Current Update

Management of VAP

George Dimopoulos MD, PhD, FCCP

Professor, Critical Care Medicine

Chair of Infection Section ERS, Former Chair INFS ESICM, Consultant WHO

University Hospital ATTIKON, Medical School, University of Athens, Greece

gdimop@med.uoa.gr

JADE, Jakarta

12-14 April 2013

Conflict of interest disclosure

Prof Dimopoulos has no, real or perceived,

conflicts of interest that relate to this

presentation.

Ventilator Associated Pneumonia

1. Main nosocomial infection in patients receiving

Mechanical Ventilation

– Incidence : 8-15 cases per 1000 ventilator-days

– Mortality : 20 -50%

2. Is not “associated ” with the ventilators but with

artificial airways

3. Duration of MV, ICU and hospital LOS

4. Inappropriate antibiotic treatment : Mortality = 3,03

5. Economic impact : $41,294 charges per patient

Rotstein C. Can J Infect Dis Med Microbiol 2008, Kuti EL. J Critical Care 2008

VAP etiology- (SENTRY 2004–2008)

Etiology (%)

Pseudomonas aeruginosa 26,6

Acinetobacter baumannii 14,3

Klebsiella spp. 10,2

Enterobacter spp. 7

Serratia spp. 4,1

Staphylococcus aureus 19,5

N = 7496 cases

Jones R. Clin Infect Dis 2010; 51(S1):S81–S87

50%

Epidemiology of VAP Potentially Resistant Microorganisms

Group 1,: early-onset pneumonia without risk factors for PRM infection;

Group 2 : early-onset pneumonia with risk factors for PRM infection (who have received prior antibiotics or who have had prior

hospitalization within the past 90 days and immunosuppressive disease and/or therapy) or late-onset pneumonia

ATS Guidelines Am J Respir Crit Care Med

Group 1 (n=152) Group 2 (333) Overall (n=485) p value

Polymicrobial, n (%) 51 (23.5) 109(23.1) 160(23.2) 0.9

Pseudomonas aeruginosa 33(21.7) 82(24.6) 115(23.7) 0.5

Stenotrophomonas maltophilia 2(1.3) 14(4.2) 16(3.3) 0.1

MRSA 24(15.8) 58(17.4) 115(23.7) 0.5

Acinetobacter baumanii 24(15.8) 77(23.1) 101(20.8) 0.07

Martin-Loeches I , Deja M, Koulenti D, Dimopoulos G, Marsh B, Torres A, Niederman M, Jordi Rello and EU-VAP

Study Investigators. Intensive Care Med. 2013 Apr;39(4):672-81

The main message is

LOCAL EPIDEMIOLOGY !!!

Epidemiology of VAP Non-Potentially Resistant Microorganisms

Group 1 (n=152) Group 2 (333) Overall (n=485) p value

Polymicrobial, n (%) 51 (23.5) 109(23.1) 160(23.2) 0.9

MSSE 36(23.7) 41(12.3) 77(15.9) 0.002

Escherichia coli 20(13.2) 56(16.8) 76(15.7) 0.3

Klebsiella pneumoniae 17(11.2) 40(12.0) 57(11.8) 0.8

Streptococcus pneumoniae 11(7.2) 10(3.0) 21(4.3) 0.05

Serratia marcescens 7(4.6) 10(3.0) 17(3.5) 0.4

Haemophilus influenzae and

Moraxella catharrhalis 16(10.5) 16(4.8) 32(6.6) 0.002

Citrobacter spp 3(2.0) 4(1.2) 7(1.4) 0.6

Morganella spp 2(0.6) 2(0.4) 0.9

Enterobacter spp 11(7.2) 29(8.7) 40(8.2) 0.7

Proteus spp 5(3.3) 13(3.9) 18(3.7) 0.9

Martin-Loeches I , Deja M, Koulenti D, Dimopoulos G, Marsh B, Torres A, Niederman M, Jordi Rello and EU-VAP

Study Investigators. Intensive Care Med. 2013 Apr;39(4):672-81

Management of VAP

John Muscedere MDa, Peter

Dodek MD, MHScb, Sean

Keenan MD, MScb,

Rob Fowler MDCM, MSc,

Deborah Cook MD, MScd,

Daren Heyland MD, MSca,

for the VAP Guidelines

Committee and the Canadian

Critical Care Trials Group1

Journal of Critical Care 2008 23, 138–147

Empiric treatment

0 h. 48 h. 72 h.

