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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