PK/PD Dosing in Critical Care

Jim Fenner Pharm D BCPS

Conflicts of Interest

• None to report• No relevant financial relationships

Learning Objectives

1. To define PKPD effect on in-vitro susceptibility Reporting

2. To identify the 3 important PKPD targets

3. To demonstrate how PKPD principles and targets effect antibiotic dosing

4. To justify the rational for extended infusion of beta-lactam antibiotics

Antimicrobial Treatment Considerations in ICU

1. Must be timely: delay in initiation potentially lethal

2. Appropriate: must cover the offending pathogen(s)

3. Administered at adequate dose and intervals consistent with pK/pD parameters

4. Timely streamlining based on clinical response and microbiological data

5. Prompt discontinuation when practicalDeresinski S. Clin Infect Dis 2007; 45:S177-S183Allerberger F et al. Clin Microbiol Infect 2008; 14: 197-199.

PHARMACOKINETIC CHANGES IN CRITICAL ILLNESS

PK Changes in Critically llL

• Heterogeneous Population • Both Drug and Disease Factors Alter PK

– Hydrophilic– Lipophilic

• Standard Dosing Regimens (no ICU pts)• Individualized Dosing Strategies likely

necessary to optimize

* Smaller Vd* Likely Renal Eliminated Unchanged* Increased Cl In Sepsis

Hydrophilic agents Beta-lactams

Amino-GlycosidesGlycopeptides

Lipophilic agents

Larger VdLikely Hepatic Elimination Metabolized

FluoroquinolonesMacrolidesRifampinLinezolid

PK Changes inCritically ill

Critical illness PK Changes

• Aminoglycosides– ↑ ↑ Vd, Cl ↑or↓

• Quinolones– Minimal ↑ Vd

• Glycopeptides– ↑ ↑ Vd, Cl ↑or↓ (variable hepatic Cl)

• Beta-Lactams– ↑ ↑ Vd, Cl ↑or↓

Optimizing Antimicrobial Therapy

Concentrationat Infection

SitePK

PathogenMIC/MBC

AntibioticPD

BacterialKilling

Outcome

Host Factors

SUSCEPTIBILITY TESTING AND BREAKPOINTS

J Infect Dis 1987;155:93-99 & Antimicrob Agents Chemother 1991;35:399-405.

Relationship: MIC vs MBC vs Breakpoint

MIC

Con

cent

ratio

n (m

g/L

)

Time (h)

MBC

Cp.max

Breakpoint

AST and PKPD

• Relationships of S to I to R, more predictable with the application of PKPD

• Recently, breakpoints have changed largely due to bacterial resistance, micro diagnostics, and PKPD

• CLSI sets BP’s, recognized by FDA but FDA still sets its own BP. Can be modified by CLSI after 2 years.

• Labreche MJ, Recent Updates on the Role of PK-PD in AST. RID June 2013

Impact of PKPD on BP

• Vancomycin – PK/PD target is AUC/MIC => 400

• Leading to higher trough’s• MRSA MIC of 0.5 or 1 trough of 15

achieves target => 400, MIC 2.0 does not• CLSI 2006 lowered BP to 2 or less due to

hMRSA, MIC creep

• Labreche MJ, Recent Updates on the Role of PK-PD in AST. RID June 2013

Impact of PKPD on BP• CLSI 2008 BP change for Strep

pneumonia– Meningitis <= 0.06– Non-meningitis <= 2.0

• CLSI 2010 Enterobacteriaceae– Cefazolin BP lowered from 8 to 1– 2011 increased BP up to 2.0 – Based on dose of 2g q8h

• Labreche MJ, Recent Updates on the Role of PK-PD in AST. RID June 2013

Impact of PKPD on BP

• CLSI 2014– Urine susceptibility BP for oral ceph’s <= 16

for UNCOMPLICATED UTI• CLSI concerns over rising ceph mic’s to

KEP bacteria – could harbor ESBL’s– Lowered BP’s to KEP, eliminated ESBL

phenotypic testing (ceftaz/clav disk)

