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Antibiotics in surgery
Antibiotics in Surgery An Overview
Donald E. Fry, MD, Albuquerque, New Mexico
Despite an ever-increasing armamentarium of antibiotics and improved culture-sensitivity testing methodologies, infection in the surgical patient continues to be a major source of morbidity. Infections occur as complications at the surgical site, and nosocomial infections are troublesome problems for many patients in the postoperative period. Infection itself may be the reason for operation in the surgical patient, particularly in soft tissue and in the intraabdominal cavity. Better adjunctive measures are necessary to assist the surgeon in treating the many complex infectious problems that complicate surgical care. Antibiotics have become important adjunctive treatments. Two areas of special concern for antimicrobial selection are surgical chemoprophylaxis and how to treat the patient with established polymicrobial infection. Antibiotic selection in both examples is usually empirical in that anticipated pathogens govern treatment choices rather than specific culture data. Antimicrobjal selection in these two particular areas certainly represent the majority of antibiotic usages for the surgeon and the surgically related specialist. This review of antibiotic usage in surgical infection will center principally on surgical chemoprophylaxis and polymicrobial infections. I will focus on the biologic characteristics of disease, the data base that justifies the use of antimicrobials, and the selection criteria that should be employed. Preventive Antibiotics
Since the 19th century pioneers Semmelweiss and Lister, physicians have attempted to use chemicals to reduce the infectious complications attendant to From the Department of Surgery, University of New Mexico School of Medicine, Albuquerque, New Mexico. Requests for reprints should be addressed to Donald E. Fry, MD, Department of Surgery, University of New Mexico School of Medicine, 2211 Lomas Boulevard NE, Albuquerque, New Mexico 87131.
Volume 155 (5A), May 31, 1988
procedures. These early efforts with antisepsis were somewhat successful. Semmelweiss employed handwashing with hypochlorite solutions to reduce postpartum infections in the female genital tract, and Lister used carbolic acid to reduce the numbers of bacteria that might potentially contaminate the amputation wound. With the introduction of antibiotics into clinical medicine in the 1940s, many physicians believed that these drugs would prove effective in the reduction of surgical site infections after operations. Initial studies created considerable disillusionment, as antibiotics were not only shown to be ineffective but, in some reports, patients receiving preventive antibiotics actually had higher wound infection Fates than did placebo-treated patients (Table I) [1-
3]. The shortcoming of many of these initial efforts in antimicrobial prophylaxis for the surgical patient stemmed from a failure to appropriately stratify patients for risk variables associated with infection as an adverse outcome. Relatively clean procedures, such as those for inguinal hernia, were compared with operations where major intraoperative contamination was likely (such as colon resection). Wound classification: The ultraviolet light study in 1964 subsequently demonstrated the significance of appropriate risk stratification in surgical site infection [4]. This study clearly demonstrated that surgical wound infection was a consequence of intraoperative contamination and that the magnitude of intraoperative contamination dictated the probability of infection. A classification system was proposed to allow for stratification of risk. Although many different classification schemes are available, surgical procedures can be broadly categorized into two major groups: clean and contaminated operations. Clean procedures are those where the quantity of bacterial contamination is small and where adjuvant factors commonly convert an otherwise subinfective inoculum of bacteria 11
Fry
into a clinically significant one. These procedures do not involve heavily colonized areas of the body such as the colon or the female genital tract. The major sources of bacterial contamination are the patient's skin, the operating room environment, and the surgical team. Pathogens are usually gram positive, and infections occur in less than 2 to 3 percent of patients given that an appropriate aseptic technique is carried out. Although preventive antibiotics have been shown to be of value in certain clean procedures, such as peripheral vascular reconstruction, surgical technique has had the greatest impact on wound infection rates in this group [5]. Those technical considerations refer not only to asepsis but to the reduction of adjuvant factors--for example, hemoglobin, foreign bodies, dead tissue, and dead space--that foster bacterial infection. The second broad category of surgical wounds are contaminated procedures. These include procedures where heavily colonized areas, gross contamination, or active infection are encountered. Such contamination is polymicrobial, with aerobes, anaerobes, and both gram-positive and gram-negative bacteria all potential pathogens. Infection is frequently related to the endogenous inoculum that soils the wound, with environmental factors being less significant. In the absence of specific preventive measures, infection rates range between 10 and 50 percent in contaminated procedures. Effective antimicrobial preventive measures have their greatest utility in these types of operations. Timing of antibiotic administration: A second consideration that resulted in the failure of chemoprophylaxis with antibiotics in the early clinical trials was the lack of consistency in the timing of antibiotic administration. Antibiotics were commonly not initiated until after the procedure was completed and the drugs were then continued for many days into the postoperative period. Experimental studies by Miles et al [6] demonstrated the importance of the timing of antibiotic administration. In an experimental model of cutaneous infection, they showed that antibiotics given before bacterial contamination significantly decreased the magnitude of cutaneous infection when 9compared with control lesions. Antibiotics given after bacterial inoculation were progressively less effective in altering the natural history of cutaneous infection such that antibiotics given 4 hours or later after contamination had no impact on the natural history of this infection model. Polk and Lopez-Mayor [7] then demonstrated the validity of these animal experiments in a prospective, randomized, double-blind study of patients undergoing elective gastrointestinal surgery. Patients who received preoperative cephaloridine versus a placebo had significantly fewer surgical site infections. It is noteworthy that patients received only two postoperative doses of the drug. Stone et al 12
