antimicrobial pharmacodynamics: concepts for rational selection and dosing of antibiotics
TRANSCRIPT
Antimicrobial Antimicrobial Pharmacodynamics: Pharmacodynamics: Concepts for Rational Concepts for Rational Selection and Dosing of Selection and Dosing of AntibioticsAntibiotics
Effect of Adequate Antimicrobial Therapy Effect of Adequate Antimicrobial Therapy For Bloodstream Infections on MortalityFor Bloodstream Infections on Mortality
0
10
20
30
40
50
60
70
80
Ho
spit
al M
ort
alit
y, %
Adequate Inadequate
Initial Antimicrobial Treatment
Ibrahim E, et al. Chest 2000; 118: 146-155.
P<0.001
0 20 40 60 80 100
VRE
Candida spp.
ORSA
CNS
P. aeruginosa
Klebsiella spp.
Enterococcus spp.
E. Coli
OSSA
Path
og
en
s
Percent
Hospital Mortality
Inadequate Antimicrobial Therapy
OSSA=oxacillin-susceptible S. aureus; CNS=coagulase-negative staphylococci; VRE=vancomycin resistant enterococci
Ibrahim E, et al. Chest 2000; 118: 146-155.
Effect of Adequate Antimicrobial Therapy Effect of Adequate Antimicrobial Therapy For Bloodstream Infections on MortalityFor Bloodstream Infections on Mortality
What does “S” Mean?What does “S” Mean? Susceptible - Isolates are inhibited by the Susceptible - Isolates are inhibited by the
usually achievable concentrationsusually achievable concentrations of of antimicrobial agent when the recommended antimicrobial agent when the recommended dose is used for the site of infection.dose is used for the site of infection.
Intermediate – Implies clinical efficacy in the Intermediate – Implies clinical efficacy in the areas where drugs are areas where drugs are physiologically physiologically concentratedconcentrated or when higher than normal or when higher than normal dosages of drugs can be useddosages of drugs can be used
Resistant – Isolates are not inhibited by the Resistant – Isolates are not inhibited by the usually achievable concentrationsusually achievable concentrations of the of the agent with normal dosage schedulesagent with normal dosage schedules
CLSI. M-100-S16. January 2006
PharmacokineticsPharmacokinetics
• AbsorptionAbsorption• DistributionDistribution• MetabolismMetabolism• EliminationElimination
““PK is what the body does to the PK is what the body does to the drug”drug”
Pharmacodynamics Peak/MIC AUC/MIC Time > MIC
Eradication/Cure
PathogenSusceptibilityMIC/MBC
PharmacokineticsSerum/TissueConcentrationsHalf-Life
Pharmacodynamic Pharmacodynamic InteractionsInteractions
MIC
Con
cent
rati
on
Time
Peak/MIC
AUC/MIC
Time>MIC
Concentration Dependent vs. Concentration Dependent vs. Concentration Independent Concentration Independent Bacterial KillingBacterial Killing
2
3
4
5
6
7
8
9
0 2 4 6 8
Log
10 C
olon
y F
orm
ing
Un
its/
ml
0 2 4 6 8 0 2 4 6 8
Control
1/8 MIC
1/2 MIC
1 MIC
4 MIC
16 MIC
64 MIC
Time (hours)
Tobramycin Ciprofloxacin Ticarcillin
Craig WA, et al. Scand J Infect Dis, 1991; Suppl (74)
Optimizing Antimicrobial Optimizing Antimicrobial TherapyTherapy
Concentrationat Infection
SitePK
PathogenMIC/MBC
AntibioticPD
BacterialKilling
Outcome
Host Factors
Pharmacokinetic-Pharmacokinetic-Pharmacodynamic Indices Pharmacodynamic Indices Correlating with EfficacyCorrelating with EfficacyAntimicrobial Antimicrobial