Diagnosis of VAP Etiology Susceptibility

Microbiological diagnosis

Diagnosis of VAP

• Suspicion !!!!!! – Established Criteria

• Samples from the LRT – Invasive vs non-invasive techniques

– Quantitative vs qualitative cultures

• 335 episodes of clinically suspected VAP

– The introduction of antibiotics 72 h prior

to BAL did not affect the validity of the

test

Linssen CF et al, Intens Care Med 2008;26:20-30,

Fagon et al, Ann Intern Med 2000

Antimicrobial Treatment of VAP

American Thoracic Society Documents Guidelines for the Management of Adults with Hospital-acquired, Ventilator-associated, and

Healthcare-associated Pneumonia. Am J Respir Crit Care Med Vol 171. pp 388–416, 2005

Carbapenem-Resistance

P. aeruginosa (12, 21, 42%)

*A. baumannii (47, 26, 85%)

K. pneumoniae (1, 15, 49%)

http://www.ecdc.europa.eu

Antimicrobial Treatment of VAP

due to MDR / PDR pathogens

Antimicrobial

drugs

MDR or PDR

A. baumannii

ESBL-producing

Enterobacteriaceae

MRSA

Conventional

agents

Carbapenem

(Meropenem or

Imipenem / Cilastatin)

+

Sulbactam

Carbapenem

(Meropenem,1 g / 8 h

or Imipenem/ Cilastatin

500 mg / 6 h or 1 g /8 h;

or

Ertapenem 1 g qd)

Glycopeptide (esp.vancomycin,

after 25 -- 30 mg/kg loading, then

maintained with 15 mg/kg / 12 h)

Recommended

alternative

agent(s), or

regimen(s)

IV Colistin (2 MU / 8h)

+

IV Rifampicin(10 mg/kg/12 h)

Tigecycline

plus imipenem or colistin

Tigecycline

plus imipenem +amikacin

IV colistin (2 MU / 8 h) Linezolid

(600 mg loading, then 600 mg /12 h)

Vancomycin (standard dose)

+

Rifampicin (300 mg bid PO)

Quinupristin/dalfopristin

(7.5 mg/kg every 8 h)

Shio-Shin J & Po-Ren H Expert Opin Pharmacother. (2011) 12(14):2146-8

The role of Polymyxins

Polypeptide antibiotics

- 5 chemically different compounds polymyxin A, B, C, D, and E (by different species of Bacillus polymyxa)

Colistin sulfate (CS) - PO for bowel decontamination

- Locally as a powder for the treatment of bacterial skin infections

Colistimethate sodium (CMS) - also called colistin methanesulfate, pentasodium colisti-

methanesulfate, and colistin sulfonylmethate

- IV and by inhalation

Polymyxins - Mechanism of action

L-α-γ-diaminobutyric acid (Dab) molecules, contained in the

molecule of polymyxins, are positively charged

Lipopolysaccharide (LPS) molecules, which are present in

the cell wall of Gram-negative bacteria, are negatively charged

Polymyxins possess a higher affinity for LPS molecules than do

divalent cations such magnesium (Mg+2) and calcium (Ca+2) which

normally stabilize the LPS molecules

The result of this process causes an increase in the permeability

of the cell envelope, leakage of cell contents, and subsequently

bacterial cell death

Polymyxins - Are not active against……

Pseudomonas mallei

Burkholderia cepacia

Proteus spp.

Providencia spp.

Serattia spp.

Edwardsiella spp., and

Brucella spp.

Gram-negative and Gram-positive aerobic cocci

Gram-positive aerobic bacilli

All anaerobes, fungi, and parasites

Colistin Breakpoints of Resistance

Polymyxin P. aeruginosa A. baumannii Enterobacteriaceae

Committee (year)

S I R S I R S I R

Colistin

≤2 4 ≥8 ≤2 >2 CLSI

(2012)

≤4 >4 ≤2 >2 ≤2 >2 EUCAST (2012)

≤4 >4 ≤2 >2 ≤2 >2 BSAC

(2011)

S: ≤2; R: >2 (no specified species) CA-SFM (2003)

Polymyxin B ≤2 4 ≥8 ≤2 >2 CLSI

(2012)

CLSI = Clinical and Laboratory Standards Institute;, EUCAST = European Committee on Antimicrobial Susceptibility Testing; BSAC = British Society for Antimicrobial Chemotherapy;, CA-SFM = CA-Comité de l'Antibiogramme de la Société Française de Microbiologie, France.

Inhaled colistin for infections due to

MDR Gram-negative

Author year Setting Patients Dose/ duration Infection Pathogen Outcome

Hamer, 2000 Medical

wards

3 2-5 MU/day

12.6 days

VAP Pseudomonas aeruginosa

Clinical cure

100%

Michalopoulos 2005 ICU 8 1.5 to 6 MU/day

12.6 days

VAP A. baumanii P. aeruginosa

Clinical cure

87.5%

Kwa, 2005 ICU

Medical

wards

21 2-4 MU/day

14 days

VAP A. baumanii P. aeruginosa

Clinical cure

85.7%

Berlana, 2005 ICU 80 12 days VAP A. baumanii P. aeruginosa

Microbiological

cure 92%

Mataouakkil 2006 ICU 26 1 MU / 8h

15 days

VAP

bacteremia (3)

