Aerococcal infections - from bedside to bench and back Senneby, Erik 2018 Document Version: Förlagets slutgiltiga version Link to publication Citation for published version (APA): Senneby, E. (2018). Aerococcal infections - from bedside to bench and back. Lund University: Faculty of Medicine. 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LUND UNIVERSITY PO Box 117 221 00 Lund +46 46-222 00 00 Aerococcal infections - from bedside to bench and back Erik Senneby DOCTORAL DISSERTATION by due permission of the Faculty of Medicine, Lund University, Sweden. To be defended at Segerfalkssalen, BMC, on May 24th 2018 at 13.00. Faculty opponent Associate professor Christian Giske Karolinska Institutet 1 Organization Document name LUND UNIVERSITY Doctoral dissertation Department of Clinical Sciences Date of issue Division of Infection Medicine 20180524 Author(s) Erik Senneby Sponsoring organization Title and subtitle Aerococcal Infections – from bedside to bench and back Abstract The genus Aerococcus comprises eight species of Gram-positive cocci. Due to difficulties in species identification of aerococci in the past, the incidence and clinical importance of aerococcal infections has been underestimated. We evaluated the usefulness of MALDI- TOF MS as a species identification method for aerococci and found that it had a high sensitivity and specificity. Two population-based studies on aerococcal bacteruria were performed. A. urinae and A. sanguinicola were isolated in approximately 1 % of all urine samples in Skåne. The patients were of old age and gender was almost equally distributed between men and women. Almost 80 % of patients with aerococcal bacteruria had symptoms of a urinary tract infection. Several antibiotics, including nitrofurantoin and amoxicillin, could serve as treatment options. Resistance against ciprofloxacin was recorded, especially in A. sanguinicola isolates. In a retrospective population-based study on aerococcal bacteremia, 77 patients were identified during a three-year period (A. urinae n=49, A. sanguinicola n=13, A. viridans n=14 and A. christensenii n=1). The A. urinae and A. sanguinicola patients were old (median age >80 years), predominately of male gender and underlying urological diseases were common. A majority of the A. urinae and A. sanguinicola patients had severe sepsis. Five patients with A. urinae bacteremia were diagnosed with infective endocarditis. A. viridans seemed to be a contaminant in most cases. The aerococcal isolates were sensitive to betalactam antibiotics and vancomycin. Two studies were conducted regarding virulence mechanisms. We demonstrated that A. sanguinicola isolates produced biofilm and activated platelets, two potentially important virulence factors. A. urinae isolates were subjected to masspectrometry-based proteomics and whole genome sequencing. Two cell wall-anchored proteins with LPXTG-motifs, with unknown functions, dominated the surface and genes encoding these proteins were localized in a conserved locus on the aerococcal chromosome. Key words: Aerococcus, bacteremia, urinary tract infections, MALDI-TOF MS, surface proteome, genes encoding surface proteins Classification system and/or index terms (if any) Supplementary bibliographical information Language English ISSN and key title 1652-8220 ISBN 978-91-7619-640-3 Recipient’s notes Number of pages Price Security classification I, the undersigned, being the copyright owner of the abstract of the above-mentioned dissertation, hereby grant to all reference sources permission to publish and disseminate the abstract of the above-mentioned dissertation. Signature Date 2 Aerococcal infections - from bedside to bench and back Erik Senneby 3 Erik Senneby Division of Infection Medicine Department of Clinical Sciences Faculty of Medicine Lund University Biomedical Center, B14 Tornavägen 10 221 84 Lund Sweden Email: [email protected] Cover picture by Erik Senneby Copyright Erik Senneby Paper I is reprinted by permission from the American Society for Microbiology Paper II is reprinted by permission from Oxford University Press Paper III is reprinted by permission from Springer Paper IV-V is reprinted by permission from Elsevier Faculty of Medicine Department of Clinical Sciences, Lund ISBN 978-91-76-19-640-3 ISSN 1652-8220 Printed in Sweden by Media-Tryck, Lund University Lund 2018 WAN E S CO IC L D A B R E O L N Media-Tryck is an environmentally certified and ISO 14001 certified 1234 5678 provider of printed material. Read more about our environmental work at www.mediatryck.lu.se 4 5 Table of Contents List of papers ............................................................................................... 8 Abbrevations.............................................................................................. 10 Abstract ...................................................................................................... 11 Aims with the thesis .................................................................................. 13 Aerococci – emerging pathogens? .............................................................. 14 1. Introduction to Aerococcus .................................................................. 17 2. A historical overview of the genus Aerococcus. .................................. 19 Taxonomic confusion and dead lobsters. .......................................... 19 Aerococcus-like organisms and human disease................................. 20 … and additional aerococcal species ................................................. 21 3. Methods in clinical bacteriology .......................................................... 23 Gram staining .................................................................................... 23 MALDI-TOF MS .............................................................................. 24 Urine culture procedures ................................................................... 25 Blood culture procedures ................................................................... 28 4. Species identification of aerococci ....................................................... 29 5. Clinical presentation of aerococcal bacteriuria.................................. 33 6. Clinical presentation of invasive aerococcal infections. .................... 37 7. Aerococcal antibiotic susceptibility. .................................................... 41 Synergistic effects of antibiotic combinations................................... 45 Antibiotic resistance mechanisms in aerococci ................................. 45 8. Virulence mechanisms and aerococci .................................................. 49 Bacterial induced platelet aggregation .............................................. 49 Biofilm formation .............................................................................. 50 Cell wall-anchored proteins with an LPXTG-motif .......................... 51 6 9. Present investigations. .......................................................................... 53 Paper I ................................................................................................ 53 Paper II .............................................................................................. 54 Paper III ............................................................................................. 55 Paper IV ............................................................................................. 56 Paper V .............................................................................................. 58 Paper VI ............................................................................................. 59 10. Conclusion and future perspectives................................................... 61 The incidence increase....................................................................... 61 Clinical significance .......................................................................... 62 Urinary tract infections .............................................................. 62 Invasive infections ..................................................................... 63 Male dominance ........................................................................ 63 Treatment of aerococcal infections.................................................... 64 Virulence mechanisms and aerococci................................................ 64 Finally, is there a human aerococcal habitat? .................................... 66 Populärvetenskaplig sammanfattning på svenska ................................. 67 Acknowledgements...................................................................................