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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%)

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Surgical site infection new solutions to a continuing problem l.jpg

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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg

Skin

Superficial incisional SSI

Subcutaneous tissue

Superficial Incisional SSI

Infection occurs within 30 days after the operation and involves only skin or subcutaneous tissue of the incision

Mangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:250-278.


Deep incisional ssi l.jpg

Deep soft tissue (fascia & muscle)

Deep 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)

Superficial incisional SSI

Mangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:250-278.


Organ space ssi l.jpg

Organ/space SSI

Organ/space

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

Superficial incisional SSI

Deep incisional SSI

Mangram AJ et al. Infect Control Hosp Epidemiol.1999;20:250-278.


Ssi risk factors operation factors l.jpg

Duration of surgical scrub

Maintain body temp

Skin antisepsis

Preoperative shaving

Duration of operation

Antimicrobial prophylaxis

Operating room ventilation

Inadequate sterilization of instruments

SSI – Risk FactorsOperation Factors

  • 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 l.jpg
SSI – Risk FactorsPatient Characteristics

  • 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

  • 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

Mangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:250-278.


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Risk of Infection

Bacterial dose

Virulence

Impaired

host resistance


Slide11 l.jpg

Risk of Infection

Bacterial dose

Virulence

Impaired

host resistance


Slide12 l.jpg

Risk of Surgical Infection

Bacterial dose

Virulence

Bacterial dose

Impaired

host resistance

Risk of Infection

Virulence

Impaired

host resistance


Ssi wound classification l.jpg

Prophylactic antibiotics indicated

Therapeutic antibiotics

SSI – Wound Classification

  • Class 1 = Clean

  • Class 2 = Clean contaminated

  • Class 3 = Contaminated

  • Class 4 = Dirty infected

Mangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:250-278.


Ssi risk stratification nnis project l.jpg
SSI – Risk Stratification NNIS Project

3 independent variables associated with SSI risk

  • Contaminated or dirty/infected woundclassification

  • 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.


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SSI – Wound Class vs NNIS Class

Wound Class All NNIS 0 NNIS 1 NNIS 2 NNIS 3

Clean 2.1% 1.0% 2.3% 5.4% N/A

Clean contaminated 3.3% 2.1% 4.0% 9.5% N/A

Contaminated 6.4% N/A 3.4% 6.8% 13.2%

Dirty infected 7.1% N/A 3.1% 8.1% 12.8%

All 2.8% 1.5% 2.9% 6.8% 13.0%

NNIS. CDC. Am J Infect Control. 2001;29:404-421.


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Campaign to PreventAntimicrobial 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


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12 Steps to Prevent Antimicrobial Resistance AmongSurgical 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 l.jpg
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 l.jpg

Preop administration, serum levels adequate throughout procedure with a drug active against expected microorganisms.

  • High Serum Levels

  • Preop timing

  • IV route

  • Highest dose of drug

  • During Procedure

  • Long half-life

  • Long procedure–redose

  • Large blood loss–redose

  • Duration

  • None after wound closed

  • 24 hours maximum

Principles of Antibiotic Prophylaxis

Mangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:250-278.


Surgical site infection ssi l.jpg
Surgical Site Infection (SSI)

Mangram AJ et al. Infect Control Hosp Epidemiol. 1999;20:250-278.


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Surgical Infection Prevention ProjectMedicare Quality Improvement Community

Clinical Infectious Diseases 2004 June; 38:1706–15


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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 l.jpg

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)

Surgical Infection PreventionPreliminary Results


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Discontinuation of Antibiotics

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.


