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Antimicrobial Pharmacodynamics: Concepts for Rational Selection and Dosing of Antibiotics

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Title: What the _at_*#! is Pharmacodynamics?? Author: John F. Mohr Last modified by: drnabil Created Date: 7/8/2003 2:16:26 PM Document presentation format – PowerPoint PPT presentation

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Title: Antimicrobial Pharmacodynamics: Concepts for Rational Selection and Dosing of Antibiotics


1
Antimicrobial Pharmacodynamics Concepts for
Rational Selection and Dosing of Antibiotics
2
Effect of Adequate Antimicrobial Therapy For
Bloodstream Infections on Mortality
Plt0.001
Ibrahim E, et al. Chest 2000 118 146-155.
3
Effect of Adequate Antimicrobial Therapy For
Bloodstream Infections on Mortality
OSSAoxacillin-susceptible S. aureus
CNScoagulase-negative staphylococci
VREvancomycin resistant enterococci
Ibrahim E, et al. Chest 2000 118 146-155.
4
What does S Mean?
  • Susceptible - Isolates are inhibited by the
    usually achievable concentrations of
    antimicrobial agent when the recommended dose is
    used for the site of infection.
  • Intermediate Implies clinical efficacy in the
    areas where drugs are physiologically
    concentrated or when higher than normal dosages
    of drugs can be used
  • Resistant Isolates are not inhibited by the
    usually achievable concentrations of the agent
    with normal dosage schedules

CLSI. M-100-S16. January 2006
5
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6
Pharmacokinetics
  • Absorption
  • Distribution
  • Metabolism
  • Elimination
  • PK is what the body does to the drug

