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Antibiotic Prescribing in Antibiotic Prescribing in Severe Severe SepsisSepsis

--

From Good to GreatFrom Good to GreatRobert G MastertonRobert G Masterton

NHS Ayrshire & ArranNHS Ayrshire & Arran

“Good to Great”“Good to Great”

Antibiotic stewardshipAntibiotic stewardshipMaximising existing antibiotic efficacyMaximising existing antibiotic efficacy

PK/PDPK/PD New dosing approachesNew dosing approaches

•• Increased drug dosesIncreased drug doses•• Increased duration of administrationIncreased duration of administration

Prolonged infusionProlonged infusion Continuous infusionContinuous infusion

Traditional Treatment ParadigmTraditional Treatment Paradigm

Conservative start with ‘workhorse’ antibioticsConservative start with ‘workhorse’ antibiotics

Reserve more potent drugs for nonReserve more potent drugs for non--respondersresponders

Does initial under treatment Does initial under treatment matter?matter?

Kreger. Am J Med 1980;68:344Kreger. Am J Med 1980;68:344––355355612 patients with Gram612 patients with Gram--negative negative

bacilli bloodstream infectionsbacilli bloodstream infectionsAppropriate antibiotic therapy Appropriate antibiotic therapy

reduced mortality rate by 50% across reduced mortality rate by 50% across all severities of underlying diseaseall severities of underlying disease

Early appropriate antibiotics reduced Early appropriate antibiotics reduced frequency of septic shock by 50%frequency of septic shock by 50%

The Effect of the Traditional ApproachThe Effect of the Traditional Approach

Kollef et al. Chest 1999;115:462–474

Inappropriate therapy (%)

0

30

50

10

Community-acquiredinfection

20

40

Hospital-acquiredinfection

Hospital-acquiredafter prior therapy forcommunity-acquired

17

34

45

0

20

40

60

80

100

McArthur Harbarth Micek Lee

AppropriateInappropriate

Morta

lity (

%)

p<0.05

MacArthur et al. Clin Infect Dis 2004;38:284–288; Harbarth et al. Am J Med 2003;115:529–35; Micek et al. Antimicrob Agents Chemother 2005;49:1306–11; Lee et al. Int J Clin Pract 2005;59:39–45.

n=2634n=2634

Suspected Suspected sepsissepsis

n=902n=902

Severe Severe sepsissepsis

n=305n=305

P. aeruginosaP. aeruginosaBSIBSI

n=132n=132

Nosocomial Nosocomial pneumoniapneumonia

Mortality Impact of Inadequate TherapyMortality Impact of Inadequate Therapy

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Ibrahim et al. Chest 2000; 118: 146-155

492 episodes of bacteremia492 episodes of bacteremiaAPACHE II score: 23.4 (8.7)APACHE II score: 23.4 (8.7)Surgical patients (30.3%)Surgical patients (30.3%)Medical patients (69.7&)Medical patients (69.7&)

p<0.001p<0.001

Adequate therapyInadequate therapy

0

30

50

10

Duration of MV

20

40

Length of ICUstay

p<0.001p<0.001p<0.001p<0.001

Length of Hospital

stay

Morbidity Impact of Inadequate TherapyMorbidity Impact of Inadequate Therapy Inadequate antibiotic therapyInadequate antibiotic therapyA risk factor for mortalityA risk factor for mortality

Vallés, et al. Chest 2003;123:1615–1624

1.0

0.8

0.6

0.4

0.2

020 4 6 8 10 12 14

A: Sepsis/severe sepsis andappropriate treatment

B: Sepsis/severe sepsis andinappropriate treatment

C: Septic shock and appropriate treatment

D: Septic shock and inappropriate treatment

D

C

B

A

Days

Cum

ulat

ive

surv

ival

(%)

Impact of appropriate antibiotic Impact of appropriate antibiotic therapy on survivaltherapy on survival

Rello et al. Crit Care Med 2003;31:2807Rello et al. Crit Care Med 2003;31:2807––28082808

Septic shockSeptic shock00

1010

2020

3030

4040

5050

SepsisSepsisSevere shockSevere shock

4343

23232020

Improved survival rate Improved survival rate (%)(%)

