SKINANTISEPSIS FOR

PREVENTING INFECTION

Rabih O. Darouiche, M.D.VA Distinguished Service Professor

Director, Center for Prostheses InfectionBaylor College of Medicine

Houston, TexasUSA

Disclosure Statement

• Received research and educational funds from CareFusion/Cardinal Health

• Co-invented antimicrobial-impregnated devices

• I will quote data published only in peer-reviewed journals

Reasons to Optimize Prevention of SSI

• Unacceptably high incidence: the 30 million annual surgical procedures in the US result in 300,000-500,000 cases of SSI

• Difficult management: may require repeated surgical interventions

• Serious medical consequences: tremendous morbidity and occasional mortality

• Soaring economic burden: annual cost of treatment in the US, >$7 billions

Perioperative Approaches for Preventing SSI

• Non-antimicrobial approaches• Normothermia• Adequate oxygenation• Tight glucose control

• Antimicrobial approaches• Systemic antibiotic prophylaxis• Nasal application of mupirocin• Skin antisepsis

Impact of Timing of Systemic Antibiotic Prophylaxis on SSI

A Prospective Randomized Trial of Nasal Mupirocin Plus Chlorhexidine Wash

Rapid identification of nasal carriage by S. aureus followed by a 5-day course of nasal mupirocin plus chlorhexidine wash:• Reduces S. aureus infection (3.4% vs. 7.7%)• Decreases S. aureus SSI by almost 60%

Bode, et al. N Engl J Med 2010;362:9-17

Importance of the Skin

• Largest bodily organ• Protective barrier • Skin flora most common

cause of SSI (and CLABSI)• 80% of bacteria reside in

epidermis

Factors that Support the Need for Optimal Skin Antisepsis

• Most Pathogens that cause SSI are skin flora

• At least 2/3 of cases of SSI are incisional

• Most SSI are considered preventable

• Other preventive measures reduce but do not eliminate SSI

Commonly used Preoperative Antiseptics

• Povidone-iodine (Iodophor)• Chlorhexidine gluconate• Alcohol • Combination products: >2 active agents

Comparison of Antimicrobial Activity of Antiseptic Preparations

Chlorhexidine-based preparations are better than alcohol or iodine-based products in:

• Reducing colonization of vascular catheters

• Preventing contamination of blood cultures

• Decreasing contamination of surgical tissues

Prospective Randomized Clinical Trial of 2% Chlorhexidine Gluconate in 70% IPA vs. 70% IPA for Disinfection of Skin

Prior to Peripheral Venous Cannulation

19.8

33.1

0

5

10

15

20

25

30

35

2% CHG/70% IPA 70% IPA

PV

C ti

ps c

olon

ized

(%)

91 PVC tips evaluated 79 PVC tips evaluated

P=0.05

• There was a statistically significant reduction in the number of PVC tips colonized with coagulase-negative staphylococci in the 2% CHG/70% IPA group vs. 70% IPA group

Small, et al. Infect Control Hosp Epidemiol, 2008.

Impact of Skin Antisepsis on Blood Culture Contamination

Contamination rate

Study 2% CHG/70% IPA Iodine Tincture

Barenfanger* 2.9% 2.7%

Smith 3.1% 6.8%

Tepus 2.2% 3.5%

Trautner* 0.5% 1.4%

*No statistically significant differenceBarenfaner J, et al. Journal of Clinical Microbiology. 2004;42(5):2216-2217.

Smith SM, et al. 28th Annual Meeting of APIC 2001; Publication #11-89.

Tepus D, et al. 2005. J Emerg Nurs. 31:133. Abstract 402-C.

Trautner BW, et al. Infect Control Hosp Epidemiol. 2002;23:397-401.

Culligan, et al. Am J Obstet Gynecol. 2005;192:422-5.

