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PK/PD Dosing in Critical Care
Jim Fenner Pharm D BCPS
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Conflicts of Interest
• None to report• No relevant financial relationships
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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
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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 practicalDeresinski S. Clin Infect Dis 2007; 45:S177-S183Allerberger F et al. Clin Microbiol Infect 2008; 14: 197-199.
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PHARMACOKINETIC CHANGES IN CRITICAL ILLNESS
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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
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* Smaller Vd* Likely Renal Eliminated Unchanged* Increased Cl In Sepsis
Hydrophilic agents Beta-lactams
Amino-GlycosidesGlycopeptides
Lipophilic agents
Larger VdLikely Hepatic Elimination Metabolized
FluoroquinolonesMacrolidesRifampinLinezolid
PK Changes inCritically ill
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Critical illness PK Changes
• Aminoglycosides– ↑ ↑ Vd, Cl ↑or↓
• Quinolones– Minimal ↑ Vd
• Glycopeptides– ↑ ↑ Vd, Cl ↑or↓ (variable hepatic Cl)
• Beta-Lactams– ↑ ↑ Vd, Cl ↑or↓
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Optimizing Antimicrobial Therapy
Concentrationat Infection
SitePK
PathogenMIC/MBC
AntibioticPD
BacterialKilling
Outcome
Host Factors
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SUSCEPTIBILITY TESTING AND BREAKPOINTS
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J Infect Dis 1987;155:93-99 & Antimicrob Agents Chemother 1991;35:399-405.
Relationship: MIC vs MBC vs Breakpoint
MIC
Con
cent
ratio
n (m
g/L
)
Time (h)
MBC
Cp.max
Breakpoint
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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
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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
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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
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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
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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 <= 2.0, > = 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
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FDA BP for Susceptible
CLSI BP for Susceptible
CLSI BP for SDD Dose for CLSI BP
For Enterobacteracae Cefazolin ≤ 8 ≤ 2 2g q8hCeftriaxone ≤ 8 ≤ 1
Cefepime ≤ 8 ≤ 24 1g q8 or 2g q12h8 2g q8h
Aztreonam ≤ 8 ≤ 1 Ertapenem ≤ 2 ≤ 0.25 Imipenem ≤ 4 ≤ 1.0 Meropenem ≤ 4 ≤ 1.0 Doripenem FDA = 0.5 ≤ 1.0 Pip-Tazo ≤ 32 ≤ 16 For Pseudomonas Meropenem ≤ 4 ≤ 2 Doripenem ≤ 2 ≤ 2 Imipenem ≤ 4 ≤ 2 Pip-Tazo ≤ 64 ≤ 16 Cefepime ≤ 8 ≤ 8
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PK-PD TARGETSWHAT DOES IT MEAN?
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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
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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
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Pharmacodynamics
Clin Inf Dis 1998;26:1-12Crit Care Clin 2011;27:1-18Crit Care Clin 2011;27:19-34Crit Care Med 2009;37:840-51
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PD Parameters Predictive of Outcome
Drusano & Craig. J Chemother 1997;9:38–44Drusano et al. Clin Microbiol Infect 1998;4 (Suppl. 2):S27–S41
Vesga et al. 37th ICAAC 1997
Parameter correlatingwith efficacy T>MICAUC:MICCmax:MICExamples Carbapenems
CephalosporinsMacrolidesPenicillinsLinezolid
AzithromycinFluoroquinolonesKetolidesVancomycinDaptomycin
AminoglycosidesFluoroquinolonesDaptomycinKetolides
Organism kill Time-dependentConcentration-dependent
Concentration-dependent
Therapeuticgoal
Maximize durationof exposure
Maximizeexposure
Maximize drugconcentration
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ANTIBIOTIC “POTENCY”CONSIDER DRUG LEVELS, BACTERICIDAL CHARACTERISTICS, AND BACTERIAL SUSCEPTIBILITY
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Aminoglycosides
MIC
Time
C-p
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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
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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
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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
Once-daily vs. Conventional Three-times Daily Aminoglycoside Regimens
Concentration (mg/L)
00
88
1414
44
66
1010
1212
Time (hours)00 1212 2424202044 88 1616
Once-daily regimenOnce-daily regimen
22MIC
Cmax:MIC modelFor optimal response,
Peak concentration: MIC ratio should be between 8-12 to 1
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Gentamicin monitoring 1
Hartford Nomogram
7 mg/Kg OD
•Precise Times of collection required
•Collection 6-12Hrs after dose
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Aminoglycosides —Relationship Between Cmax:MIC Ratio and Clinical Response
55
6570
8389 92
0
10
20
30
40
50
60
70
80
90
100
2 4 6 8 10 12+
Cmax:MIC
Clinical response
(%)
Moore RD et al. J Infect Dis. 1987;155:93-99.
