Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

101. Antimicrobial Prophylaxis in Surgery

Salmaan Kanji


KEY CONCEPTS

 Images Prophylactic antibiotic therapy differs from presumptive and therapeutic antibiotic therapy in that the latter two involve treatment regimens for documented or presumed infections, whereas the goal of prophylactic therapy is to prevent infections in high-risk patients or procedures.

 Images The risk of a surgical site infection (SSI) is determined from both the type of surgery and the patient-specific risk factors; however, most commonly used classification systems account for only procedure-related risk factors.

 Images The timing of antimicrobial prophylaxis is of paramount importance. Antibiotics should be administered within 1 hour before surgery to ensure adequate drug levels at the surgical site prior to the initial incision.

 Images Antimicrobial agents with short half-lives (e.g., cefazolin) may require intraoperative redosing during long (>3 hours) procedures.

 Images The type of surgery, intrinsic patient risk factors, most commonly identified pathogenic organisms, institutional antimicrobial resistance patterns, and cost must be considered when choosing an antimicrobial agent for prophylaxis.

 Images Single-dose prophylaxis is appropriate for many types of surgery. First-generation cephalosporins (e.g., cefazolin) are the mainstay for prophylaxis in most surgical procedures because of their spectrum of activity, safety, and cost.

 Images Vancomycin as a prophylactic agent should be limited to patients with a documented history of life-threatening β-lactam hypersensitivity or those in whom the incidence of infections with organisms resistant to cefazolin (e.g., methicillin-resistant Staphylococcus aureus) is documented or high enough to justify use.


According to the National Center for Health Statistics, some 46 million surgical procedures are performed annually in the United States, the majority of which are done in an outpatient setting.1 Infection is the most common complication of surgery.2 Surgical site infections (SSIs) occur in – 3% to 6% of patients and prolong hospitalization by an average of 7 days at a direct annual cost of $5 billion to $10 billion.3,4SSIs are the third (14% to 16%) most frequent cause of nosocomial infections among hospitalized patients and the primary (40%) cause of nosocomial infection in surgical patients.3 Prophylactic administration of antibiotics decreases the risk of infection after many surgical procedures and represents an important component of care for this population.

Antibiotics administered prior to the contamination of previously sterile tissues or fluids are called prophylactic antibiotics. The goal of therapy is to prevent an infection from developing. Although eradication of distal (preexisting, unrelated to surgery) infections lowers the risk for subsequent postoperative infections, it does not per se constitute a prophylactic regimen. In fact, surgical prophylaxis often is prescribed concurrently under these circumstances because of important antimicrobial spectrum- and timing-related concerns. Both SSIs and infections not directly related to the surgical site (e.g., urinary tract infections and pneumonia) are termed nosocomial. Prevention of hospital-acquired infections is a major goal of antibiotic prophylaxis.

Images Presumptive antibiotic therapy is administered when an infection is suspected but not yet proven. Clinical scenarios where presumptive therapy is used commonly include acute cholecystitis, open compound fractures, and acute appendicitis of less than 24 hours’ duration. In these situations, if signs of perforation or infection are absent during surgery, then routine prophylactic treatment rather than presumptive therapy is warranted. An operative finding of a gangrenous gallbladder or a perforated appendix, however, is suggestive of an established infectious process, and a therapeutic antibiotic regimen is required.3

According to the Centers for Disease Control and Prevention’s (CDC) National Nosocomial Infections Surveillance System (NNIS),3 SSIs can be categorized as either incisional (e.g., cellulitis of the incision site) or organ/space (e.g., meningitis; Fig. 101-1). Incisional SSIs are subcategorized into superficial (involving only the skin or subcutaneous tissue) and deep (fascial and muscle layers) infections. Organ/space SSIs can involve any anatomic area other than the incision site. For example, a patient who develops bacterial peritonitis after bowel surgery has an organ/space SSI. By definition, SSIs must occur within 30 days of surgery. If a prosthetic implant is involved, a deep incisional or organ/space SSI can be reported up to 1 year from the date of surgery. Although microbiologic testing of surgical drainage material or sites may help to guide care, the specificity of a negative culture is poor and generally does not rule out an SSI.3

Images

FIGURE 101-1 Cross section of abdominal wall depicting Centers for Disease Control and Prevention classifications of surgical site infections (SSI). (Reprinted from reference 3 with permission from Elsevier and the Association for Professionals in Infection Control and Epidemiology.)

RISK FACTORS FOR SURGICAL SITE INFECTIONS

Images SSI incidence depends on both procedure- and patient-related factors. Traditionally, the risk for SSIs has been stratified by surgical procedure in a classification system developed by the National Research Council (NRC; Table 101-1).5 The NRC classification system proposes that the risk of an SSI depends on the microbiology of the surgical site, the presence of a preexisting infection, the likelihood of contaminating previously sterile tissue during surgery, and the events during and after surgery.5,6 A patient’s NRC procedure classification is the primary determinant of whether antibiotic prophylaxis is warranted. However, because a patient’s NRC wound classification is influenced by surgical findings (e.g., gangrenous gallbladder) and perioperative events (e.g., major technique breaks), categorization generally occurs intraoperatively.7

TABLE 101-1 National Research Council Wound Classification, Risk of Surgical Site Infection, and Indication for Antibiotics

Images

Inherent Patient Risk

The NRC classification system does not account for the influence of underlying patient risk factors for SSI development, instead categorizing the risks for SSIs simply based on a specific surgical procedure. Disease states and conditions known to increase SSI risk are listed in Table 101-2. Preexisting distal infections increase SSI rates and should be resolved prior to surgery whenever possible. Diabetic patients have an increased risk for SSIs, especially those with uncontrolled perioperative blood sugars. Preoperative smoking has been identified as an independent risk factor for SSI because of the deleterious effects of nicotine on wound healing. Preoperative immunosuppression, including corticosteroid use, may increase infection risk. Patients coinfected with human immunodeficiency virus (HIV) and hepatitis C are at approximately double the risk of SSI as the general population.8 Malnutrition is a well-described risk factor for postoperative complications, including SSI, impaired wound and colonic anastomosis healing, and prolonged hospital stay. Although enteral feeding during the perioperative period can reduce bacterial translocation by maintaining the integrity of the intestinal mucosa, nutritional supplementation does not decrease the incidence of infection.9

TABLE 101-2 Patient and Operation Characteristics That May Influence the Risk of Surgical Site Infection

Images

Colonization of the nares with Staphylococcus aureus is a well-described SSI risk factor.3 Although intranasal application of mupirocin ointment reduces the rate of nasal carriage of S. aureus, one large, randomized, double-blind study of 4,030 surgical patients found that prophylactic intranasal mupirocin did not reduce the rate of S. aureus SSI, although it did reduce the rate of nosocomial S. aureusinfections among patients who were S. aureus carriers.10Other factors shown to increase the risk of SSI are age, length of preoperative hospital stay, and obesity.3

Identifying SSI Risk

Two large epidemiologic studies have objectively quantified SSI risk based on specific patient- and procedure-related factors. The Study on the Efficacy of Nosocomial Infection Control (SENIC) analyzed more than 100,000 surgery cases to identify and validate risk factors for SSI.11 Abdominal operations, operations lasting longer than 2 hours, contaminated or “dirty” procedures (as per NRC classification), and more than three underlying medical diagnoses each was associated with an increased incidence of SSI. When NRC classification was stratified by number of SENIC risk factors present, SSI incidence varied by as much as a factor of 15 within the same NRC operative category (Table 101-3).12

TABLE 101-3 Surgical Site Infection Incidence (%) Stratified by NRC Wound Classification and SENIC Risk Factorsa

Images

In a subsequent analysis of more than 84,000 surgical cases, the NNIS attempted to simplify and refine the SENIC system by quantifying intrinsic patient risk using the American Society of Anesthesiologists’ (ASA) preoperative assessment score (Table 101-4).14,15 An ASA score ≥3 was a strong predictor for the development of an SSI. Other factors associated with increased SSI incidence are contaminated or “dirty” operations (NRC criteria) and surgical procedures lasting longer than average. As in the SENIC study, the SSI rate was linked to the number of risk factors present and varied considerably within NRC class. The NNIS basic SSI risk index is composed of the following criteria: ASA score = 3, 4, or 5; wound class; and duration of surgery. Overall, for 34 of the 44 NNIS procedure categories, SSI rates increased proportionally with the number of risk factors present.13 The SSI rate was generally lower when the procedure was done laparoscopically.

TABLE 101-4 American Society of Anesthesiologists’ Physical Status Classification

Images

Although evidence-based recommendations for antimicrobial prophylaxis during surgery are best established using the results of randomized clinical trials, many studies have small sample sizes and do not stratify patients according to overall SSI risk. Future studies, particularly those involving clean procedures, should be stratified by SSI risk so that the subset of high-risk patients who might benefit the most from prophylaxis is clearly established.