Acinetobacter baumanii

Clinical cure

100%

Michalopoulos 2008 ICU 60 1 MU / 8 h for 5 to

49 days +IV colistin

or meropenem

VAP A. baumanii P. aeruginosa K. pneumoniae

Clinical and

Microbiologic

cure 83.3%

Falagas 2009 Hospital

ICU

5 1MU/8 h or 0.5

MU/6 h for 6 to 11

days

VAP

HAP

A. baumanii P. aeruginosa K. pneumoniae

Clinical cure

80%

Inferior Clinical Efficacy of Colistin

• Suboptimal dosing

– lower total daily dosage of intravenous colistin

is associated with increased mortality

Falagas et al. Int J Antim Ag 2010; 35:194 – 199

• Delay in attaining an efficacious drug concentration

– Necessity to give a loading dose Plachouras et al. AAC 2009; 53:3430 –3436

• Optimal dosing regimen

– Once daily, twice daily or three times daily?

Which loading dose ?

0

1

2

3

0 12 24 36 48 60 72 84 96

Time after first dose (hours)

Co

listin

Co

ncen

tratio

n (

mg

/L)

3 MU x 39 MU + 4.5 MU x 212 MU + 4.5 MU x 29 MU (2h infusion) + 4.5 MU x 212 MU (2h infusion) + 4.5 MU x 2

The administration of a loading dose of 6 MU CMS resulted in colistin plasma concentrations above 1mg/L within 4 hours in the majority of the patients.

Mohamed AF, I.Karaiskos et al . AAC

2012;56:4241-9

Plachouras et al. AAC 2009; 53:3430 –3436

Couet W. CMI 2012:18:30-39.

Colistin clinical studies

Spread of colistin resistant isolates in parallel with the increased colistin consumption from pharmacy data

Among 30 patients colonized by ColRKP

27(90%) had received colistin (p < 0.001;

OR, 6.98; 95% CI, 2.0–24.3)

Among 94 patients exposed to colistin

27 (28.7%) were colonized by ColRKP.

These patients had received colistin for a

median of 20.0 days, compared with

14.5 days for patients not colonized by a

ColR strain (p 0.048)

Genotypic analysis of the isolates revealed

that the majority of the CRKP isolates

belonged to different clones. Clin Microbiol Infect 2011

Breakpoints of Tigecycline against

Enterobacteriacecae and Acinetobacter baumannii

MIC(μg/ml) Inhibition Zone (mm) Implementing

Organism or

proposing

authors S I R S I R

Enterobacteriaceae* ≤2 4 ≥8 ≥19 15-18 ≤14 US FDA

≤1 2 >2 - - - EUCAST

≤1 2 >2 ≥24 20-23 ≤19 BSAC

A.baumannii - - - - - - US FDA**

IE IE IE - - - EUCAST

≤1 2 >2 ≥24 20-23 ≤19 BSAC

≤2 4 ≥8 ≥16 13-15 ≤12 Jones RN et al

Giamarellou H and Poulakou G, Drugs, 2009

Tigecycline per type of infection

and treatment group

M group PAM group M group+ PAM group Total

N=22 N =23 VAP

N =21

BSI

N =10

SI

N=14

N =45

Clinical outcome (%) 81.8 78.3 90.5 80 64.3 80

Microbiological

outcome (%)

63.6 56.5 57.1 80 50 60

14 day mortality %

attributable

crude

9.1

9.1

4.3

21.7

4.8

19

10

10

7.1

14.3

6.7

15.6

Hospital mortality %

attributable

crude

27.3

36.4

13

43.5

19

42.9

20

30

21.4

42.9

20

40

Poulakou et al, J of Infection 2009;58:273-84

Tigecycline vs imipenem/cilastatin

for the treatment of HAP

• A phase 3, multicenter, randomized, double-blind, study

– tigecycline vs imipenem/cilastatin regimen in 945 HAP patients

• Cure rates

– 67.9% for tigecycline and 78.2% for imipenem

– absolute difference -10.4 [-17.8 to -3.0]; p= 0.120

– non-inferiority criteria NOT MET

• In VAP

– Tigecycline 47.9% versus 70.1% for imipenem/cilastatin

– Tigecycline was noninferior to imipenem

Freire A et al, Diagn Microbiol Infect Dis 2010; 18 140-151

Tigecycline - Issues to be considered

• No adequate activity in bacteremias

• No licensed for VAP

• Possibility of breakthrough bacteremias with Proteus spp

inherently resistant to tigecycline, particularly in patients

pretreated with colistin

• Probably higher doses of tigecycline (i.e 100-150mg/12hrs)

are needed in order to achieve adequate levels for borderline

MICs (4-8μg/ml) or difficult body compartments

Antimicrobial susceptibilities of KPC-Kp Microbiological data from 18 infections, “ATTIKON” Hospital