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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)
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MIC
Time
C-p
AUC
Fluoroquinolones
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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 ≤0.125-0.25 and ≤0.25-0.5, 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).
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Relationship Between AUC24/MIC and Efficacy of Ciprofloxacin in Patients with Serious Bacterial Infections
0
20
40
60
80
100
% E
ffic
acy
0-62.5 62.5-125 125-250 250-500 >500
24-Hour AUC/MIC
Clinical Microbiologic
Forrest A, et al. AAC, 1993; 37: 1073-1081
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Fluoroquinolone Pharmacodynamics: S. pneumoniae
Antibiotic Outcome Parameter and Value Source
Levofloxacin, ciprofloxacin, trovafloxacin AUC:MIC > 35 IVPDM
Ciprofloxacin, levofloxacin AUC:MIC 30-35 IVPDM
Ciprofloxacin, ofloxacin, trovafloxacin AUC:MIC 44-49 IVPDM
Ciprofloxacin, levovfloxacin AUC:MIC 32-64 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. 2001 Nov;21(11 Pt 2):302S-318S
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Fluoroquinolone Pharmacodynamics: Gram Negative Bacilli
Antibiotic Organism/Class Outcome Parameter and Value Source
Enoxacin P. aeruginosa, E. coli Cmax:MIC>8 IVPDM
Ciprofloxacin P. aeruginosa Cmax:MIC>8 IVPDM
Ciprofloxacin, ofloxacin
P. aeruginosa AUC:MIC>100 IVPDM
Lomefloxacin P. aeruginosa Cmax:MIC>10 Neutropenic rat sepsis model
Gatifloxacin Enterobacteriacae AUC:MIC=48 Murine thigh and lung infection model
Sitafloxacin Enterobacteriacae AUC:MIC=43 Murine thigh and lung infection model
Ciprofloxacin GNR, mostly LRTI AUC:MIC>125 Human, retrospective
Ciprofloxacin GNR, vent dependent AUC:MIC>100 Human, retrospective
Gunderson BW, et al. Pharmacotherapy. 2001 Nov;21(11 Pt 2):302S-318S
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MIC
Time
C-p
AUC
Glycopeptides
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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
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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
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MIC
Time
Beta LactamsPenicillins, Cephalosporins, Carbapenems, Monobactams
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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
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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.2-4
1Craig WA. Clin Infect Dis. Jan 1998;26(1):1-10; quiz 11-12. 2Drusano GL. Nat Rev Microbiol. Apr 2004;2(4):289-300. 3Ambrose PG et al. Clin Infect Dis. Jan 1 2007;44(1):79-86. 4Lodise TP et al. Pharmacotherapy. Sep 2006;26(9):1320-1332.
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PROBABILITY OF TARGET ATTAINMENT (PTA)
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Beta-Lactam Agents
• PD Target – Time above MIC:– Penicillin 50% T > MIC– Cephs 60-70% T > MIC– Carbs 40% T > MIC
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Prolonged Infusion – B lactams
• Conventional Infusion: 30-60 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
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Time Above MIC Antibiotic Y (q12h)
1
10
100
0 4 8 12 16 20 24
Time (hours)Ant
ibio
tic
Y C
once
ntra
tion
(ug
/ml) MIC=8 %T>MIC=50% DI
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Time Above MIC Antibiotic Y (q8h)
1
10
100
0 4 8 12 16 20 24
Time (hours)Ant
ibio
tic
Y C
once
ntra
tion
(ug
/ml) MIC=8 %T>MIC>90% DI
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Monte Carlo Simulations
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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
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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 PDparameter
AUC MIC
AUC:MIC
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PTA of 50% fT>MIC Pip/Tazo 3.375g q6h (0.5)
MIC (mcg/ml)
0.25 0.5 1 2 4 8 16 32 64 128
Pro
ba
bilit
y o
f T
arg
et
Att
ain
me
nt
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
50% fT>MIC
Lodise TP, et al. Antimicrob Agents Chemother 2004;48:4718-24.DeRyke CA, et al. Diagn Microbiol Infect Dis 2007;58:337-44.
