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Understanding Antibiotic Resistance in Scottish Pneumococci

Explore the definitions, mechanisms, and prevalence of antibiotic resistance in Scottish pneumococci from 1999-2007, highlighting penicillin and erythromycin resistance. Identify susceptibility profiles and contribution of serogroups and sequence types.

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Understanding Antibiotic Resistance in Scottish Pneumococci

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  1. Resistance is futile ? – antibiotic resistance in Scottish pneumococci Andrew Smith Professor of Clinical Bacteriology

  2. Acknowledgements • Ben Cooke • Mathew Diggle • Karen Lamb • Christopher Robertson • Donald Inverarity • Johanna Jefferies • Giles Edwards • Stuart Clarke • Jim McMenamin • Tim Mitchell • All staff at SHLMPRL • Prof T Mitchell Pneumococcal Research Group

  3. Resistance is futile? Defining resistance • Resistance may be defined from a clinical perspective High breakpoint Low breakpoint Likely to respond Indeterminate response Not likely to respond % of isolates Sensitive Intermediate Resistant Antibiotic concentration ug/ml • Clinical resistance: When infection is highly unlikely to respond even to maximum doses of antibiotic (EUCAST)

  4. Defining resistance • Resistance may be defined from a biological perspective • National variations in breakpoints • Resistance definitions usually based on in-vitro quantitative testing of bacterial suspensions to antibacterial agents Minimum inhibitory concentration

  5. Defining resistance Microbiological resistance % of isolates • Microbiological resistance: bacteria that possess any resistance mechanism demonstrated either phenotypically or genotypically (EUCAST) Resistant Sensitive Breakpoint Antibiotic concentration ug/ml

  6. Confounding variables • Laboratory • Inoculum size, growth phase, planktonic, pH, atmosphere… • Clinical • Co-morbidities, pus collections, foreign bodies, site of infection ……….. • Pharmacokinetics • Pharmacodynamics

  7. Mechanisms of resistance in pneumococci • Penicillin resistance: Pencillin binding proteins (PBPs) • 6 PBP’s described in the pneumococcus • Alterations in PBP’s = resistance • Resistance= mosiacism in PBP 2b, 2x and 1a

  8. Mechanisms of resistance in pneumococci • Erythromycin resistance • Methylation Erm(B) MLSb • Macrolide efflux Mef(A) • Other mechanisms (less prevalent)

  9. Penicillin resistance in pneumococcus • 1st Reported in 1967 (Hansman & Bullen 1967) • Serotype 23 Pen MIC = 0.6ug/ml • Subsequent reports from Papua New Guinea • 1974 12% - 1980 30% resistant • 1974-1984 • Foci with >10% include New Guinea, Israel, Spain, Poland, South Africa & USA (states) Klugman Clin Micro Rev 1990 171

  10. Penicillin resistance in pneumococcus (1990’s) • Rates 5-80% (Forward Sem Resp Infect 1999 243-254, Thornberg et al AAC 199943: 2612; Song et al CID 1999 28: 1206) • USA 2/3 of PRP’s have MICs of 2ug/ml & others = 4ug/ml (Doern et al EID 1999; 5: 757) • MIC values of 8ug/ml reported from Spain (Baquero et al AAC 1999; 43: 357) & USA (Doern et al AAC 1996; 40: 1208) • MIC of 16ug/ml reported from Eastern Europe & USA (Applebaum CID 1992; 15:77; Gross et al AAC 1996; 39: 1166-68)

  11. Prevalence of penicillin non-susceptible pneumococcus in Europe (EARS 2008) • 1-5% UK, Germany , Austria, Norway & Sweden • 10-25% Portugal, Ireland, Finland & Turkey • 25-50% Spain, France, Greece & Israel

  12. Prevalence of erythromycin resistant pneumococci in Europe (EARS 2008) • 1-5% Latvia & Sweden • 10-25% UK, Spain, Portugal, Germany, Poland, Norway & Finland • 25-50% France, Italy & Greece

  13. Aims • Identify susceptibility profiles (1999-2007) to • Penicillin & erythromycin • Establish contribution that different serogroups and sequence types make to the burden of antibiotic resistance. • Explore extent to which internationally recognised PMEN (Pneumococcal molecular epidemiology Network) clones are seen in Scotland

  14. Methods • Isolates obtained from SHLMPRL • Received from diagnostic labs in Scotland from all invasive isolates • Typing & antimicrobial testing as part of Electronic Communication of Surveillance in Scotland (ECOSS) • 4,727 isolates available covering 1999 - 2007

  15. Methods • Susceptibility testing • Using E-tests • Breakpoints derived from BSAC • Typing of isolates • Serogrouping 1999-2002 • Serotyping 2003-2007 • MLST 2003-2007 • Multi-Locus Sequence Typing (MLST): • Based on sequences from 7 housekeeping genes • 7 sequences assigned a number - barcode • Each barcode assigned a number - sequence type (ST)

  16. IPD Serotypes (2001-2006) total PCV7 SeroST 4 205 6B 138 9V 162 14 9 18C 113 19F 162 23F 37

  17. PCV7 Sero ST 4 205 6B 138 9V 162 14 9 18C 113 19F 162 23F 37 Sequence types (2001-2006) total

  18. 2001 serogroups Blood /CSF under 5 PCV7 Sero ST 4 205 6B 138 9V 162 14 9 18C 113 19F 162 23F 37

  19. 2001 serogroups Blood /CSF over 65 PCV7 Sero ST 4 205 6B 138 9V 162 14 9 18C 113 19F 162 23F 37