MIC range

mg/L

MIC50

mg/L

MIC90 mg/L %

susceptible

Meropenem 4->256 64 >256 2

Minocycline 1->16 4 >16 55.2

Tigecycline 0.5-8 2 8 15.4*

Colistin 0.125-48 0.5 8 86

Gentamicin 2->256 4 16 70

Amikacin <8->32 32 >32 14

Fosfomycin 8->256 32 256 55

Souli M et al, CID 2010

*Susceptibility breakpoint: ≤1mg/L according to EUCAST 65.4% of isolates had an MIC ≤2mg/L

The main message is

LOCAL EPIDEMIOLOGY !!!

Aminoglycosides - Spectrum and Activity

Aminoglycosides are active

o against Gram (-) and some Gram (+)

o against Mycobacteria

Aminoglycosides + b-lactams = Synergy (?)

o β-lactam affects the cell wall of the bacteria providing the

increased penetration of aminoglycoside

o the increased entrance of aminoglycoside increases the

inhibition of proteino-synthesis of bacteria

In vitro : the greatest likelihood of synergy

o aminoglycoside + antipseudomonal penicillin (~ 90%)

o aminoglycoside + cephalosporin (~ 80%)

o aminoglycoside + carbapenem (~ 50%)

Hsin-Yun Sun et al, Chest 2011; 139(5):1172–1185

Aminoglycosides in clinical practice (I)

Aminoglycosides + broad-spectrum β-lactams

- should not be added to achieve synergism in treating Gram (-)

infections as combination

does not improve efficacy and adds side effects

The evidence from RTCTs in humans

- does not support the use of aminoglycosides in staphylococcal

or streptococcal endocarditis and is lacking for endocarditis

caused by enterococci

Leibovici et al, JAC;63(2)246-251

Proposed RCTs for answers about aminoglycosides

in clinical practice…………

Treatment Comparator Patients with

Anti-pseudomonal

β-lactam drug

Same

anti-pseudomonal β-lactam

+ an aminoglycoside

Infections caused

by P. aeruginosa

β-lactam drug β-lactam

+ an aminoglycoside

Bacterial endocarditis caused

by S. aureus, streptococci or

enterococci

Aminoglycoside Colistin or tigecycline Infections caused

by Gram (-) susceptible only to

these agents

Aminoglycoside

drug

a β-lactam drug Infections caused

by Gram-negative pathogens

A randomly selected sample of o 30 Klebsiella pneumoniae,

o 30 Pseudomonas aeruginosa, and

o 30 Acinetobacter baumannii

The MIC of fosfomycin for each isolate was

determined by the agar dilution method

Provisional breakpoint of susceptibility ≤ 64 μg/ml

according to CLSI criteria

What about fosfomycin ?

In vitro antimicrobial susceptibility of fosfomycin

K. pneumoniae P. aeruginosa A. baumannii

All isolates were ESBL and MBL (blaVIM-1) producers

All isolates were ESBL

producers

MIC range: 8-64 μg/ml

MIC range: 4 to >512 μg/ml

MIC range: 64 to >512

μg/ml

MIC range: 8-64 μg/ml MIC50 16 μg/ml MIC90 32 μg/ml

MIC50 32 μg/ml

and

MIC90 128 μg/ml

MIC50 256 μg/ml and

MIC90 >512 μg/ml

None of the isolates was

resistant

20% of the isolates were

resistant to fosfomycin

A randomly selected sample of 30 Klebs. pneumoniae, 30 P. aeruginosa, and 30 A. baumannii

The MIC of fosfomycin for each isolate was determined by the agar dilution method

Provisional breakpoint of susceptibility ≤ 64 μg/ml

Dimopoulos et al Eur J Clin Micr Infect Dis 2008

Fosfomycin in Critically-ill Patients

with KPC-Klebsiella infections

Michalopoulos A et. al Clin Microbiol Infect 2010; 16: 184-6

Characteristic

Mean age, years 67.5

APACHE II score 23.4

No. of organ dysfunction,

median 3

VAP

Primary bacteremia

Other

5

2

4

All cause hospital mortality 18.2%

Efficacy of Fosfomycin (F) in XDR and PDR

Gram-negative infections in ICU patients

In vivo efficacy of fosfomycin ?

