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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MPM-H MPM-M MPM-L

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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CPM-H CPM-M CPM-L

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.