UTILIZING PK-PD

TO OPTIMIZE THERAPY
Rontgene M. Solante, MD
Infectious Disease Specialist

Overview of the pharmacologic and nonpharmacologic factors

that may influence clinical outcomes in patients.

Using PK-PD Data to Optimize Therapy

Adequacy of antibiotic dosing + microbial
exposure = eradication of organisms
Knowledge of pharmacodynamic killing
activity will provide guidance as to the dosing
of antibiotic
Application PK-PD strategies to enhance the
efficacy of antibiotic and predict clinical
outcome
Drusano GL Clin Infect Dis. 2007 Jul 15;45 Suppl 1:S89-95
McKinnon PS, Davis SL Eur J Clin Microbiol Infect Dis. 2004;23:271-88

The antimicrobial therapy

puzzle

Pea F, Viale P. Bench-to-bedside Review: Appropriate antibiotic therapy in severe sepsis

And Septic Shock does the dose matter? Crit Care 2009; 13: 214

Pharmacodynamics
Three different classes depending on the
PK/PD indices associated with their optimal killing activity

Plasma
conc

Target
site
conc

Pharma
effects

Relationship among pharmacokinetics, pharmacodynamics, and PK/PD

Chest 2011;139;1210-1220

Optimizing Antimicrobial Effectiveness

AE
Profile

PK
Drug
Adherence

[C] @
Infection
Site
Pathogen
MIC

Drug
Dosing
Pharmacodynamics
In Vivo Potency

Outcome
Clinical
Success/failure
Rate of response

Microbiologic
Economic

Pharmacodynamics of Antimicrobial by David Nicolau , FCCP,FIDSA

Bacterial Killing of Cefepime: Time-Dependent

Antibiotic (C)

Antimicrobial Pharmacodynamic parameter

to optimize therapy

MIC
T>MIC
Time (h)

Drusano GL Clin Infect Dis. 2007 Jul 15;45 Suppl 1:S89-95

McKinnon PS, Davis SL Eur J Clin Microbiol Infect Dis. 2004;23:271-88

Issues of Adequacy of Antimicrobial

Dosing and Exposure in critically ill
1. Proper dosing is essential especially in
patients with trauma, or in the ICU
2. Patients usually vary with drug
clearance and distribution problems
e.g. renal failure, obese, elderly

Optimizing Initial Dosing of Antibiotics in MODS

Therapeutic drug monitoring

(TDM)

Clinical scenarios likely to alter antibiotic PK in MODS.

Maintenance dosing should be guided by the level of organ function
and in the context of the main elimination pathways for the drug and, where possible, guided by TDM.

Chest 2011;139;1210-1220

Insufficient beta-lactam
concentrations in the early phase of
severe sepsis and septic shock

Each patient was classified as having an adequate or inadequate PK profile

according to the % of time during which serum drug concentrations remained
above 4 times the clinical breakpoint for Pseudomonas aeruginosa (% T > 4 x
MIC): 32 g/mL (ceftazidime,cefepime), 64 g/mL (pip-taz), and 8 g/mL
Taccone FS, et al. Critical Care 2010
(meropenem).

Optimizing -lactam Therapy:

Maximizing Percent T>MIC

Higher dose
Increased dosing frequency
Increased duration of infusion
a. Prolonged infusion
- Same dose and dosing interval,
however, change duration of
infusion (0.5 hr 3hr)
b. Continuous infusion
- Administer loading dose, then use
pump to give total daily dose IV
over 24 hr period

Improved Potency
(In Vivo Exposure)

Pharmacodynamics of Antimicrobial by David Nicolau , FCCP,FIDSA

Consensus Principles
on Specific Antimicrobial Use

Appropriate prescribing conforms to these criteria.

Ball P, et al. Int J Antimicrobial Agents 2007;30S:S139S141

The escalating drug-resistance crisis due to selection and

overgrowth of less-susceptible subpopulations
as a result of inadequate drug exposure

Cachexia, hypoalbuminemia, and effusions

common in patients with cancer may lead to
increased drug Vd and enhanced renal clearance
accompanied by reduced exposure of hydrophilic
antibacterial agents eg. -lactams, aminoglycosides,
glycopeptides and colistin
Hypoalbuminemia in patients with terminal cancer,
severe sepsis, or cancer resection surgery, increases the
unbound fraction of highly protein-bound antibiotics,
enabling both more rapid distribution and enhanced
renal clearance, resulting in lower antibacterial
exposures
Clinical Infectious Diseases 2012;54(12):178592

The escalating drug-resistance crisis due to selection and

overgrowth of less-susceptible subpopulations
as a result of inadequate drug exposure

In patients at risk of disease-related

unfavorable
PK, a low MIC (several dilutions below the
break point) will balance the PK/PD ratio
without requiring dosage modification.
Hospitalized severely ill patients with multiple
recent antibiotic exposures are at higher risk
for pathogens with elevated MICs.
Clinical Infectious Diseases 2012;54(12):178592

