Disclosures

online.web.presentations.com

Disclosures

Disclosures

Research support: Daiichi, Wyeth, Theravance,

Merck, CIHR, NIH,

Employee: N/A

Consultant: BiondVax, Atox-Bio, Astellas, Bayer,

Merck, Theravance

Major Stockholder: N/A

Scientific Advisory Board: Pfizer-Wyeth, Merck-

Schering, Bayer, Astellas, Theravance, BiondVax,

Atox-Bio, Coronis-Partners

Speakers’ Bureau: Pfizer-Wyeth, Astellas, Cubist.


Motto of the presentation

Because of the need to initiate appropriate

treatment early prior to the causative

pathogen(s) being known, empiric antibiotic

therapy that will cover all likely pathogens is

recommended

American Thoracic Society, Infectious Diseases

Society of America. Guidelines for the

management of adults with hospital-acquired,

ventilator-associated, and healthcare-associated

pneumonia.

Am J Respir Crit Care Med. 2005;171:388-416.


Facts about nosocomial pneumonia (NP)

• NP is the 2nd most common nosocomial infection

and the leading cause of mortality in the

ICU. Flanders SA, Am J Infect Control. 2006;34:84-

93

• NP occurs at a rate of 5 to 10 cases /1000 hospital

admissions, with the incidence increasing by 20-fold

in mechanically ventilated patients (=VAP)

• NP increases hospital stay by 7 to 10 days

• NP produces an excess cost of more than $40,000

per patient.

• NP is responsible for more than 50% of all antibiotics

prescribed in the ICU


ATS and IDSA. Guidelines for the management of adults with hospitalacquired,

ventilator-associated, and healthcare-associated pneumonia.

Am J Respir Crit Care Med. 2005 ;171:388-416


Facts about nosocomial pneumonia (NP)

• Mortality rates in NP vary depending on the patient

population, with HAP mortality as high as 30% to 60%,

lower in clinical drug trials 18-25%, higher in

epidemiological trials

• Mortality in VAP varies from 24% to 60%, with the higher

mortality rates occurring when VAP is accompanied by

acute lung injury (ALI) or adult respiratory distress

syndrome (ARDS).

• The majority of deaths that occur during or after an episode

of NP are commonly related to the underlying medical

conditions rather than being directly attributable to NP

Leroy et al. Treat Respir Med. 2004;3:123-31.

Edis EC, et-al. Respiration. 2009;78:416-422.

Connelly SM, et-al. Am J Infect Control. 2009;37:143-9.)

Fagon J,et-al . Am J Respir Crit Care Med. 2000 ;161(3 Pt 1):753-62.

Fagon JY & Chastre J.. Eur Respir J Suppl. 2003 Aug;42:77s-83s.

Markowicz P, et-al.. ARDS Study Group. Am J Respir Crit Care Med. 2000 161:1942-8.


Facts about staphylococcal NP

• The proportion of staphylococcal infections that

were MRSA in U.S. ICUs was 2% in 1974 22% in

1995, and 64% in 2004. Klevens RM,et-al. Clin Infect Dis. 2006

;42:389-91

• Institutional infection control measures used over

a 15-year period (1993 to 2008) have effectively

reduced the overall MRSA infection rate in 38

French hospitals from 41.0% to 26.6%. rate in 38

French hospitals MRSA still remains a major

pathogen. Jarlier V, et al. Arch Intern Med. 2010 ;170:552-9

• Nosocomial Infection Control Consortium (INICC)

reported resistance rates from 2003 to 2008,

showing that MRSA was responsible for 84.1% of

.

hospital associated infections in international ICUs

Rosenthal VD, et-al. Am J Infect Control. 2010;38:95-104.


Facts about MRSA NP

• Patients with VAP due to MRSA had a longer

stay in the ICU than those with (MSSA),

regardless of appropriate initial antibiotic therapy

(Shorr AF, et-al.Crit Care. 2006;10:R97)

• The risk of death in patients with nosocomial

pneumonia due to S.aureus was increased 2.6-

fold (95% [CI], 1.7 to 4.0) when the pathogen

was MRSA .( Gastemeier P et al. Infection. 2005;33:50-5.)


MRSA prolongs ICU stay in VAP,

despite initially appropriate Abx Rx

Shorr AF, et al.

Crit Care Med. 2006;34:700.


Facts about Gram (-) NP

• Ps.aeruginosa is the most common organism

24%, associated with a mortality of ~50%

• Other emerging organisms resistant to Rx

include: Acinetobacter spp. KPC, NDM-1, VIM’s,

AMP-C Enterobacter, Klebsiella, E.coli etc’ ,

Stenotrophomonas sp.

