Maximizing the efficacy of antibiotic therapy

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Maximizing the efficacy

of antibiotic therapy

João Gonçalves Pereira,

MD, PhD

ICU Director

Hospital Vila Franca Xira

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Survival in Bacteremic Pneumococcal Bacteremia Treated with

Penicillin or Serum

Austrian Ann Intern Med 1964;60:759

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Houck Arch Intern Med 2004; 164: 637

Time until start of antibiotic therapy

(CAP)

Antibiotics and Pneumonia

Povoa CCM 2009;37:410

Community acquired Sepsis

N = 897 63% CAP

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Wiemken Semin Respir Crit Care Med 2012;33:213

Pneumonia Bundle

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Early antibiotics and outcome

Author n Setting Odds Ratio (death)

Gaieski (Crit Care Med 2010; 38:1045) 261 ED (Shock) First hour – OR 0.30

Daniels (Emerg Med J 2010; doi:10.1136) 567 Whole hospital First hour – OR 0.62

Kumar (Crit Care Med 2006;34:1589) 2154 ED (Shock) First vs second hour – OR 0.59

Appelboam (Crit Care 2010;14:50) 375 Whole hospital First hour –OR 0.74

Levy (Crit Care Med 2010; 38:1) 15022 Multi-centre First 3h – OR 0.86

Barie (Surg Infect (Larchmt) 2005;6:41) 356 Surgical ICU Per hour delay – 1.021

Ferrer (Crit Care Med 2014;42:1749) 17990 Multi-centre Progressive increase in risk per _{hour (1.07-1.52)}

Jalili (Acta Med Iran 2013; 51:454) 145 ED (sepsis) First 2h – OR 0.44

No difference in a metanalysis (11 studies included). OR 1.16

Sterling Crit Care Med. 2015;43:1907

Author n Setting Odds Ratio (death)

De Groot (Critical Care 2015; 19:194) 1168 3 ED No difference independent of _{PIRO score}

Hranjec (Lancet Infect Dis 2012;12:774) 201 Surgical ICU: Before-_after

Aggressive antibiotic therapy – OR for mortality 2.5

Puskarich (Crit Care Med 2011;39:12066) 372 Hospital-acquired _{surgical infections} No difference in mortality up to _{6h after diagnostic}

Villela (Am J Emerg Med 2014;32:7) 184 ED admitted to the ICU No improvement with decrease _{in time to antibiotics (5h to 3h)}

Pelletier(Surg Infect (Larch) 1999;134:1300) 372 Surgical patients No difference 0h,>12h, >24h

Castellanos-Ortega (Crit Care Med

2010;38:1036) 480 ED: Before-after

Early antibiotics OR 0.68, p=0.11

Davies (Shock 2014;42:185) 7158 Surgical patients Inappropriate vs. appropriate OR _1.0

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Infection rate in patients with presumed “sepsis” upon presentation

Klein Klouwenberg Crit Care 2015;19:319

Accuracy of sepsis diagnosis

Ø

 

Over 50% of patients with suspected pneumonia probably did not had infection

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Wiemken Semin Respir Crit Care Med 2012;33:213

Pneumonia Bundle

1

2

3 v

 

Better diagnostic tools

v

 

Early directed therapy

v

 

Adequate dose

²

 

Minimize antibiotic

exposure

²

 

Reassess diagnostic

²

 

PK and antibiotic dose

²

 

Response to therapy

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Antimicrobial dose

Pharmacokinetics

Antibiotics

PD

Bacterial

Killing

Dose antibiotics to maximize its exposure to bacteria

Craig WA - CID 1998; 26.1

PK

Pathogen

MIC/MBC

Concentration

at Infection

Site

Absorption

Distribution

Elimination

Effect of the antibiotic at

the site of infection

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Aminoglycosides

Metronidazol

Azithromycin

Fluoroquinolones

Glycopeptides

Beta-lactams

Carbapenems

Time (hours)

Concentration

C

_max

T>MIC

Area under the concentration curve

MIC

Patterns of Antimicrobial Activity

Log ₁₀ CFU/ mL

9 8 7 6 5 4 3 2

0 2 4 6

0 2 4 6 8

Control

¼ x MIC 1 x MIC 4 x MIC 16 x MIC

64 x MIC

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10 20 30 40 50 60

Volume of Distribution (L) Piperacillin

Cefpirome

Cefepime

Ceftazidime

○

■

Meropenem

Imipenem

○

■

ü

 

