SURGICAL INFECTIONS Volume 17, Number 3, 2016 ª Mary Ann Liebert, Inc. DOI: 10.1089/sur.2015.271
Review Articles
Antimicrobial Bowel Preparation for Elective Colon Surgery Donald E. Fry1,2
Abstract
Background: Mechanical bowel preparation continues to be a controversial subject for the pre-operative management of patients undergoing elective colon resection. Methods: The English literature on bowel preparation was searched to identify pertinent publications. Results: The published literature over the past 80 y confirms that mechanical bowel preparation alone does not reduce surgical site infections. However, the use of appropriate oral antibiotics following mechanical bowel preparation with pre-operative systemic antibiotics reduces rates of surgical site infections and anastomotic leaks when compared with systemic antibiotics alone. Conclusions: Mechanical bowel preparation with pre-operative oral antibiotics and pre-operative systemic antibiotics are the standard of care for elective colon surgery. Refinement in methods of bowel preparation needs additional clinical investigations to further enhance outcomes.
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that included colon surgery were first demonstrated by Polk and Lopez-Mayor [9]. Over a decade later, Baum et al. [10] identified that placebo-controlled clinical trials of systemic antibiotics for the prevention of elective colon surgery were no longer necessary because of the compelling evidence, and Song and Glenny [11] did an extensive meta-analysis that showed that systemic preventive antibiotics only needed to cover the perioperative period of time and did not required post-operative administration. Although the role of systemic antibiotics has become firmly established, the value of colonic preparation has remained controversial. Mechanical preparation of the colon has traditionally been used for elective colon surgery and for other abdominal operations where intended or unintended entrance into the colon lumen was anticipated as a possible event. It could rationally be expected that mechanical removal of the microbial load of human fecal material might reduce infection rates, but rational practices are not necessarily translated into positive impacts upon outcomes of care. Over the last decade a vigorous debate has emerged about abandonment of the mechanical bowel preparation in elective colon surgery. It will be the premise of this presentation that mechanical preparation of the colon still has a useful role in elective colon surgery, but only in the context of simultaneously employing orally administered, poorly absorbed antibiotics for purposes of reducing the concentration of colonic microflora.
he human colon is the most heavily colonized area of the human body. The concentration of bacteria ranges from 106–107 bacteria/g of stool content in the right colon to 1011–1012 bacteria/g in the rectosigmoid colon [1]. We have more bacterial cells in the human colon than eukaryotic cells in our body [2]. It is not surprising that operative procedures that involve resection of the colon are associated with the highest rates of surgical site infections (SSIs) among elective operations today. In a review of his lifetime interest in infection following colon surgery, Poth noted that elective colon surgery in the 1930s was associated with a 10%–12% mortality rate, 70%–90% rate of SSI, and a greater than 20% rate of anastomotic leak [3]. Although overall improvement in outcomes have occurred, it is likely that current SSI rates for elective colon surgery remain in excess of 20% when a full 30-d of post-discharge follow-up is included in the evaluation [4,5]. Anastomotic leak rates from colorectal anastomoses are still identified in 3%–6% of cases [6,7]. Overall in-hospital mortality rate for colectomy in 2010 is at 3% with infection the major contributor to deaths [8]. There remains opportunity for improvement in the infectious morbidity and mortality rates observed in these patients. The use of preventive systemic antibiotics has become a standard of clinical practice to prevent SSI in colon resection patients. The merits of pre-operative systemic administration of an antibiotic with activity against the anticipated contamination of the surgical site in gastrointestinal operations 1 2
Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Department of Surgery, University of New Mexico School of Medicine, Albuquerque, New Mexico.