• Therapy options for these organisms:

carbapenems (include. doripenem), colistinpolymyxin,

amikacin, intra-tracheal amikacin,

colistin,levofloxacin and aztreonam


Emergency department

radiograph


MRSA susceptibility

• Oxacillin

• Fluoroquinolone

• Erythromycin

• Vancomycin

• Linezolid

• Clindamycin

• Cephalosporins

• Trimethoprim–

sulphamethoxazole

Resistant

Intermediate

Resistant

Sensitive

Sensitive

Sensitive

Resistant

Sensitive


STAPHYLOCOCCAL

PNEUMONIA (SP)

• Post flu – classically described post-world war 1, healthy

young; high mortality pre-antibiotics & complications but

also recently

• Staphylococcal pneumonia- not post flu; young adults,

predisposing risk factors, infections in hospital, high

mortality

• Right sided endocarditis or SSTIs in IVDU leading to SP;

less severe

• Post inhalation/aspiration; less severe

• HAP/VAP


Confluent staphylococcal bronchopneumonia with invasion of vessels in the

lungs, producing a florid vasculitis (arrow). Secondary thrombosis is occluding

the pulmonary vascular system. (Haematoxylin–eosin stain; original

magnification × 100)


Virulence Factors

• PSM (=phenol soluble protein)

• PVL

• δ toxin

• Agr II- less vancomycin susceptible

• Agr III- in CA MRSA strains more

commonly

(Agr operon upregulates secretion of

virulence factors and downregulates

expression of virulence factors on the

bacterial surface)


S.aureus aetiology of CAP:

culture + and hospitalised

?

Author S.aureus (%) MRSA

Kollef et al 2005 25.5% - Large US

outcomes

database

Stralin &

Soderquist 2006

7.3% - Single institution

Marrie . 2001 2.9% - Review of seven

studies

Torres et al 2009

Woodhead 2002

0-11.73%

4.9 %

-

-

Country specific

across Europe

Review of 41

prospective

studies


Hayward et al. Emerg Inf Dis. 2008;14:720


Brazil


MRSA Load in the UK

Male age standaradized

rate of death due to

MRSA

2001 2005

12.5/mio

25/mio than

decreasing in

2008 31%

Female 6.7/Mio 14.5/Mio than

decreasing in

200813%

MRSA change in death

certificates

+39%

http://www.statistics.gov.uk


HAP /VAP


Incidence of Nosocomial pneumonia caused

by S. aureus

50%

45%

40%

35%

30%

25%

20%

15%

10%

5%

0%

2%

50%

1974 1997

Pujol et al. Eur J Clin Microbiol Inf Dis 1998;17:622

Germaud et al. Rev Pneumol. Clin 1999;55:83


France

• 13.1% of 169 French ICU’s (1993-5) 55.7%

MRSA

(Trouillet JL et al.Am J Respir Crit Care Med 1998; 157: 531-9; Chastre et

al. idem 2002;165: 867-903)

• VAP caused by MRSA 11 additional ICU days

stay compared to MSSA (Schorr et al. Crit Care Med 2006;

34: 700-6)

• Universal screening and preventive isolationcost

benefit of $600-700/ patient in 6 ICU’s (Lucet

et al. Arch Intern Med 2003; 163: 181)


USA

• S.aureus in 20% of cases of HAP or 1%

of all hospitalizations, MRSA 10% of HAP

(NNIS data)

• MRSA VAP- adds 4.4 additional days of

MV and 5 additional ICU days (compared

to MSSA) excess cost $7731 (Schorr et al. Crit

Care 2006; 10: R97)


The Vancomycin ‘Creep’


Vancomycin MIC creep

80

70

60

MIC ≤0.5mg/L

MIC=0.75mg/L

MIC=1.0mg/L

MIC>1.0mg/L

Percentage

50

40

30

20

10

0

2001 2002 2003 2004 2005

Year

Steinkraus, White and Friedrich. J Antimicrob Chemother 2007;60:788-794


Vancomycin MIC significantly

predicts mortality in MRSA

Treatment group

Risk of mortality

(OR [95% CI])

P-value

Vancomycin MIC=1 1

Vancomycin MIC=1.5 2.86 (0.87, 9.35) 0.08

Vancomycin MIC=2 6.39 (1.68, 24.3)


