2

0d

The American Journal of Surgery (2011) 202, 225–232

Review

Colon preparation and surgical site infection

Donald E. Fry, M.D.*

Department of Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA; Michael Pine andAssociates, 5020 S Lake Shore Dr., #304N, Chicago, IL 60615-6061, USA; Department of Surgery, University of New

Mexico School of Medicine, Albuquerque, NM, USA

AbstractBACKGROUND: Colon preparation for elective colon resection to reduce surgical site infection (SSI)

remains controversial.METHODS: A review of the published literature was undertaken to define evidence-based practices

for colon preparation for elective colon resection.RESULTS: Seventy years of surgical literature has documented that mechanical bowel preparation

alone does not reduce SSI. A body of clinical trials has documented the benefits of oral antibiotic bowelpreparation compared with a placebo in the reduction of SSI. Clinical trials show the addition of the oralantibiotic bowel preparation to appropriate systemic preoperative preventive antibiotics provide thelowest rates of SSI.

CONCLUSIONS: Mechanical bowel preparation alone does not reduce rates of SSI, but oral antibi-otic preparation and systemic preoperative antibiotics are superior when compared with systemicantibiotics alone. Additional clinical trials are necessary to define the best combined overall mechanicaland oral antibiotic regimen for elective colon surgery.© 2011 Elsevier Inc. All rights reserved.

KEYWORDS:Surgical site infection;Preventive antibiotics;Mechanical bowelpreparation;Colon surgery;Oral antibiotics;Sodium phosphate;Polyethylene glycol

ttra

Among the millions of elective surgical proceduresperformed each year, none has a rate of surgical siteinfection (SSI) that is greater than elective resection ofthe colon. The rectosigmoid colon may have bacterialcounts that approach 1012 cfu/g of content,1 which meansthat any surgery that transgresses the lumen of the colonwill have millions of microbial contaminants at the sur-gical site. Although the exact rate of SSI in colon surgeryremains elusive, the only 2 large clinical trials that havebeen reported in recent years in which systemic antibi-otics were being evaluated for federal indications forcolorectal surgical prophylaxis had rates of about 20%

* Corresponding author. Tel.: �1-773 643 1700; fax: �1-773 6436601.

E-mail address: dfry@consultmpa.comManuscript received April 23, 2010; revised manuscript August 2,

010

002-9610/$ - see front matter © 2011 Elsevier Inc. All rights reserved.oi:10.1016/j.amjsurg.2010.08.038

when postoperative surveillance was continued for 4weeks after discharge.2,3 Reasonable estimates of na-ional rates remain obscure because of variable defini-ions of infection, variable risk factors present in colonesection patients, and variable intensity of postoperativend postdischarge surveillance.4 For all of these reasons,

public reporting of SSIs in colorectal and other surgicalprocedures likely will be quite problematic in the future.

Prevention of SSI using systemic preoperative antibi-otics appears to be firmly established at the current time.Foundation studies of Bernard and Cole5 and Polk andLopez-Mayor6 documented the effectiveness of preoper-ative preventive systemic antibiotics in gastrointestinalsurgical procedures that included colon cases. In a sum-mary of the published literature that included a detailedmeta-analysis of preoperative systemic antibiotics versusplacebos, Baum et al7 concluded that no additional pla-

cebo-controlled trials need be performed. Song and

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226 The American Journal of Surgery, Vol 202, No 2, August 2011

Glenny8 similarly performed a large meta-analysis thatconfirmed that preoperative administration of the drug iscritical and that sustained administration of the antibioticfor days after the procedure offers no benefit to thepatient. The principals established in these studies havebeen the basis for consensus performance measures thatsubsequently have been developed including those fromthe Surgical Infection Prevention Project and its succes-sor the Surgical Care Improvement Project.9,10

Although the academic community of surgery progres-sively moved toward a consensus opinion on the role ofsystemic antibiotics, such has not been the case for the useof colonic preparation. There continues to be confusionabout whether mechanical bowel preparation (MBP) aloneis of any value in reducing SSI rates, and whether oralantibiotics given in the preoperative period in conjunctionwith MBP is a useful technique in the prevention of infec-tion. This presentation attempts to review the evolution ofthe strategies to prepare the colon for surgical resection,identify the current evidence for and against MBP and oralantibiotic preparation, and provide some perspective on thefuture of colonic preparation that will optimize outcomesfor these patients.

