Download Diagnosis, Treatment and Prevention of Hospital Acquired

Diagnosis, Treatment and Prevention
of Hospital Acquired Pneumonia
Michael Zgoda, MD
Asst. Professor, Division of Pulmonary,
Critical Care and Sleep Medicine
Director, Interventional Pulmonology
University of Kentucky, Lexington, KY
A Case Study
Day 1
 A 76-year-old white male is sent to the local
hospital from a long-term care (LTC) facility for
evaluation of a pneumonic process
 Past medical history reveals multiple
admissions, with a history of diabetes,
hypertension, and foot ulcer
 The patient was discharged 10 days ago
following a cholecystectomy.
 The patient is admitted for pneumonia.
Necessary blood work, cultures, and labs are
performed. Ceftriaxone and azithromycin IV
are started.
Chest X-Ray
A Case Study
Day 3
 The patient is still febrile and has developed a cough (mucoid). He is
uncomfortable and very restless. Staff notes that he is somewhat
disoriented to time and place. The patient has no history of dementia
 Follow-up information sent from the LTC facility shows that the patient has
been on oral dicloxacillin, for previous infections, with poor results
 Current laboratory test values denote increased white blood cell count and
Gram-positive cocci
A Case Study
Days 5 to 7
 The patient’s therapy was reviewed by the attending physician:
– Therapy was changed on day 3 by adding levofloxacin
– At present the patient is worsening and requires intubation and mechanical
ventilation
– Several hours later he continues to spike temperatures at 102 degrees and
becomes hypotensive despite 6 liters of lactated ringers IVF.
– Pressors are started and the patient is then transferred to a tertiary care
hospital
A Case Study
Day 7
 Culture results from referring hospital reveal:
– Species of bacteria; S aureus
– Strain of bacteria; MRSA
 The patient is treated with appropriate antibiotics upon arrival to tertiary
care hospital and the pneumonia resolves. He has a prolonged ICU stay of
28 days at which point the family decides to withdraw care because
profound malnutrition and subsequent ICU associated complications from
his underlying diabetes including a NSTEMI, pseudomonas sinusitis, and
Pseudomembranous colitis with associated diarrhea and a stage 3 sacral
ulcer requiring debridement.
Nosocomial Infections and Resistance
 2 million nosocomial infections per year in US hospitals
 60% involve antibiotic-resistant bacteria
– Staphylococcus aureus is the most common overall bacterial cause of
infection involving bloodstream, respiratory tract, and skin/soft tissue,
according to the SENTRY Antimicrobial Surveillance Program
– Strains of S aureus that have acquired resistance to β-lactam antibiotics,
most commonly through inheritance of the mecA resistance gene, are
known as methicillin-resistant S aureus (MRSA)
– MRSA accounts for 29% to 35% of all clinical isolates of S aureus in US
and European hospitals
 Estimated excess costs related to antibiotic resistance approach $30 billion
per year in US hospitals
Haddadin AS et al. Postgrad Med J. 2002;78:385-392.
Diekema DJ et al. Clin Infect Dis. 2001;32(suppl 2):S114-S132.
Deresinski S. Clin Infect Dis. 2005;40:562-573.
Zetola N et al. Lancet Infect Dis. 2005;5:275-286.
The MRSA Story
 Infections due to gram-positive cocci, eg, S aureus,
particularly MRSA, are:
– Rapidly emerging in the United States
– More common in certain patient populations
• Diabetes mellitus
• Head trauma
• Intensive-care unit (ICU)
 50% of ICU infections (US) caused by S aureus are MRSA
ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.
Progression of Methicillin Resistance:
S aureus Among Intensive Care Unit (ICU) Patients
63%
Incidence of MRSA (%)
70
60
50
40
30
20
10
19
87
19
88
19
89
19
90
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
19
75
0
Year
CDC. Available at: http://www.cdc.gov/ncidod/hip/ARESIST/ICU_RESTrend1995-2004.pdf.
Accessed August 30, 2005.
Lowy FD. J Clin Invest. 2003;111:1265-1273.
Definitions
 Hospital-acquired
pneumonia (HAP)
– Pneumonia occurring
48 hours post-hospital
admission
 Ventilator-associated
pneumonia (VAP)
– Pneumonia occurring
48-72 hours post-intubation
ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.
 Health care-associated
pneumonia (HCAP)
– Includes HAP and VAP
– Pneumonia in patients
• Hospitalized for 2 days in an acute
care facility within 90 days of
infection
• Residing in a nursing home or longterm care (LTC) facility
• Attending a hospital or
hemodialysis clinic
• Receiving immunosuppressive
therapy or wound care within 30
days of infection
How Do Pathogens Find the Patient?
