PK/PD Dosing in Critical Care Jim Fenner Pharm D BCPS

Conflicts of Interest None to report No relevant financial relationships

Learning Objectives 1.To define PKPD effect on in-vitro susceptibility Reporting 2.To identify the 3 important PKPD targets 3.To demonstrate how PKPD principles and targets effect antibiotic dosing 4.To justify the rational for extended infusion of beta- lactam antibiotics

Antimicrobial Treatment Considerations in ICU 1.Must be timely: delay in initiation potentially lethal 2.Appropriate: must cover the offending pathogen(s) 3.Administered at adequate dose and intervals consistent with pK/pD parameters 4.Timely streamlining based on clinical response and microbiological data 5.Prompt discontinuation when practical Deresinski S. Clin Infect Dis 2007; 45:S177-S183 Allerberger F et al. Clin Microbiol Infect 2008; 14:

PHARMACOKINETIC CHANGES IN CRITICAL ILLNESS

PK Changes in Critically llL Heterogeneous Population Both Drug and Disease Factors Alter PK –Hydrophilic –Lipophilic Standard Dosing Regimens (no ICU pts) Individualized Dosing Strategies likely necessary to optimize

* Smaller Vd * Likely Renal Eliminated Unchanged * Increased Cl In Sepsis Hydrophilic agents Beta-lactams Amino- Glycosides Glycopeptides Lipophilic agents Larger Vd Likely Hepatic Elimination Metabolized Fluoroquinolones Macrolides Rifampin Linezolid PK Changes in Critically ill

Critical illness PK Changes Aminoglycosides –↑ ↑ Vd, Cl ↑or↓ Quinolones –Minimal ↑ Vd Glycopeptides –↑ ↑ Vd, Cl ↑or↓ (variable hepatic Cl) Beta-Lactams –↑ ↑ Vd, Cl ↑or↓

Optimizing Antimicrobial Therapy Concentration at Infection Site PK Pathogen MIC/MBC Antibiotic PD Bacterial Killing Outcome Host Factors

SUSCEPTIBILITY TESTING AND BREAKPOINTS

J Infect Dis 1987;155:93-99 & Antimicrob Agents Chemother 1991;35: Relationship: MIC vs MBC vs Breakpoint MIC Concentration (mg/L) Time (h) MBC Cp. max Breakpoint

AST and PKPD Relationships of S to I to R, more predictable with the application of PKPD Recently, breakpoints have changed largely due to bacterial resistance, micro diagnostics, and PKPD CLSI sets BP’s, recognized by FDA but FDA still sets its own BP. Can be modified by CLSI after 2 years. Labreche MJ, Recent Updates on the Role of PK-PD in AST. RID June 2013

Impact of PKPD on BP Vancomycin – PK/PD target is AUC/MIC => 400 Leading to higher trough’s MRSA MIC of 0.5 or 1 trough of 15 achieves target => 400, MIC 2.0 does not CLSI 2006 lowered BP to 2 or less due to hMRSA, MIC creep Labreche MJ, Recent Updates on the Role of PK-PD in AST. RID June 2013

Impact of PKPD on BP CLSI 2008 BP change for Strep pneumonia –Meningitis <= 0.06 –Non-meningitis <= 2.0 CLSI 2010 Enterobacteriaceae –Cefazolin BP lowered from 8 to 1 –2011 increased BP up to 2.0 –Based on dose of 2g q8h Labreche MJ, Recent Updates on the Role of PK-PD in AST. RID June 2013

Impact of PKPD on BP CLSI 2014 –Urine susceptibility BP for oral ceph’s <= 16 for UNCOMPLICATED UTI CLSI concerns over rising ceph mic’s to KEP bacteria – could harbor ESBL’s –Lowered BP’s to KEP, eliminated ESBL phenotypic testing (ceftaz/clav disk) Labreche MJ, Recent Updates on the Role of PK-PD in AST. RID June 2013

Impact of PKPD on BP Cefepime and Susceptible Dose- dependent (SDD) –Clinical data higher cefepime MIC = worse outcomes despite “susceptible” –2014 CLSI lowered BP to = 8.0 as resistant and 4 to 8 as SDD based in part on Time > MIC estimations Labreche MJ, Recent Updates on the Role of PK-PD in AST. RID June 2013

