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Bacteria with increased mutation frequency and antibiotic resistance are enriched in the commensal flora of patients with high antibiotic usage
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
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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.

Place, publisher, year, edition, pages
2003. Vol. 52, no 4, p. 645-650
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-92063DOI: 10.1093/jac/dkg427PubMedID: 12972454OAI: oai:DiVA.org:uu-92063DiVA, id: diva2:165014
Available from: 2004-09-15 Created: 2004-09-15 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Development and Stability of Antibiotic Resistance
Open this publication in new window or tab >>Development and Stability of Antibiotic Resistance
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
Microbiology, antibiotic resistance, selection, mutation frequency, biological cost of resistance, compensatory evolution, Helicobacter pylori, normal microbiota, Mikrobiologi
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-4523 (URN)91-554-6026-7 (ISBN)
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
2. Biological and Pharmacological Factor that Influence the Selection of Antibiotic Resistance
Open this publication in new window or tab >>Biological and Pharmacological Factor that Influence the Selection of Antibiotic Resistance
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antibiotic treatment causes an ecological disturbance on the human microflora. Four commensal bacteria: E. coli, enterococci, a-streptococci and coagulase-negative staphylococci, from patients with extensive, high antibiotic usage were investigated with regard to resistance pattern and mutation frequency. Among 193 investigated strains it was found that high antibiotic usage selected for resistant bacteria and enriched for bacteria with a small but significantly increased mutation frequency.

The relative biological fitness cost of resistance in Staphylococcus epidermidis was assessed in a human in vivo model where the indigenous flora was present. In vitro data of the bacterial growth rate correlated well to in vivo fitness assayed in the competition experiments on skin.

An in vitro kinetic model was shown to be a useful tool to establish the pharmacokinetic and pharmacodynamic (PK/PD) indices for efficacy of antibiotics. It was confirmed that the time, when the concentration exceeds the minimal inhibitory concentration (MIC), correlates with efficacy for b-lactam antibiotics. To achieve maximal killing for penicillin-resistant pneumococci, with an MIC of 2 mg/L, the peak concentration was also of importance.

Suboptimal dosing regimen facilitates selection of resistance. Penicillin-resistant pneumococci were easily selected in a mixed population with penicillin-sensitive, -intermediate and -resistant pneumococci in an in vitro kinetic model. The selection of the resistant strain was prevented when the benzylpenicillin concentration exceeded the MIC for approximately 50% of 24 h.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2003. p. 49
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1228
Keywords
Microbiology, Human microflora, antibiotic resistance, selection, mutation frequency, biological fitness, pharmacokinetics, pharmacodynamics, β-lactam antibiotics, suboptimal dosing regimen, Mikrobiologi
National Category
Microbiology
Research subject
Clinical Bacteriology
Identifiers
urn:nbn:se:uu:diva-3355 (URN)91-554-5549-2 (ISBN)
Public defence
2003-04-11, Hörsalen, Klinisk mikrobiologi, Uppsala, 13:15
Opponent
Supervisors
Available from: 2003-03-19 Created: 2003-03-19 Last updated: 2013-09-16Bibliographically approved

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Torell, ErikJohannesson, MarieEngstrand, LarsCars, OttoAndersson, Dan I.

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