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History of Colonic Preparation
senberg et al. in 1971 [22]. This was a three armed trial of mechanical preparation only, oral phthalylsulphathiazole for 5 d pre-operatively, or oral phthalylsulphathiazole and oral neomycin for 5 d pre-operatively. The study demonstrated lower SSIs and anastomotic leaks in the two groups receiving the oral antibiotics when compared with those patients with only mechanical preparation, but no added advantage of neomycin to the oral phthalylsulphathiazole was observed. The study has numerous problems, which include that only a total of 128 patients were in the three arms, and 40% did not have an anastomosis performed. Washington et al. [23] at the Mayo Clinic performed the first randomized clinical trial that clearly favored the use of the oral antibiotic bowel preparation. In a trial where all operations were performed by the same surgeon, all patients received mechanical bowel preparation and were then randomized to one of three groups: 1) oral placebo, 2) oral neomycin, or 3) oral neomycin and tetracycline. With nearly 200 randomized patients, those receiving the placebo had SSI rates of 43%, those with neomycin 41%, and those with neomycin and tetracycline 5% (p < 0.05). Following a preliminary study in 20 patients that demonstrated the effectiveness of the oral neomycin and erythromycin preparation on suppressing colonic aerobic and anaerobic bacteria by Nichols et al. [24], a randomized clinical trial by Clarke et al. of this oral antibiotic combination was evaluated versus patients receiving only mechanical bowel preparation for elective colon surgery [25]. These data demonstrated a SSI rate of 35% in the placebo-control group and only a 9% rate in the oral antibiotic group (p < 0.05). The oral antibiotic group had no anastomotic leaks, whereas leaks occurred in 10% of placebo patients. The mechanical preparations used by Nichols et al. [24] and Clarke et al., and that were used in the Washington et al. [23] study are detailed in Table 1. No systemic antibiotics were used in either study. Other prospective clinical trials demonstrated favorable outcomes using oral neomycin/ metronidazole [26] and kanamycin/erythromycin [27]. Yet another three arm study demonstrated effectiveness with oral phthalysulfathiazole, neomycin, and tetracycline all used together compared with placebo patients, but no statistical improvement with phthalysulfathiazole and neomycin without the tetracycline [28]. Three additional studies demonstrated improved clinical outcomes in SSI rates when systemic preventive antibiotics were added to the oral antibiotic bowel preparation [29–31].
Because of the high rates of infection and anastomotic leaks in colon surgery, mechanical preparation of the colon was employed but was recognized to not reduce surgical site infections from the 1930s. With the discovery of antibiotics, a large number of experimental and clinical efforts to use poorly absorbed, oral antibiotics to reduce the concentration of intra-luminal bacteria during or following mechanical preparation in studies were performed by Poth [12–14], Firor and Poth [15], Firor and Jonas [16], and Garlock and Seley [17]. Mechanical preparation with oral antibiotics was deemed to be necessary, not because it reduced SSIs, but because it reduced the large bulk of bacteria from formed stool and provided for timely delivery of the antibiotic to the entire length of the colon that cannot be achieved when an unprepared colon is present. During the 1940s, multiple sulfa derivatives were studied with respect to reductions in the bacterial concentrations within the colon lumen. Sulfathalidine was identified to have the most antibacterial effective [18]. Sulfathalidine was combined with neomycin in selected studies but failed to substantially alter SSI rates. Cohn and Rives demonstrated experimental benefits of intra-luminal tetracycline in the protection of colonic anastomoses [19] and Cohn and Longacre chose to combine neomycin with tetracycline [20]. However, the emergence of resistance to tetracycline led to abandonment of this combination. Based upon experimental studies, Cohn advocated kanamycin in combination with mechanical bowel preparation as the best method for prevention of SSI [21]. Thus, during the late 1950s and through the 1960s, considerable interest focused upon oral antibiotic bowel preparation as a means to reduce SSI and perhaps reduce leaking anastomoses following colon resection. Considerable experimental evidence supported the use of oral antibiotics, bacteriologic studies documented reductions in bacteria concentrations within the lumen, and studies with retrospective control groups provided some evidence for the use of several different oral regimens. However, there remained no randomized, prospective clinical trials to validate the method. Clinical Evidence for Oral Antibiotic Preparation
The initial effort at a randomized clinical trial of the oral antibiotic preparation in major colon surgery was by Ro-
Table 1. Mechanical Bowel Preparation Methods Used over Multiple Days in the Washington et al., Nichols et al., and Clarke et al. Studies Washington et al. [23]
Nichols et al. [24] and Clarke et al. [25]
Residue-free diet for 48 h before operation. Sodium phosphate and biphosphate 16 mL twice daily for 48 h before operation. Two tap water enemas 2 d before operation. Two tap water enemas each on the morning and afternoon of the day before operation. 500 mg neomycin and 250 mg tetracycline taken four times daily for 48 h before operation.
Day 1: Low residue diet; Bisacodyl, 1 capsule orally at 6 p.m. Day 2: Continue low residue diet; Magnesium sulfate, 30 mL 50% solution (15 Gm.) orally at 10:00 a.m., 2:00 p.m. and 6:00 p.m; Saline enemas in evening until return clear. Day 3: Clear liquid diet; supplemental IV fluids as needed. Magnesium sulfate, in dose above, at 10:00 a.m. and 2:00 p,m. No enemas. Neomycin (1 gm) and erythromycin base (1 gm) at 1300 hrs, 1400 hrs, and 2300 hrs. Day 4: Operation scheduled at 8:00 a.m.
