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Developments in pK/pD: optimising efficacy & prevention of resistance

Developments in pK/pD: optimising efficacy & prevention of resistance A critical review of pK/pD in in vitro models Alasdair MacGowan Bristol Centre for Antimicrobial Research & Evaluation University of Bristol & North Bristol NHS Trust Southmead Hospital Bristol, UK.

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Developments in pK/pD: optimising efficacy & prevention of resistance

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  1. Developments in pK/pD: optimising efficacy & prevention of resistance A critical review of pK/pD in in vitro models Alasdair MacGowan Bristol Centre for Antimicrobial Research & Evaluation University of Bristol & North Bristol NHS Trust Southmead Hospital Bristol, UK

  2. OBJECTIVES OF STUDYING pK/pD IN IN VITRO MODELS • tests of efficacy determination of dominant pK/pD parameter determination of the magnitude of the dominant pK/pD parameter • emergence of resistance • determination of dominant pK/pD parameter • determination of the magnitude of the dominant pK/pD parameter

  3. TESTS OF EFFICACY • human dosing or other • activity of agent vs target pathogen  co resistance's • activity of agent and comparator(s) vs target pathogen • activity of agent v target pathogen with various MIC values of the agent • activity of agent vs target pathogen with various mechanisms of resistance to the agent • activity of agent vs different bacterial species of target pathogen

  4. ACTIVITY AGAINST TARGET PATHOGENS i.e. moxifloxacin 400mg 24hrly species MIC50 strain log reduction (mg/L) MIC viable count (mg/L) 24h S pneumoniae 0.06 0.08 5.6  0.4 H influenzae 0.03 0.06 6.5  0.2 M catarrhalis 0.06 0.08 5.1  1.2 S aureus 0.06 0.06 2.4  1.1 Group A strep 0.12 0.16 3.1  1.9 MacGowan, 1999; MacGowan et al, 1998; MacGowan et al, 1999a; MacGowan et al, 1999b

  5. ACTIVITY OF AGENT AND COMPARATOR AGAINST TARGET agents target reference pathogen trova/cipro S aureus Firsov et al, 1999 trova/cipro S aureus O’Brien et al, 1999 levo/cipro S pneumoniae Lister & Saunders, 1999 moxi/grepa/clari S aureus Esposito et al, 2000 Gp A streptococci trova/gati/clina S pneumoniae Hershberger & Rybak, 2000 spar/levo/cipro moxi/levo/gati/cipro S pneumoniae Firsov et al, 2000 various

  6. ACTIVITY OF AGENTS AGAINST TARGET PATHOGENS WITH VARIOUS MICs - USUALLY INCREASING gemifloxacin 320mg 24hrly vs S. pneumoniae (MIC50 0.015; MIC90 0.03/6mg/L) Strains MIC log reduction in viable count (mg/L) 24h 48h 0.016 5.3  0.3 5.3  0.3 0.06 3.4  1.4 6.2  0.1 0.10 4.1  0.5 5.7  0.2 0.16 0.6  1.4 3.9  0.9 0.24 0.2  0.4 0.5  0.2 MacGowan et al, (in press)

  7. ACTIVITY OF AGENTS AGAINST PATHOGENS WITH DIFFERENT MECHANISM OF RESISTANCE (1) S aureus with Nor A efflux pump S aureus (Nor A expression induced) log cfu/ml at 72h levofloxacon 4.8  0.4 levofloxacin + omeprazole 4.8  0.4 ciprofloxacin 9.5  0.3 ciprofloxacin + omeprazole 7.4  0.5 Aeschlimann et al, 1999

  8. ACTIVITY OF AGENTS AGAINST PATHOGEN WITH DIFFERENT MECHANISMS OF RESISTANCE (2) gemifloxacin 320mg od, for 72hr log reduction time to kill MIC count at 99.9% (mg/L) mechanism 72h (h) 0.06 none 5.3  0.3 26  2 efflux pump 5.8  0.3 15  12 gyr A mutation 1.2  0.3 > 72 par C mutation 1.2  0.3 > 72 0.12 efflux pump 3.8 21  8 gyr A mutation 0.4  0.4 > 72

