Contributions of alimentary tract surgery to modern infection control

PRESIDENTIAL ADDRESS

Contributions of Alimentary Tract Surgery to Modern

Infection Control

Hiram C. Polk, Jr., MD, Louisville, Kentucky

My respected predecessors in this address often chose to focus their dissertations on diseases directly arising in the alimentary tract or the treatment thereof. Such analyses have both classified the state of the art and addressed important new issues that both directly and indirectly influence the practice of general surgery and the management of related problems. I will direct my comments toward the unique contributions of alimentary tract operations to the modern understanding of infection control in the surgical patient. It is the special characteristic of operations on the alimentary tract that they provide a setting in which specific, clinically useful questions can be answered. They will continue to provide a laboratory for meaningful clinical assessment of a variety of infection control measures.

Historical Perspectives

The transition from Listerism to applied asepsis took place at the turn of this century, and the latter has been broadly accepted as the fundamental mea- sure of value to the surgeon and his patient in operations on the alimentary tract. Contrary to the theme of this address, it is the “clean” operation that best characterizes the degree to which asepsis is being achieved and provides the best possible standard for assessment of personal and institutional discipline. Simply stated, the sources of infection in the patient undergoing a clean operation, that is, one not contaminated by the contents of the alimentary tract, are such that sterilization, aseptic technique, personal discipline, and quality control are crucial. Infection rates for such procedures continue to be the best method by which an institution can assess practices and performance in these many areas, in-

From the Department of Surgery and Price lnstrtute of Surgical Research, Unwersity of Louisville School of Medtcrne, Loursville, Kentucky

Requests for reprints should be addressed to Hiram C. Polk, Jr., MD, Department of Surgery, Unwersity of Louisville School of Medrclne. Louis- ville, Kentucky 40292

Presented at the 27th Annual Meebng of the Society for Surgery of the Akmentary Tract, San Francisco, California, May 20-21, 1988

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eluding the ultimate expression of technical finesse. However, it is the very success of these practices that has rendered the clean operation unlikely to provide additional data about the value of further adjunctive measures [I]. When the clinical wound infection rate reaches 1 to 2 percent, the statistical likelihood of identifying further advances becomes remote. Those interested in more complex problems of infection control rapidly recognized operations on the alimentary tract as a suitable laboratory for further study.

The unique role of alimentary tract surgery in the modern concepts of infection control: Un- like some of their scientific descendants, even to this day, early practitioners of complex surgery on the alimentary tract recognized that there was a substantial and continuing problem with infection in the incision itself and in the peritoneal cavity, either as peritonitis or as intraabdominal abscess formation. A number of measures were undertaken to minimize the-likelihood of these problems.

Antimicrobial Chemotherapy

The chronicles of the curious interaction between and different emphases provided by Alexander Fleming and Howard Florey are, to whatever extent possible, now a matter of historical record [2,3]. Clearly, they, among others [4], contributed to the identification and understanding of potent antimicrobial agents. Curiously enough, it was the oral application of such agents to reduce the density of bowel flora that first came under intense and pro- ductive study. Although the clinical analogy may be farfetched, it was the rather remarkable experiments of Edgar Poth and his colleagues that first illuminated these processes. Taken in their simplest forms, Poth’s work indicated that isolated small bowel loops are most likely to remain viable and that the host animal survives when the density of intraluminal bacteria are reduced by the administration of a poorly absorbed sulfa compound before deliber-

The American Journal of Surgery

ate interference with blood flow [5]. The exact process by which this set of clinical experiments was extrapolated into broad clinical use has not been precisely defined.

Inquiries as to this sequence of events have produced remarkably fresh insights into what actually happened. Mark Ravitch wrote:

My recollection of the way the whole thing developed was that there was a guy in one of the pharmaceutical houses,. whichever one it was that had sulfaguamdme, [who] was a good friend of Monty Firor’s and wanted Monty to try these things out and Monty got Ed Poth to work on them. Poth was very convincing in his studies of the effect on thk bacterial content in the stools of does. the decrease in the bulk and the weight-as the organisms practically disappeared from the stools. I was on the house staff in those days, of course, and my recollection was that we were all simply convinced that if you are so strikingly reducing the bacterial content of the feces, it had td be better for the patients and that the clinical use was undertaken almost at once...my recollection [was] that the mortality of anastomoses in the colon had been about 14 nercent at the Johns Honkins before then and dropped down sharply.*

Isidore Cohn responded to our inquiry saying: Most of the information I can give you regard- ing the rapid acceptance of intestinal antisepsis is probably based on conjecture, though some of it can be documented by reference to dates and places in the literature.

