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Extended-Spectrum ß-Lactamase-Producing Enterobacteriaceae: Antibiotic consumption, Detection and Resistance Epidemiology
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Infectious Diseases. (Antibiotikaresistens)ORCID iD: 0000-0002-5035-2915
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

ESBL-producing Enterobacteriaceae are emerging worldwide and they are frequently multi-drug resistant, thus limiting treatment options for infections caused by these pathogens.

The overall aim of the thesis was to investigate ESBL-producing Enterobacteriaceae in a Swedish county.

First, we developed a molecular method, a multiplex PCR assay for identification of SHV, TEM and CTX-M genes in clinical isolates of Enterobacteriaceae with an ESBL phenotype.

From 2002 until the end of 2007 all isolates of ESBL-producing Enterobacteriaceae in Östergötland, Sweden were further investigated. The prevalence of ESBL-producing Enterobacteriaceae was low, <1%, but increasing,while the antibiotic consumption remained unchanged. CTX-M enzymes, particularly CTX-M group 1, dominate in our region as well as in the rest of Europe.

Furthermore, we have investigated antimicrobial susceptibility by performing MIC-testing in a large, well-characterized population of CTX-M-producing E. coli. Only three oral antimicrobial agents (fosfomycin, nitrofurantoin and mecillinam) demonstrated susceptibility above 90%. High susceptibility, >90%, was also demonstrated for carbapenems, colistin, tigecycline and amikacin. Sixty-eight per cent of ESBL-producing E. coli was multi-resistant, and the most common multi-resistance pattern was the ESBL phenotype with decreased susceptibility to trimethoprim, trimethoprim-sulfamethoxazole, ciprofloxacin, gentamicin and tobramycin. Isolates belonging to CTX-M group 9 are generally more susceptible to antibiotics than the CTX-M group 1-producing E. coli.

Finally, a prospective multicentre case-control study examined the prevalence of ESBL-producing Enterobacteriaceae in faecal samples before and after travel abroad and the risk factors of acquisition. Sixty-eight of 226 travellers (30%) had ESBL-producing Enterobacteriaceae in the faecal flora. The geographical area visited had the highest impact on acquisition, with highest the risk for travellers visiting the Indian subcontinent, followed by Asia and Africa north of the equator. Also, acquisition of ESBL-producing Enterobacteriaceae during travel is associated with abdominal symptoms such as diarrhoea. Age also seemed to affect the risk of acquiring ESBL-producing Enterobacteriaceae, the highest risks were found among travellers ≥ 65 years.

This thesis has contributed to increased understanding of the epidemiology of ESBL-producing Enterobacteriaceae and their susceptibility to both beta-lactam and non-beta-lactam agents.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. , 69 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1394
Keyword [en]
Extended-Spectrum ß-Lactamase-Producing Enterobacteriaceae, Antibiotic consumption, Detection Methods, Multiplex PCR, Resistance Epidemiology, Multi-resistance, E. coli, ESBL, fecal carriage, faecal carriage, travel
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-104216DOI: 10.3384/diss.diva-104216ISBN: 978-91-7519-404-2 (print)OAI: oai:DiVA.org:liu-104216DiVA: diva2:695475
Public defence
2014-04-11, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Funder
County Council of Östergötland
Available from: 2014-02-11 Created: 2014-02-11 Last updated: 2014-03-04Bibliographically approved
List of papers
1. Multiplex PCR amplification assay for the detection of blaSHV, blaTEM and blaCTX-M genes in Enterobacteriaceae
Open this publication in new window or tab >>Multiplex PCR amplification assay for the detection of blaSHV, blaTEM and blaCTX-M genes in Enterobacteriaceae
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2007 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 115, no 12, 1400-1408 p.Article in journal (Refereed) Published
Abstract [en]

Extended-spectrum β-lactamases (ESBLs) are often mediated by bla-SHV, blaTEM and blaCTX-M genes in Enterobacteriaceae and other Gram-negative bacteria. Numerous molecular typing methods, including PCR-based assays, have been developed for their identification. To reduce the number of PCR amplifications needed we have developed a multiplex PCR assay which detects and discriminates between bla-SHV, blaTEM and blaCTX-M PCR amplicons of 747, 445 and 593 bp, respectively. This multiplex PCR assay allowed the identification of bla-SHV, blaTEM and blaCTX-M genes in a series of clinical isolates of Enterobacteriaceae with previously characterised ESBL phenotype. The presence of blaSHV, blaTEM and blaCTX-M genes was confirmed by partial DNA sequence analysis. Apparently, the universal well-established CTX-M primer pair used here to reveal plasmid-encoded blaCTX-M genes would also amplify the chromosomally located K-1 enzyme gene in all Klebsiella oxytoca strains included in the study.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-41186 (URN)10.1111/j.1600-0463.2007.00722.x (DOI)55314 (Local ID)55314 (Archive number)55314 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
2. Prevalence of extended-spectrum beta-lactamase-producing Enterobacteriaceae and trends in antibiotic consumption in a county of Sweden
Open this publication in new window or tab >>Prevalence of extended-spectrum beta-lactamase-producing Enterobacteriaceae and trends in antibiotic consumption in a county of Sweden
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2010 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 42, no 11-12, 831-838 p.Article in journal (Refereed) Published
Abstract [en]

