Multidrug Resistant Pseudomonas aeruginosa. Presenter: Andrew Webb Block Lecturer: George Zhanel Date: 10 January 2019

Transcription

1 Multidrug Resistant Pseudomonas aeruginosa Presenter: Andrew Webb Block Lecturer: George Zhanel Date: 10 January

2 Pseudomonas aeruginosa Not a member of human microbiome Inhabitant of soil and moist environments Opportunistic bacterial pathogen in people Self-resolving in healthy individuals Link to immunocompromised individuals Common nosocomial (i.e. hospital-acquired) infectious agent Persists on medical equipment, particularly water sources and surgical tubing Commonly isolated pathogen from patients with ventilator associated pneumonia. Multiple sites of infection respiratory tract, urinary tract, skin and soft skin tissue, ocular tissue,outer ear 2

3 Risk assessment Accumulation of antimicrobial resistance Natural resistance to carbapenem antibiotics, drugs of last resort reserved for multidrug-resistant bacterial infections High risk of adaptive resistance due to incorrect MIC Multidrug resistant (MDR) or extensive drug resistance (XDR) High morbidity and mortality rates in immunocompromised individuals 60-80% morbidity in patients with cystic fibrosis (CF), 30% mortality in patients with ventilator associated pneumonia Progression to chronic infections More than 20 years in CF patients Rapid exacerbation of existing condition and/or gradual but relentless deterioration of infected organ 3

4 Diseases linked to P. aeruginosa Common link damage to lung tissues and/or immune response mechanisms Bronchiectasis Chronic obstructive pulmonary disease Cystic fibrosis By National Heart Lung and Blood Institute - National Heart Lung and Blood Institute, Public Domain, By National Heart Lung and Blood Institute - //dci/diseases/copd/copd_wha tis.html, Public Domain, w/index.php?curid=

5 Cystic fibrosis and P. aeruginosa Of CF patients, 60-80% colonized by P. aeruginosa Most information about association with P. aeruginosa Patients suffer continuous damage to lung tissues P. aeruginosa adapts to CF host conditions By National Heart Lung and Blood Institute (NIH) - National Heart Lung and Blood Institute (NIH), Public Domain, Folkesson A, Jelsbak L, Yang L, Johansen HK, Ciofu O, Høiby N, Molin S Adaptation of Pseudomonas aeruginosa to the cystic fibrosis airway: an evolutionary perspective. Nature Reviews Microbiology

6 Population structure Genotyping Subspecies differentiation to identify evolutionary history, in epidemiology used to track transmission events Some P. aeruginosa subtypes are widespread (e.g. ST235, ST111, ST175) Oliver A, Mulet X, Lopez-Causape C, Juan C The increasing threat of Pseudomonas aeruginosa high-risk clones. Drug Resistance Updates

7 Population structure Some P. aeruginosa subtypes are linked to specific areas or people ST277 associated with Brazil ST146 with CF patients Non-clonal epidemic structure Populations contain many subtypes Limited number of dominant subtypes Subtypes undergo mutation and recombine with each other Result = rapid development and sharing of acquired resistance factors Oliver A, Mulet X, Lopez-Causape C, Juan C The increasing threat of Pseudomonas aeruginosa high-risk clones. Drug Resistance Updates

8 Which P. aeruginosa subtypes become high-risk? Many MDR/XDR subtypes exist, but few are widespread Study of association of biological parameters as factors of high-risk subtypes Motility Biofilm-forming capacity Iron acquisition Pyocyanin toxin (persistence-related) Competitive growth High risk clones have reduced motility and increased mutation frequencies and biofilm formation Is survival and persistence prioritized over growth and virulence? Study publication: Lee J-Y, Peck KR, Ko KS Selective advantages of two major clones of carbapenem-resistant Pseudomonas aeruginosa isolates (CC235 and CC641) from Korea: antimicrobial resistance, virulence and biofilm-forming activity. Journal of Medical Microbiology 62 (7):