Comparison of Povidone-Iodine vs. Chlorhexidine for Skin Antisepsis before Vaginal Hysterectomy

Pressing Need to Compare Clinical Efficacy of Antiseptic Preparations in Preventing SSI

• CDC guidelines for prevention of infections related to vascular catheters recommend antiseptic cleansing of the skin with 2% chlorhexidine-containing productsO’Grady, et al. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 2002;51(RR-10): 1-29

• CDC has not previously issued a preference as to type of preoperative skin antiseptics

Intraoperative phase• Prepare the skin at the surgical site immediately before incision using an antiseptic (aqueous or alcohol-based) preparation: povidone-iodine or chlorhexidine are most suitable.

NICE 2008 Guidelines for Prevention of Surgical Site Infection

www//:nice.org.uk/guidance

How to convince surgeons to study SSI?They do not have a problemThey do not observe any wound infectionsThey do not need any help

Prospective, Randomized, 6-Center Clinical Trial of 849 Patients

• Population: adult patients scheduled for abdominal or non-abdominal clean-contaminated surgery

• Randomization: hospital-stratified• Intervention: preoperative skin cleansing with:

• ChloraPrep® (2% chlorhexidine gluconate-70% isopropyl alcohol = CA) 26-ml applicators; OR

• 10% povidone-iodine (PI) scrub and paint• Evaluation: SSI was assessed by blinded evaluators

Darouiche, et al. NEJM 2010;362:18-26

Proportion of Patients with Surgical-Site Infection, According to Type of Infection (Intention-to-Treat Population).

Type of Infection

Chlorhexidine-Alcohol (N=409)no. (%)

Povidone-Iodine

(N=440)no. (%)

Relative Risk(95% CI) P-Value

Any surgical-site infection

39 (9.5) 71 (16.1) 0.59 (0.41-0.85)

0.004

Superficial incisional infection

17 (4.2) 38 (8.6) 0.48 (0.28-0.84)

0.008

Deep incisional infection 4 (1.0) 13 (3.0) 0.33 (0.11-1.01)

0.05

Organ-space infection 18 (4.4) 20 (4.6) 0.97 (0.52-1.80)

>0.99

Sepsis from surgical site infection

11 (2.7) 19 (4.3) 0.62 (0.30-1.29)

0.26

Kaplan-Meier Curves for Freedom from Surgical-Site Infection (Intention-to-Treat Population)

Proportion of Patients with Surgical-Site Infection, According to Type of Surgery (Intention-to-Treat Population).

Chlorhexidine-Alcohol Povidone-Iodine

Type of Surgery Nno.

Infected(%)

Infected Nno.

Infected(%)

Infected Abdominal 297 37 (12.5) 308 63 (20.5)

Colorectal 186 28 (15.1) 191 42 (22.0)Biliary 44 2 (4.6) 54 5 (9.3)Small intestinal 41 4 (9.8) 34 10 (29.4)Gastroesophageal 26 3 (11.5) 29 6 (20.7)

Non-abdominal 112 2 (1.8) 132 8 (6.1)

Thoracic 44 2 (4.5) 57 4 (7.0)Gynecologic 42 0 (0.0) 40 1 (2.5)Urologic 26 0 (0.0) 35 3 (8.6)

Univariate and Multivariate Analyses of Any Surgical-Site Infection (Intention-To-Treat Population)

Factor

Univariate Analyses Multivariate AnalysisOdds Ratio 95% CI P-Value

Odds Ratio 95% CI P-Value

Use of chlorhexidine-alcohol (vs. povidone-iodine)

0.55 (0.36-0.83) 0.004 0.45 (0.26-0.78) 0.004

Abdominal surgery (vs. non-abdominal)

4.63 (2.38-9.04) <0.001 3.21 (1.60-6.42) 0.001

ASA score of 4 (vs. 1) 15.43 (3.55-67.01) <0.001 4.99 (0.33-74.55) 0.24

ASA score of 3 (vs. 1) 5.26 (1.35-23.51) 0.006 1.81 (0.15-22.15) 0.64

ASA score of 2 (vs. 1) 2.78 (0.62-12.47) 0.25 2.05 (0.25- 6.47) 0.50

Age (per year) 1.02 (1.01-1.03) 0.003 1.00 (0.98-1.02) 0.78

Female sex (vs. male sex)