AgentAgentBactericidaBactericidal Pattern of l Pattern of in-vitroin-vitro ActivityActivity
PK-PD PK-PD measure(s)measure(s)
AminoglycosidesAminoglycosides ConcentratioConcentrationn
AUCAUC0-240-24:MIC, :MIC, CCmaxmax:MIC:MIC
LactamsLactams
PenicillinsPenicillins TimeTime T>MICT>MIC
CephalosporinsCephalosporins
TimeTime T>MICT>MIC
CarbapenemsCarbapenems TimeTime T>MICT>MIC
MonobactamsMonobactams TimeTime T>MICT>MIC
Glycopeptides/ Glycopeptides/ LipopeptidesLipopeptides
DaptomycinDaptomycin ConcentratioConcentrationn
AUCAUC0-240-24:MIC, :MIC, CCmaxmax:MIC:MIC
OritavancinOritavancin ConcentratioConcentrationn
T>MICT>MIC
VancomycinVancomycin TimeTime AUCAUC0-240-24:MIC:MIC
FluoroquinoloneFluoroquinolone ConcentratioConcentrationn
AUCAUC0-240-24:MIC, :MIC, CCmaxmax:MIC:MIC
Antimicrobial Antimicrobial AgentAgent
Bactericidal Bactericidal Pattern of Pattern of in-in-vitrovitro Activity Activity
PK-PD PK-PD measure(s)measure(s)
MacrolidesMacrolides ConcentrationConcentration AUCAUC0-240-24:MIC, :MIC, Cmax:MICCmax:MIC
AzithromyciAzithromycinn
TimeTime AUCAUC0-240-24:MIC:MIC
ClarithromycinClarithromycin
TimeTime AUCAUC0-240-24:MIC:MIC
TelithromycinTelithromycin
ConcentrationConcentration AUCAUC0-240-24:MIC:MIC
MetronidazoleMetronidazole ConcentrationConcentration AUCAUC0-240-24:MIC, :MIC, CCmaxmax:MIC:MIC
TetracyclinesTetracyclines
DoxycyclineDoxycycline TimeTime AUCAUC0-240-24:MIC:MIC
TigacyclineTigacycline TimeTime AUCAUC0-240-24:MIC:MIC
ClindamycinClindamycin TimeTime AUCAUC0-240-24:MIC:MIC
OxazolidinonesOxazolidinones
LinezolidLinezolid TimeTime AUCAUC0-240-24:MIC:MIC
In-vitro Pharmacodynamic In-vitro Pharmacodynamic ModelsModels
Cyclophosphamide Organism107 CFU
Antimicrobial
2 hours
CFU determination
Bacteriostatic dose
Pharmacokinetic parameters
Vesga A, et al. 37th ICAAC. 1997..
Murine Thigh Infection Murine Thigh Infection Pharmacodynamic ModelPharmacodynamic Model
lactamslactams
Correlation of PK/PD Parameters Correlation of PK/PD Parameters With Effect of Cefotaxime Against With Effect of Cefotaxime Against K. K. pneumoniaepneumoniae in Lungs of Neutropenic in Lungs of Neutropenic MiceMice
5
6
7
8
9
10
1 10 100 1000 1 10 100 1000 0 25 50 75 100
CF
U/T
hig
h a
t 24
Hr
T>MICPeak/MIC 24-Hr AUC/MIC
Craig WA. Diagn Microbiol Infect Dis 1995: 22:89-96
Relationship Between Time Serum Relationship Between Time Serum Levels Exceed the MIC and Mortality Levels Exceed the MIC and Mortality for B-Lactams Against for B-Lactams Against S. S. pneumoniaepneumoniae
0
20
40
60
80
100
0 20 40 60 80 100
Time above MIC (%)
Mor
talit
y (%
)
Penicillins
Cephalosporins
Craig WA. Diagn Microbiol Infect Dis 1996:25:213-7
Craig WA. Diagn Microbiol Infect Dis 1996:25:213-7
Relation Between PD Parameters Relation Between PD Parameters and Efficacy for Ticarcillin and Efficacy for Ticarcillin against against P. aeruginosaP. aeruginosa
0
2
4
6
8
10
1 10 100 1000 1 10 100 1000 0 25 50 75 100
CF
U/T
hig
h a
t 24
Hr
T>MICPeak/MIC24-Hr AUC/MIC
Vogelman B., et al. J Infect Dis 1988. 158(4).
What %T>MIC is our target for What %T>MIC is our target for ββ-lactams?-lactams?
0
2
4
6
8
10
1 10 100 1000 1 10 100 1000 0 25 50 75 100
CF
U/T
hig
h a
t 24
Hr
T>MICPeak/MIC24-Hr AUC/MIC
Vogelman B., et al. J Infect Dis 1988. 158(4).