BACTERIOLOGY

The most important consideration when choosing antibiotic prophylaxis is the bacteriology of the surgical site. Organisms involved in an SSI are acquired by one of two ways: endogenously (from the patient’s own normal flora) or exogenously (from contamination during the surgical procedure). Based on the type and anatomic location of the procedure and the NRC classification (see Table 101-1), resident flora can be predicted and appropriate antibiotic choices made. According to NNIS data, S. aureus, coagulase-negative staphylococci, enterococci, Escherichia coli, and Pseudomonas aeruginosa are the pathogens most commonly isolated (Table 101-5).14 With the widespread use of broad-spectrum antibiotics, however, Candida species and methicillin-resistant Staphylococcus aureus (MRSA) are becoming more prevalent.14

TABLE 101-5 Major Pathogens in Surgical Wound Infections

Images

Factors affecting the ability of an organism to induce an SSI depend on organism count, organism virulence, and host immunocompetency. Organisms in the commensal flora generally are not pathogenic. These organisms often serve the host as a form of protection against invasive organisms that otherwise would colonize the surgical site. Opportunistic organisms usually are kept in check by normal flora and rarely are problematic unless they are present in large numbers. The loss of normal flora through the use of broad-spectrum antibiotics can destabilize homeostasis, allowing pathogenic bacteria to proliferate and infection to occur.4

Normal flora translocated to a normally sterile tissue site or fluid during a surgical procedure can become pathogenic. For example, S. aureus or Staphylococcus epidermidis may be translocated from the surface of the skin to deeper tissues or E. coli from the colon to the peritoneal cavity, bloodstream, or urinary tract. Studies in animals and healthy volunteers have shown bacterial virulence to be an important determinant in the development of secondary infections.16,17 Whereas more than one million S. aureus per square centimeter or gram of tissue are required to produce infection in animals, less than 100,000 Streptococcus pyogenes per square centimeter or gram of tissue are required at the same site.17,18

Impaired host defense reduces the number of bacteria required to establish an infection. A breach of normal host defenses through surgical intervention (e.g., insertion of a prosthetic device) may enable organisms to cause infection. In addition, the loss of specific immune factors, such as complement activation, tissue-derived inhibitors (e.g., proinflammatory cytokines), cell-mediated response (e.g., T-cell function), and granulocytic or phagocytic function (e.g., neutrophils or macrophages) can greatly increase the risk for SSI development.19 Vascular occlusive states related to the surgical procedure or those occurring from hypovolemic shock can greatly affect blood flow to the surgical site, thus diminishing host defense mechanisms against microbial invasion. Traumatized tissue, hematomas, and the presence of foreign material also lead to more infections. When a foreign body is introduced during a surgical procedure, fewer than 100 bacterial colony-forming units are required to cause an SSI.20 Studies examining S. aureus-contaminated wound infections on the skin of healthy volunteers demonstrate a 10,000-fold reduction in the number of organisms required to establish a wound infection if sutures are not present.16

ANTIMICROBIAL RESISTANCE

Colonization of the host with antibiotic-resistant hospital flora prior to or during surgery may lead to an SSI that is unresponsive to routine antibiotic therapy. The most common cause of nosocomially acquired multiresistant organisms is transmission from hospital personnel.21 Patients treated with broad-spectrum antibiotic therapy are at increased risk for colonization with hospital flora.

With cephalosporins established as first-line agents for prophylaxis, organisms resistant to cephalosporins represent the majority of pathogens causing SSIs. MRSA and coagulase-negative staphylococci have emerged as the most common pathogens in patients who develop SSIs despite prophylaxis with cephalosporins particularly in cardiothoracic, vascular, orthopedic, and neurologic surgery. Methicillin resistance not only limits the treatment/prophylaxis options available, but it also is associated with increased mortality, longer hospital lengths of stay, and increased costs.22,23 Although the use of vancomycin for prophylaxis may be appropriate for some operations performed in hospitals with a high rate of infection due to MRSA, there is little guidance on what constitutes a “high rate” of MRSA infection and whether providing prophylaxis with vancomycin alone will result in fewer SSIs.24 A more effective strategy would be to screen elective surgical candidates for MRSA colonization preoperatively. MRSA colonization is predictive of MRSA SSI and thus effective prophylaxis with vancomycin is then reserved for carriers only. Some single center studies evaluating the decolonization of MRSA carriers preoperatively (i.e., with intranasal mupirocin, chlorhexidine showers) yield mixed results and may not be cost-effective.25,26

Although cefazolin remains a mainstay in cardiovascular SSI prophylaxis, its failure has been reported in cases involving methicillin-sensitive Staphylococcus aureus (MSSA). In a comparison trial between cefamandole and cefazolin, significantly more failures were attributed to cefazolin, even though the primary pathogen was MSSA.27 However, a similar trial comparing cefazolin and cefuroxime did not show any difference in SSI incidence between the two regimens.27 The β-lactamase expressed by some MSSA may be capable of hydrolyzing cefazolin more readily than cefuroxime or cefamandole. Although this trend is disturbing, the overall incidence of cefazolin failure remains low, and cefazolin remains the drug of choice for SSI prophylaxis in cardiovascular surgery.27

The increase in frequency of fungal infections in surgical patients has drawn concern. In hospitalized patients, the incidence of nosocomial Candida infections nearly doubled from 1992 to 2004.14,28Overzealous use of broad-spectrum antibiotics is the most likely cause for this increase. A study of patients undergoing cardiovascular surgery identified sex (female), length of stay in the ICU, and duration of central venous catheterization as risk factors for postoperative Candida infections.29 Although presurgical Candida colonization is associated with a higher risk of fungal SSIs, routine preoperative use of prophylactic antifungal agents is not being advocated at this time.28,30

SCHEDULING ANTIBIOTIC ADMINISTRATION

ImagesImages The following principles must be considered when providing antimicrobial surgical prophylaxis: (a) the agents should be delivered to the surgical site prior to the initial incision, and (b) bactericidal antibiotic concentrations should be maintained at the surgical site throughout the surgical procedure. Although animal and human models have demonstrated the efficacy of a single dose of an antibiotic administered just prior to bacterial contamination, long operations often require intraoperative doses of antibiotics to maintain adequate concentrations at the surgical site for the duration of surgery.31Antibiotics should be administered with anesthesia just prior to the initial incision. Administration of antibiotics too early may result in concentrations below the MIC toward the end of the operation, and administration too late leaves the patient unprotected at the time of initial incision. In a study examining the timing of antibiotic administration to 2,847 patients receiving prophylaxis, Classen et al.31evaluated patients who received prophylaxis early (2 to 24 hours before surgery), preoperative prophylaxis (0 to 2 hours prior to surgery), perioperative prophylaxis (up to 3 hours after first incision), and postoperative prophylaxis (>3 hours after the first incision). The risk of infection was lowest (0.6%) for patients who received preoperative prophylaxis, moderate (1.4%) for those who received perioperative antibiotics, and greatest for those who received postoperative antibiotics (3.3%) or preoperative antibiotics too early (3.8%). The risk for an SSI increases dramatically with each hour from the time of initial incision to the time when antibiotics are eventually administered. For these reasons, prophylactic antibiotics should not be prescribed to be given “on call to the operating room (OR),” which can occur two or more hours prior to the initial incision, nor should concurrent therapeutic antibiotics be relied on to provide adequate protection. In both situations, the chance for improperly timed doses is high. Although the landmark study by Classen et al.31 confirmed that antimicrobial prophylaxis should be administered within 2 hours prior to the initial incision, administration immediately prior to the incision may not allow enough time for the drug to distribute throughout the tissues involved in the surgery.

In a large prospective observational study of 3,836 visceral, trauma, and vascular surgeries where antimicrobial prophylaxis with cefuroxime and metronidazole was employed, the incidence of SSIs was analyzed according to the timing of antimicrobial administration. When antimicrobial prophylaxis was administered within 30 minutes or between 1 and 2 hours before the initial incision, the risk of SSI was greater when compared to antimicrobial prophylaxis administered 30 to 59 minutes prior to the initial incision. The authors conclude that the optimal window for antimicrobial (cefuroxime and metronidazole) is between 30 and 59 minutes prior to the initial incision.32 This effect may be a function of the pharmacodynamics and pharmacokinetics of the antimicrobial chosen for the prophylactic regimen. A larger study of 4,472 patients undergoing cardiac, orthopedic, and gynecologic surgery with a variety of antimicrobial prophylactic regimens also evaluated the temporal relationship between SSI occurrence and the timing of antibiotics. After excluding patients who received drugs with prolonged infusion times (i.e., fluoroquinolones and vancomycin), there was a statistically nonsignificant trend toward fewer SSIs in patients who received their prophylactic regimen within the 30 minutes prior to incision as compared with those who received the regimen 31 to 60 minutes prior to incision (odds ratio, OR: 1.74; 95% confidence interval: 0.98 to 3.04).33

Despite the importance of appropriately timed prophylactic antibiotic therapy, few patients receive antibiotics at the optimal time in relation to surgery. Potential barriers include antibiotics ordered after the patient has arrived in the OR, delayed antibiotic preparation or delivery, and use of antibiotics that require long infusion times. One study assessed the timing of prophylactic antibiotics in 100 patients and found that only 26% of patients received an antibiotic dose within 2 hours of the initial surgical incision.34

Although most studies comparing single versus multiple doses of prophylactic antibiotics have failed to show a benefit of multidose regimens, the duration of operations in these studies may not be as long as that frequently observed in clinical practice. Proponents of administering a second antibiotic dose during lengthy operations suggest that the risk for SSI is just as great at the end of surgery (during wound closing) as it is during the initial incision. One study of patients undergoing clean–contaminated operations suggests that procedures longer than 3 hours require a second intraoperative dose of cefazolin or substitution of cefazolin with a longer-acting antimicrobial agent.4 A second study of patients undergoing elective colorectal surgery suggests that low serum antimicrobial concentrations at the time of surgical closure is the strongest predictor of postoperative SSI.35 Studies of patients undergoing cardiac surgery also have demonstrated a higher infection rate among patients with undetectable antibiotic serum concentrations at the conclusion of the procedure.36

One strategy to ensure appropriate redosing of prophylactic antibiotics during long operations is use of a visual or auditory reminder system. One hospital reported its experience with such a system, finding that an automated reminder improved compliance and reduced SSIs. However, even with the reminder system, intraoperative redosing was done in only 68% of eligible patients.37 Another strategy currently being evaluated is the role of continuous infusions of cefazolin, which one pilot study has found to be a feasible way to ensure adequate serum concentrations of antibiotic during prolonged surgeries.38 Further trials are required before such an intervention can be recommended.