 Sources of infections
– Healthcare devices
– Environment (air, water, equipment,
fomites)
– Staff-patient/patient-patient transfer of
microorganisms
 Host- and treatment-related
colonization factors
– Severity of underlying disease
– Prior surgery
– Exposure to antibiotics
– Other medications
– Exposure to invasive respiratory
devices and equipment
ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.
 Routes of bacterial entry into the lower
respiratory tract
– Aspiration of oropharyngeal pathogens
– Leakage around endotracheal
tube cuff
 Embolization of infected biofilm in the
endotracheal tube to distal airways may
play a role
Most Common Isolates: All ICU HAP vs VAP
20
18
18
18
18
17
16
Pneumonia (%)
All HAP*
14
†
VAP
12
12
11
10
8
7
7
6
5
5
4
4
4
4
4
2
0
S aureus
Pseudomonas
aeruginosa
Enterobacter spp
*January 1992-May 1999. †1990-1995.
NNIS. Am J Infect Control. 1999;27:520-532.
Fridkin SK et al. Infect Dis Clin North Am. 1997;11:479-496.
Klebsiella
pneumoniae
Candida
albicans
Escherichia coli
Haemophilus
influenzae
Risk Factors for Multidrug-Resistant (MDR)
Pathogens Causing HAP, HCAP, and VAP
 Antimicrobial therapy in preceding 90 days
 Current hospitalization of 5 days
 High frequency of community or hospital-unit antibiotic resistance
 Presence of risk factors for HCAP
– Hospitalization for 2 days in preceding 90 days
– Residence in a nursing home or LTC facility
– Home infusion therapy (including antibiotics)
– Chronic dialysis within 30 days
– Home wound care
– Family member with MDR pathogen
 Immunosuppressive disease and/or therapy
ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.
HAP, VAP, and HCAP Mortality
 Crude mortality rate for HAP may be as high as 30% to 70%
– However, many critically ill patients with HAP do not die of
pneumonia, but rather of their underlying disease
 Mortality attributable to HAP estimated at 33% to 50%
 Increased mortality rates were associated with
– Bacteremia
– P aeruginosa or Acinetobacter spp
– Medical, not surgical, illness
– Ineffective antibiotic therapy
ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.
Heyland DK et al. Am J Respir Crit Care Med. 1999;159:1249-1256.
Improving Outcomes
 Prevention
 Decreasing resistance
 Improving our antibiotic selections
Benefits of Early, Appropriate Therapy
Cumulative evidence from multiple studies has demonstrated
that early, appropriate therapy is associated with:
 Shorter duration of antibiotic therapy
– Short-course therapy is only an option when the right antibiotic
is used from the start
 Decreased length of ICU or hospital stay
 Lower total cost
 Decreased mortality
– Appropriate antimicrobial therapy reduces infection-related and
all-cause mortality
Craven DE et al. Infect Dis Clin North Am. 2004;18:939-962.
Singh N et al. Am J Respir Crit Care Med. 2000;162:505-511.
Lodise TP et al. Cin Infect Dis. 2003;36:1418-1423.
Kollef MH et al. Chest. 1999;115:462-474.
Importance of Initial, Appropriate Antibiotic Therapy
“…selection of initial appropriate antibiotic therapy (ie, getting the antibiotic treatment right
the first time) is an important aspect of care for hospitalized patients with serious infections.”
– ATS/IDSA Guidelines
A Study by Kollef and Colleagues Evaluating the Impact of Inadequate Antimicrobial Therapy on Mortality
Hospital Mortality (%)
60
*P<.001
52*
50
42*
40
30
24
18
20
10
0
All-Cause Mortality
Inadequate antimicrobial treatment
(n=169)
ATS=American Thoracic Society; IDSA=Infectious Diseases Society of America.
Adapted from Kollef MH et al. Chest. 1999;115:462-474.
ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.
Infection-Related Mortality
Adequate antimicrobial treatment
(n=486)
Initial Empiric Therapy in Patients
Without Risk Factors for MDR Pathogens
Potential Pathogens
Recommended Antibiotic
Streptococcus pneumoniae*
H influenzae
Methicillin-sensitive
S aureus (MSSA)
Ceftriaxone/Azithromycin
or
Levofloxacin, moxifloxacin, or
ciprofloxacin†
or
Ampicillin/sulbactam
or
Ertapenem
Antibiotic-sensitive, enteric,
gram-negative bacilli
E coli
K pneumoniae (ESBL-)
Enterobacter spp
Proteus spp
Serratia marcescens
ESBL=extended-spectrum β-lactamase producer.
*The frequency of penicillin-resistant S pneumoniae and MDR S pneumoniae is increasing.
