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

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Presentation on theme: "How predictive is PK/PD ? Niels Frimodt-Møller, MD DrSci Microbiological R & D Antibiotic Resistance Surveillance Unit Statens Serum Institut Copenhagen,"— Presentation transcript:

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

4 AUC vs. Peak MIC Peak,bPeak,a Bacterial growth curve T max,aT max,b AUC/MIC,a = AUC/MIC,bPeak,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 Log MIC mg/l Knudsen et.al. AAC 1995;39: NF-M 2001

10 Pharmacokinetics of penicillin in mice determined at the ED-50 for 10 pneumococci Pk-Pd Parameter Median (range) Ratio high/low T > MIC, min 42 (24-60) 2,5 C-max, mg/L 38 (0,8-70) 87,5 AUC, mg x min/L ( ) 152,2 C-max/MIC 38 (9-96) 10,7 AUC/MIC ( ) 9,8 Knudsen et.al. AAC 1995;39: 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: , MIC (mg/l) Change in log CFU 16 2 NF-M 2001

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

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

16 Interaction of Beta-lactams with PBB´s of S. pneumoniae Williamson et.al. AAC 1980, 18: ; Frimodt-Møller et.al JID 1986,154: MIC R6 MIC a 1b 2a 2b 3 Cefotaxim * Cefaloridine Cephalothin < Cefoxitin <0.037 Cefadroxil <0.14 Cephalexin Cefsulodin * IC50, nmol/ml NF-M 2001

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

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

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

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 urethritis Jaffe et.al. AAC, 1979, 15: 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 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 (%) Pc-G 2.2 MIU i.m. 2 g po 2 g po + probenecid 1 g x 2 with 5 h interval Ampicillin N= NF-M 2001

23 Single injection treatment of meningococcal meningitis Macfarlane et.al. Transact Royal Trop Med Hygiene,1979,73 Time (in hours) after start of treatment Serum: Crystal. penicillin4.7* Triplopen CSF: Crystal. penicillin Triplopen0.03<0.02 * mean, units/ml NF-M 2001

24 Single injection treatment of meningococcal meningitis Macfarlane et.al. Transact Royal Trop Med Hygiene,1979,73 Clinical dataCrystalline penicillin Triplopen Age (years) Length of history (days) Coma level Death 4 2 Poor clin.response 72 h 6 7 Positive culture 1 4 P = NS NF-M 2001

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

28 Clarithromycin vs. Grepafloxacin in chronic bronchitis: H. influenzae Tran et.al., JAC, 2000, 45: 9-17 Anti- Biotic H. influ., eradicated AUIC(24) SIT(-1)*h C(max): MIC ratio T>MIC % of interval Clarithro -mycin 2/10 (20%) % Grepaflo -xacin 13/14 (93%) % NF-M 2001

29 Treatment and outcome of S. aureus bacteremia: A prospective study of 278 cases A.G.Jensen et.al. Arch Intern Med in press. + Risk factor Died/total,% -Risk factor Died/total,% Univariate P Focus not eradicated 42/125 34% 4/61 7% 7.2 <0.001 Septic shock 18/38 47% 28/148 19% Diclox daily dose < 4g 40/142 28% 6/44 14% Age > 60 y 32/96 33% 14/90 16% 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 infections Raber et.al. 36th ICAAC 1996 Abst, No. A104 Same effect in the two treatment groups a) 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 (> 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 Aminopenicillins for uncomplicated UTI: Literature study Only female patients: Charlton et.al Eriksson et.al Hoover et.al Sutton et.al Sigurdsson et.al Kleinschmidt et.al Morgan et.al McAllister et.al Nicolle et.al Whitby et.al Masterton et.al Female and male patients: Grüneberg et.al Bresky 1977 Grob et.al Rotschafer et.al Leigh et.al Iravani et.al studies, 20 treatment groups with aminopenicillins 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) V d = distribution vol. (amox 0,26 l/kg, ampi 0,24 l/kg) Patient weight = 60 kg fu = degree non-proteinbound (83%) T ½ = 1 h MIC = 8 mg/l NF-M 2001