ANTIMICROBIAL CHOICE

Images The choice of prophylactic antibiotic depends on the type of surgical procedure, the most frequent pathogens seen with this procedure, safety and efficacy profiles of the antimicrobial agent, current literature evidence supporting its use, and cost. Although most SSIs involve the patient’s normal flora, antimicrobial selection also must take into account the susceptibility patterns of nosocomial pathogens within each institution. Typically, gram-positive coverage should be included in the choice of surgical prophylaxis because organisms such as S. aureus and S. epidermidis are encountered commonly as skin flora. The decision to broaden antibiotic prophylaxis to agents with gram-negative and anaerobic spectra of activity depends on both the surgical site (e.g., upper respiratory, GI, or genitourinary tract) and whether the operation will transect a hollow viscous or mucous membrane that may contain resident flora.3

Although antimicrobial prophylaxis can be administered through a variety of routes (e.g., oral, topical, or intramuscular), the parenteral route is favored because of the reliability by which adequate tissue concentrations may be acheived.39 Cephalosporins are the most commonly prescribed agents for surgical prophylaxis because of their broad antimicrobial spectrum, favorable pharmacokinetic profile, low incidence of adverse side effects, and low cost. First-generation cephalosporins, such as cefazolin, are the preferred choice for surgical prophylaxis, particularly for clean surgical procedures.3,4,7 In cases where broader gram-negative and anaerobic coverage is desired, antianaerobic cephalosporins, such as cefoxitin and cefotetan, are appropriate choices. Although third-generation cephalosporins (e.g., ceftriaxone) have been advocated for prophylaxis because of their increased gram-negative coverage and prolonged half-lives, their inferior gram-positive and anaerobic activity and high cost have discouraged the widespread use of these agents.3,4,7

Allergic reactions are the most common side effects associated with cephalosporin use. Reactions can range from minor skin manifestations at the site of infusion to rash, pruritus, and rarely anaphylaxis (<0.02%). The structural similarity between penicillins and cephalosporins (each contains a β-lactam ring) has led to considerable confusion about the cross-allergenicity between these two classes of drugs. Twenty percent of the general population is labeled “penicillin allergic,” yet of these patients, only 10% to 20% have positive results of a penicillin skin test.40 The rate of cross-reactivity is –2%, but as only 20% of all “penicillin-allergic” patients truly are penicillin allergic, the true incidence of cross-reactivity likely is less than 1%. Routine penicillin skin testing is not cost-effective.40 In summary, the administration of cephalosporins is both safe and cost-effective for many patients who are labeled “penicillin allergic,” and they can be used by patients who have not experienced an immediate or type I penicillin allergy.

Vancomycin can be considered for prophylactic therapy in surgical procedures involving implantation of a prosthetic device in which the rate of MRSA is high.23,41 If the risk of MRSA is low, and a β-lactam hypersensitivity exists, clindamycin can be used for many procedures instead of cefazolin to limit vancomycin use. Infusion-related side effects, such as thrombophlebitis and hypotension, particularly with vancomycin, usually can be controlled by adequate dilution and slower administration rates.42

Pseudomembranous colitis secondary to cephalosporins is uncommon and generally easily treated with a short course of oral metronidazole. Although infrequent, bleeding abnormalities related to cephalosporin use have been reported.43 The primary hematologic effect appears to be inhibition of vitamin K-dependent clotting factors that results in prolongation of the prothrombin time. The mechanism for this effect, most commonly seen with cefotetan, is related to the methylthiotetrazole side chain of the β-lactam molecule. Patients at greatest risk for this hypoprothrom-binemic effect have received a prolonged course of these agents and have underlying risk factors for vitamin K deficiency, such as malnutrition.44

Because inappropriate prophylactic antibiotic use not only can induce antibiotic resistance but also can negatively affect an institution’s antibiotic budget, initiatives to curtail inappropriate antibiotic use have become the focus of many drug use evaluation efforts. Potential sources of inappropriate antibiotic prophylaxis include the use of broad-spectrum antimicrobials when a narrow-spectrum agent is warranted, extending prophylaxis for durations beyond that recommended in published guidelines, and using expensive antibiotics when equivalent, less expensive agents are available. The most effective tools for ensuring appropriate prophylactic antibiotic prescribing are knowledge of the institutional postoperative infection rate for each type of surgical procedure and familiarity with the bacterial epidemiology patterns for each surgical population. Individualized institutional guidelines that take into account the best literature evidence, institution-based antibiotic susceptibility data, and surgeon preference are important tools for rationalizing antibiotic prophylaxis use.45

RECOMMENDATIONS FOR SPECIFIC TYPES OF SURGERY

Guidelines for surgical prophylaxis usually are structured according to the tissues affected during an operation. Although many different surgical procedures may be performed at any one anatomic site, this method of categorization still is optimal because the factors related to the success of a prophylactic regimen, such as the endogenous flora that are expected and the pharmacokinetics, pharmacodynamics, and spectrum of selected antimicrobials, generally are constant for a particular surgical site (see the discussion above). The choice of antimicrobial prophylaxis is always best evaluated using the results of properly conducted clinical trials. In the absence of studies specific to the procedure in question, extrapolation from data on regimens for different procedures in the same anatomic site in question usually can be made. Subsequent modifications to each prophylactic regimen should be based on intraoperative findings or events.

Images A comprehensive review of the surgical prophylaxis literature is beyond the scope of this chapter, but important factors are reviewed here for each type/site of surgery. Specific recommendations are summarized in Table 101-6. The reader is referred to published guidelines and review articles.2,3,4,7,39,46,47

TABLE 101-6 Most Likely Pathogens and Specific Recommendations for Surgical Prophylaxis

Images

Images

Images

Gastrointestinal Surgery

GI surgery can be categorized according to surgical site and infectious risk. Gastroduodenal surgery and hepatobiliary surgery generally are considered to be clean or clean–contaminated surgeries, with SSI rates generally less than 5%. Colorectal surgery, including appendectomies, is considered contaminated because of the large quantities and polymicrobial nature of bacterial flora within the colon. SSI rates for these types of surgeries generally range from 15% to 30%. Emergent abdominal surgery involving bowel perforation or peritonitis is considered a dirty surgical procedure, associated with a greater than 30% risk of SSI, and should be treated with therapeutic rather than prophylactic antibiotics.3

Gastroduodenal Surgery

Insignificant numbers of bacteria usually are found in the stomach and duodenum because of their acidity. The rate of SSIs in gastroduodenal surgery generally is low, so procedures in this region can be classified as clean. The risk for an SSI in this population increases with any condition that can lead to bacterial overgrowth, such as obstruction, hemorrhage, or malignancy, or increasing the pH of gastroduodenal secretions with concomitant acid suppression therapy. Antimicrobial prophylaxis is of clinical benefit only in this high-risk population. In most cases, a single dose of IV cefazolin will provide adequate prophylaxis.48 For patients with a β-lactam allergy, oral ciprofloxacin is as efficacious as parenteral cefuroxime as prophylactic therapy for gastroduodenal surgery.48 Antimicrobial prophylaxis is indicated in esophageal surgery only in the presence of obstruction. Postoperative therapeutic antibiotics may be indicated if perforation is detected during surgery, depending on whether an established infection is present.

Use of antibiotic prophylaxis for percutaneous endoscopic gastrostomy placement is controversial.49 Although postoperative peristomal infection can occur in up to 30% of patients, clinical trials with cefazolin given 30 minutes preoperatively in this population are conflicting.49 A pharmacoeconomic study that incorporated a meta-analysis of available studies to determine efficacy suggested that antibiotic prophylaxis was cost-effective for patients undergoing percutaneous endoscopic gastrostomy placements.50

Hepatobiliary Surgery

Although bile normally is sterile, and the SSI rate after biliary surgery is low, antibiotic prophylaxis is of benefit in this population. Bile contamination (bactobilia) can increase the frequency of SSIs and is present in many patients (e.g., those with acute cholecystitis or biliary obstruction and those of advanced age).46 In general, however, the correlation between bactobilia in surgical specimens and the subsequent pathogens implicated in an SSI is poor. The most frequently encountered organisms are E. coliKlebsiella species, and enterococci. Pseudomonas is an uncommon finding in the absence of cholangitis. Trials comparing first-, second-, and third-generation cephalosporins have not demonstrated benefit over single-dose cefazolin prophylaxis even in high-risk patients (e.g., age >60 years, previous biliary surgery, acute cholecystitis, jaundice, obesity, diabetes, and common bile duct stones).51 Ciprofloxacin and levofloxacin are effective alternatives for β-lactam-allergic patients undergoing open cholecystectomy.52,53 In fact, orally administered levofloxacin appears to provide similar intraoperative gallbladder tissue concentrations.53For low-risk patients undergoing elective laparoscopic cholecystectomy, antibiotic prophylaxis is not of benefit and is not recommended.54 The risk for SSIs in cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt surgery may be reduced with a single prophylactic dose of ceftriaxone,55 but not with single doses of shorter-acting cephalosporins.56

Although surgeons may use presumptive antibiotic therapy for patients with acute cholecystitis or cholangitis and defer surgery until the patient is afebrile in an effort to decrease the risk of subsequent infections, this practice is controversial. Detection of an active infection during surgery (e.g., gangrenous gallbladder and suppurative cholangitis) is an indication for a course of postoperative therapeutic antibiotics. In either case, antibiotics with additional antianaerobic activity (e.g., cefoxitin or cefotetan) are indicated.57