BOWEL PREPARATION FOR ELECTIVE COLON SURGERY
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By the 1990s, the practice for the prevention of SSIs in elective colon surgery in North America was documented in two separate surveys to be the use of mechanical bowel preparation with oral antibiotics to reduce intra-luminal concentrations of potential pathogens, and perioperative systemic antibiotics to address contaminants at the surgical site itself [32,33]. Disillusionment with Mechanical Bowel Preparation
Mechanical bowel preparation was a critical consideration in the use of oral antibiotics to prevent SSIs in elective colon surgery. It was well documented in the Clarke et al. [25] study that intra-luminal bacterial concentrations declined by five logarithms with the oral neomycin-erythromycin combination. Hence the clinical trials of the 1970s that demonstrated favorable outcomes compared with the placebo group commonly pursued 48–72 h of vigorous mechanical cleansing before the oral antibiotics were initiated (Table 1). However, as the 1990s unfolded in the U.S., clinical practice for elective colonic surgery was undergoing a change. Economic pressures resulted in the elimination of pre-operative hospitalization, which compromised the comprehensive inpatient mechanical preparation of the prior decades. Ambulatory and quicker mechanical preparation became the order of the day. Large volumes of polyethylene glycol solution were consumed prior to hospitalization and the oral antibiotics were similarly administered at home on the day prior to hospitalization and operation. Discomfort with preparation prior to admission resulted in poor mechanical preparation from the huge mandatory volumes of oral liquids with bloating and abdominal discomfort. In addition, abdominal discomfort was experienced from the gastrointestinal motility effects of oral erythromycin. These problems of home-based mechanical preparation and oral antibiotic administration were particularly an issue among the elderly. Poor compliance and poor preparation led to ineffective antibiotic delivery throughout the colon, and the benefits of oral antibiotic bowel preparation were lost. This has led to a backlash of opinion that mechanical preparation and the oral antibiotic bowel preparation should be eliminated with only systemic preventive antibiotics used. Concerns about effectiveness have led to a large number of clinical trials, which demonstrated no reduction in SSI rates when mechanical preparation was compared with no preparation when patients in both arms of the clinical trials received preventive systemic antibiotics [34–42]. Aggregation of the studies in meta-analyses similarly demonstrated no outcome benefit from mechanical bowel preparation [43]. Oral antibiotics were not given in these studies. These studies essentially re-confirmed the studies of Poth and others from 70 y ago which demonstrated no benefit to mechanical preparation alone. The net effect was that mechanical bowel preparation has fallen into disfavor by the most recent survey results [44– 48] and with that disillusionment, the elimination of the benefits of the oral antibiotic bowel preparation.
FIG. 1. Illustrates the improvement in SSI rates in eight clinical trials of systemic and oral antibiotics versus systemic antibiotics alone. neomycin-metronidazole and systemic amikacin and metronidazole in one group, and systemic amikacin and metronidazole without oral antibiotics in the second group [49]. Both groups of patients received mechanical bowel preparation. This study demonstrated a remarkable reduction in SSI rates from 17% with systemic antibiotics alone to only 6% in those patients receiving the systemic antibiotics and oral antibiotics (p < 0.01). This publication also reported a meta-analysis, which was highly substantial in the support of using the oral antibiotic bowel preparation with systemic antibiotics for the reduction of SSI. Additional meta-analyses have similarly demonstrated the benefits of the oral antibiotic bowel preparation in conjunction with mechanical preparation and systemic antibiotics [50–53]. Fewer than 20 studies have been identified in the several meta-analyses of oral antibiotics plus systemic antibiotics versus systemic antibiotics alone in the prevention of SSI in elective colon surgery. A total of eight studies in addition to that of Lewis have had patient numbers that exceeded 100 patients in the randomization [54–61]. These are identified in Figure 1. Recently, clinical reports are re-discovering the benefits of the oral antibiotic bowel preparation. The Michigan Surgical Quality Collaborative has made several reports, which have consistently demonstrated the benefits of the oral antibiotic bowel preparation in the reduction of SSIs [62–64]. They have included the oral antibiotic bowel preparation as one of six elements of the Colon Surgery Bundle to prevent SSIs [65]. Several studies from the VA Surgical Quality Improvement project have similar identified that oral antibiotics make a difference in SSI rates [66,67], which can be further enhanced with the selection of appropriate pre-operative systemic antibiotics [68]. They have even reported that preoperative oral antibiotics may be effective without mechanical preparation, although this remains to be validated [69]. As was reported in the original study by Clarke et al., oral antibiotic bowel preparation reduces the frequency of leaking anastomoses [70,71].