“Static” dose 1
log
2 log
3 log
-lactam Pharmacodynamics-lactam Pharmacodynamics
AntibioticAntibiotic Organism/Organism/ClassClass
Outcome Outcome Parameter and Parameter and
ValueValue
SourceSource
CefazolinCefazolin E. coli, E. coli, KlebsiellaKlebsiella
T>MICT>MIC IVPDMIVPDM
CeftriaxoneCeftriaxone S. pneumoniaeS. pneumoniae T>MIC=100%T>MIC=100% Rabbit meningitis Rabbit meningitis modelmodel
CefazolinCefazolin E. coliE. coli T>MIC, max effect T>MIC, max effect 4xMIC4xMIC
IVPDMIVPDM
CephalosporinsCephalosporins EnterobacteriacEnterobacteriacaeaeStreptococciStreptococciS. aureusS. aureus
T>MIC 60-70%T>MIC 60-70%T>MIC 60-70%T>MIC 60-70%T>MIC 40-50%T>MIC 40-50%
Animal data reviewAnimal data review
Cefazolin, Cefazolin, ticarcillin, ticarcillin, penicillinpenicillin
E. coliE. coliS. aureusS. aureusP. aeruginosaP. aeruginosaS. pneumoniaeS. pneumoniae
T>MIC 100%T>MIC 100%T>MIC 55%T>MIC 55%T>MIC 100%T>MIC 100%T>MIC 100%T>MIC 100%
Neutropenic murine Neutropenic murine thigh infection modelthigh infection model
CefmenoximeCefmenoxime Gram-negativeGram-negative T>DRCT>DRC Human, nosocomial Human, nosocomial pneumoniapneumonia Gunderson BW, et al. Pharmacotherapy. 2001 Nov;21(11 Pt 2):302S-318S
Concentration Time Concentration Time Profile: Antibiotic YProfile: Antibiotic Y
1
10
100
0 4 8 12 16 20 24
Time (hours)Ant
ibio
tic
Y C
once
ntra
tion
(ug
/ml)
MIC=2
%T>MIC >90% DI
Concentration Time Concentration Time Profile: Antibiotic Y Profile: Antibiotic Y
(q12h)(q12h)
1
10
100
0 4 8 12 16 20 24
Time (hours)Ant
ibio
tic
Y C
once
ntra
tion
(ug
/ml)
MIC=8
%T>MIC=50% DI
Concentration Time Concentration Time Profile: Antibiotic Y Profile: Antibiotic Y
(q8h)(q8h)
1
10
100
0 4 8 12 16 20 24
Time (hours)Ant
ibio
tic
Y C
once
ntra
tion
(ug
/ml)
MIC=8
%T>MIC>90% DI
Continuous Infusion Beta-Continuous Infusion Beta-lactamslactams
Beta
-lact
am
S
eru
m
Beta
-lact
am
S
eru
m
Con
cen
trati
on
sC
on
cen
trati
on
s Intermittent
Continuous
MIC
MIC
Time (h)
Cefamandole: Continuous Cefamandole: Continuous vs. Intermittent infusionvs. Intermittent infusion
0%
10%
20%
30%
40%
50%
60%
Cu
re R
ate
Cefamandole CI Cefamandole II
p=NSBodey, GP, et al. Am J Med 1979. 67.
Cure Rate of Infections in Cure Rate of Infections in Persistently Febrile Persistently Febrile Neutropenic PatientsNeutropenic Patients
0
10
20
30
40
50
60
70
Cu
re R
ate
Cefamandole CI Cefamandole II
p=0.03 Bodey, GP, et al. Am J Med 1979. 67.
FluoroquinolonesFluoroquinolones
Correlation of PK/PD Parameters With Correlation of PK/PD Parameters With Effect of Levofloxacin Against Effect of Levofloxacin Against S. S.