FDA BP for Susceptible CLSI BP for Susceptible CLSI BP for SDDDose for CLSI BP For Enterobacteracae Cefazolin≤ 8≤ 2 2g q8h Ceftriaxone≤ 8≤ 1 Cefepime≤ 8≤ 2 41g q8 or 2g q12h 82g q8h Aztreonam≤ 8≤ 1 Ertapenem≤ 2≤ 0.25 Imipenem≤ 4≤ 1.0 Meropenem≤ 4≤ 1.0 DoripenemFDA = 0.5≤ 1.0 Pip-Tazo≤ 32≤ 16 For Pseudomonas Meropenem≤ 4≤ 2 Doripenem≤ 2 Imipenem≤ 4≤ 2 Pip-Tazo≤ 64≤ 16 Cefepime≤ 8

PK-PD TARGETS WHAT DOES IT MEAN?

How to Pick an Antibiotic ? You Want the Most “Potent” Abx So You Line Them up & Pick the Lowest MIC - No! You Can Not Just Compare the MIC’s –Differing Intrinsic Activity = Different MIC’s –Antibiotics tested at different MIC ranges –Abx have Very Different Serum Blood Concentrations

Antibiotic “Potency” - Concentration Dependent Cp A 1 mcg/ml= Ratio = 10 MIC 0.1mcg/ml Cp B 10 mcg/ml=Ratio = 10 MIC 1 mcg/ml Cp C 100 mcg/ml=Ratio = 10 MIC 10 mcg/ml

Pharmacodynamics Clin Inf Dis 1998;26:1-12 Crit Care Clin 2011;27:1-18 Crit Care Clin 2011;27:19-34 Crit Care Med 2009;37:840-51

PD Parameters Predictive of Outcome Drusano & Craig. J Chemother 1997;9:38–44 Drusano et al. Clin Microbiol Infect 1998;4 (Suppl. 2):S27–S41 Vesga et al. 37th ICAAC 1997 Parameter correlating with efficacy T>MIC AUC:MIC C max :MIC ExamplesCarbapenems Cephalosporins Macrolides Penicillins Linezolid Azithromycin Fluoroquinolones Ketolides Vancomycin Daptomycin Aminoglycosides Fluoroquinolones Daptomycin Ketolides Organism killTime-dependentConcentration- dependent Concentration- dependent Therapeutic goal Maximize duration of exposure Maximize exposure Maximize drug concentration

ANTIBIOTIC “POTENCY” CONSIDER DRUG LEVELS, BACTERICIDAL CHARACTERISTICS, AND BACTERIAL SUSCEPTIBILITY

Aminoglycosides MIC Time C-p

Aminoglycosides Concentration Dependent Killing Significant Post Antibiotic Effect “Optimal” Peak:mic Ratio 8-10:1 Higher Peak = Greater Bactericidal effect Clinical Data supports Improved Outcome with Higher Peak

Aminoglycosides in Critical Illness Increased Vd Reduced Cmax Optimized PK/PD Dosing Strategy Uses 7mg/kg large daily dosing –Maximize Cmax/MIC ratio –Reduced Toxicity Recommend Individualized Dose Monitoring – with Interval Extension

Conventional (three-times daily regimen) Nicolau DP et al. Antimicrob Agents Chemother. 1995;39:650–655 Once-daily vs. Conventional Three-times Daily Aminoglycoside Regimens Concentration (mg/L) Time (hours) Once-daily regimen 2 2 MIC Cmax:MIC model For optimal response, Peak concentration: MIC ratio should be between 8-12 to 1

Gentamicin monitoring 1 Hartford Nomogram 7 mg/Kg OD Precise Times of collection required Collection 6-12Hrs after dose

Aminoglycosides — Relationship Between C max :MIC Ratio and Clinical Response C max :MIC Clinical response (%) (%) Moore RD et al. J Infect Dis. 1987;155:93-99.