Reduced vancomycin efficacy

with higher MIC

Data taken from 30* MRSA bloodstream isolates from US hospitals

100

80

P=0.01

Success, %

60

40

56

20

0

10

n=9 n=21

≤0.5 1.0–2.0

Vancomycin MIC, µg/ml

*23 isolates were vancomycin treatment failures, 7 were treatment successes

Sakoulas G et al. J Clin Microbiol. 2004;42:2398–2402


Therapy


Risk Factors for Multidrug-Resistant

Pathogens Causing HAP or VAP

• ABx Rx in the preceding 90 days

• Current hospital stay > 5 days

• ABX resistance that is highly prevalent in hospital/unit

• Immunosuppressive disease or therapy

• Hospitalization of > 2 days in the last 90 days

• Residence in a nursing home or extended care facility

• Infusion home therapy

• Receipt of long-term dialysis in the last 30 days

• Wound care

• Family member with MDR pathogen

Guidelines for the management of adults with hospital-acquired, ventilator-associated,

and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388.


*Mortality refers to crude or infection-related mortality

Alvarez-Lerma F et al. Intensive Care Med 1996;22:387-394.

Ibrahim EH et al. Chest 2000;118L146-155.

Kollef MH et al. Chest 1999; 115:462-474

Kollef MH et al. Chest 1998;113:412-420.

Luna CM et al. Chest 1997;111:676-685.

Rello J et al. Am J Resp Crit Care Med 1997;156:196-200.

Mortality Associated With Initial Inadequate

Therapy In Critically Ill Patients With

Serious Infections in the ICU

Alvarez-Lerma,1996

Rello, 1997

Kollef, 1999

Kollef, 1998

Initial appropriate

therapy

Initial inadequate

therapy

Ibrahim, 2000

Luna, 1997

Mortality*

0% 20% 40% 60% 80% 100%


Mortality Rates Associated With Inadequate, Inappropriate,

Delayed, or Lack of Antibiotic Treatment for NP

Random effects model. Heterogeneity: Cochran’s Q (15 df)=79.04, p


Random Effects Model for Imputed Placebo Eliminating

Three Studies to Reduce Heterogeneity

Heterogeneity: Cochran’s Q (12 df)=8.38, p=0.75

Note: Imputed placebo may be an underestimate since most patients received some treatment.


Mortality Risk with Increasing Delays in

Initiation of Effective Antimicrobial Therapy

Kumar et al, CCM 2006:34:1589-96

Odds Ratio of Death

(95% Confidence Interval)

100

10

1

>36

24-35.99

12-23.99

9-11.99

6-8.99

5-5.99

4-4.99

3-3.99

2-2.99

1-1.99

Time (hrs)


Linezolid vs Comparator(s) in HAP/VAP

Study

Pneumonia

Linezolid

Comparator

Cepeda et al 86 15/18 (83%) 24/29 (72%)

Wilcox et al 88 42/45 (93%) 42/46 (91%)

Kaplan et al 89 9/10 (90%) 10/10 (100%)

Wunderink et al 91 114/168 (68%) 111/171 (65%)

San Pedro et al 92 63/71 (89%) 62/70 (89%)

Stevens et al 93 9/12 (75%) 12/16 (75%)

Rubinstein et al 94 71/107 (66%) 62/91 (68%)

Total 323/431 (74·9%) 323/433 (74·6%)


Linezolid vs vancomycin for Gram-positive

nosocomial pneumonia: clinical cure rates

Linezolid

Vancomycin

80

P=0.182

P=0.009

Clinical cure, %

60

40

20

51.5

43.4

59.0

35.5

0

S. aureus (n=272) MRSA* (n=123)

Wunderink R et al. Chest 2003;124:1789–1797

Type of pneumonia

Data from patients with indeterminate or missing clinical outcomes were excluded

*A subset of patients with S. aureus pneumonia


Wunderink RG, et al. Chest. 2008;134:1200


Wunderink RG, et al. Chest. 2008;134:1200


Vanco(popotamus)

Large molecule

Penetrates slowly

Slowly cidal

Difficult to measure


Not such smart therapy

• Vanco in the lung::

• Concentrations in Plasma:ELF=6:1

• 36% of patients ELF vanco conc. < 4 mg/L


Vancomycin therapy for MRSA

VAP

• Patients with MRSA VAP treated with

vancomycin have 50% mortality, patients with

MSSA VAP treated with vancomycin have a

47% mortality

(Gonzalez et al. Clin Inf Dis 1999;29:1171-7)

• Patients with MSSA VAP treated with betalactam

have a mortality of ~5%

(Rello et al. A J R C C M 1994;150:1545).