TABLE I
Infection Rates ( % ) in General Surgical Patients With Respect to Timing of Drug Initiation Antibiotics Administered
Investigator
None
Postop
Sanchez-Ubeda et al [ 1] Barnes et al [2] Johnstone [3]
5.6 9.8 9
9.5 11.4 25
[8] reported that the initiation of antibiotic prophylaxis in the postoperative period resulted in no reduction of infection rates compared with placebotreated patients. Stone et al [9] also identified that 5 postoperative days of antibiotic prophylaxis offered no advantages over the conventional regimen of preoperative antibiotic administration and limited postoperative administration. The results of these experimental and clinical studies are clear. Effective systemic antibiotic prophylaxis requires that the antibiotic be present in the tissue at the time that contamination occurs, and that prolonged antibiotic administration into the postoperative period has no measurable benefit for the patient. Oral antibiotics for colon surgery: Because elective colon surgery has the greatest probability of surgical site infection, the desirability of using poorly absorbed, orally administered preoperative antibiotics to reduce the viable inoculum of contaminants during operation, in addition to mechanical preparation, has been explored. Despite testimonial speculation about the merits of certain oral sulfa or aminoglycoside preparations, Washington et al [10] first demonstrated the merits of oral preoperative antibiotic administration in the reduction of wound infection. They showed that the preoperative oral administration of neomycin and tetracycline significantly decreased wound infection after colon resection. It is noteworthy that neomycin alone was no more effective than the placebo. These investigators concluded that coverage of both aerobic and anaerobic microflora with neomycin and tetracycline, respectively, was necessary to prevent infection. Because tetracycline was not an optimum choice for coverage of Bacteroides fragilis, the tetracycline preparation in the oral bowel preparation was replaced by erythromycin base in studies by Nichols et al [11,12] and by Clarke and associates [13]. Erythromycin base has the advantage of being very poorly absorbed with subsequent high intraluminal drug concentrations, as well as being comprehensively effective against anaerobic species likely to be encountered in the human colon. An unresolved issue in the comparison of oral versus systemic antibiotic prophylaxis is whether one technique is better than the other, or whether there are potential advantages to the combination The American Journal of Surgery
Symposium on the New Cephalosporins
of the two methods. Condon et al [14] have shown the superiority of the oral neomycin and erythromycin combination to systemic cephalothin prophylaxis, and have likewise demonstrated no benefit by including systemic cepha!othin with oral antibiotic administration [15]. However, the undesirable pharmacologic properties of cephalothin are a potential shortcoming of these reports [16]. Lewis et al [17] showed no difference between systemic antibiotic prophylaxis and the oral neomycin and erythromycin preparation, although the number of patients in this study was small. Edmundson and Rissing [18] reported the superiority o f an oral intestinal preparation compared with systemic antibiotics, but they reported rates of infection in colon surgery that were effectively the same as those o f clean procedures. This latter observation has certainly not been identified elsewhere. Stone et al [8] showed additive benefits to systemic effects of combining cefazolin with an oral intestinal antibiotic preparation, whereas Hoffman et al [19] demonstrated similar benefits of systemic cefoxitin when added to an oral antibiotic preparation. Additional studies are necessary to elucidate the superiority or additive effects of these two techniques.
Polymicroblal Infection The traditional teachings of Koch's postulates have dictated that a single pathogen could be identified for each clinical infection and that the isolation of that solitary pathogen should permit inoculation into an experimental animal to recreate the infection. However, the numerous advances in the methodology of anaerobic culturing in the last several decades have identified that intraabdominal, female genital trac t , and certain soft tissue infections have an abundantly polymicrobial character where the virulence of the pathogens together is greater than would be expected from their 'individual summed virulences. Experimental studies by Onderdonk et al [20] with an intraabdominal model illustrated the bacterial synergism that exists in polymicrobial infection with both anaerobic and anaerobic participation. When experimental intraabdominal infection in the rat is created with Es= cherichia coli alone, a high mortality rate among the animals is clearly identified. However, similar inocula of enterococci, Bacteroides fragilis, or Fusobacterium varium as commonly identified isolates in murine fecal peritonitis failed to result in any mortalities or any pathologic observations, such as abscesses, when the animals were sacrificed and examined after the expected acute phase of infection. When organisms are mixed together, a different pattern of disease expression is identified. Acute mortality rates continue to be dictated by the presence or absence of the endotoxin-bearing E. coli organism. However, the presence of an oxygen-conVolume 185 (5A), May 31, 1988
suming organism and an obligate anaerobe together results in the nearly uniform presence of abscess in those surviving animals that are then autopsied. The mix of different species of obligate anaerobes without the facultative aerobic partner results in no expression of virulence. Data from our laboratory has similarly shown that B. fragilis given intravascularly or intradermally has little or no virulence [21,22]. However, the addition of sublethal inocula of E. coli to ~the B. fragilis bacteremia results in significant death rates in the experimental model [21]. E. coli and B. fragilis together in a cutaneous infectious model similarly show a synergistic effect
[22].
