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Biological and Pharmacological Factor that Influence the Selection of Antibiotic Resistance
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
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
Keyword [en]
Microbiology, Human microflora, antibiotic resistance, selection, mutation frequency, biological fitness, pharmacokinetics, pharmacodynamics, β-lactam antibiotics, suboptimal dosing regimen
Keyword [sv]
Mikrobiologi
National Category
Microbiology
Research subject
Clinical Bacteriology
Identifiers
URN: urn:nbn:se:uu:diva-3355ISBN: 91-554-5549-2 (print)OAI: oai:DiVA.org:uu-3355DiVA, id: diva2:162483
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
List of papers
1. 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
2. Fitness of antibiotic resistant Staphylococcus epidermidis assessed by competition on skin of human volunteers
Open this publication in new window or tab >>Fitness of antibiotic resistant Staphylococcus epidermidis assessed by competition on skin of human volunteers
(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-90205 (URN)
Available from: 2003-03-19 Created: 2003-03-19 Last updated: 2011-06-30Bibliographically approved
3. Pharmacokinetic and pharmacodynamic parameters for antimicrobial effects of cefotaxime and amoxicillin in an in vitro kinetic model
Open this publication in new window or tab >>Pharmacokinetic and pharmacodynamic parameters for antimicrobial effects of cefotaxime and amoxicillin in an in vitro kinetic model
2001 In: Antimicrobial Agents and Chemotherapy, Vol. 45, no 9, p. 2436-2440Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-90206 (URN)
Available from: 2003-03-19 Created: 2003-03-19Bibliographically approved
4. Suboptimal antibiotic dosage as a risk factor for selection of penicillin-resistant Streptococcus pneumoniae: In vitro kinetic model
Open this publication in new window or tab >>Suboptimal antibiotic dosage as a risk factor for selection of penicillin-resistant Streptococcus pneumoniae: In vitro kinetic model
2003 In: Antimicrobial Agents and Chemotherapy, Vol. 47, no 2, p. 518-523Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-90207 (URN)
Available from: 2003-03-19 Created: 2003-03-19Bibliographically approved

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