Pharmacodynamics and theDosing of Antibacterials
William A. Craig, MD
University of Wisconsin and
Wm S. Middleton Memorial VA Hospital
Madison, WI USA
PRESENTATION OUTLINE• History of pharmacodynamics• Different patterns of antimicrobial activity• Pharmacodynamic target setting in animal
models• Identify major factors that alter the
pharmacodynamic target• Correlation between animal and human
studies• Uses of pharmacodynamic modeling • Application to susceptibility breakpoints for
gram-negative bacilli
What is Pharmacodynamics ?
• Relationship between concentration and pharmacologic and toxicologic effects of a drug
• Relationship between measures of in vivo drug exposure and microbiologic (and clinical) efficacy
Why Interest in Pharmacodynamics?
• Always occurs when there is narrow difference between MICs and obtainable drug concentrations
- early days of penicillin in 1940s (low doses used)
- appearance of pseudomonas infections in 1960s and 1970s (high MICs)
- appearance of resistant Streptococcus pneumoniae and other bacteria
in 1990s
Bactericidal Activity of Tobramycin
and Ticarcillin againstPseudomonas aeruginosa
Time (hours)
0 2 4 6 8 12
Log
CF
U p
er T
high
og
4
5
6
7
8
9
4 mg/kg 12 mg/kg20 mg/kg
0 2 4
300 mg/kg 800 mg/kg2400 mg/kg
Tobramycin Ticarcillin
Vogelman et al. J Infect Dis 157, 1988
1st Pattern of Antimicrobial Activity
Concentration-dependent killing and prolonged persistent effects
Seen with quinolones, aminoglycosides, ketolides, and daptomycin
Goal of dosing regimen: maximize concentrations
2nd Pattern of Antimicrobial Activity
Time-dependent killing and minimal or no persistent effects (except with staphylococci)
Seen with all beta-lactams
Goal of dosing regimen: optimize duration of exposure; maximum killing when levels constantly above 4-5 times MIC
3rd Pattern of Antimicrobial Activity
Time-dependent killing and moderate to prolonged persistent effects
Seen with macrolides, azithromycin, clindamycin, tetracyclines, glycylcyclines, streptogramins, glycopeptides, oxazolidinones, deformylase inhibitors
Goal of dosing regimen: optimize amount of drug; maximum killing when T>MIC 100%
Major Goal of Pharmacodynamics
Establish the PK/PD TARGET required for effective antimicrobial therapy
- identify which PK/PD indice (T>MIC, AUC/MIC, peak/MIC) best predicts in vivo antimicrobial activity
- determine the magnitude of the PK/PD parameter required for in vivo efficacy (static effect, 1 or 2 log kill)
Neutropenic Mouse Thigh-Infection Model
2. Bacteria injected into thighs on day 0 (106-7)
1. Neutropenia induced by 2injections of cyclophosphamideon days -4 and -1
3. Treatment (usually given SQ)started 2 hr after infection and continued for 1-5 days
4. Thighs removed, homogenized, serially diluted and plated forCFU determinations
Time Course of Antimicrobial Activity of Ciprofloxacin Against Klebsiella ATCC
43816in Lungs of Neutropenic Mice
Days0 1 2 3 4 5
Lo
g10
CF
U/L
un
g
2
4
6
8
10
Saline0.29 q 6h1.17 q 6h4.69 q 6h18.8 q 6h75.0 q 6h
DeathDeath Death
Correlation of PK/PD Parameters with Efficacy Levofloxacin against Streptococcus
pneumoniae in Thighs of Neutropenic Mice
24-Hr AUC/MIC
10 100 1000
Log
10 C
FU /
Thig
h at
24
Hrs
0
2
4
6
8
10
Peak/MIC
1 10 100 1000
Time Above MIC
0 25 50 75 100
Andes & Craig, Int J Antimicrob Agents, 2002
Relationship Between PK/PD Parameters and Efficacy for Cefpirome against Klebsiella
pneumoniae in Lungs of Neutropenic Mice
24-Hr AUC/MIC
10 100 1000
Log
10 C
FU/T
high
at 2
4 H
rs
2
3
4
5
6
7
8
9
10
Peak/MIC
1 10 100 1000
Time Above MIC
0 25 50 75 100
Craig Antimicrobial Pharmacodynamics in Theory and Practive 2002
Mathematical Analysis of Dose-Response Data from Animal Models
after 24 Hours of Therapy
Nonlinear regression and Hill equation to estimate Emax (difference from untreated control), P50 (dose giving 50% of Emax) and slope (N) of the dose-response relationship
Dose (mg/kg/6 hrs)10 30 100 300
Lo
g1
0 C
FU
pe
r T
hig
h a
t 2
4 H
rs
5
6
7
8
9
Static Dose
1 Log K ill
P50
Emax
CFU=(Emax) DoseN
DoseN + P50N
Craig Diagn Microbiol Infect Dis 1995
Factors That Affect the Magnitude of PK/PD Parameters
- dosing regimen
- drug class
- protein binding
- infecting pathogen
- presence or absence of neutrophils
- site of infection
Magnitude of PK/PD Parameters
Does the magnitude of the parameter vary with:
1. different dosing regimens? NO, unless the clearance is too rapid in the animal model
Impact of Dosing Interval on Static Dose for Amikacin against K. pneumoniae and E. coli
in Mice with Normal and Impaired Renal Function
Dosing Interval (Hours)
3 6 12 24Sta
tic D
ose
(mg/
kg/2
4 hr
s)
1
10
100
1000
K. pneumoniaeE. coliNormal T1/2=17 min K. pneumoniae E. coliRenal Impaired T1/2=104 min
Reddington and Craig, JAC 1995
Magnitude of PK/PD Parameters
Does the magnitude of the parameter vary with:
1. different dosing regimens? NO
2. different drugs within the same class? NO, if free drug levels are used
Protein binding is important !!