• Labreche MJ, Recent Updates on the Role of PK-PD in AST. RID June 2013

Impact of PKPD on BP

• Cefepime and Susceptible Dose-dependent (SDD)– Clinical data higher cefepime MIC = worse

outcomes despite “susceptible”– 2014 CLSI lowered BP to <= 2.0, > = 8.0 as

resistant and 4 to 8 as SDD based in part on Time > MIC estimations

• Labreche MJ, Recent Updates on the Role of PK-PD in AST. RID June 2013

FDA BP for Susceptible

CLSI BP for Susceptible

CLSI BP for SDD Dose for CLSI BP

For Enterobacteracae      Cefazolin ≤ 8 ≤ 2   2g q8hCeftriaxone ≤ 8 ≤ 1    

Cefepime ≤ 8 ≤ 24 1g q8 or 2g q12h8 2g q8h

Aztreonam ≤ 8 ≤ 1    Ertapenem ≤ 2 ≤ 0.25    Imipenem ≤ 4 ≤ 1.0    Meropenem ≤ 4 ≤ 1.0    Doripenem FDA = 0.5 ≤ 1.0    Pip-Tazo ≤ 32 ≤ 16    For Pseudomonas      Meropenem ≤ 4 ≤ 2    Doripenem ≤ 2 ≤ 2    Imipenem ≤ 4 ≤ 2    Pip-Tazo ≤ 64 ≤ 16    Cefepime ≤ 8 ≤ 8    

PK-PD TARGETSWHAT DOES IT MEAN?

How to Pick an Antibiotic ?

• You Want the Most “Potent” Abx• So You Line Them up & Pick the Lowest

MIC - No!• You Can Not Just Compare the MIC’s

– Differing Intrinsic Activity = Different MIC’s– Antibiotics tested at different MIC ranges– Abx have Very Different Serum Blood

Concentrations

Antibiotic “Potency” - Concentration Dependent

• Cp A 1 mcg/ml = Ratio = 10

MIC 0.1mcg/ml• Cp B 10 mcg/ml = Ratio =

10

MIC 1 mcg/ml• Cp C 100 mcg/ml = Ratio = 10

MIC 10 mcg/ml

Pharmacodynamics

Clin Inf Dis 1998;26:1-12Crit Care Clin 2011;27:1-18Crit Care Clin 2011;27:19-34Crit Care Med 2009;37:840-51

PD Parameters Predictive of Outcome

Drusano & Craig. J Chemother 1997;9:38–44Drusano et al. Clin Microbiol Infect 1998;4 (Suppl. 2):S27–S41

Vesga et al. 37th ICAAC 1997

Parameter correlatingwith efficacy T>MICAUC:MICCmax:MICExamples Carbapenems

CephalosporinsMacrolidesPenicillinsLinezolid

AzithromycinFluoroquinolonesKetolidesVancomycinDaptomycin

AminoglycosidesFluoroquinolonesDaptomycinKetolides

Organism kill Time-dependentConcentration-dependent

Concentration-dependent

Therapeuticgoal

Maximize durationof exposure

Maximizeexposure

Maximize drugconcentration

ANTIBIOTIC “POTENCY”CONSIDER DRUG LEVELS, BACTERICIDAL CHARACTERISTICS, AND BACTERIAL SUSCEPTIBILITY

Aminoglycosides

MIC

Time

C-p

Aminoglycosides

• Concentration Dependent Killing• Significant Post Antibiotic Effect• “Optimal” Peak:mic Ratio 8-10:1• Higher Peak = Greater Bactericidal

effect• Clinical Data supports Improved

Outcome with Higher Peak

Aminoglycosides in Critical Illness

• Increased Vd• Reduced Cmax• Optimized PK/PD Dosing Strategy Uses

7mg/kg large daily dosing– Maximize Cmax/MIC ratio– Reduced Toxicity

• Recommend Individualized Dose Monitoring – with Interval Extension

Conventional (three-times daily regimen)