These data demonstrate that polymicrobial infection represents a complex synergistic and interactive relationship between the facultative aerobic and anaerobic species present in the microenvironment. Tti'e facultative aerobe consumes the oxygen in the microenvironment and maintains a reduced oxidation-reduction: potential, which optimizes growth conditions for the obligate anaerobe. As:a consequence, the anaerobe may then express its own virulence by means of various enzyme systems. The anaerobe may help to elaborate certain growth fac'tors that may accelerate the growth and prolifera: tion of its aerobic partner. Finally, B. fragilis organisms are known to have a capsular polysaccharide that may retard phagocytosis and explain the pro: pensity to form abscesses identified in t h e various animal models of intraabdominal infection [23]. The presence of this capsular polysaccharide no doubt provides protection for both the anaerobic organism and its aerobic symbiont. ', A final issue to be addressed in polymicrobial infection concerns the emerging debate over the virulence of the enterococcus. In recent years, the enterococcus appears to be identified with increased frequency in polymicrobial infection. For example, Lorber and Swenson [24] noted 0nly a 9 percent frequency of group D streptococci in'a study of intraabdominal microbiology in 1975. More recently, Stone et al [25] have noted a greater than 20 percent frequency of the eneterococcus in polymicrobial infection. Although the significance of this perceived increase in the enterococcus can be only the subject of conjecture, the prevalence of cephalosporin antibiotic usage must be viewed as a potential cause for the emergence of this organism. The potential virulence of the enterococcal organism and the necessity for specific antibiotic coverage in polymicrobial infection remain unclear. The experimental intraabdominal studies of 0nderdonk et al [20] demonstrated the synergisticrelationship between the enterococcus and the obligate anaerobe, although this may be a nonspecific relationship of any oxygen-consuming organism with an obligate anaerobe. Our own experimental data suggest a potential synergism between E. coli and the enterococ13
Fry
cus [22]. However, clinical observations have not confirmed that specific antibiotic coverage for the enterococcal organism improves the outcome of treatment in these patients [26]. Despite considerable attention and empirical recommendations for antimicrobial coverage Of the enterococcus, prospective data that demonstrate improved results with enterococcal coverage are not presently available. Thus, the virulence of this species of bacteria remains an enigma that requires further definition. Antibiotic selection: The complex nature of mi~ croflora in polymicrobial infection has generated considerable debate over the proper selection of antibiotics for these patients. At one end of the spectrum, the polypharmaceutical approach has dictated that individual drugs be given to address all organisms identified in the infection. This has resulted in quadruple drug therapy in some quarters, with four drugs being given to cover gramnegative rods (aminoglycosides), obligate anaerobes (clindamycin or metronidazole), enterococci (ampicillin), and staphylococci (vancomycin). Although this comprehensive coverage may provide the clinician with confidence that so-called coverage has been achieved, the expense and toxicity of this approach make it one of dubious value except perhaps for manufacturers of antifungal therapy. At the opposite end of the treatment spectrum, a growing c o n t i n g e n t of m o n o t h e r a p i s t s have emerged i n t h e wake of the growing technology of the expanded-spectrum cephalosporins. These newer cephalosporins with both enterobacteriacae and obligate anaerobe activity have fostered the hope that perhaps single drug therapy may replace the multiple drugs, frequent administration, pharmacokinetic dosing, risks of toxicity, and staggering costs of the polypharmacy approach. Criticisms of monotherapy have focused on the lesser activity of the newer cephalosporins against anaerobes and their near-total inactivity against the enterococcus. As just noted, the active participation of aerobic and anaerobic species in polymicrobial infection has been well established. The animal models of experimental infection used by Weinstein et al [27], Nichols et al [28], and Dunn et al [29] have demonstrated that coverage of both the aerobic and anaerobic components of the synergistic pair are necessary. Based on these experimental observations, combination therapy became the gold standard for the treatment of intraabdominal infection. Gentamicin, tobramycin, netilmycin, or amikacin are the aminoglycosides commonly employed to cover the enterobacteriacae. Clindamycin or metronidazoie have been commonly chosen as the second drug for anaerobic coverage. Potential alternative expandedspectrum cephalosporins have been studied and have been identified as providing equal results to combination therapy (Table II). The published comparative trials to this point 14
TABLE II
Expanded.Spectrum Antibiotics and Their Half-Lives (h)
Antibiotic
Brand Name
Serum Half-Life
Cefoxitin Cefotetan Cefotaxime Moxalacam Cefoperazone Ceftizoxime Ceftriaxone
Metoxm Cefotan Claforan Moxam Cefobid Cefizox Rocephin
0.8-0.9 3.5 1 2-2.3 2 1.4-1.7 6.5-8
have demonstrated some trends that are not completely conclusive. Some data have shown comparable results in polymicrobial infection rates between Conventional combination therapy and cefoxitin, cefotaxime, cefoperazone, moxalactam, ceftizoxime, and ceftriaxone [25, 30-33], One report identified poorer results with cefoperazone compared with gentamicin and clindamycin [34]. Yet another report identified poorer results with cefotaxime but good results with moxalactam compared with combination therapy [35]. Because cefotaxime and moxalactam have very different serum elimination halflife kinetics, this latter report may be a consequence of a drug's pharmacologic properties and not necessarily fundamental differences between the two compounds. On the other hand, the acknowledged superior anaerobic activity of moxalactam may have been responsible for noted differences. Although trends among the various reports are favoring the expanded-spectrum cephalosporins because of equivalent results but lesser cost and toxicity, additional studies are needed, Most studies have clearly not involved seriously ill patients where antibiotic selection may have a significant effect. Aminoglycosides have generally not been administered in pharmacokinetic doses in these studies, and this may have resulted in underdosing. The optimum dosing regimen for the newer cephalosporins may similarly not be clearly defined when examined in the critically ill patient as opposed to those pa= tients studied for modeling of drug therapy.
Summary Antibiotic utilization in the surgical patient has t h e two unique features of preventive use in highrisk procedures a n d frequent use in Suspected or documented polymicrobial infection. These two features have resulted in the search for agents with broader spectrums. Although numerous antibiotics or combinations of antibiotics can be shown to provide comparable results for both preventive and therapeutic indications, no superior choice has been identified in either area, Indeed, the search for broader spectrums of antibiotics may not further improve the identified results. If this is so, newer The AmericanJournalof Surgery
Symposium on the New Cephalosporins
areas of exploration in antibiotic therapy in the surgical patient will need to focus on optimizing pharmacologic, toxic, and economic features while preserving comparability in clinical outcome.
