Högskolan i Skövde

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.

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.

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.

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.