How predictive is PK/PD ?. Niels FrimodtMøller, MD DrSci Microbiological R & D Antibiotic Resistance Surveillance Unit Statens Serum Institut Copenhagen, Denmark. NFM 2001. Pharmacodynamic parameters. Pharmacokinetic parameters: Peak/MIC ratio AUC/MIC ratio Time > MIC
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How predictive is PK/PD ?
Niels FrimodtMøller, MD DrSci
Microbiological R & D
Antibiotic Resistance Surveillance Unit
Statens Serum Institut
Copenhagen, Denmark
NFM 2001
(minimal bactericidal concentration (MBC) (time kill activity)
MIC
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Timedependent, concentration
independent:
Betalactams
Macrolides
Tmp/sulfa
Glycopeptides

Concentration dependent:
Aminoglycosides
Fluoroquinolones
Streptogramins


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Bacterial growth curve
Peak,a
Peak,b
MIC
Tmax,a
Tmax,b
AUC/MIC,a = AUC/MIC,b
Peak,a = Peak,b
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How predictive is the MIC ?
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1) linearly increasing resistance levels
e.g. PBP changes in pneumococci,
stepwise gyrA mutations
2) resistance mechanisms expressed in whole
bacterial population
e.g. TEM1 betalactamase in E. coli
sulI and sulII in Enterobacteriaceae
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e.g. vanB in E.faecium, certain erm genes
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Steven C. Ebert
Handbook of Pharmacokinetic/Pharmacodynamic Correlation, CRC Press 1995
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Log ED50 mg/mouse
100
10
1
Log MIC
mg/l
0.01
0.1
1
10
Knudsen et.al. AAC 1995;39:125358.
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Knudsen et.al. AAC 1995;39:125358.
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2.5
0.0
Change in log CFU
2.5
5.0
8
4
16
2
0
5
10
15
20
MIC (mg/l)
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Effect of penicillin on S. pneumoniae infection in peritoneum (P), thigh (TH) and lung (L) of miceErlendsdottir et.al. AAC, 2001, 45: 107885.
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 %
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Generation time,min
Yellow = mouse lung model
Erlendsdottir et.al., AAC, 2001, 45: 107885
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Dose response experiment in mouseperitonitis model: S.pneumoniae D39 and mutant,D39T6(D39T6 = D39 transformed with mosaic pbp2B gene from highly PRP)
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Dose response experiment in mouseperitonitis model: S.pneumoniae D39 and mutant,D39T6(D39T6 = D39 transformed with mosaic pbp2B gene from highly PRP)
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* IC50, nmol/ml
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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, 18:62937; FrimodtMøller et.al JID 1986,154: 51117
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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
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NB: NCCLS breakpoint < 4 mg/l
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How predictive is the Time>MIC for effect of betalactams (and macrolides) in clinical studies
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Cure was best predicted by the time the SePenicillin Conc. remained above 34 x MIC; those cured had SePenicillin Conc. in this range for 710 h.
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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
PcG
2.2 MIU i.m.
Ampicillin
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* mean, units/ml
P = NS
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Bacte
riolo
gic
cure
(%)
Time > MIC (% of dosing interval)
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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
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Experimental UTI in mice with E. coli
4 days treatment BID with 5 betalactams
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Experimental UTI in mice:
Pharmacodynamics of Betalactams
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Age > 14 years
Female : male ratio > 4:1
Uncomplicated, symptomatic UTI
Urine culture before (> 100.000 cfu/ml) and
after (410 days) = bacteriological cure(%)
1)Susceptible – E. coli 2) all
Normal renal function
No attempts on localization studies e.g. abcoatedbact.
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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
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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 nonproteinbound (83%)
T½ = 1 h
MIC = 8 mg/l
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No. of strains
MIC, mg/l
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Ciprofloxacin vs. Pondocillin for epididymitis in men > 40 years (prosp,rand,db): N=55 E. coliEickhoff et.al. Brit J Urol 1999, 84: 827834
P = 0.001
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Optimal time > MIC – const. infus
Intermittent dosing > 50% interval
Intermittent dosing < 50% interval
Bact./ml
Control
Time
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How predictive isPeak/MIC ratio or AUC/MIC ratio for effect of aminoglycosides and quinolones ?
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P < .01
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Response rate, %
Maximum Peak/MIC ratio
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ratio > 10/1
ratio < 10/1
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* P < 0.005; ** P<0.001
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AUIC >125
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24 – 48 h predictive of good effect
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