Inadequate therapy more Inadequate therapy more likely if resistance present, likely if resistance present, and resistant organisms and resistant organisms more commonly associated more commonly associated with inadequate therapywith inadequate therapy

Kollef. Clin Infect Dis 2000;31(Suppl. 4):S131–S138

Inadequate treatment (%)

0

10

20

30

40

P. aeruginosa S. aureus Acinetobacterspp.

Other K. pneumoniae

Pathogens associated with inadequate Pathogens associated with inadequate VAP antimicrobial therapyVAP antimicrobial therapy

Delay versus OutcomeDelay versus Outcome

0102030405060708090

0.5 1 2 3 4 5 6

Delay in treatment (hours) from hypotension onset

Surv

ivia

l (%

)

Each hour off delay carries 7.6% reduction

in survival

Kumar et al. Crit Care Med 2006; 34:1589-1596.

Delay versus OutcomeDelay versus Outcome

Kumar et al. Crit Care Med 2006; 34:1589-1596.

1 1.1 1.2 1.3

Adjusted Odds Ratio of Death

Culture +

Culture -

Community

Nosocomial

Respiratory

1546

608

1242

912

838

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Outcome Predictors in ESBL Outcome Predictors in ESBL Enterobacteriaceae BacteraemiaEnterobacteriaceae Bacteraemia

Tumbarello et al. AAC, 2007; 51: 1987–1994

Overall 21-day mortality rate (MR)

38.2% (71 of 186)

MR for patients (89 of 186 [47.8%]) with initial inadequate treated

59.5% versus 18.5%; OR 2.38; 95% CI 1.76 to 3.22; P < 0.001

Multivariate analysis of Multivariate analysis of MR in inadequate initial MR in inadequate initial antimicrobial therapyantimicrobial therapy

OR 6.28; 95% CI 3.18 to 12.42; P < 0.001

Multivariate analysis of Multivariate analysis of MR in MR in unidentified primary infection site

(OR 2.69; 95% CI 1.38 to 5.27; P 0.004)

New Treatment ParadigmNew Treatment Paradigm

Hit hard and early with appropriate antibioticHit hard and early with appropriate antibiotic

Short treatment durationShort treatment durationDeDe--escalate where possibleescalate where possible

The New Treatment ParadigmThe New Treatment Paradigm

Getting therapy right first timeGetting therapy right first time BroadBroad--spectrum initial empiric treatmentspectrum initial empiric treatmentOptimise antibiotic dosing and Optimise antibiotic dosing and

administration using PK/PD principles administration using PK/PD principles Knowledge of local patternsKnowledge of local patterns Tailor antibiotic therapy based on Tailor antibiotic therapy based on

microbiological results (demicrobiological results (de--escalation)escalation)Correct durationCorrect duration

Adequate treatment n=82Adequate treatment n=82 Inadequate treatment n=69Inadequate treatment n=69

Teixeira et al. J Hosp Infect 2007;65:361Teixeira et al. J Hosp Infect 2007;65:361––367367

Risk factors for inadequate treatment of VAP = MultidrugRisk factors for inadequate treatment of VAP = Multidrug--resistant bacteria (OR resistant bacteria (OR = 3.07), polymicrobial infection (OR = 3.67) and late= 3.07), polymicrobial infection (OR = 3.67) and late--onset VAP onset VAP (OR = 2.93)(OR = 2.93)

1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

00

Cum

ulat

ive su

rviva

lCu

mul

ative

surv

ival AdequateAdequate

InadequateInadequate

00 77 1414 2121 2828Time after VAP onset (days)Time after VAP onset (days)

New Paradigm New Paradigm –– recognising the risks!recognising the risks!

Peralta et al. J Antimicrob Chemother 2007;60:855Peralta et al. J Antimicrob Chemother 2007;60:855––886886

Frequency of the appropriateness of Frequency of the appropriateness of empiric antimicrobial therapy empiric antimicrobial therapy (a) and proportion of deaths (b) in (a) and proportion of deaths (b) in relation to the number of antibiotics relation to the number of antibiotics to which the to which the E. coliE. coli isolated from isolated from blood cultures was nonblood cultures was non--susceptiblesusceptible

Non-adequate

Adequate

Freq

uenc

y (%

)

40

30

20

10

00 1 2 ≥3

362

111

6250

12

24

26

9

Number of resistances

New Paradigm New Paradigm –– “right” and “right” and resistance”resistance”