†Levofloxacin or moxifloxacin are preferred to ciprofloxacin and the role of other new quinolones, such as
gatifloxacin, has not been established.
Adapted from ATS/IDSA. Am J Respir Crit Care Med. 2005;171:401. Table 3.
Initial Empiric Therapy for Late-Onset Disease, Risk
Factors, or MDR Pathogens
Potential Pathogens
MDR pathogens*
P aeruginosa
K pneumoniae (ESBL+)†
Acinetobacter spp†
Non-MDR, gram-negative bacilli
Legionella pneumophila†
MDR, gram-positive cocci
MRSA
Initial, Broad-Spectrum,
Combination Antibiotic Therapy
Antipseudomonal cephalosporin
or
Antipseudomonal carbepenem
or
-Lactam/-lactamase inhibitor
plus
Antipseudomonal fluoroquinolone‡
or
Aminoglycoside‡
plus¶
Linezolid 600 mg q12h or
Vancomycin 15 mg/kg q12h§
*Including pathogens from slide 19, (S pneumoniae, H influenzae, MSSA, E coli, K pneumoniae (ESBL-), Enterobacter spp, Proteus spp, S marcescens.
†If an ESBL+ strain K pneumoniae or MDR Acinetobacter spp is suspected, a carbepenem is suggested as initial therapy.
‡If L pneumophila is suspected, the combination antibiotic regimen should include a macrolide or a fluoroquinolone rather than an aminoglycoside.
¶If MRSA is suspected or there is a high incidence locally.
§Trough levels for vancomycin should be 15 µg/mL to 20 µg/mL.
Adapted from ATS/IDSA. Am J Respir Crit Care Med. 2005;171:402. Tables 4 and 5.
Inpatient Antibiogram of SOMC
SOMC Annual Antibiogram
Inpatients
July 1, 2004 - June 30, 2005
Tobramycin
Trimeth/Sulfa
Vancomycin
572 49 53 NI
91 98 97 94 100 81 NI
97 NI
61 97
513
2 24 30 24 NT 24 90 NT
32 24 NT
1 NT NT
389
0
0
0
0 NT
0 94
0 NI
0 NT
0 NT NT
322 98 98
7 NI NI NI NT NT
42
0 97
1 NT NT
312 56 63 35 60 NI
60 NI
NI
52 58 NT
47 NI
NI
211
0
0 NI
0 75 14 76 83 59 NI
0 NI
87 92
172
0 76 NI
85 93 93 93 100 92 NI
74 NI
82 90
148 48 87 NI
91 99 98 82 98 43 NI
4 NI
75 100
124 10 100 77 100 NT 100 100 100 97 100 NT
10 NT NT
101 100 100 62 100 NI 100 NT NT
98 79 100 100 NT NT
69 95 95 47 95 NT 98 NT NT
88 43 80 97 NT NT
60 69 69 56 69 NT 98 NI NT
98 68 NT
66 NT NT
47
0 12 NI
4 80 65 70 100 72 NI
63 NI
65 68
45 80 100 93 45 NT 97 NT NT 100
2 NT
75 NT NT
38 13 13
0 NI NI NI NT NT
0
0 45
0 NT NT
35
2 79 NI
0 28
8 20 94 20 NI
0 NI
11 85
35
5
7 NI
0 97 91 88 100 91 NI
0 NI
80 71
32
3
9 NI
12 93 84 90 100 93 NI
61 NI
77 84
28 10 57 NI
14 89 85 82 100 82 NI 100 NI
80 89
24
0
0 NI
0 26
0
8
0 65 NI
NI NT
21
14
0 10 NI
7 14 14 28 64 50 NI
0 NI
71 78
13
0
0 NI
15 92 92 30 100
0 NI
0 NI
40 84
11
0
0 NI
9 72 72 72 100 54 NI NI
NI 100 100
Tetracycline
Piperacillin/Tazo
Piperacillin
Penicillin
Nitrofurantoin
Nafcillin
Levofloxacin
Imipenem
Gentamicin
Ceftriaxone
Cefepime
Cefazolin
Azithromycin
Amp/Sulbactam
Ampicillin
Escherichia coli
Staphylococcus aureus
Staphylococcus aureus (MRSA)
Enterococcus faecalis
Staphylococcus - Coag Negative
Pseudomonas aeruginosa
Klebsiella pneumoniae
Proteus mirabilis
Staphylococcus aureus (MSSA)
Streptococcus, Group B
Streptococcus, viridans
Streptococcus pneumoniae
Enterobacter cloacae
Haemophilus influenzae
Enterococcus faecium
Acineotbacter anitratus
Serratia marcescens
Enterobacter aerogenes
Citrobacter freundii
Stentrophomonas maltophilia
Alcaligenes species
Providencia stuartii
Morganella morganii
Number of isolates
ORGANISM NAME
85
95
90
31
87
17
NT
0
100
0
71
85
NT
100
37
NT
NT
NT
NT
16
NT
NT
NT
95
NT
NT
76
94
98
68
61
5
90
49
100
NT
59
94
76
82
7
22
94
87
82
95
85
38
72
NI
100
100
95
100
NI
NI
NI
100
100
100
100
NI
NI
2
NI
NI
NI
NI
NI
NI
NI
NI
NI
90
93
81
NT
NT
NT
NI
68
NT
NT
25
58
90
85
12
28
7
90
Green - Antibiotic of choice for most infections due to this organism
Blue - Combination of both antibiotics is recommended
Special thanks to Timothy R. Cassity, Ph. D.