Part of it can be related to the time in which all of this occurred. The sulfonamides were very new to this country in the late 1930s and earlv 1940s and were the first real antimicrobial; that any of us knew. They were touted as being the answer to all problems in infection, and since everybody was eager to accept any new miracle drug - then as now - people went overboard. Then came the war, and ap- parently immediately after Pearl Harbor, Dr. Ravdin and a group were dispatched to Pearl Harbor to see whether or not local use of sulfonamides would be effective in the management of burns, infections, and other similar problems. Dr. Ravdin’s prominence no doubt contributed to the rapid and widespread use of anything that would lower the infection rate.

Another factor must deal with certain people and their “positions of prominence,” with Firor and Poth at Hopkins, Ravdin at Penn- sylvania, Fine and his group in Boston, and then the report by Garlock and Seley in 1939 [6] of the specific use of sulfonamides for intestinal antisepsis. The race was on. This meant that there were clearly supporters of antimicrobials for controlling infections in gastrointestinal surgery in Boston, New York, Philadelphia, and Baltimore, then probably considered the meccas of surgery in this country.

And finally, I suppose one must consider the problem of priority. According to my reading of the literature, Garlock and Seley were the first to present a report in a major

journal in English of the use of intestinal sepsis. Ravdin, I believe, claimed priority in the actual use of the agents but I do not think he documented this in the literature.

Claude Welch provided some similar insights: In a word, I would say that the rapid acceptance of these preparations was due to several factors: (1) antibiotics were proved to be valuable in other fields of surgerv: (2) World War II played an important r”ole’ & popularizing antibiotics; (3) as soon as oral preparations for use in colon surgery appeared, many leaders in American surgery supported them strongly; and (4) drug manufacturers pro- moted them vigorously.

World War II stimulated the demand for antibiotics; both doctors and soldiers partici- pated. At the time, all soldiers were given a package of sulfadiazine to sprinkle in their wounds. Thus all of the troops, when they returned home, had already been indoctri- nated with the belief that antibiotics were excellent. In fact, many endowed them with an almost mystical significance and found that they were as effective as many Hail Marys. Thus, the public became acquainted with and supported the use of antibiotics.

After Edgar Poth presented his material before the American Surgical Association in 1941, there continued to be doubting Tho- mases for a long period of time... However, other leaders of the profession accepted Poth’s work almost immediately. My revered former chief, Dr. Arthur Allen, in a presenta- tion before the Southern Surgical Association in 1946, indicated that at that time, we were using sulfathalidine, 8 g daily for 5 days, pre- ceding elective colon surgery. Hence, word of the value of antibiotic preparations had spread rapidly.

As noted, Path’s thoughtful and unchallenged experiments were rapidly transformed into clinical practice by means of first 5 day, then 4 day, then 3 day, then 2 day, and now 1 day regimens for the administration of oral antibiotics, which in general, were absorbed poorly or not, at all. The principle involved reduction of the intraluminal bacterial density, intending that whatever fecal material was spilled at operation would have fewer bacteria and be less likely to produce operative wound infection or the other complications already noted herein.