History of Mechanical Colon Preparation

The origin of MBP is likely to date from the verybeginning of resection as a treatment method for colonicdisease. Refinements in general anesthesiology and theadvent of blood banks in the 1930s resulted in moreventuresome surgical interventions into the microbe-laden colon and infection became a predominant compli-cation. Colon resections from the era of the 1930s wereaccompanied by mortality rates of 10% to 12% and hadSSI rates reported to be as high as 80% to 90%.11 Fromhe beginning of clinical microbiology, it was apparenthat the human colon contained an unusually high con-entration of microbes. Cleansing the colon of gross fecalaterial was a logical strategy to reduce microbial con-

amination at the surgical site and thus potentially reducenfections. Many surgeons believed that mechanicalleansing enhances the manipulation of the colon withinhe abdomen during laparotomy, but MBP has been pur-ued principally for its theoretical benefits in the reduc-ion of SSI. In many abdominal surgeries in which colonesection was not a planned part of the procedure, pre-perative MBP of the colon also was undertaken with thessumption that inadvertent colon wounds from dissec-ion could safely be repaired primarily. From the 1930shrough the subsequent decades, MBP became a part ofurgical lore even though no prospective randomizedrials validated the assumption.

As a pioneer in the use of oral antibiotics for colonicurgery, Poth11 noted that although MBP reduced the bur-

en of total bacteria in the colon, it did not reduce the c

oncentration of bacteria. Nichols et al12 similarly con-rmed that MBP alone had no impact on microbial concen-

ration in the colon. The only conclusion that can be reacheds that there is no clinical or microbiologic evidence toupport MBP alone as a method to reduce SSI rates forlective colon surgery.

Oral Antibiotic Bowel Preparation

Indeed, from the earliest time of the introduction ofantibiotics into clinical practice with sulfanilamide prep-arations in the 1930s, surgical investigators were explor-ing the use of antimicrobials in the lumen of the colonbecause it was recognized that MBP did not reduce eitherthe concentration of bacteria or SSIs.13–15 The severitynd frequency of infectious complications in colon sur-ery, the availability of new antibiotics that were beingarketed by companies, and the recognition from animal

xperiments that dramatic reductions in colonic bacteriaensity could be achieved with oral antibiotics led tonthusiastic investigations of intestinal antisepsis.16 Ed-ar Poth11 became the champion of colonic preparationor elective surgical intervention beginning in 1940. Heecognized from the beginning that MBP was a require-ent for effective intestinal antimicrobial use, not be-

ause it reduced the concentration of bacteria, but be-ause the massive colonic burden of intraluminal bacteriaad to be diminished if any antimicrobial action wasoing to occur on the mucosal surface with orally admin-stered drugs. The vigor of MBP to rid the colon of anyetained fecal material often extended for several daysefore the actual procedure. He formulated requirementsor the ideal oral antibiotic (Table 1). Succinylsulfathia-ole and Sulfathalidine (phthalsulfathiazole) were drugsf choice because of poor absorption, high intraluminal

Table 1 Provides the requirements of an ideal antibioticbowel preparation as defined by Poth

Low toxicity for the hostBroad antimicrobial spectrumChemical stability in the presence of digestive enzymesCapacity to prevent overgrowth or development of resistant

bacteriaRapidity of actionActivity in the presence of nutrientsLow absorption from the enteric tractAid to mechanical cleansing without causing dehydrationNonirritant to enteric mucosaNoninhibitor of healingLow bacteriocidal dosageWater solublePalatableAntifungal activityUse restricted to intestinal antisepsis

oncentrations, and effective reduction in aerobic bacte-

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227D.E. Fry Colon preparation and SSI

rial species within the colon.17,18 Although these sulfapreparations did not have activity against the anaerobicspecies of the colon, Poth11 believed that disruption ofthe anaerobic environment and the synergistic relation-ship between aerobes and anaerobes would result in anobligatory reduction in anaerobic concentrations.