0.59 (0.38-0.90) 0.02 0.87 (0.69-1.09) 0.21

Univariate and Multivariate Analyses of Any Surgical-Site Infection (Intention-To-Treat Population)

FactorUnivariate Analyses Multivariate Analysis

Odds Ratio 95% CI P-Value Odds Ratio 95% CI P-Value

Alcohol abuse 1.11 (0.67-1.83) 0.69 1.12 (1.05-1.19) <0.001

Liver cirrhosis 3.28 (1.31-8.24) 0.02 2.14 (1.15-3.99) 0.02

Immunologic disease

2.72 (1.32-5.62) 0.01 1.79 (1.00-3.22) 0.05

Cancer 2.05 (1.31-3.21) 0.002 1.65 (1.04-2.64) 0.03

Diabetes mellitus 1.90 (1.16-3.11) 0.01 1.75 (1.05-2.92) 0.03

Malnutrition 3.02 (1.57-5.84) 0.003 2.62 (1.23-5.55) 0.01

Gastrointestinal disease

2.96 (1.75-5.01) <0.001 1. 27 (1.00-1.61) 0.05

Univariate and Multivariate Analyses of Any Surgical Site Infection (Intention-To-Treat Population)

Univariate Analyses Multivariate Analysis

Odds Ratio 95% CI P-Value Odds Ratio 95% CI P-Value

Infection at another bodily site (vs. no infection)

0.92 (0.32-2.68) 1.00 0.89 (0.50-1.58) 0.68

Duration of surgery(per hour)

1.33 (1.17-1.51) <0.001 1.11 (1.02-1.21) 0.01

Days that surgical drain was in place (per day)

1.03 (1.00-1.06) 0.02 1.04 (1.02-1.05) <0.001

Preop shower withChlorhexidine (vs. no shower)

1.56 (0.57-4.25) 0.38 0.95 (0.78 -1.15) 0.19

Preop shower withpovidone-iodine(vs. no shower)

0.13 (0.02-0.92) 0.01 0.36 (0.32-0.39) <0.001

Preop shower with soap (vs. no shower)

1.08 (0.65-1.82) 0.79 0.96 (0.75-1.21) 0.72

Clinical Adverse Events (Intention-to-Treat Population)

Clinical Adverse Event

Chlorhexidine-Alcohol (N=409)no. (%)

Povidone-Iodine

(N=440)no. (%)

Absolute Difference(95% CI) P-Value

Adverse events in >5% of patients in either group

228 (55.7) 256 (58.2) -2.4(-9.1 to 4.2)

0.49

Type of event- Abnormal cardiac rhythm or rate

25 (6.1) 25 (5.7) 0.4 (-2.7 to 3.6)

0.88

- Nausea 30 (7.3) 34 (7.7) -0.4(-3.9 to 3.2)

0.90

- Urinary tract infection 23 (5.6) 28 (6.4) -0.7 (-3.9 to 2.5)

0.67

- Abdominal pain 25 (5.1) 29 (6.6) -1.5(-4.6 to 1.7)

0.39

- Ileus 19 (4.6) 24 (5.5) -0.8(-3.8 to 2.1)

0.64

Drug-related adverse events 3 (0.7) 3 (0.7) 0.1(-1.1 to 1.2)

>0.99

Clinical Adverse Events (Intention-to-Treat Population)

Serious Adverse Event

Chlorhexidine-Alcohol (N=409)no. (%)

Povidone-Iodine

(N=440)no. (%)

Absolute Difference(95% CI) P-Value

Serious adverse events in >1% of patients in either group

72 (17.6) 70 (15.9) 1.7(-3.3 to 6.7)

