Antibiotics in Colon Surgery

Symposium on Colon and Rectal Surgery

Antibiotics in Colon Surgery H. Harlan Stone, M.D.*

Before surgeons realized that the contents of the colon were primarily composed of live and dead bacteria, operations on the large bowel were uniformly followed by significant infection, which of itself almost as frequently caused the death of the patient. The ingenuity of surgeons then led to the development of many different methods to avoid such soilage. These methods included the performance of a proximal colostomy by Mikulicz, creation of a double-barreled colostomy that could be closed nonoperatively by application of a crushing clamp at some future date (Mikulicz), extraperitoneal techniques for bowel anastomosis, special clamps to prevent the spill of feces at bowel anastomosis (Rankin), and the socalled "closed suture technique" or "no touch technique" for intestinal anastomosis. Still, despite all of these various maneuvers, infection rates seldom were less than 50 per cent for open colon surgery. PREPARATION OF THE BOWEL Surgeons reasoned that if the large bowel could be cleared of all contained bacteria, then this type of surgery would be converted into a "near-clean" category. Resultant infection rates should thereby become equal to what was routinely being noted with the truly clean case. Two techniques for accomplishing this end therefore evolved. With one, there was fastidious mechanical cleansing of the bowel; with the other, various antimicrobial agents were given to sterilize the intestinal tract. Mechanical Cleansing Many different ways to rid the intestinal lumen of fecal matter have been developed. Most techniques were based upon varied combinations of cathartic with enema and even assumed an almost religious connotation for the individual surgeon. No single technique received wide acceptance as a true standard until the United States Veterans Administration carried out a multihospital study on the value of preoperative bowel preparation. The use of magnesium sulfate as the laxative and a specific enema schedule *Professor of Surgery, Emory University School of Medicine, Atlanta, Georgia

Surgical Clinics of North America-Vol. 63, No. 1, February 1983

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were established as part of the protocol. As a result, these steps have become the accepted standard in recent years. 4 Despite even prolonged attempts at mechanical cleansing with this method, the contents of the colon cannot be completely eliminated in a moderate number of patients, especially in patients who have considerable bowel atony. Use of the liquid diet is also not uniformly successful. Diet failures have primarily been caused by the fact that liquids provide the required nutrient media for bacterial growth and thus formation of stool. Only relatively expensive elemental diets (Vivonex by Eaton and Criticare by Mead-Johnson) appear to permit almost total absorption of such nourishment proximally so that a mechanically clean colon can be achieved distally. Recently, the washout of intestine from above through the instillation of large volumes of electrolyte solution into the stomach has been tried at several centers. 6 • 13 Excellent results have consistently been obtained with this gavage technique, although the attendant water and salt overload has occasionally caused problems in those patients with marginal cardiac function. Appropriate selection of patients to receive simultaneously a diuretic has apparently eliminated the problem. However, only patients free of obstructive symptoms are candidates for this particular technique. To avoid the occasional problem created by water and salt overload, surgeons can use mannitol as an oral agent rather than some form of saline gavage. Results have been excellent. 13· 16 Patients generally prefer taking mannitol, yet there is the risk of an explosion in the operating room whenever the bovie is used in such cases. Mannitol is a substrate from which various anaerobic bacteria can produce explosive gases, such as methane. However, if an antibiotic is added to the mannitol preparation, insufficient bacteria remain within the intestinal tract and thus the risk of explosion can almost be eliminated. 28 Probably the best of all methods for mechanical cleansing of the bowel is a whole gut irrigation (gavage) that also includes mannitol in the electrolyte solution. This technique, in combination with an oral antibiotic, is quite safe and gives consistently good results. Patients then need be admitted only the night before surgery, since only a few hours are required for this form of mechanical cleansing. Oral Antimicrobial Agents Although various potions had been used with indifferent results, not until1939 was the benefit of oral antimicrobial agents such as a sulfonamide reported. 8 • 10• 20 Still, infection rates despite the use of these drugs remained unacceptably high, approximately 35 per cent. Substitution of the sulfonamide by an aminoglycoside affected the incidence of postoperative sepsis: the frequency of infection decreased to approximately 20 per cent. 30 The addition of an agent active against the anaerobes, such as erythromycin, to the oral aminoglycoside (neomycin) has given perhaps an even better result. 4 Wound, or intraabdominal infection, or both now occur in only 5 to 15 per cent of such cases. About 15 years ago, surgeons first realized that metronidazole was very active against most species of anaerobic bacteria. Throughout Europe, South Africa, and Australia, the combination of neomycin and metronidazole

