Dose optimization as an antimicrobial stewardship strategy - PowerPoint Presentation

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

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

What dose do you want to give? Floor patient with bacteremia (source unclear), low grade fever, but hemodynamically stable, and normal renal function P. Aeruginosa MIC Interpretation Cefepime 0.25SPiperacillin/ tazobactam8/4SMeropenem0.5SCiprofloxacin8R 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?

Goals of Antimicrobial Stewardship Optimize outcomes for patients with infectious diseases Drug, Dose , Route, Duration Minimize the undesired consequences from antimicrobial use Adverse eventsDevelopment of drug-resistant infectionsSuperinfectionsCost

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

PK/PD targets associated with efficacy T>MIC B-lactams Macrolides Oxazolidinones AUC/MIC VancomycinFluoroquinolonesTetracyclinesPolymyxinsDaptomycinAminoglycosidesCmax/MIC AminoglycosidesFluoroquinolones

It is not that simple though….. There is a significant debate of what the target should be….. Bacteriostasis versus 1 log 10 kill, versus 2+ log 10 killThese targets can differ based on the model employedBreakpoints (for the most part) target a 1 log10 killIs the desire always the same???

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

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

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

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

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 livesExceptions: Ceftriaxone and Ertapenem (kind of)Key safety considerationPretty well tolerated!!!Major adverse event (hypersensitivity) not dose relatedLimited association between higher doses (maximal package insert dose) and toxicityCefepime? Carbapenems?

You already take this into account… MIC CONC Time

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

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

Lodise T P et al. Clin Infect Dis. 2007;44:357-363 How many people use 3.375 q8 h as a 4 hour infusion? I bet you have heard of this before….

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

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

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

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

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 beJust because outcomes are improved with optimal certain dosing strategies does NOT mean they can’t be improved furtherAnd 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 toxicityTam VH J Antimicrob Chemother. 2017 May 1;72(5):1421-1428.

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-pseudomonalsBut I could make a compelling argument for cefazolinCeftriaxone and (maybe) ertapenem are likely okay without extended infusionsBut dose optimization still important, are we doing that?Renal insufficiency patients? Fair exception, but logisticsSmaller doses (to save money) with “equal” PD exposures have no place in antimicrobial stewardshipYou should stop giving meropenem 500 mg q6h, pip/tazo 3.375 q8h (4 hr infusion) tomorrow

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 efficacyThere is definitely an exposure/toxicity thresholdThere is conflicting evidence that MIC > 1 mg/L worsen outcomesThere is…. tremendous opportunity for you to improve the care of your patients

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

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

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.” Rybak MJ, et al. Am J Health- Syst Pharm 2009 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

Troughs ≥ 15 mg/L Troughs < 15 mg/L Odds RatioBosso et al (3) 42 142 13 146 10.7% 4.30 [2.19, 8.43] Cano et al (4) 22 89 7 99 8.1 4.32 [1.74, 10.69] Chung et al (7) 12 25 16 48 7.4 1.85 [0.69, 4.96] Hermsen et al (19) 5 16 4 39 4.3 3.98 [0.91, 17.46] Hidayat et al (20) 11 63 0 32 1.4 14.24 [0.81, 249.87] Jeffres et al (24) 27 49 13 45 8.6 3.02 [1.28, 7.11] Kralovicova et al (26) 21 60 29 138 10.7 2.02 [1.04, 3.96] Kullar et al (27) 27 139 23 141 11.5 1.24 [0.67, 2.28] Kullar et al (28) 8 116 1 84 2.4 6.15 [0.75, 50.13] Lodise et al (36) 7 27 14 139 7.1 3.13 [1.12, 8.69] McKamy et al (38) 16 57 8 110 8.0 4.98 [1.98, 12.52] Minejima et al (40) 17 72 25 155 10.5 1.61 [0.80, 3.21] Prabaker et al (49) 7 54 24 294 8.2 1.68 [0.68, 4.11] Zimmerman et al (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] Total events 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 Odds RatioM-H, Random, 95% Cl 0.1 1 Troughs < 15mg/L 10 100 Troughs >15mg/L UH OH!!!!!! Study Events Total Events Total Weight M-H, Random, 95% Cl Van Hal SJ, Paterson DL, Lodise TP. Antimicrob Agents Chemother . 2013 Feb;57(2):734-44.

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

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

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 AKISo…..Remember the resistance suppression part!!

Switching from trough to AUC at the DMC… Finch et al Antimicrob Agents Chemother . 2017 Nov 22;61(12)

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

Anyone feel differently? Floor patient with bacteremia (source unclear), low grade fever, but hemodynamically stable, and normal renal function P. Aeruginosa MIC Interpretation Cefepime 0.25SPiperacillin/ tazobactam8/4SMeropenem0.5SCiprofloxacin8R 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?

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