Preventive Systemic Antibiotics in Colorectal Surgery: Criteria for … · 2009-07-01 ·...

Preventive Systemic Antibiotics in Colorectal Surgery:

Criteria for Drug Selection

Donald E. Fry, MD, FACSProfessor Emeritus

University of New Mexico Executive Vice-President

Michael Pine and AssociatesChicago, IL

Disclosure

Dr Fry reports receiving honoraria and serving on the speakers’ bureau for Astra-Zeneca, Cubist Pharmaceuticals, Merck and Company, and Pfizer Inc.

Frequency of Colorectal Surgery

290,000295,000300,000305,000310,000315,000320,000325,000330,000

2000 2001 2002 2003 2004

ColorectalSurgery

Data from National Inpatient Sample, HCUP Database, Agency for Healthcare Research and Quality; Definition of Colorectal Surgery; Bratzler et al Arch Surg 2005, 140:174-82.

• Over 30 million operations in the U.S. in 2006

• SSI Rate is unknownNo standardized definitionSurveillance after hospital discharge is problematic

• Colorectal surgery is highest risk for SSI among elective surgical procedures

Total Colorectal Cases: 2000-2004

Prevention of Surgical Site Infections (SSIs) in Colorectal Surgery

Preventive Systemic Antibiotics• Experimental studies by Miles (1957)1 and Burke

(1961)2

• Clinical studies by Polk and Lopez-Mayor.3• A total of 26 placebo controlled trials documented

the effectiveness of preoperative systemic antibiotics in colorectal surgery.4

1. Miles AA et al: Br J Exper Pathol 1957; 38:79-96.2. Burke JF: Surgery 1961; 50:161-8.3. Polk HC Jr, Lopez-Mayor JF: Surgery 1969; 66:97-103. 4. Baum ML et al: N Engl J Med 1981; 305:795-799.

Preventive Systemic Antibiotics Experimental Evidence

• Cutaneous injection of bacteria

• Inflammation at 24-48 hrs is proportional to the logarithm of the bacterial inoculum.

Prevention of Surgical Site Infection Use of Preventive Antibiotics: GI Surgery

Cephaloridine PlaceboPatients (Pts) 101 98Colon Pts 54 50Infections (Inf) 6 29Colon Inf 7% 30%

Polk and Lopez-Mayor, Surgery 1969; 66:97

Song and Glenny: Brit J Surg 1998; 85:1232

Systemic Preventive Antibiotics Why Postoperative Administration Fails

• Systemically Administered Antibiotic does not penetrate the Established Fibrin Matrix in the Wound.1

• The Closed Surgical Wound has continued Inflammation and Edema, which creates a “Halo” of Ischemia.2

1. Dunn D, Simmons DL: Surgery 1982; 92:513-9.2. Lee JT: Surgical Infections, Fry DE(Ed), Little-Brown, Boston. Pp. 145-59, 1995.

Prevention of SSIs in Colorectal Surgery

Principles of Preventive Antibiotic Use• Antibiotic administration should occur in the window

of time immediately before the skin incision.• The antibiotic that is employed should have activity

against the likely pathogens to be encountered, and should have clinical data that demonstrates effectiveness.

• The antibiotic need not be given for an extended period of time following skin closure.

Preventive Antibiotics in Colorectal Surgery

Criteria for Drug Selection• Antibiotic must have activity against the likely

pathogens to contaminate the wound• Antibiotic should have a favorable therapeutic

ratio• Antibiotic should have an extended biological

elimination half-life• There should be prospective, randomized data to

document efficacy of the Antibiotic Selection• The Antibiotic should be cost-effective

Systemic Preventive Antibiotics Elimination Half-life Counts

• Cephalothin is gone from the wound in 90 minutes from time of administration

• Cefazolin in therapeutic concentrations beyond 2½ hours

Fry and Pitcher: Arch Surg 1990; 125:1490

Preventive Systemic Antibiotics Colorectal Surgery

Recommended Antibiotics• Cefoxitin*

• Cefotetan*

• Ampicillin/Sulbactam*

• Cefazolin/Metronidazole*

• Trovafloxacin**

• Ertapenem**

*Recommended by Surgical Care Improvement Project**FDA Approved


Cefoxitin Placebo

Number of Patients 32 33

Infections 1 (3%) 9 (27%)

Hoffman CE et al: Ann Surg 1981; 193:353-6.

Cefotetan Cefoxitin


Infections 18 (9%) 23 (11%)


Periti et al, Dis Colon Rectum 1989; 32:121-7.

Cefotetan Cefoxitin


Infections 20 (12%) 6 (8%)


Jagelman DG, Fabian, Nichols, Wilson, et al: Am J Surg 1988; 155: 71-6

Cefazolin Cefazolin/Metronidazole


Infections 1 (4%) 0


McDermott FT, et al: Aust N Z J Surg 1981; 51:351-3.

