Is There Any Role for Oral Antimicrobial Prophylaxis in Colorectal Is There Any Role for Oral Antimicrobial Prophylaxis in Colorectal Surgery? Samuel Eric Wilson, MD Department of Surgery University of California, Irvine Irvine, CA

Disclosure Dr Wilson reports having no financial or advisory relationships with corporate organizations related to this activity.

Adverse Effects in NY Hospitals 1133 of 30,195 Hospitalized Patients EventsDisability Nonoperative534 (52.3%)25.3% Operative599 (47.7%)24% Wound infection16018% Technical15712% Late comp % Surgical failure5817.5% Other8744% Harvard Med. Practice Study. Leape LL et al. N Engl J Med. 1991;324:

Antibiotic Administration in Surgery “The Chaos Continues”* New York Methodist Hospital—560 beds 156/211 inappropriate antibiotic administration 2 cases Clostridium difficile colitis Excessive duration of antibiotics Did not distinguish prophylactic from therapeutic *Gorecki P et al. World J Surg. 1999;23:

Timing of Prophylaxis and Surgical Site Infection (SSI) Rate in Colon Surgery Hours before incision IncisionHours after incision Data from University Hospitals Consortium 2004.

National Initiatives to Prevent SSI Surgical Care Improvement Program (SCIP) Save 100,000 Lives Campaign National Academy of Medicine: “To Err Is Human” National VA Surgical Quality Improvement Program (NSQIP) extended to private sector Financed by Center for Medicare & Medicaid Services (CMS) Reporting of adherence to guidelines required and ? pay for performance

Bowel Preparation for Elective Colon Resection: State of the Art in North America* Surgeons performing elective colorectal resection with primary anastomosis consider a mechanically cleansed bowel a prerequisite along with oral antimicrobials *Nichols RL, Smith JW, Garcia RY, et al. Current practices of preoperative bowel preparation among North American Colorectal Surgeons. Clin Infect Dis. 1997;24:

Wound Classification National Research Council, 1964 Clean wound—gastrointestinal (GI), genitourinary (GU), or respiratory tract not entered, no apparent inflammation, no break in a septic technique Clean contaminated—GI and respiratory tract entered, but no spill of contents Contaminated—acute inflammation, gross spillage Dirty—perforated viscus, pus, abscess

Distribution of Viable Bacteria in the Small Intestine

Prevention of Infection After GI Surgery Anatomical SiteNormal FloraBacterial Count Upper GI (esophagus, stomach, duodenum, proximal small bowel) Streptococci, Lactobacilli, Corynebacteria, oral anaerobes 0–10 3 Biliary treeSterile0 Lower GI (ileum, colon, rectum) Escherichia coli, Bacteroides fragilis group, Clostridium, Enterococci, anaerobic cocci 10 8 –10 12

Type of ProcedureRisk of SSI Clean<2% Clean-contaminated5–15% Contaminated15–30% Dirty*>30% Nichols RL. Am J Surg. 1996;172: Traditional Classification of Operative Procedures and Risk of Infection *Dirty wounds  infection—antibiotics indicated as therapy

Surgical Patients at Risk for Infection* VariableOrderP Value Abdominal operation1<.0001 Operation >2 h2<.0001 Class III and IV3< Diagnoses4<.0001 *Study on the Efficacy of Nosocomial Infection Control (SENIC), Centers for Disease Control and Prevention. Haley RW et al. Am J Epidemiol. 1985;121:

PREVENT Trial Baseline Patient Risk Factors* Risk Factors Polyethylene GlycolSodium Phosphate P Value (n=303)(n=367) Obesity (body mass index >30 kg/m 2 ), % Chronic obstructive pulmonary disease, % <.001 Time from dosing to surgery, min 55.9  23.1 (0–120)59.6  24.3 (8–12).044 Duration of surgery, min   Occurrence of perforation/spillage, % Good to excellent bowel preparation, % *Itani K et al. Am J Surg. 2007;193:

Is Incidence of Postoperative SSI Within Your Control? Postoperative infection rates decrease as residents gain experience Lau WY et al. Am J Surg. 1988;155: Unique surgeon rates in Portland for colorectal surgery Peck JJ et al. Am J Surg. 1984;147: In review of 2809 patients, surgeon was independent variable Tang R et al. Ann Surg. 2001;234:

Influence of Surgeons’ Experience on Postappendectomy Sepsis According to Degree of Appendicitis Normal Appendix Acutely Inflamed Late Appendicitis Trainees (n=7) Stage 1 Operations Infection1710 Stage 2 Operations Infection045 Stage 3 Operations Infection099 Senior Surgeons (n=6) Overall Operations Infection022 Lau WY et al. Am J Surg. 1988;155:

Postappendectomy Sepsis Rates for Seven Individual Trainees Normal Appendix Acutely Inflamed Late Appendicitis All Appendicitis 1/9 (11.1%)3/63 (4.8%)3/30 (10%)7/102 (6.9%) 0/8 (0%)2/77 (2.6%)1/27 (3.7%)3/112 (2.7%) 0/5 (0%)1/39 (2.6%) 3/33 (9.1%)4/77 (5.2%) 0/7 (0%)2/72 (2.8%)7/41 (17.1%)9/120 (7.5%) 0/3 (0%)4/29 (13.8%)4/20 (20%)8/52 (15.4%) 0/2 (0%)4/52 (7.7%)5/26 (19.2%)9/80 (11.3%) 0/5 (0%)4/72 (5.6%)1/15 (6.7%)5/92 (5.4%) Lau WY et al. Am J Surg. 1988;155:

Colorectal Surgery: Each Surgeon’s Infection Rate Differs SurgeonPatients, nInfection, % B E895.6 F646.3 I728.3 M N O St. Vincent’s Medical Center, Portland. Peck JJ et al. Am J Surg. 1984;147:

Antibiotic Effects on Surgeons’ Wound Infection Rates Percentage Surgeons No. of Patients No or Poor Antibiotics Effective Antibiotics P Value Group I NS Group II <.01 Group III <.001 NS=not significant. St. Vincent’s Medical Center, Portland. Peck JJ et al. Am J Surg. 1984;147:

History of Intestinal Antisepsis 1941 Poth—Nonabsorbable sulfas  Sulfasuxidine, sulfathalidine 1950 Tetracycline—enterocolitis 1964 Gordon and Finegold  Neomycin—Staphylococcus wound Infections 1975 Clarke and Condon  VA Cooperative Studies Mortality 10–12%; Infection 80% Staged resections; Closed anastomoses

Antimicrobial Prophylaxis in Colorectal Surgery Antibiotic began preoperatively Prospective, controlled, randomized Precise definition of wound infection Appropriate spectrum for flora (aerobic and anaerobic) No established infection Study Design* *Guglielmo BJ et al. Arch Surg. 1983;118:

Wound Infection After Elective Colorectal Resection Detailed review of 176 patients/2 years with 3-month follow-up; oral antibiotics Age 62 (48–72) years; 57% cancer; 20% diverticulitis 40% had ileostomy or colostomy 45 (25.6%) had SSI: 22 diagnosed after discharge Mean home health care cost $ risk factors: obesity (P =.024); length of operation (P =.031); ↓blood pressure (P =.1) “A surgeon with considerable intestinal fortitude!” Smith RL et al. Ann Surg. 2004;239:

Preventing Infection in Colorectal Surgery Field isolation GIA for bowel division Clean set (Mayo stand) for wound closure; change gowns and gloves Inflammatory bowel disease, active infection, and perineal wound were exclusions Independent RN epidemiologist collected outcome data Technical Methods in VA Cooperative Trials

Oral Antimicrobials Highly Effective in First VA Cooperative Trial 116 evaluable patients; 56 erythromycin + neomycin; 60 placebo 3-day bowel prep Septic complications: 43% placebo; 9% erythromycin + neomycin (P <.001) 4- to 5-log decrease in concentrations of both aerobes and anaerobes in colonic lumen Clarke JS et al. Ann Surg. 1977;186:

Colorectal Prophylaxis: Parenteral Cephalothin Alone Fails Complication, n (%) Intravenous Cephalothin (n = 67) Erythromycin + Neomycin ± Cephalothin (n = 126) P Value (chi-square) Wound infection20 (30)7 (6)<.001 Peritonitis/abscess12 (18)2 (2)<.001 Anastomotic leak7 (10)0<.001 Septicemia5 (7)1 (1)<.04 Death4 (6)2 (2)<.2 Total complications4812 Total septic patients26 (39)7 (6)<.001 Condon RE et al. Am J Surg. 1979;137:68-74.

