Transcript Surgical Site Infection: New Solutions to a Continuing Problem

Surgical Site Infection:
New Solutions to a
Continuing Problem
R. Lawrence Reed, II, MD, FACS, FCCM
Professor of Surgery
Loyola University Medical Center
Director, SICU, Hines VA Medical Center
Maywood, IL
Surgical Site Infections (SSI)
• Third most common nosocomial infection
(14%–16%)
• Most common nosocomial infection among
surgical patients (38%)
– 2/3 incisional
– 1/3 organs or spaces accessed during surgery
• 7.3 additional postoperative days at cost of
$3,152 in extra charges
Mangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:250-278.
Colonization vs Contamination –
Definitions
• Colonization
– Bacteria present in a wound with no signs or
symptoms of systemic inflammation
– Usually less than 105 cfu/mL
• Contamination
–
–
–
–
Transient exposure of a wound to bacteria
Varying concentrations of bacteria possible
Time of exposure suggested to be < 6 hours
SSI prophylaxis best strategy
SSI – Definitions
• Infection
–
–
–
–
–
Systemic and local signs of inflammation
Bacterial counts ≥ 105 cfu/mL
Purulent versus nonpurulent
LOS effect
Economic effect
• Surgical wound infection is SSI
LOS=length of stay.
Superficial Incisional SSI
Infection occurs within 30
days after the operation
and involves only skin or
subcutaneous tissue
Skin
of the incision
Subcutaneous
tissue
Mangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:250-278.
Superficial
incisional SSI
Deep Incisional SSI
Infection occurs within 30
days after the operation if
no implant is left in place
or within 1 year if implant
is in place and the infection
appears to be related to the
operation and the infection
involves the deep soft
tissue (e.g., fascia and
muscle layers)
Deep soft tissue
(fascia & muscle)
Mangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:250-278.
Superficial
incisional SSI
Deep incisional
SSI
Organ/Space SSI
Infection occurs within 30 days
after the operation if no implant
is left in place or within 1 year
if implant is in place and the
infection appears to be related
to the operation and the
infection involves any part of
the anatomy, other than the
incision, which was opened or
manipulated during the
operation
Organ/space
Mangram AJ et al. Infect Control Hosp Epidemiol.
1999;20:250-278.
Superficial
incisional SSI
Deep incisional
SSI
Organ/space SSI
SSI – Risk Factors
Operation Factors
•
•
•
•
•
•
•
•
Duration of surgical scrub
Maintain body temp
Skin antisepsis
Preoperative shaving
Duration of operation
Antimicrobial prophylaxis
Operating room ventilation
Inadequate sterilization of
instruments
• Foreign material at
surgical site
• Surgical drains
• Surgical technique
– Poor hemostasis
– Failure to obliterate
dead space
– Tissue trauma
Mangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:250-278.
SSI – Risk Factors
Patient Characteristics
• Age
• Diabetes
– HbA1C and SSI
– Glucose > 200 mg/dL
postoperative period
(<48 hours)
• Nicotine use: delays primary
wound healing
• Steroid use: controversial
• Malnutrition: no
epidemiological association
• Obesity: 20% over ideal body
weight
• Prolonged preoperative stay:
surrogate of the severity
of illness and comorbid conditions
• Preoperative nares colonization
with Staphylococcus aureus:
significant association
• Perioperative transfusion:
controversial
• Coexistent infections at a remote
body site
• Altered immune response
Mangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:250-278.
Risk of Infection
Bacterial dose
Virulence
Impaired
host resistance
Risk of Infection
Bacterial dose
Virulence
Impaired
host resistance
RiskRisk
of Surgical
of Infection
Infection
Virulence
Bacterial
Bacterial
dosedose
Virulence
Impaired
Impaired
host resistance
host resistance
SSI – Wound Classification
•
•
•
•
Class 1 = Clean
Class 2 = Clean contaminated Prophylactic
antibiotics
Class 3 = Contaminated
indicated
Class 4 = Dirty infected Therapeutic antibiotics
Mangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:250-278.