Outpatient Antibiogram SOMC (2004-2005)
SOMC Annual Antibiogram
Outpatients
July 1, 2004 - June 30, 2005
Tetracycline
Tobramycin
Trimeth/Sulfa
Vancomycin
21
0 NI
0 50 23 38 100 42 NI
26 15 90 NI
90
20 NI
0 20 20 30 90 30 NI
0 NI
0
10
0 100 NI 100 94 100 100 100 100 NI 100 NI 100
18
0 NT
0 52
0
2 NI NI NI NT NT
37 10 10
92 NT
26 92 100 76 92 NT 100 NT NT 100 19 NT
91 NT
8 NT
12 91 100 100 83 NT 100 NT NT 100
17 NT
17 70 100 100 88 NT 100 NT NT 100 17 NT
84 NT
70 87 88 41 85 NT 82 NT NT 100 43 NT
19 100 100 73 100 NT 100 NT NT 100 100 NT 100 NT
47 NI
50 55 NT
NI
82 NI
259 54 61 31 59 NI
50
14 81 75 85 100 84 NI 100 NI
54 11 66 NI
69
65 NI
9 82 85 96 98 97 NI
1 23 NI
82
80
66 NI
10 81 75 87 98 81 NI
4 NI
70 31
92
NI
18 74 92 59 96 46 NI NI
9 44 NI
54
69
2 NI
93 99 99 86 99 53 NI
419 60 88 NI
3 NI NT
9 NI
18 87 93 33 100
6 33 NI
33
0 NI 21
0 46 NI
0 28
7
0
0 NI
0
14
99 80 99 100 NT
591 99 100 61 100 NI 100 NT NT
87 53 86 97 NT
122 96 96 50 99 NT 99 NT NT
0 NT
0 98
52
532 98 98 10 NI NI NI NT NT
71
98 NI
95 99 99 96 100 88 NI
2856 55 66 NI
69 NT
6 NT
62 77 100 90 64 NT 100 NT NT 100
87
77 NI
89 96 97 96 100 97 NI
0 74 NI
492
73
2 NI
0 83 24 80 87 59 NI
0 NI
0
282
9 NT
46 48 NT
9 48 20 48 NT 38 89 NT
160
Piperacillin/Tazo
Piperacillin
Penicillin
Nitrofurantoin
Nafcillin
Levofloxacin
Imipenem
Gentamicin
Ceftriaxone
Cefepime
Cefazolin
Azithromycin
Amp/Sulbactam
Ampicillin
Acineotbacter anitratus
Alcaligenes species
Citrobacter diversus
Enterococcus faecium
Haemophilus parahaemolyticus
Haemophilus parainfluenzae
Moraxella catarrhalis
Staphylococcus saprophyticus
Sterptococcus, Group A
Staphylococcus - Coag Negative
Citrobacter freundii
Enterobacter aerogenes
Enterobacter cloacae
Morganella morganii
Proteus mirabilis
Providencia stuartii
Stentrophomonas maltophilia
Streptococcus, Group B
Streptococcus, viridans
Enterococcus faecalis
Escherichia coli
Haemophilus influenzae
Klebsiella pneumoniae
Pseudomonas aeruginosa
Staphylococcus aureus
Number of isolates
ORGANISM NAME
64
90
100
NT
NT
NT
NT
NT
NT
NI
85
80
80
92
99
78
21
NT
NT
NT
99
NT
95
92
NT
NT
NT
NT
29
92
100
100
87
73
83
NT
NT
NT
NI
0
NT
0
0
61
24
86
98
NT
27
92
38
40
100
NT
NT
NT
NT
NT
NT
NI
92
96
87
79
86
27
28
NT
NT
NT
96
NT
96
90
NT
46
60
94
13
96
91
82
92
10
58
77
97
81
70
57
45
71
NT
45
70
81
90
95
3
92
NI
NI
NI
5
NI
NI
NI
100
100
100
NI
NI
NI
NI
NI
NI
NI
100
100
97
NI
NI
NI
NI
100
Special thanks to Timothy R. Cassity, Ph. D.