Nicolau DP et al. Antimicrob Agents Chemother. 1995;39:650–655

Once-daily vs. Conventional Three-times Daily Aminoglycoside Regimens

Once-daily vs. Conventional Three-times Daily Aminoglycoside Regimens

Concentration (mg/L)

00

88

1414

44

66

1010

1212

Time (hours)00 1212 2424202044 88 1616

Once-daily regimenOnce-daily regimen

22MIC

Cmax:MIC modelFor optimal response,

Peak concentration: MIC ratio should be between 8-12 to 1

Gentamicin monitoring 1

Hartford Nomogram

7 mg/Kg OD

•Precise Times of collection required

•Collection 6-12Hrs after dose

Aminoglycosides —Relationship Between Cmax:MIC Ratio and Clinical Response

55

6570

8389 92

0

10

20

30

40

50

60

70

80

90

100

2 4 6 8 10 12+

Cmax:MIC

Clinical response

(%)

Moore RD et al. J Infect Dis. 1987;155:93-99.

Extended Interval Dosing of Aminoglycosides

Clin Infect Dis 2000 Mar;30(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: > 5 mg/Kg 47% used extended interval in case of decline in renal function (38%

with Hartford nomogram)

MIC

Time

C-p

AUC

Fluoroquinolones

Quinolones

• MOA: Interfere with DNA Replication• Rate of kill increases with concentration• AUC/MIC ratio >= 125 drives effect• PK/PD analyses suggest that ciprofloxacin and

levofloxacin MICs should be ≤0.125-0.25 and ≤0.25-0.5, respectively, for isolates to be considered susceptible

• PTA cipro 400 q8h less than 90% for MIC 0.5, over 90% for 0.25

•(DeRyke, et al. 2007; Frei, et al. 2008).

Relationship Between AUC24/MIC and Efficacy of Ciprofloxacin in Patients with 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 Pharmacodynamics: S. pneumoniae

Antibiotic Outcome Parameter and Value Source

Levofloxacin, ciprofloxacin, trovafloxacin AUC:MIC > 35 IVPDM

Ciprofloxacin, levofloxacin AUC:MIC 30-35 IVPDM

Ciprofloxacin, ofloxacin, trovafloxacin AUC:MIC 44-49 IVPDM

Ciprofloxacin, levovfloxacin AUC:MIC 32-64 IVPDM

Quinolones AUC:MIC > 40 IVPDM

Sitafloxacin AUC:MIC = 37 Murine thigh and lung infection model

Gatifloxacin AUC:MIC = 52 Murine thigh and lung infection model

Gemifloxacin AUC:MIC = 35 Murine thigh and lung infection model

Gunderson BW, et al. Pharmacotherapy. 2001 Nov;21(11 Pt 2):302S-318S

Fluoroquinolone Pharmacodynamics: Gram Negative Bacilli

Antibiotic Organism/Class Outcome Parameter and Value Source

Enoxacin P. aeruginosa, E. coli Cmax:MIC>8 IVPDM

Ciprofloxacin P. aeruginosa Cmax:MIC>8 IVPDM

Ciprofloxacin, ofloxacin

P. aeruginosa AUC:MIC>100 IVPDM

Lomefloxacin P. aeruginosa Cmax:MIC>10 Neutropenic rat sepsis model

Gatifloxacin Enterobacteriacae AUC:MIC=48 Murine thigh and lung infection model

Sitafloxacin Enterobacteriacae AUC:MIC=43 Murine thigh and lung infection model

Ciprofloxacin GNR, mostly LRTI AUC:MIC>125 Human, retrospective

Ciprofloxacin GNR, vent dependent AUC:MIC>100 Human, retrospective

Gunderson BW, et al. Pharmacotherapy. 2001 Nov;21(11 Pt 2):302S-318S

MIC

Time

C-p

AUC

Glycopeptides

Vancomycin

• Time Dependent v Concentration Dependent

• PD Target: AUC/MIC Ratio > 400 to optimize MRSA eradication

• Monte Carlo Simulations:– Trough 15 – 20 mg/l and MIC ≤1.0 to

achieve ratio >400– Not achievable for MIC > 1.0

Vancomycin

• May be associated with higher failure rates with MRSA bacteremia or pneumonia or if hVISA