pneumoniaepneumoniae in Thighs of Neutropenic in Thighs of Neutropenic MiceMice
0
2
4
6
8
10
1 10 100 1000 1 10 100 1000 0 25 50 75 100
CF
U/T
hig
h a
t 24
Hr
T>MICPeak/MIC24-Hr AUC/MIC
Handbook of Experimental Pharmacology. Vol 127: Quinolone Antibacterials. 1998
Pharmacodynamic Pharmacodynamic InteractionsInteractions
MIC
Con
cent
rati
on
Time
Peak/MIC
AUC/MIC
Time>MIC
Relationship Between 24-Hour Relationship Between 24-Hour AUC/MIC and Mortality for AUC/MIC and Mortality for Fluoroquinolones AgainstFluoroquinolones Against S. pneumoniaeS. pneumoniae
0
20
40
60
80
100
% M
orta
lity
2.5 10 25 100 250
24-Hour AUC/MICCraig, WA 37th IDSA, 1999
Clin Infect Dis. (in press)
Relationship Between 24-Hour AUC/MIC Relationship Between 24-Hour AUC/MIC and Mortality for Fluoroquinolones Against and Mortality for Fluoroquinolones Against Gram-Negative Bacilli in a Murine ModelGram-Negative Bacilli in a Murine Model
0
20
40
60
80
100
% M
orta
lity
2.5 10 25 100 250
24-Hour AUC/MICCraig, WA 37th IDSA, 1999
Clin Infect Dis. (in press)
Relationship Between AUCRelationship Between AUC2424/MIC and /MIC and Efficacy of Ciprofloxacin in Patients Efficacy of Ciprofloxacin in Patients with Serious Bacterial Infectionswith Serious Bacterial Infections
0
20
40
60
80
100
% E
ffic
acy
0-62.5 62.5-125 125-250 250-500 >500
24-Hour AUC/MIC
Clinical Microbiologic
Forrest A, et al. AAC, 1993; 37: 1073-1081
Fluoroquinolone Fluoroquinolone Pharmacodynamics: Pharmacodynamics: S. S. pneumoniaepneumoniae
AntibioticAntibioticOutcome Outcome
Parameter and Parameter and ValueValue
SourceSource
Levoflooxacin, ciprofloxacin, Levoflooxacin, ciprofloxacin, trovafloxacintrovafloxacin
AUC:MIC > 35AUC:MIC > 35 IVPDMIVPDM
Ciprofloxacin, levofloxacinCiprofloxacin, levofloxacin AUC:MIC 30-35AUC:MIC 30-35 IVPDMIVPDM
Ciprofloxacin, ofloxacin, trovafloxacinCiprofloxacin, ofloxacin, trovafloxacin AUC:MIC 44-49AUC:MIC 44-49 IVPDMIVPDM
Ciprofloxacin, levovfloxacinCiprofloxacin, levovfloxacin AUC:MIC 32-64AUC:MIC 32-64 IVPDMIVPDM
QuinolonesQuinolones AUC:MIC > 40AUC:MIC > 40 IVPDMIVPDM
SitafloxacinSitafloxacin AUC:MIC = 37AUC:MIC = 37 Murine thigh and Murine thigh and lung infection lung infection modelmodel
GatifloxacinGatifloxacin AUC:MIC = 52AUC:MIC = 52 Murine thigh and Murine thigh and lung infection lung infection modelmodel
GemifloxacinGemifloxacin AUC:MIC = 35AUC:MIC = 35 Murine thigh and Murine thigh and lung infection lung infection modelmodel Gunderson BW, et al. Pharmacotherapy. 2001 Nov;21(11 Pt 2):302S-318S
Fluoroquinolone Fluoroquinolone Pharmacodynamics: Gram Pharmacodynamics: Gram Negative BacilliNegative Bacilli
AntibioticAntibiotic Organism/ClassOrganism/ClassOutcome Outcome
Parameter and Parameter and ValueValue
SourceSource
EnoxacinEnoxacin P. aeruginosa, E. P. aeruginosa, E. colicoli
Cmax:MIC>8Cmax:MIC>8 IVPDMIVPDM
CiprofloxacinCiprofloxacin P. aeruginosaP. aeruginosa Cmax:MIC>8Cmax:MIC>8 IVPDMIVPDM