  9. ACTIVITY AGAINST DIFFERENT TARGET PATHOGENS i.e. moxifloxacin 400mg od vs S pneumoniae or P aeruginosa both MIC 0.25mg/L S pneumoniae P aeruginosa log reduction count @ 24h 3.4  1.2 0.1  0.2 @ 48h 4.2  1.0 0.7  0.5 @ 72h 4.8  0.5 0.1  0.6 time to kill 99.9% (h) 16  7 >72

  10. CONCLUSIONS ON TESTS OF EFFICACY - easy, descriptive, limited but useful information

  11. DETERMINATION OF DOMINANT pK/pD PARAMETER  dosing regimen employed (differentiation between AUC/MIC; Cmax/MIC; T > MIC)  end point chosen  analytic tools used  susceptibilities of target strains  effects of aggregation of data (i.e. species or mechanisms)

  12. PRODUCING VARIABILITY IN pK/pD PARAMETERS dose escalation MIC differences dose fractionation ranges in pD/pK parameters (AUC/MIC; Cm/MIC; T > MIC)

  13. DOSING REGIMENS dose conclusion ciprofloxacin Cm 5mg/L AUC/MIC related to ofloxacin 5mg/L, 8mg/L; outcome different t/12 Madaras-kelly et al, 1996a ofloxacin Cm 3.5-62mg/L AUC/MIC related ciprofloxacin Cm 1.1-20mg/L to outcome plus others Madaras-Kelly et al, 1996b gemifloxacin AUC/MIC or T>MIC 160mg bd; 320mg od; related to outcome 640mg 48h Bowker et al, 2000

  14. GEMIFLOXACIN DOSE FRACTIONATION PLUS MIC RANGE 0.016 - 0.24mg/L Spearman rank Correlation (95% CI) AUC/MIC v Cm/MIC 0.77 (0.42 - 0.92) AUC/MIC v T > MIC 0.87 (0.60 - 0.96) Cm/MIC v T > MIC 0.42 (0.14 - 0.77)

  15. END POINTS - measures of antibacterial effect (ABE) measures in time (X axis) time to kill 90, 99, 99.9 etc time to maximum kill measures in viable count (Y axis) log kill at 12, 24, 36 etc h log kill after dose (~) maximum kill “integrated” measures (X and Y) slope of kill curve areas around the kill curve

  16. AREA MEASURES control IE log cfu/ml test AAC AUBC time AAC: area above the curve AUBC: area under the bacterial (kill) curve AUBKC IE: intensity of effect (area between curves, (log C - log T) xt) AUBKC (test) /AUBKC (control) ratio

  17. PERCENTAGE CO-EFFICIENTS OF VARIATION OF ANTIBACTERIAL EFFECT MEASURES moxifloxacin 69 simulations number of occasions measure measurable % CV (median; range) log change @ 12hr 15 32 (9 - 100) 24hr 13 55 (8 - 72) 36hr 10 25 (4 - 97) 48hr 12 43 (6 - 132) maximum log 12 17 (4 - 88) T99 17 25 (0 - 70) T99.9 17 27 (5 - 75) AUBKC24 21 14 (1 - 65) AUBKC48 21 14 (1 - 74

  18. EFFECT OF CHOSEN ANTIBACTERIAL EFFECT MEASURE ON DOMINANT pK/pD PARAMETER gemifloxacin 160mg x 4 over 48 hr 320mg x 2 over 48 hr 640mg x 1 over 48 hr five strains of S pneumoniae (MIC 0.016; 0.06; 0.1; 0.16; 0.24 mg/L) pD parameters: AUC/MIC (72 - 1219) Cmax/MIC (3 - 131) T > MIC (38 - 100%)

