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How predictive is PK/PD ?

How predictive is PK/PD ?. Niels Frimodt-Møller, MD DrSci Microbiological R & D Antibiotic Resistance Surveillance Unit Statens Serum Institut Copenhagen, Denmark. NF-M 2001. Pharmacodynamic parameters. Pharmacokinetic parameters: Peak/MIC ratio AUC/MIC ratio Time > MIC

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How predictive is PK/PD ?

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  1. How predictive is PK/PD ? Niels Frimodt-Møller, MD DrSci Microbiological R & D Antibiotic Resistance Surveillance Unit Statens Serum Institut Copenhagen, Denmark NF-M 2001

  2. Pharmacodynamic parameters • Pharmacokinetic parameters: • Peak/MIC ratio • AUC/MIC ratio • Time > MIC • Minimal inhibitory concentration (MIC) (minimal bactericidal concentration (MBC) (time kill activity) MIC NF-M 2001

  3. Time-dependent, concentration- independent: Beta-lactams Macrolides Tmp/sulfa Glycopeptides - Concentration dependent: Aminoglycosides Fluoroquinolones Streptogramins - - Pharmacodynamics as related to time-kill activity in vitro/in vivo NF-M 2001

  4. AUC vs. Peak Bacterial growth curve Peak,a Peak,b MIC Tmax,a Tmax,b AUC/MIC,a = AUC/MIC,b Peak,a = Peak,b NF-M 2001

  5. How predictive is the MIC ? NF-M 2001

  6. Qualities of the MIC (Minimal Inhibitory Concentration) • ”Exact” measure of antibiotic activity vs. bacterium (variation: + one two-fold dilution step) • MIC as good measure of antibacterial activity/mechanism of resistance: 1) linearly increasing resistance levels e.g. PBP changes in pneumococci, stepwise gyrA mutations 2) resistance mechanisms expressed in whole bacterial population e.g. TEM-1 beta-lactamase in E. coli sulI and sulII in Enterobacteriaceae NF-M 2001

  7. MIC: Examples of incomplete measure of antibacterial activity; interpretative methods or gene detection needed • mecA gene in staphylococci (inoculum,salt,temp.) • Penicillinase in S. aureus (clover leaf, mecillinam) • ESBL in Enterobacteriaceae • Type-1 non-derepressed beta-lactamase in certain Enterobacteriaceae (species diagnosis) • Inducible resistance genes, e.g. vanB in E.faecium, certain erm genes • gyrA mutations in Salmonella (nalidixic acid) NF-M 2001

  8. MIC as pharmacodynamic parameter: • ”..while MICs and MBCs provide useful information regarding the intrinsic activity of antimicrobials against pathogens, the information is inadequate for designing dosing regimens aimed at optimizing drug effect in vivo” Steven C. Ebert Handbook of Pharmacokinetic/Pharmacodynamic Correlation, CRC Press 1995 NF-M 2001

  9. Mouse protection test: Correlation between MIC and ED50 for pneumococci with varying penicillin susceptibility Log ED50 mg/mouse 100 10 1 Log MIC mg/l 0.01 0.1 1 10 Knudsen et.al. AAC 1995;39:1253-58. NF-M 2001

  10. Pharmacokinetics of penicillin in mice determined at the ED-50 for 10 pneumococci Knudsen et.al. AAC 1995;39:1253-58. NF-M 2001

  11. Changes in CFU of S. pneumoniae in thighs of infected mice treated with CEFPROZIL for 24 h.Nicolau et.al. AAC 44: 1291-5, 2000 2.5 0.0 Change in log CFU -2.5 -5.0 8 4 16 2 0 5 10 15 20 MIC (mg/l) NF-M 2001

  12. Effect of penicillin on S. pneumoniae infection in peritoneum (P), thigh (TH) and lung (L) of miceErlendsdottir et.al. AAC, 2001, 45: 1078-85. Change in CFU MIC = 1 mg/L Th P L Th P L Th P L Th P L Th P L Peak/MIC T>MIC 7,4 x 13 % 3,7 x 16 % 105 x 65 % 47 x 71 % 15 x 100 % NF-M 2001

  13. Mouse thigh, lung, peritonitis - and rabbit cage models: Generation time of control vs. Max. Effect of Penicillin Dosing Regimen • log CFU/ml, 6h Generation time,min Yellow = mouse lung model Erlendsdottir et.al., AAC, 2001, 45: 1078-85 NF-M 2001

  14. Dose response experiment in mouse-peritonitis model: S.pneumoniae D39 and mutant,D39-T6(D39-T6 = D39 transformed with mosaic pbp2B gene from highly PRP) NF-M 2000-01

