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Does susceptibility testing have a role in predicting clinical or microbiological outcome? Alasdair MacGowan North Bris

Does susceptibility testing have a role in predicting clinical or microbiological outcome? Alasdair MacGowan North Bristol NHS Trust & University of Bristol Southmead Hospital Bristol, UK. The paradigm pharmacodynamic microbiological clinical

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Does susceptibility testing have a role in predicting clinical or microbiological outcome? Alasdair MacGowan North Bris

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  1. Does susceptibility testing have a role in predicting clinical or microbiological outcome? Alasdair MacGowan North Bristol NHS Trust & University of Bristol Southmead Hospital Bristol, UK

  2. The paradigm pharmacodynamic microbiological clinical index size outcome outcome Cmax/MIC AUC/MIC T>MIC

  3. The Pharmacodynamic world - students view AUC/MIC fluoroquinolones daptomycin aminoglycosides ketolides metronidazole tetracyclines glycopeptides oxazolidinones Cmax/MIC fluoroquinolones aminoglycosides daptomycin (metronidazole) T > MIC macrolides clindamycin oxazolidinones B lactams glycopeptides

  4. The Pharmacodynamic world - shades of grey AUC/MIC tetracyclines ketolides AUC/MIC; Cmax/MIC fluoroquinolones aminoglycosides (daptomycin) Cmax/MIC Oxazolidinones glycopeptides ? Dalbavancin T > MIC Blactams erythromycin clindamycin

  5. Clinical studies showing a relationship between pharmacodynamic index and outcome

  6. Pharmacokinetics and susceptibility

  7. Which is dominant - pharmacokinetics or susceptibility?

  8. Pharmacokinetic variability

  9. Susceptibility variability - MICs (www.bsacsurv.org; www.EUCAST.org) Wild type (EUCAST) Variation ciprofloxacin - E. coli 0.002-0.06 mg/L x30 levofloxacin - E. coli 0.002-0.06 mg/L x30 moxifloxacin - E. coli 0.008-0.25 mg/L x30 Present (BSAC) ciprofloxacin - E. coli 0.002 - > 512 >250,000

  10. Which is dominant - pharmacokinetics or susceptibility? Usually susceptibility drives changes in pD index; hence in situations where MIC ranges are large, categorical sensitivity testing should be predictive.

  11. Antibiotic resistance and bacteraemia (1) General cases Phillips et al, 1990 St Thomas’ Hospital, London bacteraemias 1969-88, retrospective analysis Staphylococci, Enterococci, Enterobacteriaceae, P. aeruginosa Outcomes

  12. Antibiotic resistance and bacteraemia (2) Behrendit et al, 1999 Department of Medicine, University Hospital, Frankfurt 1989-93, retrospective analysis Outcome: 28d mortality

  13. Antibiotic resistance and bacteraemia (3) Specific settings - ICU Ibrahim et al, 2000 St Louis USA, Medical & Surgical ICU (37 beds) 1997-99 Prospective cohort study Multiple logistic regression:- inadequate antimicrobial therapy as independent determinant of mortality RR 6.9 (5.1 - 9.3, p < 0.001) Commonest resistant isolates - VRE, Candida sp, MRSA, CONS, P. aeruginosa - also highest mortality

  14. Antibiotic resistance and bacteraemia (4) Specific settings - ICU Harbarth et al, 2002 Geneva, Switzerland, Surgical ICU (22 beds) 1994-7 retrospective cohort study of 244 bacteraemias In multivariate analysis

  15. Antibiotic resistance and bacteraemia (5) Specific pathogens: S. aureus Gonzalez et al, 1999 Madrid, Spain, 1990-1994 S. aureus, pneumonia + bacteraemia prospective cohort study

  16. Antibiotic resistance and bacteraemia (6) Specific pathogen - S. aureus Chang et al, 2003 Multi centre, prospective observational study of 505 patients in USA. End points were persistent and relapsed infection Factors relate to relapse in multi variant analysis - • infective endocarditis • vancomycin therapy (vs nafcillin) for MSSA Outcomes when IE excluded

  17. Antibiotic resistance and bacteraemia (7) Specific pathogen - S. aureus Sakoulas et al, 2004 30 patients with S. aureus bacteraemia recruited into clinical trials. (PIII/IV) treated with vancomycin logistic regression indicated significant relationship between MIC (and killing) and treatment success

  18. Antibiotic resistance and bacteraemia (8) Specific pathogen: S. aureus Conterno et al, 1998 Sâo Paulo, Brazil, 1991-92 retrospective case control study comparing MSSA to MRSA (n = 136) Multivariate analysis - 3 risk factors for death - lung as site of entry OR 17.0 shock OR 8.9 MRSA OR 4.2 MRSA bacteraemia more likely to have inappropriate therapy in first 48h

  19. Antibiotic resistance in bacteraemia (9) Specific pathogen: P. aeruginosa appropriate therapy improves outcome Yes - acute leukaemia Bodey et al, 1985 Yes - general group in HIV Vidal et al, 1996 No - general group Hilf et al, 1989 No - ICU patients Carmeli et al, 1999 combination therapy improves outcome Yes - general group Hilf et al, 1989 Yes - acute leukaemia Bodey et al, 1985 (monotherapy with aminoglycoside) No - general group inc HIV Vidal et al, 1996 No - cancer Chatzinikolaou et al, 2000 (monotherapy with ceftazidime or imipenem)

  20. Antibiotic resistance in bacteraemia (10) Specific pathogen P. aeruginosa Chamot et al, 2003 115 patients with P. aeruginosa in historical cohort between 1988-98, in Switzerland Cox proportional hazard model to 30d follow-up