Ciprofloxacin, Ciprofloxacin, ofloxacinofloxacin
P. aeruginosaP. aeruginosa AUC:MIC>100AUC:MIC>100 IVPDMIVPDM
LomefloxacinLomefloxacin P. aeruginosaP. aeruginosa Cmax:MIC>10Cmax:MIC>10 Neutropenic rat Neutropenic rat sepsis modelsepsis model
GatifloxacinGatifloxacin EnterobacteriacaeEnterobacteriacae AUC:MIC=48AUC:MIC=48 Murine thigh and Murine thigh and lung infection lung infection modelmodel
SitafloxacinSitafloxacin EnterobacteriacaeEnterobacteriacae AUC:MIC=43AUC:MIC=43 Murine thigh and Murine thigh and lung infection lung infection modelmodel
CiprofloxacinCiprofloxacin GNR, mostly LRTIGNR, mostly LRTI AUC:MIC>125AUC:MIC>125 Human, Human, retrospectiveretrospective
CiprofloxacinCiprofloxacin GNR, vent GNR, vent dependentdependent
AUC:MIC>100AUC:MIC>100 Human, Human, retrospectiveretrospective
Gunderson BW, et al. Pharmacotherapy. 2001 Nov;21(11 Pt 2):302S-318S
AminoglycosidesAminoglycosides
Max Peak/MIC Ratio and Clinical Max Peak/MIC Ratio and Clinical Response with AminoglycosidesResponse with Aminoglycosides
Moore,et al. J Inf Disease, 1987; 155(1): 93-98
50
60
70
80
90
100
2 4 6 8 10 12+
Maximum Peak / MIC ratio
Resp
onse
Rate
(%
)
Pharmacodynamic Pharmacodynamic InteractionsInteractions
MIC
Con
cent
rati
on
Time
Peak/MIC
AUC/MIC
Time>MIC
Aminoglycoside Pharmacodynamics: Aminoglycoside Pharmacodynamics: Human StudiesHuman Studies
AntibioticAntibiotic OrganismOrganismOutcome Outcome
Parameter and Parameter and ValueValue
Gent, Tob, Gent, Tob, AmikAmik
GNR(63% E. coli, GNR(63% E. coli, 27% Klebsiella); UTI, 27% Klebsiella); UTI, LRTI, bacteremia, LRTI, bacteremia, SSISSI
Cmax:MICCmax:MIC>>1010
Gent, Tob, Gent, Tob, AmikAmik
GNR; UTI, LRTI, GNR; UTI, LRTI, URTI, SSI, SepsisURTI, SSI, Sepsis
Cmax:MIC>8Cmax:MIC>8
Gent, TobGent, Tob GNRGNR Cmax:MIC>10Cmax:MIC>10
Moore,et al. J Inf Disease, 1987; 155(1): 93-98Deziel-Evans LM, et al. Clin Pharm 1986; 5:319-324Nicolau DP, et al. Antimicrob Agents Chemother 1995; 39:650-5
0
5
10
15
20
25
1 2 3 4 5 6 7 8 9 10 12 14 16 17 18 20 22 24
Time
Seru
m C
once
ntrat
ion (m
g/L)
Extended Interval Dosing Traditional Dosing
Methods for AG Methods for AG DosingDosing
Single Daily Dosing Single Daily Dosing Aminoglycosides: EfficacyAminoglycosides: Efficacy
Bailey TC, et al. Clin Infect Dis 1997; 24: 786-95.
Zaki M, Goetz MB. Clin Infect Dis 1997; 24: 796-809
Single Daily Dosing Single Daily Dosing Aminoglycosides: ToxicityAminoglycosides: Toxicity
Bailey TC, et al. Clin Infect Dis 1997; 24: 786-95.
Zaki M, Goetz MB. Clin Infect Dis 1997; 24: 796-809
Extended Interval Dosing of Extended Interval Dosing of AminoglycosidesAminoglycosides
Clin Infect Dis 2000 Mar;30(3):433-9Clin Infect Dis 2000 Mar;30(3):433-9
National survey of extended-interval aminoglycoside dosing (EIAD).National survey of extended-interval aminoglycoside dosing (EIAD).
Chuck SK, Raber SR, Rodvold KA, Areff D.Chuck SK, Raber SR, Rodvold KA, Areff D.
