1. Dose optimization as an antimicrobial stewardship strategy
Jason M. Pogue, PharmD, BCPS, BCIDP
Clinical Pharmacist, Infectious Diseases
Sinai-Grace Hospital; Detroit Medical Center
Clinical Assistant Professor of Medicine
Wayne State University School of Medicine

2. Objectives
Identify the key considerations that go into the development of an optimal dosing regimen/strategy for a given antibacterial
Discuss the rationale for routine use of extended infusion beta lactams for the management of infections due to Gram-negative pathogens
Explain why AUC based dosing is the optimal dosing strategy for vancomycin
Obj 1: Also appreciate that does not mean that an agent is optimal for use

3. What dose do you want to give?
Floor patient with bacteremia (source unclear), low grade fever, but hemodynamically stable, and normal renal function
The decision is made to start the patient of cefepime.
How do you want to dose?
A) 1 gram q12h
B) 1 gram q8h
C) 2 grams q12h
D) 2 grams q8h
Anyone want to do an extended infusion?
P. Aeruginosa
MIC
Interpretation
Cefepime
0.25 S
Piperacillin/ tazobactam
8/4
Meropenem
0.5
Ciprofloxacin 8 R

4. Goals of Antimicrobial Stewardship
Optimize outcomes for patients with infectious diseases
Drug, Dose, Route, Duration
Minimize the undesired consequences from antimicrobial use
Adverse events
Development of drug-resistant infections
Superinfections
Cost

5. Optimizing dose requires an understand of Pharmacokinetics (PK) and Pharmacodynamics (PD)

6. PK/PD targets associated with efficacy
T>MIC
B-lactams
Macrolides
Oxazolidinones
AUC/MIC
Vancomycin
Fluoroquinolones
Tetracyclines
Polymyxins
Daptomycin
Aminoglycosides
Cmax/MIC

7. It is not that simple though…..
There is a significant debate of what the target should be…..
Bacteriostasis versus 1 log10 kill, versus 2+ log10 kill
These targets can differ based on the model employed
Breakpoints (for the most part) target a 1 log10 kill
Is the desire always the same???

8. And even if you think you know the target
Berkhout et al AAC; 60:368-75
Bhanvnani et al ASM Microbe 2018

9. Did I mention that it is not that simple?
Minimum Inhibitory Concentrations: Do you believe what you see?
Can vary as a function of:
Testing methodology used
Strain isolated
User proficiency
At BEST a reported MIC value is ± 1 double dilution
For example: A reported MIC of 4 is really a MIC of 2-8 mg/L
And these are just the PD issues- we are going to talk about PK considerations a bit later

10. BUT……
Figure 2. Percent response of efficacy and toxicity according to Cmax
Pogue JM, Scheetz MH What Every Steward Should Know About Pharmacokinetics and Pharmacodynamics In Practical Implementation of an Antibiotic Stewardship Program

11. Bringing it all together
For a number of reasons, you need to be as aggressive as possible with your dosing in patients
However, toxicodynamic considerations need to come into play as well
The maximal tolerable dose (and PD optimized administration strategy) should be employed to both optimize efficacy and minimize toxicity
The dose administered and MIC value that can be successfully targeted may or may not be consistent with labeled doses or established breakpoints

12. Let’s talk about beta-lactams
Time-dependent agents
Concentration-independent (kind of…)
Optimize efficacy (stasis or kill) by optimizing T > MIC
Targets can differ based off of agent, degree of kill desired, and organism
Key pharmacokinetic considerations
These drugs (for the most part) have very short half lives
Exceptions: Ceftriaxone and Ertapenem (kind of)
Key safety consideration
Pretty well tolerated!!!
Major adverse event (hypersensitivity) not dose related
Limited association between higher doses (maximal package insert dose) and toxicity
Cefepime? Carbapenems?

13. You already take this into account…
CONC
MIC
Time

14. The benefit of more frequent intervals
Cmax may be lower
T>MIC is greater
Possible utility of loading dose
CONC
MIC
Time

15. Extended infusions just take this concept to the next level….
Pogue JM, Scheetz MH What Every Steward Should Know About Pharmacokinetics and Pharmacodynamics In Practical Implementation of an Antibiotic Stewardship Program

16. I bet you have heard of this before….
How many people use q8 h as a 4 hour infusion?
Lodise T P et al. Clin Infect Dis. 2007;44:

17. Uh oh…..
Antimicrob Agents Chemother 2012; 56(8):

18. To be honest though…that only scratches the surface of the issue
Abdul-Aziz MH et al Intensive Care Med (2016) 42:1535–1545

19. Rhodes et al Crit Care Med. 2018 Feb;46(2):236-243.

20. International Journal of Antimicrobial Agents 31 (2008) 345–351

21. So they question I most commonly get…
Can I limit this extended infusion strategy to critically ill patients or target agents?
You can, but….
Why would you?
Remember
You have no clue what the exposures are on a patient level
There is significant debate about what our target should be
Just because outcomes are improved with optimal certain dosing strategies does NOT mean they can’t be improved further
And what outcomes are we assessing? Do we are about things other than mortality?
The higher doses (or same doses with different infusion strategies) do NOT seem to impact toxicity
Tam VH J Antimicrob Chemother May 1;72(5):

22. So answer the question, Jason!
Personally, I cannot think of a compelling reason to not give the maximal tolerable dose with extend infusions for all Gram-negative beta-lactams!
To be clear that means all patients, maximum dose, optimized infusions
The biggest “bang“ is certainly with anti-pseudomonals
But I could make a compelling argument for cefazolin
Ceftriaxone and (maybe) ertapenem are likely okay without extended infusions
But dose optimization still important, are we doing that?
Renal insufficiency patients?
Fair exception, but logistics
Smaller doses (to save money) with “equal” PD exposures have no place in antimicrobial stewardship
You should stop giving meropenem 500 mg q6h, pip/tazo q8h (4 hr infusion) tomorrow

