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Development and Stability of Antibiotic Resistance
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antibiotic resistance is of current concern. Bacteria have become increasingly resistant to commonly used antibiotics and we are facing a growing resistance problem. The present thesis was aimed at studying the impact of antibiotic treatment on pathogenic bacteria as well as on the normal human microbiota, with focus on resistance development.

Among the factors that affect the appearance of acquired antibiotic resistance, the mutation frequency and biological cost of resistance are of special importance. Our work shows that the mutation frequency in clinical isolates of Helicobacter pylori was generally higher than for other studied bacteria such as Enterobacteriaceae; ¼ of the isolates displayed a mutation frequency higher than Enterobacteriaceae defective mismatch repair mutants and could be regarded as mutator strains.

In H. pylori, clarithromycin resistance confers a biological cost, as measured by decreased competitive ability of the resistant mutants in mice. In clinical isolates, this cost could be reduced, consistent with compensatory evolution stabilizing the presence of the resistant phenotype in the population. Thus, compensation is a clinically relevant phenomenon that can occur in vivo.

Furthermore, our results show that clinical use of antibiotics selects for stable resistance in the human microbiota. This is important for several reasons. First, many commensals occasionally can cause severe disease, even though they are part of the normal microbiota. Therefore, stably resistant populations increase the risk of unsuccessful treatment of such infections. Second, resistance in the normal microbiota might contribute to increased resistance development among pathogens by interspecies transfer of resistant determinants.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2004. , p. 63
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1370
Keywords [en]
Microbiology, antibiotic resistance, selection, mutation frequency, biological cost of resistance, compensatory evolution, Helicobacter pylori, normal microbiota
Keywords [sv]
Mikrobiologi
National Category
Microbiology in the medical area
Identifiers
URN: urn:nbn:se:uu:diva-4523ISBN: 91-554-6026-7 (print)OAI: oai:DiVA.org:uu-4523DiVA, id: diva2:165017
Public defence
2004-10-08, Hörsalen, Dag Hammarskjölds väg 17, Dag Hammarskjöldsv 17, Uppsala, 13:15
Opponent
Supervisors
Available from: 2004-09-15 Created: 2004-09-15 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Mutation frequency and biological cost of resistance in Helicobacter pylori.
Open this publication in new window or tab >>Mutation frequency and biological cost of resistance in Helicobacter pylori.
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2001 (English)In: Proc Natl Acad Sci U S A, Vol. 98, no 25, p. 14607-12Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92062 (URN)
Available from: 2004-09-15 Created: 2004-09-15 Last updated: 2011-06-30Bibliographically approved
2. Bacteria with increased mutation frequency and antibiotic resistance are enriched in the commensal flora of patients with high antibiotic usage
Open this publication in new window or tab >>Bacteria with increased mutation frequency and antibiotic resistance are enriched in the commensal flora of patients with high antibiotic usage
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2003 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 52, no 4, p. 645-650Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: We examined how prolonged antibiotic treatment affected the resistance and mutation frequency of human microflora isolated from intestine (Escherichia coli, enterococci spp.), pharynx (alpha-streptococci) and nostril (coagulase-negative staphylococci, CoNS).

METHODS: Samples were collected from patients at the Center of Cystic Fibrosis (n=18) and the haematology ward (n=18) of the University Hospital, Uppsala, Sweden. The individually used amount of antibiotics for 1 year was recorded as the defined daily dose (DDD). Primary health care patients (n=30), with no antibiotic treatment for 1 year before sampling, were used as controls. Three isolates of each bacterium from each patient were examined. Antibiotic susceptibilities were determined by disc diffusion. Mutation frequencies to rifampicin resistance were measured on 30 independent cultures of each bacterial species from each individual by plating on rifampicin agar plates. For alpha-streptococci the mutation frequency to streptomycin resistance was also determined.

RESULTS: Isolates from patients with high antibiotic use showed a pronounced shift towards increased resistance and a small but significant increase in the mutation frequency compared with isolates from the controls. For E. coli, enterococci and CoNS the increase in geometric mean mutation frequency in the patient group was 3-, 1.8- and 1.5-fold, respectively (P values 0.0001, 0.016 and 0.012). For alpha-streptococci there was a significant difference in geometric mean mutation frequency between patient and control groups for streptomycin resistance (P=0.024) but not for rifampicin resistance (P=0.74).

CONCLUSIONS: High antibiotic use selected for commensals with highly increased resistance and a slight increase in mutation frequency.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-92063 (URN)10.1093/jac/dkg427 (DOI)12972454 (PubMedID)
Available from: 2004-09-15 Created: 2004-09-15 Last updated: 2017-12-14Bibliographically approved
3. Long-term persistence of resistant Enterococcus species after antibiotics to eradicate Helicobacter pylori
Open this publication in new window or tab >>Long-term persistence of resistant Enterococcus species after antibiotics to eradicate Helicobacter pylori
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2003 (English)In: Ann Intern Med, Vol. 139, no 6, p. 483-7Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92064 (URN)
Available from: 2004-09-15 Created: 2004-09-15 Last updated: 2011-06-30Bibliographically approved
4. Fitness of Antibiotic-Resistant Staphylococcus epidermidis
Open this publication in new window or tab >>Fitness of Antibiotic-Resistant Staphylococcus epidermidis
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(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-92065 (URN)
Available from: 2004-09-15 Created: 2004-09-15 Last updated: 2011-06-30Bibliographically approved

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