SSI – Risk Stratification NNIS Project
3 independent variables associated
with SSI risk
– Contaminated or dirty/infected wound
classification
– ASA > 2
– Length of operation > 75th percentile of the
specific operation being performed
NNIS=National Nosocomial Infections Surveillance.
NNIS. CDC. Am J Infect Control. 2001;29:404-421.
SSI – Wound Class vs NNIS Class
Wound Class
All
NNIS 0
Clean
Clean contaminated
Contaminated
Dirty infected
2.1%
3.3%
6.4%
7.1%
1.0%
2.1%
N/A
N/A
2.3%
4.0%
3.4%
3.1%
5.4%
9.5%
6.8%
8.1%
N/A
N/A
13.2%
12.8%
All
2.8%
1.5%
2.9%
6.8%
13.0%
NNIS. CDC. Am J Infect Control. 2001;29:404-421.
NNIS 1 NNIS 2 NNIS 3
Campaign to Prevent
Antimicrobial Resistance
• Centers for Disease
Control and
Prevention
• National Center for
Infectious Diseases
• Division of Healthcare
Quality Promotion
Clinicians hold the solution!
Link to: Campaign to Prevent Antimicrobial Resistance Online
Link to: Federal Action Plan to Combat Antimicrobial Resistance
12 Steps to Prevent Antimicrobial
Resistance Among
Surgical Patients
• Step 1 – Prevent SSIs
– Monitor and maintain normal
glycemia
– Maintain normothermia
– Perform proper skin preparation using
appropriate antiseptic agent and, when
necessary, hair removal techniques
– Think outside the wound to stop
surgical site infections
CDC. Available at http://www.cdc.gov/drugresistance/healthcare/surgery/12steps_surgery.htm.
Accessed July 16, 2004.
Opportunity to Prevent SSI
• An estimated 40%–60% of SSIs are
preventable
• Overuse, underuse, improper timing, and
misuse of antibiotics occurs in 25%–50%
of operations
Mangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:250-278.
Principles of Antibiotic Prophylaxis
Preop administration, serum levels adequate
throughout procedure with a drug active
against expected microorganisms.
High Serum Levels
1. Preop timing
2. IV route
3. Highest dose
of drug
During Procedure
1. Long half-life
2. Long procedure–
redose
3. Large blood loss–
redose
Mangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:250-278.
Duration
1. None after wound
closed
2. 24 hours maximum
Surgical Site Infection (SSI)
Mangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:250-278.
Surgical Infection Prevention Project
Medicare Quality Improvement Community
Clinical Infectious Diseases 2004 June; 38:1706–15
National Data Collection
• State-level baseline description from random
sample of 788 cases per state
• Data collected from records by two
professional clinical data abstraction centers
• Abstraction tool for hospitals is available….Is
JCAHO compatible
Surgical Infection Prevention
Preliminary Results
N (%)
Number of cases reviewed
39,086 (100)
General Exclusions
Surgery of interest not performed
Infection present pre-operatively
Missing antibiotic dates and times
Patient on antibiotics prior to admission
Patient on antibiotics for more than 24 hours pre-op
Other
205 (0.52)
1,817 (4.7)
2 (0.01)
1,461 (3.74)
1,432 (3.66)
36 (0.09)
Cases eligible for analysis
34,133 (87.3)
Discontinuation of Antibiotics
100
88
85.8
100
90.7
79.5
60
60
50.7
40.7
40
40
26.2
22.6
14.5
20
20
10
9.3
6.3
6.2
2.7
2.2
96
>
-9
6
>8
4
-8
4
>7
2
-7
2
>6
0
-6
0
>4
8
-4
8
>3
6
-3
6
>2
4
>1
2
le
or
-2
4
0
ss
0
Hours After Surgery End Time
Patients were excluded from the denominator of this performance measure if there was
any documentation of an infection during surgery or in the first 48 hours after surgery.