Two fold variability of PK parameters (Vd and Cl)

ü

 

Usually increase

ü

 

No clear correlation with clinical parameters

Gonçalves-Pereira and PóvoaCritical Care2011,15_:R206

http://ccforum.com/content/15/5/R206

Antibiotics in critically ill patients: a systematic

review of the pharmacokinetics of

b

-lactams

ARC

Augmented renal Clearance

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Longo. Pharmacoepidemiology and Drug Safety 2013; 22: 970

Dose of Antibiotics

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Aminoglycosides

Vancomycin Fluoroquinolones

Beta-lactams

Carbapenems Time

Concentration

C

_max

:MIC

T>MIC

AUC:MIC

MIC=0.5

MIC and resistance

²

 

Increase in MIC 0.5 1mg/L: Bacteria remain sensitive.

²

 

However AUC:MIC and Cmax:MIC decrease to one half; T>MIC also decreases

²

 

Changes in PK may impact clinical efficacy

Aminoglycosides

Vancomycin Fluoroquinolones

Time Concentration

C

_max

:MIC

T>MIC

AUC:MIC

MIC=1

Beta-lactams Carbapenems

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Bacterial load and mortality

Rello Chest 2009;136:832

Rt-PCR positive – 26,3%

(36,5% positive BC)

Septic shock – OR 6.29

Mech. Ventilation – OR 7.96

Mortality – OR 7.08

Pneumococcal Pneumonia

n=353

Patients with positive Rt-PCR

Bacterial Load > 10

3 _cop/mL

₍

_29%)

Shock OR 8 Mech. Vent OR 10.5

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Figure 3. Macrolide versus nonmacrolide therapy and mortality in critically ill patients with community-acquired pneumonia: pooled adjusted risk

Use of a macrolide in CAP

Sligl Crit Care Med 2014; 42:420

Selection of initial antibiotics

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Rodriguez Crit Care Med 2007;35:1493

Shock

Survival HR 1.69 (95%CI 1.09-2.6)

Death HR 0.48 (95%CI 0.23-0.97)

Macrolides

Martin-Loeches Intensive Care Med 2010; 36:612

The CAPUCI study

p = 0.99

No Shock

Selection of initial antibiotics

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Dose of Antibiotics

Clinical Success by PSI Class

80

85

90

95

100 Class I/II

Class III

Class IV

C

li

n

ic

a

l S

u

c

e

s

(

%

)

750 mg

500 mg

93.4

n=122

92.6

n=27

89.8

n=49

96.2

n=106

84.4

n=32

86.3

n=51

Patients in Each PSI

*Clinically evaluable patients at the 7- to 14-day post therapy visit

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Freiet al_.BMC Infectious Diseases_2011,₁₁_:188

http://www.biomedcentral.com/1471-2334/11/188

A clinical pathway for community-acquired

pneumonia: an observational cohort study

PK/PD guided dose

²

 

Lower adjusted 90d

mortality

(p=0.02)

²

 

Lower LOS

(3.9 vs. 5d, p<0.001)

²

 

Lower Costs

($2485 vs. $3281, p=0.02)

Frei, BMC Infect Dis 2011,11: 188 5.0 3.9

0.0 1.0 2.0 3.0 4.0 5.0 6.0

HospitalLOS(Days)

NonͲPathway(n=287) Pathway(n=505)

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A Multicenter Randomized Trial of Continuous versus Intermittent

b

-Lactam Infusion in Severe Sepsis

Joel M. Dulhunty1,2, Jason A. Roberts1,2,3, Joshua S. Davis4,5, Steven A. R. Webb6,7, Rinaldo Bellomo8,9,

Charles Gomersall10,11, Charudatt Shirwadkar12, Glenn M. Eastwood8, John Myburgh13,14, David L. Paterson15,16,

Therese Starr1,2, Sanjoy K. Paul17, and Jeffrey Lipman1,2; for the BLING II Investigators for the ANZICS Clinical Trials Group*

N=432

BLING II study

• 25 ICUs

• APACHE II – 20

• 90 day survival

74.3% vs. 72.5%

HR 0.91 (0.63-1.31)

Dulhunty Am J Resp Crit Care Med 2015; 192: 1298

Conclusions:

_{In critically ill patients with severe sepsis, there was no}

difference in outcomes between

b

-lactam antibiotic administration

by continuous and intermittent infusion.