  20. Results Penicillin non-susceptibility I=0.12-1mg/L R=≥2mg/L

  21. Results Penicillin non-susceptibility I=0.12-1mg/L R=≥2mg/L

  22. Pneumococcal penicillin resistance is rare • MIC ≥ 2mgl-1 • Highest MIC found = 2mgl-1 • N=7 (0.15%) • Mainly represented by serogroup 14

  23. Pneumococcal penicillin intermediate sensitivity • MIC 0.12-1mgl-1 • N=148 (3%) • Mainly represented by serogroup 14

  24. Pneumococcal penicillin non-susceptible • MIC >0.12mgl-1 • N=155 (3%) • N=87 (56%) from >65yrs • N=22 (14%) from <16 years • N=13 (8%) from <2yrs

  25. Pneumococcal penicillin non-susceptible • MIC >0.12mgl-1 • Varied with age (P=0.01) • 4.1 % >65yrs (95% CI 3.3-5.0%) • 2.4% 16-64 yrs (95% CI 1.8-3.2%) • 3.1% <16 yrs (95% CI 2.1-4.7%)

  26. Pneumococcal blood culture isolates • N=4531 (96%) • N= 143 (3%) were pen non-susceptible (MIC >0.12mgl-1) • Pneumococcal CSF isolates • N=171 (4%) • N=6 were pen non-susceptible (MIC >0.12mgl-1)

  27. Total CSF isolates & MIC >0.12

  28. All invasive isolates Serogroup contribution: penicillin intermediate & resistant PCV7 SeroST 4 205 6B 138 9V 162 14 9 18C 113 19F 162 23F 37

  29. Clinical significance of intermediate sensitivity? • Non-meningeal pneumococcal infections • Doubtful (Choi & Lee 1998) • Drug levels usually >MIC (Heiber & Nelson 1977) • Pharmacodynamics: T>40% MIC • Meningeal pneumococcal infections • Impact of blood brain barrier • Lower levels of resistance associated with failure (Friedland 1992) • Increased failure of monotherapy if MIC>1

  30. Results Erythromycin resistance

  31. Macrolide resistance (>0.5mgl-1) • N=585 (12.3%) • 95% recovered from blood cultures • Significant reduction over the study period • (P<0.0001)

  32. Macrolide resistance & serogroup • 22 different serogroups • Serotype 14 = 467 (80%)

  33. PMEN clones identified in Scottish invasive pneumococcal isolates (2003-2007) • PMEN clones • Internationally distributed clones identified by serotype and MLST • should have wide geographic distribution (isolated on at least 2 continents) • Can be resistant to one or more antibiotics that are in wide clinical use; or a global susceptible clone known to be important in disease http://www.sph.emory.edu/PMEN/pmen_ww_spread_clones.html

  34. PMEN clones identified in Scottish invasive pneumococcal isolates (2003-2007) • 1,124 identified (37% of 3073 isolates) • PMEN Clones accounted for 28 penicillin non-susceptible isolates (35% 28/81) • Spain 9v ST156 N=14 • Utah 35B ST377 N=6 • Spain 6B ST90 N=2

  35. PMEN clones identified in Scottish invasive pneumococcal isolates (2003-2007) • 1,124 identified (37% of 3073 isolates) • PMEN Clones accounted for 248 of the macrolide resistant isolates (75% 248/330) • England 14 ST9 N=230

  36. PMEN clones identified in Scottish invasive pneumococcal isolates (2003-2007) • Frequency of PMEN clones • England 14 ST9 n= 239 • Sweden 1 ST306 = 225 • Netherlands 8 ST53 = 154 • Netherlands 7F ST 191 = 136 • Netherlands 3 ST180 = 126

  37. Multi-drug resistant pneumococci? • Overlap between macrolide and pencillin non-susceptibility was 0.9% (n=44) • France and Spain 40% of pneumococci = multidrug resistance (Reinert Clin Micro Infect 2009)

  38. Antimicrobial use in Scotland • Ab use in primary care increased by 18.4% between 2004-2008 • Amoxicillin accounted for 24% of ab used • Phenoxymethyl penicillin accounted for 4%

  39. Is Ab resist associated with a fitness cost? • Yes • Adult pneumonia with PRSP = milder clinical manifestations (Einarsson et al SCJID 1998) • ICU admin No sig diff pen MIC>25 vs lower (Moroney et al CID 2001) • Adult pneumococcal pneumonia (10.5% isolates MIC>1 no signif diff (N=465 adults) (Bedas et al 2001) • In vitro (mice) virulent phenotype was predictive of pen susceptibility (Azoulay-Dupuis et al AAC 2000)

  40. Is Ab resist associated with a fitness cost? • NO (i.e. increased mortality) • Adult pneumonia with PRSP (>4) (Feiken et al AJPH 2000) • Pen MIC>2 independent predictor of mortality (bacteraemia) (Turett et al CID 1999 ) • But • Old age remains biggest predictor of mortality (Mufson et al AJM 1999) • Also chronic renal failure • APACHE II score predict prognosis of bacteraemic disease (Kalin et al 1999)

  41. Conclusions • Relatively low levels of ab resist in invasive pneumococci from Scotland 1999-2007 • Most common penicillin non-susceptible clone is serogroup 9 MLST 156 clone (PMEN Spain 9v) • Most common macrolide resistant clone is the serotype 14 MLST 9 clone (PMEN England 14) • Non-susceptibility was rare among non vaccine (PCV7) serogroups • Pen non-susceptible serotype not covered by PCV7 or PCV13 is 35B ST377

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