Utilizing PKPD to Optimize Therapy

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

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

• 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

The antimicrobial therapy puzzle

Pea F, Viale P. Bench-to-bedside Review: Appropriate antibiotic therapy in severe sepsisAnd Septic Shock – does the dose matter? Crit Care 2009; 13: 214

PharmacodynamicsThree different classes depending on the

PK/PD indices associated with their optimal killing activity

Chest 2011;139;1210-1220

Relationship among pharmacokinetics, pharmacodynamics, and PK/PD

Plasma conc

Target site conc

Pharmaeffects

Optimizing Antimicrobial Effectiveness

DrugAdherence

PK

PharmacodynamicsIn Vivo Potency

[C] @Infection

Site

PathogenMIC

• Clinical• Success/failure

• Rate of response

• Microbiologic

• Economic

Outcome

AEProfile

DrugDosing

Pharmacodynamics of Antimicrobial by David Nicolau , FCCP,FIDSA

Bacterial Killing of Cefepime: Time-Dependent

Antimicrobial Pharmacodynamic parameterto optimize therapy

MIC

Time (h)

T>MICAn

tibio

tic (C

)

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

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

Therapeutic drug monitoring (TDM)

Insufficient beta-lactam concentrations in the early phase of

severe sepsis and septic shock

Taccone FS, et al. Critical Care 2010

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 µg/mL (ceftazidime,cefepime), ≥ 64 µg/mL (pip-taz), and ≥ 8 µg/mL (meropenem).

Optimizing β-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

Pharmacodynamics of Antimicrobial by David Nicolau , FCCP,FIDSA

Improved Potency(In Vivo Exposure)

Consensus Principles on Specific Antimicrobial Use

Ball P, et al. Int J Antimicrobial Agents 2007;30S:S139–S141

Appropriate prescribing conforms to these criteria.

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. β-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):1785–92

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):1785–92

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 105–107

colony-forming units [CFUs]/g) require antibiotics that quickly generate a bacterial cell kill of 2–3 log10 CFUs/mL.

Clinical Infectious Diseases 2012;54(12):1785–92

Betalactams Monte Carlo simulation of 5000 patients with Pseudomonas

aeruginosa infection

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 81.3Ludwig E et al. Int J Antimicrob Agents 2006

Cumulative fraction of response for standard or prolonged infusion

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):1785–92

Effectiveness of Various Antibiotic Combinations

Against Gram-Negative Pathogens

Antibiotic Susceptibility for Combination Therapy Versus Monotherapy

Clinical Infectious Diseases 2011;53(S2):S33–S55

Appraising Contemporary Strategies to Combat Multidrug Resistant Gram-Negative Bacterial Infections–Proceedings and Data From the Gram-Negative Resistance Summit

Appropriateness of Initial Antibiotics

Stability of time-dependent antibiotics in solution for intravenous infusion

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

All refernces are from latest IDSA Guidelines

Current Indications of Cefepime in High Risk Infections based on the 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 Intermediate or SDD

Resistant

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

<8 ug/ml 16 ug/ml >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

MIC

Time (h)

T>MICAntib

iotic

(C)

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

current

20

468

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

Breakpoint

Susceptible

Intermediate or

SDD

Resistant

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

<8 ug/ml

16 ug/ml

>32 ug/ml

Cefepime Proposed Breakpoint Modification and Impact on T>MIC vs. Enterobacteriaceae

MICT>MICAn

tibio

tic (C

)

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

MIC

Time (h)

T>MIC

current proposed

20

468

2

2 gm every 12 hours= 50% T>MIC

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

Breakpoint

Susceptible

Intermediate or

SDD

Resistant

CLSI(proposed)

<2 ug/ml

4-8 ug/ml

>16ug/ml

EUCAST <1 ug/ml

2-4 ug/ml

>8 ug/ml

Cefepime Breakpoint Modification and Impact on T>MIC vs. Enterobacteriaceae

MIC

Time (h)

T>MICAntib

iotic

(C)

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

MIC

Time (h)

T>MIC

current proposed

20

468

2

2 gm every 12 hours= 50% T>MIC

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

Data Source Dose SusceptibleBreakpoint

Comment

Micro Data N/A 1 ug/ml

1g 12hours 2 ug/ml

Monte Carlo Simulation of PK/PD Data

1 g 8hours 2-4 ug/ml Based upon a target attainment of 50% T>MIC for 90% of the population

2 g 12 hours 4 ug/ml

2 g 8hours 8ug/ml

ClinicalOutcome

1 g 8 hours 2-4 ug/ml

Cefepime Breakpoint by Data Source

Cefepime Breakpoint revision and effect on dosage by severity of infection

Data Source Dose SusceptibleBreakpoint

Comment

Micro Data N/A 1 ug/ml

1g 12hours 2 ug/ml

Monte Carlo Simulation of PK/PD Data

1 g 8hours 2-4 ug/ml Mild-moderateinfection

2 g 12 hours 4 ug/ml Moderate to severe infection2 g 8hours 8ug/ml

ClinicalOutcome

1 g 8 hours 2-4 ug/ml

Drug label Doses for Cefepime Site/Infection

typeDose 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 SevereSSTI

2 grams Every 12 hours 4 grams

Complicated Intra-abdominal

infections

2 grams Every 12 hours 4 grams

Neutropenicfever

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 SevereSSTI

2 grams Every 12 hours 4 grams

Complicated Intra-abdominal

infections

2 grams Every 12 hours 4 grams

Neutropenicfever

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, PhDDeputy 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

Optimal Practice for Best Patient Outcomes

GapVariance of Care

Practical Guide TO ANTIMICROBIAL STEWARDSHIP IN HOSPITALS