24-Hr AUC/MIC with Total and Free Drug for the Static Dose of Different Fluoroquinolones
with S. pneumoniae ATCC 10813
0
40
80
120
160
Gati Sita Moxi Gemi Garen Levo Cipro
24-H
r A
UC
/MIC
Total
Free
Andes & Craig 40th and 41st ICAAC, 2000 and 2001
Time Above MIC for Total and Free Drug for
the Static Dose of Different Cephalosporins with Klebsiella pneumoniae ATCC 43816
0
10
20
30
40
50
60
70
Total
Free
Craig Infect Dis Clin N Amer 2003
Magnitude of PK/PD Parameters
Does the magnitude of the parameter vary with:
1. different dosing regimens? NO
2. different drugs within the same class? NO, if free drug levels are used
3. different organisms ? Similar for most organisms in neutropenic mice; less T>MIC with
staphylococci with ß-lactams
Drug GNB S. pneumoniae S.aureus
Ceftazidime 36 (27-42) 39 (35-42) 22 (19-24)
Cefpirome 35 (29-40) 37 (33-39) 22 (20-25)
Cefotaxime 38 (36-40) 38 (36-40) 24 (20-28)
Ceftriaxone 38 (34-42) 39 (37-41) 24 (21-27)
Time Above MIC Required for a Static Effect with 4 Cephalosporins
Time Above MIC (% of Dosing Interval)
Craig Diagn Microbiol Infect Dis 22:89, 1995
Magnitude of PK/PD Parameters
Does the magnitude of the parameter vary with:
4. resistant organisms
No
T>MIC for Free Drug for Static Doses with Cephalosporins, Penicillins and
Carbapenems against Multiple Strains of S. pneumoniae with Various Penicillin MICs
MIC (mg/L)0.008 0.03 0.12 0.5 2 8
T>
MIC
(%
)
0
10
20
30
40
50
Cephalosporins
Penicillins
Carbapenems
24-Hr AUC/MIC of Gemifloxacin (Free Drug) for the Static Doses with 61 Strains of
S. pneumoniae in Thighs of Neutropenic Mice
MIC (mg/L)
0.008 0.03 0.12 0.5 2
Fre
e D
rug
AU
C/M
IC
2.5
5
10
20
40
80
Wild typemutants
Efflux
Magnitude of PK/PD Parameters
Does the magnitude of the parameter vary with:
4. resistant organisms
NO
5. different sites of infection (e.g. blood, lung, peritoneum, soft tissue)?
NO for most drugs; vancomycin lesspotent in lung infection than thigh
Factors That Do Not Affect the Magnitude of PK/PD Parameters
- resistant organisms
- animal species
Can values obtained in animals be predictive of efficacy in humans ?
T>MIC for ß-Lactams Versus Mortalityin Animal Models: Literature Review
0 20 40 60 80 100
Mo
rta
lity
(%)
0
20
40
60
80
100 Cephalosporins Penicillins
Time Above MIC (% of Interval)Craig Antimicrobial Pharmacodynamics in Theory and Practive 2002
Double Typanocentesis Studies in Acute Otitis Media
First tap to identify the causative pathogen
Second tap at 3-5 days to determine if organisms had been eradicated
Techniques first performed by Howie. Most recent studies with resistant organisms performed by Dagan.