RECENT STUDIES IN HAP/VAP

Tigecycline – Effective in HAP but not VAP

Ceftobiprole – Effective in HAP but not VAP

(Rejected by the FDA)

Doripenem – Effective in HAP & VAP

Telavancin – Effective in HAP & VAP

(Rejected by the FDA)

Linezolid inHAP/VAP-Effective


Therapy of S.aureus CAP


Following his admission to the intensive care unit, the patient

was administered cefuroxime and prednisone intravenously


• Patient 1

• Ceftriaxone

15 h after admission

• Addition of

vancomycin

clindamycin

• Patient 2

• Ceftriaxone, amikacin,

and levofloxacin

14 h after admission

• Clindamycin and linezolid

plus Tegeline

J Clin Microbiol. 2010;48:1952-5.


Characteristics of pneumonia

caused by PVL+ S.aureus

• Rare

• Mortality 40% and rapid (within 1-4 d)

• Rapid progression

• Young patients

• Hempthysis 40%

• Leukopenia 40%

10% survival when

WBC


Diep et al. Proc Natl Acad Sci USA (2010) vol. 107 (12) pp.

5587-92

PVL contributes to virulence of USA300

in rabbit model of necrotizing

pneumonia


Clinical features of PVL-associated pneumonia

(1999 – 2010)

Sicot N et al


Similar kinetic of death for MRSA

and MSSA cases

Cumulative probability of

survival

1.0

0.8

0.6

0.4

CA-MRSA pneumonia

CA-MSSA pneumonia

0.2

Days

0.0

0 5 10 15 20 25 30

Sicot N et al (in press)


350%

300%

PVL level reported to control by MSSA

250%

200%

150%

100%

50%

0%

200%

150%

100%

50%

No antibiotic

* * * * *

*

No antibiotic

⅛ MIC

¼ MIC

½ MIC

Oxacillin Clindamycin Linezolid Fusidic acid Rifampicin

*

* * *

*

*

* *

*

0%

No antibiotic

Pristinamycin Tetracycline Ofloxacin Co-trimoxazole Vancomycin


β-lactams which bind PBP1 enhance PVL

production

Level of PVL production

PVL mRNA fold change

No atb OXA IMI CTX CCL FOX

Selective ligand : PBP1-4 PBP1 PBP2 PBP3 PBP4

Dumitrescu et al Antimicrob Agents Chemother 2007;51:1515-9

Dumitrescu et al Clin Microbiol Infect 2008; 14: 384–388


Which antibiotics on MRSA?

Vancomycin

(in vitro)

Linezolid

(in vivo)

Ceftobiprole

(in vivo)

ATCC 33591

Log 10 CFU / Thigh

T>MIC

0 2 4 8 12 18 24

Time (hours)

Linezolid better than vancomycin

But only ceftobiprole kills rapidly MRSA

Palmer SM et al. Antimicrob Agents Chemother 1996;40:701–705

Houlihan HH et al Antimicrob Agents Chemother. 1997;41:2497-501.

Craig WA et al. Antimicrob Agents Chemother. 2008;52:3492-6.


Guidelines for treatment

• Guidelines for CA-MRSA pneumonia only in UK :

• combination of clindamycin 1.2 g iv qds, linezolid 600 mg iv

bd and rifampicin 600 mg bd until the patient has improved

and is clinically stable,

• 1-2g/kg of IVIG, be repeated after 48 h if there is still evidence

of sepsis, or failure to respond

• US Guidelines for MRSA pneumonia :

• American Thoracic Society/Infectious Disease Society of

America: vancomycin trough concentrations of 15–20 mg/mL

and linezolid as alternative choice.


New therapeutic options for

Resistant Gram (-) NP

• Colistin (IT + systemic) ~50-66% efficacy

• Tigecycline and alike

• IT amikacin, aztreonam, ciprofloxacin,

levofloxacin-phase II clinical trials.

• New fluoroquinolones with activity in acidic

pH and with anaerobic activity.

• New vaccines

• Biologic modifiiers


Remaining issues to be discussed

• Place of IT Abx therapy

• Is vanco creep an issue?

• Is renal failure in MRSA patients an

indication for linezolid?

• Is step down therapy important? When?

• How long to treat?

• Single vs. combi?


• The real world utilization of the ‘bundle’

approach in the ICU, is it applicable toall

patients?

• The role of antecedent partially

preventable LRTI (H1N1, H5N1,

pneumococcal pneumonia, COPD, etc’)


Rubinstein et al. A A C 2003;47:1824-31


Liang Beibei, et al. International Journal of Antimicrobial Agents 2010; 35: 3-12.

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