Oral Antibiotics Revisited
Published studies that have evaluated the merits of combining mechanical bowel preparation with oral antibiotics have been sparse since the convincing studies that were published in the 1970s. Lewis reported a randomized controlled trial of elective colon resections, which compared oral
The Future of Oral Antibiotics in Elective Colon Surgery
The evidence supports the routine use of the oral antibiotic bowel preparation in conjunction with mechanical preparation for elective colon surgery. Recommendations that the mechanical bowel preparation should be omitted
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from the preparation of elective colon resection patients are ignoring the true merits of using mechanical bowel preparation with oral antibiotics together [72]. Many questions remain about the optimum methods to be used in the oral antibiotic bowel preparation and additional clinical trials are necessary. The evidence indicates that the mechanical preparation must be complete if orally administered antibiotics are to access the full length of the colon lumen. Retained stool yields a huge bulk of microbes, dietary fiber, and exfoliated cells that will not permit reduction of the density of potential pathogens on the colonic mucosal surface with oral antibiotics. Effective mechanical preparation may require more than a few hours of oral polyethylene glycol, especially in the outpatient setting with elderly patients. Furthermore, ingestion of the antibiotics while the mechanical process is actively ongoing may result in un-dissolved tablets and capsules passing though the gastrointestinal tract with no antimicrobial effect. As much as payers of care may object, it may be cost-effective in elderly patients or those with compliance issues in their own home environments to have the additional day of pre-operative admission so that the complete colon preparation is done in a fashion to optimize clinical outcomes. Effective home-health programs or daycare centers for seniors to provide effective colon preparation are alternatives to pre-operative admission. With episodebased payment for colon resections in the future [73], hopefully clinicians will have the flexibility to exercise judgments about pre-operative stays and management support in the interest of patient outcomes, which will reduce overall costs. Little research has focused upon which mechanical preparation method will best meet the needs of the oral antibiotic administration strategy. Although there have been a plethora of studies using mechanical preparation alone without benefit to patients, there have been few studies to evaluate which mechanical preparation actually efficiently and effectively removes all particulate waste from the colon. Itani et al. [74] have identified lower SSI rates when sodium phosphate mechanical preparation was used versus polyethylene glycol as a subset analysis of a randomized trial, which compared two different systemic antibiotics in elective colon surgery. One study has identified a better mechanical preparation with oral sodium phosphate than polyethylene glycol, and with a smaller oral volume of administration [75]. This observation is particularly interesting in light of basic research studies that have identified phosphate ion as a potential modulation variable in reducing the virulence of enteric gram-negative bacteria [76], and the prospects for binding phosphate to polyethylene glycol for bowel preparation [77]. Enthusiasm for phosphate-based bowel preparations will need to be tempered by known potential toxicities of hyperphosphatemia [78]. Few investigations have pursued the most desirable oral antibiotic. There is reason to challenge whether oral neomycin adds anything to the clinical outcome of the oral antibiotic bowel preparation [79]. Oral metronidazole has replaced erythromycin in some studies. Many other poorly absorbed antibiotics are available but comparative studies of alternative drugs have virtually been non-existent in the last 20 y. Furthermore, the timing of completion of the oral antibiotics prior to the surgical intervention has not had the best analytical evaluation and deserves further study. Finally, the risks of
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Clostridium difficile infection as a complication of the oral antibiotic bowel preparation remain to be fully explored [80]. In summary, published experience is consistent in the observation that mechanical bowel preparation when performed alone is not of value in the reduction of SSI following elective colon surgery. However, the evidence is equally convincing that the addition of the oral antibiotic bowel preparation to mechanical preparation provides improvement in outcomes when combined with appropriate systemic preventive antibiotics. The search for better mechanical and oral preparation strategies need to be re-vitalized. Author Disclosure Statement
The author discloses potential conflicts of interest with Merck and Co (Speakers Program), CareFusion (Speakers Program, Ethicon (Consultant), and IrriMax (Consultant and Speaker). References
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Address correspondence to: Dr. Donald E. Fry MPA Healthcare Solutions 1 East Wacker Drive, Suite 1210 Chicago, IL 60601 E-mail: [email protected]
Review Articles
Antimicrobial Bowel Preparation for Elective Colon Surgery Donald E. Fry1,2
Abstract
Background: Mechanical bowel preparation continues to be a controversial subject for the pre-operative management of patients undergoing elective colon resection. Methods: The English literature on bowel preparation was searched to identify pertinent publications. Results: The published literature over the past 80 y confirms that mechanical bowel preparation alone does not reduce surgical site infections. However, the use of appropriate oral antibiotics following mechanical bowel preparation with pre-operative systemic antibiotics reduces rates of surgical site infections and anastomotic leaks when compared with systemic antibiotics alone. Conclusions: Mechanical bowel preparation with pre-operative oral antibiotics and pre-operative systemic antibiotics are the standard of care for elective colon surgery. Refinement in methods of bowel preparation needs additional clinical investigations to further enhance outcomes.
