Me? Debunk a Vancomycin myth?... Take my life in my hands?

Transcription

1 Me? Debnk a Vancomycin myth?... Take my life in my hands? BRUCE DALTON PHARM.D. ALBERTA HEALTH SERVICES CALGARY BRUCE.DALTON@ALBERTAHEALTHSERVICES.CA

2 Disclosres No financial or other conflicts of interest

3 At yor instittion, do yo crrently se AUC gided dose adjstment for vancomycin? 1. Yes 2. No 3. Unsre

4 Trail to skepticism abot AUC/MIC Upon review of key literatre; a) Animal/experimental data àproblematic b) Unstandardized determination of AUC/MIC24 c) Observational stdy(s) of AUC/MIC to determine threshold are challenging Clinical importance of AUC/MIC; a) No relevant change to post test probability b) Interventional stdies ths far have not shown improved otcome c) Instittional reqirements for AUC/MIC monitoring Trogh monitoring has poor predictive as well à stats qo? My goal: Consider/critiqe data à not blindly accept (either side).

5 Reliable sorce tells me AUC monitoring will be in next gidelines Optimal trogh to improve penetration (for IE, OM, meningitis, HAP) For a pathogen with an MIC of 1mg/L, minimm trogh of 15 mg/l to generate the target of AUC:MIC of 400

6 AUC/MIC Best Pharmacodynamic Parameter? Animal and Experimental Data in Staph ares Reviewed in ; Craig W et al. Infect Dis NA : Ebert S et al. ICAAC abstract 1987 Ddley M et al. ICAAC abstract 1999 Larsson JAC 1996 High vanco concentrations all 100%>MIC. No analysis of AUC Dffll SB et al. AAC Comparison of 2 dose regimens no difference Pavie AAC 2003 Vanco concentration >MIC for entire dosing interval. AUC/MIC ratio >=80 effective (data not shown)

7 AUC/MIC variation ~300% Etest vs Vitek Krzel et al J Clin Microbiol (6);

8 What is AUC? Drg exposre (in blood) Troghs = Cmin AUC/MIC is a ratio (not area above MIC)

9 How do we determine AUC? Citation AUC method Comment Holmes et al AAC :1654 Moise-Broder CPK AUC 24 = Dose/ {[(CLCR x 0.79)+15.4] x 0.06} Varios methods of determining CLCR imprecision and bias Joon-Jin et al. Infect and Chemo ssauc24 = D/Clvan (2 levels) 2. cauc24 = D/[[(CLcr 0.79) ] 0.06] The ssauc24 was significantly higher than the cauc24 (P < ) Finch et al. AAC : 1293 AUC = ([Cmax + Cmin]/2 time of infsion) + ([Cmax Cmin]/elimination rate constant) Two vancomycin levels reqired. Neely et al AAC : 309 Neely et al AAC : e02042 Peak/trogh or trogh Bayesian estimation (two compartment model) Old version of BestDose software available at New version coming soon. Lodise T et al. Clin Infect Dis 2014 Bayesian estimation Free software USC ADAPT-V / With 6 different AUC methods and 6 different MIC methods there are 36 different possible methods to determine AUC/MIC (not even considering when AUC/MIC is determined)

10 AUC: Not jst the sond of an angry Scot Brns Analysis Best laid plans o mice & men often go awry AUC determination: Two serm levels Time for distribtion Accrate time recording for dosing and drawing levels Precision of vancomycin assay Immnoassay interference Protein binding and free level at site of infection Calclation method of AUC Calclation error Changing volme of distribtion, renal fnction of patient One or no levels Poplation data average vs yor patient? Formla Bayesian modelling

11 Clinical Stdies Observational approach What AUC/MIC threshold predicts poor(er) otcome (risk)? Retrospective, non randomized trials association (not casation) Classification and regression tree analysis (CART) to categorize AUC/MIC as a dichotomos variable (high or low) AUC/MIC determined at 1 time point à assmed to represent the AUC/MIC of the whole treatment corse? à the later in treatment corse AUC/MIC vales are niformly within target? à the later AUC/MIC vales do not matter?