0.52

Type of event- Bloodstream infection 11 (2.7) 23 (5.2) -2.5

(-5.1 to 0.1)0.08

- Abscess 6 (1.5) 11 (2.5) -1.0(-2.9 to 0.8)

0.33

- Pneumonia 6 (1.5) 9 (2) -0.6 (-2.3 to 1.2)

0.61

- Bowel ischemia 7 (1.7) 8 (1.8) -0.1(-1.9 to 1.7)

>0.99

- Anastomotic leak 9 (2.2) 4 (0.9) 1.3(-0.4 to 3.0)

0.16

- Acute renal failure 5 (1.2) 7 (1.6) -0.4(-1.9 to 1.2)

0.77

Clinical Adverse Events (Intention-to-Treat Population)

Serious Adverse Event

Chlorhexidine-Alcohol (N=409)no. (%)

Povidone-Iodine

(N=440)no. (%)

Absolute Difference(95% CI) P-Value

Patients with serious adverse events

72 (17.6) 70 (15.9) 1.7(-3.3 to 6.7)

0.52

Type of event- Respiratory failure 4 (1) 8 (1.8) -0.8

(-2.4 to 0.7)0.39

- Bowel obstruction 3 (0.7) 5 (1.1) -0.4(-1.7 to 0.9)

0.73

Serious drug-related adverse events

0 0 --- ---

Death 4 (1) 3 (0.7) 0.3(-0.9 to 1.5)

0.72

ConclusionEfficacy and safety of CA vs. PI

• Significantly reduces SSI• Number of patients needed to receive CA

instead of PI to prevent one case of SSI: 17 • Delays onset of SSI • Its superior protection is largely due to

significant reduction in rates of superficial and deep incisional infections

• As safe as PI

Antiseptic Spectrum of activity Rapidity of action

Residual activity

Affected by

organic matter

Gram +bacteria

Gram –bacteria

Fungi

Isopropyl alcohol (IPA) +++ ++ +++ Rapid Minimal Yes

Aqueous chlorhexidine +++ ++ ++ Intermediate Excellent Minimal

Chlorhexidine in IPA +++ ++ +++ Rapid Excellent Minimal

Aqueous povidone-iodine

+++ ++ + Intermediate Minimal Yes

Povidone-iodine in IPA +++ ++ +++ Rapid Minimal Yes

Characteristics of Antiseptics

Cost of Antiseptic Products in the US

• Mean cost of PI prep tray per patient: ~$3• Mean cost of one CA applicator: ~$7• Mean no. of CA applicators/patient: 2 • Mean cost of CA applicators per patient: $14• Extra cost of CA vs. PI/1,000 patients: $11,000

Cost of Superficial SSI

($500/case)

Cost of Deep SSI

($20,000/case)

Cost of 80:20 mix SSI($4,400/case)

CA group $49,50099 SSI cases

$1,980,00099 SSI cases

$435,60099 SSI cases

PI group $83,500167 SSI cases

$3,340,000167 SSI cases

$734,800167 SSI cases

Savings(CA vs. PI)

$34,000 $1,360,000 $299,200

Cost Savings(CA vs. PI)

$23,000 $1,349,000 $288,200

Potential Cost-SavingsPer 1,000 Surgeries in the US

Perspective on the CA applicatorCPSI

• Cost-saving• Practical• Safe• Infection-reducing

Quality Management

Patient1. Surveillance

2. Analysis

3. Intervention 4. Evaluation

Future Considerations

• Investigate the efficacy of 2% chlorhexidine-70% isopropyl alcohol in other types of surgery

• Assess the actual cost-savings associated with use of different antiseptic preparations

• Examine the potential role of complementing preoperative use of 2% chlorhexidine-70% isopropyl alcohol with other approaches

Too much skin

antisepsis

Similarities Between CRBSI and SSI• Both infections are caused mostly by skin

organisms• Both infections result primarily from

breaking skin integrity • Both infections occur at unacceptably high

rates, can be difficult to manage, may require future interventions, and are costly to treat

