PK/PD considerations for optimizing beta-lactam/beta-lactam inhibitor

combinations

Vincent Tam, Pharm.D., FIDSAProfessor

University of Houston

Disclosures

• Research funding– ScPharmaceuticals

Objectives

• Recognize the value of BL/BLI combinations

• Understand limitations of current susceptibility testing methods

• Appreciate potential utility of a novel approach

Background

• Combination therapy – Often used in clinical practice for TB, HIV– Standard of care

• Less well accepted for bacteria / fungus– Increasing use due to emergence of resistance– MDR P. aeruginosa, A. baumannii, K. pneumoniae

• Last viable resort

β-lactamase Inhibitors

• Lack intrinsic antimicrobial efficacy– Potentiate (restore) activity of partnering agent

• MIC reduction based on concentration or time

• Traditional PK/PD not applicable– No fixed MIC

Lessons Learnt• Piperacillin / Tazobactam

– Presumptive treatment … nosocomial pneumonia should start with … 4.5 g every six hours plus an aminoglycoside…. continued in patients from whom P. aeruginosa is isolated.

• Ceftazidime / Avibactam

Stereotypic Expectations

Clinicians

Rapid turnaround for bedside decisions

Microbiologists

Non-labor intensive

PK/PD Scientists

Maximal information capture in bacterial / drug behavior, influence of infection site, immunology, protein binding…. predicting ability

Checker Board Method

8.04.02.01.00.5

0.250.125

0

Lewis RE. Pharmacotherapy 2001

Increasing concentration of Drug A

Increasing concentration of Drug B

Isobolograms - FIC Index

Additive

Synergy

Antagonism

Limitations of FIC Index

• Based Loewe additivity– Similar (linear) concentration-effect relationship

• Subjective endpoint (cloudy vs. clear)– Growth inhibition vs. killing– Majority of (intermediate) information not captured

• Predictive of clinical outcomes?– Hilf M. Am J Med 1989– Saballs M. JAC 2006

Critical Factors to ConsiderPathogen• Bacterial density• Enzyme types • Enzyme efficiency • Enzyme expression level

Drug / Inhibitor• Potency / PK of inhibitor• Potency / PK of drug• Need both agents to work

– Concentration at infection site– Binding / Metabolic route – Elimination t1/2

Semi-mechanistic Model

Bacteria

Inhibitor

β-lactam

Kg - growth

Kk - kill

Enzyme

0 2 0 4 0 6 0 8 00 .0

0 .5

1 .0

T im e (s )

Ab

so

rba

nc

e (

nm

)

K P 3 C T X M -1 5 (+ c tr l)

K P 1 2 5 5K P 1 4 1 6

K P 1 5 6 2

K P 2 3 0 1

K P 2 3 6 6

A K P 1 3 8 8 3 ( - c t r l)

Hydrolysis - MIC Correlation

0 5 10 15 200

5

10

15

20

25

C o m p a ra t iv e M IC

Co

mp

arat

ive

Act

ivit

y

r 2= 0 .9 8

A .

Abodakpi H. J Chemother 2018

Optimal Susceptibility Testing• What concentration combinations considered

clinically and dynamically relevant ?

– Fixed inhibitor concentration at trough– Fixed inhibitor concentration at peak – Concentrations at steady state average– Fixed concentrations of both (ratio)

β-lactamase Inhibitor Pharmacodynamics

• Fixed effect over expected concn range– Alternative resistance

mechanism(s)?

• Fluctuating effect over concn range– Inhibitor potency – Residual drug activity

Fluctuating MIC Profile • Instantaneous susceptibility (MICi)

– In reverse relationship of inhibitor concentration

TAZ Dose Cmax (mg/L) *%fT>MICi

0.5 g 30 39.6

1 g 60 51.6

1.5 g 90 55.1

2 g 120 58.6

Abodakpi H. Antimicrob Agents Chemother 2019 (in press)

* Given with piperacillin 4 g q8h

Optimal Dosing Ratio

• K. pneumoniae + for CTX-M15 • Pip/Taz MIC = 32/4 mg/L

TAZ concn 0 1 4 16 64 256

Pip MIC > 512 512 32 16 8 4

TAZ Dose Cmax (mg/L) *%fT>MICi

0.5 g 30 39.6

1 g 60 51.6

1.5 g 90 55.1

2 g 120 58.6

Abodakpi H. Antimicrob Agents Chemother 2019 (in press)

Optimal Agent Pairing

Abodakpi H. Clin Microbiol Infect 2019 (accepted)

• K. pneumoniae 2301 – local hyperproducer CTX-M15 • Pip/Taz MIC = >512/4 mg/L

Remaining (Key) Questions

• Customized regimen design for combinations– Agent pairing– Fixed dose ratio(s) – Dosing frequency (dose staggering?)

• Can combination prevent / delay resistance?

• Rapid results for real-time application

• Regulatory / Marketing Hurdles

Summary

• Combination therapy will be increasingly used for MDR infections

• Designing combination therapy is not trivial

• Several prototype models showing promise for clinical application

All models are wrong, some are useful.

George E.P. BoxProfessor Emeritus

University of Wisconsin - Madison

Acknowledgments

University of Houston UT Health Science Center • Henrietta Abodakpi,

PharmD, PhD• Kimberly Ledesma• Kai-Tai Chang, PhD (late)• Michael Nikolaou, PhD• Song Gao, PhD• Weiqun Wang, PhD• Amelia Sofjan, PharmD• Katrina Chan

• Audrey Wanger, PhD

Hospital Universitario Ramón y Cajal• Ana María Sánchez Díaz, PharmD• Rafael Cantón, PhD

Baylor St. Luke’s Medical Center

• Todd Lasco, PhD

Federal Funding SupportPrevious

– National Science Foundation• CBET-0730454 (Co-PI)

– National Institutes of Health• R56AI111793-01 (Co-PI)

Active– National Institutes of Health

• R01AI140287-01 (Co-PI)

PK/PD considerations for optimizing beta-lactam/beta-lactam inhibitor

combinations

Vincent Tam, Pharm.D., FIDSAProfessor

University of Houston

PK/PD considerations for optimizing beta-lactam/beta-lactam inhibitor

combinationsVincent Tam,Pharm.D. Professor

University of Houston

Credit code: sdi4Pharmacists: to receive credit for participation in this live educational session, you must claim your credit via the TSHP Education Portal (http://tshp.wcea.education/) no later than Monday, March 9, 2019.