90% Target Attainment
S I R
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PTA of 50% fT>MICPip/Tazo 4.5g q6h (0.5)
MIC (mcg/ml)
0.06 0.125 0.25 0.5 1 2 4 8 16 32 64 128
Pro
ba
bili
ty o
f T
arg
et
Att
ain
me
nt
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
50% fT>MIC
90% Target Attainment
S R
DeRyke CA, et al. Diagn Microbiol Infect Dis 2007;58:337-44.
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PTA for Prolonged Infusion Regimens of Piperacillin/tazobactam
MIC (mcg/ml)
8e-30.0160.0320.060.1250.25 0.5 1 2 4 8 16 32 64 128
Pro
bab
ility
of
Tar
ge
t A
tta
inm
ent
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
3.375g q8h (4hr INF)4.5g q8h (4hr INF)4.5g q6h (3hr INF)
* Bactericidal Exposure defined as 50% fT>MIC
Kim A, et al. Pharmacotherapy 2007;27:1490-7.
90% Target Attainment
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PTA Profiling of Cefepime SENTRY Bloodstream Isolates
Probability of 67% fT>MIC
0
20
40
60
80
100
<.25 0.25 0.5 1 2 4 8 16
MIC (mg/L)
Pro
bab
ilit
y o
f T
arg
et
Att
ain
men
t (%
)
0
20
40
60
80
100
MIC
dis
trib
uti
on
(%
)
Cefepime 2 G Q12H
Cefepime 1 G Q6H
Cefepime 2 G Q8H
Pseudomonas
E. coli
Klebsiella
S R
Lodise TP et al. Pharmacotherapy. Sep 2006;26(9):1320-1332.
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PTA Profiling:Cefepime
CLCR 90 mL/min (67% DI)
0
20
40
60
80
100
<.25 0.25 0.5 1 2 4 8 16
MIC (mg/L)
Pro
bab
ilit
y o
f T
arg
et A
ttai
nm
ent
(%)
0
20
40
60
80
100
2 G Q12H (30 min)
2 G Q12H (6 hr)
2 G Q8H (30min)
4 G over 24 hr
1 G Q6H (30 min)
Tam et al. Pharmacotherapy 2003;23:291-295.
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Pharmacodynamic Profiling: Meropenem
40% T>MIC (free drug)
0
20
40
60
80
100
0.25 0.5 1 2 4
MIC (mg/L)
Pro
bab
ilit
y o
f T
arg
et
Att
ain
men
t (%
)
0
20
40
60
80
100
1 G Q8H (30 min)
0.5 G Q8H (1 hr)
0.5 G Q6H (30min)
0.5 G Q8H (3 hr)
1 G Q8H (3 hr)
S
Lodise TP et al. Pharmacotherapy. Sep 2006;26(9):1320-1332.
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% Target Attainment: Meropenem 1000 mg
Probability of
Target
Attainment /
MIC distribution
(%)
100
90
80
70
60
50
40
30
20
10
00.01 1 10 100
MIC (mg/L)
0.5 h infusion
1.0 h infusion
2.0 h infusion
3.0 h infusion
MIC distributionDistribution of P. aeruginosa MICsto meropenem
Pharmacodynamic Target: 40% T>MIC
Lomaestro BM, Drusano GL. AAC 2005. 49: 461-3.
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SUMMARY
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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 0.41-
0.83)– PNA subgroup (RR 0.50, CI 0.26-0.96)
• Data from mainly non-randomized studies• Need for blinded RCT to confirm
• Matthew E. Falagas et al• CID 2013:56 (15 January) • 273
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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
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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
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