Cumulative Percent
80
73.3
12
Percent
80
Most Common Pathogens Associated With
Nosocomial Infections
(NNIS 1989–1998) Medical & Surgical Combined
Relative Percentage by Site of Infection
Pathogen
All Sites
n=235,758
BSI
n=50,091
Pneumonia
n=64,056
SSI
n=22,043
Coag-neg Staph
S aureus
14.3
11.4
39.3
10.7
2.5
16.8
13.5
12.6
Enterococci spp.
P aeruginosa
Enterobacter spp.
E coli
C albicans
K pneumoniae
Others
8.1
9.9
7.3
7.0
6.6
4.7
30.7
10.3
3.0
4.2
2.9
4.9
2.9
21.8
1.9
16.1
10.7
4.4
4.0
6.5
37.1
14.5
9.2
8.8
7.1
4.8
3.5
26.0
BSI=bloodstream infection; SSI=surgical site infection.
Fridkin SK et al. Clin Chest Med. 1999;20:303-316.
Predominance of S aureus in Skin and Skin
Structure Infections (SSSIs)
SENTRY – US and Canada 2000
Other
17.3%
MSSA 30.9%
Klebsiella 5.1%
Enterobacter 5.8%
E coli
7.0%
Enterococci
8.2%
10.8%
P aeruginosa
N=1,404 isolates
Rennie RP et al. Diagn Microbiol Infect Dis. 2003;45:287-293.
MRSA ~15%
Progression of Methicillin Resistant
S aureus – United States
Resistant isolates (%)
60
13%
57.1%
55.3%
50
40
30
20
10
20
00
20
02
99
98
97
96
95
94
93
92
91
90
89
88
87
19
75
0
CDC. MMWR. 1997;46:624-628, 635. (1975 data); Lowy FD. N Engl J Med. 1998;339:520-532.
(1987-1997 data); CDC. NNIS System Report, January–November 1998. (1998 data); CDC. NNIS System
Report, January 1990–May 1999, issued June 1999. Am J Infect Control. 1999;27:520-532. (1999 data); CDC.
NNIS System Report, January 1992–June 2001. Am J Infect Control. 2001;29:404-421. (2000 data); NNIS.
CDC. Am J Infect Control. 2003;31:481-498.
Impact of MRSA on SSI
Median Hospital Charges
100,000
90,000
80,000
70,000
60,000
50,000
40,000
30,000
20,000
10,000
0
92,363
52,971
29,455
• N=479 patients
• MRSA greater 90-d
mortality vs MSSA
(adjusted odds ratio, 3.4;
95% CI: 1.5–7.2)
• MRSA longer LOS after
infection (median
additional days=5;
P<0.001)
• MRSA associated with
greater hospital charges
(1.19-fold increase in
hospital charges, P=0.03)
Engemann JJ et al. Clin Infect Dis. 2003;36:592-598.
Vascular SSI
• Retrospective review (1993–2000)
– Leicester Royal Infirmary, United Kingdom
– 172 patients MRSA-positive (4.4% of total)
– 75 infected, 97 colonized
• Proportion of wound/graft infections caused by MRSA has
increased
– 4% in 1994, increased to 63% in 2000
• All patients with aortic graft infection died
• All patients with infected prosthetic infrainguinal bypass
required amputations
Nasim A et al. Eur J Vasc Endovasc Surg. 2001;22:211-214.
MRSA in Orthopedic SSI
•
•
•
•
•
Prospective study, London, United Kingdom
12-month study, January through December 2000
Total of 1,879 patients admitted, 121 screened
1.6% of total with MRSA infection/colonization
Higher risk for MRSA infection
– Hip surgery
– Emergency surgery for femoral neck fracture
– Presence of wound
• MRSA infection – increased hospital LOS (88 vs 11 days)
• 41% of positive patients still carried MRSA on discharge
Tai CC et al. Int Orthop. 2004;28:32-35.