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Most Common Pathogens Associated With Nosocomial Infections (NNIS 1989–1998) Medical & Surgical Combined

Relative Percentage by Site of Infection

Pathogen All Sites BSI Pneumonia SSI n=235,758 n=50,091 n=64,056n=22,043

Coag-neg Staph 14.3 39.3 2.5 13.5

S aureus 11.4 10.7 16.8 12.6

Enterococci spp. 8.1 10.3 1.9 14.5

P aeruginosa 9.9 3.0 16.1 9.2

Enterobacter spp. 7.3 4.2 10.7 8.8

E coli 7.0 2.9 4.4 7.1

C albicans 6.6 4.9 4.0 4.8

K pneumoniae 4.7 2.9 6.5 3.5

Others 30.7 21.8 37.1 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 l.jpg

Other 17.3%

MSSA 30.9%

Klebsiella 5.1%

Enterobacter 5.8%

S aureus 45.9%

E coli 7.0%

MRSA ~15%

Enterococci 8.2%

10.8%

P aeruginosa

Predominance of S aureus in Skin and Skin Structure Infections (SSSIs)SENTRY – US and Canada 2000

N=1,404 isolates

Rennie RP et al. Diagn Microbiol Infect Dis. 2003;45:287-293.


Progression of methicillin resistant s aureus united states l.jpg

57.1%

55.3%

Progression of Methicillin Resistant S aureus – United States

13%

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 l.jpg

Median Hospital Charges

100,000

92,363

90,000

80,000

70,000

60,000

52,971

50,000

40,000

29,455

30,000

20,000

10,000

0

MSSA

MRSA

Control

Impact of MRSA on SSI

  • 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 l.jpg
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 l.jpg
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 l.jpg
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 l.jpg

Survival Rates

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

Mekontso-Dessap A et al. Clin Infect Dis. 2001;32:877-883.


Nasal mupirocin and ssi l.jpg

All postoperative S aureus Infections

7.7

P=0.02

Percent of patients with S aureus (%)

4

Mupirocin

Placebo

Nasal Mupirocin and SSI

  • 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

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 l.jpg
Surgical Wound ManagementSSI 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 l.jpg
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 anti-staphylococcal penicillins and cephalosporins

  • Re-emergence as an important antibiotic in 1980s & 1990s


Historical yearly usage of vancomycin l.jpg
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.


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12 Steps to Prevent Antimicrobial Resistance AmongSurgical 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.


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Vancomycin Tissue Penetration

  • 33 open-heart surgery patients, mean vancomycin concentrations after 15 mg/kg IV dose

    • Below the mean MICs for many strains of staphylococci

MIC=minimum inhibitory concentration.

Daschner FD et al. J Antimicrob Chemother. 1987;19:359-362.


Slide39 l.jpg

CNS:<10%

Epitheliallining fluid3:18%

Lung tissue2:17%–24%

Bone5:7%–13%

Fat4: 14%

Muscle4:9%

Sternal Bone1:57%Heart Valve4:

12%

Vancomycin Penetration

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 l.jpg
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 synercid41 l.jpg
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 l.jpg
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.


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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.


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Average Steady-State Plasma Linezolid Concentrations After Oral Administration of 400 or 600 mg Twice Daily

600 mg BID

400 mg BID

MIC-90 Staph

MIC-90 Entero

MIC-90 Strep

Linezolid concentration (μg/mL)

Time After Last Dose (hours)

Linezolid Research Update. Denver, Colo: Infectious Diseases Society of America; November 13, 1998.


Slide45 l.jpg

CNS Oral Administration of 400 or 600 mg Twice Daily1:70%*

Epitheliallining fluid4:450%

Alveolar cells4:15%

Saliva2:120%

Sweat2:55%

Skin Blister Fluid5:100%

Bone3:40%–60%

Linezolid Penetration

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.


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Comparison of Tissue Concentrations Oral Administration of 400 or 600 mg Twice Daily (% Tissue/Serum)

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.


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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.


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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†

*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.


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Quinupristin/Dalfopristin † (Q/D) Efficacy

  • Design: 2 randomized, open-label, controlled clinical trials in cSSSI

    Summary of Clinical and Microbiologic Results*

*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.

Nichols RL et al. J Antimicrob Chemother. 1999;44:263-273.

†Not FDA approved for MRSA.