References 1. Sanchez-Ubeda R, Fernand E, Rousselot LM. Complication rate in general surgery cases: the value of penicillin and streptomycin as postoperative prophylaxis. New Engl J Med 1958; 259: 1045-50. 2. Barnes J, Pace WG, Trump DS, Ellison EH. Prophylactic postoperative antibiotics. Arch Surg 1959; 79: 190-6. 3. Johnstone FRC. An assessment of prophylactic antibiotics in general surgery. Surg Gynecol Obstet 1963; 116: 1-i0. 4. Postoperativewound infections: The influence of ultraviolet irradiation of the operating room and Of various other factors. National Academy of Sciences, National Research Council, Division of Medical Sciences, Ad Hoc Committee on Trauma. Ann Surg 1964; i60 (suppl 2):1-196, 5. Kaisei"AB, Clayson KR, Mulherin JL Jr, et al. Antibiotic prophylaxis in vascular surgery. Ann Surg 1978; 188: 283-9. 6. Miles AA, Miles EM, Burke JF. The value and duration of defense reactions of the skin to the primary lodgement of bacteria. Brit J Exp Pathol 1957; 38: 79-96. 7. Polk HC Jr, Lopez-Mayo r JF. Postoperative wound infection: a prospective study of determinant factors and prevention. Surgery 1969; 66: 97-103. 8. Stone HH, Hooper CA, Kolb LD, et al. Antibiotic proPhylaxis in gastric, biliary, and colonic Surgery. Ann Surq 1976; 184: 443-50. 9. Stone HH, Haney BB, Kolb LD, et al. Prophylactic and preventive antibiotic therapy: timing, duration and economics. Ann Surg 1979; 189: 691-9. 10. Washington JA, Dear!ng WH; Judd ES, Elveback LR. Effect of preoperative antibiotic regimen on development of infection after intestinal surgery. Ann Surg 1974; 180: 567-72. 11. Nichols RL, Condon RE, Gorbach SL, Nyhus LM. EffiCacY of preoperative antimicrobial preparation of the bowel. Ann Surg 1972; 176: 227-32. 12. Nichols RL, Broido P, Condon RE, et al. Effect of preoperative neomycin-erythr0mycin intestinal preparation on the incidence of infectious complications following colon surgery. Ann Surg 1973; 178: 453-62. 13. Clarke JS, Condon RE, Bartlett JG, et al. Preoperative oral antibiotics reduce septic complications of colon operations: results of a prospective, randomize d, double-blind clinical study. Ann Surg 1977; 186: 251-9. 14. Condon RE, Bartlett JG, Nichols RL, et al. Preoperative prophylactic cephalothin fails to control septic complications of colorectal operations: results of a controlled clinical trial. Am J Surg 1979; 137: 68-74. 15. Condon RE, Bartlett JG, Nichols RL, et al. Efficacy of oral and systemic antibiotic prophylaxis in colorectal operations. Arch Surg 1983; 118: 496-502. 16. Fry DE, Trachtenberg L, Polk HC Jr. The significance of antibiotic activity in the surgical wound in systemic antibiotic prophylaxis. Aktuel Probi Chir Orthop 1981; 19: 47-50. 17. Lewis RT, Allan CM, Go0dali RG, et al. Antibiotics in surgery of
Volume 155 (5A), May 31, 1988
the colon. Can J Surg 1978; 21: 339-41. 18. Edmonson HT, Rissing JP. Prophylactic antibiotics in colon surgery. Arch Surg 1983 ;, 118: 227-31. 19. Hoffman CEJ, McDonald PJ, Watts JM. Use of preoperative cefoxitin to prevent infection after colonic and rectal surgery. Ann Surg 1981; 193: 353-6. 20. Onderdonk AB, Bartlett JG, Louie TJ, et al. Microbial synergy in experimental intraabdominal abscess. Infect ImmUn 1976; 13: 22-6. 21. Rink RD, Kaelin CR, Raque G, et al. Effects of pure or combined inocula of E. coil and B. fragilis on the liver and related metabolism. Lab Invest 1982; 46: 282-8. 22. Fry DE, Berberich S, Garrison RN. Bacterial synergism between the enterococcus and E. coll. J Surg Res 1985; 38: 475-8. 23. Kasper DL, Hayes ME, Reinap BG, et al. Isolation and identification of encapsulated strains of Bacteroides fragilis. J Infect Dis 1977; 136: 75-81. 24. Lorber B, Swenson RM. The bacteriology of intraabdominal infections. Surg Clin North Am 1975; 55:1349-55, 25. Stone HH, Strom PR, Fabian TC, Dunlop WE. Third-generation cephalospoi'ins for polymicrobial surgical sepsis. Arch Surg 1983; 118: 193-200. 26. Garrison RN, Fry DE, Berberich S, Polk HC Jr. Enterococcal bacteremia: clinical implications and determinants of death. Ann Surg 1982; 196: 43-7. 27. Weinstein W, Onderdonk AB, Bartlett JG, et al. Antimicrobial therapy of intraabdominal sepsis. J Infect Dis 1975; 132; 282-8. 28. Nichols RL, Smith JW, Fossedal EN, Condon RE. Efficacy of parenteral antibiotics in the treatment of experimentally induced intraabdominal sepsis. Rev Infect Dis 1979; 1: 302-9. 29. Dunn DL, Rotstein OD, SimmonS RL. Fibrin in peritonitis. IV: Synergistic intraperitoneal infection caused by Escherichia coil and Bacteroides fragilis within fibrin clots. Arch Surg 1984; 119: 139-44. 30. Malangoni MA, Condon RE, Spiegel CA. Treatment of intraabdomlnal infections is appropriate with single,gent or combination antibiotic therapy. Surgery 1985; 98: 648-55. 31. Baird IM. Mutticentered study of cefoperazonefor treatment of intraabdominal infections and comparison of vefoperazone with cefamandole and clindamycin plus gentamicin for treatment of appendicitis and peritonitiS. Rev Infect Dis 1983; 5(suppl): $165-72. 32. Harding G, Vincelette J, Rachlis A, et al. A preliminary report on the use of ceftizoxime versus clindamycin/tobramycin for the therapy of intra-abdominal and pelvic infections. J Antimicrob Chemother 1982; 10(suppl): 191-2. 33. Stone HH, Mullins RJ, Strom PR, et al. Ceftriaxone versus combined gentamicin and clindamycin for polymicrobial surgical sepsis. Am J Surg 1983; 148(suppl): 30-4. 34. Berne TV, Yellin AE, Appleman MD, Heseltine PNR. Antibiotic management of surgically-treated gangrenous or perforated appendicitis. Comparison of gentamicin and clindamycin versus cefoperazone. Am J Surg 1982; 144: 8-13. 35. Lau WY, Fan ST, Chu KW, et al. Randomized, prospective and double-blind trial of new beta-lactams in the treatment of appendicitis. Antimicrob Agents Chemother 1985; 28: 639-42.