Peralta et al. J Antimicrob Chemother 2007;60:855Peralta et al. J Antimicrob Chemother 2007;60:855––886886

Adequacy of empiric antibiotic Adequacy of empiric antibiotic treatment is an independent risk treatment is an independent risk factor for mortality in factor for mortality in E. coli E. coli bacteraemiabacteraemia

Dead

Surviving

Morta

lity (

%)

20

15

10

5

00 1 2 ≥3

363

118

78

67

5

8

10

12

Number of resistances

New Paradigm New Paradigm –– “right” and “right” and resistance”resistance”

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Mortality in ESBL Mortality in ESBL vs.vs. nonnon--ESBL ESBL Enterobacteriaceae bacteraemiaEnterobacteriaceae bacteraemia

Schwaber & Carmeli JAC 2007 60:913

Predictors of mortality in patients with BSI caused by Predictors of mortality in patients with BSI caused by ESBLESBL--producing producing EnterobacteriaceaeEnterobacteriaceae

59.5

18.5

0

10

20

30

40

50

60

70

Morta

lity (

%)

Inadequate initial therapy(n=89)

Adequate initial therapy(n=97)

p<0.001

n=186n=186Tumbarello et al. Antimicrob Agents Chemother 2007;51:1987Tumbarello et al. Antimicrob Agents Chemother 2007;51:1987––19941994

New Paradigm New Paradigm –– ESBL SepsisESBL Sepsis

Clinical impact of bacteraemia with ESBLClinical impact of bacteraemia with ESBL--producing producing EnterobacteriaceaeEnterobacteriaceae

0

10

20

30

40

50

60

70

Mortality Mortalitydue to

infection

Delay in appropriate

therapy

Dischargedto chronic

care

Inci

denc

e (%

)

CasesControls

Schwaber et al. Antimicrob Agents Chemother 2006; 50: 1257-1262All differences = p < 0.05All differences = p < 0.05

New Paradigm New Paradigm –– ESBL SepsisESBL SepsisMortality in ESBLMortality in ESBL--producing producing K. K.

pneumoniapneumonia

Paterson et al CID 2004;39: 31-7.

3.7

36.340

50

0

10

20

30

40

50

60

Type of therapy

All cause 14-day mortality (%)

Carbapenemmonotherapy

Quinolonemonotherapy

Cephalosporinmonotherapy

b-lactam / b-lactamase

inhibitor

(n=27) (n=11) (n=5) (n=4)

27.822.2

5.5

44.4

14

36.7 34.2

10.1

0

10

20

30

40

50

Non-survivors Survivors

p=0.40p=0.40

p=0.24p=0.24p=0.01p=0.01

p<0.001p<0.001

Patie

nts (

%)

Patie

nts (

%)

AminoglycosidesAminoglycosides(n=20)(n=20)

ββ--lactam/ lactam/ ββ--lactamase inhibitors lactamase inhibitors

(n=33)(n=33)

CarbapenemsCarbapenems(n=28)(n=28)

CiprofloxacinCiprofloxacin(n=16)(n=16)

n=97

n=97

Tumbarello et al. Antimicrob Agents Chemother 2007;51:1987Tumbarello et al. Antimicrob Agents Chemother 2007;51:1987––19941994

4 of Cipro failed isolates had a mutation at codon 83 of gyrA, and other 4 qnrB gene detected

Outcome by Class Outcome by Class v.v. Active Active AntimicrobialAntimicrobial

Carbapenems Carbapenems v.v. other betaother beta--lactams in lactams in severe infections severe infections

Systematic review of ICU RCTs 265 papers, 12 in meta-analysis (four 4GC and eight APP).

Carbapenems showed significant reduction in all-cause mortality (RR 0.62, 95% CI: 0.41 to 0.95; p=0.03).

Carbapenems showed significant reduction in withdrawals from adverse events (RR 0.65, 95% CI: 0.45 to 0.96; p=0.03).