The microbial coverage of the sulfa derivatives subse-quently was considered inadequate, and with the introduc-tion of the aminoglycosides, these drugs were consideredfor intestinal antisepsis. As a group they were not absorbedfrom the gut and high intraluminal concentrations wereachieved. Streptomycin was first used in conjunction withsulfathalidine,19 but streptomycin was replaced with neo-mycin.20 Cohn21 subsequently popularized the use of kana-

ycin as a single oral antibiotic preoperatively.The litany of studies during the 1950s and 1960s were

ased largely on microbiologic effects of the respectiverugs, with no prospective and randomized clinical studieshowing reduced rates of SSI.

In the 1970s, a greater appreciation for the pathologicole of anaerobic bacteria in infection emerged.22,23 Despitehe recognition that anaerobes were in greatest concentra-ion in the colon, they had largely been ignored in theelection of oral antibiotics in colon surgery. In 1974,

ashington et al24 published the first prospective random-zed trial of oral neomycin alone versus oral neomycin plusetracycline versus a placebo in a 3-armed trial. In a uniquelinical study, a single surgeon performed all the proce-ures. A vigorous MBP was used with a low residue diet,ral sodium phosphate and biphosphate, and tap water en-mas during 48 hours before the procedure (Table 2). Thentibiotics or placebo were given over the same 48-houreriod. Tetracycline was added because of its anaerobicctivity, although it was absorbed to some degree and likely

Table 2 Diversity of MBP that has been used in those studiesbe effective

Washington et al,24 1974 Nichols,25 1973

Residue-free diet for 48 h beforesurgery

Sodium phosphate andbiphosphate 16 mL twice dailyfor 48 h before surgery

Two tap water enemas 2 dbefore surgery

Two tap water enemas each onthe morning and afternoon ofthe day before surgery

500 mg neomycin and 250 mgtetracycline taken 4 times/dfor 48 h before surgery

Day 1, low-residue dietorally at 6 PM

Day 2, continue low-remagnesium sulfate, 3(15 g) orally at 10:06:00 PM; Saline enemreturn clear

Day 3 clear liquid diet;intravenous fluids as

Magnesium sulfate, at10:00 AM and 2:00 PM

No enemasNeomycin (1 g) and ery

at 1:00, 2:00, and 11Day 4, surgery schedule

ad systemic effects, as was pointed out by Altemeier in the i

iscussion of the manuscript by Washington et al.24 Thetrial results were dramatic: 43% SSIs in the placebo group,41% in the neomycin-only group, but only 5% in the neo-mycin plus tetracycline group.

A year before the Washington study, Nichols et al25

published a small series (N � 20) with bacteriology resultsthat showed both aerobic and anaerobic effectiveness ofneomycin and erythromycin base in the colon after MBP.Erythromycin was chosen because of its superior activityagainst Bacteroides fragilis and the base preparation wasselected because of poor absorption and high intraluminalconcentrations, even though therapeutic systemic concen-trations of this preparation had been documented after oraladministration.26 The MBP was a 3-day regimen (Table 2).The oral antibiotics (1 g of each drug) were given at 1:00PM, 2:00 PM, and 11:00 PM the day before the surgery.

By using this mechanical and oral antibiotic regimen, arospective and randomized clinical trial within the Veter-ns’ Administration followed this preliminary study byhese same investigators. A placebo was compared witheomycin/erythromycin and showed a statistically signifi-ant reduction in SSIs (35% vs 9%) and in anastomoticeaks (10% vs 0%).27 Additional oral antibiotic studies

documented the value of metronidazole in place of eryth-romycin,28 and one study examined 3 oral drugs of neomy-cin, phthalsulfathiazole, and tetracycline in the reduction ofSSIs.29 Further studies examined the merits of systemicntibiotics with the oral antibiotic bowel preparation andhowed reductions in SSI rates compared with using the oralowel preparation only.30–32 The rationale of both strategieseing used together was that oral antibiotics reduced thenoculum of bacteria contaminating the surgical site fromhe colon, and systemic antibiotics provided a safety net offfective drug in the soft tissues to minimize the risk of

ich the oral antibiotic bowel preparation has been shown to

1-day preparation

odyl, 1 capsule

iet;50% solution:00 PM, andvening until

mentaldated earlier, at

ycin base (1 g)