15
Donald E. Fry, MD, Albuquerque, New Mexico
Despite an ever-increasing armamentarium of antibiotics and improved culture-sensitivity testing methodologies, infection in the surgical patient continues to be a major source of morbidity. Infections occur as complications at the surgical site, and nosocomial infections are troublesome problems for many patients in the postoperative period. Infection itself may be the reason for operation in the surgical patient, particularly in soft tissue and in the intraabdominal cavity. Better adjunctive measures are necessary to assist the surgeon in treating the many complex infectious problems that complicate surgical care. Antibiotics have become important adjunctive treatments. Two areas of special concern for antimicrobial selection are surgical chemoprophylaxis and how to treat the patient with established polymicrobial infection. Antibiotic selection in both examples is usually empirical in that anticipated pathogens govern treatment choices rather than specific culture data. Antimicrobjal selection in these two particular areas certainly represent the majority of antibiotic usages for the surgeon and the surgically related specialist. This review of antibiotic usage in surgical infection will center principally on surgical chemoprophylaxis and polymicrobial infections. I will focus on the biologic characteristics of disease, the data base that justifies the use of antimicrobials, and the selection criteria that should be employed. Preventive Antibiotics
Since the 19th century pioneers Semmelweiss and Lister, physicians have attempted to use chemicals to reduce the infectious complications attendant to From the Department of Surgery, University of New Mexico School of Medicine, Albuquerque, New Mexico. Requests for reprints should be addressed to Donald E. Fry, MD, Department of Surgery, University of New Mexico School of Medicine, 2211 Lomas Boulevard NE, Albuquerque, New Mexico 87131.
Volume 155 (5A), May 31, 1988
procedures. These early efforts with antisepsis were somewhat successful. Semmelweiss employed handwashing with hypochlorite solutions to reduce postpartum infections in the female genital tract, and Lister used carbolic acid to reduce the numbers of bacteria that might potentially contaminate the amputation wound. With the introduction of antibiotics into clinical medicine in the 1940s, many physicians believed that these drugs would prove effective in the reduction of surgical site infections after operations. Initial studies created considerable disillusionment, as antibiotics were not only shown to be ineffective but, in some reports, patients receiving preventive antibiotics actually had higher wound infection Fates than did placebo-treated patients (Table I) [1-
3]. The shortcoming of many of these initial efforts in antimicrobial prophylaxis for the surgical patient stemmed from a failure to appropriately stratify patients for risk variables associated with infection as an adverse outcome. Relatively clean procedures, such as those for inguinal hernia, were compared with operations where major intraoperative contamination was likely (such as colon resection). Wound classification: The ultraviolet light study in 1964 subsequently demonstrated the significance of appropriate risk stratification in surgical site infection [4]. This study clearly demonstrated that surgical wound infection was a consequence of intraoperative contamination and that the magnitude of intraoperative contamination dictated the probability of infection. A classification system was proposed to allow for stratification of risk. Although many different classification schemes are available, surgical procedures can be broadly categorized into two major groups: clean and contaminated operations. Clean procedures are those where the quantity of bacterial contamination is small and where adjuvant factors commonly convert an otherwise subinfective inoculum of bacteria 11
Fry
into a clinically significant one. These procedures do not involve heavily colonized areas of the body such as the colon or the female genital tract. The major sources of bacterial contamination are the patient's skin, the operating room environment, and the surgical team. Pathogens are usually gram positive, and infections occur in less than 2 to 3 percent of patients given that an appropriate aseptic technique is carried out. Although preventive antibiotics have been shown to be of value in certain clean procedures, such as peripheral vascular reconstruction, surgical technique has had the greatest impact on wound infection rates in this group [5]. Those technical considerations refer not only to asepsis but to the reduction of adjuvant factors--for example, hemoglobin, foreign bodies, dead tissue, and dead space--that foster bacterial infection. The second broad category of surgical wounds are contaminated procedures. These include procedures where heavily colonized areas, gross contamination, or active infection are encountered. Such contamination is polymicrobial, with aerobes, anaerobes, and both gram-positive and gram-negative bacteria all potential pathogens. Infection is frequently related to the endogenous inoculum that soils the wound, with