Nursing Home Patients Antibiogram SOMC
SOMC Annual Antibiogram
Nursing Home Patients
July 1, 2004 - June 30, 2005
Special thanks to Timothy R. Cassity, Ph. D.
Vancomycin
NT
28
72
NT
NT
NT
0
NT
0
43
80
100
NT
7
NT
86
Trimeth/Sulfa
36
NT
NI
NT
35
100
98
75
NT
NT
98
NT
96
83
13
NT
Tobramycin
Tetracycline
Piperacillin
100
9 NI
0 NI
12
NT
0
0 60
0 NT
NI
13 13 NT
13 NI
100 90 NI
66 NI
72
100 35 NI
80 NI
35
100 21 NI NI
NI 100
100 25 NI
2 NI
50
100
0 NI
5 NI NT
NT 100 90 100 100 NT
NT
25
0 96
0 NT
100 46 NI
95 NI
16
NT 100
0 NT
70 NT
100 88 NI
62 NI NT
80 37 NI
0 NI
57
100 93 NI NT NI
13
NT
12 17 NT
0 NT
Penicillin
0
NT
NI
81
71
28
76
20
NT
NT
85
NT
90
67
100
91
Piperacillin/Tazo
Nitrofurantoin
0
NI
18
81
28
100
98
90
100
NI
100
100
90
6
93
17
Nafcillin
Imipenem
Levofloxacin
Gentamicin
11
0 80 NI
0
9
25
8
8
4 NI NI
22 13 22 18 22 NI
11
0
0 NI
9 81
14
0
0 NI
0 50
14
7 66 NI
28 85
197 41 78 NI
92 99
20
0 33 NI
5 95
19 100 100 75 100 NI
104 96 97
7 NI NI
283 30 30 NI
92 99
10 70 100 80 50 NT
60
0 33 NI
80 90
77
0
0 NI
0 67
15
0
0 NI
0 93
96
6 19
4 17 NT
Ceftriaxone
Cefepime
Cefazolin
Azithromycin
Amp/Sulbactam
Ampicillin
Acineotbacter anitratus
Enterococcus faecium
Staphylococcus - Coag Negative
Enterobacter aerogenes
Enterobacter cloacae
Morganella morganii
Proteus mirabilis
Providencia stuartii
Streptococcus, Group B
Enterococcus faecalis
Escherichia coli
Haemophilus influenzae
Klebsiella pneumoniae
Pseudomonas aeruginosa
Serratia marcescens
Staphylococcus aureus
Number of isolates
ORGANISM NAME
0 18 NI
NT
16
0
NI
31 100
81 81 NI
71 50 NI
57 64 NI
76 31 NI
20 25 NI
NT NT 100
NT
64 97
86 46 NI
NT
90 NI
88 80 NI
83
0 NI
13 100 NI
NT
90 100
Oxazolidinone: Birth of a New Antimicrobial Agent Class
 1987: First report of oxazolidinone family of molecules at the 27th ICAAC
meeting. Early studies illustrated:
– Potent activity against Gram-positive organisms, including S aureus (MSSA
and MRSA), Staphylococcus epidermidis, Streptococcus pneumoniae, and
enterococci; modest activity against a few fastidious Gram-negative bacteria
was noted
– Equally effective when administered orally
– Novel inhibition of protein synthesis
 1995: 25 presentations at the 35th ICAAC meeting, including the first phase I
study results
 2000: FDA approval based on 9 trials in more than 4000 patients
Ford CW et al. Curr Drug Targets Infect Disord. 2001;1:181-199.
Linezolid Characteristics
A Small Molecule With Good Penetration Into Lung and Skin Tissue
O
O
N
N
F
O
O
H
N
H
C
C H3
 Available in oral and intravenous formulations
– Oral formulation has 100% bioavailability
 Has activity against most clinically important Gram-positive pathogens
 Resistance remains uncommon
– Linezolid inhibits bacterial protein synthesis through a mechanism of action different from
that of the other antibacterial agents; therefore, cross-resistance between linezolid and
other classes of antibiotics is unlikely
Pharmacokinetics in healthy volunteers and in vitro activity do not necessarily imply a correlation
with clinical effectiveness.
Conte JE Jr et al. Antimicrob Agents Chemother. 2002;46:1475-1480.
Adapted from French G. Int J Clin Pract. 2001;55:59-63.
Meka VG et al. Clin Infect Dis. 2004;39:1010-1015.