7
Pharmacokinetics Serum/Tissue Concentrations Half-
Life
Pathogen Susceptibility MIC/MBC
Pharmacodynamics Peak/MIC AUC/MIC
Time gt MIC
Eradication/Cure
8
Pharmacodynamic Interactions
Peak/MIC
AUC/MIC
Concentration
MIC
TimegtMIC
Time
9
Concentration Dependent vs. Concentration
Independent Bacterial Killing
Tobramycin
Ciprofloxacin
Ticarcillin
Time (hours)
Craig WA, et al. Scand J Infect Dis, 1991 Suppl
(74)
10
Optimizing Antimicrobial Therapy
Concentration at Infection Site
Host Factors
PK
PD
Bacterial Killing
Pathogen MIC/MBC
Antibiotic
Outcome
11
Pharmacokinetic-Pharmacodynamic Indices
Correlating with Efficacy
Antimicrobial Agent Bactericidal Pattern of in-vitro Activity PK-PD measure(s)
Aminoglycosides Concentration AUC0-24MIC, CmaxMIC
b-Lactams
Penicillins Time TgtMIC
Cephalosporins Time TgtMIC
Carbapenems Time TgtMIC
Monobactams Time TgtMIC
Glycopeptides/ Lipopeptides
Daptomycin Concentration AUC0-24MIC, CmaxMIC
Oritavancin Concentration TgtMIC
Vancomycin Time AUC0-24MIC
Fluoroquinolone Concentration AUC0-24MIC, CmaxMIC
Antimicrobial Agent Bactericidal Pattern of in-vitro Activity PK-PD measure(s)
Macrolides Concentration AUC0-24MIC, CmaxMIC
Azithromycin Time AUC0-24MIC
Clarithromycin Time AUC0-24MIC
Telithromycin Concentration AUC0-24MIC
Metronidazole Concentration AUC0-24MIC, CmaxMIC
Tetracyclines
Doxycycline Time AUC0-24MIC
Tigacycline Time AUC0-24MIC
Clindamycin Time AUC0-24MIC
Oxazolidinones
Linezolid Time AUC0-24MIC
12
In-vitro Pharmacodynamic Models
13
Murine Thigh Infection Pharmacodynamic Model
Antimicrobial
Cyclophosphamide
Organism 107 CFU
CFU determination
Bacteriostatic dose
Pharmacokinetic parameters
2 hours
Vesga A, et al. 37th ICAAC. 1997.
14
b-lactams
15
Correlation of PK/PD Parameters With Effect of
Cefotaxime Against K. pneumoniae in Lungs of
Neutropenic Mice
TgtMIC
Peak/MIC
24-Hr AUC/MIC
Craig WA. Diagn Microbiol Infect Dis 1995
2289-96
16
Relationship Between Time Serum Levels Exceed the
MIC and Mortality for B-Lactams Against S.
pneumoniae
Penicillins
Cephalosporins
Craig WA. Diagn Microbiol Infect Dis 199625213-7
17
Craig WA. Diagn Microbiol Infect Dis 199625213-7
18
Relation Between PD Parameters and Efficacy for
Ticarcillin against P. aeruginosa
TgtMIC
Peak/MIC
24-Hr AUC/MIC
Vogelman B., et al. J Infect Dis 1988. 158(4).
19
What TgtMIC is our target for ß-lactams?
Static dose
1 log
2 log
3 log
TgtMIC
Peak/MIC
24-Hr AUC/MIC
Vogelman B., et al. J Infect Dis 1988. 158(4).
20
b-lactam Pharmacodynamics
Antibiotic Organism/Class Outcome Parameter and Value Source
Cefazolin E. coli, Klebsiella TgtMIC IVPDM
Ceftriaxone S. pneumoniae TgtMIC100 Rabbit meningitis model
Cefazolin E. coli TgtMIC, max effect 4xMIC IVPDM
Cephalosporins Enterobacteriacae Streptococci S. aureus TgtMIC 60-70 TgtMIC 60-70 TgtMIC 40-50 Animal data review
Cefazolin, ticarcillin, penicillin E. coli S. aureus P. aeruginosa S. pneumoniae TgtMIC 100 TgtMIC 55 TgtMIC 100 TgtMIC 100 Neutropenic murine thigh infection model
Cefmenoxime Gram-negative TgtDRC Human, nosocomial pneumonia
Gunderson BW, et al. Pharmacotherapy. 2001
Nov21(11 Pt 2)302S-318S
21
Concentration Time Profile Antibiotic Y
MIC2 TgtMIC gt90 DI
22
Concentration Time Profile Antibiotic Y (q12h)
MIC8 TgtMIC50 DI
23
Concentration Time Profile Antibiotic Y (q8h)
MIC8 TgtMICgt90 DI
24
Continuous Infusion Beta-lactams
Intermittent
  • Beta-lactam Serum Concentrations