environmental factors being less significant. In the absence of specific preventive measures, infection rates range between 10 and 50 percent in contaminated procedures. Effective antimicrobial preventive measures have their greatest utility in these types of operations. Timing of antibiotic administration: A second consideration that resulted in the failure of chemoprophylaxis with antibiotics in the early clinical trials was the lack of consistency in the timing of antibiotic administration. Antibiotics were commonly not initiated until after the procedure was completed and the drugs were then continued for many days into the postoperative period. Experimental studies by Miles et al [6] demonstrated the importance of the timing of antibiotic administration. In an experimental model of cutaneous infection, they showed that antibiotics given before bacterial contamination significantly decreased the magnitude of cutaneous infection when 9compared with control lesions. Antibiotics given after bacterial inoculation were progressively less effective in altering the natural history of cutaneous infection such that antibiotics given 4 hours or later after contamination had no impact on the natural history of this infection model. Polk and Lopez-Mayor [7] then demonstrated the validity of these animal experiments in a prospective, randomized, double-blind study of patients undergoing elective gastrointestinal surgery. Patients who received preoperative cephaloridine versus a placebo had significantly fewer surgical site infections. It is noteworthy that patients received only two postoperative doses of the drug. Stone et al 12
TABLE I
Infection Rates ( % ) in General Surgical Patients With Respect to Timing of Drug Initiation Antibiotics Administered
Investigator
None
Postop
Sanchez-Ubeda et al [ 1] Barnes et al [2] Johnstone [3]
5.6 9.8 9
9.5 11.4 25
[8] reported that the initiation of antibiotic prophylaxis in the postoperative period resulted in no reduction of infection rates compared with placebotreated patients. Stone et al [9] also identified that 5 postoperative days of antibiotic prophylaxis offered no advantages over the conventional regimen of preoperative antibiotic administration and limited postoperative administration. The results of these experimental and clinical studies are clear. Effective systemic antibiotic prophylaxis requires that the antibiotic be present in the tissue at the time that contamination occurs, and that prolonged antibiotic administration into the postoperative period has no measurable benefit for the patient. Oral antibiotics for colon surgery: Because elective colon surgery has the greatest probability of surgical site infection, the desirability of using poorly absorbed, orally administered preoperative antibiotics to reduce the viable inoculum of contaminants during operation, in addition to mechanical preparation, has been explored. Despite testimonial speculation about the merits of certain oral sulfa or aminoglycoside preparations, Washington et al [10] first demonstrated the merits of oral preoperative antibiotic administration in the reduction of wound infection. They showed that the preoperative oral administration of neomycin and tetracycline significantly decreased wound infection after colon resection. It is noteworthy that neomycin alone was no more effective than the placebo. These investigators concluded that coverage of both aerobic and anaerobic microflora with neomycin and tetracycline, respectively, was necessary to prevent infection. Because tetracycline was not an optimum choice for coverage of Bacteroides fragilis, the tetracycline preparation in the oral bowel preparation was replaced by erythromycin base in studies by Nichols et al [11,12] and by Clarke and associates [13]. Erythromycin base has the advantage of being very poorly absorbed with subsequent high intraluminal drug concentrations, as well as being comprehensively effective against anaerobic species likely to be encountered in the human colon. An unresolved issue in the comparison of oral versus systemic antibiotic prophylaxis is whether one technique is better than the other, or whether there are potential advantages to the combination The American Journal of Surgery
Symposium on the New Cephalosporins
of the two methods. Condon et al [14] have shown the superiority of the oral neomycin and erythromycin combination to systemic cephalothin prophylaxis, and have likewise demonstrated no benefit by including systemic cepha!othin with oral antibiotic administration [15]. However, the undesirable pharmacologic properties of cephalothin are a potential shortcoming of these reports [16]. Lewis et al [17] showed no difference between systemic antibiotic prophylaxis and the oral neomycin and erythromycin preparation, although the number of patients in this study was small. Edmundson and Rissing [18] reported the superiority o f an oral intestinal preparation compared with systemic antibiotics, but they reported rates of infection in colon surgery that were effectively the same as those o f clean procedures. This latter observation has certainly not been identified elsewhere. Stone et al [8] showed additive benefits to systemic effects of combining cefazolin with an oral intestinal antibiotic preparation, whereas Hoffman et al [19] demonstrated similar benefits of systemic cefoxitin when added to an oral antibiotic preparation. Additional studies are necessary to elucidate the superiority or additive effects of these two techniques.