Time above MIC calculated from serum levels and MICs
Craig & Andes, Pediatr Infect Dis J 15:255, 1996; Multiple studies by Dagan et al
Relationship Between T>MIC and Bacterial Eradication with
ß-Lactams in Acute Otitis Media
Time Above MIC (%)
0 20 40 60 80 100
Bac
teri
al E
rad
icat
ion
(%
)
0
20
40
60
80
100
PSSP PISP-PRSPH. fluBest Fit
Craig Infect Dis Clin N Amer 2003
Uses of Pharmacodynamic Studies
• Drug development- new formulations active against organisms with high MICS (e.g. high dose amoxicillin/clavunate)- dosage regimens for phase II and III clinical trials- drug selection for clinical studies
• Optimize dosing regimens- longer infusions and continuous infusion
of beta-lactams - once-daily dosing of aminoglycosides
Uses of Pharmacodynamic Studies
• Guidelines for antimicrobial usage
• Reduction of emergence of resistance organisms
• Modifications of susceptibility and resistance breakpoints - oral ß-lactams for S. pneumoniae - parenteral cephalosporins for S.
pneumoniae - fluoroquinolones for S. aureus
ESBLs and Clinical Failures• Emergence of Enterobacteriaceae with
increased MICs due to novel ß-lactamases (ESBLs)
• Associated with clinical failures and existing breakpoints fail to detect all these enzymes
• Development by NCCLS of reference methods for screening and confirmation of ESBLs in some Enterobacteriaceae; does not work for all Enterobacteriaceae.
• Elevated MICs in may also arise from mechanisms not targeted by the current ESBL test
Pharmacodynamic Studies of Extended-Spectrum Cephalosporins against
Enterobacteriaceae with and without ESBLs in Thighs of Neutropenic Mice
Drugs: Cefotaxime, Ceftriaxone, Ceftazidime and Cefepime
ESBLs: TEM-3, TEM-7, TEM-10, TEM-12, TEM-26, SHV-2, SHV-4, SHV-5, SHV-7, CTX-M2, CTX-M3 alone or in combination with OXA-1, OXA-2, TEM-1, and/or AMP-C
Non-ESBLs: TEM-1, TEM-1 and OXA-1, AMP-C, wild-type
High inocula – 107-8
Activity of 4 Cephalosporins against Various Enterobacteriacea with and without ESBLs
inMurine Thigh-Infection Model
Time Above MIC (percent)
0 20 40 60 80 100
Cha
nge
in L
og10
CF
U/T
high
over
24
Hou
rs
-3
-2
-1
0
1
2
3
0 20 40 60 80 100
-3
-2
-1
0
1
2
3ESBLs Non-ESBLs
Monte Carlo Simulation
PK Variation In Normal Volunteersor Patients
PK Variation in10,000 Patients
Simulate
Determine Percentage of Patientsthat would meet the PK/PD Targetrequired for efficacy
Drusano et al
Monte Carlo Simulation: CefotaximePercent of 10,000 Patients Attaining Indicated PK/PD Exposure Target
T>MIC with 2g every 8 hr
MIC 30% 40% 50% 60% 70%
0.5 100 100 99 96 88
1 100 99 97 89 73
2 99 98 89 71 49
4 98 91 67 41 22
8 92 62 29 11 4
16 65 15 3 0 0
Ambrose & Dudley, ICAAC 2002
Clinical Outcome in 42 Patients with ESBL-Producing Klebsiella/E. coli
Bacteremia and Treated with Cephalosporin Monotherapy
Outcome
MIC
<1 ųg/L
MIC
2 ųg/L
MIC
4 ųg/L
MIC
8 ųg/L
Success 13 (81%) 4 (67%) 3 (27%) 1 (11%)
Failure 3 (19%) 2 (33%) 8 (73%) 8 (89%)
Paterson et al J Clin Micro 39:2206, 2001; Kim et al AAC 46:1481,2002; Wong-Beringer et al Clin Infect Dis 34:135, 2002; Kang et alAAC In press 2004; Bhavani et al 44rd ICAAC, Abstract K-1588, 2004
Distribution of Enterobacteriaceawith MICs of 4 and 8 mg/L
Total Strains
E. coli Kleb spp Other
Ceftazidime 464 89
(19%)
158
(34%)
217
(47%)
Ceftriaxone 532 46
(9%)
169
(32%)
317
(59%)
2002-2003 Sentry Program
Total 0f 11, 913 Isolates from ICU Patients
Jones, R
Acknowledgements
Pharmacodyamics
Andes DR
Bundtzen R
Ebert S
Fantin B
Gerber A
Gudmundsson S
Kiem S
Leggett J
MacDonald
Mouton J
Redington J
Totska K
Turnidge JVan Ogtrop MVogelman BWalker RWatanabe Y
OtitisDagan R
ESBLsAmbrose PDudley MJones R
It all started with a mouse.
-Walt Disney
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