Microbiologically documented infections by Gram (-)

S : Fosfom, R : Ceph, Quinolones, beta-lactamase inhibitors

- 45 pts / 12 ICUs, Mean (age 55.6 years, APACHE II 19.8, SOFA 8.6)

- Primary/ secondary bacteremia (16 /6), CVCBSIs (8), VAP (14), IAIs(7)

- Sepsis, severe sepsis and septic shock 21.4%, 7.1%, 21.4%

- K. pneumoniae KPC(+) 83.7%, P. aeruginosa 35.7%, PDR 15, XDR 30

K. Pontikis, I. Karaiskos, Ch. Paskalis, A. Koutsoukou, E. Roilides, G. Dimopoulos, G. Nakos, N. Maggina, S. Bastani, A.

Prekates, G. Poulakou, H. Giamarellou on behalf of the Hellenic Study Group of "ICU Infections“

ECCMID 2013: Abstract received - Abst. Nr. 2653

Fosfomycin IV, 6gr x 4 per day, for a mean of 12 days

+

Colistin (28 pts) and Tigecycline (17 pts)

Clinical Outcome o Successful by day 14 in 55.8% including 10 pts with PDR strains

o Failure in 27.9%

o Relapse in 4.7%

o Superinfection in 4.7%.

Microbiological Outcome o Bacterial eradication was observed in 54.8%

o Resistance development to F in 4 cases.

Main adverse event

o reversible hypokalemia (6 pts)

K. Pontikis, I. Karaiskos*, Ch. Paskalis, A. Koutsoukou, E. Roilides, G. Dimopoulos, G. Nakos, N. Maggina, S. Bastani, A. Prekates, G.

Poulakou, H. Giamarellou on behalf of the Hellenic Study Group of "ICU Infections ECCMID 2013: Abstract received - Abst. Nr. 2653

Vancomycin and the Lung

Vancomycin penetration into lung tissue

was evaluated in 30 pts following 1g vancomycin.

Ratios of lung tissue to serum concentration ranged 0.24 to 0.41 at

1 and 12h, respectively.

1 of 6 pts at 6h, and 3 of 7 pts at 12h

had NO detectable levels of vancomycin

in lung tissue.

A 1h iv infusion of a 1g dose of vancomycin

does not achieve sustained lung concentrations above the MIC.

Cruciani et al J Antimicrob Chemother 1996;38:865-9

Boselli et al Crit Care Med 2005:33;1529-33

ZEPHyR Trial - Clinical Success Rates

PP at EOS MITT at EOS PP at EOT MITT at EOT 0

20

40

60

80

100

Clin

ical success r

ate

Linezolid Vancomycin

P = 0.042 P = 0.049

P = 0.002 P = 0.004

57.6% 95/165

54.8% 102/186

83.3% 150/180 80.1%

161/201

46.6% 81/174

44.9% 92/205

69.9% 130/186

67.8% 145/214

Wunderink RG et al Clin Infect Dis 2012; 54:621–9.

Short- vs

long- duration

antibiotic

regimens for

VAP: a

systematic

review and

meta-analysis

Mortality between the two arms.

Antibiotic-free days between the two arms.

Relapses between the two arms

Dimopoulos et al , Chest 2013 (in press)

Salvage Therapy for Pan-Drug Resistant

Enterobacteriaceae: The Available Antibiotics

1. Chloramphenicol, Co-trimoxazole, Nitrofurantoin

for Klebsiella pneumoniae carbapenemase(+)

2. Temocillin: active against ESBL(+) and AmpC(+)

Enterobacteriaceae. Available only in Belgium and the UK

3. High dose Amikacin (50mg/kg) plus hemofiltration

4. Combination of 2 carbapenems: Ertapenem + Doripenem?

In vitro chemostat model (doripenem MIC, 4 g/ml).

Control

Erta alone

Dori alone

Dori+erta

In vivo murine thigh infection model (doripenem MIC, 4 g/ml)

Antimicrobial agents and chemotherapy 2011; 55(6): 3002–3004

Exploiting increased in vitro affinity of KPC enzymes for ertapenem “a suicide substrate”

Prevention of VAP

• Pharmacological and non-pharmacological measures

• Airway care methods major development

– Efficacy, feasibility and low cost

Passive humidifiers (heat and moisture exchangers)

Open vs closed tracheal suction system

Continuous or intermittent subglottic secretion systems

New materials for the endotracheal tube cuff

Polyurethane vs polyvinyl cuff (avoids the leakage of secretions)

Coated endotracheal tube with silver (antibacterial properties)

• Bundles (group of measures) • Semi-recumbent position, hand hygiene, staff education, adequate

nurse/patient staffing ratios, microbiological surveillance,

antibiotic control policies, no change of ventilator circuits, standarized protocols

for sedation and weaning

Siempos I et al, Crit Care Med 2007; 35;2843-51, Polaert J et al, J Thorac Cardiovasc Surg 2008;135:771-8,

Kollef M et al, JAMA 2008;300;805-813, Kuti El et al, Crit Care 2008;2391-100

Impact of patient position on the

incidence of VAP

Incidence of clinically diagnosed VAP

semirecumbent (treatment) to supine position (control) and prone

(treatment) to supine position (control).

Death incidence comparing semirecumbent

(treatment) to supine position (control) and prone (treatment) to

supine position (control).