The escalating drug-resistance crisis due to selection and

overgrowth of less-susceptible subpopulations
as a result of inadequate drug exposure

The Patient Factor

Antibacterial therapy aims to reduce the number
of bacteria but, in most cases, relies on the
immune system to eliminate them completely
VAP with a high bacterial burden above the
limit of saturation (approximately 7 x 105107
colony-forming units [CFUs]/g) require antibiotics
that quickly generate a bacterial cell kill of 23
log10 CFUs/mL.
Clinical Infectious Diseases 2012;54(12):178592

Betalactams Monte Carlo simulation

of 5000 patients with Pseudomonas
aeruginosa infection
Cumulative fraction of response for standard or prolonged infusion
Antibiotic Regimen

Bactericidal CFR (%)

30-minute infusion

3-4 hour infusion

Cefepime 1 gm q 8H

67.1

72.1

Cefepime 2 gm q 8H

74.4

79.2

Imipenem 1 gm q 8H

69.3

72.0

Meropenem 1 gm q 8H

77.1

83.8

Meropenem 2 gm q 8H

84.1

88.1

Pipera/Tazo 4.5 gm q 8H

56.4

80.7

Pipera/Tazo 4.5 gm q 6H

72.4

81.3

Ludwig E et al. Int J Antimicrob Agents 2006

Variability and relationship between dosing, drug exposure

(PKs), MIC (PDs), and microbiological effect that predicts the
probability of clinical cure

Clinical Infectious Diseases 2012;54(12):178592

Appraising Contemporary Strategies to Combat Multidrug

Resistant Gram-Negative Bacterial InfectionsProceedings
and Data From the Gram-Negative Resistance Summit

Antibiotic Susceptibility for Combination Therapy Versus Monotherapy

Effectiveness of Various Antibiotic Combinations

Against Gram-Negative Pathogens

Appropriateness of Initial Antibiotics

Clinical Infectious Diseases 2011;53(S2):S33S55

Stability of time-dependent antibiotics in solution

for intravenous infusion

Pea F, Viale P. Bench-to-bedside Review: Appropriate antibiotic therapy in severe sepsis

And Septic Shock does the dose matter? Crit Care 2009; 13: 214

2013 Update on Cefepime Breakpoint

revision for Enterobacteriaceae
presented by Dr. Jean Patel of the Centers for
Diseases Control
Deputy Director, Office of Antimicrobial Resistance;
Division of Healthcare Quality Promotion ;
Center for Disease Control (CDC)

2013 Interscience Conference on

Antimicrobial and Chemotherapy (ICAAC)
September 2013 Denver, Colorado

Jean B Patel, PhD

Deputy Director, Office of Antimicrobial Resistance; Division of Healthcare Quality
Promotion ; Center for Disease Control (CDC)

2013 CDC Cefepime

Breakpoint Update

Current Indications and dosage of Cefepime

in High Risk Infections based on the IDSA guidelines

All refernces are from latest Infectious Disease Society of America Guidelines

Current Indications of Cefepime

in High Risk Infections based on the IDSA guidelines

All refernces are from latest IDSA Guidelines

In practice, a dose of 2 grams/day or less is

used almost 50% of the time
Cefepime Regimens at 120 US Hospitals (27,696/6
months)
< 2 grams/day = 22%
2 grams/day = 33%
3 grams/day = 17%
4 grams/day = 12%
> /=6 grams/day = 9%

Data c/o Vitas Gupta, PharmD, BCPS, Director, CareFusion Medmined, USA

Why is CDC looking at Cefepime breakpoint

revision for Enterobacteriaceae?
Concerns with cefepime breakpoints
Current breakpoints were set at a higher dose of
cefepime and lower doses are used
Evidence of clinical failures for isolates with MICs of 4
ug/ml and 8 ug/ml, especially when low to mid-range
doses were used
There are limited new drugs in the pipeline for infections
caused by resistant gram negative bacteria; need to
make the most of the drugs we have (which
include cefepime)

Cefepime Breakpoint Summary

for Enterobacteriaceae
Breakpoint

Susceptible
<8 ug/ml

Intermediate or
SDD
16 ug/ml

CLSI (current)
1gm q 8H/2gm
q 12H

Resistant
>32 ug/ml

CLSI (proposed)

<2 ug/ml

4-8 ug/ml

>16 ug/ml

EUCAST

<1 ug/ml

2-4 ug/ml

>8 ug/ml

Cefepime Current Breakpoint and Impact on

T>MIC vs Enterobacteriaceae
Antibiotic (C)

current
1-2 gm every 8-12 hours
= 50% T>MIC

8
6
4
2
0

MIC
T>MIC

Break
point
CLSI
(current)
1gm q
8H/2gm
q 12H

Suscep Interme Resistant

tible diate or
SDD
<8
ug/ml

Time (h)
Drusano GL Clin Infect Dis. 2007 Jul 15;45 Suppl 1:S89-95
McKinnon PS, Davis SL Eur J Clin Microbiol Infect Dis. 2004;23:271-88