Polymicroblal Infection The traditional teachings of Koch's postulates have dictated that a single pathogen could be identified for each clinical infection and that the isolation of that solitary pathogen should permit inoculation into an experimental animal to recreate the infection. However, the numerous advances in the methodology of anaerobic culturing in the last several decades have identified that intraabdominal, female genital trac t , and certain soft tissue infections have an abundantly polymicrobial character where the virulence of the pathogens together is greater than would be expected from their 'individual summed virulences. Experimental studies by Onderdonk et al [20] with an intraabdominal model illustrated the bacterial synergism that exists in polymicrobial infection with both anaerobic and anaerobic participation. When experimental intraabdominal infection in the rat is created with Es= cherichia coli alone, a high mortality rate among the animals is clearly identified. However, similar inocula of enterococci, Bacteroides fragilis, or Fusobacterium varium as commonly identified isolates in murine fecal peritonitis failed to result in any mortalities or any pathologic observations, such as abscesses, when the animals were sacrificed and examined after the expected acute phase of infection. When organisms are mixed together, a different pattern of disease expression is identified. Acute mortality rates continue to be dictated by the presence or absence of the endotoxin-bearing E. coli organism. However, the presence of an oxygen-conVolume 185 (5A), May 31, 1988
suming organism and an obligate anaerobe together results in the nearly uniform presence of abscess in those surviving animals that are then autopsied. The mix of different species of obligate anaerobes without the facultative aerobic partner results in no expression of virulence. Data from our laboratory has similarly shown that B. fragilis given intravascularly or intradermally has little or no virulence [21,22]. However, the addition of sublethal inocula of E. coli to ~the B. fragilis bacteremia results in significant death rates in the experimental model [21]. E. coli and B. fragilis together in a cutaneous infectious model similarly show a synergistic effect
[22].
These data demonstrate that polymicrobial infection represents a complex synergistic and interactive relationship between the facultative aerobic and anaerobic species present in the microenvironment. Tti'e facultative aerobe consumes the oxygen in the microenvironment and maintains a reduced oxidation-reduction: potential, which optimizes growth conditions for the obligate anaerobe. As:a consequence, the anaerobe may then express its own virulence by means of various enzyme systems. The anaerobe may help to elaborate certain growth fac'tors that may accelerate the growth and prolifera: tion of its aerobic partner. Finally, B. fragilis organisms are known to have a capsular polysaccharide that may retard phagocytosis and explain the pro: pensity to form abscesses identified in t h e various animal models of intraabdominal infection [23]. The presence of this capsular polysaccharide no doubt provides protection for both the anaerobic organism and its aerobic symbiont. ', A final issue to be addressed in polymicrobial infection concerns the emerging debate over the virulence of the enterococcus. In recent years, the enterococcus appears to be identified with increased frequency in polymicrobial infection. For example, Lorber and Swenson [24] noted 0nly a 9 percent frequency of group D streptococci in'a study of intraabdominal microbiology in 1975. More recently, Stone et al [25] have noted a greater than 20 percent frequency of the eneterococcus in polymicrobial infection. Although the significance of this perceived increase in the enterococcus can be only the subject of conjecture, the prevalence of cephalosporin antibiotic usage must be viewed as a potential cause for the emergence of this organism. The potential virulence of the enterococcal organism and the necessity for specific antibiotic coverage in polymicrobial infection remain unclear. The experimental intraabdominal studies of 0nderdonk et al [20] demonstrated the synergisticrelationship between the enterococcus and the obligate anaerobe, although this may be a nonspecific relationship of any oxygen-consuming organism with an obligate anaerobe. Our own experimental data suggest a potential synergism between E. coli and the enterococ13
Fry
cus [22]. However, clinical observations have not confirmed that specific antibiotic coverage for the enterococcal organism improves the outcome of treatment in these patients [26]. Despite considerable attention and empirical recommendations for antimicrobial coverage Of the enterococcus, prospective data that demonstrate improved results with enterococcal coverage are not presently available. Thus, the virulence of this species of bacteria remains an enigma that requires further definition. Antibiotic selection: The complex nature of mi~ croflora in polymicrobial infection has generated considerable debate over the proper selection of antibiotics for these patients. At one end of the spectrum, the polypharmaceutical approach has dictated that individual drugs be given to address all organisms identified in the infection. This has resulted in quadruple drug therapy in some quarters, with four drugs being given to cover gramnegative rods (aminoglycosides), obligate anaerobes (clindamycin or metronidazole), enterococci (ampicillin), and staphylococci (vancomycin). Although this comprehensive coverage may provide the clinician with confidence that so-called coverage has been achieved, the expense and toxicity of this approach make it one of dubious value except perhaps for manufacturers of antifungal therapy. At the opposite end of the treatment spectrum, a growing c o n t i n g e n t of m o n o t h e r a p i s t s have emerged i n t h e wake of the growing technology of the expanded-spectrum cephalosporins. These newer cephalosporins with both enterobacteriacae and obligate anaerobe activity have fostered the hope that perhaps single drug therapy may replace the multiple drugs, frequent administration, pharmacokinetic dosing, risks of toxicity, and staggering costs of the polypharmacy approach. Criticisms of monotherapy have focused on the lesser activity of the newer cephalosporins against anaerobes and their near-total inactivity against the enterococcus. As just noted, the active participation of aerobic and anaerobic species in polymicrobial infection has been well established. The animal models of experimental infection used by Weinstein et al [27], Nichols et al [28], and Dunn et al [29] have demonstrated that coverage of both the aerobic and anaerobic components of the synergistic pair are necessary. Based on these experimental observations, combination therapy became the gold standard for the treatment of intraabdominal infection. Gentamicin, tobramycin, netilmycin, or amikacin are the aminoglycosides commonly employed to cover the enterobacteriacae. Clindamycin or metronidazoie have been commonly chosen as the second drug for anaerobic coverage. Potential alternative expandedspectrum cephalosporins have been studied and have been identified as providing equal results to combination therapy (Table II). The published comparative trials to this point 14
TABLE II
Expanded.Spectrum Antibiotics and Their Half-Lives (h)
Antibiotic
Brand Name
Serum Half-Life
Cefoxitin Cefotetan Cefotaxime Moxalacam Cefoperazone Ceftizoxime Ceftriaxone
Metoxm Cefotan Claforan Moxam Cefobid Cefizox Rocephin
0.8-0.9 3.5 1 2-2.3 2 1.4-1.7 6.5-8
have demonstrated some trends that are not completely conclusive. Some data have shown comparable results in polymicrobial infection rates between Conventional combination therapy and cefoxitin, cefotaxime, cefoperazone, moxalactam, ceftizoxime, and ceftriaxone [25, 30-33], One report identified poorer results with cefoperazone compared with gentamicin and clindamycin [34]. Yet another report identified poorer results with cefotaxime but good results with moxalactam compared with combination therapy [35]. Because cefotaxime and moxalactam have very different serum elimination halflife kinetics, this latter report may be a consequence of a drug's pharmacologic properties and not necessarily fundamental differences between the two compounds. On the other hand, the acknowledged superior anaerobic activity of moxalactam may have been responsible for noted differences. Although trends among the various reports are favoring the expanded-spectrum cephalosporins because of equivalent results but lesser cost and toxicity, additional studies are needed, Most studies have clearly not involved seriously ill patients where antibiotic selection may have a significant effect. Aminoglycosides have generally not been administered in pharmacokinetic doses in these studies, and this may have resulted in underdosing. The optimum dosing regimen for the newer cephalosporins may similarly not be clearly defined when examined in the critically ill patient as opposed to those pa= tients studied for modeling of drug therapy.