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that included colon surgery were first demonstrated by Polk and Lopez-Mayor [9]. Over a decade later, Baum et al. [10] identified that placebo-controlled clinical trials of systemic antibiotics for the prevention of elective colon surgery were no longer necessary because of the compelling evidence, and Song and Glenny [11] did an extensive meta-analysis that showed that systemic preventive antibiotics only needed to cover the perioperative period of time and did not required post-operative administration. Although the role of systemic antibiotics has become firmly established, the value of colonic preparation has remained controversial. Mechanical preparation of the colon has traditionally been used for elective colon surgery and for other abdominal operations where intended or unintended entrance into the colon lumen was anticipated as a possible event. It could rationally be expected that mechanical removal of the microbial load of human fecal material might reduce infection rates, but rational practices are not necessarily translated into positive impacts upon outcomes of care. Over the last decade a vigorous debate has emerged about abandonment of the mechanical bowel preparation in elective colon surgery. It will be the premise of this presentation that mechanical preparation of the colon still has a useful role in elective colon surgery, but only in the context of simultaneously employing orally administered, poorly absorbed antibiotics for purposes of reducing the concentration of colonic microflora.
he human colon is the most heavily colonized area of the human body. The concentration of bacteria ranges from 106–107 bacteria/g of stool content in the right colon to 1011–1012 bacteria/g in the rectosigmoid colon [1]. We have more bacterial cells in the human colon than eukaryotic cells in our body [2]. It is not surprising that operative procedures that involve resection of the colon are associated with the highest rates of surgical site infections (SSIs) among elective operations today. In a review of his lifetime interest in infection following colon surgery, Poth noted that elective colon surgery in the 1930s was associated with a 10%–12% mortality rate, 70%–90% rate of SSI, and a greater than 20% rate of anastomotic leak [3]. Although overall improvement in outcomes have occurred, it is likely that current SSI rates for elective colon surgery remain in excess of 20% when a full 30-d of post-discharge follow-up is included in the evaluation [4,5]. Anastomotic leak rates from colorectal anastomoses are still identified in 3%–6% of cases [6,7]. Overall in-hospital mortality rate for colectomy in 2010 is at 3% with infection the major contributor to deaths [8]. There remains opportunity for improvement in the infectious morbidity and mortality rates observed in these patients. The use of preventive systemic antibiotics has become a standard of clinical practice to prevent SSI in colon resection patients. The merits of pre-operative systemic administration of an antibiotic with activity against the anticipated contamination of the surgical site in gastrointestinal operations 1 2
Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Department of Surgery, University of New Mexico School of Medicine, Albuquerque, New Mexico.