Linezolid vs vancomycin for cssti presumed or known to be caused by mrsa l.jpg

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

Linezolid vs Vancomycin for cSSTI Presumed or Known to Be Caused by MRSA

  • Study design:Open-label, randomized, comparator-controlled, multicenter, multinational clinical study

  • Population: 1,200 hospitalized adult patients with cSSTI

  • Treatment arms:

Vancomycin (IV only) 1 g every 12 hours

Linezolid (oral or IV) 600 mg every 12 hours

OR

Weigelt JA et al. Infectious Diseases Society of America, 2003, poster 314. San Diego, CA.


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Linezolid vs Vancomycin for cSSTI Clinical Cure Rates in Clinically Evaluable Subset

P=0.023

Weigelt JA et al. Infectious Diseases Society of America, 2003, poster 314. San Diego, CA.


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Linezolid vs Vancomycin for cSSTI Clinically Evaluable SubsetClinical Cure Rates in MRSASubgroup

*P=0.011

126/134

112/134

Weigelt JA et al. Infectious Diseases Society of America, 2003, poster 314. San Diego, CA.


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Linezolid Reduces LOS vs Vancomycin Clinically Evaluable Subsetin cSSTI due to MRSA

Mean LOS (days)

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.


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Linezolid vs Vancomycin for cSSTI Clinically Evaluable SubsetIV Antibiotic Treatment Days

Duration of IV treatment (days)

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.


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Cost Effectiveness of Linezolid vs Vancomycin in cSSTI Clinically Evaluable Subset

$5,187

CI (4,691–5,714)

$4,143

CI (3,750–4,576)

C

O

S

T

($)

Linezolid

Vancomycin

2003 Per diem hospital cost, administration of IV therapy, wholesale acquisition cost

Fleming T, ed. RedBook. 2004 edition. Montvale NJ: Thompson PDR;2004.


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Total Patients With SSI Clinically Evaluable Subset

135

Linezolid

66

Vancomycin

69

Linezolid vs Vancomycin for Surgical Site Infection (SSI )

Total Patients With cSSTI

1,200

-Weigelt J et al.: Am J Surg 2004;188:760-766.


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Linezolid vs Vancomycin in SSI Clinically Evaluable SubsetStudy Population

Baseline demographics:

No significant difference

Baseline comorbidities/MRSA risk factors:

No significant difference

-Weigelt J et al.: Am J Surg 2004;188:760-766.


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Linezolid vs Vancomycin in SSI: Clinically Evaluable SubsetClinical Cure Rates at TOC

P=0.06

-Weigelt J et al.: Am J Surg 2004;188:760-766.


Linezolid vs vancomycin in ssi microbiological cure rates at toc l.jpg
Linezolid vs Vancomycin in SSI: Microbiological Cure Rates at TOC

P=0.007

-Weigelt J et al.: Am J Surg 2004;188:760-766.


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Linezolid vs Vancomycin in SSI: at TOCMicrobiological Cure Rates at TOC in MRSA Pts.

P=0.002

-Weigelt J et al.: Am J Surg 2004;188:760-766.


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Daptomycin for cSSSIs at TOC

  • 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.


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Daptomycin Efficacy at TOC

  • 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

*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.


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Vancomycin at TOC

FDA approved for MRSA

Multiple

Route(s)

Parenteral

Dosing

Variable depending upon renal function

Sales pitch

“Cheap”

Disadvantages

Toxicity, resistance (VRE, VISA, VRSA)

Advantages

Familiarity

Comparison of MRSA Antimicrobials

Quinupristin/ Dalfopristin

Daptomycin

Linezolid

cSSSI (not MRSA)

cSSSI

cSSSI and pneumonia

Parenteral (central?)

Parenteral

Parenteral, oral

q8-12h

QD

BID

“Works when vancomycin won’t”

“Faster cure” (rapidly cidal)

“Gets patients home”

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)

Alternative to vancomycin

Potential for less resistance

Oral dosingremoval of catheters, early discharge, evidence of superiority to vancomycin in cSSTI


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Summary at TOC

  • 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.


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