Perhaps as much as anyone, the personal laboratory and clinical studies of our past president, Isi- dore Cohn, converted this practice into catechism and provided a strong basis for the regular utilization of oral antimicrobial agents in conjunction with mechanical preparation before elective operations on the lower alimentary tract [7J. Despite such en- dorsement, Cohn was among the most persistent in reminding surgeons that intestinal sterilization was never approached in human subjects, and that the best regimens produced only 2 or 3 log reductions in colonic flora. Curiously enough, it was a very long time until the studies of Washington et al [8] finally proved on a clinical and sound scientific basis that

Volume 153, January 1997 3

Polk

oral neomycin and tetracycline were more effica- cious than placebos, both in terms of control of operative wound infection and death due to such infection. It is interesting that in the discussion of their definitive paper before the American Surgical Association, William Altemeier, the premier Ameri- can surgical microbiologist, questioned how much of the effect might be due to the systemic absorption of allegedly nonabsorbed drugs [9]. Indeed, DiPiro et al [IO] have recently provided further evidence of absorption of a significant component of the popu- lar neomycin and erythromycin base combination that provides serum levels compatible with antimicrobial activity. One can only wonder how much of the apparent efficacy of this combination is related to its ability to inefficiently, but finally, achieve the practical goal of systemic antibiotic prophylaxis, that being the circulation of antimicrobial activity, which produces effective wound antibiotic levels.

A similar line of evidence, which is very close to Poth’s original experiments, is the consistent data indicating that when a patent inferior mesenteric artery must be sacrificed in the course of abdominal aortic aneurysmectomy, clinically significant ischemic changes in the left side of the colon are more uncommon when oral, poorly absorbed antibiotic bowel preparation has been used [II]. The aneu- rysm patient and his colon are well served by preoperative antimicrobial bowel preparation.

It is clear that certain highly specialized situa- tions continue to show oral antimicrobial bowel preparation in the best light. Herter and Slanetz [12] were the first to point out the value of such preparation directed toward aerobic bacteria in an- terior resections, a value that could not be confirmed for ileocolic or colocolic anastomoses.

More recently, there has been a remarkable emphasis on the role of anaerobic bacteria in infection after operations on the colon and rectum. The im- portance of this role may or may not be valid, but there is no question that the contributions of anaerobic bacteria to infections in surgery and medicine in general were underestimated before the widely publicized discoveries of medical witnesses who professed the wonders of antimicrobial therapy directed toward anaerobic bacteria [13,14]. Further- more, there have been few, if any, critical examina- tions of substantially misleading animal models of intraabdominal infection. The model most widely quoted has no parallel in clinical illness; furthermore, the value judgment that intraabdominal abscess formation is a bad outcome, rather than a favorable sign, has likewise not been confirmed in human disease or in long-term follow-up of the animal model itself. Notwithstanding my firm convic- tion that this emphasis is overrated, it is now common practice to attempt to prepare the colon of the patient undergoing elective operation on the colon with a combination of mechanical cleansing and

antibiotic agents directed toward both the aerobic and anaerobic components of common bowel flora. Although it is a very long way scientifically from positive intraoperative cultures to the presence of subsequent clinical infection, this is common practice, and we can only share de Gaulle’s sentiments in saying that 50 million Frenchmen cannot all be wrong. As they have done so often, Stone et al [15] contrasted the relative prevalence of anaerobic bacteria in specimens obtained at the time of operation and their comparative infrequency in the inoculum of subsequently significant clinical infection.

Needless to say, anaerobes are commonly considered very important. Whether one happens to think erythromycin base, clindamycin, or metronidazole is the most appropriate agent for dealing with these organisms, their use is so prevalent it approaches orthodoxy. There is, of course, little evidence to suggest whether the pure aerobic regimen of kana- mycin is better or worse than the broadly used neomycin and erythromycin base. As a matter of fact, newly published well-controlled data show that parenteral ceftriaxone and metronidazole are superior to oral neomycin and erythromycin base in elective operations on the colon and rectum [16].

The sole clinically proven value of adding specific anaerobic therapy to ordinary aerobic antibiotic coverage seems to be complicated appendicitis, as documented by Berne et al [17] and by Donovan et al [18]. The very specificity of these observations is curious, but the evidence is not faulty.

Stone and others [19,20] indicated that it may be sufficient to kill either the aerobic or anaerobic component of the infection, and in the absence of one or the other, infection seldom, if ever, progresses. Giv- en this situation, the substantially lesser toxicity associated with agents directed toward aerobic bacteria would justify their utilization in preference to the substantially more toxic agents that are regularly recommended for use in prophylaxis of anaerobic infection. Once again, irrespective of one’s political preferences, it is operations on the alimentary tract and illnesses arising from them that have crystal- lized this significant debate and will, no doubt, allow for its ultimate clarification.