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History of Colonic Preparation
senberg et al. in 1971 [22]. This was a three armed trial of mechanical preparation only, oral phthalylsulphathiazole for 5 d pre-operatively, or oral phthalylsulphathiazole and oral neomycin for 5 d pre-operatively. The study demonstrated lower SSIs and anastomotic leaks in the two groups receiving the oral antibiotics when compared with those patients with only mechanical preparation, but no added advantage of neomycin to the oral phthalylsulphathiazole was observed. The study has numerous problems, which include that only a total of 128 patients were in the three arms, and 40% did not have an anastomosis performed. Washington et al. [23] at the Mayo Clinic performed the first randomized clinical trial that clearly favored the use of the oral antibiotic bowel preparation. In a trial where all operations were performed by the same surgeon, all patients received mechanical bowel preparation and were then randomized to one of three groups: 1) oral placebo, 2) oral neomycin, or 3) oral neomycin and tetracycline. With nearly 200 randomized patients, those receiving the placebo had SSI rates of 43%, those with neomycin 41%, and those with neomycin and tetracycline 5% (p < 0.05). Following a preliminary study in 20 patients that demonstrated the effectiveness of the oral neomycin and erythromycin preparation on suppressing colonic aerobic and anaerobic bacteria by Nichols et al. [24], a randomized clinical trial by Clarke et al. of this oral antibiotic combination was evaluated versus patients receiving only mechanical bowel preparation for elective colon surgery [25]. These data demonstrated a SSI rate of 35% in the placebo-control group and only a 9% rate in the oral antibiotic group (p < 0.05). The oral antibiotic group had no anastomotic leaks, whereas leaks occurred in 10% of placebo patients. The mechanical preparations used by Nichols et al. [24] and Clarke et al., and that were used in the Washington et al. [23] study are detailed in Table 1. No systemic antibiotics were used in either study. Other prospective clinical trials demonstrated favorable outcomes using oral neomycin/ metronidazole [26] and kanamycin/erythromycin [27]. Yet another three arm study demonstrated effectiveness with oral phthalysulfathiazole, neomycin, and tetracycline all used together compared with placebo patients, but no statistical improvement with phthalysulfathiazole and neomycin without the tetracycline [28]. Three additional studies demonstrated improved clinical outcomes in SSI rates when systemic preventive antibiotics were added to the oral antibiotic bowel preparation [29–31].
Because of the high rates of infection and anastomotic leaks in colon surgery, mechanical preparation of the colon was employed but was recognized to not reduce surgical site infections from the 1930s. With the discovery of antibiotics, a large number of experimental and clinical efforts to use poorly absorbed, oral antibiotics to reduce the concentration of intra-luminal bacteria during or following mechanical preparation in studies were performed by Poth [12–14], Firor and Poth [15], Firor and Jonas [16], and Garlock and Seley [17]. Mechanical preparation with oral antibiotics was deemed to be necessary, not because it reduced SSIs, but because it reduced the large bulk of bacteria from formed stool and provided for timely delivery of the antibiotic to the entire length of the colon that cannot be achieved when an unprepared colon is present. During the 1940s, multiple sulfa derivatives were studied with respect to reductions in the bacterial concentrations within the colon lumen. Sulfathalidine was identified to have the most antibacterial effective [18]. Sulfathalidine was combined with neomycin in selected studies but failed to substantially alter SSI rates. Cohn and Rives demonstrated experimental benefits of intra-luminal tetracycline in the protection of colonic anastomoses [19] and Cohn and Longacre chose to combine neomycin with tetracycline [20]. However, the emergence of resistance to tetracycline led to abandonment of this combination. Based upon experimental studies, Cohn advocated kanamycin in combination with mechanical bowel preparation as the best method for prevention of SSI [21]. Thus, during the late 1950s and through the 1960s, considerable interest focused upon oral antibiotic bowel preparation as a means to reduce SSI and perhaps reduce leaking anastomoses following colon resection. Considerable experimental evidence supported the use of oral antibiotics, bacteriologic studies documented reductions in bacteria concentrations within the lumen, and studies with retrospective control groups provided some evidence for the use of several different oral regimens. However, there remained no randomized, prospective clinical trials to validate the method. Clinical Evidence for Oral Antibiotic Preparation
The initial effort at a randomized clinical trial of the oral antibiotic preparation in major colon surgery was by Ro-
Table 1. Mechanical Bowel Preparation Methods Used over Multiple Days in the Washington et al., Nichols et al., and Clarke et al. Studies Washington et al. [23]
Nichols et al. [24] and Clarke et al. [25]
Residue-free diet for 48 h before operation. Sodium phosphate and biphosphate 16 mL twice daily for 48 h before operation. Two tap water enemas 2 d before operation. Two tap water enemas each on the morning and afternoon of the day before operation. 500 mg neomycin and 250 mg tetracycline taken four times daily for 48 h before operation.
Day 1: Low residue diet; Bisacodyl, 1 capsule orally at 6 p.m. Day 2: Continue low residue diet; Magnesium sulfate, 30 mL 50% solution (15 Gm.) orally at 10:00 a.m., 2:00 p.m. and 6:00 p.m; Saline enemas in evening until return clear. Day 3: Clear liquid diet; supplemental IV fluids as needed. Magnesium sulfate, in dose above, at 10:00 a.m. and 2:00 p,m. No enemas. Neomycin (1 gm) and erythromycin base (1 gm) at 1300 hrs, 1400 hrs, and 2300 hrs. Day 4: Operation scheduled at 8:00 a.m.