:00 AM

Day before procedure49: 48 g of sodiumphosphate with �2 L of water giventhe day before the procedure; if notclear, then saline enemas until clearwith all completed by 6:00 PM

Then, 2 g of neomycin and 2 g ofmetronidazole at 7:00 and 11:00 PM

orDay before procedure36: 4 L of

polyethylene glycol (60 g) and salts(CoLyte®[Alaven Pharmaceuticals,Marietta, GA], GoLYTELY®[BraintreeLaboratories, Braintree, MA]) to becompleted by 12:00 PM; thenneomycin 1 g and erythromycin 1 gat 1:00, 2:00, and 10:00 PM

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228 The American Journal of Surgery, Vol 202, No 2, August 2011

By the 1980s and 1990s, the use of the oral antibioticbowel preparation was firmly accepted and practiced forcolon surgery in the United States. Two separate surveys ofcolorectal surgeons of practices during this time intervalshowed that more than 85% of survey participates claimedto use both oral antibiotics and preoperative systemic anti-biotics for elective resections.33,34 All claimed the use ofMBP and the majority used polyethylene glycol, which wasviewed as the most efficient and the best quality of intestinalpreparation with the best patient tolerance.35,36

Although traditional laxatives, cathartics, and enemashad been used for MBP, the transition to the polyethyleneglycol– based preparations in the late 1980s and early1990s was driven by several factors. The proliferation ofdiagnostic and therapeutic colonoscopy required the de-velopment of a rapid and effective bowel preparationwithout the inconvenience of several days of preparation.In addition, for elective colon surgery, the strong eco-nomic pressures to reduce the hospital length of stayresulted in the elimination of the 1 or 2 days of preop-erative hospitalization for MBP under hospital direction,and patients were expected to take the preparatory solu-tions and the oral antibiotics at home before same-dayhospitalization and surgery. It certainly can be speculatedthat home-based MBP of the colon and the home admin-istration of oral antibiotics has led to significant compli-ance problems, dissatisfaction of patients with the pro-cess of home mechanical preparation, and ultimately todissatisfaction of clinicians with the quality of prepara-tion that existed at the time of surgery. The dissatisfac-tion among physicians and patients alike led to a re-appraisal of the necessity for MBP at all. Evidence of thisdissatisfaction is seen in the 2010 survey of colon andrectal surgeons, which is in striking contrast to the priorsurveys of the 1980s and 1990s cited earlier. In thissurvey only 76% stated that they always use MBP and55% stated that they never use the oral antibiotic bowelpreparation.37

Table 3 Prospective randomized trials of no MBP versus patie

Study

No mechanical preparation

Number of patients Infections

Miettinen, 2000*41 129 10 (8%)Bucher, 2005*45 75 6 (8%)

Fa-Si-Oen, 2005*39 125 13 (10%)Ram, 2005†43 165 10 (6%)Zmora, 2006*46 129 17 (13%)Jung, 2006*40 657 106 (16%)Contant, 2007†38 684 96 (14%)Pena-Soria, 2008*42 64 11 (17%)Van’t Sant, 2010†44 213 36 (17%)

Only 1 article concluded a statistically significant difference in infe*Reports include all SSIs.†Reports include only surgical incision infections.