Patients positioned semirecumbently 45° have significantly lower incidence of clinically diagnosed VAP compared to patients

positioned supinely. On the other hand, the incidence of clinically diagnosed VAP among patients positioned pronely does not

differ significantly from the incidence of clinically diagnosed VAP among patients positioned supinely.

Alexiou V, Ierodiakonou V and Dimopoulos G. J Crit Care 2009

Using a surveillance method… ..concordance between VAP and BSI pathogenic isolates and

prior respiratory tract (RT) or gastrointestinal tract (GT) colonization

Surveillance cultures Acinetobacter, Pseudomonas, Klebsiella - VAP (PPV 67–94%, NPV 73–100%)

- Bacteremia (PPV 43–54%, NPV 88-100%)

Surveillance-guided initial

antibiotic therapy - appropriate in 91% and 86% of

patients with VAP and bacteremia

respectively.

Papadomichelakis et al Intensive Care Med (2008) 34:2169–2175

REP-PCR molecular typing

Patient A

Bloodstream infection

A1 blood, A2 tracheal aspirate,

A3 stool, A4 pus

Patient B

VAP

B5 tracheal aspirate, B6 BAL

Patient C

VAP

C7 tracheal aspirate, C8 stool,

C9 BAL, C10 pus

Patient D

Bloodstream infection,

D11 stool, D12 blood

Papadomichelakis et al Intensive Care Med (2008) 34:2169–2175

Hand Hygiene

• Handwashing – Washing hands with

plain soap and water

• Antiseptic handwash – Washing hands with

water and soap or other

detergents containing

an antiseptic agent

• Alcohol-based handrub – Rubbing hands with an

alcohol-containing

preparation

• Surgical hand hygiene

/antisepsis – Handwashing or using an

alcohol-based handrub

before operations by

surgical personnel

Guideline for Hand Hygiene in Health-care Settings. MMWR 2009;51:RR-16

X represents VRE culture positive sites

The hand

of a doctor

in the agar

Hand flora

“transient” flora

Εnterobacteriacae

E. coli, Klebsiella spp.,

Proteus spp., Serratia

spp., Enterobacter spp.

Pseudomonas spp

Acinetobacter spp

MRSA

VRE

“resident” flora

• CοNS

• Micrococci,

• Propionibacterium spp

Hand Hygiene - the right way

Hand Hygiene - avoiding the recontamination

Hand Hygiene - with the appropriate solution

Good Better Best

Plain Soap is good at reducing

bacterial counts

Antimicrobial

soap

is better

Alcohol-based handrub

are the best

Use of artificial nails by healthcare workers poses

risk to patients?

5

35

10

0

10

20

30

40

p<0.05

% R

eco

very

of

gra

m

neg

ati

ve b

acte

ria

Natural (n=31)

Artificial (n=27)

Polished (n=31)

ARTIFICIAL

POLISHED

NATURAL

Edel et. al, Nursing Research 1998: 47;54-59

Avoid wearing artificial nails, keep natural nails <1/4 inch

if caring for high risk patients (ICU, OR)

Compliance in ATTIKON hospital

What is different in critical illness ?

• Capillary leak*

- increased body fluid

• Organ dysfunctions elimination

accumulation of metabolites

• Administration of multiple drugs - drug interactions

- altered protein binding

* Capillary leak lead to ………..

…...important changes in concentrations

of antibiotics with low volumes of

distribution

(penicillins, cephalosporins, carbapenems and aminoglycosides

Concentration (

mg/L

)

Time (hours) 0

Cmin (Trough))

Cmax (Peak)

MIC

AUC

MIC

t>MIC Time dependent

Concentration dependent

AUC/MIC = AUIC

PK-PD Dose concentration effect

Volume of distribution (Vd)

500 mg 500 mg

Beta-lactams

Vd approx. 15 - 20 L

Quinolones

Vd approx 80 - 200 L

. . . . . .

.

. . . .

. . .

.

. . .

. .

Dimopoulos G. Curr Drugs Metab 2009;10(1):13-21

Vd = dose [mg] / concentration [mg / L]

Sepsis pathophysiology and

antibiotic pharmacology

SEPSIS

Increased Cardiac Index

Leaky Capillaries &/or altered protein binding End Organ

Dysfunction

Increased Clearances

Increased Volume of Distribution

Decreased Clearances

Low Serum

Concentrations

High Serum

Concentrations

Roberts & Lipman Clin pharmacokinet 2006

Creatinine clearance

0

50

100

150

200

250

0 50 100 150 200 250 300

Creatinine Clearance (mL/min)

Dru

g C

lea

ran

ce

(m

L/m

in)

Cefepime

Cefpirome

Lipman et al Anesth Analg 2003

Is continuous infusion better ?

