i>K</i>. <i>pneumoniae</i> (3B) isolates non-susceptible against third-generation cephalosporins plotted against the ratios of <i>K</i>. <i>pneumoniae/E</i>. <i>coli</i> (KP/EC ratio) among 20 European countries 2006–2012.</b> Each dot (n = 140) represents one country a certain year.</p