New CMS Regulations (effective 10/08) Changes to Inpatient Prospective Payment System

10 non-reimbursable conditions met these criteria:• High cost• High volume• Triggers a high-paying MS-DRG• May be considered reasonably preventable through

application of evidence-based guidelinesFederal Register, Volume 73, No. 161; 08/19/08

Non-reimbursable Infectious Conditions

• Catheter-associated urinary tract infection• Vascular catheter-associated infection• Surgical site infection-mediastinitis after CABG• Surgery on various joints, including shoulder,

elbow, and spine

Differences Between CRBSI and SSI• CRBSI manifests while the catheter is still in

place, whereas SSI can manifest at any time after surgery, usually by 30 days post-op

• Microbiologic cause of CRBSI is almost always identified, whereas the microbiologic cause of SSI is unknown in many patients

• Occurrence of CRBSI can be attributed to various healthcare providers, whereas SSI is typically linked to the surgeon

Nosocomial Infections in the ICU

PNEU27%

OTHER6%LRI

4%EENT

4%CVS4%

GI5%

BSI19%

UTI31%

National Nosocomial Infections Surveillance (NNIS) (97 hospitals)

87% central lines

86% Mechanical Ventilation95% Urinary Catheters

N= 14,177

< 55 = 33%55 – 70 = 32%>70 = 35%

Impact of CRBSI

• Incidence: of the 6 million CVC inserted annually in the US, 250,000 result in BSI

• Management: cure often requires removal of the infected catheter and long antibiotic therapy

• Medical sequelae: attributable mortality 5-25%• Economic burden: cost of treatment is $10-56

thousand; annual cost in US, $3–$16.8 billions

Annual Death Rates in the US for Selected Infectious Diseases

0

5,000

10,000

15,000

20,000

25,000

30,000

CRBSI MRSA AIDS Hep B Tbc Measles

Dea

ths p

er Y

ear

Comprehensive Protective StrategyInfection Control Bundle

• Hand washing• Maximal barrier precautions• 2% chlorhexidine-based skin antisepsis• Avoiding femoral site if possible• Removing unnecessary catheters

Although very essential, they: • Are not easily enforceable• Are not very durable• Do not completely prevent infection• Saves some, but not enough, lives

Potential Limitations of Traditional Infection Control Measures

Perspective

Optimal prevention of SSI and CRBSI can:• Improve patient care• Incur cost-savings• Enhance infection control measures

Screening, Randomization, and Follow-up of Study Participants

Systemic Prophylactic Antibiotics for Colorectal Surgery (Intention-to-Treat Population).

Chlorhexidine-Alcohol Povidone-Iodine(n=186) (n=191) P-Value

Cephalosporin - % 64.5 67.5 0.59

Glycopeptide - % 10.2 11.0 0.87

Nitroimidazole - % 16.1 14.7 0.78

Aminoglycoside - % 14.5 17.3 0.48

Carbapenem - % 15.1 13.6 0.77

Penicillin - % 3.8 3.7 >0.99

Macrolide - % 3.2 4.2 0.79

Fluroquinolone - % 2.7 1.6 0.50

Monobactam - % 1.1 0 0.24

Tetracycline - % 0.5 0.5 >0.99

Microbiology of Infection

• 60/110 (55%) infections had identifiable cause(s)

• 23 infections in CA group vs. 37 in PI group

• 14 more superficial or deep incisional infections by Staphylococcus aureus and streptococci in PI group

• 43% of cases were polymicrobial (total, 107 isolates)

• GP bacteria outnumbered GN bacteria by 2.5 fold

• Most common organism: S. aureus (24/60=40%)

• No significant differences in frequency of organisms, except streptococci (3% in CA vs. 16% in PI; P=0.02)

• All 4 Candida infections were in PI group (P=NS)

Clinical Manifestations of infected CVC

• Exit site infection• Tunnel infection• Thrombophlebitis• BSI