MRSA in Cardiac Surgery
• 3,443 CABG patients, all received antimicrobial prophylaxis
• June 1997 through December 2000
• Sternal SSI developed in 122 (3.5%)
– 71 (58.2%) were superficial SSI
– 51 (41.8%) were deep SSI
• Gram-positive cocci were most frequently recovered (81%)
• S aureus was the most frequently isolated pathogen (49%)
• S aureus bacteremia occurred in 18% and was significantly
associated with deep SSI (P=0.002)
CABG=coronary artery bypass grafting.
Sharma M et al. Infect Control Hosp Epidemiol. 2004;25:468-471.
Impact of MRSA in Cardiac Surgery
• Retrospective review
(41 patients)
– Poststernotomy S aureus
mediastinitis
– MRSA: 15 patients
– MSSA: 26 patients
• Logistic regression
analysis: MRSA was the
only independent risk
factor for increased
mortality, P=0.04
Survival Rates
90
80
70
60
50
1 month
1 year
3 years
40
30
20
10
0
Mekontso-Dessap A et al. Clin Infect Dis. 2001;32:877-883.
MRSA
MSSA
• 4,030 patients enrolled,
3,864 ITT patients
• PRDBPCT, intranasal
mupirocin
• 891 patients (23.1%) had
S aureus in anterior nares
– 444 mupirocin,
– 447 placebo
• S aureus SSI:
– 2.3% mupirocin
– 2.4% placebo
Percent of patients with S aureus (%)
Nasal Mupirocin and SSI
All postoperative S aureus Infections
7.7
P=0.02
4
Mupirocin
Placebo
ITT=intent-to-treat; PRDBPCT=prospective, randomized, double-blind placebo-controlled trial.
Perl TM et al. N Engl J Med. 2002;346:1871-1877.
Surgical Wound Management
SSI Prophylaxis in MRSA-Colonized Patient
• Must use same principles
• Drug choice difference
• MRSA drugs
–
–
–
–
Vancomycin
Quinupristin/dalfopristin*
Linezolid
Daptomycin
*Not FDA approved for MRSA.
Vancomycin
• Bactericidal glycopeptide
– Discovered in 1956
– Produced by Streptococcus
orientalis, an actinomycete
isolated from soil samples
from Indonesia & India
• Introduced clinically in
1958
• Quickly overshadowed by
less toxic antistaphylococcal penicillins
and cephalosporins
• Re-emergence as an
important antibiotic in
1980s & 1990s
Historical Yearly Usage of Vancomycin
2001: 1.8 million courses of vancomycin annually in U.S.
30 million doses of vancomycin estimated
Kirst HA et al. Antimicrob Agents Chemother. 1998;42:1303-1304; NNIS. Am J Infect Control. 2001;29:
404-421.
12 Steps to Prevent Antimicrobial
Resistance Among
Surgical Patients
• Step 9. Know when to say
“no” to vanco
– Vanco should be used to treat
known infections, not for routine
prophylaxis
– Treat staphylococcal infection,
not contaminants or colonization
– Consider other antimicrobials in
treating MRSA
CDC. Available at http://www.cdc.gov/drugresistance/healthcare/surgery/12steps_surgery.htm.
Accessed July 16, 2004.
Vancomycin Tissue Penetration
– Below the mean
MICs for many
strains of
staphylococci
4.5
4
Level (mg/L)
• 33 open-heart
surgery patients,
mean vancomycin
concentrations after
15 mg/kg IV dose
3.5
Tissue Level (mg/L)
3
MIC (mg/L)
2.5
2
1.5
1
0.5
0
Cardiac Valve
Myocardium
Tissue
MIC=minimum inhibitory concentration.
Daschner FD et al. J Antimicrob Chemother. 1987;19:359-362.