37 Distribution of E. coli MIC´s for ampicillin 100 strains, 30 resistant MIC, mg/l No. of strains NF-M 2001

38 Amoxicillin Time serum > MIC calculated for MIC=8 mg/L Amoxicillin doseTime > MIC, h (calculated) 250 mg1,3 375 mg1,9 500 mg2, mg3, mg4,9 NF-M 2001

39 Aminopenicillins for uncomplicated UTI: T>MIC in serum vs. Bacteriological cure AntibioticDosing regimenT > MICse, h accumulated Bacteriological cure, % Amoxicillin (7 studies) 3 g, single dose 4,9 72 (44 – 82) Pivampicillin0,5g BID, 5 days 19,0 93 Amoxicillin1,0g BID, 3 days 19,6 88 Amoxicillin0,5g TID, 3 days 20,4 78 (77 – 81) Amoxicillin (4 studies) 0,25g TID, 7-10 days 26,7 – 38,1 86 (79 – 94) Amoxicillin (4 studies) 0,375-0,5g TID, 7-10 days 47,7 – 68,1 86 (80 – 89) NF-M 2001

40

41 Optimal dose of amoxicillin for uncomplicated UTI (T>MIC(total) = 30 h) Individual dose size, g T(serum)>MIC h Duration (d): 30/T>MIC/3(=tid) Total dose g 0,2501,2786 0,5002,2746 1,0003,2739 3,0004,862 (bid)12 NF-M 2001

42 Ciprofloxacin vs. Pondocillin for epididymitis in men > 40 years (prosp,rand,d-b): N=55 E. coli Eickhoff et.al. Brit J Urol 1999, 84: Total N = 158 Pivampicillin 700 mg x 2 N = 25 Ciprofloxacin 500 mg x 2 N = 30 Cured 8 (32%) 27 (90%) No effect: Persisting fever, septicaemia or constant local symptoms, shift of treatm 17 (68%) 3 (10%) P = 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 is Peak/MIC ratio or AUC/MIC ratio for effect of aminoglycosides and quinolones ? NF-M 2001

45 Aminoglycosides: Pharmacodynamics in vivo Gram-negative bacteraemia Moore 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 aminoglycosides Moore 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. Bacteria Kashuba et.al. AAC, 1999, 43: 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 rats Drusano et.al., AAC, 1993, 37: 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 patients Forrest et.al. AAC, 1993, 37: AUC/MIC range Total no. patients Results for the following cure Clinical No.ptts % Microbiol. No. ptts. % 0 – NF-M 2001

50 Pharmacodynamics of iv ciprofloxacin in seriously ill patients Forrest et.al. AAC, 1993, 37: AUIC-24 h (inverse serum inhibitory titer integrated over time) Clinical Cure, % Microbiologic Cure, % < > *82 ** * P < 0.005; ** P<0.001 NF-M 2001

51 Pharmacodynamics of Antibiotics AUIC >125 NF-M 2001

52 Pharmacodynamics of i.v. Ciprofloxacin in seriously ill patients: AUIC > 125 Forrest et.al. AAC, 1993, 37: MIC´s > 0.25 mg/l sign. worse for microbiologic cure and > 0.5 mg/l sign. worse for clinical cure (i.e. Pseudomonas and S. aureus) Concomitant azlocillin improved likelihood of cure with Pseudomonas infections (P=0.028) High correlation betwen Peak/MIC ratio and AUC/MIC ratio (R=0.92) prevented detection of Peak/MIC as important covariate. Increase of AUC/MIC above 250 no further improvement NF-M 2001

53 Pharmacodynamics of levofloxacin in clinical study Preston et.al. JAMA, 1998, 279: ptts with bacterial infections of respiratory tract, skin or urinary tract Clinical and microbiological outcome best predicted by Peak/MIC ratio > 12.2 NF-M 2001

54 Conclusion: Aminoglycosides/quinolones Peak/MIC ratio > within first 24 – 48 h predictive of good effect Leads to shorter duration of treatment NF-M 2001

55 How predictive is PK/PD ? MIC as predictive for antibacterial activity in vivo depends on drug/bacterial species/ type of resistance For susceptible bacteria and selected types of resistance mechanisms: Time>MIC (e.g. beta-lactams, macrolides) and Peak/MIC (AUC/MIC) ratio ( e.g. aminogly- cosides, quinolones) are excellent predictors of effect in vivo NF-M 2001


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