Historical Perspective

After antibiotics came into widespread use in the 1940s and 1950s, the possibility that giving antibiotics perioperatively might prevent surgical site infection (SSI) became a matter of debate. Miles and colleagues used a guinea pig model to demonstrate that appropriate antibiotics were effective in preventing invasive infection and necrosis only when given within 2 hours before or after intradermal injection. This gave rise to the concept of a “decisive period” during which antibiotics are effective, which remains a guiding principle of antibiotic prophylaxis. Miles and colleagues also established the crucial role of local perfusion in delivering antibiotics when they showed that intradermal injection of epinephrine prior to antibiotic administration led to antibiotic failure.

Knighton and colleagues, using the same model, demonstrated that increased inspired oxygen was equally as effective as antibiotics in preventing infection by Escherichia coli and that the two effects were additive. He also concluded that the decisive period for oxygen is considerably longer (up to 6 hours) than that of antibiotics.

The first controlled clinical trial of the efficacy of antibiotic prophylaxis in 1964 demonstrated a benefit in abdominal operations. Thereafter, numerous clinical trials were performed with somewhat variable results, likely due to the wide range of approaches to antibiotic prophylaxis in terms of dosage, antibiotic selection, and timing of administration, among other factors. Eventually, in terms of timing, the use of antibiotic prophylaxis immediately prior to incision was demonstrated to be most effective.

By the 1970s, antibiotic prophylaxis for high-risk surgery—meaning clean contaminated and contaminated cases—was becoming well accepted and widely used. In 1985, DiPiro and colleagues showed that higher serum and tissue cephalosporin concentrations were better achieved when the drugs were given at the time of anesthesia induction compared with administration later in the operating room. Classen and colleagues published a prospective series of 2,847 patients in 1992 and introduced the 0- to 60-minute interval that subsequently became the clinical standard. While the decisive period for human (as opposed to guinea pig) SSI extends about 60 minutes both before and after incision, dosing before incision was chosen as the standard. Resident bacteria become enmeshed in fibrin clot that forms after incision, while antibiotics generally do not penetrate the fibrin clot. Thus, it is important that antibiotics are present at adequate levels in the wound at the time of incision so that they are incorporated into the fibrin clot as it forms.

Introduction

Between 2006 and 2009, SSIs complicated approximately 1.9% of surgical procedures in the United States. Rates vary widely, however, depending on site of surgery, surgical technique, patient comorbidities, and other factors. Moreover, the number of SSIs is likely underestimated given that approximately 50% of SSIs become evident after discharge from the hospital.

The United States Centers for Disease Control and Prevention (CDC) define SSI as an infection related to operative procedures that occurs near or at the surgical incision (incisional or organ/space) within 30 days of the procedure or within 90 days if a prosthetic implant was left after surgery.

The prevention of SSI remains a national priority, particularly as the number of surgical procedures performed in the United States continues to increase. SSIs are a major cause of morbidity, mortality, patient suffering, intensive care unit admissions, prolonged length of stay, hospital readmission, and increased health care cost. It has been estimated that approximately half of SSIs are preventable by application of evidence-based strategies.

National quality-improvement initiatives have been established as joint efforts by professional organizations and government agencies to further improve the safety and outcomes of surgery and health care. These efforts have identified antibiotic prophylaxis before surgery as the standard of care and a keystone for the prevention of SSI.

Surgical Antibiotic Prophylaxis

Ideally, the antimicrobial of choice for prophylaxis should prevent SSI, prevent SSI-related morbidity and mortality, be cost-effective, avoid adverse effects, and have no adverse consequences on the microbial flora of the patient or the hospital. The agent for antibiotic prophylaxis must therefore cover the most likely spectrum of bacteria present in the surgical field, and ensure adequate serum and tissue concentrations during the period of potential contamination when the surgical site is open. See Fig. 39.1 for antibiotic choice by site of surgery.

Common surgical microbial organisms and antibiotic prophylaxis. Alternatives may be used when there is a patient history of hypersensitivity, contraindications, or resistance, as outlined in reference 21; note that use of alternatives should be avoided when possible, as alternatives are often less effective.

(Information incorporated from Bratzler DW, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Surg Infect (Larchmt) . 2013;14:73. Antimicrobial prophylaxis for surgery. Med Lett Drugs Ther 2016; 58:63)

Wounds are divided into four classes according to the degree of expected microbial contamination during surgery ( Table 39.1 ). The most common surgical-site pathogens in clean procedures are skin flora, including Staphylococcus aureus and coagulase-negative staphylococci (e.g., Staphylococcus epidermidis ). In clean-contaminated procedures, the most common pathogens include gram-negative rods and enterococci in addition to skin flora. Data from the National Nosocomial Infections Surveillance (NNIS) system for 2006 to 2007 indicated that the proportion of SSI caused by S. aureus has increased to 30%, with about half of those caused by methicillin-resistant S. aureus (MRSA), although there is considerable local variability. Colonization with S. aureus , primarily in the nares, occurs in roughly 1 in 4 persons and increases the risk of SSI by 2- to 14-fold. MRSA infections are associated with higher mortality rates, longer hospital stays, and higher hospital costs compared with other infections.