Fat
CNS:
<10%
Epithelial
lining fluid3:
18%
Sternal Bone1:
57%
Heart Valve4:
12%
Lung tissue2:
17%–24%
Vancomycin Penetration
Bone5:
7%–13%
Fat4:
14%
Muscle4:
9%
1. Massias L et al. Antimicrob Agents Chemother. 1992;36:2539-2541; 2. Cruciani M et al. J Antimicrob
Chemother. 1996;38:865-869. 3. Lamer C et al. Antimicrob Agents Chemother. 1993;37:281-286;
4. Daschner FD et al. J Antimicrob Chemother. 1987;19:359-362; 5. Graziani AL et al. Antimicrob Agents
Chemother. 1988;32:1320-1322.
Quinupristin/Dalfopristin (Synercid®)
• Streptogramin class related to macrolide-lincosamides
– Quinupristin is a Group B streptogramin
– Dalfopristin is a Group A streptogramin
• Activity against:
– MSSA – potently bactericidal
– Streptococcus pneumoniae (including PRSP) – potently
bactericidal
– MRSA – moderately active
– E faecium – moderately active against most E faecium strains
– NO activity against E faecalis
PRSP=penicillin-resistant Streptococcus pneumoniae.
Synercid® IV (quinupristin/dalfopristin for injection) [package insert]. Bristol, Tenn: Monarch
Pharmaceuticals, Inc; 2002.
Quinupristin/Dalfopristin (Synercid®)
• Central line access used to decrease incidence of
infusion-related venous irritation
• 3%–30% incidence of severe myalgias and
arthralgias
• Resistance has already been reported
• Bacteriostatic
• Does not have indication for pneumonia
– Did not perform as well as vancomycin
Synercid® IV (quinupristin/dalfopristin for injection) [package insert]. Bristol, Tenn: Monarch
Pharmaceuticals, Inc; 2002.
Daptomycin (Cubicin™)
•
•
•
•
•
•
•
•
Lipopeptide natural product
Activity in Gram-positive organisms
Distinct mechanism of action
Rapidly bactericidal in vitro and in vivo
No mechanisms of resistance identified
No cross-resistance with other antibiotics
Safety profile similar to comparators
Once-daily IV dosing
Cubicin™ (daptomycin for injection) [prescribing information]. Lexington, MA: Cubist
Pharmaceuticals; September 2003.
Linezolid (ZYVOX®)
•
•
•
•
•
•
•
•
An oxazolidinone: a novel antimicrobial class
100% oral bioavailability
Equivalent dosing oral/IV
No dose adjustment in renal failure
Bacteriostatic
No cross-resistance with other antibiotics
Reversible thrombocytopenia with prolonged use
Binds selectively to the 50S ribosomal subunit
– Inhibits the formation of a functional initiation complex
ZYVOX® (linezolid injection, tablets, and oral suspension) [package insert]. Kalamazoo, Mich:
Pharmacia & Upjohn, a Pfizer Company; revised June 2004.
Average Steady-State Plasma Linezolid
Concentrations After Oral Administration
of 400 or 600 mg Twice Daily
Linezolid concentration (μg/mL)
20
18
600 mg BID
16
400 mg BID
14
MIC-90 Staph
12
MIC-90 Entero
10
MIC-90 Strep
8
6
4
2
0
0
5
10
15
20
Time After Last Dose (hours)
Linezolid Research Update. Denver, Colo: Infectious Diseases Society of America; November 13, 1998.
CNS1:
70%*
Epithelial
lining fluid4:
450%
Alveolar cells4:
15%
Saliva2:
120%
Linezolid Penetration
Bone3:
40%–60%
Sweat2:
55%
Skin Blister Fluid5:
100%
1. Cottagnound et al. J Antimicrob Chemother. 2000;46:981-985; 2. ZYVOX® (linezolid injection, tablets,
and oral suspension) [package insert]. Kalamazoo, Mich: Pharmacia & Upjohn, a Pfizer Company; revised
2003; 3. Lovering AM et al. J Antimicrob Chemother. 2002, 50:73-77; 4. Conte JE et al. Antimicrob Agents
Chemother. 2002;46:1475-1480; 5. Gee T. Antimicrob Agents Chemother. 2001;45:1843-1846.