12 N=108 Staph ares LRTI, 68% ICU, 68% ventilator N= 70 presented previosly in Am J HP : Sppl 2 S4-9 Clinical cre & eradication greater when AUC24:MIC >350 58% Vancomycin was primary Tx agent (many had MSSA)

13 AUC/MIC ratio Clinical Cre 655+/ /-225 In mltivariate analysis AUC/MIC >350 OR for sccess 7.1 (95% CI )

14 102 MRSA HAP Patients treated with Vancomycin

15 Initial dose 25 mg/kg q12h Levels h adjsted dose to trogh mg/l All case mortality and attribtable mortality regressed against AUC/MIC (determined retrospectively)

16 A priori threshold of interest A posteriori identified threshold Mltivariate model also spported 373 threshold

17 Vancomycin level is not a applicable? diagnostic test are principles

18 9 + 2 stdies Calclation of pooled Likelihood ratio

19 Combined Performance Characteristics AUC/MIC (all methods) did not fail/srvive failed/died >=threshold <threshold ppv= 69.44% Sens= 67.25% npv= 51.13% Spec= 53.65% LR= 1.45

20 Pretest probability = 1-mortality from SAB = 80% LR of 1.45 à post test likelihood to ~85%

21 How does trogh >15 mg/l perform as diagnostic test? Citation Sens Spec PPV NPV LR combined Gain in pretest to posttest probability by sing AUC/MIC is ~2-3% Using non-niform threshold Post test probability ~83%

22 Clinical Stdies Interventional approach Instittion adopts AUC monitoring and compares to historic otcomes (sing Cmin monitoring)

23 Neely MN, et al AAC, Feb 2018 Yr 1 contined togh monitoring Yr 2 /3 changed to AUC monitoring goal > 400 No failres, 0% mortality all 3 years Nephrotoxicity 8% vs 0% vs 2% (42% power to detect this difference, alpha 0.05)

24 : e Before/after AUC monitoring target mg.h/l MIC not considered, pt micro reslts not discssed, infection otcome NA Lower vancomycin daily dose (median daily dose 2500 mg vs 2333 (p=0.001) Lower median trogh (12.0 vs 15.0 p = 0.001) Lower nephrotoxicity by bivariate (NS, OR 0.72, 95% CI [ ] and mltivariate analysis ( % CI [ ])

25 A U C / M I C Stdy design that wold help resolve the qestion Above threshold AUC/MIC Above threshold AUC/MIC Otcome? Threshold Low AUC/MIC Below threshold AUC/MIC 96 etc Otcome?

26 Compare to trogh monitoring Cmin Above threshold Cmin Above threshold Cmin Low Cmin Below threshold Cmin 96 etc Otcome? Threshold (15mg/L?) Otcome?

27 Pediatrics Data are limited in pediatrics to gide dosing 15mg/kg/dose q6h for serios or invasive MRSA infection in children Efficacy of targeting mg/l reqires additional stdy bt shold be considered in serios infections

28 Pediatrics AUC determination Bayesian programs based on adlt PK profiles. Creatinine clearance based AUC formlae Two serm levels needed trapezoidal rle formla Tkachk S, Collins K and Ensom M. Ped Drgs Systematic Qalitative Review correlation btn AUC/MIC and Cmin 11 stdies 6-10 mg/l trogh achieves AUC:MIC >=400 (if MIC<=1) 1 critical care stdy otlier AUC/MIC never above 400 with troghs ~ 7.7

29 Daily dose of vancomycin vs probability of AUC/MIC24 >= 400 in Pediatric patients - Monte Carlo simlation Frymoyer et al. Clin Ther 2010

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31 AUC determination on day 3-5 on a Bayesian platform validated for pediatrics