In febrile neuropaenia carbapenems showed significant increase in: clinical response in first 72 h treatment (RR 1.37, 95% CI:

1.09 to 1.74; p=0.008) bacteriologic response (RR 1.73, 95% CI: 1.03 to 2.89;

p=0.04). Edwards et al. Eur J Clin Microbiol Infect Dis 2008: DOI 10.1007/s10096-008-0472-z

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Definition of DeDefinition of De--escalationescalation

“De-escalation of antibiotic therapy can be thought of as a strategy to balance the need to provide adequate initial antibiotic treatment of high-risk patients with the avoidance of unnecessary antibiotic utilization, which promotes resistance.”

Kollef. Kollef. Critical Care 2001, 5:189–195.

What DeWhat De--escalation escalation meansmeans………………..

Start with broad spectrum appropriate Start with broad spectrum appropriate agentagent

Stop if infection unlikelyStop if infection unlikelyChange to a narrower spectrum agent Change to a narrower spectrum agent Use single rather than multiple agentsUse single rather than multiple agentsShorten the course of therapy as Shorten the course of therapy as

much as possiblemuch as possibleVidaur. Vidaur. Resp Care 2005, 50: 965–974.

DeDe--escalation in VAPescalation in VAP Change of therapy was documented in 56.2%Change of therapy was documented in 56.2% DeDe--escalation = 31.4% (increasing to 38% if escalation = 31.4% (increasing to 38% if

isolates were sensitive)isolates were sensitive) De-escalation mortality rate lower than those who

continued initial regimen (18% vs 43%; p<0.05) Inappropriate antibiotic therapy = 9% of cases and Inappropriate antibiotic therapy = 9% of cases and

associated with 14.4% excess mortalityassociated with 14.4% excess mortality DeDe--escalation lower (p < .05) with nonfermenting escalation lower (p < .05) with nonfermenting

GramGram--negative bacilli (2.7% vs. 49.3%) and in latenegative bacilli (2.7% vs. 49.3%) and in late--onset pneumonia (12.5% vs. 40.7%)onset pneumonia (12.5% vs. 40.7%)

When the pathogen remained unknown, half of the When the pathogen remained unknown, half of the patients died and depatients died and de--escalation was not performedescalation was not performed

Rello J, et al. Crit Care Med 2004;32:2183–2190

Guidelines and DeGuidelines and De--escalationescalation

ICU imipenemICU imipenem--based regimenbased regimen After D3, therapy based on susceptibility resultsAfter D3, therapy based on susceptibility results Better empirical cover (81 vs 46%; p<0.01)Better empirical cover (81 vs 46%; p<0.01) No change in imipenem resistance ratesNo change in imipenem resistance rates

Soo Hoo et al. Chest 2005;128:2778–87

DeDe--escalation in Practiceescalation in PracticeDe-escalated (n=88)

Escalated (n=61)No change (n=245)

0

60

100

30

50

1020

40

Mortality %Mortality %

2040

80

Quinolone

% P

atter

ns o

f Mod

ificati

on%

Patt

erns

of M

odific

ation

Cefepime CarbapenemUreido/Mono

Kollef MH. Chest 2006; 129: 1210-1218

DeDe--escalation in VAPescalation in VAP(Surgical patients with septic shock)(Surgical patients with septic shock)

De-escalation No de-escalationRecurrent pneumonia 27.3% 35.1%Overall mortality 33.8% 42.1%

•• 138 Patients138 Patients•• Appropriate initial therapy (AIT) in 93%Appropriate initial therapy (AIT) in 93%•• DeDe--escalation in 55% of AIT patientsescalation in 55% of AIT patients•• Escalation in 8% of AIT patientsEscalation in 8% of AIT patients

Eachempati et al. J Trauma. 2009 ;66:1343-8.

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DeDe--escalation Dilemmasescalation Dilemmas When to deWhen to de--escalate to a escalate to a ““stopstop””

Day 3 and Microbiology negativeDay 3 and Microbiology negative No Systemic Inflammatory Response Syndrome (SIRS)No Systemic Inflammatory Response Syndrome (SIRS) White blood cell count and temperature not markedly and White blood cell count and temperature not markedly and

increasingly abnormalincreasingly abnormal

When not to deWhen not to de--escalate and to consider escalationescalate and to consider escalation Day 3 and Microbiology negativeDay 3 and Microbiology negative Patient clinically septicPatient clinically septic

•• SIRSSIRS•• Markedly abnormal temperatureMarkedly abnormal temperature•• Markedly abnormal white blood cell countMarkedly abnormal white blood cell count