Comparison of Tissue Concentrations
(% Tissue/Serum)
Tissue
Vancomycin
Linezolid
Bone
7%–13%1
60%8
Cerebral Spinal Fluid
0%–18%2,3
70%9
Epithelial Lining Fluid (Lung)
11%–17%4,5
450%9
----
104%10
Muscle
~30%6
94%8
Peritoneal dialysis fluid
~20%7
61%11
Inflammatory Blister Fluid
1. Graziani AL et al. Antimicrob Agents Chemother. 1988;32:1320-1322; 2. Matzke et al. Clin
Pharmacokinet. 1986;11:257-282; 3. Albanese J et al. Antimicrob Agents Chemother. 2000;44:1356-1358; 4.
Georges H et al. Eur J Clin Microbiol Infect Dis. 1997;16:385-388; 5. Lamer C et al. Antimicrob Agents
Chemother. 1993;37:281-286; 6. Daschner FD et al. J Antimicrob Chemother. 1987;20:776-782; 7. Blevins
RD et al. Antimicrob Agents Chemother. 1984;25:603-606; 8. Lovering AM et al. J Antimicrob Chemother.
2002;50:73-77; 9. Conte JE et al. Antimicrob Agents Chemother. 2002;46:1475-1480; 10. Gee T et al.
Antimicrob Agents Chemother. 2001;45:1843-1846; 11. Gendjar SR et al. 2001 ASN/ISN World Congress of
Nephrology; 2001; San Francisco, Calif. Abstract 550865.
Complicated Skin and Soft Tissue
Infection (cSSTI) Treatment
• Staph most common cause
• Staph resistance continues to increase
– 57.1% in 2002
• Treatment for MRSA cSSTI prior to 2000
– Vancomycin
– Quinupristin/dalfopristin*
• New alternatives for treatment of MRSA cSSTI
– Linezolid
– Daptomycin
*Not FDA approved for MRSA.
NNIS. CDC. Am J Infect Control. 2003;31:481-498.
Quinupristin/Dalfopristin† (Q/D) Efficacy
• Design: 2 randomized, open-label, controlled clinical trials in cSSSI
– Study 1: Q/D (7.5 mg/kg q12h IV) vs oxacillin (2 g q6h IV)*
– Study 2: Q/D (7.5 mg/kg q12h IV) vs cefazolin (1 g q8h IV)*
Efficacy in the Clinically Evaluable Population†
Q/D
(n=450)
Comparator
(n=443)
Study 1 (US)
49.5%
51.9%
Study 2 (International)
66.4%
64.2%
Postoperative infections‡
14/38 (36.8%)
24/42 (57.1%)
Traumatic wound infections‡
33/55 (60.0%)
33/55 (60.0%)
*Vancomycin 1 g q12h IV could be substituted if the pathogen was suspected or confirmed
methicillin-resistant Staphylococcus or the patient was allergic to penicillin, cephalosporins, or
carbapenems. †Patients cured or improved. ‡Results are combined from the 2 clinical trials.
Statistical conclusions could not be reached due to the small number of patients in the subsets.
†Not FDA approved for MRSA.
Synercid® IV (quinupristin/dalfopristin for injection) [package insert]. Bristol, Tenn: Monarch
Pharmaceuticals, Inc; 2002.
Quinupristin/Dalfopristin† (Q/D) Efficacy
• Design: 2 randomized, open-label, controlled clinical trials in cSSSI
Summary of Clinical and Microbiologic Results*
Q/D
(n=450)
Comparator
(n=443)
Clinical efficacy†
68.2%
70.7%
Microbiologic eradication‡
66.6%
77.7%
MSSA
64.3%
76.6%
MRSA
77.8%
50.0%
Gram-positive cocci only
56.3%
69.7%
*Results are combined from the 2 clinical trials. †Patients cured or improved in the
clinically evaluable population. ‡Overall and by-pathogen bacteriologic eradication
rates in the microbiologically evaluable population.
cSSSIs=complicated skin and skin structure infections.