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has been the preferred oral antimicrobial regimen and has given even better results; infection rates vary between 2 and 10 per cent. 15 Nevertheless, without excellent mechanical cleansing of the colon, oral antimicrobial agents have had little impact on the incidence of postoperative, woundrelated sepsis.

PARENTERAL ANTIBIOTIC PROPHYLAXIS Use of parenteral antibiotics prophylactically appeared to be of little value until the study of Polk and Lopez-Mayor. 18 Their report clearly demonstrated in a prospective, double-blind, randomized test that parenteral antibiotics, administered just before operation, could significantly reduce the infection rate in the absence of an oral antimicrobial agent. With colon surgery, a wound-related infection occurred in only 5 per cent of cases. In another prospective, double-blind, randomized study, it was shown that antibiotics begun after an operation consistently failed to reduce the infection rate below that of control cases given only a parenteral placebo. 24 The critical issue has appeared to be the availability of antibiotic in tissues and blood during bacterial challenge. Administration of antibiotics at a later time has little to no benefit, for such therapy is being delivered to the site of contamination well beyond the so-called "determinate period." Physicians have tended to continue administering antibiotics during the postoperative phase for as long as two to even seven days. In another study, continuation of parenteral antibiotic therapy once the skin incision had been closed resulted only in extra drug expenditures. Absolutely no additional benefit could be demonstrated for receiving antibiotics beyond the immediate perioperative phase. 22 Accordingly, at the present time, the parenteral prophylactic agents should be administered just before the induction of anesthesia, another dose repeated every second half-life during operation, and the last dose to be given in the recovery room. Oral versus Parenteral Antibiotics

Considerable argument exists about whether parenteral antibiotics are ever warranted if the patient has been given an oral antimicrobial preparation. The absorption of aminoglycoside from the intestine is approximately 3 to 5 per cent of the administered dose, whereas essentially all of the erythromycin and all of the metronidazole are absorbed. Thus, it can be argued that the oral method may offer an advantage because of absorption of antibiotic, thereby providing both sterilization of the bowel and protection of the parenteral tissue. In one study, addition of a parenteral agent to an oral antibiotic regimen failed to lower the infection rate more than could be accomplished with an oral antimicrobial preparation alone. 5 However, timing for administration of the parenteral antibiotic did not seem to be appropriate for the operative interval. Another study, in contrast, demonstrated that parenteral antibiotics begun before operation significantly reduced infection rates

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despite the routine use of the oral antimicrobial preparation. 24 Keighley et al. compared oral kanamycin plus metronidazole with the same agents given parenterally at the appropriate time intervals. 14 All patients had been prepared by an excellent mechanical cleansing regimen. Postoperative sepsis occurred in only 7 per cent assigned to receive parenteral antibiotic prophylaxis; an infection developed in 36 per cent of those managed by the oral antimicrobial preparation. Bacteria causing the postoperative woundrelated sepsis were almost always resistant to the antibiotics used and appeared to have been selected out by just a few hours of oral therapy. Thus, the expeditious parenteral administration of antibiotic so that protected tissue concentrations can be achieved before bacterial challenge is apparently the most important step of all. Although both the oral and parenteral techniques are excellent alone, an adequate amount of antibiotic must be absorbed from the intestinal tract to provide the necessary protection. Should resistant strains evolve, the physician must only rely on the parenteral route of administration.