Lung Penetration Concentration vs MIC90 of Linezolid Against
Gram-Positive Organisms
 Plasma and pulmonary
epithelial lining fluid (ELF)
linezolid concentrations
exceeded MIC90 for
staphylococci and
streptococci through the
dosing interval
Epithelial lining fluid
Plasma
MIC90 S aureus
Concentration (µg/L)
 5 doses of linezolid
600 mg q12h were
administered orally to 25
healthy volunteers
MIC90 Enterococcus spp
MIC90 S pneumoniae
Time After Last Dose (h)
MIC90=minimum concentration needed to inhibit 90% of organisms.
Adapted from Conte JE Jr et al. Antimicrob Agents Chemother. 2002;46:1475-1480.
Pharmacokinetic Characteristics of Linezolid in Adults
Parameter
Effect
Oral bioavailability
100%
Ingestion of food
No dose adjustment
Volume of distribution
Total body water, 40 L to 50 L
Dosage formulations
IV, tablets, oral suspension (PO)
Distribution
Readily distributes into well-perfused tissues
Protein binding
31%, independent of drug concentration
Linezolid Pharmacokinetics in VAP
 16 critical-care patients with
late-onset VAP (≥5 days on
the ventilator)
 Pharmacokinetic profile was
evaluated after 2 days of
linezolid (600 mg q12h IV)
therapy. ELF samples were
collected by mini-BAL brush
Steady State Concentrations in 16 VAP Patients
Peak
Trough
Plasma (mg/L)
17.7±4
2.4±1.2
ELF (mg/L)
14.4±5.6
2.6±1.7
Boselli E et al. Crit Care Med. 2005;33:1520-1533.
First Prospective Comparison of Linezolid vs Vancomycin for
Empiric Treatment of Nosocomial Pneumonia (NP)
A randomized, double-blind, multicenter, multinational, comparator-controlled
trial to compare the safety and efficacy of linezolid versus vancomycin for NP
Clinical Cure (%)
70
60
53
58
55
52
50
46
50
40
30
20
10
86/161 74/142
31/56
19/41
18/31
10/20
0
Intent-to-treat (ITT)
S aureus NP
Linezolid 600 mg q12h IV
MRSA NP
Vancomycin 1 g q12h IV
Safety and efficacy of linezolid versus vancomycin were compared in 402 patients with NP, including VAP; 398 patients received at least 1 dose
of study medication. Patients were treated for 7 to 21 days, with optional aztreonam 1 g to 2 g q8h. Clinical cure rates were assessed 12 to
28 days after end of therapy.
Rubinstein E et al. Clin Infect Dis. 2001;32:402-412.
Data on file. Pfizer Inc.
Second Prospective Comparison of Linezolid vs Vancomycin
for Empiric Treatment of NP
A randomized, double-blind, multicenter, multinational, comparator-controlled
trial to compare the safety and efficacy of linezolid versus vancomycin for NP.
Clinical Cure (%)
70
60
60
53
52
50
49
42
40
29
30
20
10
0
135/256 128/245
ITT
40/81
40/95
S aureus NP
Linezolid 600 mg q12h IV
18/30
12/41
MRSA NP
Vancomycin 1 g q12h IV
The safety and efficacy of linezolid IV versus vancomycin IV were compared in 623 patients with NP, including VAP. Patients were treated for
7 to 21 days, with optional aztreonam 1 g to 2 g q8h. Clinical cure rates were assessed 15 to 21 days after end of therapy.
Wunderink RG et al. Clin Ther. 2003;25:980-992.
Data on file. Pfizer Inc.
Linezolid Demonstrates Excellent Efficacy in a Retrospective
Analysis of Two Prospective Clinical Trials
A retrospective analysis of the combined results from the 2 prospective,
identical design trials in 1019 patients with NP including ventilator-associated
pneumonia (VAP)
Clinical Cure (%)
70
60
59
53
52
52
50
43
36
40
30
20
10
221/417 202/387
70/136 59/136
ITT
S aureus NP
36/61
22/62
0
Linezolid 600 mg q12h IV
MRSA NP
Vancomycin 1 g q12h IV
Linezolid was equally effective in the ITT and S aureus NP populations (P=NS).
The outcome difference in the MRSA NP subgroup is provided as a descriptive measure only.
No further inference should be drawn due to the retrospective nature of the analysis (P<.01).
Wunderink RG et al. Chest. 2003;124:1789-1797.
Data on file. Pfizer Inc.
Linezolid Demonstrates Excellent Efficacy in a Retrospective
Analysis of Two Prospective Clinical Trials
A retrospective analysis of 544 patients with VAP from the two prospective,
identical design trials in 1019 patients with NP.