Extended Interval Dosing of Aminoglycosides Clin Infect Dis 2000 Mar;30(3):433-9 National survey of extended-interval aminoglycoside dosing (EIAD). Chuck SK, Raber SR, Rodvold KA, Areff D. 500 acute care hospitals in the United States EIAD adopted in 3 of every 4 acute care hospitals 4-fold increase since 1993 written guidelines for EIAD in 64% of all hospitals rationale 87.1% : equal or less toxicity, 76.9% : equal efficacy 65.6% :cost-savings dose: > 5 mg/Kg 47% used extended interval in case of decline in renal function (38% with Hartford nomogram)

MIC Time C-p AUC Fluoroquinolones

Quinolones MOA: Interfere with DNA Replication Rate of kill increases with concentration AUC/MIC ratio >= 125 drives effect PK/PD analyses suggest that ciprofloxacin and levofloxacin MICs should be ≤ and ≤ , respectively, for isolates to be considered susceptible PTA cipro 400 q8h less than 90% for MIC 0.5, over 90% for 0.25 (DeRyke, et al. 2007; Frei, et al. 2008).DeRyke, et al.Frei, et al.

Relationship Between AUC 24 /MIC and Efficacy of Ciprofloxacin in Patients with Serious Bacterial Infections Forrest A, et al. AAC, 1993; 37:

Fluoroquinolone Pharmacodynamics: S. pneumoniae Antibiotic Outcome Parameter and Value Source Levofloxacin, ciprofloxacin, trovafloxacin AUC:MIC > 35 IVPDM Ciprofloxacin, levofloxacin AUC:MIC IVPDM Ciprofloxacin, ofloxacin, trovafloxacin AUC:MIC IVPDM Ciprofloxacin, levovfloxacin AUC:MIC IVPDM Quinolones AUC:MIC > 40 IVPDM Sitafloxacin AUC:MIC = 37 Murine thigh and lung infection model Gatifloxacin AUC:MIC = 52 Murine thigh and lung infection model Gemifloxacin AUC:MIC = 35 Murine thigh and lung infection model Gunderson BW, et al. Pharmacotherapy Nov;21(11 Pt 2):302S-318S

Fluoroquinolone Pharmacodynamics: Gram Negative Bacilli AntibioticOrganism/Class Outcome Parameter and Value Source Enoxacin P. aeruginosa, E. coli Cmax:MIC>8IVPDM Ciprofloxacin P. aeruginosa Cmax:MIC>8IVPDM Ciprofloxacin, ofloxacin P. aeruginosa AUC:MIC>100IVPDM Lomefloxacin Cmax:MIC>10 Neutropenic rat sepsis model GatifloxacinEnterobacteriacaeAUC:MIC=48 Murine thigh and lung infection model SitafloxacinEnterobacteriacaeAUC:MIC=43 Ciprofloxacin GNR, mostly LRTI AUC:MIC>125 Human, retrospective Ciprofloxacin GNR, vent dependent AUC:MIC>100 Human, retrospective Gunderson BW, et al. Pharmacotherapy Nov;21(11 Pt 2):302S-318S

MIC Time C-p AUC Glycopeptides

Vancomycin Time Dependent v Concentration Dependent PD Target: AUC/MIC Ratio > 400 to optimize MRSA eradication Monte Carlo Simulations: –Trough 15 – 20 mg/l and MIC ≤1.0 to achieve ratio >400 –Not achievable for MIC > 1.0

Vancomycin May be associated with higher failure rates with MRSA bacteremia or pneumonia or if hVISA Brown et al found 4x higher failure for ratio < 211 (complicated MRSA bacteremia and IE) Park et al found no outcome effect of MIC >1 or ≤ 1 Brown J et al. AAC 2012 Park S et al AAC 2013

MIC Time Beta Lactams Penicillins, Cephalosporins, Carbapenems, Monobactams

Beta-Lactam Agents MOA: acylation of PBP Reaction occurs over time –Slow, continuous kill characteristics –Shorter than the dosing interval –Maximal Kill 4-5x MIC PD Target – Time above MIC: –Penicillin 50% T > MIC –Cephs 60-70% T > MIC –Carbs 40% T > MIC