BOWEL PREPARATION FOR ELECTIVE COLON SURGERY
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By the 1990s, the practice for the prevention of SSIs in elective colon surgery in North America was documented in two separate surveys to be the use of mechanical bowel preparation with oral antibiotics to reduce intra-luminal concentrations of potential pathogens, and perioperative systemic antibiotics to address contaminants at the surgical site itself [32,33]. Disillusionment with Mechanical Bowel Preparation
Mechanical bowel preparation was a critical consideration in the use of oral antibiotics to prevent SSIs in elective colon surgery. It was well documented in the Clarke et al. [25] study that intra-luminal bacterial concentrations declined by five logarithms with the oral neomycin-erythromycin combination. Hence the clinical trials of the 1970s that demonstrated favorable outcomes compared with the placebo group commonly pursued 48–72 h of vigorous mechanical cleansing before the oral antibiotics were initiated (Table 1). However, as the 1990s unfolded in the U.S., clinical practice for elective colonic surgery was undergoing a change. Economic pressures resulted in the elimination of pre-operative hospitalization, which compromised the comprehensive inpatient mechanical preparation of the prior decades. Ambulatory and quicker mechanical preparation became the order of the day. Large volumes of polyethylene glycol solution were consumed prior to hospitalization and the oral antibiotics were similarly administered at home on the day prior to hospitalization and operation. Discomfort with preparation prior to admission resulted in poor mechanical preparation from the huge mandatory volumes of oral liquids with bloating and abdominal discomfort. In addition, abdominal discomfort was experienced from the gastrointestinal motility effects of oral erythromycin. These problems of home-based mechanical preparation and oral antibiotic administration were particularly an issue among the elderly. Poor compliance and poor preparation led to ineffective antibiotic delivery throughout the colon, and the benefits of oral antibiotic bowel preparation were lost. This has led to a backlash of opinion that mechanical preparation and the oral antibiotic bowel preparation should be eliminated with only systemic preventive antibiotics used. Concerns about effectiveness have led to a large number of clinical trials, which demonstrated no reduction in SSI rates when mechanical preparation was compared with no preparation when patients in both arms of the clinical trials received preventive systemic antibiotics [34–42]. Aggregation of the studies in meta-analyses similarly demonstrated no outcome benefit from mechanical bowel preparation [43]. Oral antibiotics were not given in these studies. These studies essentially re-confirmed the studies of Poth and others from 70 y ago which demonstrated no benefit to mechanical preparation alone. The net effect was that mechanical bowel preparation has fallen into disfavor by the most recent survey results [44– 48] and with that disillusionment, the elimination of the benefits of the oral antibiotic bowel preparation.
FIG. 1. Illustrates the improvement in SSI rates in eight clinical trials of systemic and oral antibiotics versus systemic antibiotics alone. neomycin-metronidazole and systemic amikacin and metronidazole in one group, and systemic amikacin and metronidazole without oral antibiotics in the second group [49]. Both groups of patients received mechanical bowel preparation. This study demonstrated a remarkable reduction in SSI rates from 17% with systemic antibiotics alone to only 6% in those patients receiving the systemic antibiotics and oral antibiotics (p < 0.01). This publication also reported a meta-analysis, which was highly substantial in the support of using the oral antibiotic bowel preparation with systemic antibiotics for the reduction of SSI. Additional meta-analyses have similarly demonstrated the benefits of the oral antibiotic bowel preparation in conjunction with mechanical preparation and systemic antibiotics [50–53]. Fewer than 20 studies have been identified in the several meta-analyses of oral antibiotics plus systemic antibiotics versus systemic antibiotics alone in the prevention of SSI in elective colon surgery. A total of eight studies in addition to that of Lewis have had patient numbers that exceeded 100 patients in the randomization [54–61]. These are identified in Figure 1. Recently, clinical reports are re-discovering the benefits of the oral antibiotic bowel preparation. The Michigan Surgical Quality Collaborative has made several reports, which have consistently demonstrated the benefits of the oral antibiotic bowel preparation in the reduction of SSIs [62–64]. They have included the oral antibiotic bowel preparation as one of six elements of the Colon Surgery Bundle to prevent SSIs [65]. Several studies from the VA Surgical Quality Improvement project have similar identified that oral antibiotics make a difference in SSI rates [66,67], which can be further enhanced with the selection of appropriate pre-operative systemic antibiotics [68]. They have even reported that preoperative oral antibiotics may be effective without mechanical preparation, although this remains to be validated [69]. As was reported in the original study by Clarke et al., oral antibiotic bowel preparation reduces the frequency of leaking anastomoses [70,71].
