Dose optimization as an antimicrobial stewardship strategy

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

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?

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 • Aminoglycosides • Fluoroquinolones

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

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 3.375 q8 h as a 4 hour infusion? Lodise T P et al. Clin Infect Dis. 2007;44:357-363

17. Uh oh….. Antimicrob Agents Chemother 2012; 56(8):4087-94

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 AntimicrobChemother. 2017 May 1;72(5):1421-1428.

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 3.375 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 • 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 15-20 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 “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.” Rybak MJ, et al. Am J Health-Syst Pharm 2009

27. OddsRatio M-H, Random, 95%Cl 10 100 Troughs >15mg/L 0.1 1 Troughs < 15mg/L UH OH!!!!!! Troughs ≥15 mg/L Troughs < 15 mg/LOddsRatio Bosso etal(3) 42 142 13 146 10.7% 4.30 [2.19,8.43] Cano etal(4) 22 89 7 99 8.1 4.32 [1.74,10.69] Chung etal(7) 12 25 16 48 7.4 1.85 [0.69,4.96] Hermsen etal(19) 5 16 4 39 4.3 3.98 [0.91,17.46] Hidayat etal(20) 11 63 0 32 1.4 14.24 [0.81,249.87] Jeffres etal(24) 27 49 13 45 8.6 3.02 [1.28,7.11] Kralovicova etal(26) 21 60 29 138 10.7 2.02 [1.04,3.96] Kullar etal(27) 27 139 23 141 11.5 1.24 [0.67,2.28] Kullar etal(28) 8 116 1 84 2.4 6.15 [0.75,50.13] Lodise etal(36) 7 27 14 139 7.1 3.13 [1.12,8.69] McKamy etal(38) 16 57 8 110 8.0 4.98 [1.98,12.52] Minejima etal(40) 17 72 25 155 10.5 1.61 [0.80,3.21] Prabaker etal(49) 7 54 24 294 8.2 1.68 [0.68,4.11] Zimmerman etal(63) 8 12 0 33 11.3 126.56 [6.19,2585.90] Total(95%Cl) 921 1,503 100.0% 2.76 [1.94,3.93] Totalevents 230 177 Heterogeneity: Tau2 = 0.18; Chi2 =23.80, df =13 (P = 0.03); I2 =45% Test for overall effect: Z = 5.66 (P <0.00001) 0.01 Van Hal SJ, Paterson DL, Lodise TP. Antimicrob Agents Chemother. 2013 Feb;57(2):734-44.

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

29. Data are emerging for AUC toxicity cutoffs… Zasowski et al Antimicrob Agents Chemother. 2017 Dec 21;62(1).

30. 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 15-20 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 15-20 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…..

31. Switching from trough to AUC at the DMC… Finch et al Antimicrob Agents Chemother. 2017 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?

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