optimization of dosing of beta-lactams to prevent emergence of … symposium... · 2017. 5. 10. ·...
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Optimization of Dosing of Beta-lactams to Prevent Emergence
of Resistance
Vincent Tam, Pharm.D.University of Houston
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Antimicrobial Resistance
• Inevitable consequence– Unfavorable outcomes– Shorten drug lifespan
• Emergence likelihood– Predictable?– Delayed by strategies in
drug (re-)development?
http://www.pbs.org/wgbh/nova/sciencenow/0303/04-arms-nf.html
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Clinical Experience
• Ciprofloxacin– Multiple post-approval dose escalations– 100mg q12 200mg q12 400mg q12 400mg q8
• AN3365 (GSK 2251052)– Phase 2 study termination– “Microbiological findings of resistance on therapy”
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Key Factors in Resistance Development
Singh R. Curr Opin Pharmacol 2011
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Resistance Counter-selection
‘Inverted-U’ Phenomenon• Resistant sub-population
rises initially & then declines with increasing drug exposure
0
1
2
3
4
5
6
0 1 2 3 4 5 6 7
Dose Intensity
Log1
0 C
FU/m
L
ResistantSub-Population
Tam VH. Antimicrob Agents Chemother 2007
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Susceptible (wild-type)Resistant
Heterogeneous populationNo Rx
Optimal Rx
Suboptimal Rx
Tam VH. In: Fundamentals of Antimicrobial Pharmacokinetics and Pharmacodynamics. Springer 2014
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Beta-lactam Pharmacodynamics
Craig WA. Infect Dis Clin North Am 2003
Ceftazidime vs P. aeruginosa (murine thigh infection model for 24h)
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Ceiling Effect with %T>MIC
0
5
10
15
20
25
0 6 12 18 24
Time (h)
Cmin
Concn
MIC0
5
10
15
20
25
0 6 12 18 24
Time (h)
Cmin
Concn
MIC
T>MIC 100%
Cmin/MIC = 6
T>MIC 100%
Cmin/MIC = 1
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Studies correlating Cmin/MIC to Efficacy
Studies Drug Patients Breakpoint
Tam 2012 Cefepime Bacteremia 4.3
Li 2007 Meropenem Lower RT Infection 5.0
MacVane 2014 Ceftazidimeand cefepime VAP 12.0
Aitken 2015 Cefepime VAP 2.1
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Wide Inter-subject Variability
Roberts JA. Clin Infect Dis 2014
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Adopted PK/PD Targets• Beta-lactam TDM - part of routine clinical care• 9 ICUs in 7 countries
Target Threshold fT > Target Exposure
1x MIC 100%
2-4x MIC 100%
4x MIC 40%
4x MIC 50%
4x MIC 70%
4x MIC 100%
Wong G. J Antimicrob Chemother 2014
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Therapeutic Beta-Lactam Monitoring for Stratified Treatment of Hospital-acquired Pneumonia:
improved dose-dependent efficacy, decreased treatment duration, and prevention of emergence of resistance
11 partner institutions in 5 countrieswith complementary expertise
Funding from EU Framework Program for research, technological development and demonstration
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Overarching Goals
• Leveraging on past experience to advance the standard of medical care
• Prospective, randomized, controlled study– In 3 European clinical sites
• TDM guided dosing of beta-lactams– Benchtop device in ICU– Real time data for adaptive feedback design
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Bacterial Isolates
Bacteria Source Cefepime(mg/l)
Ceftazidime (mg/l)
Meropenem (mg/l)
Resistance Mechanism
K. pneumoniae Respiratory 0.25 0.5 0.06 Wild-type
K. pneumoniae Urine 16 64 0.06 CTX-M15
P. aeruginosa Respiratory 0.5 1 0.13 Wild-type
P. aeruginosa Respiratory 16 64 0.25 AmpC
Resistant phenotype
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Hollow-Fiber Infection Model
Tam VH. J Infect Dis 2007
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PK Simulation in HFIM
• Simulation of meropenem 2g IV q8h (each dose given over 30 mins)
Time (h)
Concentration (mg/l) Target Cmax = 120 mg/lTarget half-life = 1 hTarget Cmin = 0.66 mg/l
Open squares – observed concnSolid line – best-fit modelR^2 = 0.991Best-fit Cmax = 124 mg/lBest-fit half-life = 0.93 hBest-fit Cmin = 0.51 mg/l
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Dose-fractionation/ranging Design
Tam VH. Antimicrob Agents Chemother 2005Tam VH. PLoS Comput Biol 2011
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PK Simulation Parameters
Agent Target Cmax(mg/l)
CmaxRange (mg/l)
Target t1/2 (h)
t1/2 Range (h)
N
Meropenem 120 (2g) 20-120 1 1-2 13
Cefepime 160 (2g) 120-560 2 1-4 10
Ceftazidime 120 (2g) 30-300 2 2 8
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P. aeruginosa WT Ceftazidime MIC = 1 mg/l
0.5g q8hCAZ Cmin/MIC = 2.9
2g q8hCAZ Cmin/MIC = 7.7
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Overall Response
Agent Suppression Regrowth N
Meropenem 11 2 13
Cefepime 6 4 10
Ceftazidime 5 3 8
Total 22 9 31
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PK/PD Correlation - Targets
Meropenem Cefepime
Ceftazidime
7.5 +/- 6.3 vs. 1.6 +/- 1.2, p < 0.001
Cmin/MIC = 3.8100% vs. 44%, p = 0.001
Suppressio
n
Regro
wth0.1
1
10
100
Cm
in/M
IC
Tam VH. J Antimicrob Chemother 2017 (in press)
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Dosing Ladder (normal renal function)
MEM Regimen 1g q8h (0.5h) 1g q8h (3h) 2g q8h (3h) 6g q24h (CI) 8g q24h (CI)*
ETA (4x 0.5 mg/l) 58.5% 69.0% 80.6% 100.0% 100.0%
ETA (4x 2 mg/l) 13.9% 20.9% 48.2% 96.9% 98.6%
• Balancing computation burden and practicality in ICU
• Patient-specific MIC• Based on serial measurements and
dosing escalations towards:– Target attainment (e.g., Cmin >= 4xMIC) or– Highest dosing level
Empiric (both groups) Intervention group TDM guided when MIC available
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Conclusions
• Antimicrobial resistance– Inevitable consequence– Multi-factorial
• Emergence likelihood delayed by – Judicious use– Rational dosing strategies
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Optimization of Dosing of Beta-lactams to Prevent Emergence
of Resistance
Vincent Tam, Pharm.D.University of Houston