The issue of systemic antibiotic use to prevent surgical incisional infection, of course, is a relatively old one. Given the immediate acceptance of intestinal antisepsis, exactly why it took so long for the precisely defined laboratory concepts of administration of the systemic agent before bacterial contamination is hard to fathom, and perhaps it is no longer pertinent. On the other hand, the laboratory evidence supporting that concept was unequivocal [21] and, indeed, a few clinicians began to challenge the curious concept of waiting until after the operation was over to begin preventive treatment [22]. Once again, the alimentary tract and operations thereon provided the best climate for assessing this

4 The American Journal of Surgery

Presidential Address

concept. We were fortunate to be able to initiate the first fully controlled trial of this process and found that systemic cephaloridine, administered just before operation and then again immediately after operation in two additional doses produced a highly statistically significant reduction in incisional infection [23]. Other antimicrobial agents were withheld and all known risk factors were similarly distributed between the placebo and drug groups. This control of incisional infection was seen in every subgroup of operation studied, including operations on the esophagus, stomach, duodenum, small bowel, and colon.

The stomach, perhaps, is worthy of discussion separately because in this particular patient popu- lation, a relatively high proportion were being oper- ated on for gastric ulcer, gastric cancer, or both, and it may be that this was not fully representative of gastric operations as a whole. Present thoughts, of course, suggest that patients who have normal gastric acidity have relatively low infection rates after procedures in which the stomach is opened. Pa- tients with gastric ulcer, gastric cancer, or bleeding or obstructing duodenal ulcers are at a genuinely high risk, and will benefit from systemic antibiotic prophylaxis [24,25]. When Hz antagonists have been administered therapeutically, the infection rate tends to climb, and when the operation is performed in the presence of little or no gastric acid, major increases in infection rates do occur [26].

The reasons why alimentary tract operations were initially selected for antibiotic trial are clear. One needed to be certain that what was being studied was a group of operations in which infection was sufficiently common as to make any differences in preoperative preparation, including antibiotic coverage, meaningful. Clearly, even using the best possible mechanical methods of preparation, infection occurred in between 10 and 25 percent of patients undergoing elective operations of that type, and there was every likelihood that if the antibiotics indeed would make a difference, one could show it with a reasonable number of patients in a single trial and in a single institution. This, of course, proved to be the case and those observations have now been confirmed by nearly 300 published reports in the English language literature [27-291.

Antibiotic Wound Activity

The concept now prevalent is that the antibiotic administered systemically before operation suf- fuses the operative incision and causes a wound to be more resistant than usual to bacterial contamination. In addition, it is hoped that normal local defenses are enhanced by the presence of additional antibiotic in the surgical wound [23]. Specifically, it is the level of antibiotic at the wound site that means everything; levels in the serum relate only indirectly

and imperfectly to levels in the wound. For example, cephalothin, a widely used drug and the first to be approved for prophylaxis by the Food and Drug Administration despite widespread reports of its clinical failure, produced relatively high levels of antibiotic in the serum and high levels in the wound, but the wound levels persisted for such a short time that virtually no antibiotic activity of a meaningful degree was present by the time the potentially contaminated alimentary tract operation was terminat- ed 2 to 3 hours later [30]. In retrospect, we now realize that, had that agent been given by continu- ous infusion, we may have been able to alter these characteristics and provide clinically significant protection. On the other hand, so much hindsight is exactly hindsight, and the decision to pursue agents with more favorable wound levels, such as cephaloridine and cefazolin, followed in predictable fashion. Cefazolin is the subject of several studies which indicate that its period of wound protection is only approximately 2 hours and that if a procedure is going to last significantly longer than that, the patient surely should receive another dose during the operation [31]. Supplementary protection may also be required when cefoxitin is utilized for colorectal operations of long duration [32].