Continuous
MIC
MIC
Time (h)
25
Cefamandole Continuous vs. Intermittent infusion
pNS
Bodey, GP, et al. Am J Med 1979. 67.
26
Cure Rate of Infections in Persistently Febrile
Neutropenic Patients
p0.03
Bodey, GP, et al. Am J Med 1979. 67.
27
Fluoroquinolones
28
Correlation of PK/PD Parameters With Effect of
Levofloxacin Against S. pneumoniae in Thighs of
Neutropenic Mice
TgtMIC
Peak/MIC
24-Hr AUC/MIC
Handbook of Experimental Pharmacology. Vol 127
Quinolone Antibacterials. 1998
29
Pharmacodynamic Interactions
Peak/MIC
AUC/MIC
Concentration
MIC
TimegtMIC
Time
30
Relationship Between 24-Hour AUC/MIC and
Mortality for Fluoroquinolones Against S.
pneumoniae
Craig, WA 37th IDSA, 1999 Clin Infect Dis. (in
press)
31
Relationship Between 24-Hour AUC/MIC and
Mortality for Fluoroquinolones Against
Gram-Negative Bacilli in a Murine Model
Craig, WA 37th IDSA, 1999 Clin Infect Dis. (in
press)
32
Relationship Between AUC24/MIC and Efficacy of
Ciprofloxacin in Patients with Serious Bacterial
Infections
Forrest A, et al. AAC, 1993 37 1073-1081
33
Fluoroquinolone Pharmacodynamics S. pneumoniae
Antibiotic Outcome Parameter and Value Source
Levoflooxacin, ciprofloxacin, trovafloxacin AUCMIC gt 35 IVPDM
Ciprofloxacin, levofloxacin AUCMIC 30-35 IVPDM
Ciprofloxacin, ofloxacin, trovafloxacin AUCMIC 44-49 IVPDM
Ciprofloxacin, levovfloxacin AUCMIC 32-64 IVPDM
Quinolones AUCMIC gt 40 IVPDM
Sitafloxacin AUCMIC 37 Murine thigh and lung infection model
Gatifloxacin AUCMIC 52 Murine thigh and lung infection model
Gemifloxacin AUCMIC 35 Murine thigh and lung infection model
Gunderson BW, et al. Pharmacotherapy. 2001
Nov21(11 Pt 2)302S-318S
34
Fluoroquinolone Pharmacodynamics Gram
Negative Bacilli
Antibiotic Organism/Class Outcome Parameter and Value Source
Enoxacin P. aeruginosa, E. coli CmaxMICgt8 IVPDM
Ciprofloxacin P. aeruginosa CmaxMICgt8 IVPDM
Ciprofloxacin, ofloxacin P. aeruginosa AUCMICgt100 IVPDM
Lomefloxacin P. aeruginosa CmaxMICgt10 Neutropenic rat sepsis model
Gatifloxacin Enterobacteriacae AUCMIC48 Murine thigh and lung infection model
Sitafloxacin Enterobacteriacae AUCMIC43 Murine thigh and lung infection model
Ciprofloxacin GNR, mostly LRTI AUCMICgt125 Human, retrospective
Ciprofloxacin GNR, vent dependent AUCMICgt100 Human, retrospective
Gunderson BW, et al. Pharmacotherapy. 2001
Nov21(11 Pt 2)302S-318S
35
Aminoglycosides
36
Max Peak/MIC Ratio and Clinical Response with
Aminoglycosides
Moore,et al. J Inf Disease, 1987 155(1) 93-98
37
Pharmacodynamic Interactions
Peak/MIC
AUC/MIC
Concentration
MIC
TimegtMIC
Time
38
Aminoglycoside Pharmacodynamics Human Studies
Antibiotic Organism Outcome Parameter and Value
Gent, Tob, Amik GNR(63 E. coli, 27 Klebsiella) UTI, LRTI, bacteremia, SSI CmaxMICgt10
Gent, Tob, Amik GNR UTI, LRTI, URTI, SSI, Sepsis CmaxMICgt8
Gent, Tob GNR CmaxMICgt10
Moore,et al. J Inf Disease, 1987 155(1)
93-98 Deziel-Evans LM, et al. Clin Pharm 1986
5319-324 Nicolau DP, et al. Antimicrob Agents
Chemother 1995 39650-5
39
Methods for AG Dosing
40
Single Daily Dosing Aminoglycosides Efficacy
Bailey TC, et al. Clin Infect Dis 1997 24
786-95. Zaki M, Goetz MB. Clin Infect Dis 1997
24 796-809
41
Single Daily Dosing Aminoglycosides Toxicity
Bailey TC, et al. Clin Infect Dis 1997 24
786-95. Zaki M, Goetz MB. Clin Infect Dis 1997
24 796-809
42
Extended Interval Dosing of Aminoglycosides
  • Clin Infect Dis 2000 Mar30(3)433-9
  • National survey of extended-interval
    aminoglycoside dosing (EIAD).
  • Chuck SK, Raber SR, Rodvold KA, Areff D.
  • 500 acute care hospitals in the United States
  • EIAD adopted in 3 of every 4 acute care hospitals
  • 4-fold increase since 1993
  • written guidelines for EIAD in 64 of all
    hospitals
  • rationale
  • 87.1 equal or less toxicity,
  • 76.9 equal efficacy
  • 65.6 cost-savings
  • dose gt 5 mg/Kg
  • 47 used extended interval in case of decline in
    renal function (38 with Hartford nomogram)