• 57 ICU patients

• Randomised to bolus/CI

• 50 met a priori analysis criteria

• ie >3 days Rx

Better

clinical + bacteriological response

Roberts et al JAC 2007;59:285-91

Continuous infusion

• Continuous infusion • beta-lactam antibiotics may

optimize PK / PD profile

• For pathogens with MICs

close to the breakpoint

• Empirical therapy

• For carbapenems, prolonged

infusions (3 h) t.i.d. seem the

most suitable way of

administration

Through Infection Section of ESICM

New agents

Agent Class/mode of action Spectrum/phase

Avibactam(nxl104)

Diazabicyclooctane

Class a & c b-lactamase inhibit or(paired

with ceftaroline / ceftazidime & aztreonam)

Ps aeruginosa

MDR enterobacteriae

Phase II, III

mk-7655 Class a & c b-lactamase inhibitor

(paired with imipenem)

Ps aeruginosa

MDR enterobacteriae

Phase III

rpx7009 Boronic acid

derivative-paired with biapenem

MDR enterobacteriae

ME-1071 Maleic acid inhibitor

MBL inhibitor

(paired with carbapenems)

MBL producing bacteria

New agents with new mode of action

• LpxC inhibitors (CHIR-090)

– LpxC: deacetylase involved in the biosynthesis of lipid A of LPS

Mansoor UF, et al. Bioorg. Med. Chem. Lett. 2011;21(4):1155-1161

Rapid resistance and regrowth in phase II study!!! It was withdrawn

Leucyl-tRNA synthetase (LeuRS)

Future options The revival of isepamicin?

• Antimicrobial susceptibility for the 1,040 K.

pneumoniae isolates was highest for isepamicin

(95.3%), followed by colistin (89.3%)

• Regarding resistant K. pneumoniae isolates,

susceptibility to isepamicin was observed for

91.1%, 87.7%, and 85.6% of the isolates that

were non-susceptible to the carbapenems, all

other aminoglycosides, and colistin, respectively

Maraki S, Antimicrob Agents Chemother 2012 Mar 5

Future options

• PK/PD applications of

- Meropenem

- Doripenem

- Tigecycline

- colistin

PK-PD target attainment for β-lactams

Bacteriostatic and bactericidal activity of β-lactams depends on duration of time free (unbound) drug levels exceed MIC (% T>MIC)

Antimicrobials

Free Drug % Time >MIC

Bacteriostatic (%) Bactericidal (%)

Cephalosporins 35-40 60-70

Penicillins 30 50

Carbapenems 20-30 30-40

* 3 log reduction in colony –forming units

Drusano 2004, Nat Rev Microbiol 2:289

Bulic CC et al Antimicrob Agents Chemother 2010; 54: 804

fT > MIC 100% fT > MIC 75%

In Vivo Killing Kinetics of VIM and Non-VIM-Producing K. pneumoniae in the Thighs of Neutropenic

Mice Treated with Imipenem

MIC=0.125 μg/ml MIC=2 μg/ml

VIM-negative VIM-positive

Daikos GL et al Clin Microbiol Infect 2007; 13: 202-205

Pharmacokinetics of three different dosing regimens of meropenem

Simulated Target Attainment Probabilities for 50%T>MIC of three Different Dosing

Regimens of Meropenem

How To Optimize De-Escalation:

Use of Clinical Parameters To Modify or Stop Therapy

Luna CM et al. Crit Care Med (2003)

• Evolution of the CPIS

correlated with mortality.

• PaO2/FIO2 ratio was the best

correlate of clinical

response and outcome

Survivors (n=31)

Non-Survivors (n=32)

All (n=63)

Therapy Serial CPIS

Measurements to Determine

the Outcome in VAP

4

5

6

7

CP

IS

VAP-3 VAP VAP+3 VAP+5 VAP+7

Days 1

2

3

0

Back to the copper era? ATTIKON Hospital ICU- 2011

The Prorata trial Bouadma L et al, The Lancet 2010

Patients receiving antibiotics for days 1–28

Significantly fewer patients assigned to the procalcitonin group received antibiotics than did those assigned to the control

group (p<0·0001, generalised linear model test for repeated measures).

An ESICM systematic review and meta-analysis

of procalcitonin-guided antibiotic therapy algorithms

in adult critically-ill patients

• 7 RCTs

• in the duration of first episode of antibiotic treatment

pooled WMD of -3.15 days FEM, 95% CI – 4.36 to 1.95, P<0.001

• No difference in 28-day mortality

FEM, OR=0.96, 95% CI 0.79 to 1.15, P=0.63

• in antibiotic free days within the first 28 days of hospitalization

pooled WMD of 3.08 days FEM, 95% CI 2.06 to 4.10, P<0.001)

• No difference between regarding the remaining outcomes

• Sensitivity analyses yielded similar results

Matthaiou D, Ntani G, Kontogeorgi M, Poulakou G, Armaganidis A, Dimopoulos G. Intensive Care Med. 2012 Jun;38(6):940-9