  19. using Emax model AUC/MIC related to AUBKC48 best Cmax/MIC and T>MIC less well weighted least squares regression analysis AUC/MIC and T>MIC predictors of AUBKC48 Cmax/MIC not predictive of AUBKC48

  20. Cox proportional hazards regression - ABE: time to kill 99.9% inoculum univariate analysis AUC/MIC, Cm/MIC and T > MIC related to T99.9 multivariate model Cmax/MIC related to T99.9 Cm/MIC relative risk 95% CI <5 1.0 5 - 9.9 7.7 2.2 - 27.2 10 - 29.9 11.6 4.3 - 31.8 >30 20.7 2.3 - 68.3

  21. WHY AUC/MIC AND T > MIC PREDICT AUBKC48 log change count dosing regimen MIC (mg/L) 160mg x 4 320mg x 2 640mg x 1 0.016 maximum - 5.2 - 5.3 - 4.8 final - 4.8 - 5.3 - 4.8 0.06 maximum - 4.5 - 6.2 - 6.2 final - 4.0 - 6.2 + 0.1 0.10 maximum - 6.6 - 5.7 - 6.2 final - 5.2 - 3.9 0 0.16 maximum - 2.8 - 3.9 - 4.6 final - 2.3 - 0.6 0 0.24 maximum - 3.3 - 0.5 - 4.7 final - 0.8 + 0.3 + 0.3

  22. If exclude simulation with T > MIC of <70% then AUC/MIC predicts AUBKC48 in multi variate analysis

  23. COX PROPORTIONAL HAZARDS REGRESSION ANALYSIS FOR T99.9 AND REGROWTH 81 experiments with gemifloxacin and moxifloxacin against S. pneumoniae In 59/81 experiment T99.9 achieved In 24/59 regrowth occurred AUC/MIC, Cm/MIC and T > MIC related to both measures T99.9 related to Cm/MIC especially > 5 Regrowth related to T > MIC AUC/MIC did not predict T99.9 or regrowth

  24. THEREFORE - T99.9 Cm/MIC slope  log cfu/ml Regrowth IE  T > MIC AUBKC  AUC/MIC

  25. ANTIBACTERIAL EFFECT MEASURES Strengths Weakness T99.9 • easy to understand • highly variable • easy to measure • not always related to pD • suitable for time to parameters event analysis • doesn’t capture regrowth data intensity of effect • less variable • depends on regrowth • strong comparative • T > MIC driven (inter quinolone predictor) database • linear over a large • linear over therapeutic AUC/MIC range AUC/MIC range • AUC/MIC an intra quinolone predictor i.e. FQ specific

  26. ANTIBACTERIAL EFFECT MEASURES Strengths Weakness area under curve • less variable • size-counter intuitive • AUC/MIC driven i.e. AUC/MIC  1/AUBKC • sigmoid relationship to AUC/MIC

  27. CONCLUSION - DETERMINATION OF Pd PARAMETER end point matters

  28. DETERMINATION OF THE MAGNITUDE OF THE pK/pD PARAMETER AUC/MIC for optimal outcome v S. pneumoniae (1) AUC/MIC 30-55 sustained 4 log reduction with levofloxacin Lacey et al, 1999a AUC/MIC >45 sustained 5 log reduction with trovafloxacin and ofloxacin Lister & Saunders, 1999b AUC/MIC of 44 sustained 5 log reduction with levofloxacin Lister & Saunders,

  29. AUC/MIC AND S. PNEUMONIAE (2) AUC/MIC 50 = 60 for In AUBKC levofloxacin, ofloxacin ciprofloxacin Madaras - Kelly et al, 1997 AUC/MIC >250 for lowest AUBKC gemifloxacin Bowker et al, 2000 AUC/MIC >250 for lowest AUBKC moxifloxacin Bowker et al, 2001