How to improve deHow to improve de--escalation?escalation?Tracheal Aspirate (n = 81)Tracheal Aspirate (n = 81) BAL (n=62)BAL (n=62)

DeDe--escal (21%)escal (21%) NoNo DeDe--escal (66%)escal (66%) NoNo

15D15DMortalityMortality

5.8% 5.8% 34.3%34.3% 4.8%4.8% 23.8%23.8%

28D28DMortalityMortality

11.6%11.6% 45.3%45.3% 12.1%12.1% 38%38%

LOSLOSICUICU

17.2 +/17.2 +/-- 1.61.6 22.4 +/22.4 +/-- 6.46.4 17.2 +/17.2 +/-- 1.11.1 23.2 +/23.2 +/-- 66

LOSLOSHospitalHospital

23.1 +/23.1 +/-- 4.4*4.4* 29.9 +/29.9 +/-- 11.111.1 23.8 +/23.8 +/-- 2.4*2.4* 29.8 +/29.8 +/-- 11.411.4

* = p < 0.05* = p < 0.05

Giantsou et al. Intensive Care Med. 2007:33:1533Giantsou et al. Intensive Care Med. 2007:33:1533--40. 40.

Do you practice ‘deDo you practice ‘de--escalation’ escalation’ therapy?therapy?

Yes No

18%

82%1.1. YesYes2.2. NoNo

In my unit, most of my colleagues In my unit, most of my colleagues practice depractice de--escalation:escalation:

True

False

58%

42%

1.1. TrueTrue2.2. FalseFalse

SEPSIS

Increased Cardiac Index

Leaky Capillaries &/or altered

protein bindingEnd Organ

Dysfunction

Increased Clearances

Increased Volume of Distribution

Decreased Clearances

Low Serum Concentrations

High Serum Concentrations

Roberts & Lipman Clin Pharmacokinet 2006; 45:755-73

Sepsis pathophysiology v. Antibiotic

pharmacologyAntibiotic dosing in severe sepsisAntibiotic dosing in severe sepsis

Provided:Provided: There is acceptance that the ratio of serum antibiotic There is acceptance that the ratio of serum antibiotic

concentration to MIC has a definite impact on clinical concentration to MIC has a definite impact on clinical outcomeoutcome

That the exact target values to be reached are knownThat the exact target values to be reached are known Both the MIC and the serum concentration of an Both the MIC and the serum concentration of an

antibiotic can be determined antibiotic can be determined

The dosing of critically ill patients should be adapted in order to achieve target values based on serum

antibiotic concentrations and MICs

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Target Attainment: An Aid to CliniciansTarget Attainment: An Aid to Clinicians

TA provides insightinto the appropriate antibioticoptions for empiric therapy

Ensure maximal bacterial killing

Offers another indicator of clinical success

Complements MIC/susceptibility data

TA: Shifting the ParadigmTA: Shifting the Paradigm

Probability ofTARGET

ATTAINMENT

Probabilitycalculation

Input variables

Microbiologydata

Pharmacokineticdata

Dosingregimens

Monte Carlosimulation

using defined bactericidal target

values

Simulation

S. marcescensA. baumanniiP. aeruginosaS. marcescensA. baumanniiP. aeruginosa

0.5 h Inf(%)

98.589.789.4 94.572.772.5

1.0 h Inf(%)

98.991.491.296.276.476.0

2.0 h Inf(%)

99.494.194.498.183.782.6

3.0 h Inf(%)

99.695.896.798.989.287.9

Target attainment rates for a 2000Target attainment rates for a 2000--subject Monte Carlo subject Monte Carlo simulation of q 8 h dose at steady statesimulation of q 8 h dose at steady state

Target endpoint Target endpoint –– maximal cell killmaximal cell kill

Prolonged Infusion and DoseProlonged Infusion and Dose-- making the best of both worldsmaking the best of both worlds

Mer

oM

ero

2000

mg

2000

mg

Mer

oM

ero

500m

g50

0mg

Drusano G. Personal Communication.