This issue of wound antibiotic activity in alimentary tract operations continues to be important. We are now seeing a sequence of reports that stress the value of a single preoperative dose of some agents for prophylaxis [33,34]. The crucial proposition is that they are being studied in a randomized, prospective, controlled fashion, are being reported in the refereed literature, and the drugs in question generally have very substantial durations of activity within the operative wound. Once again, the operation in which a portion of the alimentary tract is opened, creating a wound with a high bacterial density, provides a virtually perfect clinical model for the assessment of wound antibiotic activity [35].

One cannot venture very far into the area of systemic prophylaxis without facing the creditable issue of an appropriate antibiotic spectrum. Indeed, there is a choice of multiple agents with a relatively broad spectrum, single agents inevitably with a somewhat narrower spectrum, or both. It must be kept in mind that although a broader spectrum of protection may be achieved, it could be at the direct expense of using agents that are often multiple and of greater risk to the patient. The first premise of effective prophylaxis is low risk, and as the number of drugs and their complexity increases, one is faced with a situation in which the therapeutic ratio may be inverted, that is, the risk of the agents being used for prophylaxis may exceed the likelihood of the complication to be avoided, that being surgical wound infection. The vast majority of studies continue to focus on single-agent systemic prophylaxis and accept certain gaps in the spectrum in return for


Polk

the remarkable apparent safety of most cephalospo- rins and semisynthetic penicillins.

It is both logically appealing and widely practiced to utilize a combination of oral antimicrobial agents to minimize the number of the bacteria in the lumen of the alimentary tract and systemic drugs to heighten the resistance in the operative wound itself because the effect should be, if not synergistic, at least additive. Curiously, the great weight of evidence indicates that we have not been able to clinically prove that concept yet. In other words, it ap- pears that infection may be reduced to the range of 5 to 10 percent after operations on the colon with either a selected oral antimicrobial preparation package or by systemic drugs, but the administration of both does not seem to provide a further reduction. The report of Coppa and associates [36] is a pertinent exception. It shows that parenteral cefoxitin added to oral neomycin and erythromycin base produced lower infection rates than did the oral agent alone. It may be that what is needed is simply a large enough series of patients in a properly constructed trial to prove this additive effect. Once again, standard operations on the alimentary tract provide the ideal environment to clarify such issues.

Local Measures

In terms of further clarifying the issues involved in operative wound infection, one inevitably may also choose other methods to reduce the contamination or heighten the resistance in the wound. The logical appeal of the new generation of wound pro- tectors is considerable, and although they are not amenable to blinded trials, it does seem likely that they reduce the number of bacteria that reach the subcutaneous fat [37]. Furthermore, the use of topical antibiotics in such wounds has been recommended in innumerable studies [38], many of which are relatively well designed. On the other hand, whether there is a clinical use for topical antibiotics in addition to systemic ones has not been clearly defined. In fact, the best work of this sort seems to be from two different groups who have worked in my laboratory, Galland et al [39] and Bergamini et al [40]. Both groups have suggested that there is an additive effect when a topical antibiotic, antiseptic, or both is used in combination with systemic drugs only when the degree of bacterial contamination in the operation is severe. No additional protection is afforded when contamination is less severe.

Although their work did not differentiate between the contributions of systemic and local ef- fects, Dixon and associates [41] found the preincisional use of cefamandole to be more protective than the same agent administered parenterally, suggesting a “best of both worlds” local effect followed by whatever protection attends systemic absorption of the same agent. Armstrong et al [42] and Taylor and associates [43] have reported similar

methods to be effective with both cefamandole and cefoxitin.

It is noteworthy that the alimentary tract struc- ture and system most often requiring operation have been relatively difficult to analyze in this process. We chose, and I think correctly at the time, to exclude biliary tract operations from our original trial, because we realized that infection after some complex biliary tract operations was quite prevalent but after simple cholecystectomy, it was relatively rare [I]. It took the leadership of Chetlin and Elliott [44] to clarify this. In a fairly simple analysis, they showed that persons over the age of 70, patients with subsiding acute cholecystitis, and patients undergoing common duct exploration for various reasons constitute three groups in which bacteria are present in the bile in nearly 50 percent of the patients and in which the patients are vulnerable to postoperative infectious complications. Accordingly, the researchers administered systemic antibiotic prophylaxis to these high-risk biliary patients, once again using cephaloridine in exactly the dose regimen we had outlined for such patients, and showed a statistically significant reduction in infection in a randomized, prospective, but not blinded, trial. There have been several attempts to improve upon this segregation of high-risk and low-risk patients [45,46], but these attempts have yet to be successful. Antibiotic prophylaxis in the biliary tract ought to be confined to those patients who meet the published criteria.