†Not FDA approved for MRSA.
Nichols RL et al. J Antimicrob Chemother. 1999;44:263-273.
Linezolid vs Vancomycin for cSSTI
Presumed or Known to Be Caused by MRSA
• Study design: Open-label, randomized, comparatorcontrolled, multicenter, multinational clinical study
• Population: 1,200 hospitalized adult patients with cSSTI
• Treatment arms:
Linezolid (oral or IV) 600
mg every 12 hours
OR
Vancomycin (IV only) 1 g
every 12 hours
If MSSA, vancomycin could be switched to
oxacillin/nafcillin/flucloxacillin (IV only)
1–2 g q6h or dicloxacillin (oral) 500 mg q6h
4- to 14-day treatment duration
Weigelt JA et al. Infectious Diseases Society of America, 2003, poster 314. San Diego, CA.
Linezolid vs Vancomycin for cSSTI Clinical
Cure Rates in Clinically Evaluable Subset
Linezolid 600 mg q12h IV/PO
100
94
Vancomycin 1g q12h IV*
90
Clinical cure rate (%)
80
P=0.023
60
40
20
0
436/462
394/436
Weigelt JA et al. Infectious Diseases Society of America, 2003, poster 314. San Diego, CA.
Linezolid vs Vancomycin for cSSTI
Clinical Cure Rates in MRSA Subgroup
Linezolid 600 mg q12h IV/PO
Clinical cure rate (%)
100
Vancomycin 1g q12h IV*
94
84
80
*P=0.011
60
40
20
0
126/134
112/134
Weigelt JA et al. Infectious Diseases Society of America, 2003, poster 314. San Diego, CA.
Linezolid Reduces LOS vs Vancomycin
in cSSTI due to MRSA
Mean LOS (days)
Study Sample
(linezolid/vancomycin)
Linezolid
Vancomycin
P Value
ITT (592/588)
7.4
9.8
<0.0001
CE (491/472)
7.4
9.9
<0.0001
ME (349/334)
7.6
9.8
<0.0001
MRSA (143/146)
8.1
10.7
0.0026
CE=clinically evaluable; ITT=intent-to-treat; LOS=length of stay; ME=microbiologically evaluable.
Weigelt JA et al. Infectious Diseases Society of America; 2003, poster 315. San Diego, CA.
Linezolid vs Vancomycin for cSSTI
IV Antibiotic Treatment Days
Duration of IV treatment (days)
Linezolid
Vancomycin
14
12.6
12
10
9.9
9.1
9
9.9
8
6
4
1.9
2
1.9
2
1.8
2
0
ITT
MITT
CE
ME
MRSA
Sample population
CE=clinically evaluable; ITT=intent-to-treat; ME=microbiologically evaluable; MITT=modified
intent-to-treat.
Weigelt JA et al. Infectious Diseases Society of America, 2003, poster 315. San Diego, CA.
Cost Effectiveness of Linezolid vs
Vancomycin in cSSTI
$5,187
6000
5000
C
O
S
T
($)
$4,143
CI (4,691–5,714)
CI (3,750–4,576)
4000
3000
2000
1000
0
Linezolid
Vancomycin
2003 Per diem hospital cost, administration of IV therapy,
wholesale acquisition cost
Fleming T, ed. Red Book. 2004 edition. Montvale NJ: Thompson PDR;2004.
Linezolid vs Vancomycin for Surgical Site
Infection (SSI )
Total Patients With cSSTI
1,200
Total Patients With SSI
135
Linezolid
66
Vancomycin
69
-Weigelt J et al.: Am J Surg 2004;188:760-766.
Linezolid vs Vancomycin in SSI
Study Population
Study Population
Linezolid
(n, %)
Vancomycin
(n, %)
All patients
66 (100)
69 (100)
MRSA
34 (52)
31 (45)
Baseline demographics:
No significant difference
Baseline comorbidities/MRSA risk factors:
No significant difference
-Weigelt J et al.: Am J Surg 2004;188:760-766.