Appendectomy

Suspected appendicitis is a frequent cause of abdominal surgery. Numerous antibiotic regimens, all with activity against gram-positive and gram-negative aerobes and anaerobic pathogens, are effective in reducing SSI incidence.46 A cephalosporin with antianaerobic activity, such as cefoxitin or cefotetan, is recommended as first-line therapy; however, a comparative trial of cefoxitin and cefotetan suggests that cefotetan may be superior, possibly because of its longer duration of action.58 In patients with β-lactam allergy, metronidazole in combination with gentamicin is an effective regimen. Broad-spectrum antibiotics covering nosocomial pathogens (e.g., Pseudomonas) do not further reduce SSI risk and instead may increase the cost of therapy and promote bacterial resistance.59 Although single-dose therapy with cefotetan is adequate, prophylaxis with cefoxitin may require intraoperative dosing if the procedure extends beyond 3 hours. Established intraabdominal infections (e.g., gangrenous or perforated appendix) require an appropriate course of postoperative therapeutic antibiotics. Laparoscopic appendectomy produces lower postoperative infection rates than open appendectomy; however, antimicrobial prophylaxis was used for all patients in these studies; thus, the role for prophylaxis in this population remains poorly studied.60

Colorectal Surgery

In the absence of adequate prophylactic therapy, the risk for SSI after colorectal surgery is high because of the significant bacterial counts in fecal material present in the colon (frequently >109 per gram). Anaerobes and gram-negative aerobes predominate, but gram-positive aerobes also may play an important role. Reducing this bacterial load with a thorough bowel preparation regimen (4 L of polyethylene glycol solution or 90 mL of sodium phosphate solution administered orally the day before surgery) is controversial; however, 99% of surgeons in a survey routinely use mechanical preparation.61 Risk factors for SSIs include age over 60 years, hypo-albuminemia, poor preoperative bowel preparation, corticosteroid therapy, malignancy, and operations lasting longer than 3.5 hours.7

Antimicrobial prophylaxis reduced mortality from 11.2% to 4.5% in a pooled analysis of trials comparing antimicrobial prophylaxis with no prophylaxis for colon surgery.62 Effective antibiotic prophylaxis reduces even further the risk for an SSI. Several oral regimens designed to reduce bacterial counts in the colon have been studied.46 The combination of 1 g neomycin and 1 g erythromycin base given orally 19, 18, and 9 hours preoperatively is the regimen most commonly used in the United States.63 Neomycin is poorly absorbed, but provides intraluminal concentrations that are high enough to effectively kill most gram-negative aerobes. Oral erythromycin is only partially absorbed but still produces concentrations in the colon that are sufficient to suppress common anaerobes. If surgery is postponed, the antibiotics must be readministered to maintain efficacy. Optimally, the bowel preparation regimen should be completed prior to starting the oral antibiotic regimen. This is of particular concern because most procedures now are performed electively on a “same-day surgery” basis. In this case, the bowel preparation regimen is self-administered by the patient at home on the day prior to hospital admission, and compliance cannot be monitored carefully.

Patients who cannot take oral medications should receive parenteral antibiotics. Cefoxitin or cefotetan is used most commonly, but other second- and some third-generation cephalosporins also are effective.64The role of metronidazole in combination with cephalosporin therapy is unclear. Only retrospective evidence suggests that the addition of metronidazole to a cephalosporin or extended-spectrum penicillin provides additional benefit.65 Until this finding is confirmed in prospective studies, metronidazole should be reserved for combination therapy with cephalosporins with poor anaerobic coverage (e.g., cefazolin). At this time, the evidence recommending the addition of metronidazole to cephalosporins with anaerobic activity (e.g., cefotaxime, cefoxitin, and ceftriaxone) is insufficient.66 For β-lactam-allergic patients, perioperative doses of gentamicin and metronidazole have been used. Combination therapy (i.e., oral and IV therapy) is controversial. A Cochrane review suggests that combination therapy is superior to either oral or IV antibiotics alone.66 However, the largest study (491 patients) comparing combination therapy with only IV therapy, which showed no benefit with combination therapy, was not included in the meta-analysis.67 Postoperative antibiotics generally are unnecessary in the absence of any untoward events or findings during surgery. IV antibiotics are required for colostomy reversal and rectal resection because enterally administered antibiotics will not reach the distal segment that is to be reanastomosed or resected.68


Clinical Controversy…

A randomized trial of 380 patients undergoing elective colorectal surgery suggests that SSIs are not reduced by preoperative mechanical bowel preparation.69 This finding was confirmed in a meta-analysis showing that mechanical bowel preparation does not reduce the risk of anastomotic leakage or other complications, including postoperative infection.70 Despite this new evidence, mechanical bowel preparations continue to be a standard of practice prior to elective bowel surgery.

Gastrointestinal Endoscopy

Despite the large number of endoscopic procedures performed each year, the rate of postprocedural infection is relatively low. The highest bacteremia rates have been reported in patients undergoing esophageal dilation for stricture or sclerotherapy for management of esophageal varices. Although postprocedural bacteremia can occur in as many as 22% of patients, the bacteremia usually is transient (<30 minutes) and rarely results in clinically significant infection. Therefore, antimicrobial prophylaxis is routinely recommended only for high-risk patients (e.g., patients with prosthetic heart valves, a history of endocarditis, systemic-pulmonary shunt, synthetic vascular graft <1 year old, complex cyanotic congenital heart disease, obstructed bile duct, or liver cirrhosis, as well as immunocompromised patients) undergoing high-risk procedures (e.g., stricture dilation, variceal sclerotherapy, and endoscopic retrograde cholangiopancreatography, ERCP).71 Single-dose preprocedural regimens similar to those for endocarditis prophylaxis are most common (amoxicillin for patients who can tolerate oral pre-medication or either IV ampicillin or cefazolin). A meta-analysis of antimicrobial prophylaxis for endoscopic placement of percutaneous feeding tubes also suggests that a single preoperative dose of antibiotics reduces the risk of postoperative infection compared with no antibiotic (6.4% vs. 24%).72 Consensus guidelines have adopted this recommendation and suggest a single dose of cefazolin within 30 minutes prior to the procedure.71

Urologic Surgery

Preoperative bacteriuria is the most important risk factor for development of an SSI after urologic surgery. All patients should have a preoperative urinalysis and should receive therapeutic antibiotics if bacteriuria is detected. Patients with sterile urine preoperatively are at low risk for developing an SSI, and the benefit of prophylactic antibiotics in this setting is controversial. Antibiotic prophylaxis is recommended for all patients undergoing transurethral resection of the prostate or bladders tumors, shock-wave lithotripsy, percutaneous renal surgery, or ureteroscopy.73 The exact incidence of SSIs in this population is obscured by the frequent use of postoperative urinary catheters and the subsequent risk of bacteriuria. E. coli is the most frequently encountered organism. Routine use of broad-spectrum antibiotics, such as third-generation cephalosporins and fluoroquinolones, does not decrease SSI rates more than cefazolin, but the ability to administer fluoroquinolones orally rather than IV makes antimicrobial prophylaxis with ciprofloxacin easier and less expensive.74 First- or second-generation cephalosporins are considered the antimicrobial agents of choice for patients undergoing open or laparoscopic procedures involving entry into the urinary tract and any urologic surgical procedures involving the intestine, rectum, vagina, or implanted prosthesis.73 The evidence for antimicrobial prophylaxis for the removal of external urinary catheters, cystography, urodynamic studies, simple cystourethroscopy, and open or laparoscopic urologic procedures that do not involve entry into the urinary tract is not as evident. Only patients considered to have risk factors (patients of advanced age; those with anatomic anomalies, poor nutritional history, externalized catheters, colonized endogenous/exogenous material, or distant coexistent infection; smokers; immunocompromised patients; and those who are hospitalized for a prolonged stay) should receive antimicrobial prophylaxis.73

Obstetric and Gynecologic Surgeries

Cesarean Section

Cesarean section is the most frequently performed surgical procedure in the United States.7 Prophylactic antibiotics are given to prevent endometritis, the most commonly occurring SSI. In the past, antibiotics were recommended for only high-risk patients, including those with premature membrane rupture or those not receiving prenatal care. Several large trials, as well as a meta-analysis of 81 trials, have shown benefit in administering prophylactic antibiotics to all women undergoing emergent or elective cesarean section regardless of their underlying risk factors.75 Cefazolin remains the drug of choice despite the wide spectrum of potential pathogens, and a single 2 g dose appears to be superior to single or multiple 1 g doses.76 Providing a broader spectrum of coverage with cefoxitin (for anaerobes) or piperacillin (for Pseudomonas or enterococci) does not further reduce postoperative infection rates. For patients with a β-lactam allergy, preoperative metronidazole is an acceptable alternative.75


Clinical Controversy…

During a cesarean section, unlike other surgical procedures, the most appropriate timing of antibiotic administration is controversial. Traditionally, antimicrobials were administered after the initial incision and when the umbilical cord was clamped in an attempt to minimize infant drug exposure, which theoretically could mask the signs of neonatal sepsis and select resistant organisms in infants who develop infections. Recent studies and systematic reviews, however, suggest that preincision antibiotics are more effective at preventing postoperative endometritis and other SSIs.7779

Hysterectomy

The most important factor affecting the incidence of SSI after hysterectomy is the type of procedure performed. Vaginal hysterectomies are associated with a high rate of postoperative infection when performed without the benefit of prophylactic antibiotics because of the polymicrobial flora normally present at the operative site.80 As with cesarean sections, cefazolin is the drug of choice for vaginal hysterectomies despite the wide spectrum of possible pathogens.80 The American College of Obstetricians and Gynecologists (ACOG) recommends a single dose of either cefazolin or cefoxitin.81 For patients with a β-lactam allergy, a single preoperative dose of either metronidazole or doxycycline also is effective.81

Prophylactic antibiotics are recommended for abdominal hysterectomy despite the lack of bacterial contamination from the vaginal flora. Both cefazolin and antianaerobic cephalosporins (e.g., cefoxitin and cefotetan) have been studied extensively. Single-dose cefotetan is superior to single-dose cefazolin,82 and the investigators suggest that cefotetan should be the drug of choice for abdominal hysterectomies. However, other investigators suggest that either agent is appropriate, provided 24 hours of antimicrobial coverage is not exceeded.7 The ACOG guidelines suggest that first-, second-, or third-generation cephalosporins can be used for prophylaxis.81 Metronidazole also is effective and can be used if patients are allergic to β-lactam antibiotics.80 Antibiotic prophylaxis may not be required in laparoscopic gynecologic surgery or tubal microsurgery.83 As with other surgical procedures, perioperative events and findings may require the use of therapeutic antibiotics after surgery.