43
Optimal Pharmacodynamic Indices
Drug Class TgtMIC AUC/MIC Peak/MIC
Cephalosporins 60 70
Penicillins 40 50
Carbapenems 30 40
Fluoroquinolones
Gram 30 - 50
Gram - 125
Aminoglycosides 10
Craig WA. Infect Dis Clin N Am 2003.
17479-501 Gunderson BW, et al. Pharmacotherapy
2001. 21 302S-318S
44
Conclusions
  • There are associations between antibiotic
    concentrations and microbiologic effects.
  • WHAT CONCENTRATION AM I GOING TO ACHIEVE WITH A
    GIVEN DOSE AND HOW DOES THIS CONCENTRATION RELATE
    TO THE CONCENTRATION NEEDED TO INHIBIT/KILL IN
    VITRO
  • These associations are dependent on the organisms
    and the antibiotic class.
  • GN vs GP
  • CEPHALOSPORINS/PENICILLINS/CARBAPENEMS
  • Investigations have led to new knowledge and
    application of these principles to optimizing
    antibiotic doses.
  • NEW DRUGS COMING TO MARKET
  • WHAT ABOUT OLDER DRUGS??
  • AMINOGLYCOSIDES
  • CONTINUOUS INFUSION B-LACTAMS
  • Organisms can be susceptible (by MIC) to an
    antibiotic that can not kill the organism.
  • P. AERUGINOSA
  • FLUOROQUINOLONES PIPERACILLIN/TAZOBACTAM
  • Additional studies evaluating the outcome of
    patients are needed to refine these principles.

45
Selection of Antimicrobial Therapy
I think your patient needs Imipenem 1gmq6h
46
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47
Impact of PD on Outcomes Examples of Drug-Bug
Combinations with Low ConcMIC Ratios
  • Staphylococcus sp. cephalosporins, FQ,
    vancomycin
  • Streptococcus sp. FQ, oral beta-lactams
  • Enterobacter sp. 3rd Generation cephalosporins
  • Pseudomonas sp. Beta-lactams, FQ,
    aminoglycosides
  • Acinetobacter sp. Beta-lactams, FQ

May be unlikely to achieve optimal PD targets
48
Mathematical Expression of Pharmacodynamic Indices
  • Dose t1/2 24
  • AUC24/MIC ----------- ------ -------
  • Vd MIC 0.693 DI
  • Dose t1/2 100
  • TgtMIC ln ----------- ------ -------
  • Vd MIC 0.693 DI

Dose (mg) DI Dosing Interval (q6h, DI6) t1/2
Half life of the Drug (hr) Vd Apparent Volume
of Distribution (Liters/kg) MIC Minimum
Inhibitory Concentration (mg/L)
49
Pharmacokinetic Changes in Critically Ill
Critically Ill Critically Ill Normal Patients Normal Patients
Vd (L/kg) T1/2 (hr) Vd (L/kg) T1/2 (hr)
0.31 2.5 Cefepime 0.22 2
0.31 1.5 P/T 0.14 0.75
0.4 1.5 Imipenem 0.16 1
0.27 2.5 Meropenem 0.17 1
2 3.3 Ciprofloxacin 1.3 3.3
50
Cefepime Pharmacokinetics in Critically Ill
Adults with Sepsis
  • 13 patients with CrClgt50
  • Received Cefepime 2gm x 1 dose
  • Vd
  • Mean 21.8 5.1 L
  • Range 16.2 L 31.4 L
  • t1/2
  • Mean 3 1.2 hours
  • Range 1.5 5.6 hrs