In the last decade extended-spectrum beta-lactamase (ESBL)-producing bacteria have become an increasing problem. Our aims were to investigate the prevalence of ESBL-producing Enterobacteriaceae and trends in antibiotic use in the county of Ostergotland, Sweden. From 2002 through 2007 there were 224 ESBL-producing Escherichia coli and 23 Klebsiella pneumoniae isolates with an ESBL-phenotype identified among all Enterobacteriaceae isolated at the clinical laboratory. Trends in antibiotic consumption expressed as defined daily doses (DDD) per 1000 inhabitants and day (DID) were studied. The prevalence of ESBL-producing isolates among Enterobacteriaceae in our region is still low (andlt; 1%). Patients with ESBL-producing E. coli increased significantly (p andlt; 0.001) from 5 in y 2002 to 47 in y 2007. CTX-M group 1 was the dominant enzyme group in both E. coli and K. pneumoniae. Antibiotic susceptibility testing of ciprofloxacin, gentamicin and trimethoprim-sulfamethoxazole revealed that 58% of E. coli and 50% of K. pneumoniae isolates were multi-resistant. Antibiotic use remained unchanged from 2001 through 2009, but there was a trend towards increased use of drugs with low ESBL selection potential, which was probably due to the increased prevalence of ESBL producers.

Place, publisher, year, edition, pages
Informa Healthcare, 2010
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-63145 (URN)10.3109/00365548.2010.498017 (DOI)000284168300006 ()
Available from: 2010-12-13 Created: 2010-12-13 Last updated: 2017-12-11Bibliographically approved
3. In vitro activity of beta-lactam antibiotics against CTX-M-producing Escherichia coli
Open this publication in new window or tab >>In vitro activity of beta-lactam antibiotics against CTX-M-producing Escherichia coli
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2011 (English)In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 30, no 8, 981-987 p.Article in journal (Refereed) Published
Abstract [en]

Beta-lactam antibiotics have been discussed as options for the treatment of infections caused by multiresistant extended-spectrum beta-lactamase (ESBL)-producing bacteria if the minimum inhibitory concentration (MIC) is low. The objective of this study was to investigate the in vitro activity of different beta-lactam antibiotics against CTX-M-producing Escherichia coli. A total of 198 isolates of E. coli with the ESBL phenotype were studied. Polymerase chain reaction (PCR) amplification of CTX-M genes and amplicon sequencing were performed. The MICs for amoxicillin-clavulanic acid, aztreonam, cefepime, cefotaxime, ceftazidime, ceftibuten, ertapenem, imipenem, mecillinam, meropenem, piperacillin-tazobactam, and temocillin were determined with the Etest. Susceptibility was defined according to the breakpoints of the European Committee on Antimicrobial Susceptibility Testing (EUCAST). MIC(50) and MIC(90) values were calculated. Isolates from CTX-M group 9 showed higher susceptibility to the beta-lactam antibiotics tested than isolates belonging to CTX-M group 1. More than 90% of the isolates belonging to CTX-M group 9 were susceptible to amoxicillin-clavulanic acid, ceftazidime, ceftibuten, piperacillin-tazobactam, and temocillin. The susceptibility was high to mecillinam, being 91%, regardless of the CTX-M group. All isolates were susceptible to imipenem and meropenem, and 99% to ertapenem. This study shows significant differences in susceptibility to different beta-lactam antibiotics among the CTX-M-producing E. coli isolates and a significant difference for many antibiotics tested between the CTX-M-producing groups 1 and 9. The good in vitro activity of other beta-lactam antibiotics compared to carbapenems indicate that clinical studies are warranted in order to examine the potential role of these beta-lactam antibiotics in the treatment of infections caused by multiresistant ESBL-producing E. coli.