lntraperitoneal Antibiotics

Current standard clinical practice utilizes vari- able-spectrum systemic antibiotics given parenterally as soon as the diagnosis of peritonitis is strongly suspected or confirmed [47]. Despite this practice, peritonitis continues to bear major infectious mor- bidity and mortality rates [48,49]. Logical appeal and much experimental data suggest that a wiser course might involve the intraperitoneal administration of antibiotics in addition to, or in lieu of, systemic agents. Surely, an agent or agents so administered would first attack the site of sepsis and then be absorbed through the inflamed peritoneum into the circulation, which is a more appealing plan than that currently practiced as the latter depends on a reverse pattern of drug diffusion.

Intraperitoneal antibiotic use represents the last real surgical frontier and demands a properly strati- fied, randomized clinical trial; however, there are real problems with such a trial: supplementary systemic therapy; proper stratification of disease, duration, and associated illnesses; duration and spectrum of intraperitoneal chemotherapy; relative role of peritoneal lavage; and, no doubt, others as well. The nonrandomized experience with intraperitoneal agents for severe peritonitis is impressive. Schat- ten [50], Noon et al [51], and McMullan and Barnett

6 The Amerlcsn Journal of Surgery

Presidential Address

1521 described very favorable responses to treatment. Most persuasive was the consecutive trial reported by Stephen and Loewenthal [53] of con- ventional systemic therapy versus application of intraperitoneal antibiotics with peritoneal lavage (1 liter/hour) for 3 days in patients with severe peritonitis. The outcomes of the two forms of treatment were very significantly different. A major prospective test of the efficacy of intraperitoneal antibiotic is needed.

Intrinsic Risks and the Challenge of Progress

Advances, notably those that involve antibiotic chemotherapy, have borne subsequently defined risks, such as the drug-resistant Staphylococcus, antibiotic-induced bacterial enterocolitis, Clostrid- ium difficile colitis, and the overt ototoxicity and nephrotoxicity of some drugs. It requires a biologi- cally wise surgeon to examine the evidence and to consistently select the more effective and less dan- gerous course. Current obsessions with cost contain- ment further complicate the choices. Clearly, peri- operative systemic antibiotics in legitimately high- risk alimentary tract operations are the best defined of such cost-responsive surgical trends [54]. It is even more clear that additional therapy and broader-spectrum antibiotic coverage are by no means better!

As great a challenge as the definition of clinically meaningful truth in this complex field is the need to disseminate and regularly implement those princi- ples elucidated by randomized, prospective clinical trials. Condon et al [55], Fry et al [56], and Gardner et al [571 have demonstrated that this is far more difficult than one might wish.

The challenge offered to our successors in both alimentary tract surgery and other areas of surgery who battle with infection is far more daunting than that which we have inherited, those being Listerism and sepsis, facile and secure technique, antibiotic prophylaxis and therapy. Further advances in understanding and practice will require much more discriminating laboratory and clinical inquiries. What is the role of specific active and passive immu- nization? Can we truly enhance nonspecific host defenses? When these and other surgically pertinent questions have been answered, I believe that the lion’s share of the work will have been done by the informed and inquiring general surgeon.

Summary

The continuing contributions of alimentary tract operations to a clarification of the clinical utility of devices, procedures, and medications for control of surgical wound infection have been crucial to the advancement of modern surgical practice. Indeed, the foregoing essay has outlined several areas in which additional analysis and clarification should

be able to further define valuable methods and com- binations thereof. It has been the willingness of the individual surgeon oriented to the alimentary tract to include his operations and his patients in these kinds of rigid trials that have, indeed, allowed a final emergence of these useful adjuncts to the surgical armamentarium, an effect that now pervades all surgical practice.

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Contributions of alimentary tract surgery to modern infection control