Utilizing PKPD to Optimize Therapy
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UTILIZING PK-PD TO OPTIMIZE THERAPY
Rontgene M. Solante, MD
Infectious Disease Specialist
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Overview of the pharmacologic and nonpharmacologic factors that may influence clinical outcomes in patients.
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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
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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
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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
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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
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Bacterial Killing of Cefepime: Time-Dependent
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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
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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
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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)
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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).
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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)
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Consensus Principles on Specific Antimicrobial Use
Ball P, et al. Int J Antimicrobial Agents 2007;30S:S139–S141
Appropriate prescribing conforms to these criteria.
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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
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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
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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
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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
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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
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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
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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
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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
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Jean B Patel, PhDDeputy Director, Office of Antimicrobial Resistance; Division of Healthcare Quality Promotion ; Center for Disease Control (CDC)
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2013 CDC Cefepime Breakpoint Update
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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
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All refernces are from latest IDSA Guidelines
Current Indications of Cefepime in High Risk Infections based on the IDSA guidelines
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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
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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)
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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
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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
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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
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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)
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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
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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
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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
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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
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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)
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The Goal of Antibacterial Therapy
Appropriate and Adequate Antibacterial Therapy Guided by PK/PD
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Best Practice ≠ Actual Practice
Optimal Practice for Best Patient Outcomes
GapVariance of Care
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Practical Guide TO ANTIMICROBIAL STEWARDSHIP IN HOSPITALS