MBP revisited

Although it already had been validated since the late1930s that MBP did not reduce the concentration of bacteriain the colon or reduce SSIs, the mythology of its usefulnessin the absence of concomitant oral antibiotics continued.Because the oral antibiotic bowel preparation achieved onlylimited popularity outside the United States and Canada, itis not surprising that surgeons from other countries withinthe past decade have led the challenge against MBP. In thepast decade (2000–2010) numerous clinical trials have onceagain confirmed the null hypothesis: MBP for elective colonsurgery does not reduce SSI rates38–44 (Table 3). One studyhowed an actual increase in SSIs in the patients whoeceived the MBP,45 but then the polyethylene glycol wasot initiated until 12 to 16 hours before the start of therocedure and one can only speculate about the conse-uences of retained lavage solution in the colon at the timef resection. One study even used oral neomycin and eryth-omycin in the study population that did not receive MBP.46

The lack of benefit of MBP for elective resection has beenvalidated further with the obligatory meta-analyses thathave reproven the observations of Poth in the 1930s.47–49

Without oral antibiotics, MBP of the colon is indeed uselessin the prevention of SSI and no further studies are needed toprove that point.

Oral antibiotic bowel preparation revisited

It appears that MBP of the colon, and with it the use ofthe oral antibiotic bowel preparation, has fallen into disre-pute and is being abandoned by many surgeons for electivecolon surgery. The most recent publication to resurrect theoral antibiotic bowel preparation was by Lewis.50 In thistudy, patients in both arms of the trial received an identicalegimen of systemic antibiotics (amikacin and metronida-ole). All patients received a standard MBP with sodium

eiving MBP in elective colon surgery from 2000 through 2010

mechanical preparation

Statistical significanceer of patients Infections

13 (10%) Not significant17 (22%) P � .03 higher with

mechanical preparation16 (13%) Not significant16 (10%) Not significant15 (12.5%) Not significant

103 (15%) Not significant90 (13%) Not significant19 (29%) Not significant39 (16.5%) Not significant

tes.

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229D.E. Fry Colon preparation and SSI

phosphate that was completed by 6:00 PM. Patients wereandomized to oral neomycin (2 g) and metronidazole (2 g)t 7:00 PM and 11:00 PM the night before the surgery. Resultshowed a reduction in infections in the surgical incisionrom 17% in the oral placebo group to 5% among thoseeceiving the preoperative oral antibiotics. Lewis then pro-eeded in the same publication to incorporate his data with2 other studies in which oral antibiotics had been random-zed to elective colon surgery and in which all patientseceived a standard preoperative systemic antibiotic regi-en.51–62 The meta-analysis of the aggregated studies was

significant (P � .0001) in favor of combined mechanicaland oral bowel preparation that is used with preoperativesystemic antibiotics for the reduction of SSIs in electivecolon surgery (Fig. 1).

The meta-analysis of Lewis50 has been further refined byaking only those nine studies which were randomized,ontrolled trials and had N � 100 total patients. In Table 4,he data of these nine clinical trials have been summarized.sing Peto’s Method for randomized,63 controlled trials

Figure 1), the meta-analysis demonstrated a summary oddsatio of 0.47 (95% CI: 0.16–.77) in favor of using combinedystemic antibiotics with the oral antibiotic bowel prepara-ion (P � 0.0001). An additional meta-analysis was per-

Figure 1 Meta-analysis of the 9 randomized clinical trials ofral antibiotics and systemic antibiotics versus systemic anti-iotics only in patients undergoing elective colon surgery. Thebscissa presents the odds ratios of each study for oral antibi-tics and systemic antibiotics used together in log10 units. The

author of each study is identified with the reference. The arrowidentifies the specific odds ratio for each study. The horizontalline indicates the 95% confidence interval for the odds ratios ofeach study. The summary meta-analysis is at the bottom of thefigure.

ormed using a variance-based method for differences in the

SI occurrences as an effect measure.64 SSIs were 6.18 %(95% CI: 3.43–8.94; Standard Deviation � 1.40) less whencombining systemic and oral antibiotics compared to sys-temic antibiotics alone. This second analysis identifies thesummary rate of SSIs of all combined studies at 4 standarddeviations less than the null hypothesis of no difference(P � .0001).