Head and Neck Surgery

The use of prophylactic antibiotics during head and neck surgery depends on the procedure type. Clean procedures (per NRC definition), such as parotidectomy and simple tooth extraction, are associated with a low incidence of SSI. Head and neck procedures involving an incision through a mucosal layer are associated with a higher risk for SSI. The normal flora of the mouth is polymicrobial; both anaerobes and gram-positive aerobes predominate. Although typical doses of cefazolin usually are ineffective for anaerobic infections, a 2 g dose produces concentrations high enough to inhibit these organisms. A pharmacokinetic study suggested that a single dose of clindamycin is adequate for prophylaxis in maxillofacial surgery unless the procedure lasts longer than 4 hours, when a second dose should be administered intraoperatively.84 For most head and neck cancer resection surgeries, including free-flap reconstruction, 24 hours of clindamycin is appropriate, and no additional benefit of extending therapy beyond 24 hours is seen. A combination of clindamycin and gentamicin to cover aerobic, anaerobic, and gram-negative bacteria in clean-contaminated oncologic surgery is recommended.85 Topical therapy with clindamycin, amoxicillin–clavulanate, and ticarcillin–clavulanate has been described in small trials, but the exact role of topical antibiotics is not defined.86 Antimicrobial prophylaxis is not indicated for endoscopic sinus surgery without nasal packing.39

Cardiothoracic Surgery

Although cardiac surgery generally is considered a clean procedure, antibiotic prophylaxis lowers SSI incidence.46 The substantial morbidity related to an SSI in this population, coupled with the routine implementation of prosthetic devices, further justifies the routine use of prophylaxis.87 Patients who develop SSIs after coronary artery bypass graft surgery have a mortality rate of 22% at 1 year compared with 0.6% for those who do not develop an SSI.88 Risk factors for developing an SSI after cardiac surgery include obesity, renal insufficiency, connective tissue disease, reexploration for bleeding, and poorly timed administration of antibiotics.87 Skin flora pathogens predominate; gram-negative organisms are rare.

Cefazolin has been studied extensively and is considered the drug of choice. Although several studies and a meta-analysis advocate the use of second-generation cephalosporins (e.g., cefuroxime) rather than cefazolin, various methodologic flaws in these studies have limited the extrapolation of these results to practice. Cefazolin was as effective as cefuroxime in a large randomized trial of 702 patients undergoing open heart surgery and thus remains the standard of care.89 Both patient weight and timing of cefazolin administration relative to surgery must be considered when developing a dosing strategy. Patients weighing >80 kg (176 lb) should receive 2 g cefazolin rather than 1 g. Doses should be administered no earlier than 60 minutes before the first incision and no later than the beginning of induction.85Extending therapy beyond 48 hours does not further reduce SSI rates. Single-dose cefazolin therapy may be sufficient but is not recommended by the Society of Thoracic Surgeons at this time pending further study.90

Images Routine vancomycin administration may be justified in hospitals having a high incidence of MRSA or when sternal wounds are to be explored surgically for possible mediastinitis. However, a large comparative trial enrolling almost 900 patients in a single center with a high prevalence of MRSA infections found that both cefazolin and vancomycin had similar efficacy in preventing SSI in patients undergoing cardiac surgery that required sternotomy.91Mediastinitis constitutes a failure of a prior prophylactic regimen. Continued postoperative vancomycin should be guided by culture and sensitivity data.40 Subsequent antibiotic therapy is guided by intraoperative findings.

Pulmonary resection is associated with significant SSI risk, and prophylactic antibiotics have an established role in preventing postoperative infectious morbidity. Pleuropulmonary infections are much more common than wound infections, and pathogenic organisms likely migrate from the oral cavity or pharynx.92 First-generation cephalosporins are inadequate; 48 hours of cefuroxime is preferred. A regimen of ampicillin–sulbactam is superior to first-generation cephalosporins, but further studies are required before this agent can be recommended as first-line prophylactic therapy.93

Vascular Surgery

Vascular surgery, like cardiac surgery, generally is considered clean by NRC criteria. Although vascular graft infections occur infrequently (3% to 5%), the associated morbidity and mortality are extensive because treatment often requires surgical graft removal along with therapeutic antibiotic therapy.94 Prophylactic antibiotics are of benefit, particularly for procedures involving the abdominal aorta and the lower extremities. Cefazolin is regarded as the drug of choice.95 Twenty-four hours of prophylaxis with cefazolin is adequate; longer courses may lead to bacterial resistance.96 For patients with β-lactam allergy, 24 hours of oral ciprofloxacin has been shown to be effective.94

Orthopedic Surgery

Most orthopedic surgery is clean by definition; thus, prophylactic antibiotics generally are indicated only when prosthetic materials (e.g., pins, plates, and artificial joints) are implanted.20 A late-occurring infectious complication in this surgical population can result in substantial morbidity and may lead to prosthesis failure and subsequent removal. Staphylococci are the most frequently encountered pathogens; gram-negative aerobes are infrequent. The use of cefazolin is supported by substantial evidence in the literature and therefore is the prophylactic agent of choice. Vancomycin, although effective, is not recommended for routine use unless a patient has a documented history of a serious allergy to β-lactams, or the propensity for MRSA infections at a particular institution necessitates its use. The current recommended duration of prophylaxis for joint replacement and hip fracture surgery is 24 hours.7Antibiotic-impregnated cement and beads have been used to lower SSI rates, but conclusive data regarding their efficacy are lacking.20

Duration of prophylaxis for the surgical repair of long bone fractures depends on the nature of the fracture. Multiple doses of prophylactic antibiotics offer no advantage over a single preoperative dose for repair of closed bone fractures and is more cost effective.97,98 Patients suffering open (compound) fractures are particularly susceptible to infection because bacterial contamination almost always has occurred already. Under these circumstances, the use of antibiotics is presumptive. In this setting, cefazolin often is combined with an aminoglycoside, but controlled trials are lacking.99 A clinical trial comparing clindamycin and cloxacillin suggests that clindamycin is superior and may be appropriate as monotherapy for Gustilo type I and II open fractures but not for type III fractures, for which added gram-negative activity is recommended.100 Duration of antibiotic therapy is highly variable and depends on surgical findings during debridement, results of intraoperative cultures, and clinical status. A prospective trial comparing short (<24 hours) and long (>24 hours) courses of antimicrobial prophylaxis for severe trauma suggests that longer courses of antibiotics do not offer additional benefit and may be associated with the development of resistant infections.101 However, established joint infections and osteomyelitis require an extended course of therapeutic antibiotics.

Neurosurgery

Definitive recommendations on the role of antibiotic prophylaxis in neurosurgery cannot be made at this time.102 Although the rates of SSI after these generally clean operations are low, the morbidity and mortality of SSI, should they occur, are high. Procedures involving cerebrospinal fluid (CSF) shunt placement should be considered separately because this procedure involves placement of a foreign body and is associated with higher infection rates. When choosing an antibiotic, considerations include not only the spectrum of activity but also the penetration of the agent into the site of action (CSF). A meta-analysis suggested that single doses of cefazolin or, where required, vancomycin appear to lower SSI risk after craniotomy.103 The largest prospective randomized trial to date of 826 patients undergoing clean neurosurgical procedures suggested that a single dose of ceftizoxime was as effective as a combination regimen of single-dose vancomycin and gentamicin. The authors also reported that ceftizoxime was better tolerated and more consistently achieved adequate CSF levels to inhibit the most common organisms.104 A study of 780 patients undergoing neurosurgical procedures that included shunt surgery reported that single doses of cefotaxime and trimethoprim–sulfamethoxazole were equally effective in preventing SSIs.105 Most studies of procedures involving a shunt have been small in size and do not consistently show lower infection rates with antibiotic prophylaxis, although the results of a systematic review and meta-analysis suggest that a significant improvement in the incidence of shunt infection with 24 hours of systemic antibiotics (i.e., cefazolin) and the use of antibiotic-impregnated catheters independently.106

SSIs associated with spinal surgery are rare but devastating when they occur. The use of antimicrobial prophylaxis in this setting is warranted and recommended by a meta-analysis.107 Large randomized, controlled trials are lacking, but cefazolin is the antibiotic recommended most commonly. Cephalosporin penetration into the vertebral disk has been questioned. Some small studies suggest that the addition of gentamicin, which has better penetration, might be warranted; however, there is a paucity of clinical trials comparing these two regimens.108

Minimally Invasive and Laparoscopic Surgery

Laparoscopic surgeries are being performed frequently for a variety of different operations, including gynecologic, orthopedic, and colorectal surgeries. This minimally invasive technique is associated with smaller wounds, fewer infectious complications, smaller inflammatory response, and therefore a better-preserved immune response to infection compared with the open surgical approach.109 In colorectal surgery the laparoscopic approach is associated with a 40% reduction in SSI when compared to the open surgical approach.110,111 The role of antimicrobial prophylaxis in this setting depends on the type of surgery performed and preexisting risk factors for infection. Unfortunately, few large prospective, placebo-controlled trials have determined in which patients and surgeries antimicrobial prophylaxis is warranted.