Target AttainmentTarget Attainment

►►Target attainment for maximum Target attainment for maximum bactericidal effectbactericidal effect

►►Commonly accepted maximum targets are:Commonly accepted maximum targets are:

Forrest ,1993; Drusano, 1997Forrest ,1993; Drusano, 1997

Carbapenems

b-Lactams

Quinolones

40% of time >MIC

50% of time >MIC

AUC:MIC ratio >125

Antibiotic Target

Improving TA by prolonging Improving TA by prolonging infusion timeinfusion time

30 min30 min 3 hr3 hr 4 hr4 hrIncrease*Increase*

(%)(%)

MeropenemMeropenem 1 g q8h1 g q8h 77.177.1 83.883.8 —— +6.7+6.7

2 g q8h2 g q8h 84.184.1 88.188.1 —— +4.7+4.7

Pip/tazoPip/tazo 4.5 g q8h4.5 g q8h 56.456.4 —— 80.780.7 +24.3+24.3

Ludwig, et al. Int J Antimicrob Agents 2006;28:433–438

*PD attainment

Calculated probability Calculated probability of TA of TA vs clinical cure and microbiological outcomevs clinical cure and microbiological outcomePatients with complicated skin and skin structure infectionsPatients with complicated skin and skin structure infections

treated with meropenem 500 mg q8htreated with meropenem 500 mg q8h

Cure rate (%)Cure rate (%)

AActual ctual responseresponse

(n=96) (n=96)

PredictedPredictedresponseresponse(n=1000)(n=1000)

ClinicalClinical 9292 9797(Bacteriostatic (Bacteriostatic T>MIC 20%)T>MIC 20%)

MicrobiologicalMicrobiological 8383 9797

ClinicalClinical 9292 91.991.9((BBactericidactericidal al T>MIC 40%) T>MIC 40%)

MicrobiologicalMicrobiological 8383 91.991.9

‘The use of Monte Carlo simulation to predict the clinical response of meropenem in complicated skin and skin structure infections is accurate’

Kuti, et al. Int J Antimicrob Agents 2006;28:62–68

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Meropenem 1000 mg Meropenem 1000 mg -- Percent target attainment for maximal killPercent target attainment for maximal kill

100908070605040302010

00.01

%

1 10 100MIC (mg/L)

0.5 h infusion1.0 h infusion2.0 h infusion3.0 h infusion

Drusano G. Clin Infect Dis 2003;36 (Suppl 1):S42-50.

Prolonged infusion Prolonged infusion -- making the most of dosemaking the most of dose

100908070605040302010

00.01

%

1 10 100MIC (mg/L)

0.5 h infusion1.0 h infusion2.0 h infusion3.0 h infusionMIC Distribution

Distribution of P. aeruginosaMICs to meropenem

Drusano G. Clin Infect Dis 2003;36 (Suppl 1):S42-50.

Meropenem 1000 mg Meropenem 1000 mg -- Percent target attainment for maximal kill Percent target attainment for maximal kill

Prolonged infusion Prolonged infusion -- making the most of dosemaking the most of dose

MetaMeta--analysis of Continuous analysis of Continuous Infusion TherapyInfusion Therapy

9 RCTs of beta-lactams, aminoglycosides, and vancomycin. Clinical failure lower (not statistical significant), in

continuous infusion (pooled OR 0·73, 95% CI 0·53–1·01) difference statistically significant in RCT subset where

same total daily antibiotic dose for both intervention arms (OR 0·70, 95% CI 0·50–0·98)

No differences in mortality and nephrotoxicity mortality OR 0·89, 95% CI 0·48–1·64; nephrotoxicity OR 0·91, 95% CI 0·56–1·47

Kasiakov et al. Kasiakov et al. Lancet Inf Dis, 2005; 5, 581–89

12 evaluable trials 2 fourth generation cephalosporin 4 third generation cephalosporin 1 second generation cephalosporin 3 beta-lactam/BL inhibitor 2 meropenem

Clinical indications 7 Severe Sepsis/Critically ill 3 VAP 1 intra-abdominal sepsis 1 P aeruginosa infection

Roberts et al. Int J Antimicrob Agents. 2007;30:11-8.

BetaBeta--lactamlactam Continuous InfusionContinuous Infusionin Severe Infectionsin Severe Infections

BetaBeta--lactam Continuous Infusionlactam Continuous Infusionin Severe Infectionsin Severe Infections

Role of continuous infusion beta-lactams unclear. Increasing evidence suggests potential benefits. Superior C ss of continuous administration v. C

min of bolus dosing translates into better pharmacodynamic target attainment.