• Brown et al found 4x higher failure for ratio < 211 (complicated MRSA bacteremia and IE)

• Park et al found no outcome effect of MIC >1 or ≤ 1

• Brown J et al. AAC 2012• Park S et al AAC 2013

MIC

Time

Beta LactamsPenicillins, Cephalosporins, Carbapenems, Monobactams

Beta-Lactam Agents

• MOA: acylation of PBP• Reaction occurs over time

– Slow, continuous kill characteristics– Shorter than the dosing interval– Maximal Kill 4-5x MIC

• PD Target – Time above MIC:– Penicillin 50% T > MIC– Cephs 60-70% T > MIC– Carbs 40% T > MIC

Beta-lactams in Critical Care• Increased Vd – lower serum levels• MOA: acylation of PBP• Reaction occurs over time

– Slow, continuous kill characteristics– Shorter than the dosing interval– Maximal Kill 4-5x MIC

• Data support better outcomes extended/continuous • Advances in mathematical modeling allow clinicians to

apply antimicrobial pharmacodynamics in practice.2-4

1Craig WA. Clin Infect Dis. Jan 1998;26(1):1-10; quiz 11-12. 2Drusano GL. Nat Rev Microbiol. Apr 2004;2(4):289-300. 3Ambrose PG et al. Clin Infect Dis. Jan 1 2007;44(1):79-86. 4Lodise TP et al. Pharmacotherapy. Sep 2006;26(9):1320-1332.

PROBABILITY OF TARGET ATTAINMENT (PTA)

Beta-Lactam Agents

• PD Target – Time above MIC:– Penicillin 50% T > MIC– Cephs 60-70% T > MIC– Carbs 40% T > MIC

Prolonged Infusion – B lactams

• Conventional Infusion: 30-60 min• Prolonged Infusion: 3-4 hr:

– Lower peak concentrations– Drug concentration remain in excess of MIC

longer– Results in a more favorable PTA– Can also be achieved with more frequent

dosing– Can address higher MIC values

Time Above MIC Antibiotic Y (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

Time Above MIC Antibiotic Y (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

Monte Carlo Simulations

COMPUTER MODELING AND MONTE CARLO SIMULATION

• computer-based mathematical construct • integrate different variables:

– tissue concentrations of an antibiotic– antimicrobial susceptibility – the PK-PD measure associated with efficacy

• The Point: to estimate the likelihood of achieving the PK-PD target (and thus, the likelihood of achieving cure).

• With these data inputs, antimicrobial exposures associated with a particular dosing regimen for a virtual population (often 5000, but any number can be selected) can be simulated, determining the proportion of infected patients expected to achieve the PK-PD target

Drusano GL.

Monte Carlo Simulation: Applied to PK/PD Models

Random PK and MIC values from data set

Plot results in a probability chart

Calculate PDparameter

AUC MIC

AUC:MIC

PTA of 50% fT>MIC Pip/Tazo 3.375g q6h (0.5)

MIC (mcg/ml)

0.25 0.5 1 2 4 8 16 32 64 128

Pro

ba

bilit

y o

f T

arg

et

Att

ain

me

nt

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

50% fT>MIC

Lodise TP, et al. Antimicrob Agents Chemother 2004;48:4718-24.DeRyke CA, et al. Diagn Microbiol Infect Dis 2007;58:337-44.

90% Target Attainment

S I R

PTA of 50% fT>MICPip/Tazo 4.5g q6h (0.5)

MIC (mcg/ml)

0.06 0.125 0.25 0.5 1 2 4 8 16 32 64 128

Pro

ba

bili

ty o

f T

arg

et

Att

ain

me

nt

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

50% fT>MIC

90% Target Attainment

S R

DeRyke CA, et al. Diagn Microbiol Infect Dis 2007;58:337-44.