32 Economic analyses & Resorce Stdies NA Who does calclations & what else cold they do with their time?

33 Conclsions AUC/MIC methods reqire standardization Too mch variability in determining both AUC and MIC A vale of threshold mst be consistently demonstrated (good qality stdies) AUC/MIC = 400 not adeqately established A mltifactorial scale developed cold be à AUC/MIC as a continos variable Post test probability needs to be improved with this test Data on monitoring by trogh are eqivalent

34 Conclsions Implementation of AUC monitoring lack of sbstantive otcome change Trogh monitoring à similar otcome to AUC gided dosing? Target Cmin <15 mg/l Caveat MIC<=1 mg/l No additional training, hman resorce reqirements Pediatrics & Neonates Nmber of blood samples Correlation of trogh to AUC or dose to probability of AUC target attainment àlower levels generally adeqate

35 Sometimes the faster it gets the less yo need to know. Bt yo gotta remember, the smarter it gets the frther it s gonna go

36 Qestions? me;

37 Spplementary Slides To spport answers to qestions

38 ORGANISM PANEL ANTIBIOTIC MRSA Vitek (84) Microscan (39) Vancomycin Row Labels <= Grand Total Cont of MIC

39 Stability of Vancomycin levels Ampe E et al. IJAA :439

40 AUC/MIC24 target of >400 is an evidence-based threshold that has reasonable predictive vale. 1. Yes 2. No 3. It depends/i have no knowledge or preconception

41 How does trogh >15 mg/l perform as diagnostic test? Citation Sens Spec PPV NPV LR Zelenitsky et al AAC Ghosh et al. CMI Ashrad et al Clemens et al Jng et al Kllar et al Lodise et al combined Gain in pretest to posttest probability by sing AUC/MIC is ~2-3% Using non-niform threshold Post test probability ~83%

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43 Vancomycin AUC/MIC Enterococcs/Strep pnemo other Gram positives no or minimal evidence reqirements nknown Staphylococcs ares retrospective stdies first 24-48h of therapy Patient with possible Staphylococcs ares sepsis Moderate dosing of vancomycin for 98% of Staph that are MSSA and/or MIC<=1 Aggressive dosing with vancomycin incase MIC >1 Daptomycin for Staphylococcs ares sepsis in case MIC to vanco >1

44 FROM THE PERSPECTIVE of ninvolved observers, antibiotic dosing has alternated between nmanaged chaos and despair over its total irrationality To s, it matters little what dose method clinicians se to accomplish changes in dosing, becase over 90% of the seflness of dosing comes from the small effort expended to consider and incorporate the MIC. The Annals of Pharmacotherapy 1996 September, Volme

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46 Systematic Review PloSone Otcome Grops compared Mortality Treatment Failre Method RR 95% CI High MIC/AUC Fixed effects vs low High MIC/AUC Random vs low effects

47 Reslts 252 adlt pt enrolled in 3 years of stdy (75,88 & 89 respectively) SSTI most common, bacteremia & pnemonia increased in latter years. Organisms isolated per table 2:

48 Otcome Measres Intended target at the time comparison Yr 1 to Yr2 improved. However year 2 looks to be poorest performer wrt target achievement.

49 Patient Otcomes Nephrotoxicity 6 (8) 0 (0) 2 (2) P= 0.01

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51 Adjsted & Bivariate Analyses No data on otcome of infection

52 Interventional Approach (2 stdies) Findings Patients with mostly SSTI & mostly not cased by MRSA have similar infection resoltion regardless of monitoring target. Nephrotoxicity is infreqent bt higher rate in those dosed more aggressively and with other nephrotoxin exposre and high illness severity Less nephrotoxicity if sing AUC/MIC = 400 as target, or lower toghs of vancomycin

53 Evalation of clinical otcome in children and adolescents receiving vancomycin for invasive infections de to methicillin-resistant Staphylococcs ares: impact of increasing vancomycin MICs Arn A et al Minereva Pediatrica Poor otcome with vancomycin MIC >1 Treatment failre 52% Vancomycin trogh levels > 15 µg/ml - 18% AUC/MIC > 400-0%