9 Pathogenesis initial infection (acute phase) Motility Adherence Exotoxins Cell death Increased permeability Reduced wound healing Type 3 secretion system Four effector proteins (ExoS, ExoT, ExoU, ExoY) Inhibited immune response Gellatly SL, Hancock REW Pseudomonas aeruginosa: new insights into pathogenesis and host defenses. Pathogens and Disease 67 (3):

10 Virulent motility Flagellum and pili perform motility and adherence function Motility mechanism matters Swimming uses only flagellum and takes place in liquid Twitching uses only pili and takes place on solid (but moist) surface Swarming uses flagellum and pili and takes place on semi-solid surface Wild-type Mutant Aires J, Plesiat P, Kocjancic Curty L, Köhler T Selection of an Antibiotic-Hypersusceptible Mutant of Pseudomonas aeruginosa: Identification of the GlmR Transcriptional Regulator, vol

11 Pathogenesis host response (acute phase) Detection by toll-like receptors Response by macrophages Secretion of cytokines and chemokines (especially IL8) to recruit neutrophils for phagocytosis Activation of dendritic cells to signal adaptive immune response Gellatly SL, Hancock REW Pseudomonas aeruginosa: new insights into pathogenesis and host defenses. Pathogens and Disease 67 (3):

12 Pathogenesis colonization (chronic phase) P. aeruginosa infection is no cleared in immunocompromised biofilm formation and upregulation of evasion and survival factors. Suppression of host cell adaptive immune signaling activity Constant host immune dysregulation leading to inflammatory damage over time In CF patients, neutrophils do not clear infection but continue to be recruited, which leads to inflammatory damage. Sousa A, Pereira M Pseudomonas aeruginosa Diversification during Infection Development in Cystic Fibrosis Lungs A Review. Pathogens 3 (3):

13 Biofilm formation Substrate adherent, protective coating Reduced virulence, increased evasion factors and signaling activity Impacts P. aeruginosa survival and antimicrobial resistance AR Hauser and EA Ozer (2011). Pseudomonas aeruginosa. Nature reviews microbiology. 9 (3). 13

14 Quorum sensing Population-level detection and response Autoinducer molecules released by individual cells until threshold is reached Critical for regulation of complex shifts between phenotypes Wagner VE, Frelinger JG, Barth RK, Iglewski BH Quorum sensing: dynamic response of Pseudomonas aeruginosa to external signals. Trends in Microbiology 14 (2):

15 Antimicrobial resistance Intrinsic Blockage of entry Beta lactamases Efflux pumps Acquired Transposon and plasmids New gene or a gene copy Genetic mutation Alter target structure or change regulation of factor Adaptive Biofilm formation Loss of motility structures Reduced membrane permeability Pires DP, Vilas Boas D, Sillankorva S, Azeredo J Phage Therapy: a Step Forward in the Treatment of Pseudomonas aeruginosa Infections. Journal of Virology 89 (15):

16 Treatment issues and solutions Utilize older drugs Used less often, so lower chance of pre-existing resistance Somewhat effective, but many have toxic side effects Combine multiple antibiotics Greater chance of completely clearing infection Toll on patient, risk of adaptive resistance may remain Develop adjuvants that boost antibiotic effectiveness Directly target biofilm in combination with antibiotic against bacterial cell Shift treatment towards a focus on limiting P. aeruginosa virulence Bacteriophage therapy Shows promise Pathogen can develop phage resistance, host may inhibit phage activity, hyper-specificity toward species or subtype may be too limited 16

17 Conclusion Many mechanisms and interactions between P. aeruginosa, host cells, and the microbiome have yet to be elucidated Current therapies for P. aeruginosa are a temporary measure (at best) and will not remain effective, but new approaches may succeed where traditional antibiotic development has failed P. aeruginosa is a powerful example of the antimicrobial arms race taking place between high-risk bacterial pathogens and humanity 17

18 Questions? 18