  15. Dose response experiment in mouse-peritonitis model: S.pneumoniae D39 and mutant,D39-T6(D39-T6 = D39 transformed with mosaic pbp2B gene from highly PRP) NF-M 2000-01

  16. Interaction of Beta-lactams with PBB´s of S. pneumoniaeWilliamson et.al. AAC 1980, 18: 629-37; Frimodt-Møller et.al JID 1986,154: 511-17 * IC50, nmol/ml NF-M 2001

  17. Correlation between logED50 (mg/mouse), and logPBP3(I-50,nmol/ml) for pneumococci Multiple regr. ED50 vs. MIC, PBP1a,1b,2a, 2b, 3 : logPBp3 only, p=0.0078 cefsulodin cefalexin cefoxitin cefalothin cefadroxil cefotaxime cefaloridin Williamson et.al. AAC 1980, 18:629-37; Frimodt-Møller et.al JID 1986,154: 511-17 NF-M 2001

  18. Correlation between logMIC and logED50 for cefepime, ceftriaxone, cefotaxime, cefuroxime and cephalothin against 3 pneumococci LogED50, mg/kg 2 1,5 1 0,5 0 -0,5 Cefepime -1,5 -1 -0,5 0 0,5 1 1,5 Log MIC, mg/L Knudsen et.al. JAC 40: 679, 1997 NF-M 2001

  19. Ciprofloxacin-resistance in Salmonella:Clinical failures NB: NCCLS breakpoint < 4 mg/l NFM/2001

  20. How predictive is the Time>MIC for effect of beta-lactams (and macrolides) in clinical studies NF-M 2001

  21. Pharmacokinetic determinants of penicillin cure of gonococcal urethritisJaffe et.al. AAC, 1979, 15: 587-591 • 47 male inmates of US Penitentiary, Atlanta, age > 21 years, received intraurethral inoculation with 2-mm platinum loop of 15 x 10-9 cfu of N. gonorrhoeae – 45 developed purulent discharge. • 2 days after inoculation subejcts were treated im with penicillin in following doses: Single doses of 0.9, 1.2, or 2.4 Mill. Units or 1.0 + 0.4 Mill.Units at 3 h . • Serum penicillin conc. measured in all subjects. • RESULTS: Cure was best predicted by the time the Se-Penicillin Conc. remained above 3-4 x MIC; those cured had Se-Penicillin Conc. in this range for 7-10 h. NF-M 2001

  22. Treatment of gonorrhoeae in men: Comparison of Ampicillin with Penicillin-G Eriksson, Acta Dermatovener, 1970,50: 451 Treatment failure (%) N= 833 341 329 343 3.4 8.8 3.0 1.7 2 g po 2 g po + probenecid 1 g x 2 with 5 h interval Pc-G 2.2 MIU i.m. Ampicillin NF-M 2001

  23. Single injection treatment of meningococcal meningitisMacfarlane et.al. Transact Royal Trop Med Hygiene,1979,73 NF-M 2001 * mean, units/ml

  24. Single injection treatment of meningococcal meningitisMacfarlane et.al. Transact Royal Trop Med Hygiene,1979,73 P = NS NF-M 2001

  25. Pharmacodynamics of beta-lactams, macrolides and TMP/SMZ in otitis mediaCraig & Andes Pediatr Infect Dis J 1996;15:255-9 Bacte- riolo- gic cure (%) Time > MIC (% of dosing interval) NF-M 2001

  26. Penicillin-resistant pneumococci: Treatment with beta-lactam antibiotics - Time>MIC in % of dosing interval (MIC) NF-M 2001

  27. Pharmacokinetic parameters for macrolidesand MIC´s against H. influenzae NF-M 2001

  28. Clarithromycin vs. Grepafloxacin in chronic bronchitis: H. influenzaeTran et.al., JAC, 2000, 45: 9-17 NF-M 2001

  29. Treatment and outcome of S. aureus bacteremia: A prospective study of 278 casesA.G.Jensen et.al. Arch Intern Med in press. NF-M 2001

  30. Dicloxacillin dose vs. Time > MIC of free (non-proteinbound) concentration • Dose Time > MIC • 1 g x 3 78 % • 1 g x 4 > 100 % • 2 g x 3 > 100 % NF-M 2001

  31. Continuous vs. Intermittent infusion of oxacillin in patients with staphylococcal infectionsRaber et.al. 36th ICAAC 1996 Abst, No. A104 a) a) Same effect in the two treatment groups NF-M 2001