PTA for Prolonged Infusion Regimens of Piperacillin/tazobactam

MIC (mcg/ml)

8e-30.0160.0320.060.1250.25 0.5 1 2 4 8 16 32 64 128

Pro

bab

ility

of

Tar

ge

t A

tta

inm

ent

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

3.375g q8h (4hr INF)4.5g q8h (4hr INF)4.5g q6h (3hr INF)

* Bactericidal Exposure defined as 50% fT>MIC

Kim A, et al. Pharmacotherapy 2007;27:1490-7.

90% Target Attainment

PTA Profiling of Cefepime SENTRY Bloodstream Isolates

Probability of 67% fT>MIC

0

20

40

60

80

100

<.25 0.25 0.5 1 2 4 8 16

MIC (mg/L)

Pro

bab

ilit

y o

f T

arg

et

Att

ain

men

t (%

)

0

20

40

60

80

100

MIC

dis

trib

uti

on

(%

)

Cefepime 2 G Q12H

Cefepime 1 G Q6H

Cefepime 2 G Q8H

Pseudomonas

E. coli

Klebsiella

S R

Lodise TP et al. Pharmacotherapy. Sep 2006;26(9):1320-1332.

PTA Profiling:Cefepime

CLCR 90 mL/min (67% DI)

0

20

40

60

80

100

<.25 0.25 0.5 1 2 4 8 16

MIC (mg/L)

Pro

bab

ilit

y o

f T

arg

et A

ttai

nm

ent

(%)

0

20

40

60

80

100

2 G Q12H (30 min)

2 G Q12H (6 hr)

2 G Q8H (30min)

4 G over 24 hr

1 G Q6H (30 min)

Tam et al. Pharmacotherapy 2003;23:291-295.

Pharmacodynamic Profiling: Meropenem

40% T>MIC (free drug)

0

20

40

60

80

100

0.25 0.5 1 2 4

MIC (mg/L)

Pro

bab

ilit

y o

f T

arg

et

Att

ain

men

t (%

)

0

20

40

60

80

100

1 G Q8H (30 min)

0.5 G Q8H (1 hr)

0.5 G Q6H (30min)

0.5 G Q8H (3 hr)

1 G Q8H (3 hr)

S

Lodise TP et al. Pharmacotherapy. Sep 2006;26(9):1320-1332.

% Target Attainment: Meropenem 1000 mg

Probability of

Target

Attainment /

MIC distribution

(%)

100

90

80

70

60

50

40

30

20

10

00.01 1 10 100

MIC (mg/L)

0.5 h infusion

1.0 h infusion

2.0 h infusion

3.0 h infusion

MIC distributionDistribution of P. aeruginosa MICsto meropenem

Pharmacodynamic Target: 40% T>MIC

Lomaestro BM, Drusano GL. AAC 2005. 49: 461-3.

SUMMARY

Extended/Continuous Infusion and Better Outcomes ?

• EI/CI Carbapenem or Pip-Tazo vs Conventional• 14 studies (1229 patients)• Mortality lower with EI/CI (RR 0.59, CI 0.41-

0.83)– PNA subgroup (RR 0.50, CI 0.26-0.96)

• Data from mainly non-randomized studies• Need for blinded RCT to confirm

• Matthew E. Falagas et al• CID 2013:56 (15 January) • 273

Take Home Points

• Pay attention to pathogen MIC– Ensure CLSI BP being used– Elevated MIC ?, SDD ?, ESBL ?, amp-C ?,

CRE ?– Low mic may not need EI dosing– Target higher MIC/Breakpoint MIC for EI

dosing (or select different agent)– EI dosing results in serum levels above

MIC for longer than standard dosing

Take Home Points

• Start with a loading dose• Extended Infusion maintenance doses:

– Zosyn 4hr infusion/dose– Meropenem 3 hr infusion/dose– Cefepime q6h or 3-4 hr infusions/dose

• Protocoled or Case by Case