More reliable pharmacokinetic parameters expected from continuous infusion especially in seriously ill patients

When MIC of pathogen ≥4 mg/L continuous administration provides pharmacodynamic advantages even at lower doses.

Roberts et al. Int J Antimicrob Agents. 2007;30:11-8.

Carbapenem by InfusionCarbapenem by Infusion

Meropenem by continuous infusion (1 g Meropenem by continuous infusion (1 g over 360 min every 6 h), over 360 min every 6 h), v,v, intermittent intermittent infusion (1 g over 30 min every 6 h). (Plus infusion (1 g over 30 min every 6 h). (Plus tobramycin; 14 days)tobramycin; 14 days) Continuous infusion greater clinical cure rate Continuous infusion greater clinical cure rate

(38 of 42, 90.47%, vs 28 of 47, 59.57%, (38 of 42, 90.47%, vs 28 of 47, 59.57%, respectively, with OR 6.44 [95% CI 1.97 to respectively, with OR 6.44 [95% CI 1.97 to 21.05; p < 0.001]). 21.05; p < 0.001]).

Lorente et al. Ann Pharmacother. 2006;40:219-23.

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Doripenem in Extended InfusionDoripenem in Extended Infusion 531 VAP cases treated for 7531 VAP cases treated for 7--14 days 14 days

doripenem 500 mg q 8 hrs via a 4doripenem 500 mg q 8 hrs via a 4--hr intravenous hr intravenous infusion infusion

imipenem 500 mg q 6 hrs or 1000 mg every 8 hrs via imipenem 500 mg q 6 hrs or 1000 mg every 8 hrs via 3030-- or 60or 60--min intravenous infusions respectivelymin intravenous infusions respectively

Clinically evaluable cure rates = 68.3% Clinically evaluable cure rates = 68.3% doripenem and 64.2% imipenem doripenem and 64.2% imipenem

Pseudomonas aeruginosa clinical cure = 80.0% Pseudomonas aeruginosa clinical cure = 80.0% doripenem and 42.9% imipenem doripenem and 42.9% imipenem

Microbiological cure was 65.0% doripenem and Microbiological cure was 65.0% doripenem and 37.5% imipenem 37.5% imipenem

Chastre et al. Crit Care Med. 2008;36:1089-96.

Doripenem in Extended InfusionDoripenem in Extended Infusion

18% (5 of 28) of P. aeruginosa isolates had 18% (5 of 28) of P. aeruginosa isolates had minimum inhibitory concentration ≥ 8 minimum inhibitory concentration ≥ 8 µµ/mL at /mL at baseline or following therapy in the doripenem baseline or following therapy in the doripenem arm compared with 64% (16 of 25) in the arm compared with 64% (16 of 25) in the imipenem treatment group (p = .001). imipenem treatment group (p = .001).

Clinical cure rate was higher with doripenem Clinical cure rate was higher with doripenem than imipenemthan imipenem Higher APCHE II scores Higher APCHE II scores Older ages. Older ages.

Chastre et al. Crit Care Med. 2008;36:1089-96.

Extended Infusion MeropenemExtended Infusion Meropenem

Day 3 % Success 40% (6/15) 33.33% (5/15) p>0.05Day 3 % Success 40% (6/15) 33.33% (5/15) p>0.05Day 5 % Success 86.67% (13/15) 93.33% (14/15) p>0.05Day 5 % Success 86.67% (13/15) 93.33% (14/15) p>0.05Day 7 % Success 100% (15/15) 100% (15/15) p>0.05Day 7 % Success 100% (15/15) 100% (15/15) p>0.05Relapse ratio 6.67% (1/15) 0 p>0.05Relapse ratio 6.67% (1/15) 0 p>0.05Days of treatment* 5.27Days of treatment* 5.27±±1.95 4.801.95 4.80±±1.36 p>0.051.36 p>0.05Meropenem Cost 7115.25Meropenem Cost 7115.25±±349.84 4685.33349.84 4685.33±±248.26 p<0.01 248.26 p<0.01 (RMB)(RMB)

traditional traditional groupgroup

infusion infusion groupgroup p Valuep Value

*Days of treatment = Mean *Days of treatment = Mean ±± 1 Standard Deviation1 Standard Deviation

Extended infusion meropenem in VAP due to MDR A baumanii1g q8 over 1 hour versus 500mg q6 over 3 hours

Wang. IJAA 2008 In Press

Meropenem Infusion in the Meropenem Infusion in the Critically IllCritically Ill

Critically ill patients with sepsis and Critically ill patients with sepsis and without renal dysfunction.without renal dysfunction.