WMD = weighted mean differences, FEM= fixed effects model

NOTE: Weights are from random effects analysis

Overall (I-squared = 88.7%, p = 0.000)

Schroeder et al

Nobre et al

Study

Hochreiter et al

Stolz et al

Bouadma et al

2009

2008

Year

2009

2009

2010

-3.15 (-4.35, -1.95)

-1.70 (-2.39, -1.01)

-4.00 (-6.64, -1.36)

WMD (95% CI)

-2.00 (-2.46, -1.54)

-5.00 (-6.13, -3.87)

-3.80 (-4.83, -2.77)

100.00

23.06

11.36

Weight

24.07

20.44

21.08

%

-3.15 (-4.35, -1.95)

-1.70 (-2.39, -1.01)

-4.00 (-6.64, -1.36)

WMD (95% CI)

-2.00 (-2.46, -1.54)

-5.00 (-6.13, -3.87)

-3.80 (-4.83, -2.77)

100.00

23.06

11.36

Weight

24.07

20.44

21.08

%

0-4 -2 0 2 4

Favors PCT arm Favors control arm

Weighted mean difference of

duration of first episode

of antibiotic treatment.

Overall (I-squared = 0.0%, p = 0.906)

Schroeder et al

Study

Hochreiter et al

Bouadma et al

Nobre et al

Stolz et al

Jensen et al

Svoboda et al

2009

Year

2009

2010

2008

2009

2011

2007

0.96 (0.79, 1.15)

0.91 (0.15, 5.58)

OR (95% CI)

0.99 (0.43, 2.32)

1.05 (0.71, 1.55)

0.99 (0.27, 3.63)

0.59 (0.22, 1.59)

0.97 (0.76, 1.24)

0.58 (0.21, 1.57)

100.00

1.11

Weight

4.87

22.70

2.09

4.65

%

59.98

4.60

0.96 (0.79, 1.15)

0.91 (0.15, 5.58)

OR (95% CI)

0.99 (0.43, 2.32)

1.05 (0.71, 1.55)

0.99 (0.27, 3.63)

0.59 (0.22, 1.59)

0.97 (0.76, 1.24)

0.58 (0.21, 1.57)

100.00

1.11

Weight

4.87

22.70

2.09

4.65

%

59.98

4.60

1.148 1 6.76Favors PCT arm Favors control arm

An ESICM systematic review and meta-analysis

of procalcitonin-guided antibiotic therapy algorithms

in adult critically-ill patients

Odds ratios of

28-day mortality

Matthaiou D, Ntani G, Kontogeorgi M, Poulakou G, Armaganidis A, Dimopoulos G. Intensive Care Med. 2012 Jun;38(6):940-9

Resistance emergence and spread

SELECTION

of resistant strains

Eradication of the susceptible strains

Growth of the resistant strains

Function of antimicrobial activity and

the pharmacokinetics of the antibiotic

Environmental factors

and fitness of the resistant strain

TRANSMISSION

amplification and

spread of resistance

GENETIC EVENT

emergence of the

resistant strain

Spontaneously

Independent of antibiotic presence

A function of the bacterial

and of the antibiotic

Hawkey, BMJ 1998; 317:657–60; Freney, Précis de bactériologie Clinique Ed. ESKA 2000; Andremont,Med Mal Inf.2005;35 sup3:S207-11; Rice, Clin

Infect Dis 2000; 31:762–9; Livermore, Clin Infect Dis 2003;36Sup1:S11-23

• The emergence of bacterial resistance is

through two mechanisms

Mutation Acquisition of foreign DNA +

Control of Resistance by Antibiotic Restriction

• Rise in the rate of multiresistant (including gentamicin) Enterobacteriaceae in neuro-units.

• Unable to control with hygiene methods:

– education

– hand washing

– barrier precautions.

• Added temporary restrictive antibiotic policy (TRAP) in Period III

0

5

10

15

20

25

30

35

40

I II III IV

% with GRE

SEL/SUP Ratio

TRAP

*Period I (week 23 to week 45, 1995), Period II (week 46, 1995, to week 22, 1996), period III (week 23 to week 45, 1996), Period IV (week 46, 1996, to week 22, 1997)

Leverstein-van Hall et al. Eur J Clin Microbiol Infect Dis 2001;20:785–791

Nu

mb

er

of p

atie

nts

Period*

Conclusions

Antimicrobial treatment of VAP - early adequate and appropriate empiric therapy

- local epidemiology

- short duration of antibiotics

Treatment of MDR pathogens

- carbapenems, colistin, gentamicin, tigecycline

- synergistic actions (TIGE- + MERO-) ?

- the role of fosfomycin ?

Use of antibiotics

- Pk/PD properties in septic patients

- Surveillance

- Avoiding development of resistance