16
ug/ml

>32
ug/ml

Cefepime Proposed Breakpoint Modification and

Impact on T>MIC vs. Enterobacteriaceae
Antibiotic (C)

Break
point

current
Suscep
Intermed Resistant
tible
iate or
2 gm every 12 hours
SDD

CLSI
<2
(proposed) ug/ml
EUCAST
8
6
4
2
0

proposed
1-2 gm every 8-12 hours
= >65% T>MIC
( greater exposure of
organism to cefepime
Higher killing rate)

= 50% T>MIC

4-8
ug/ml

>16
ug/ml

<1
T>MIC 2-4
ug/ml ug/ml

MIC
>8
ug/ml

T>MIC
MIC
2

Time (h)
Drusano GL Clin Infect Dis. 2007 Jul 15;45 Suppl 1:S89-95
McKinnon PS, Davis SL Eur J Clin Microbiol Infect Dis. 2004;23:271-88

Cefepime Breakpoint Modification and

Impact on T>MIC vs. Enterobacteriaceae
Antibiotic (C)

current

proposed
2 gm every 12 hours
= 65% T>MIC
( greater exposure of
organism to cefepime
Higher killing rate)

2 gm every 12 hours
= 50% T>MIC

8
6
4
2
0

MIC
T>MIC

T>MIC
MIC
2

Time (h)

Time (h)

Drusano GL Clin Infect Dis. 2007 Jul 15;45 Suppl 1:S89-95

McKinnon PS, Davis SL Eur J Clin Microbiol Infect Dis. 2004;23:271-88

Cefepime Breakpoint by Data Source

Data Source
Micro Data

Monte Carlo
Simulation of
PK/PD Data

Clinical
Outcome

Dose
N/A

Susceptible
Breakpoint
1 ug/ml

1g 12hours
1 g 8hours

2 ug/ml
2-4 ug/ml

2 g 12 hours

4 ug/ml

2 g 8hours

8ug/ml

1 g 8 hours

2-4 ug/ml

Comment

Based upon a
target attainment
of 50% T>MIC for
90% of the
population

Cefepime Breakpoint revision and effect on

dosage by severity of infection
Data Source
Micro Data

Monte Carlo
Simulation of
PK/PD Data

Clinical
Outcome

Dose
N/A

Susceptible
Breakpoint
1 ug/ml

1g 12hours
1 g 8hours

2 ug/ml
2-4 ug/ml

2 g 12 hours
2 g 8hours

4 ug/ml
8ug/ml

1 g 8 hours

2-4 ug/ml

Comment

Mild-moderate
infection
Moderate to
severe infection

Drug label Doses for Cefepime

Site/Infection
type
Mild to
Moderate UTI
Severe UTI
Mild to Severe
Pneumonia
Mild to Severe
SSTI
Complicated
Intra-abdominal
infections
Neutropenic
fever

Dose

Frequency

0.5 1 gram

Every 12 hours

Total Daily
Dose
1-2 grams

2 grams
1-2 grams

Every 12 hours
Every 12 hours

4 grams
2-4 grams

2 grams

Every 12 hours

4 grams

2 grams

Every 12 hours

4 grams

2 grams

Every 8 hours

6 grams

The non-UTI doses for Cefepime range

from 2-6 grams/day
Site/Infection
type

Dose

Frequency

Total Daily
Dose

Mild to
Moderate UTI

0.5 1 gram

Every 12 hours

1-2 grams

Severe UTI

2 grams

Every 12 hours

4 grams

Mild to Severe
Pneumonia

1-2 grams

Every 12 hours

2-4 grams

Mild to Severe
SSTI

2 grams

Every 12 hours

4 grams

Complicated
Intra-abdominal
infections

2 grams

Every 12 hours

4 grams

Neutropenic
fever

2 grams

Every 8 hours

6 grams

Other Considerations of this revision?

Preserve cefepime for the treatment of emerging
MDR-GNB with little or no other choice
The paucity of new broad spectrum anti-GNB
agents in the pipeline
Recent national emphasis on Antibiotic
Stewardship is increasing awareness and hopefully
should facilitate appropriate utilization of SDD
(susceptible daily dose)
Jean B Patel, PhD
Deputy Director, Office of Antimicrobial Resistance; Division of Healthcare Quality
Promotion ; Center for Disease Control (CDC)

The Goal of Antibacterial Therapy

Appropriate and Adequate Antibacterial
Therapy Guided by PK/PD

Best Practice Actual Practice

Gap
Variance of Care

Optimal Practice for

Best Patient Outcomes

Practical Guide TO ANTIMICROBIAL STEWARDSHIP IN HOSPITALS