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. Bacterial growth curve
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. mecA gene in staphylococci (inoculum,salt,temp.)
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:
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: , 2000
2.5
0.0
Change in log CFU
-2.5
-5.0 2 4 5 8 10 15 16 20
MIC (mg/l)
NF-M 2001

12. Effect of penicillin on S
Effect of penicillin on S. pneumoniae infection in peritoneum (P), thigh (TH) and lung (L) of mice Erlendsdottir et.al. AAC, 2001, 45:
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:
NF-M 2001

14. Dose response experiment in mouse-peritonitis model: S
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
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
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
68034 1a 1b 2a 2b 3
Cefotaxim
0.026
0.02
0.015*
0.0072
0.0052
0.056
0.0086
Cefaloridine
0.057
0.05
0.018
0.042
1.45
0.0066
Cephalothin
0.49
0.4
<0.016
0.19
0.86
0.08
Cefoxitin
3.7
6.8
0.145
2.4
8.0
<0.037
Cefadroxil
4.3
3.1
4.6
1.3
12.0
<0.14
Cephalexin
8.8
6.2
7.2
4.5
2.2
28.0
0.29
Cefsulodin
22.2
25.0
23.0
37.0
6.7
52.0
1.55
* IC50, nmol/ml
NF-M 2001

17. ED50 vs. MIC, PBP1a,1b,2a, 2b, 3 : logPBp3 only, p=0.0078
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:
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
-0,5
Cefepime
-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 urethritis Jaffe et.al. AAC, 1979, 15:
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 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 meningitis Macfarlane et
Single injection treatment of meningococcal meningitis Macfarlane et.al. Transact Royal Trop Med Hygiene,1979,73
Time (in hours) after start of treatment 24 48 72
Serum:
Crystal. penicillin
4.7*
4.0
2.0
Triplopen
1.4
0.3
0.2
CSF:
0.15
0.22
0.08
0.03
<0.02
NF-M 2001
* mean, units/ml

24. Crystalline penicillin
Single injection treatment of meningococcal meningitis Macfarlane et.al. Transact Royal Trop Med Hygiene,1979,73
Clinical data
Crystalline penicillin
Triplopen
Age (years)
Length of history (days)
Coma level
1.1
1.2
Death 4 2
Poor clin.response 72 h 6 7
Positive culture 1
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
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 macrolides and MIC´s against H
Pharmacokinetic parameters for macrolides and MIC´s against H. influenzae
NF-M 2001

28. Clarithromycin vs. Grepafloxacin in chronic bronchitis: H
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%)
8.1
0.7 0%
Grepaflo-xacin
13/14
(93%)
169
23.6
100%
NF-M 2001

29. Treatment and outcome of S
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
Univariate P
Focus not eradicated
42/125
34%
4/61 7%
7.2
<0.001
Septic shock
18/38
47%
28/148
19%
3.9
0.001
Diclox daily dose < 4g
40/142
28%
6/44
14%
2.5
0.05
Age > 60 y
32/96
33%
14/90
16%
2.7
0.006
NF-M 2001

30. Dicloxacillin dose vs. Time > MIC of free (non-proteinbound) concentration
Dose Time > MIC
1 g x %
1 g x > 100 %
2 g x > 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 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 (> 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. 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
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 ampicillin 100 strains, 30 resistant
No. of strains
MIC, mg/l
NF-M 2001

38. Amoxicillin Timeserum > MIC calculated for MIC=8 mg/L
Amoxicillin dose
Time > MIC, h
(calculated)
250 mg
1,3
375 mg
1,9
500 mg
2,3
1000 mg
3,2
3000 mg
4,9
NF-M 2001

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

40. NF-M 2001

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
0,250
1,27 8 6
0,500
2,27 4
1,000
3,27 3 9
3,000
4,86
2 (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 = 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 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. Maximum Peak/MIC ratio
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. If Cmax/MIC > 10 mg/l within first 48 h
Optimizing aminoglycoside therapy for nosocomial pneumonia (NP) caused by Gram-neg. Bacteria Kashuba et.al. AAC, 1999, 43:
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. Survival linked to Peak/MIC when ratio > 10/1
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
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 – 62.5 9 4 44 2 22 10 40 3 30 16 14 88 13 81 7 5 71 6 86 17 77 18 82
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
< 125 42 26
> 125
80 *
82 **
* P < 0.005; ** P<0.001
NF-M 2001

51. Pharmacodynamics of Antibiotics
AUIC >125
NF-M 2001

52. Pharmacodynamics of i. v
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
Pharmacodynamics of levofloxacin in clinical study Preston et.al. JAMA, 1998, 279:
313 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