S ON D SP IOTIC EPT NEUM

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 rates of resistant pneumococci are mainly due to the spread of strains belonging to few clones, interventions for controlling pneumococcal transmission in the community were assessed. Model predictions suggested that interventions for efficiently control organism transmission should include reducing the group size in the day-care centers. Besides, simulations indicated that it appears extremely difficult to reduce the rates of penicillin-non susceptible pneumococci by simply decreasing the penicillin consumption if no bacterial resistance cost exists. 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 has constituted the primary mechanism for the rapid emergence of resistance in pneumococci, the pneumococcal feature of natural competence for genetic transformation also had implications. 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 proposal that the down-regulation of competence possibly occurs at transcriptional level. Despite the globally emerging frequency of resistant pneumococci, we conclude in a prospective study that the impact of 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 since isolates with decreased susceptibility were more often seen among the serotypes included in the 7-valent vaccine. LIST OF PUBLICATIONS This thesis is based on the following papers, which will be referred in the text by their Roman numerals: I. D. Karlsson, A. Jansson, B. Henriques Normark, and P. Nilsson. An individual-based network model to evaluate interventions for controlling pneumococcal transmission. BMC Infect Dis 2008, 8:83. II. D. Karlsson. Probabilistic network modelling of the impact of penicillin consumption on pneumococcal spreading. Submitted manuscript. III. D. Karlsson, S. Karlsson, E. Gustafsson, B. Henriques Normark, and P. Nilsson. Modeling the regulation of the competence-evoking quorum sensing network in Streptococcus pneumoniae. BioSystems 2007, 90(1):211-23. IV. E. Backhaus, S. Berg, B. Trollfors, R. Andersson, E. Persson, B. E. Claesson, P. Larsson, E. Ek, L. Jonsson, G. Rådberg, S. Johansson, T. Ripa, D. Karlsson, and K. Andersson. Antimicrobial susceptibility of invasive pneumococcal isolates from a region in south-west Sweden 1998-2001. Scand J Infect Dis 2007, 39(1):19-27.