Summary Antibiotic utilization in the surgical patient has t h e two unique features of preventive use in highrisk procedures a n d frequent use in Suspected or documented polymicrobial infection. These two features have resulted in the search for agents with broader spectrums. Although numerous antibiotics or combinations of antibiotics can be shown to provide comparable results for both preventive and therapeutic indications, no superior choice has been identified in either area, Indeed, the search for broader spectrums of antibiotics may not further improve the identified results. If this is so, newer The AmericanJournalof Surgery
Symposium on the New Cephalosporins
areas of exploration in antibiotic therapy in the surgical patient will need to focus on optimizing pharmacologic, toxic, and economic features while preserving comparability in clinical outcome.
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the colon. Can J Surg 1978; 21: 339-41. 18. Edmonson HT, Rissing JP. Prophylactic antibiotics in colon surgery. Arch Surg 1983 ;, 118: 227-31. 19. Hoffman CEJ, McDonald PJ, Watts JM. Use of preoperative cefoxitin to prevent infection after colonic and rectal surgery. Ann Surg 1981; 193: 353-6. 20. Onderdonk AB, Bartlett JG, Louie TJ, et al. Microbial synergy in experimental intraabdominal abscess. Infect ImmUn 1976; 13: 22-6. 21. Rink RD, Kaelin CR, Raque G, et al. Effects of pure or combined inocula of E. coil and B. fragilis on the liver and related metabolism. Lab Invest 1982; 46: 282-8. 22. Fry DE, Berberich S, Garrison RN. Bacterial synergism between the enterococcus and E. coll. J Surg Res 1985; 38: 475-8. 23. Kasper DL, Hayes ME, Reinap BG, et al. Isolation and identification of encapsulated strains of Bacteroides fragilis. J Infect Dis 1977; 136: 75-81. 24. Lorber B, Swenson RM. The bacteriology of intraabdominal infections. Surg Clin North Am 1975; 55:1349-55, 25. Stone HH, Strom PR, Fabian TC, Dunlop WE. Third-generation cephalospoi'ins for polymicrobial surgical sepsis. Arch Surg 1983; 118: 193-200. 26. Garrison RN, Fry DE, Berberich S, Polk HC Jr. Enterococcal bacteremia: clinical implications and determinants of death. Ann Surg 1982; 196: 43-7. 27. Weinstein W, Onderdonk AB, Bartlett JG, et al. Antimicrobial therapy of intraabdominal sepsis. J Infect Dis 1975; 132; 282-8. 28. Nichols RL, Smith JW, Fossedal EN, Condon RE. Efficacy of parenteral antibiotics in the treatment of experimentally induced intraabdominal sepsis. Rev Infect Dis 1979; 1: 302-9. 29. Dunn DL, Rotstein OD, SimmonS RL. Fibrin in peritonitis. IV: Synergistic intraperitoneal infection caused by Escherichia coil and Bacteroides fragilis within fibrin clots. Arch Surg 1984; 119: 139-44. 30. Malangoni MA, Condon RE, Spiegel CA. Treatment of intraabdomlnal infections is appropriate with single,gent or combination antibiotic therapy. Surgery 1985; 98: 648-55. 31. Baird IM. Mutticentered study of cefoperazonefor treatment of intraabdominal infections and comparison of vefoperazone with cefamandole and clindamycin plus gentamicin for treatment of appendicitis and peritonitiS. Rev Infect Dis 1983; 5(suppl): $165-72. 32. Harding G, Vincelette J, Rachlis A, et al. A preliminary report on the use of ceftizoxime versus clindamycin/tobramycin for the therapy of intra-abdominal and pelvic infections. J Antimicrob Chemother 1982; 10(suppl): 191-2. 33. Stone HH, Mullins RJ, Strom PR, et al. Ceftriaxone versus combined gentamicin and clindamycin for polymicrobial surgical sepsis. Am J Surg 1983; 148(suppl): 30-4. 34. Berne TV, Yellin AE, Appleman MD, Heseltine PNR. Antibiotic management of surgically-treated gangrenous or perforated appendicitis. Comparison of gentamicin and clindamycin versus cefoperazone. Am J Surg 1982; 144: 8-13. 35. Lau WY, Fan ST, Chu KW, et al. Randomized, prospective and double-blind trial of new beta-lactams in the treatment of appendicitis. Antimicrob Agents Chemother 1985; 28: 639-42.
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