500 acute care hospitals in the United States500 acute care hospitals in the United States EIAD adopted in 3 of every 4 acute care hospitalsEIAD adopted in 3 of every 4 acute care hospitals
4-fold increase since 19934-fold increase since 1993 written guidelines for EIAD in 64% of all hospitalswritten guidelines for EIAD in 64% of all hospitals
rationalerationale 87.1% : equal or less toxicity,87.1% : equal or less toxicity, 76.9% : equal efficacy76.9% : equal efficacy 65.6% :cost-savings65.6% :cost-savings
dose: > 5 mg/Kgdose: > 5 mg/Kg 47% used extended interval in case of decline in renal function (38% 47% used extended interval in case of decline in renal function (38%
with Hartford nomogram)with Hartford nomogram)
Optimal Pharmacodynamic Optimal Pharmacodynamic IndicesIndices
Drug Class % T>MIC 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. 17:479-501Gunderson BW, et al. Pharmacotherapy 2001. 21: 302S-318S
ConclusionsConclusions There are associations between antibiotic concentrations and There are associations between antibiotic concentrations and
microbiologic effects.microbiologic effects. ““WHAT CONCENTRATION AM I GOING TO ACHIEVE WITH A WHAT CONCENTRATION AM I GOING TO ACHIEVE WITH A
GIVEN DOSE AND HOW DOES THIS CONCENTRATION RELATE GIVEN DOSE AND HOW DOES THIS CONCENTRATION RELATE TO THE CONCENTRATION NEEDED TO INHIBIT/KILL IN VITRO”TO THE CONCENTRATION NEEDED TO INHIBIT/KILL IN VITRO”
These associations are dependent on the organisms and the These associations are dependent on the organisms and the antibiotic class.antibiotic class. GN vs GPGN vs GP CEPHALOSPORINS/PENICILLINS/CARBAPENEMSCEPHALOSPORINS/PENICILLINS/CARBAPENEMS
Investigations have led to new knowledge and application of Investigations have led to new knowledge and application of these principles to optimizing antibiotic doses.these principles to optimizing antibiotic doses. NEW DRUGS COMING TO MARKETNEW DRUGS COMING TO MARKET WHAT ABOUT OLDER DRUGS??WHAT ABOUT OLDER DRUGS??
AMINOGLYCOSIDESAMINOGLYCOSIDES CONTINUOUS INFUSION B-LACTAMSCONTINUOUS INFUSION B-LACTAMS
Organisms can be susceptible (by MIC) to an antibiotic that Organisms can be susceptible (by MIC) to an antibiotic that can not kill the organism. can not kill the organism. P. AERUGINOSAP. AERUGINOSA FLUOROQUINOLONES & PIPERACILLIN/TAZOBACTAMFLUOROQUINOLONES & PIPERACILLIN/TAZOBACTAM
Additional studies evaluating the outcome of patients are Additional studies evaluating the outcome of patients are needed to refine these principles.needed to refine these principles.
Selection of Antimicrobial Selection of Antimicrobial TherapyTherapy
I think your patient needs Imipenem 1gmq6h
Impact of PD on Outcomes Impact of PD on Outcomes Examples of Drug-Bug Combinations Examples of Drug-Bug Combinations
with Low Conc:MIC Ratioswith Low Conc:MIC Ratios Staphylococcus spStaphylococcus sp. . cephalosporins, FQ, cephalosporins, FQ,
vancomycinvancomycin
Streptococcus spStreptococcus sp. . FQ, oral beta-lactamsFQ, oral beta-lactams
Enterobacter sp.Enterobacter sp. 33rdrd Generation Generation cephalosporinscephalosporins
Pseudomonas sp.Pseudomonas sp. Beta-lactams, FQ, Beta-lactams, FQ,
aminoglycosidesaminoglycosides
Acinetobacter sp.Acinetobacter sp. Beta-lactams, FQBeta-lactams, FQ
* May be unlikely to achieve optimal PD targets* May be unlikely to achieve optimal PD targets
Mathematical Expression of Mathematical Expression of Pharmacodynamic IndicesPharmacodynamic Indices