  32. Experimental UTI in mice with E. coli 4 days treatment BID with 5 beta-lactams NF-M 2001

  33. Experimental UTI in mice: Pharmacodynamics of Beta-lactams NF-M 2001

  34. Aminopenicillins for uncomplicated UTI:Literature study • Criteria for evaluation Age > 14 years Female : male ratio > 4:1 Uncomplicated, symptomatic UTI Urine culture before (> 100.000 cfu/ml) and after (4-10 days) = bacteriological cure(%) 1)Susceptible – E. coli 2) all Normal renal function No attempts on localization studies e.g. ab-coated-bact. NF-M 2001

  35. Only female patients: Charlton et.al. 1976 Eriksson et.al. 1981 Hoover et.al. 1982 Sutton et.al. 1983 Sigurdsson et.al. 1983 Kleinschmidt et.al. 1983 Morgan et.al. 1984 McAllister et.al. 1984 Nicolle et.al. 1993 Whitby et.al. 1993 Masterton et.al. 1995 Female and male patients: Grüneberg et.al. 1967 Bresky 1977 Grob et.al. 1977 Rotschafer et.al. 1979 Leigh et.al. 1980 Iravani et.al. 1988 17 studies, 20 treatment groups with aminopenicillins Aminopenicillins for uncomplicated UTI:Literature study NF-M 2001

  36. Aminopenicillins for uncomplicated UTI:Calculation of T > MIC • T > MIC calculated from population pharmacokinetics: T>MIC = (ln (dose/Vd /fu) – ln MIC)/(0.693/T½) Vd = distribution vol. (amox 0,26 l/kg, ampi 0,24 l/kg) Patient weight = 60 kg fu = degree non-proteinbound (83%) T½ = 1 h MIC = 8 mg/l NF-M 2001

  37. Distribution of E. coli MIC´s for ampicillin100 strains, 30 resistant No. of strains MIC, mg/l NF-M 2001

  38. Amoxicillin Timeserum > MICcalculated for MIC=8 mg/L NF-M 2001

  39. Aminopenicillins for uncomplicated UTI: T>MIC in serum vs. Bacteriological cure NF-M 2001

  40. NF-M 2001

  41. Optimal dose of amoxicillin for uncomplicated UTI (T>MIC(total) = 30 h) NF-M 2001

  42. Ciprofloxacin vs. Pondocillin for epididymitis in men > 40 years (prosp,rand,d-b): N=55 E. coliEickhoff et.al. Brit J Urol 1999, 84: 827-834 P = 0.001 NF-M 2001

  43. Pharmacodynamics of Beta-lactams: Time > MIC Optimal time > MIC – const. infus Intermittent dosing > 50% interval Intermittent dosing < 50% interval Bact./ml Control Time NF-M 2001

  44. How predictive isPeak/MIC ratio or AUC/MIC ratio for effect of aminoglycosides and quinolones ? NF-M 2001

  45. Aminoglycosides: Pharmacodynamics in vivoGram-negative bacteraemiaMoore et.al. J Infect Dis 149: 443, 1984 P < .01 NF-M 2001

  46. Relationship between max. Peak/MIC ratio and the rate of clinical response for aminoglycosidesMoore et.al. J Infect Dis, 1987, 155: 93 Response rate, % Maximum Peak/MIC ratio NF-M 2001

  47. Optimizing aminoglycoside therapy for nosocomial pneumonia (NP) caused by Gram-neg. BacteriaKashuba et.al. AAC, 1999, 43: 623-29 • 78 patients with NP caused by Gram-neg. bacteria treated with gentamicin or tobramycin: • Cox hazard model of C(max), AUC, total dose, duration of therapy, MIC, age, ICU adm., nutritional status, Pseudomonas infection, concurrent therapy with beta-lactam: • 90% probability of temperature - and leucocyte count resolution by 7 days: • If Cmax/MIC > 10 mg/l within first 48 h NF-M 2001

  48. Pharmacodynamics of fluoroquinolones against Pseudomonas infection in neutropenic ratsDrusano et.al., AAC, 1993, 37: 483-90. • Survival linked to Peak/MIC when ratio > 10/1 • Survival linked to AUC/MIC when ratio < 10/1 NF-M 2001

  49. Pharmacodynamics of i.v. Ciprofloxacin in seriously ill patientsForrest et.al. AAC, 1993, 37: 1073-81. NF-M 2001

  50. Pharmacodynamics of iv ciprofloxacin in seriously ill patientsForrest et.al. AAC, 1993, 37: 1073-81. * P < 0.005; ** P<0.001 NF-M 2001

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