Download Preventive Systemic Antibiotics in Colorectal Surgery: Criteria for

Preventive Systemic Antibiotics in
Colorectal Surgery:
Criteria for Drug Selection
Donald E. Fry, MD, FACS
Professor Emeritus
University of New Mexico
Executive Vice-President
Michael Pine and Associates
Chicago, 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
Total Colorectal Cases: 2000-2004
• Over 30 million operations in
the U.S. in 2006
• SSI Rate is unknown
ƒ No standardized definition
ƒ Surveillance after hospital
discharge is problematic
• Colorectal surgery is highest
risk for SSI among elective
surgical procedures
330,000
325,000
320,000
315,000
Colorectal
Surgery
310,000
305,000
300,000
295,000
290,000
2000 2001 2002 2003 2004
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.
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
Patients (Pts)
101
Colon Pts
54
Infections (Inf)
6
Colon Inf
7%
Polk and Lopez-Mayor, Surgery 1969; 66:97
Placebo
98
50
29
30%
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
Preventive Systemic Antibiotics
Colorectal Surgery
Number of Patients
Infections
Hoffman CE et al: Ann Surg 1981; 193:353-6.
Cefoxitin
Placebo
32
33
1 (3%)
9 (27%)
Preventive Systemic Antibiotics
Colorectal Surgery
Number of Patients
Infections
Periti et al, Dis Colon Rectum 1989; 32:121-7.
Cefotetan
Cefoxitin
197
206
18 (9%)
23 (11%)
Preventive Systemic Antibiotics
Colorectal Surgery
Cefotetan
Cefoxitin
164
75
20 (12%)
6 (8%)
Number of Patients
Infections
Jagelman DG, Fabian, Nichols, Wilson, et al: Am J Surg 1988; 155: 71-6
Preventive Systemic Antibiotics
Colorectal Surgery
Number of Patients
Infections
McDermott FT, et al: Aust N Z J Surg 1981; 51:351-3.
Cefazolin
Cefazolin/Metronidazole
26
22
1 (4%)
0
Preventive Systemic Antibiotics
Colorectal Surgery
Ampicillin/Sulbactam
Number of Patients
Infections
AhChong et al: J Hosp Infect 1994; 27:149-54
Gent/Metro
63
65
6 (9.5%)
7 (11%)
Preventive Antibiotics
in Colorectal Surgery
Trovafloxacin vs. cefotetan
• Mechanical bowel preparation only
• One dose of each preoperatively
Trovafloxacin
Cefotetan
Milsom et al: Am J Surg 176(6A Suppl):46S
No. Cases
161
SSIs
34(21%)
156
28(18%)
Ertapenem v Cefotetan
Outcomes: CE Patients
Ertapenem
(n=346)*
Reason for Failure
Cefotetan
(n=339)
n
%
n
%
102
29.5
145
42.8
Surgical Site
Infection
63
18.2
105
31
Unexplained Antibiotic
Use
29
8.4
26
7.7
Anastomotic Leak
10
2.9
14
4.1
Any Failure
*
P<0.001
Itani KMF et al: New Engl J Med 2006; 355:2640-51
Ertapenem v. Cefotetan
Bacteriology: Ertapenem-Associated Infections
Type of Bacteria
Aerobes
Gram Pos Cocci (n=24)
Gram Neg Rods (n=11)
Ertepenem
Resistant
Cefotetan
Resistant
14 (58%)
1(9%)
18(75%)
2(18%)
Anaerobes
Gram Pos (n=24)
Gram Neg Rods (n=33)
TOTAL (n=92)
Itani KMF et al: New Engl J Med 2006; 355:2640-51
0
0
5(21%)
17(52%)
15(16%)
42(46%)
Ertapenem v. Cefotetan
Bacteriology: Ertapenem-Associated Infections
Type of Bacteria
Aerobes
Gram Pos Cocci (n=24)
Gram Neg Rods (n=15)
Ertepenem
Resistant
Cefotetan
Resistant
14 (58%)
1(10%)*
19(79%)
8(53%)
0
1(3%)
0
24(65%)
Anaerobes
Gram Pos (n=29)
Gram Neg Rods (n=33)
TOTAL (n=92)
*5 isolates not tested against ertepenem
Itani KMF et al: New Engl J Med 2006; 355:2640-51
16(16%)*
70(67%)
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
Compliance with National Surgical Infection Prevention (SIP)
Performance Measures
80
% Compliance
70
60
50
40
Colorectal
Surgery
30
20
10
0
SIP #1
Bratzler et al Arch Surg 2005, 140:174-82.
SIP #2
SIP #3
Discontinuation of Antibiotics
100
90.7
88
85.8
79.5
Percent
80
73.3
60
50.7
40.7
40
26.2
22.6
14.5
20
10
9.3
6.3
6.2
2.7
2.2
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.
Bratzler DW, Houck PM, et al. Arch Surg. 2005;140:174-182.
96
>
-9
6
>8
4
>7
2
-8
4
-7
2
>6
0
-6
0
>4
8
-4
8
>3
6
-3
6
>2
4
-2
4
>1
2
12
or
le
ss
0
Systemic Preventive Antibiotics
Consequences of Prolonged Postoperative Use
• Excessive Antibiotic and Drug Delivery Costs.
• Increased Patterns of Antibiotic Resistance.
• Increased Antibiotic-Associated Complications.
Bratzler et al Arch Surg 2005, 140:174-82.
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 Enterocolitis:
Progressive Increase in U.S. Hospitals
Clostridium difficile cases per year: 1995-2004
300,000
250,000
200,000
150,000
100,000
50,000
0
1995
1996
1997
1998
1999
Weighted National Estimates from HCUP Nationwide Inpatient Sample
2000
2001
2002
2003
2004
Oral vs. Systemic Antibiotics
Elective Colon Surgery
• All patients received systemic preoperative amikacin
and metronidazole.
• Oral neomycin and metronidazole were randomized
# Patients
Surgical Site Infections
(P<0.01)
Lewis RT: Can J Surg 2002; 45:173.
Oral Drugs
109
No Oral Drugs
106
5(5%)
17(16%)
Preventive Antibiotics in Colon Surgery:
Systemic vs. Systemic + Oral Antibiotics
Lewis RT: Can J Surg 2002; 45:173.
Preventive Systemic Antibiotics
Colorectal Surgery
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
Preventive Systemic Antibiotics
Colorectal Surgery
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