Efficacy of Oral and Systemic Prophylaxis in Colorectal Operations 5-year study of oral neomycin + erythromycin vs orals and parenteral cephalothin 1128 patients studied in VA Cooperative Study Overall septic complications: orals = 7.8%; orals + cephalothin = 5.7% (NS) “…no discernable benefit from adding parenteral antibiotics…” Condon RE et al. Arch Surg. 1983;118:

Prophylaxis in Colon Surgery Baum ML et al. N Engl J Med. 1981; 305:

Postoperative Infection in Colorectal Surgery Protected by mucous blanket from oral antibiotics (Rotstein et al; 1985) Colonoscopic biopsies of mucosa; SEM Greatest suppression with both oral and parenteral antimicrobials 3.4  10 7  1.8  10 2 mean CFU/g Musocal-related Microflora SEM = scanning electron microscope. World J Surg. 1990

Mean Serum Erythromycin Concentration

Wound Infection Rates (% Infections) After Colorectal Surgery: Effect of Combination of Oral and Parenteral Antimicrobials Perioperative Antibiotics* InvestigatorOral Oral and Parenteral Significance (P Value)Regimen Copa et al I 18.0% II 6.6% <.01 I Erythromycin (oral) + Neomycin (oral) II Erythromycin (oral) + Neomycin (oral) + Cefoxitin Portnoy et al I 29.0% II 4.7% <.01 I Erythromycin (oral) + Neomycin (oral) III 2.3% <.001 II Erythromycin (oral) + Neomycin (oral) + Cefazolin III Erythromycin (oral) + Neomycin (oral) + Cefazolin Condon et al I 7.8% septic II 5.7% septic NS I Erythromycin (oral) + Neomycin (oral) + Placebo 5.6% wound 3.7% wound NS II Erythromycin (oral) + Neomycin (oral) + Cephalothin *All patients had mechanical preparation. NS = not significant. 1. Copa et al. 2. Portnoy J et al. Dis Colon Rectum. 1983;26: Condon RE et al. Arch Surg. 1983;118:

Colorectal Surgery Effect of Duration of Operation Duration, h Orals and Cefazolin, n/total (%) Cefoxitin, n/total (%) <30/290/17 3–43–42/21 (9.5)2/25 (8.0) >40/135/14 (35.7)* *Cefoxitin IV “on call”: 1 h 40 min before incision Kaiser AB et al. Ann Surg. 1983;198:

Antimicrobials for GI/Colorectal Surgery—SIP Guidelines Parenteral Cefotetan, cefoxitin, ampicillin or cefazolin + metronidazole (if penicillin allergy, use gentamicin, azithromycin, or quinolone) Oral Neomycin + erythomycin

Resection and Primary Anastomosis of the Colon and Rectum Without Mechanical Bowel Preparation (MBP) (Controlled, Randomized Series) Wound Infection, n/total (%) Leak, n/total (%) MBPNo MBPMBPNo MBP Brownson /86 (5.8)7/93 (7.5)8/67 (11.9)1/67 (1.5) Burke /82 (4.9)3/87 (3.4)3/82 (3.7)4/87 (4.6) Miettmen /138 (3.6)3/129 (2.3)5.125 (4)3/117 (2.6) 1. Brownson et al (abstract). Brit J Surg. 1992;77: Burke P et al. Brit J Surg. 1994;81: Miettmen RP et al. Dis Colon Rectum. 2000;43:

Prevention of Infection in Colorectal Surgery: Status 2007 Oral antibiotics plus mechanical bowel preparation established in North America Broad spectrum, intravenous antibiotics plus oral agents perioperatively in most patients and always in longer procedures (>3 hours) Incidence of major wound and intra-abdominal infection approximately 7–10% for elective resection Emphasis on avoidance of colostomy, staged operations New data from Europe question mechanical preparation given good perioperative antimicrobials

Prevention of Infection in Colorectal Surgery: Next Steps Extension of indications for primary colon resection/anastomosis Changes in bowel preparation: de-emphasis Longer procedures (ileoanal, low anterior) Demand Parenteral Antimicrobial  Highly effective aerobic and anaerobic agent  Must have low toxicity  Achieve rapid serum MIC 90 level  No nausea or vomiting  Avoid redosing and timing errors accurately with long half-life MIC = minimum inhibitory concentration.