Clinical success

Cefepime or ceftazidime

• AUIC

_≥

250 Cure 79% vs. 33%;

P

= 0.002

• T

>MIC of 100%

Cure 82% vs. 33%;

P

= 0.002

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Optimization of minimum

concentration/MIC ratio

T>MIC=100% Cmin/MIC=1.7+ tobramycin

Placebo

T>MIC=84%

T>MIC=100% & Cmin/MIC=10

0 1 2 3 4 5

12 8 4

0 Time (days)

Log 1 0 cf u /mL

0 1 2 3 4 5

10 8 4

0 Time (days)

Log 1 0 cf u /mL

0 1 2 3 4 5

10 8 4 0 6 2

0 1 2 3 4 5

10 8 4 0 6 2 Time (days) Time (days) Log 1 0 cf u /mL Log 1 0 cf u /mL

Tam Antimicrob Agents Chemother 2005; 49. 4920

Wild type

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Critically ill septic patient

Large Volume of Distribution

• Large volume

resuscitation

• Invasive Ventilation

• Surgical procedure

Initial High Loading Dose

Renal or Hepatic failure

Yes

Adjust Dose

accordingly

No

Increased Clearance

(measure Cr Clearance)

• Vasopressors

• Cardiac output

• Diuresis

Maintain High Dose

Reassess after 48-72h

Any of:

• Bacteria with a low MIC

• Normalization of (measured)

Cr Clearance

• Sepsis resolution

Adjust Dose

Dose modulation: A new concept of antibiotic therapy in

the critically ill patient?

☆,☆☆,★

Joao Goncalves-Pereira MD

a,⁎

_{, José-Artur Paiva MD, PhD}

b

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Accumulation and Toxicity

Ceftriaxone

2 g/d – Increase 2-3* from D1 to D7

Cr Cl

>50 mL/min

<50 mL/min

Day 1

19,5 µg/mL

46,5 µg/mL

Day7

38,5 µg/mL

125 µg/mL

Heinemeyer Int Care Med 1990; 16; 448

Betalactamin-induced central nervous

side effects

include confusion, disturbances of

behaviour, hallucinations, asterixis, myoclonic jerks,

and generalised convulsive or nonconvulsive seizures.

Those are probably underreported but may

contribute to morbidity and mortality.

Chatellier Int Care Med 2002; 28. 214

Singer. Plos Med 2005. e167

F 

May promote mitochondrial

damage and shutdown.

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Siegel et al (1999, [10])

Leophonte et al (2002, [11]) Dunbar et al

(2003, [12])

Dunbar et al (2004, [13])

Leophonte et al (2004, [14])

Tellier et al (2004, [15])

El Moussaoui et al (2006, [16])

File et al (2007, [17])

Cefuroxime 750mg q8h IV, 2d, then cefuroxime axetil 500mg q12 PO, 5d, 7d in total

Cefuroxime 750mg q8h IV, 2d, then cefuroxime axetil 500mg q12 PO, 8d, 10d in total

52 No difference in clinical cure

Ceftriaxone 1g IV qd, 5d Ceftriaxone 1g IV qd, 10d 244 No difference in clinical cure Levofloxacin 750mg

IV/PO qd, 5d

Levofloxacin 500mg IV/PO qd, 10d

528 No difference in clinical cure and bacteriological outcome

atypical

Levofloxacin

750mg IV/PO qd, 5d

Levofloxacin 500mg IV/PO qd, 10d

149 Noninferiority in clinical cure and bacteriological outcome Gemifloxacin

320mg qd, 7d

Amoxicillin/clavulanate 1000/125mg, 10d

320 No difference in

clinical, bacteriological, and radiological efficacy Telithromycin 800mg

PO qd, 5d

Telithromycin 800mg PO qd, 7d 378 No difference in clinical cure and bacteriological outcome

Telithromycin 800mg PO qd, 5d or 7d

Clarithromycin 500mg PO bid, 10d

559 No difference in clinical cure and bacteriological outcome

Amoxicillin 1g IV q6h, 3d Amoxicillin 1g IV q6h, 3d, then amoxicillin 750mg PO q8h, 5d, 8d in total

119 Noninferiority in clinical and radiological success

Gemifloxacin 320mg PO qd, 5d

Gemifloxacin 320mg PO qd, 7d 510 Non-inferiority in clinical, bacteriological, and radiological efficacy

Duration of Antimicrobial Activity

Reduction of exposure

3-7 d vs. 7-10 d

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