CLOSURE OF THE WOUND Various techniques have been advocated for closure of the skin and subcutaneous tissue. When there has been significant contamination, infection rates of superficial wounds can be reduced to the 10 to 15 per cent range, either by carrying out a delayed primary closure 23 • 29 or by instillation of antibiotic directly into the wound. 17• 19• 23 However, with appropriate mechanical cleansing of the intestinal tract and with the timely use of parenteral, or oral antimicrobial agents, or both, the infection rate for a primarily closed wound seldom exceeds a 5 per cent. Accordingly, these special techniques for managing the skin and subcutaneous tissue do not appear to be applicable in the elective case of colon surgery unless fecal matter has spilled from a poorly prepared colon or unless a preoperative dose of prophylactic antibiotic has been omitted. Topical Antimicrobial Agents Of the various antimicrobial agents that might be applied topically into the wound, povidone iodine (Betadine) has been quite popular, yet little objective evidence can be found to substantiate its use. 7• 8• 21 Indeed, objective studies in man advocate its abandonment rather than its continued use. The efficacy of topical application of antibiotic, on the other hand, has been often noted. 12• 17• 19• 23 In two trials, topical therapy was equal to preoperative parenteral prophylaxis with the same antibiotic. 17• 19 One of the critical factors appears to be the ready diffusibility of the agent. Antibiotics poorly bound to protein seem to be the most effective. · Whether it is more important for the agent to be active against anaerobes than against aerobic species is as yet unsettled. Some very convincing studies have stressed a need for anaerobic coverage alone. 31 Nevertheless, the only clinical trials to compare an antibiotic having primarily an anaerobic spectrum of activity (clindamycin) with one having

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one good aerobic and only poor anaerobic coverage (cephaloridine) clearly demonstrated a superiority for the agent directed against the aerobic pathogens in the polymicrobial flora. 12

INFECTION Bacteria that contaminate the wound and peritoneal cavity because of a spill from the opened colon comprise both aerobic and anaerobic species. 2• 3• 11 • 25 Although a culture may fail to grow either set, primarily because of antibiotics in intestinal secretions, or wound exudate, or both, at least 102 to 106 can be demonstrated if techniques are used to inhibit antibiotic influence. Approximately 90 per cent of the bulk of stool is composed of live and dead bacteria; 90 to 95 per cent of these microbes are anaerobic species. Mter the use of oral antimicrobial agents, the major pathogens that can be isolated from the large bowel are primarily aerobic Gram-positive cocci. Staphylococcus aureus and the enterococcus are the major contaminants. Such bacteria account for many of the postoperative infections in which there is no anaerobe participation. 14· 25· 27 Selection of Antibiotics Aerobic pathogens, particularly the Gram-negative rod, present the greatest threat to patient survivaL 3 • 26 Accordingly, this threat must make the selection of antibiotics a major consideration. With this purpose in mind, surgeons have preferred the aminoglycosides as well as the advanced generation cephalosporins. Unfortunately, one of the major drawbacks of the aminoglycoside group of antibiotics is nephrotoxicity, which can be noted in approximately 5 to 10 per cent of surgical patients treated with this agent. 1· 26 The addition of a hypovolemic state, or a loop-active diuretic, or both appears to increase the risk significantly. For this reason, the advanced generation cephalosporin antibiotics have appeared to offer a unique alternative. In a prospective, randomized trial, there was at least equivalence between several of the third generation cephalosporins (cefotaxime, moxalactam, and cefoperazone) with one of the standard aminoglycosides (gentamicin). 27 Other problems related to aminoglycoside use include the need to increase the dose in the hyperdynamic patient, for standard regimens seldom provide effective blood levels. Thus, both to avoid toxic trough levels and to maintain effective therapeutic concentrations at the peak, one must run almost daily determinations of serum aminoglycoside concentrations. Some test of renal function must also be obtained at least every other day to avoid unnecessary accumulation of the antibiotic, which is primarily excreted by glomerular filtration. Careful analysis of clinical and laboratory data consistently fails to document a reduction in mortality whenever antibiotics active against the anaerobic flora are incorporated into the treatment program. 3 • 27 The striking benefit of such agents appears to be a reduction in the incidence of recurrent sepsis, most notably the postoperative infection developing in