23. What about vancomycin? Vancomycin is used a lot
We dose this drug poorly
Which is quite amazing, given that we spend so much damn time on it
It is also the perfect example of how stewardship can dose optimize
The facts
AUC/MIC ratio of ~400 or greater has been shown to increase efficacy
There is definitely an exposure/toxicity threshold
There is conflicting evidence that MIC > 1 mg/L worsen outcomes
There is…. tremendous opportunity for you to improve the care of your patients

24. AUC/MIC and outcomes… going on 15 years…
Moise-Broder PA, et al. Clin Pharmacokin 2004

25. Vancomycin guidelines knew this….
Summary and recommendation:
“An AUC/MIC ratio of ≥400 has been advocated as a target to achieve clinical effectiveness with vancomycin. Animal studies and limited human data appear to demonstrate that vancomycin is not concentration dependent and that the AUC/MIC is a predictive pharmacokinetic parameter for vancomycin.”
Rybak MJ, et al. Am J Health-Syst Pharm 2009

26. Surrogate Schmurrogate
“However, because it can be difficult in the clinical setting to obtain multiple serum vancomycin concentrations to determine the AUC and subsequently calculate the AUC/MIC, trough serum concentration monitoring, which can be used as a surrogate marker for AUC, is recommended as the most accurate and practical method to monitor vancomycin.”
Trough goal of 15 – 20 mg/L for serious infections
Ensure achievement of AUC/MIC ratio of ≥ 400, as long as the vancomycin MIC is ≤ 1 mg/L
But you need to understand , the trough of mg/L was not initially meant to ensure a AUC target achievement
And for AUC based drugs, how you divide the daily dose shouldn’t matter
Rybak MJ, et al. Am J Health-Syst Pharm 2009 26

27. UH OH!!!!!!
Troughs ≥ 15 mg/L Troughs < 15 mg/L Odds Ratio
Bosso et al (3) % 4.30 [2.19, 8.43]
Cano et al (4) [1.74, 10.69]
Chung et al (7) [0.69, 4.96]
Hermsen et al (19) [0.91, 17.46]
Hidayat et al (20) [0.81, ]
Jeffres et al (24) [1.28, 7.11]
Kralovicova et al (26) [1.04, 3.96]
Kullar et al (27) [0.67, 2.28]
Kullar et al (28) [0.75, 50.13]
Lodise et al (36) [1.12, 8.69]
McKamy et al (38) [1.98, 12.52]
Minejima et al (40) [0.80, 3.21]
Prabaker et al (49) [0.68, 4.11]
Zimmerman et al (63) [6.19, ]
Total (95% Cl) 921 1, % 2.76 [1.94, 3.93]
Total events
Heterogeneity: Tau2 = 0.18; Chi2 =23.80, df =13 (P = 0.03); I2 = 45%
Test for overall effect: Z = 5.66 (P < )
Odds Ratio
M-H, Random, 95% Cl
0.1 1
Troughs < 15mg/L
10 100
Troughs >15mg/L
Study
Events
Total
Weight
M-H, Random,
95% Cl
0.01
Van Hal SJ, Paterson DL, Lodise TP. Antimicrob Agents Chemother Feb;57(2): 27

28. Oh wait, it is even worse…..
Pai MP Adv Drug Deliv Rev. 2014 28

29. Data are emerging for AUC toxicity cutoffs…
Zasowski et al Antimicrob Agents Chemother Dec 21;62(1).

30. So let’s put this altogether
Remember the resistance suppression part!!
So let’s put this altogether
AUC/MIC ratio of ~ 400 or greater associated with efficacy for invasive MRSA infections
A trough of will (largely) hit this target if the MIC is ≤ 1 mg/L
Therapeutic concentrations cannot be safely (and reliably) obtained if MIC >1
But a trough of also increases the risk of AKI
Trough is actually a very poor surrogate of AUC, and AUC > 400 can be met with troughs < 15 mg/L
Data emerging that AUC’s ~650 or higher increase risk for AKI
So…..
Comment on don’t dose to MIC (cant target >1, cant trust <1)

31. Switching from trough to AUC at the DMC…
Finch et al Antimicrob Agents Chemother Nov 22;61(12)

32. Summary/Conclusions
Dose optimization is one of the most important roles for antimicrobial stewards
Although PK/PD targets are known for most agents there are still some significant unknowns and one size does not fit all
The PK exposures on an individual patient level are unknown and can vary greatly
Giving just enough drug can be dangerous
For all of these reasons the maximum tolerable dose and administrations strategy should be employed….
….but remember that doesn’t mean “S” means what you want it too

33. Anyone feel differently?
Floor patient with bacteremia (source unclear), low grade fever, but hemodynamically stable, and normal renal function
The decision is made to start the patient of cefepime.
How do you want to dose?
A) 1 gram q12h
B) 1 gram q8h
C) 2 grams q12h
D) 2 grams q8h
Anyone want to do an extended infusion?
P. Aeruginosa
MIC
Interpretation
Cefepime
0.25 S
Piperacillin/ tazobactam
8/4
Meropenem
0.5
Ciprofloxacin 8 R

34. Dose optimization as an antimicrobial stewardship strategy
Jason M. Pogue, PharmD, BCPS, BCIDP
Clinical Pharmacist, Infectious Diseases
Sinai-Grace Hospital; Detroit Medical Center
Clinical Assistant Professor of Medicine
Wayne State University School of Medicine