Dose tDose t1/21/2 100100
%T>MIC = ln ----------- * ------ * %T>MIC = ln ----------- * ------ * --------------
VVdd * MIC 0.693 * MIC 0.693 DI DI
Dose tDose t1/21/2 2424
AUCAUC2424/MIC = ----------- * ------ * /MIC = ----------- * ------ * --------------
VVdd * MIC 0.693 * MIC 0.693 DI DI
Dose (mg)
DI = Dosing Interval (q6h, DI=6)
t1/2 = Half life of the Drug (hr)
Vd = Apparent Volume of Distribution (Liters/kg)
MIC = Minimum Inhibitory Concentration (mg/L)
Pharmacokinetic Pharmacokinetic Changes in Critically IllChanges in Critically IllCritically IllCritically Ill Normal Normal
PatientsPatientsVd Vd
(L/kg)(L/kg)T1/2 T1/2
(hr)(hr)Vd Vd
(L/kg)(L/kg)T1/2 T1/2
(hr)(hr)
0.310.31 2.52.5 CefepimeCefepime 0.220.22 22
0.310.31 1.51.5 P/TP/T 0.140.14 0.750.75
0.40.4 1.51.5 ImipenemImipenem 0.160.16 11
0.270.27 2.52.5 MeropenemMeropenem 0.170.17 11
22 3.33.3 CiprofloxacinCiprofloxacin 1.31.3 3.33.3
Cefepime Pharmacokinetics Cefepime Pharmacokinetics in Critically Ill Adults with in Critically Ill Adults with
SepsisSepsis 13 patients with 13 patients with CrCl>50CrCl>50
Received Cefepime Received Cefepime 2gm x 1 dose2gm x 1 dose
VVdd
Mean: 21.8 Mean: 21.8 ++ 5.1 L 5.1 L Range: 16.2 L – 31.4 LRange: 16.2 L – 31.4 L
tt1/21/2
Mean: 3 Mean: 3 ++ 1.2 hours 1.2 hours Range: 1.5 – 5.6 hrsRange: 1.5 – 5.6 hrs
Dudley MN, Ambrose PG. Curr Opin Microbiol. 2000;3:515-521.
Random pharmacokinetics and MIC values
from data set
Plot results in a probability chart
Calculate pharmacodynamic
parameter
AUC MIC
AUC:MIC
Monte Carlo Simulation: Applied to Monte Carlo Simulation: Applied to Pharmacokinetic-Pharmacodynamic Pharmacokinetic-Pharmacodynamic
ModelsModels
Pharmacodynamics of Ciprofloxacin 400mg IV Pharmacodynamics of Ciprofloxacin 400mg IV q8H Against q8H Against P. aeruginosa P. aeruginosa in Critically Ill in Critically Ill
PatientsPatients
0
5
10
15
20
25
0.008 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 64 128 256
MIC
MIC
Fre
qu
ency
(%
)
0
10
20
30
40
50
60
70
80
90
100
Pro
bab
ilit
y o
f A
chie
vin
g D
ynam
ic T
arg
et
MIC Distribution AUC/MIC > 125 By MIC AUC/MIC > 125 Cumulative
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. 17:479-501
Pharmacodynamics of Cefepime 2gm q12h Pharmacodynamics of Cefepime 2gm q12h against against P. aeruginosa P. aeruginosa in Critically Ill in Critically Ill
PatientsPatients
0
5
10
15
20
25
30
35
0.12 0.25 0.5 1 2 4 8 16 32 64 128 256
MIC
MIC
Fre
qu
ency
(%
)
0
10
20
30
40
50
60
70
80
90
100
Pro
bab
ilit
y o
f A
chie
vin
g D
ynam
ic T
arg
et
MIC Distribution T>MIC 70% DI T>MIC 50% DIMIC 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. 17:479-501
CLSI BP = 8 ug/ml84% Susceptible
Probability of 50% T>MIC Probability of 50% T>MIC (Free) for (Free) for
Piperacillin/TazobactamPiperacillin/Tazobactam
0
20
40
60
80
100
0.25 0.5 1 2 4 8 16 32 64
MIC
Pro
babi
lity
of T
arge
t Attai
nmen
t
3.375 Gm Q6h 3.375 Gm Q4h
Lomaestro BM, Drusano GL. 41st Annual ICAAC 2002. Abstract A-2190
Optimizing Optimizing -lactam -lactam AntibioticsAntibiotics
0
20
40
60
80
100
0.25 0.5 1 2 4
MIC
Pro
babi
lity
T>M
IC 4
0% (free
dru
g)
1 Gm q8h (0.5 hr inf.)0.5 Gm q6h (0.5 hr inf.)1 Gm q8h (3 hr inf.)
0102030405060708090
100
0.25 0.5 1 2 4 8
MIC
Pro
babi
lity
T>M
IC 7
0% (free
dru
g)2 Gm q12h (0.5 hr inf.)1 Gm q6h (0.5 hr inf)4 Gm CI over 24 hours
Meropenem
Cefepime
Lomaestro BM, Drusano GL. Antimicrob Agents Chemother 2005; 49:461-3.