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the surgical incision, or the peritoneal cavity, or both. To avoid these postoperative infections, surgeons as a standard practice add some agent active against the anaerobe (clindamycin or metronidazole) with the aminoglycoside. 2 • 3 • u, 31 Significant decreases in postoperative sepsis have been recorded because of these various antibiotic combinations. Nevertheless, the undesirable aspects of aminoglycoside use become the major drawback. As with therapy directed against the aerobic component, third generation cephalosporins also offer a variable spectrum of activity against the anaerobe. In prospective studies, the incidence in postoperative sepsis was significantly reduced to the same degree when a third generation cephalosporin, such as cefotaxime or moxalactam, was used on comparison with clindamycin. 27 In the very near future, there will be a reversal in which antibiotics are selected for prophylaxis and which will be used for therapy. Single dose or short courses of aminoglycosides carry no risk of renal damage, provide an adequate interval of protection because of a long half-life, diffuse readily into tissues when applied topically because of low protein binding, and have reliable activity against the aerobic pathogen, which indeed might be the most important component in prophylaxis. The third generation cephalosporin, on the other hand, has proven reliability in therapy and eliminates the risk of nephrotoxicity as well as the need for multiple drug therapy. It is interesting how the development and initial major use of each set of these antibiotics are somewhat opposite of what appears to be their future role. Cost Infection of the wound, or peritoneal cavity, or both is more common after operations on the colon than for any other elective surgical procedure. In a two-year study ending in 1975, it was estimated that the average cost of such an infection was $2700.00. With present day inflation, this has probably increased to more than $5,000.00 per single infected case. With a lO percent infection rate representing the best result obtainable with colon preparation excluding antibiotic use, there is at least an additional $500.00 expenditure per patient at risk. Thus, efforts directed toward limiting unnecessary health care expenditure appear to be most worthwhile for the patient undergoing elective colon surgery. REFERENCES l. Appel, G. B., and Neu, H. C.: The nephrotoxicity of antibacterial agents. N. Engl. J. Med., 296:784, 1977. . 2. Barlett, J. G., Miao, P. V. W., and Gorbach, S. L.: Empiric treatment with clindamycin and gentamicin of suspected sepsis due to anaerobic and aerobic bacteria. J. Infect. Dis., 135:S80, 1977. 3. Bartlett, J. G., Onderdonk, A. B., Louie, T., eta!.: A review: Lessons from an animal model of intra-abdominal sepsis. Arch. Surg., 113:853, 1978. 4. Clark, J. S., Condon, R. E., Bartlett, J. G., eta!.: Preoperative oral antibiotics reduce septic complications of colon operations: Results of a prospective, randomized, doubleblind clinical study. Ann. Surg., 186:251, 1977. 5. Condon, R. E., Bartlett, J. G., Nichols, R. L., eta!.: Preoperative prophylactic cephalothin fails to control septic complications of colorectal operations: Results of controlled clinical trial. Am. J. Surg., 137:68, 1979.

