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Studies on emergence and spread of antibiotic resistant Streptococcus pneumoniae
University of Skövde, The Systems Biology Research Centre. University of Skövde, School of Life Sciences. University of Skövde, Incentive level 1.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Streptococcus pneumoniae is one of the major contributors to mortality and morbidity around  the  world.  It  causes  a  wide  variety  of  diseases  ranging  from  uncomplicated respiratory  infections  to  life-threatening  invasive  infections  such  as  meningitis  and septicemia. In recent years, the effectiveness of antibiotic therapy has been hampered by  the  increasing  rates  of  resistant  pneumococci.  As  antibiotic  resistance  increases, there is a growing need for interventions that minimize opportunities for development and spread  of resistant  pneumococci.  The aim  of this  thesis  was  to learn  more  about emergence  and  spread  of  antibiotic  resistant  pneumococci  using  both  theoretical  and empirical methods.  Since the increasing prevalence of resistant pneumococci is mainly due to the spread of strains belonging to few clones, interventions for controlling pneumococcal transmission  in  the  community  were  studied.  Model  predictions  suggested  that interventions for efficiently control organism transmission should include reduction of group sizes in the day-care centers. Simulations also indicated that it appears extremely difficult  to  reduce  the  rates  of  penicillin  non-susceptible  pneumococci  by  simply decreasing  the  penicillin  consumption  assumed  that  reduced  penicillin  susceptibility does not imply a fitness cost for the organism. Managing the penicillin resistance rates in pneumococci then probably requires a more restrictive use of penicillin together with other  control  measures  such  as  vaccine  programs.  Although  clonal  spread  is  the primary  mechanism  for  the  rapid  emergence  of  resistance  in  pneumococci,  natural competence  for  genetic  transformation  also  seems  to  be  involved.  Further  molecular understanding  of competence regulation  is  important  to be  able  to prevent  horizontal spread  of  resistance  genes.  Studying  the  competence  regulation  by  theoretical  means led  to  the  conclusion  that  down-regulation  of  competence  is  probably  caused  by  a repressor acting on the comCDE operon at the level of transcription.  Despite the globally emerging frequency of resistant pneumococci, we conclude in a prospective study that antimicrobial resistance in invasive pneumococci in south-west Sweden remains limited. Any correlations between resistance pattern and clinical parameters could not be revealed. However, the serotype distribution was observed to differ  between  strains  with  reduced  susceptibility  and  fully  susceptible  strains  as isolates  with  decreased  susceptibility  more  frequently  belonged  to  the  serotypes included in the 7-valent vaccine.

Place, publisher, year, edition, pages
Stockholm: Karolinska Institutet , 2010. , 82 p.
National Category
Natural Sciences
Research subject
Natural sciences
Identifiers
URN: urn:nbn:se:his:diva-4699ISBN: 978-91-7457-027-4OAI: oai:DiVA.org:his-4699DiVA: diva2:393941
Funder
Knowledge Foundation
Available from: 2011-04-27 Created: 2011-02-01 Last updated: 2014-10-24Bibliographically approved
List of papers
1. An individual-based network model to evaluate interventions for controlling pneumococcal transmission
Open this publication in new window or tab >>An individual-based network model to evaluate interventions for controlling pneumococcal transmission
2008 (English)In: BMC Infectious Diseases, ISSN 1471-2334, Vol. 8, 83- p.Article in journal (Refereed) Published
Abstract [en]

Background: Streptococcus pneumoniae is a major cause of morbidity and mortality worldwide, but also a common colonizer of the upper respiratory tract. The emergence and spread of antibiotic resistant pneumococcal strains has threatened effective therapy. The long-term effects of measures aiming to limit pneumococcal spread are poorly understood. Computational modeling makes it possible to conduct virtual experiments that are impractical to perform in real life and thereby allows a more full understanding of pneumococcal epidemiology and control efforts. Methods: We have developed a contact network model to evaluate the efficacy of interventions aiming to control pneumococcal transmission. Demographic data from Sweden during the mid-2000s were employed. Analyses of the model's parameters were conducted to elucidate key determinants of pneumococcal spread. Also, scenario simulations were performed to assess candidate control measures. Results: The model made good predictions of previous findings where a correlation has been found between age and pneumococcal carriage. Of the parameters tested, group size in day-care centers was shown to be one of the most important factors for pneumococcal transmission. Consistent results were generated from the scenario simulations. Conclusion: We recommend, based on the model predictions, that strategies to control pneumococcal disease and organism transmission should include reducing the group size in day-care centers.

Identifiers
urn:nbn:se:his:diva-6868 (URN)10.1186/1471-2334-8-83 (DOI)000257399500002 ()18559109 (PubMedID)2-s2.0-47349104286 (ScopusID)
Available from: 2012-11-29 Created: 2012-11-29 Last updated: 2014-10-27Bibliographically approved
2. Probabilistic network modelling of the impact of penicillin consumption on spread of pneumococci
Open this publication in new window or tab >>Probabilistic network modelling of the impact of penicillin consumption on spread of pneumococci
2011 (English)In: Epidemiology and Infection, ISSN 0950-2688, E-ISSN 1469-4409, Vol. 139, no 9, 1351-1360 p.Article in journal (Refereed) Published
Abstract [en]

The worldwide increase of resistant S. pneumoniae is a growing clinical problem. In several countries, a more restrictive use of penicillin has been promoted in hope of slowing the rates of resistant pneumococci. However, the consequences of such an action on pneumococcal population dynamics are not fully understood. Thus, a network model was constructed to assess the impacts of penicillin consumption and between-strain competition on the spread of penicillin non-susceptible pneumococci. Model simulations suggest that the age distribution for carriage of penicillin non-susceptible pneumococci, in contrast to susceptible pneumococci, is affected by penicillin consumption. Furthermore, it appears extremely difficult to reduce the incidence of penicillin non-susceptible pneumococci by simply controlling penicillin consumption, assuming that reduced penicillin susceptibility does not confer a fitness cost for the organism. A more judicious use of penicillin together with control measures are in that case required to manage penicillin resistance in pneumococci.