Mohr JF, et al. 41st IDSA 2003. Abstract# 34.
In-vitro Pharmacodynamic In-vitro Pharmacodynamic ModelsModels
Minimum-inhibitory Minimum-inhibitory concentrations (MICs) of concentrations (MICs) of P. P. aeruginosaaeruginosa tested in an tested in an in-in-
vitrovitro Pharmacodynamic Pharmacodynamic ModelModel
Organism Organism ## CefepimeCefepime MeropenemMeropenem
Piperacillin/ Piperacillin/ TazobactamTazobactam
22 32 (H)32 (H) >32 (H)>32 (H) >256 (H)>256 (H)
2525 2 (L)2 (L) 0.25 (L)0.25 (L) 4 (L)4 (L)
2929 8 (M)8 (M) 0.25 (L)0.25 (L) 64 (M)64 (M)
3131 4 (L)4 (L) 4 (M)4 (M) 8 (L)8 (L)
3535 64 (H)64 (H) 4 (M)4 (M) >256 (H)>256 (H)
4040 4 (L)4 (L) 0.5 (L)0.5 (L) 32 (M)32 (M)
5353 2 (L)2 (L) 16 (H)16 (H) 32 (M)32 (M)
6262 0.5 (L)0.5 (L) 0.5 (L)0.5 (L) 1 (L)1 (L)
6868 8 (M)8 (M) 1 (L)1 (L) 4 (L)4 (L)
H = “Resistant” strainsM = “Moderately Susceptible” strainsL = “Susceptible” strains
Mohr et al, Submitted ICAAC 2007
Effect of meropenem 1 gm q8h on Effect of meropenem 1 gm q8h on P. aeruginosaP. aeruginosa that that are resistant (MPM-H), moderately susceptible (MPM-are resistant (MPM-H), moderately susceptible (MPM-
M) and susceptible (MPM-L) in an M) and susceptible (MPM-L) in an in-vitroin-vitro pharmacodynamic model pharmacodynamic model
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Mohr et al, Submitted ICAAC 2007
Effect of cefepime 2 gm q12h on Effect of cefepime 2 gm q12h on P. aeruginosaP. aeruginosa that are that are resistant (CPM-H), moderately susceptible (CPM-M) resistant (CPM-H), moderately susceptible (CPM-M)
and susceptible (CPM-L) in an and susceptible (CPM-L) in an in-vitroin-vitro pharmacodynamic model of bacteremia. pharmacodynamic model of bacteremia.
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Effect of piperacillin/tazobactam 4.5 gm q6h on Effect of piperacillin/tazobactam 4.5 gm q6h on P. P. aeruginosaaeruginosa that are resistant (PT-H), moderately that are resistant (PT-H), moderately
susceptible (PT-M) and susceptible (PT-L) in an susceptible (PT-M) and susceptible (PT-L) in an in-vitroin-vitro pharmacodynamic model of bacteremia. pharmacodynamic model of bacteremia.
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Pharmacokinetic Pharmacokinetic ParametersParameters
Con
cent
rati
on
Time
Peak (Cmax)
AUC(Area Under the Curve)
Cmin
PharmacodynamicsPharmacodynamics• Describes the relationship between Describes the relationship between
drug concentration and drug concentration and pharmacologic effectpharmacologic effect
““PD is what the drug does in the PD is what the drug does in the body”body”
Antimicrobial Therapy: Antimicrobial Therapy: Appropriate vs. AdequateAppropriate vs. Adequate
Appropriate therapyAppropriate therapy—antimicrobial —antimicrobial treatment selected for efficacy based on:treatment selected for efficacy based on: Presumptive identification of causative pathogenPresumptive identification of causative pathogen Antimicrobial agent’s spectrum of activityAntimicrobial agent’s spectrum of activity Local microbial resistance patternsLocal microbial resistance patterns
Adequate therapyAdequate therapy—microbiological —microbiological documentation of an infection that was documentation of an infection that was being effectively treated at the time of its being effectively treated at the time of its identificationidentification
Kollef MH. Clin Infect Dis. 2000;31:S131–S138.