Oral Antibiotics Revisited
Published studies that have evaluated the merits of combining mechanical bowel preparation with oral antibiotics have been sparse since the convincing studies that were published in the 1970s. Lewis reported a randomized controlled trial of elective colon resections, which compared oral
The Future of Oral Antibiotics in Elective Colon Surgery
The evidence supports the routine use of the oral antibiotic bowel preparation in conjunction with mechanical preparation for elective colon surgery. Recommendations that the mechanical bowel preparation should be omitted
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from the preparation of elective colon resection patients are ignoring the true merits of using mechanical bowel preparation with oral antibiotics together [72]. Many questions remain about the optimum methods to be used in the oral antibiotic bowel preparation and additional clinical trials are necessary. The evidence indicates that the mechanical preparation must be complete if orally administered antibiotics are to access the full length of the colon lumen. Retained stool yields a huge bulk of microbes, dietary fiber, and exfoliated cells that will not permit reduction of the density of potential pathogens on the colonic mucosal surface with oral antibiotics. Effective mechanical preparation may require more than a few hours of oral polyethylene glycol, especially in the outpatient setting with elderly patients. Furthermore, ingestion of the antibiotics while the mechanical process is actively ongoing may result in un-dissolved tablets and capsules passing though the gastrointestinal tract with no antimicrobial effect. As much as payers of care may object, it may be cost-effective in elderly patients or those with compliance issues in their own home environments to have the additional day of pre-operative admission so that the complete colon preparation is done in a fashion to optimize clinical outcomes. Effective home-health programs or daycare centers for seniors to provide effective colon preparation are alternatives to pre-operative admission. With episodebased payment for colon resections in the future [73], hopefully clinicians will have the flexibility to exercise judgments about pre-operative stays and management support in the interest of patient outcomes, which will reduce overall costs. Little research has focused upon which mechanical preparation method will best meet the needs of the oral antibiotic administration strategy. Although there have been a plethora of studies using mechanical preparation alone without benefit to patients, there have been few studies to evaluate which mechanical preparation actually efficiently and effectively removes all particulate waste from the colon. Itani et al. [74] have identified lower SSI rates when sodium phosphate mechanical preparation was used versus polyethylene glycol as a subset analysis of a randomized trial, which compared two different systemic antibiotics in elective colon surgery. One study has identified a better mechanical preparation with oral sodium phosphate than polyethylene glycol, and with a smaller oral volume of administration [75]. This observation is particularly interesting in light of basic research studies that have identified phosphate ion as a potential modulation variable in reducing the virulence of enteric gram-negative bacteria [76], and the prospects for binding phosphate to polyethylene glycol for bowel preparation [77]. Enthusiasm for phosphate-based bowel preparations will need to be tempered by known potential toxicities of hyperphosphatemia [78]. Few investigations have pursued the most desirable oral antibiotic. There is reason to challenge whether oral neomycin adds anything to the clinical outcome of the oral antibiotic bowel preparation [79]. Oral metronidazole has replaced erythromycin in some studies. Many other poorly absorbed antibiotics are available but comparative studies of alternative drugs have virtually been non-existent in the last 20 y. Furthermore, the timing of completion of the oral antibiotics prior to the surgical intervention has not had the best analytical evaluation and deserves further study. Finally, the risks of
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Clostridium difficile infection as a complication of the oral antibiotic bowel preparation remain to be fully explored [80]. In summary, published experience is consistent in the observation that mechanical bowel preparation when performed alone is not of value in the reduction of SSI following elective colon surgery. However, the evidence is equally convincing that the addition of the oral antibiotic bowel preparation to mechanical preparation provides improvement in outcomes when combined with appropriate systemic preventive antibiotics. The search for better mechanical and oral preparation strategies need to be re-vitalized. Author Disclosure Statement
The author discloses potential conflicts of interest with Merck and Co (Speakers Program), CareFusion (Speakers Program, Ethicon (Consultant), and IrriMax (Consultant and Speaker). References
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Address correspondence to: Dr. Donald E. Fry MPA Healthcare Solutions 1 East Wacker Drive, Suite 1210 Chicago, IL 60601 E-mail: [email protected]