In addition to the recommendations for previously mentioned laparoscopic procedures, there is a variety of levels of evidence for prophylaxis in other laparoscopic and endoscopic procedures. Patients undergoing ERCP do not need antimicrobial prophylaxis unless biliary obstruction is evident. In these situations, a single 1 g dose of cefazolin will suffice.112 The role of antimicrobial prophylaxis for transurethral resection of the prostate is better established. A third-generation cephalosporin such as ceftriaxone (or cotrimoxazole for severely β–lactam-allergic patients) can be recommended as single-dose prophylaxis, especially for patients with nonsterile urine preoperatively or indwelling catheters.112 Insertion of peritoneal dialysis catheters by the laparoscopic technique is associated with significantly lower rates of postoperative infection. With SSI rates less than 5%, prophylactic antimicrobial therapy may not be warranted, but this has not been studied in a sufficiently large placebo-controlled trial. If the decision to provide antimicrobial prophylaxis is made, a single dose of cefazolin will suffice.112

NONPHARMACOLOGIC INTERVENTIONS

Strategies other than antimicrobial and aseptic technique for reducing postoperative infections have been investigated in different types of surgeries. The most commonly cited and practiced interventions include intraoperative maintenance of normothermia, provision of supplemental oxygen in the perioperative period, and aggressive perioperative glucose control.


Clinical Controversy…

Although interventions to maintain normothermia intraoperatively, provide supplemental oxygen in the perioperative period, and aggressively control perioperative glucose show a significant reduction in SSI, they cannot be generalized to all types of surgeries. However, given the simplicity and low cost of these interventions, many clinicians consider applying these measures outside of the studied population(s). At this time, pending further research, these interventions can be recommended for routine use only in the type of patient or surgery for which they were studied.

Core body temperature can fall by 1 to 1.5°C (33.8 to 34.7°F) intraoperatively in patients under general anesthesia. Intraoperative hypothermia has been associated with impaired immune function, decreased blood flow to the surgical site, decreased tissue oxygen tension, and an increased risk of SSI. Efforts to maintain intraoperative normothermia should be exercised and may include the use of warming blankets and IV fluid warmers to maintain core body temperature above 36.1°C (97°F). One prospective trial of 200 patients undergoing colorectal surgery found that maintenance of normothermia reduced postoperative infection rates along with other morbidity parameters, including length of stay.113


Clinical Controversy…

Several studies have investigated the role of specialized enteral formulas fortified with a variety of immunomodulating micronutrients thought to enhance the immune response and gut function after trauma or surgery. Although many clinicians are exploring the role of supplements such as glutamine, arginine, omega fatty acids, and nucleotides, no study to date has shown a significant reduction in postoperative infection rates using these formulations.

Low oxygen tension in the tissues that make up the surgical site increases the risk of bacterial colonization and subsequent SSI by decreasing the efficiency of neutrophil activity. Administration of high concentrations of oxygen (80% via ventilator or 12 L/min via a nonrebreather mask) reduced postoperative infection rates significantly in a multicenter randomized trial of 500 patients undergoing colorectal surgery.114

Diabetes and poor glucose control are well-known risk factors for SSI. The increased risk of infection is thought to be due to both macrovascular (vasculopathy and venoocclusive disease) and microvascular (subtle immunologic deficiencies, including neutrophil dysfunction and reduced complement and antibody activity) complications. Aggressive control of perioperative blood glucose level decreases the incidence of SSI in diabetics undergoing cardiac surgery and is being evaluated in other types of surgery and in non-diabetic patients.115

PERSONALIZED PHARMACOTHERAPY

Prophylactic antibiotics are only effective when therapeutic concentrations in the surgical field are maintained for the entire duration of the surgery. While consideration of drug half-life in the context of the duration of surgery has been discussed earlier in this chapter, other patient-related factors may influence the effectiveness of antibiotic prophylaxis and warrant consideration when choosing a prophylactic regimen (Table 101-7).

TABLE 101-7 Strategies for Implementing an Institutional Program to Ensure Appropriate Use of Antimicrobial Prophylaxis in Surgery

Images

Obese patients require larger doses of prophylactic antibiotics to maintain therapeutic drug levels when compared to nonobese patients. Pharmacokinetic studies suggest that patients with a body mass index greater than 40 are more likely to have subtherapeutic concentrations at the end of surgery with cefazolin 1 g preoperatively (and intraoperative for surgeries >3 hours) and thus should receive 2 g doses.116,117Underlying disease states that may affect antibiotic metabolism and/or elimination should be considered when developing a prophylactic regimen. For example, patients with thermal burn and spinal cord injuries eliminate certain classes of antibiotics, primarily the aminoglycosides and β-lactams, at unusually high rates compared with controls and will need more frequent intraoperative dosing. Conversely, individuals with renal failure may need less frequent dosing of renally cleared antibiotics. For example, while intraoperative dosing for cefazolin should be every 3 to 4 hours in patients with normal renal function, this interval should be extended to 8 hours for patients with creatinine clearances of less than 50 mL/min (83 mL/s). Individuals who are aggressively fluid resuscitated pre- or intraoperatively or those undergoing cardiac bypass may have altered antibiotic disposition related to increased volume of distribution and reduced total body clearance and may need larger doses (i.e., 2 g cefazolin).

EVALUATION OF THERAPEUTIC OUTCOMES

When evaluating the outcome of surgical antibiotic prophylaxis, it is important to differentiate any potential SSI from other postoperative infection or complication. Although fever and leukocytosis are common in the immediate postoperative period, they typically resolve with prompt ambulation, timely removal of invasive devices, prevention and/or resolution of atelectasis through optimal respiratory care, and effective analgesia. It is important to remember that the emergence of distal infections, such as pneumonia, does not constitute a failure of surgical prophylaxis. Prophylaxis should be as short as possible because prolonged prophylactic regimens may contribute to the selection of resistant organisms and may make any infection more difficult to treat.

Surgical site appearance is the most important determinant of the presence of an infection. Drainage of pus from the incision accompanied by redness, warmth, and pain or tenderness is highly suggestive of an SSI. By definition, any surgical site that requires incision and drainage by the surgeon is considered infected regardless of appearance. Failure to heal and wound dehiscence also are seen with SSIs, although the surgical technique and nutritional status may be important contributing factors.

The presentation of signs and symptoms consistent with an SSI in relation to previous surgery is an important consideration when evaluating therapeutic outcomes after surgical prophylaxis. Many SSIs will not be evident during acute hospitalization. In fact, SSIs may not become evident until up to 30 days later or, in the case of prosthesis implantation, up to 1 year later. Thus, the true incidence of SSI can be determined only by completing comprehensive postdischarge surveillance. All studies investigating the efficacy of surgical prophylaxis must include adequate postdischarge follow-up to be able to thoroughly assess the success of any prophylactic regimen.

ABBREVIATIONS

Images

REFERENCES

    1. Mitka M. Preventing surgical infection is more important than ever. JAMA 2000;283:44–45.

    2. Alexander JW, Solomkin JS, Edwards MJ. Updated recommendations for control of surgical site infections. Ann Surg 2011;253:1082–1093.

    3. Mangram AJ, Horan TC, Pearson ML, et al. Guideline for prevention of surgical site infection, 1999. Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee. Am J Infect Control 1999;27:97–132.

    4. Hendrick TL, Anastacio MM, Sawyer RG. Prevention of surgical site infection. Expert Rev Anti Infect Ther 2006; 4:223–233.

    5. National Academy of Sciences, National Research Council. Postoperative wound infections: The influence of ultraviolet irradiation of the operating room and of various other factors. Ann Surg 1964;160:32–135.

    6. Cruse PJE, Foord R. A five-year prospective study of 23,649 surgical wounds. Arch Surg 1973;107:206–210.

    7. ASHP Commission on Therapeutics. ASHP therapeutic guidelines on antimicrobial prophylaxis in surgery. In: Deffenbaugh J, ed. Best Practices for Health System Pharmacy. Bethesda, MD: ASHP, 1999:349–396.

    8. Drapeau CMJ, Pan A, Bellacosa C, et al. Surgical site infections in HIV-infected patients: Results from an Italian prospective multicenter observational study. Infection 2009;37:455–460.

    9. Dionigi R, Rovera F, Dionigi G, et al. Risk factors in surgery. J Chemother 2001;13:6–11.

   10. Perl TM, Cullen JJ, Wenzel RP, et al. Intranasal mupirocin to prevent postoperative Staphylococcus aureus infections. N Engl J Med 2002;346:1871–1877.

   11. Haley RW, Culver DH, Morgan WM, et al. Identifying patients at high risk of surgical wound infection: A simple multivariate index of patient susceptibility and wound contamination. Am J Epidemiol 1985;127:206–215.

   12. Wilson AP, Hodgson B, Liu M, et al. Reduction in wound infection rates by wound surveillance with postdischarge follow-up and feedback. Br J Surg 2006;93:630–638.

   13. Gaynes RP, Culver DH, Horan TC, et al. Surgical site infection (SSI) rates in the United States, 1992–1998: The National Nosocomial Infections Surveillance System basic SSI risk index. Clin Infect Dis 2001;33(Suppl 2):S69–S77.

   14. National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004 issued October 2004. Am J Infect Control 2004;32:470–485.

   15. Owens WD, Felts JA, Spitznagel EL. ASA physical status classifications: A study of consistency of ratings. Anesthesiology 1978;49:239–243.

   16. Elek SD, Conen PE. The virulence of Staphylococcus pyogenes for man: A study of the problems of wound infection. Br J Exp Pathol 1958;38:573–586.

   17. Burke JF. Identification of the sources of staphylococci contaminating the surgical wound during operation. Ann Surg 1963;158:898–904.

   18. Kaiser AB, Kernodle DS, Parker RA. Low-inoculum model of surgical wound infection. J Infect Dis 1992;166:393–399.

   19. Esposito S. Immune system and surgical site infection. J Chemother 2001;13:12–16.

   20. De Lalla F. Antibiotic prophylaxis in orthopedic prosthetic surgery. J Chemother 2001;13:48–53.

   21. Halwani M, Solaymani-Dodaran M, Grundman H, et al. Cross transmission of nosocomial pathogens in an adult intensive care unit: Incidence and risk factors. J Hosp Infect 2006;63:39–46.