  30. AUC/MIC and S. PNEUMONIAE (3) Moxifloxacin dose MIC AUC/MIC clearance (sustained 5 log reduction 400 OD 0.08 375 Yes 400 BD 0.25 320 Yes 800 OD 0.25 320 Yes 400 OD 0.12 167 No 400 OD 0.25 160 No 400 OD 1 30 No 400 BD 4 20 No 800 OD 4 20 No 400 OD 2 15 No 400 OD 4 10 No Gemifloxacin 320 OD 0.016 625 Yes 320 OD 0.06 166 No 320 OD 0.10 100 No 320 OD 0.16 62 No 320 OD 0.25 41 No

  31. WHY THE DIFFERENCE?  inoculum  growth phase  total organisms exposed

  32. EFFECT OF INOCULUM ON IE; CIPROFLOXACIN AND TROVAFLOXACIN relative IE S aureus E coli 8 log 1.05 1.12 6 log 0.98 (-7%) 0.92 (-18%) from Fig 4, Firsov et al, 1999

  33. IS THE AUC/MIC THE SAME FOR DIFFERENT SPECIES? Moxifloxacin AUBKC48 (log cfu/ml) MIC (mg/L) Gram + Gram -  0.1 95  44 33  15 0.1 - 0.5 170  65 63  14 > 0.5 240  30 99  21 Gram +; S pneumoniae, S aureus, GpA streptococci Gram -; H influenzae, M catarrhalis (MacGowan, 1999)

  34. IS THE AUC/MIC THE SAME FOR DIFFERENT SPECIES? (2) AUC0-72/MIC for 50% effect AUBKC 72 (log cfu/ul.h) S pneumoniae 136 P aeruginosa > 1000

  35. CONCLUSION ON MAGNITUDE OF pK/pD PARAMETER - not uniform across models or species - models need to be calibrated on the basis of good clinical studies

  36. EMERGENCE OF RESISTANCE - THE STORY SO FAR enoxacin ~ P. aeruginosa emergence of resistance observed, related to time of exposure, and total exposure (Cm/MIC) Blaser et al, 87 Ciprofloxacin ~ P. aeruginosa dose fractionation (1200 OD; 600BD; 400TDS) 1200 OD less resistance than 600 BD or 400 TDS Marchbanks et al, 1993

  37. Ciprofloxacin/ofloxacin ~ P. aeruginosa AUC/MIC or Cmax/MIC related to emergence of resistance (MIC ) Madaras-Kelly et al, 1996

  38. End points •MIC before and after exposure • subculture onto recovery with increasing FQ concentrations (MIC x 0.5; MIC x 1; MIC x 2 etc) - absolute count on plates - heterogencity of population - area-under-curve - population-analysis- profile (AUC-PAP)

  39. AUC - PAPo Log cfu/ml time 48 time 24 time 0 0 Antibiotic concentration

  40. EMERGENCE OF RESISTANCE TO MOXIFLOXACIN WITH S. PNEUMONIAE & P. AERUGINOSA P. aeruginosa MIC 0.25mg/L log cfu/ml 0hr 24hr 72hr conc in 200 400 400 800 200 400 400 800 recovery OD OD BD OD OD OD BD OD plate 0 8.5 8.3 7.6 7.5 7.5 8.3 8.2 7.6 7.5 4 4.7 8.0 7.3 2.6 3.5 8.0 8.2 4.0 4.0 16 <2 ND 3.4 <2 <2 ND 8.3 3.2 3.5

  41. AUC72/MIC for 50% effect - S. pneumoniaeP. aeruginosa ABE: AUBKC72 136 >1000 Resistance log cfu/ml MIC x 4 < 50 862 log cfu/ml MIC x 16 < 50 1186 PAP ~ AUC < 50 910

  42. Emergence of resistance depends on (i) species (P. aeruginosa > S pneumoniae) (ii) duration of exposure (long > short) (iii) exposure (large AUC/MIC > small) (iv) AUC/MIC  Cm/MIC (v) pD parameter magnitude different to effect

  43. Conclusions • in vitro models have a vital role in pD assessments • in vitro models are flexible tools to assess many pD questions, i.e. dosing • in vitro models can be used for hypothesis testing and generation • for best value they should compare with animal data but much important, human data

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