51
Monte Carlo Simulation Applied to
Pharmacokinetic-Pharmacodynamic Models
Random pharmacokinetics and MIC values from
data set
AUC
MIC
Calculate pharmacodynamic parameter
Plot results in a probability chart
AUCMIC
Dudley MN, Ambrose PG. Curr Opin Microbiol.
20003515-521.
52
Pharmacodynamics of Ciprofloxacin 400mg IV q8H
Against P. aeruginosa in Critically Ill Patients
CLSI BP 1 ug/ml 69 Susceptible
56 Ciprofloxacin Optimized
MIC Distributions adapted from Mystic
Surveillance Network, http//www.infectionacademy.
org/mystic.asp Ciprofloxacin PK adapted from
Lipman J, et al. Antimicrob Agents Chemother
1998 42(9) 2235-2239. Craig WA. Infect Dis Clin
N Am 2003. 17479-501
53
Pharmacodynamics of Cefepime 2gm q12h against P.
aeruginosa in Critically Ill Patients
CLSI BP 8 ug/ml 84 Susceptible
MIC Distributions adapted from Mystic
Surveillance Network, http//www.infectionacademy.
org/mystic.asp Cefepime PK adapted from Lipman,
et al. Antimicrob Agents Chemother 1999 43
2559-2561 Craig WA. Infect Dis Clin N Am 2003.
17479-501
54
Probability of 50 TgtMIC (Free) for
Piperacillin/Tazobactam
Lomaestro BM, Drusano GL. 41st Annual ICAAC
2002. Abstract A-2190
55
Optimizing b-lactam Antibiotics
Meropenem
Cefepime
Lomaestro BM, Drusano GL. Antimicrob Agents
Chemother 2005 49461-3. Mohr JF, et al. 41st
IDSA 2003. Abstract 34.
56
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57
In-vitro Pharmacodynamic Models
58
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59
Minimum-inhibitory concentrations (MICs) of P.
aeruginosa tested in an in-vitro Pharmacodynamic
Model
Organism Cefepime Meropenem Piperacillin/ Tazobactam
2 32 (H) gt32 (H) gt256 (H)
25 2 (L) 0.25 (L) 4 (L)
29 8 (M) 0.25 (L) 64 (M)
31 4 (L) 4 (M) 8 (L)
35 64 (H) 4 (M) gt256 (H)
40 4 (L) 0.5 (L) 32 (M)
53 2 (L) 16 (H) 32 (M)
62 0.5 (L) 0.5 (L) 1 (L)
68 8 (M) 1 (L) 4 (L)
H Resistant strains M Moderately
Susceptible strains L Susceptible strains
Mohr et al, Submitted ICAAC 2007
60
Effect of meropenem 1 gm q8h on P. aeruginosa
that are resistant (MPM-H), moderately
susceptible (MPM-M) and susceptible (MPM-L) in an
in-vitro pharmacodynamic model
Mohr et al, Submitted ICAAC 2007
61
Effect of cefepime 2 gm q12h on P. aeruginosa
that are resistant (CPM-H), moderately
susceptible (CPM-M) and susceptible (CPM-L) in an
in-vitro pharmacodynamic model of bacteremia.
62
Effect of piperacillin/tazobactam 4.5 gm q6h on
P. aeruginosa that are resistant (PT-H),
moderately susceptible (PT-M) and susceptible
(PT-L) in an in-vitro pharmacodynamic model of
bacteremia.
63
Pharmacokinetic Parameters
Peak (Cmax)
Concentration
Cmin
AUC (Area Under the Curve)
Time
64
AUIC
Peak/MIC
AUC/MIC
Cmax/MIC
MPC
TgtMIC
PAE
AUCgtMIC
PALE
PA-SME
65
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66
Pharmacodynamics
  • Describes the relationship between drug
    concentration and pharmacologic effect
  • PD is what the drug does in the body

67
Antimicrobial Therapy Appropriate vs. Adequate
  • Appropriate therapyantimicrobial treatment
    selected for efficacy based on
  • Presumptive identification of causative pathogen
  • Antimicrobial agents spectrum of activity
  • Local microbial resistance patterns
  • Adequate therapymicrobiological documentation of
    an infection that was being effectively treated
    at the time of its identification

Kollef MH. Clin Infect Dis. 200031S131S138.
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