Beta-lactams in Critical Care Increased Vd – lower serum levels MOA: acylation of PBP Reaction occurs over time –Slow, continuous kill characteristics –Shorter than the dosing interval –Maximal Kill 4-5x MIC Data support better outcomes extended/continuous Advances in mathematical modeling allow clinicians to apply antimicrobial pharmacodynamics in practice Craig WA. Clin Infect Dis. Jan 1998;26(1):1-10; quiz Drusano GL. Nat Rev Microbiol. Apr 2004;2(4): Ambrose PG et al. Clin Infect Dis. Jan ;44(1): Lodise TP et al. Pharmacotherapy. Sep 2006;26(9):

PROBABILITY OF TARGET ATTAINMENT (PTA)

Beta-Lactam Agents PD Target – Time above MIC: –Penicillin 50% T > MIC –Cephs 60-70% T > MIC –Carbs 40% T > MIC

Prolonged Infusion – B lactams Conventional Infusion: min Prolonged Infusion: 3-4 hr: –Lower peak concentrations –Drug concentration remain in excess of MIC longer –Results in a more favorable PTA –Can also be achieved with more frequent dosing –Can address higher MIC values

Time Above MIC Antibiotic Y (q12h) MIC=8 %T>MIC=50% DI

Time Above MIC Antibiotic Y (q8h) MIC=8 %T>MIC>90% DI

Monte Carlo Simulations

COMPUTER MODELING AND MONTE CARLO SIMULATION computer-based mathematical construct integrate different variables : –tissue concentrations of an antibiotic –antimicrobial susceptibility –the PK-PD measure associated with efficacy The Point: to estimate the likelihood of achieving the PK- PD target (and thus, the likelihood of achieving cure). With these data inputs, antimicrobial exposures associated with a particular dosing regimen for a virtual population (often 5000, but any number can be selected) can be simulated, determining the proportion of infected patients expected to achieve the PK-PD target

Drusano GL. Monte Carlo Simulation: Applied to PK/PD Models Random PK and MIC values from data set Plot results in a probability chart Calculate PD parameter AUCMIC AUC:MIC

PTA of 50% fT>MIC Pip/Tazo 3.375g q6h (0.5) Lodise TP, et al. Antimicrob Agents Chemother 2004;48: DeRyke CA, et al. Diagn Microbiol Infect Dis 2007;58: % Target Attainment SIR

PTA of 50% fT>MIC Pip/Tazo 4.5g q6h (0.5) 90% Target Attainment SR DeRyke CA, et al. Diagn Microbiol Infect Dis 2007;58:

PTA for Prolonged Infusion Regimens of Piperacillin/tazobactam * Bactericidal Exposure defined as 50% fT>MIC Kim A, et al. Pharmacotherapy 2007;27: % Target Attainment

PTA Profiling of Cefepime SENTRY Bloodstream Isolates SR Lodise TP et al. Pharmacotherapy. Sep 2006;26(9):

PTA Profiling: Cefepime Tam et al. Pharmacotherapy 2003;23:

Pharmacodynamic Profiling: Meropenem S Lodise TP et al. Pharmacotherapy. Sep 2006;26(9):

% Target Attainment: M eropenem 1000 mg Probability of Target Target Attainment / Attainment / MIC distribution (%) MIC (mg/L) 0.5 h infusion 1.0 h infusion 2.0 h infusion 3.0 h infusion MIC distribution Distribution of P. aeruginosa MICs to meropenem Pharmacodynamic Target: 40% T>MIC Lomaestro BM, Drusano GL. AAC :

SUMMARY

Extended/Continuous Infusion and Better Outcomes ? EI/CI Carbapenem or Pip-Tazo vs Conventional 14 studies (1229 patients) Mortality lower with EI/CI (RR 0.59, CI ) –PNA subgroup (RR 0.50, CI ) Data from mainly non-randomized studies Need for blinded RCT to confirm Matthew E. Falagas et al CID 2013:56 (15 January) 273

Take Home Points Pay attention to pathogen MIC –Ensure CLSI BP being used –Elevated MIC ?, SDD ?, ESBL ?, amp-C ?, CRE ? –Low mic may not need EI dosing –Target higher MIC/Breakpoint MIC for EI dosing (or select different agent) –EI dosing results in serum levels above MIC for longer than standard dosing

Take Home Points Start with a loading dose Extended Infusion maintenance doses: –Zosyn 4hr infusion/dose –Meropenem 3 hr infusion/dose –Cefepime q6h or 3-4 hr infusions/dose Protocoled or Case by Case