  21. Pseudomonas aeruginosa bacteraemia Zelenitsky et al, 2003 retrospective study of 38 patients serum concentrations, MIC determined Outcome measured as - persistent infection (21%) - death to 30d (21%) - cure (58%) Cmax/MIC ratio of >8 predicted > 90% cure for aminoglycosides and ciprofloxacin

  22. Extended spectrum Blactamase (1) Paterson et al, 1998 400 consecutive blood stream isolates of K. pneumoniae, 11 hospitals Overall mortality - 24% Mortality lower if carbapenem used in first 5 days (5% vs 43%, p=0.01) 21% mortality if treated with ciprofloxacin and susceptible 50% (2/4) mortality with cefipime 50% (2/4) mortality with piperacillin-tazobactam combination of active Blactam plus amikacin did not improve outcome (mortality 15% vs 17% p>0.2)

  23. Extended spectrum Blactamase (2) Kim et al, 2002 142 blood isolates in Korea, E. coli or K. pneumoniae Strain MIC > 2mg/L to 3rd generation cephlosporins Patients treated with extended spectrum cephalosporin (most received aminoglycoside)

  24. Extended spectrum Blactamase (3) Piperacillin - tazobactam Burgess (2003) ESBL + E. coli or Klebsiella overall 6/18 patients failed 4/9 piperacillin-tazobactam 2/9 other agents Ambrose et al, 2003 Piperacillin-tazobactam 3.375g 6hrly 0.50 - 0.73 target ascertainment of ESBL positive E. coli, K. pneumoniae in Monte Carlo simulations (4.5g 8hrly probably similar; 4.5g 6hrly better)

  25. Extended spectrum Blactamase (4) treatment of E. coli/Klebsiella with ESBLs in the urinary tract This page is intentionally left blank

  26. Antibiotic resistance in urinary tract infection Talan et al, 2000 Los Angeles, USA as part of a randomised double blind comparative study of ciprofloxacin & TMP/SMX conducted between 1994-7 (n = 378) Resistance to TMP/SMX 18% in E. coli (90% of pathogens) TMP/SMX associated with higher bacteriological/clinical failures

  27. Antibiotic resistance in pneumonia (1) Definition of penicillin resistance:- penicillin susceptible  0.06mg/L intermediate 0.1 - 1.0mg/L resistant  2mg/L

  28. Antibiotic resistance in pneumonia (2) • penicillin non susceptibility does not impact on clinical • response or outcomes for therapy with penicillin/amoxicillin • ± clavulanate • paediatric community acquired pneumococcal pneumonia (retrospective; • n = 207), Friedland & Klugman 1992 • adults with pneumococcal pneumonia (retrospective; n = 23) • Sandches et al 1992 • paediatric bacteraemic pneumococcal infection (prospective), Friedland, • 1995 • adults with pneumococcal pneumonia (prospective; n = 504) Pallarres • et al, 1995 • invasive pneumococcal infection + bacteraemia (retrospective; n = 106) • Choi & Lee, 1998

  29. Penicillin non susceptibility does not impact (continued) • paediatric invasive pneumococcal infection, mainly bacteraemia • (retrospective) Deeks et al, 1999 • hospitalised patients with pneumococcal community acquired • pneumonia (retrospective; n = 101; pen R  2mg/L) Ewig et al, 1999 • hospitalised patients with pneumococcal bacteraemia (retrospective; • n = 156) Farinas-Alvarez et al, 2000 • community acquired pneumococcal pneumonia (prospective, n = 465) • Bedos et al, 2001 • hospitalised patients with invasive pneumococcal pneumonia • (prospective, n = 146) Moroney et al, 2001

  30. Penicillin non susceptibility does have a clinical impact • pneumococcal pneumonia (n = 5837) • overall mortality related to older age • underlying disease • Asian race • living in Toronto • Excluding early deaths i.e. <4 days:- Feikin et al, 2000

  31. Penicillin non susceptibility does have a clinical impact • pneumococcal pneumonia (retrospective study, n = 462) • multivariate analysis identified the following as independent • predictors of mortality - older age • severe disease • multilobar infiltrate • effusion on CXR • hispanic • high level penicillin resistance • Turrett et al, 1999

  32. Penicillin non susceptibility does have a clinical impact • adults with bacteraemic pneumococcal pneumonia (n = 192) • > increased risk of suppurative complication after adjustment • for other factors • Metlay et al, 2000 • children with invasive infection - • mainly bacteraemia (n = 304) • > longer ITU stay; all other factors similar • Quach et al, 2000

  33. Conclusion for S. pneumoniae:- penicillin “resistance” probably only has therapeutic significance once MIC values are  2-4mg/L

  34. Putting it together (1) microbiological cut offs wild type distributions MIC pD index pharmacokinetics microbiological outcomes clinical breakpoints clinical outcomes

  35. Putting it together (2) microbiological cut off Wild type distributions Penicillin-S. pneumoniae MIC most drug-bacteria cephalosporin-ESBL Blactam-MRSA pD index pharmacokinetics microbiological outcome clinical outcome Vancomycin-MSSA P. aeruginosa P/T - ESBLs

  36. Conclusions > clinical data on resistance significance is weaker than animal/in vitro data > appropriate early therapy probably improves patient outcomes > applies in a wide range of clinical contexts and pathogens but not everywhere > categorical sensitivity testing (S/I/R) is a crude approximate of the true drug - pathogen - host relationship > clinical breakpoints should have improved predictive value as pD principles are understood > microbiological breakpoints may be therapeutically misleading

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