Place, publisher, year, edition, pages
Cambridge University Press, 2011
Keyword
Antbiotic resistance, infectious disease control, modelling, Streptococcus pneumoniae (pneumococcus)
National Category
Natural Sciences
Research subject
Natural sciences
Identifiers
urn:nbn:se:his:diva-5207 (URN)10.1017/S0950268810002773 (DOI)000294145300008 ()21156095 (PubMedID)2-s2.0-80053119320 (ScopusID)
Available from: 2011-07-04 Created: 2011-07-04 Last updated: 2014-10-27Bibliographically approved
3. Modeling the regulation of the competence-evoking quorum sensing network in Streptococcus pneumoniae
Open this publication in new window or tab >>Modeling the regulation of the competence-evoking quorum sensing network in Streptococcus pneumoniae
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2007 (English)In: Biosystems (Amsterdam. Print), ISSN 0303-2647, E-ISSN 1872-8324, Vol. 90, no 1, 211-223 p.Article in journal (Refereed) Published
Abstract [en]

Competence for genetic transformation seems to play a fundamental role in the biology of Streptococcus pneumoniae and is believed to account for serotype switching, evolution of virulence factors, and rapid emergence of antibiotic resistance. The initiation of competence is regulated by the quorum sensing system referred as the ComABCDE pathway. Experimental studies reveal that competence is down-regulated a short time after its induction and several hypotheses about the mechanism(s) responsible for this shut-down have been presented. Possibly, a ComX-dependent gene product, such as a repressor or a phosphatase, is involved. To better understand the down-regulation of the competence-evoking system in S. pneumoniae, a mathematical model was set up. By analyzing the model, we suggest that shut-down of competence possibly occurs at the transcriptional level on the comCDE operon. As a result of introducing a putative comX-dependent repressor, which inhibits expression of comCDE and comX, in the mathematical model, competence is demonstrated to appear in waves. This is supported by experimental studies showing the appearance of successive competence cycles in pneumococcal batch cultures.

Place, publisher, year, edition, pages
Elsevier, 2007
Identifiers
urn:nbn:se:his:diva-1887 (URN)10.1016/j.biosystems.2006.08.005 (DOI)000248966800019 ()17011700 (PubMedID)2-s2.0-34447093989 (ScopusID)
Available from: 2007-09-19 Created: 2007-09-19 Last updated: 2014-10-24Bibliographically approved
4. Antimicrobial susceptibility of invasive pneumococcal isolates from a region in south-west Sweden 1998-2001
Open this publication in new window or tab >>Antimicrobial susceptibility of invasive pneumococcal isolates from a region in south-west Sweden 1998-2001
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2007 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, Vol. 39, no 1, 19-27 p.Article in journal (Refereed) Published
Abstract [en]

Invasive disease caused by antibiotic resistant pneumococci is a worldwide problem. All invasive pneumococcal strains in an area of south-west Sweden with 1.7 million inhabitants were collected prospectively during 1998-2001. Minimum inhibitory concentrations (MICs) were determined by E-test and correlated to serotypes and clinical characteristics. Of 827 strains, 744 (90%) were susceptible (S) to all agents tested and 83 (10%) were indeterminate (I) or resistant (R) to at least 1 agent. 22 isolates (2.7%) were I to penicillin (MIC gt0.06 to ≤1.0 mg/l), but none were R (MIC gt1.0 mg/l). Numbers and proportions of decreased susceptibility against other agents tested were as follows: erythromycin R: 30 (3.6%), clindamycin R: 6 (0.7%), tetracycline R: 16 (1.9%), moxifloxacin R: 1 (0.1%), cotrimoxazole I: 17 (2%) and R: 31(4%). Non-susceptibility to at least 1 agent was not correlated with age, clinical manifestation, underlying diseases and outcome. The serotype distribution differed between non-susceptible and susceptible strains. The serotypes in the 7-valent pneumococcal conjugate vaccine covered 42% of all infections and 73% of those caused by non-susceptible strains. In conclusion, the impact of antibiotic resistance in invasive pneumococcal disease remains limited in south-west Sweden.

Place, publisher, year, edition, pages
Informa Healthcare, 2007
National Category
Medical and Health Sciences
Research subject
Medical sciences
Identifiers
urn:nbn:se:his:diva-2033 (URN)10.1080/00365540600895043 (DOI)000244148000003 ()17366008 (PubMedID)2-s2.0-33847129993 (ScopusID)
Available from: 2008-05-07 Created: 2008-05-07 Last updated: 2014-10-24Bibliographically approved

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