80
Clinical Cure (%)
70
62
60
50
49
45
37
40
35
30
21
20
10
103/227
76/207
43/88
23/37
32/91
7/33
0
ITT
MRSA NP
S aureus NP
Linezolid 600 mg q12h IV
Vancomycin 1 g q12h IV
Linezolid was equally effective in the ITT and S aureus NP populations (P=NS).
The outcome difference in the MRSA NP subgroup is provided as a descriptive measure only.
No further inference should be drawn due to the retrospective nature of the analysis (P<.01).
Kollef MH et al. Intens Care Med. 2004;30:388-394.
Wunderink RG et al. Chest. 2003;124:1789-1797.
Data on file. Pfizer Inc.
Key Points About Vancomycin Recommendations
 The new ATS/IDSA guidelines recommend dosing vancomycin by
body weight (mg/kg) and adjusted for renal impairment
– Monitor and adjust trough levels to maintain 15 μg/mL to 20
μg/mL
 Clinical trials report 40% or greater failure rate for MRSA pneumonia
with vancomycin at standard dosing (1 g q12h)
 No prospective clinical trials have shown the value of dosing
vancomycin to achieve a trough level at 15 μg/mL or more
 Combination therapy with vancomycin + rifampin, or vancomycin +
aminoglycosides has not been proven effective in randomized
controlled trials
ATS/IDSA. Am J Respir Crit Care Med. 2005;171:388-416.
Craven DE, et al. Infect Dis Clin North Am. 2004;18:939-962.
Key Points About Linezolid in Treating MRSA HAP
 linezolid is now recommended as empiric therapy, on a par with
vancomycin, for late-onset HAP or for patients with risk factors for
MRSA
 Clinical setting where linezolid may be preferred:
– Patients at risk for, or already with, renal insufficiency
• In these patients, physicians may have a stronger tendency to prescribe
less adequate doses of vancomycin
– Patients at increased risk of nephrotoxicity or on concomitant
nephrotoxic drugs
ATS/IDSA. Am J Crit Care Med. 2005;171:388-416.
Craven DE et al. Infect Dis Clin North Am. 2004;18:939-962.
Indication
Linezolid formulations are indicated for the treatment of infections caused by
susceptible strains of the designated microorganisms:
Pneumonia
 Nosocomial pneumonia caused by Staphylococcus aureus (methicillin-susceptible and
-resistant strains), or Streptococcus pneumoniae (including multi-drug resistant strains
[MDRSP*]). Combination therapy may be clinically indicated if the documented or
presumptive pathogens include gram-negative organisms
 Community-acquired pneumonia caused by Streptococcus pneumoniae (penicillinsusceptible strains only), including cases with concurrent bacteremia or S aureus
(methicillin-susceptible strains only)
*MDRSP refers to isolates resistant to 2 or more of the following antibiotics: penicillin, second-generation cephalosporins, macrolides, tetracycline, and
trimethoprim/sulfamethoxazole.
Indication
 Skin infection
 Complicated skin and skin structure infections, including diabetic foot infections
without concomitant osteomyelitis, caused by S aureus (methicillin-susceptible and resistant strains), S pyogenes, or S agalactiae. linezolid has not been studied in the
treatment of decubitus ulcers. Combination therapy may be clinically indicated if the
documented or presumptive pathogens include gram-negative organisms
 Uncomplicated skin and skin structure infections caused by S aureus (methicillinsusceptible only) or S pyogenes
Vancomycin-resistant Enterococcus
 Vancomycin-resistant E faecium infections including cases with concurrent bacteremia
Important Safety Considerations
Contraindications
 Linezolid is contraindicated in patients who have known hypersensitivity to linezolid or
any of the other product components
Warnings
Pseudomembranous colitis
 Pseudomembranous colitis has been reported with nearly all antibacterial agents,
including linezolid, and may range in severity from mild to life-threatening. It is
important to consider this diagnosis in patients who present with diarrhea subsequent
to the administration of any antibacterial agent
Important Safety Considerations
Warnings
Myelosuppression
 Myelosuppression (including anemia, leukopenia, pancytopenia, and
thrombocytopenia) has been reported in patients receiving linezolid
 In cases where the outcome is known, when linezolid was discontinued, the affected
hematologic parameters have risen toward pretreatment levels
 Complete blood counts should be monitored weekly in patients who receive linezolid,
particularly in those who receive linezolid for longer than 2 weeks, those with
preexisting myelosuppression, those receiving concomitant drugs that produce bone
marrow suppression, or those with a chronic infection who have received previous or
concomitant antibiotic therapy
 Discontinuation of therapy with linezolid should be considered in patients who develop
or have worsening myelosuppression
Important Safety Considerations
Precautions
Lactic acidosis
 Lactic acidosis has been reported with the use of linezolid. In reported cases, patients