More recently, a propensity analysis of elective colonresection patients from a prospectively gathered state-widedatabase in Michigan similarly showed a 12% SSI rate forpatients receiving only preoperative systemic drugs, whereassystemic drugs plus the oral antibiotic bowel preparation re-sulted in 4.5% SSIs.65

Conclusions

The clinical evidence indicates that MBP by itself offersno benefit for the reduction of SSIs in elective colon sur-gery. The clinical evidence supports the use of MBP as animportant adjunct to the use of the oral antibiotic bowelpreparation. The use of the oral antibiotic bowel preparationand systemic preoperative preventive antibiotics together isthe regimen with the best prospects for the prevention ofSSIs in elective colon surgery.

Important issues remain to be explored with future clin-ical trials about prevention of SSIs in elective colon surgery.Further validation of the role of oral antibiotic preparation isnecessary.

What is the best MBP? Some evidence indicates betteroutcomes with sodium phosphate than polyethylene gly-col.66 Increasing intraluminal phosphate concentrationsmay attenuate pathogenic phenotypes of gut pathogens.67

Sodium phosphate can be associated with complicatinghyperphosphatemia.68 Sodium phosphate preparationsre associated with extracellular volume depletion69

whereas polyethylene glycol appears to expand extracel-lular volume.70 Without complete MBP, oral antibioticswill be ineffective, but how best to achieve mechanicalpreparation requires refinement.

What is the best oral antibiotic regimen? Erythromycinbase has had the greatest use but may not be toleratedbecause of disordered gastrointestinal motility. Metronida-zole is better tolerated by patients, has excellent anaerobicactivity, has an enterohepatic circulation, and has beenshown to be clinically effective.71 Should neomycin be usedt all? Some evidence indicates otherwise.72

What is the best timing of MBP and administration of theoral antibiotics?

Successful studies have completed MBP by the after-noon of the day before the procedure and oral antibiotics arenot given until MBP is complete. Lavage solution remain-ing within the colon is a liability for splash and increased

infections during colectomy. Administration of oral drugs

ap

ir

230 The American Journal of Surgery, Vol 202, No 2, August 2011

during colonic lavage results in undissolved capsules andtablets in the bedpan (personal observation).

Does mechanical and oral antibiotic preparation increasethe risk for Clostridium difficile infection? Wren et al73

presented retrospective data that indicated an increased rateof C difficile infection with the oral antibiotic bowel prep-ration, whereas Lewis has not shown any such effect in hisrospective trial.50 Systemic antibiotics must not be contin-

ued for more than 24 hours after the surgical procedurebecause the host will be vulnerable to recolonization of thecolon with C difficile and other resistant microbes. Probiot-cs may have a role in recolonizing the colon after electiveesection.74

Additional clinical trials are necessary to address theseunanswered questions. One conclusion can unequivocallybe drawn: no more trials of MBP alone are warranted.Patients are best served by appropriate use of oral andsystemic preventive antibiotics together.

Acknowledgment

The author has received honoraria from Merck and Pfizer

Table 4 Summary of studies comparing the oral antibiotic boalone in elective colon surgery

StudyCombined antibioticsreceived

Oral and IVantibiotics

Surgicalwoundinfection

Numpati

Kaiser, 198354 Neomycin-erythromycin 2 (3%) 63

Lau, 198856 Neomycin-erythromycin 3 (5%) 65

Coppa, 198857 Neomycin-erythromycin 9 (5%) 169Reynolds, 198958 Neomycin-

metronidazole9 (8%) 107

Khubchandani,198959

Neomycin-erythromycin 5 (9%) 55

Stellato, 199060 Neomycin-erythromycin 3 (6%) 51

Taylor, 199461 Ciprofloxacin 17 (11%) 159

McArdle, 199562 Ciprofloxacin 8 (10%) 82

Lewis, 200250 Neomycin-metronidazole

5 (5%) 104

Only studies with a total study population of 100 or more patients wereceiving both oral and systemic antibiotics when compared with system

IV � intravenous.

for speaking programs and has been a consultant to Ethicon,

Molnlycke Medical, and Ortho-McNeal in the area of sur-gical infection.

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