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6. Crapp, A. R., Tillotson, P., Powis, S. J. A., et al.: Preparation of the bowel by whole-gut irrigation. Lancet, 2:1239, 1975. 7. deJong, T. E., Vierhout, R. J., and van Vroonhoven, T. J.: Povidine-iodine irrigation of the subcutaneous tissue to prevent surgical wound infections. Surg. Gynecol. Obstet., 15$:221, 1982. 8. Firor, W. M., and Jonas, A. F.: The use of sulfanilylguanidine in surgical patients. Ann. Surg., 114:19, 1941. 9. Galle, P. C., and Homesley, H. D.: Ineffectiveness of povidine-iodine irrigation of abdominal incisions. Obstet. Gynecol., 55:744, 1980. 10. Garlock, J. H., and Seley, G. P.: The use of sulfanilamide in surgery of the colon and rectum: Preliminary report. Surgery, 5:787, 1939. 11. Gorbach, S. L.: Management of anaerobic infections: Intra-abdominal sepsis. Ann. Intern. Med., 83:377, 1975. 12. Greenall, M. J., Froome, K., Evans, M., et al.: The influence of intra-incisional clindamycin on the incidence of wound sepsis. J. Antimicrob. Chemother., 5:511, 1979. 13. Hewitt, J., Rigby, J., Reeve, J., et al.: Whole-gut irrigation in preparation for large bowel surgery. Lancet, 2:377, 1973. 14. Keighley, M. R., Arabi, Y., Alexander-Williams, J., eta!.: Comparison between systemic and oral antimicrobial prophylaxis in colorectal surgery. Lancet, 1:894, 1979. 15. Matheson, D. M., Arabi, Y., Baxter-Smith, D., et al.: Randomized multicentre trial of oral bowel preparation and antimicrobials for elective colorectal operations. Br. J. Surg., 65:597, 1978. 16. Minervini, S., Alexander-Williams, J., Donovan, I. A., et al.: Comparison of three methods of whole bowel irrigation. Am. J. Surg., 140:400, 1980. 17. Pitt, H. A., Postier, R. G., and MacGowen, W. A.: Prophylactic antibiotics in vascular surgery. Ann. Surg., 192:356, 1980. 18. Polk, H. C., Jr., and Lopez-Mayor, J. F.: Postoperative wound infection: A prospective study of determinate factors and prevention. Surgery, 66:97, 1969. 19. Pollock, A. V.: Antibiotic prophylaxis in general surgery: A comparison of single-dose intravenous and single-dose intra-incisional cephaloridine. Aktuel Probl. Chir. Orthop. 19:71, 1981. . 20. Poth, E. J., and Knotts, E. L.: Succinylsulfathiazole: A new bacteriostatic agent locally active in the gastro-intestinal tract. Proc. Soc. Exp. Bioi. Med., 48:129, 1941. 21. Sindelar, W. F., and Mason, G. R.: Irrigation of subcutaneous tissue with povidine-iodine solution for prevention of surgical wound infections. Surg. Gynecol. Obstet., 148:227, 1979. 22. Stone, H. H., Haney, B. B., Kolb, L. D. et a!.: Prophylactic and preventive antibiotic therapy: Timing, duration, and economics. Ann. Surg., 189:691, 1979. 23. Stone, H. H., and Hester, T. R., Jr.: Incisional and peritoneal infection after emergency celiotomy. Ann. Surg., 177:669, 1973. 24. Stone, H. H., Hooper, C. A., Kolb, L. D., et al.: Antibiotic prophylaxis in gastric, biliary, and colonic surgery. Ann. Surg., 184:443, 1976. 25. Stone, H. H., Kolb, L. D., and Geheber, C. E.: Incidence and significance of intraperitoneal anaerobic bacteria. Ann. Surg., 181:705, 1975. 26. Stone, H. H., Kolb, L. D., Geheber, C. E., et al.: Use of aminoglycosides in surgical infections. Ann. Surg., 183:650, 1976. 27. Stone, H. H., Strom, P. R., Fabian, T. C., eta!.: Third generation cephalosporins for polymicrobial surgical sepsis. Arch. Surg., (in press). 28. Taylor, E. W., Bentley, S., Young, D., et al.: Bowel preparation and the safety of colonscopic polypectomy. Gastroenterology, 81:1, 1981. 29. Verrier, E. D., Bossart, K. J., and Heer, F. W.: Reduction of infection rates in abdominal incisions by delayed wound closure techniques. Am. J. Surg., 138:22, 1979. 30. Washington, J. A., II, Dearing, W. H., Judd, E. S., et al.: Effect of preoperative antibiotic regimen on development of infection after intestinal surgery: Prospective, randomized double-blind study. Ann. Surg., 180:567, 1974. 31. Willis, A. T., and Jones, P. H.: The prophylactic role of metronidazole in colorectal surgery. In Proceedings of the Second International Symposium on Metronidazole, Geneva 25--27 April 1979. Royal Society of Medicine, 1979, p. 137-148. Emory University School of Medicine 69 Butler Street, S. E. Atlanta, GA 30303