   22. Crawford T, Rodvold KA, Solomkin JS. Vancomycin for surgical prophylaxis? Clin Infect Dis 2012;54:1474–1479.

   23. Weigelt JA, Lipsky BA, Tabak YP et al. Surgical site infection: Causative pathogens and associated outcomes. Am J Infect Control 2010;38:112–120.

   24. Chambers D, Worthy G, Myers L, et al. Glycopeptide vs. non-glycopeptide antibiotics for prophylaxis of surgical site infections: A systematic review. Surg Infect (Larchmt) 2010;11:455–462.

   25. Ramirez MC, Marchessault M, Govednik-Horny C, et al. The impact of MRSA colonization on surgical site infection following major gastrointestinal surgery. J Gastrointest Surg 2013;17:144–152; DOI 10.1007/s11605-012-1995-2.

   26. Kim DH, Spencer M, Davidson SM, et al. Institutional prescreening for detection and eradication of methicillin-resistant Staphylococcus aureus in patients undergoing elective orthopaedic surgery. J Bone Joint Surg Am 2010; 92:1820–1826.

   27. Lowy FD, Waldhausen JA, Miller M, et al. Report of the National Heart, Lung and Blood Institute–National Institute of Allergy and Infectious Diseases working group on antimicrobial strategies and cardiothoracic surgery. Am Heart J 2004:147:575–581.

   28. Munoz P, Burrillo A, Bouza E. Criteria used when initiating antifungal therapy against Candida spp. in the intensive care unit. Int J Antimicrob Agents 2000;15:83–90.

   29. Lipsett PA. Surgical critical care: Fungal infections in surgical patients. Crit Care Med 2006;34:S25–S24.

   30. McKinnon PS. Goff DA, Kern JW, et al. Temporal assessment of Candida risk factors in the surgical intensive care unit. Arch Surg 2001;136:1401–1408.

   31. Classen DC, Evans RS, Pestotnik SL, et al. The timing of prophylactic administration of antibiotics and the risk of surgical wound infection. N Engl J Med 1992;326:281–286.

   32. Weber WP, Marti WR, Zwahlen M, et al. The timing of surgical antimicrobial prophylaxis. Ann Surg 2008;247:918–926.

   33. Steinberg JP, Braun BI, Hellinger WC, et al. Timing of antimicrobial prophylaxis and the risk of surgical site infections: Results from the trial to reduce antimicrobial prophylaxis errors. Ann Surg 2009;250:10–16.

   34. Bratzler DW, Houck PM, Richards C, et al. Use of antimicrobial prophylaxis for major surgery: Baseline results from the National Surgical Infection Prevention Project. Arch Surg 2005;140:174–182.

   35. Zelenitzky SA, Ariano RE, Harding GKM, et al. Antibiotic pharmacodynamics in surgical prophylaxis: An association between intraoperative antibiotic concentrations and efficacy. Antimicrob Agents Chemother 2002;46:3026–3030.

   36. Goldman DA, Hopkins CC, Karchmer AW. Cephalothin prophylaxis in cardiac valve surgery: A prospective, double-blind comparison of two-day and six-day regimen. J Thorac Cardiovasc Surg 1977;73:470–479.

   37. Zanetti G, Flanagan HL Jr, Cohn LH, et al. Improvement of intraoperative antibiotic prophylaxis in prolonged cardiac surgery by automated alerts in the operating room. Infect Control Hosp Epidemiol 2003;24:7–9.

   38. Waltrip T, Lewis R, Young V, et al. A pilot study to determine the feasibility of continuous cefazolininfusion. Surg Infect 2002;3:5–9.

   39. Weed HG. Antimicrobial prophylaxis in the surgical patient. Med Clin North Am 2003;27:59–75.

   40. Salkind AR, Cuddy PG, Foxworth JW. The rational clinical examination: Is this patient allergic to penicillin? An evidence-based analysis of the likelihood of penicillin allergy. JAMA 2001;285:2498–2505.

   41. Gemmel CG, Edwards DI, Fraise AP, et al. Guidelines for the prophylaxis and treatment of methicillin Staphylococcus aureus (MRSA) infections in the UK. J Antimicrob Chemother 2006;57:589–608.

   42. Hadaway L, Chamallas SN. Vancomycin: New perspectives on an old drug. J Infus Nurs 2003;26:278–284.

   43. Wong RS, Cheng G, Chang NP, et al. Use of cefoperazone still needs a caution for bleeding from induced vitamin K deficiency. Am J Hematol 2006;81:76.

   44. Williams KJ, Bax RP, Brown H, Machin SJ. Antibiotic treatment and associated prolonged prothrombin time. J Clin Pathol 1991;44:738–741.

   45. Frighetto L, Marra CA, Stiver HG, et al. Economic impact of standardized orders for antimicrobial prophylaxis program. Ann Pharmacother 2000;34:154–160.

   46. Bratzler DW, Houck PM. Antimicrobial prophylaxis for surgery: An advisory statement from the National Surgical Infection Prevention Project. Clin Infect Dis 2004;38:1706–1715.

   47. Anderson DJ. Surgical site infections. Infect Dis Clin North Am 2011;25:135–153.

   48. McArdle CS, Morran CG, Anderson JR, et al. Oral ciprofloxacin as prophylaxis in gastroduodenal surgery. J Hosp Infect 1995;30:211–216.

   49. Sharma VK, Howden CW. Meta-analysis of randomized, controlled trials of antibiotic prophylaxis before percutaneous endoscopic gastrostomy. Am J Gastroenterol 2000;95:3133–3136.

   50. Kulling D, Sonnenberg A, Fried M, Bauerfeind P. Cost analysis of antibiotic prophylaxis for PEG. Gastrointest Endosc 2000;51:152–156.

   51. Jewesson PJ, Stiver G, Wai A, et al. Double-blind comparison of cefazolin and ceftizoxime for prophylaxis against infections following elective biliary tract surgery. Antimicrob Agents Chemother 1996;40:70–74.

   52. Agrawal CS, Sehgal R, Singh RK, Gupta AK. Antibiotic prophylaxis in elective cholecystectomy: A randomized, double-blinded study comparing ciprofloxacin and cefuroxime. Ind J Physiol Pharmacol 1999;43:501–504.

   53. Swoboda S, Oberdorfer K, Klee F, et al. Tissue and serum concentrations of levofloxacin 500 mg administered intravenously or orally for antibiotic prophylaxis in biliary surgery. J Antimicrob Chemother 2003;51:459–462.

   54. Koc M, Zulfikaroglu B, Kece C, et al. A prospective, randomized study of prophylactic antibiotics in elective laparoscopic cholecystectomy. Surg Endosc 2003;17:1716–1718.

   55. Gulberg V, Deibert P, Ochs A, et al. Prevention of infectious complications after transjugular intrahepatic portosystemic shunt in cirrhotic patients with a single dose of ceftriaxone. Hepatogastroenterology 1999;46:1126–1130.

   56. Deibert P, Schwartz S, Olschewski M, et al. Risk factors and prevention of early infection after implantation or revision of transjugular intrahepatic portosystemic shunts: Results of a randomized study. Dig Dis Sci 1998;43:1708–1713.

   57. Sheen-Chen SM, Chen WJ, Eng HL, et al. Bacteriology and antimicrobial choice in hepatolithiasis. Am J Infect Control 2000;28:298–301.

   58. Liberman MA, Greason KL, Frame S, Ragland JJ. Single-dose cefotetan or cefoxitin versus multiple-dose cefoxitin as prophylaxis in patients undergoing appendectomy for acute nonperforated appendicitis. J Am Coll Surg 1995;180:77–80.

   59. Colliza S, Rossi S. Antibiotic prophylaxis and treatment of surgical abdominal sepsis. J Chemother 2001;13:193–201.

   60. Chung RS, Rowland DY, Li P, Diaz J. A meta-analysis of randomized, controlled trials of laparoscopic versus conventional appendectomy. Am J Surg 1999;177:250–256.

   61. Zmora O, Wexner SD, Hajjar L, et al. Trend in preparation for colorectal surgery: Survey of the members of the American Society of Colon and Rectal Surgeons. Am Surg 2003;69:150–154.

   62. Baum ML, Anish DS, Chalmers TC, et al. A survey of clinical trials of antibiotic prophylaxis in colon surgery: Evidence against further use of no-treatment controls. N Engl J Med 1981;305:795–799.

   63. Solla JA, Rothenberger DA. Preoperative bowel preparation: A survey of colon and rectal surgeons. Dis Colon Rectum 1990;33:154–159.

   64. Fujita S, Saito N, Yamada T, et al. Randomized, multicenter trial of antibiotic prophylaxis in elective colorectal surgery: Single dose vs 3 doses of a second-generation cephalosporin without metronidazole and oral antibiotics. Arch Surg 2007;142:657–661.

   65. Mittelkotter U. Antimicrobial prophylaxis for abdominal surgery: Is there a need for metronidazole? J Chemother 2001;13:27–34.

   66. Kobayashi M, Mohri Y, Tonouchi H, et al. Randomized clinical trial comparing intravenous antimicrobial prophylaxis alone with oral and intravenous antimicrobial prophylaxis for the prevention of a surgical site infection in colorectal cancer surgery. Surg Today 2007;37:383–388.

   67. Nelson RL, Glenny AM, Song F. Antimicrobial prophylaxis for colorectal surgery. Cochrane Database Syst Rev 2009;1:CD001181.

   68. Ghorra SG, Rzeczycki TP, Natarajan R, Pricolo VE. Colostomy closure: Impact of preoperative risk factors on morbidity. Am Surg 1999;65:266–269.

   69. Zmora O, Mahajna A, Bar-Zakai B, et al. Colon and rectal surgery without mechanical bowel preparation: A randomized, prospective trial. Ann Surg 2003;237:363–367.