experienced repeated episodes of nausea and vomiting. Patients who develop recurrent
nausea or vomiting, unexplained acidosis, or a low bicarbonate level while receiving
linezolid should receive immediate medical evaluation
Serotonin syndrome (linezolid + serotonergic agent)
 Spontaneous reports of serotonin syndrome associated with co-administration of
linezolid and serotonergic agents, including antidepressants such as selective
serotonin reuptake inhibitors (SSRIs), have been reported
 Patients who are treated with linezolid and concomitant serotonergic agents should be
closely observed for signs and symptoms of serotonin syndrome (eg, cognitive
dysfunction, hyperpyrexia, hyperreflexia, incoordination)
 If any signs or symptoms occur, physicians should consider discontinuation of either
one or both agents (linezolid or concomitant serotonergic agents)
Important Safety Considerations
Precautions
Peripheral/optic neuropathy
 Peripheral and optic neuropathy have been reported in patients treated with linezolid,
primarily those patients treated for longer than the maximum recommended duration of
28 days
 In cases of optic neuropathy that progressed to loss of vision, patients were treated for
extended periods beyond the maximum recommended duration
 Visual blurring has been reported in some patients treated with linezolid for less than
28 days
 If patients experience symptoms of visual impairment, such as changes in visual acuity,
changes in color vision, blurred vision, or visual field defect, prompt ophthalmic
evaluation is recommended
 Visual function should be monitored in all patients taking linezolid for extended periods
(≥3 months) and in all patients reporting new visual symptoms regardless of length of
therapy with linezolid
 If peripheral or optic neuropathy occurs, the continued use of linezolid in these patients
should be weighed against the potential risks
Important Safety Considerations
Precautions
Drug interactions
 Linezolid is a reversible nonselective inhibitor of monoamine oxidase. Therefore,
linezolid has the potential for interaction with adrenergic and serotonergic agents
 A reversible enhancement of the pressor response with either pseudoephedrine HCl or
phenylpropanolamine HCl was observed when linezolid was administered to healthy
normotensive subjects. Patients should inform their physician if they are taking
medications containing pseudoephedrine HCl or phenylpropanolamine HCl, such as
cold remedies and decongestants
 A significant pressor response has been seen in normal adult subjects receiving
linezolid and tyramine doses of more than 100 mg. Advise patients to avoid large
quantities of foods or beverages with high tyramine content while taking linezolid
Important Safety Considerations
Adverse Events
The most common adverse events include:
Incidence (%) of Adverse Events Reported in ≥2% of Adult Patients in Comparator-Controlled
Clinical Trials with linezolid
linezolid
(n=2046)
All Comparators*
(n=2001)
Diarrhea
8.3
6.3
Headache
6.5
5.5
Nausea
6.2
4.6
Vomiting
3.7
2.0
Insomnia
2.5
1.7
Constipation
2.2
2.1
Rash
2.0
2.2
Dizziness
2.0
1.9
Fever
1.6
2.1
Event
*Comparators included cefpodoxime proxetil 200 mg PO q12h; ceftriaxone 1 g IV q12h; clarithromycin 250 mg PO
q12h; dicloxacillin 500 mg PO q6h; oxacillin 2 g IV q6h; vancomvcin 1 g IV q12h.
Dosing
Special Populations
Renal insufficiency
 The pharmacokinetics of the parent drug, linezolid, are not altered in patients with any
degree of renal insufficiency
 Both linezolid and its metabolites are eliminated by dialysis. Approximately 30% of dose
was eliminated during a 3-hour dialysis; therefore, linezolid should be administered
after hemodialysis
 Two primary metabolites may accumulate in patients with renal insufficiency; in the
absence of information on the clinical significance of metabolite accumulation, use of
linezolid in patients with renal insufficiency should be weighed against the risks of
metabolite accumulation
 Because similar plasma concentrations of linezolid are achieved regardless of renal
function, no dose adjustment is recommended for patients with renal insufficiency
Hepatic Insufficiency
 No adjustment recommended for mild-to-moderate hepatic insufficiency
– Pharmacokinetics in severe hepatic insufficiency have not been evaluated
Questions?
Opening Day April 7th
Summary
 The progressive emergence of gram-positive organisms as
dominant isolates in nosocomial infections has become a primary
health care concern
 As demonstrated, a multitude of risk factors exist for the
development of MRSA, including previous hospitalization, longer
length of stay before infection, previous surgery, enteral feedings,
and previous use of antibiotics
 Linezolid is an effective treatment for NP due to MRSA
Jones RN. Clin Infect Dis. 1999;29:495-502.
Graffunder EM et al. J Antimicrob Chemother. 2002;49:999-1005.