Place, publisher, year, edition, pages
Springer Science Business Media, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-69787 (URN)10.1007/s10096-011-1183-4 (DOI)000292553500008 ()
Available from: 2011-08-10 Created: 2011-08-08 Last updated: 2017-12-08Bibliographically approved
4. High frequency of co-resistance in CTX-M-producing Escherichia coli to non-beta-lactam antibiotics, with the exception of amikacin, nitrofurantoin, colistin, tigecycline, and fosfomycin, in a county of Sweden
Open this publication in new window or tab >>High frequency of co-resistance in CTX-M-producing Escherichia coli to non-beta-lactam antibiotics, with the exception of amikacin, nitrofurantoin, colistin, tigecycline, and fosfomycin, in a county of Sweden
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2013 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 45, no 4, 271-278 p.Article in journal (Refereed) Published
Abstract [en]

Background: The objective of this study was to investigate the in vitro activity of different antibiotics against CTX-M-producing Escherichia coli in a county of Sweden, and to determine the occurrence of multi-resistance and plasmid- mediated quinolone resistance among these isolates. Methods: A total of 198 isolates of E. coli with extended-spectrum beta-lactamase (ESBL) phenotype and mainly CTX-M genotype were studied. The minimum inhibitory concentrations (MICs) for amikacin, chloramphenicol, ciprofloxacin, colistin, fosfomycin, gentamicin, nalidixic acid, nitrofurantoin, tigecycline, tobramycin, trimethoprim, and trimethoprim-sulfamethoxazole were determined with the Etest. Susceptibility was defined according to the breakpoints of the European Committee on Antimicrobial Susceptibility Testing (EUCAST). MIC(50) and MIC(90) values were calculated. Results: Ninety-five percent or more of the isolates were susceptible to amikacin, nitrofurantoin, colistin, tigecycline, and fosfomycin. CTX-M group 9 was more susceptible than CTX-M group 1 to ciprofloxacin, gentamicin, and tobramycin. Sixty-eight percent of the isolates were multi-resistant, and the most common multi-resistance pattern was ESBL phenotype with decreased susceptibility to trimethoprim, trimethoprim-sulfamethoxazole, ciprofloxacin, gentamicin, and tobramycin. Only 1 isolate carried a qnrS1 gene, but 37% carried aac(6')-Ib-cr. Conclusions: A high frequency of co-resistance between ESBL-producing E. coli and non-beta-lactam antibiotics was seen. On the other hand, very high susceptibility was seen for amikacin, nitrofurantoin, colistin, tigecycline, and fosfomycin. These data support the replacement of gentamicin and tobramycin, normally used in Sweden, with amikacin, for severe infections.

Keyword
Etest, minimum inhibitory concentration, extended-spectrum beta-lactamase
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-87612 (URN)10.3109/00365548.2012.734636 (DOI)000316693600005 ()23113731 (PubMedID)
Available from: 2013-01-19 Created: 2013-01-19 Last updated: 2017-12-06
5. Travel-associated faecal colonization with ESBL-producing Enterobacteriaceae: incidence and risk factors
Open this publication in new window or tab >>Travel-associated faecal colonization with ESBL-producing Enterobacteriaceae: incidence and risk factors
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2013 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 68, no 9, 2144-2153 p.Article in journal (Refereed) Published
Abstract [en]

Objectives To study the acquisition of extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE) among the faecal flora during travel, with a focus on risk factors, antibiotic susceptibility and ESBL-encoding genes.

Methods An observational prospective multicentre cohort study of individuals attending vaccination clinics in south-east Sweden was performed, in which the submission of faecal samples and questionnaires before and after travelling outside Scandinavia was requested. Faecal samples were screened for ESBL-PE by culturing on ChromID ESBL and an in-house method. ESBL-PE was confirmed by phenotypic and genotypic methods. Susceptibility testing was performed with the Etest. Individuals who acquired ESBL-PE during travel (travel-associated carriers) were compared with non-carriers regarding risk factors, and unadjusted and adjusted ORs after manual stepwise elimination were calculated using logistic regression.

Results Of 262 enrolled individuals, 2.4% were colonized before travel. Among 226 evaluable participants, ESBL-PE was detected in the post-travel samples from 68 (30%) travellers. The most important risk factor in the final model was the geographic area visited: Indian subcontinent (OR 24.8, P < 0.001), Asia (OR 8.63, P < 0.001) and Africa north of the equator (OR 4.94, P  = 0.002). Age and gastrointestinal symptoms also affected the risk significantly. Multiresistance was seen in 77 (66%) of the ESBL-PE isolates, predominantly a combination of reduced susceptibility to third-generation cephalosporins, trimethoprim/sulfamethoxazole and aminoglycosides. The most common species and ESBL-encoding gene were Escherichia coli (90%) and CTX-M (73%), respectively.

Conclusion Acquisition of multiresistant ESBL-PE among the faecal flora during international travel is common. The geographical area visited has the highest impact on ESBL-PE acquisition.

Place, publisher, year, edition, pages
Oxford University Press, 2013
Keyword
travel medicine, CTX-M, antibiotic resistance
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-97437 (URN)10.1093/jac/dkt167 (DOI)000323424100029 ()23674762 (PubMedID)
Note

Funding Agencies|Medical Research Council of Southeast Sweden|FORSS-12368FORSS-36511FORSS-87551|ALF grants, Ostergotland County Council|LIO-10885LIO-16741LIO-61341LIO-127281|

Available from: 2013-09-12 Created: 2013-09-12 Last updated: 2017-12-06Bibliographically approved

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