   70. Cao F, Li J, Li F. Mechanical bowel preparation for elective colorectal surgery: Updated systematic review and meta-analysis. Int J Colorectal Dis 2012;27:803–810.

   71. Hirota WK, Petersen K, Baron TH, et al. Guidelines for antibiotic prophylaxis for GI endoscopy. Gastrointest Endosc 2003;58:475–482.

   72. Sharma VK, Howden CW. Meta-analysis of randomized, controlled trials of antibiotic prophylaxis before percutaneous endoscopic gastrostomy. Am J Gastroenterol 2001;96:1951–1952.

   73. Wolf Jr JS, Bennett CJ, Dmochowski RR, Hollenbeck BK, Pearles MS, Schaeffer AJ. Best practice policy statement on urologic surgery antimicrobial prophylaxis. J Urol 2008;179:1379–1390.

   74. Christiano AP, Hollowell CM, Kim H, et al. Double-blind, randomized comparison of single-dose ciprofloxacin versus intravenous cefazolin in patients undergoing outpatient endourologic surgery. Urology 2000;55:182–185.

   75. Smaill F, Hofmeyr GJ. Antibiotic prophylaxis for cesarean section. Cochrane Database Syst Rev 2002;2:CD000933.

   76. Rouzi AA, Khalifa F, Ba’aqeel H, et al. The routine use of cefazolin in cesarean section. Int J Gynaecol Obstet 2000;69:107–112.

   77. Tita ATN, Rouse DJ, Blackwell S, Saade GR, Spong CY, Andrews WW. Emerging concepts in antibiotic prophylaxis for cesarean delivery: A systematic review. Obstet Gynecol 2009;113:675–682.

   78. Witt A, Donner M, Petricevic L, et al. Antibiotic prophylaxis before surgery vs after cord clamping in elective cesarean delivery: A double-blind, prospective, randomized, placebo-controlled trial. Arch Surg 2011;146:1404–1409.

   79. Macones GA, Cleary KL, Parry S, et al. The timing of antibiotics at cesarean: A randomized controlled trial. Am J Perinatol 2012;29:273–276.

   80. Guaschino S, De Santo D, De Seta F. New perspectives in antibiotic prophylaxis for obstetric and gynaecological surgery. J Hosp Infect 2002;50(Suppl A):S13–S16.

   81. American College of Obstetricians and Gynecologists. Antibiotic prophylaxis for gynecologic procedures. Obstet Gynecol 2006;108:225–234.

   82. Hemsell DL, Johnson ER, Hemsell PG, et al. Cefazolin is inferior to cefotetan as single dose prophylaxis for women undergoing elective total abdominal hysterectomy. Clin Infect Dis 1995;20:677–684.

   83. Sturlese E, Retto G, Pulia A, et al. Benefits of antibiotic prophylaxis in laparoscopic gynaecological surgery. Clin Exp Obstet Gynecol 1999;26:217–218.

   84. Meuller SC, Henkel KO, Neumann J, et al. Perioperative antibiotic prophylaxis in maxillofacial surgery: Penetration of clindamycin into various tissues. J Craniomaxillofac Surg 1999;27:172–176.

   85. Simo R, French G. The use of prophylactic antibiotics in head and neck oncological surgery. Curr Opin Otolaryngol Head Neck Surg 2006;14:55–61.

   86. Grandis JR, Vickers RM, Rihs JD, et al. Efficacy of topical amoxicillin plus clavulanate–ticarcillin plus clavulanate and clindamycin in contaminated head and neck surgery: Effect of antibiotic spectra and duration of therapy. J Infect Dis 1994;170:729–732.

   87. Roy MC. Surgical-site infections after coronary artery bypass graft surgery: Discriminating site-specific risk factors to improve prevention efforts. Infect Control Hosp Epidemiol 1998;19:229–233.

   88. Hollenbeak CS, Murphy DM, Koenig S, et al. The clinical and economic impact of deep chest surgical site infections following coronary artery bypass graft surgery. Chest 2000; 118:397–402.

   89. Curtis JJ, Boley TM, Walls JT, et al. Randomized, prospective comparison of first- and second-generation cephalosporins as infection prophylaxis for cardiac surgery. Am J Surg 1993;166:734–737.

   90. Edwards FH, Egleman RM, Houck P, et al. The Society of Thoracic Surgeons Practice Guidelines Series: Antibiotic prophylaxis in cardiac surgery, part 1: duration. Ann Thorac Surg 2006;81:397–404.

   91. Finkelstein R, Rabino G, Masiah T, et al. Vancomycin versus cefazolin prophylaxis for cardiac surgery in the setting of a high prevalence of methicillin-resistant staphylococcal infections. J Thorac Cardiovasc Surg 2002;123:326–332.

   92. Sok M, Dragas AZ, Erzen J, et al. Sources of pathogens causing pleuropulmonary infections after lung cancer resection. Eur J Cardiothorac Surg 2002;22:23–27.

   93. Boldt J, Piper S, Uphus D, et al. Preoperative microbiologic screening and antibiotic prophylaxis in pulmonary resection operations. Ann Thorac Surg 1999;68:208–211.

   94. Pratesi C, Russo D, Dorigo W, et al. Antibiotic prophylaxis in clean surgery: Vascular surgery. J Chemother 2001;13:123–128.

   95. Douglas A, Udy AA, Wallis S, et al. Plasma and tissue pharmacokinetics of cefazolin in patients undergoing elective and semielective abdominal aortic aneurysm open repair surgery. Antimicrob Agents Chemother 2011;55:5238–5242.

   96. Terpstra S, Noorkhoek GT, Voesten HG, et al. Rapid emergence of resistant coagulase-negative staphylococci on the skin after antibiotic prophylaxis. J Hosp Infect 1999;43:195–202.

   97. Slobogean GP, Kennedy SA, Davidson, et al. Single- versus multiple-dose antibiotic prophylaxis in the surgical treatment of closed fractures: A meta-analysis. J Orthop Trauma 2008;22:264–269.

   98. Slobogean PG, O’Brien PJ, Brauer CA. Single-dose versus multiple-dose antibiotic prophylaxis for the surgical treatment of closed fractures: A cost-effective analysis. Acta Orthop 2010;81:256–262.

   99. Gillespie WJ, Walenkamp G. Antibiotic prophylaxis for surgery for proximal femoral and other closed long bone fractures. Cochrane Database Syst Rev 2001;1:CD000244.

  100. Vasenius J, Tulikoura I, Vainionpaa S, Rokkanen P. Clindamycin versus cloxacillin in the treatment of 240 open fractures: A randomized, prospective study. Ann Chir Gynaecol 1998;87:224–228.

  101. Velmahos GC, Toutouzas KG, Sarkisyan G, et al. Severe trauma is not an excuse for prolonged antibiotic prophylaxis. Arch Surg 2002;137:537–541.

  102. Hosein IK, Hill DW, Hatfield RH. Controversies in the prevention of neurosurgical infection. J Hosp Infect 1999; 43:5–11.

  103. Barker FG. Efficacy of prophylactic antibiotics for craniotomy: A meta-analysis. Neurosurgery 1994;35:484–492.

  104. Pons VG, Denlinger SL, Guglielmo BJ, et al. Ceftizoxime versus vancomycin and gentamicin in neurosurgical prophylaxis: A randomized, prospective, blinded clinical trial. Neurosurgery 1993;33:416–422.

  105. Whitby M, Johnson BC, Atkinson RL, et al. The comparative efficacy of intravenous cefotaxime and trimethoprim/sulfamethoxazole in preventing infection after neurosurgery: A prospective, randomized study. Brisbane Neurosurgical Infection Group. Br J Neurosurg 2000;14:13–18.

  106. Ratilal B, Costa J, Sampaio C. Antibiotic prophylaxis for surgical introduction of intracranial ventricular shunts: A systematic review. J Neurosurg Pediatr 2008;1:48–56.

  107. Barker FG. Efficacy of prophylactic antibiotic therapy in spinal surgery: A meta-analysis. Neurosurgery 2002;51:391–400.

  108. Riley LH 3rd. Prophylactic antibiotics for spine surgery: Description of a regimen and its rationale. J South Orthop Assoc 1998;7:212–217.

  109. Balague Ponz C, Trias M. Laparoscopic surgery and surgical infection. J Chemother 2001;13:17–22.

  110. Aimaq R, Akopian G, Kaufman HS. Surgical site infection rates in laparoscopic versus open colorectal surgery. Am Surg 2011;77:1290–1294.

  111. Kiran RP, El-Gazzaz GH, Vogel JD, et al. Laparoscopic approach significantly reduces surgical site infections after colorectal surgery: Data from national surgical quality improvement program. J Am Coll Surg 2010;211:232–238.

  112. Wilson APR. Antibiotic prophylaxis in endoscopic and minimally invasive surgery. J Chemother 2001;13:102–107.

  113. Kurz A, Sessler DI, Lenhardt R. Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. Study of Wound Infection and Temperature Group. N Engl J Med 1996;334:1209–1215.

  114. Greif R, Akca O, Horn EP, et al. Supplemental perioperative oxygen to reduce the incidence of surgical-wound infection. Outcomes Research Group. N Engl J Med 2000;342:161–167.

  115. Kao LS, Meeks D, Moyer VA, Lally KP. Peri-operative glycaemic control regimens for preventing surgical site infections in adults. Cochrane Database Syst Rev 2009;3: CD006806.

  116. Edmiston CE, Krepel C, Kelly H, et al. Perioperative antibiotic prophylaxis in the gastric bypass patient: Do we achieve therapeutic levels? Surgery 2004;136:738–747.

  117. Ho VP, Nicolau DP, Dakin GF, et al. Cefazolin dosing for surgical prophylaxis in morbidly obese patients. Surg Infect (Larchmt) 2012;13:33–37.