Linezolid vs Vancomycin in SSI:
Clinical Cure Rates at TOC
Linezolid 600 mg q12h IV/PO
Clinical cure rate (%)
100
Vancomycin 1g q12h IV
98
87
80
P=0.06
60
40
20
0
52/53
47/54
-Weigelt J et al.: Am J Surg 2004;188:760-766.
Linezolid vs Vancomycin in SSI:
Microbiological Cure Rates at TOC
Linezolid 600 mg q12h IV/PO
Clinical cure rate (%)
100
Vancomycin 1g q12h IV
84
80
P=0.007
60
58
40
20
0
41/49
28/49
-Weigelt J et al.: Am J Surg 2004;188:760-766.
Linezolid vs Vancomycin in SSI:
Microbiological Cure Rates at TOC in MRSA
Pts.
Linezolid 600 mg q12h IV/PO
Clinical cure rate (%)
100
Vancomycin 1g q12h IV
87
80
60
P=0.002
48
40
20
0
26/30
14/29
-Weigelt J et al.: Am J Surg 2004;188:760-766.
Daptomycin for cSSSIs
• Phase III: 2 international, multicenter,
randomized, double-blind (evaluator blinded)
studies (Studies 9801 & 9901):
– Daptomycin (4 mg/kg IV qd) vs 1 of 2 comparators:
• Vancomycin (1 g q12h)
• Synthetic penicillin (4–12 g/d in 4 daily doses)
• Primary endpoint was safety and efficacy
• Both studies demonstrated equivalence of
daptomycin to the comparator
Arbeit RD et al. Clin Infect Dis. 2004;38:1673-1681.
Daptomycin Efficacy
•
•
Design: 2 randomized, multinational, multicenter investigator-blinded studies
Daptomycin 4 mg/kg IV q24h or vancomycin 1 g IV q12h or a semisynthetic penicillin
(nafcillin, oxacillin, cloxacillin, flucloxacillin)
Clinical Success Rate: CE Population
Type of Infection
Daptomycin
Comparator*
No. of Pts (Success rate %) No. of Pts (Success rate %)
Wound infection
169 (84%)
180 (87%)
Major abscess
102 (92%)
92 (88%)
Ulcer infection
47 (66%)
56 (70%)
Other infection†
47 (79%)
58 (83%)
*Comparator was vancomycin or a semisynthetic penicillin.
†Other infections included complicated cellulitis, major abscess, or traumatic wound infection.
Arbeit RD et al. Clin Infect Dis. 2004;38:1673-1681.
Comparison of MRSA Antimicrobials
Vancomycin
Quinupristin/
Dalfopristin
Daptomycin
Linezolid
FDA approved
for MRSA
Multiple
cSSSI (not MRSA)
cSSSI
cSSSI and pneumonia
Route(s)
Parenteral
Parenteral (central?)
Parenteral
Parenteral, oral
Dosing
Variable
depending upon
renal function
q8-12h
QD
BID
Sales pitch
“Cheap”
“Works when
vancomycin won’t”
“Faster cure”
(rapidly cidal)
“Gets patients home”
Disadvantages
Toxicity,
resistance (VRE,
VISA, VRSA)
Infusion site
inflammation,
myalgias, arthralgias,
and resistance
Limited indications,
acquisition cost,
myalgia, not effective
for pneumonia
Unfamiliarity and cost,
reversible hematologic
abnormalities, resistance
(ie, VRE with prolonged use)
Advantages
Familiarity
Alternative to
vancomycin
Potential for less
resistance
Oral dosingremoval of
catheters, early discharge,
evidence of superiority to
vancomycin in cSSTI
Summary
• SSI is a preventable morbidity
• Gram-positive organisms are the primary pathogens
– MRSA increasing
• Treatment alternatives in MRSA SSIs and cSSTIs
–
–
–
–
Vancomycin
Linezolid
Daptomycin
Quinupristin/dalfopristin*
*Not FDA approved for MRSA.