Ampicillin/Sulbactam Gent/Metro


Infections 6 (9.5%) 7 (11%)


AhChong et al: J Hosp Infect 1994; 27:149-54

Preventive Antibiotics in Colorectal SurgeryTrovafloxacin vs. cefotetan

• Mechanical bowel preparation only• One dose of each preoperatively

No. Cases SSIsTrovafloxacin 161 34(21%)

Cefotetan 156 28(18%)

Milsom et al: Am J Surg 176(6A Suppl):46S

Ertapenem v Cefotetan Outcomes: CE Patients

Ertapenem(n=346)*

Cefotetan(n=339)

Reason for Failure n % n %

Any Failure 102 29.5 145 42.8Surgical Site Infection 63 18.2 105 31

Unexplained Antibiotic Use 29 8.4 26 7.7

Anastomotic Leak 10 2.9 14 4.1

* P<0.001Itani KMF et al: New Engl J Med 2006; 355:2640-51

Ertapenem v. Cefotetan

Ertepenem CefotetanType of Bacteria Resistant ResistantAerobesGram Pos Cocci (n=24) 14 (58%) 18(75%)Gram Neg Rods (n=11) 1(9%) 2(18%)AnaerobesGram Pos (n=24) 0 5(21%)Gram Neg Rods (n=33) 0 17(52%)TOTAL (n=92) 15(16%) 42(46%)

Bacteriology: Ertapenem-Associated Infections

Itani KMF et al: New Engl J Med 2006; 355:2640-51

Ertapenem v. Cefotetan

Ertepenem CefotetanType of Bacteria Resistant ResistantAerobesGram Pos Cocci (n=24) 14 (58%) 19(79%)Gram Neg Rods (n=15) 1(10%)* 8(53%)AnaerobesGram Pos (n=29) 0 0Gram Neg Rods (n=33) 1(3%) 24(65%)TOTAL (n=92) 16(16%)* 70(67%)

Bacteriology: Ertapenem-Associated Infections

*5 isolates not tested against ertepenemItani KMF et al: New Engl J Med 2006; 355:2640-51

Prevention of SSIs

Surgical Infection Prevention Project• Administration of antibiotic within 60 minutes of skin

incision• Antibiotic consistent with recommended choices• Antibiotic should not be continued beyond 24 hours

after completion of the procedure

Bratzler et al Arch Surg 2005, 140:174-82.

Preventive Antibiotics in Colorectal Surgery

01020304050607080

SIP #1 SIP #2 SIP #3

ColorectalSurgery

% C

ompl

ianc

eCompliance with National Surgical Infection Prevention (SIP)

Performance Measures


26.2

10

22.6

6.2 6.32.2 2.7

9.3

14.5

40.7

50.7

73.379.5

85.8 88 90.7

0

20

40

60

80

100

12 or le

ss

>12-2

4

>24-3

6

>36-4

8

>48-6

0

>60-7

2

>72-8

4

>84-9

6

> 96

Hours After Surgery End Time

Perc

ent

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.Bratzler DW, Houck PM, et al. Arch Surg. 2005;140:174-182.

Systemic Preventive Antibiotics Consequences of Prolonged Postoperative Use

• Excessive Antibiotic and Drug Delivery Costs.• Increased Patterns of Antibiotic Resistance.• Increased Antibiotic-Associated Complications.


Preventive Systemic Antibiotics Antibiotic-Associated Complications

• Hypersensitivity • Nephrotoxicity• Hepatic Toxicity• Coagulation/Platelet Aggregation

Complications• Fungal Super-infections• Clostridium difficile Enterocolitis

Cunha BA: Med Clin N Am 2001; 85:149-85.

Clostridium difficile cases per year: 1995-2004

0

50,000

100,000

150,000

200,000

250,000

300,000

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

Clostridium difficile Enterocolitis: Progressive Increase in U.S. Hospitals

Weighted National Estimates from HCUP Nationwide Inpatient Sample

Oral vs. Systemic Antibiotics Elective Colon Surgery

• All patients received systemic preoperative amikacin and metronidazole.

• Oral neomycin and metronidazole were randomized

Oral Drugs No Oral Drugs# Patients 109 106

Surgical Site Infections 5(5%) 17(16%)(P<0.01)

Lewis RT: Can J Surg 2002; 45:173.

Preventive Antibiotics in Colon Surgery: Systemic vs. Systemic + Oral Antibiotics

Lewis RT: Can J Surg 2002; 45:173.


Conclusions• Antibiotic selection for colorectal surgery is largely

dictated by guidelines and empirical choices• Evidence about which drug is best is limited because of

limited prospective clinical data over the last 15 years • Traditional drugs of cefoxitin and cefotetan have

become unavailable• Cefazolin and metronidazole makes sense but really

lacks clinical evidence

Conclusions• Ampicillin/Sulbactam has virtually no data to support its

use (short half-life; resistance).• Ertapenem has demonstrated statistically better results

than cefotetan but questions remain (eg. resistance, C. difficile)

• Systemic antibiotics and the oral antibiotic bowel preparation together are likely to provide best outcomes


Preventive Systemic Antibiotics in Colorectal Surgery: Criteria for … · 2009-07-01 ·...

Documents

Transcript of Preventive Systemic Antibiotics in Colorectal Surgery: Criteria for … · 2009-07-01 ·...