Continuous infusion > median trough Continuous infusion > median trough concentrationsconcentrations plasma (intermittent bolus 0 versus infusion 7 plasma (intermittent bolus 0 versus infusion 7

mg/L) mg/L) subcutaneous tissue (0 versus 4 mg/L).subcutaneous tissue (0 versus 4 mg/L).

Roberts et al. J Antimicrob Chemother 2009; 64, 142–150.

Roberts et al. J Antimicrob Chemother 2009; 64, 142–150.

Meropenem Infusion in the Meropenem Infusion in the Critically IllCritically Ill

Roberts et al. J Antimicrob Chemother 2009; 64, 142–150.

Meropenem Infusion in the Meropenem Infusion in the Critically IllCritically Ill

26/06/2010

10

Meropenem Meropenem –– best of both worldsbest of both worlds

Optimized twoOptimized two--step infusion therapy (OTIT step infusion therapy (OTIT = 0.25= 0.25--1 g/0.5 h + 0.251 g/0.5 h + 0.25--1 g/4 h 1 g/4 h t.i.dt.i.d.) v. .) v. prolonged infusion therapy (PIT = 0.5prolonged infusion therapy (PIT = 0.5--2 2 g/4 h g/4 h t.i.dt.i.d) and traditional infusion therapy ) and traditional infusion therapy (TIT = 0.5(TIT = 0.5--2 g/0.5h 2 g/0.5h t.i.dt.i.d) against ) against Pseudomonas aeruginosa Pseudomonas aeruginosa

Bactericidal effect of OTIT ≥ PIT> TIT. Bactericidal effect of OTIT ≥ PIT> TIT. TA probabilities of OTIT at TA probabilities of OTIT at MICsMICs of 2of 2--8 8

mg/L > TIT and 4mg/L > TIT and 4-- and 6 hand 6 h--PITPIT

Eguchi et al. J Infect Chemother. 2010 Jan 14. [Epub ahead of print].

CI, confidence interval; ME, multiplicative effect

Outcome OR (95% CI) or ME

P-value

MortalityLength of stay

Delay in appropriate therapyCost of hospitalisation

3.6 (1.4-9.5)1.56

25.1 (10.5-60.2)1.57

0.0080.001

<0.0010.003

Schwaber et al. Antimicrob Agents Chemother 2006; 50: 1257-1262

ESBL production in Enterobacteriaceae bacteremiaESBL production in Enterobacteriaceae bacteremia

Cost and the paradigmCost and the paradigm

Economic impact of bacteraemia with ESBLEconomic impact of bacteraemia with ESBL--producing producing EnterobacteriaceaeEnterobacteriaceae

0

10000

20000

30000

40000

50000

Average hospital cost

Cost(US$)

CasesControls

Schwaber et al. Antimicrob Agents Chemother 2006; 50: 1257-1262

Cost of shortCost of short--term term meropenem treatment:meropenem treatment:

1 week: £601.65 1 week: £601.65 10 days: £859.5010 days: £859.50

Mean increase in Mean increase in equivalent cost equivalent cost attributable to ESBL attributable to ESBL production is $9620 production is $9620 (£5288)(£5288)

Cost and the paradigmCost and the paradigm ConclusionsConclusions Start broadStart broad--spectrum empiric therapy at first spectrum empiric therapy at first

suspicionsuspicion of severe infection: consider the of severe infection: consider the likelihood of antibioticlikelihood of antibiotic--resistance and resistance and sensitivities within the unitsensitivities within the unit

DDee--escalate:escalate: as soon as culture results as soon as culture results availableavailable

Stop therapyStop therapy as quickly as possibleas quickly as possible Use antibiotics toUse antibiotics to their best advantage their best advantage

Using the right doseUsing the right dose Using the right route and mechanism of deliveryUsing the right route and mechanism of delivery

Employ every means at your disposal to Employ every means at your disposal to reduce sepsisreduce sepsis