Effective antibiotic prophylaxis requires therapeutic drug concentrations to be delivered to the operative site before contamination and to remain adequate until the end of surgery. Timing of prophylactic antibiotic administration for surgical procedures depends on the pharmacology and half-life of the drug. The preoperative dose timing recommended by the American Society of Health-System Pharmacists (ASHP) involves administering doses within 60 minutes (120 minutes for vancomycin and fluoroquinolones) before surgical incision. Timing is challenging, because both early and late antibiotic administration increase SSI rates. The importance of having a standardized approach to antimicrobial prophylaxis involves institution-specific guidelines that emphasize timing and choice of appropriate agents according to the type of procedure, local sensitivity patterns, and allergy ( Table 39.2 ).

Clinical Pharmacology of Common Perioperative Antimicrobial Agents

Selection of Antimicrobial Agents for SSI Prevention

A broad variety of agents are approved for use in surgical antimicrobial prophylaxis, including first- and second-generation cephalosporins, clindamycin, gentamicin, carbapenems, fluoroquinolones, and vancomycin. Cefazolin remains the drug of choice for prophylaxis in most procedures. It is the most widely studied antimicrobial agent with proven efficacy. It has a desirable duration of action, favorable spectrum of activity against organisms commonly encountered in surgery, reasonable safety, and low cost. The use of newer, broad-spectrum agents should be avoided to reduce the emergence of resistant bacterial strains.

Cephalosporins are also the antibiotics most commonly associated with allergic reactions. When a patient develops anaphylaxis intraoperatively, the offending agent is often difficult to identify and supportive care is indicated. In patients with a documented anaphylactic (immunoglobulin E [IgE]-mediated) or other serious reaction such as angioedema, bronchospasm, Stevens-Johnson syndrome, or toxic epidermal necrolysis to a given antibiotic, the antibiotic should be avoided and replaced with antibiotics with a similar spectrum of coverage in subsequent surgeries. Cephalosporins can, however, be used safely in patients with a history of non-IgE-mediated reactions, such as rash or nausea.

The most commonly reported antibiotic allergy is to penicillin. In patients with an anaphylactic reaction to penicillin, there is a less than 1% cross-reactivity to cephalosporins. While this risk is low, it is recommended that cephalosporins be avoided in such patients and replaced with appropriate alternatives, such as vancomycin or clindamycin. Most reactions to penicillin, however, are not IgE mediated, including the development of a rash or hives, nausea, or gastrointestinal distress. For patients who report a non-IgE-mediated reaction or who do not know what their reaction was, there is no contraindication to cephalosporins, including cefazolin. Alternatives to cefazolin have less efficacy, more side effects, and are usually more expensive. Vancomycin, while it kills most S. aureus (bactericidal), prevents the growth only of enterococcus (bacteriostatic), has poor bone penetration, and must be given slowly to prevent vasodilation and hypotension. Clindamycin can induce MRSA infections and cannot be administered as a bolus dose. Blumenthal et al., in a cohort of over 8000 patients who underwent surgery for which cefazolin is the recommended agent for antibiotic prophylaxis at Massachusetts General Hospital from 2010 to 2014, found a 50% increased risk of SSI in the 11% of patients who reported an allergy to penicillin, including those who report side effects, intolerance, and non-IgE-mediated hypersensitivity in addition to true allergy. The increased rate of SSI in these patients was completely attributable to the use of alternative antibiotics—including clindamycin, vancomycin, and gentamicin—for surgical antibiotic prophylaxis. Thus, it is important to use cefazolin whenever appropriate and to reserve the alternatives for patients in whom there is a true contraindication to cephalosporins.

In the context of known or suspected MRSA colonization, vancomycin is generally the prophylactic antibiotic of choice. Screening for MRSA carriage in the general population remains controversial, but there is some evidence for cost-effectiveness in certain subgroups of patients, such as joint replacement and cardiac surgery. Screening for S. aureus requires only a nasal swab, and decolonization is relatively easy and safe, requiring nasal mupirocin ointment and showering with chlorhexidine for 5 days. Administration of vancomycin is complex, as it must be given slowly and usually requires 1 to 2 hours to infuse completely. In general, it is considered acceptable if the infusion is started within 120 minutes before incision. Because the infusion must be started preoperatively, the timing can be difficult to estimate. Therefore, it is recommended to give a dose of cefazolin, as well, in the operating room as a way to ensure adequate antibiotic levels at the time of incision while providing coverage for MRSA with vancomycin.