Infection, Antimicrobial Drugs, and Anesthesia

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.

Fig. 39.1, 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. 41

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.

TABLE 39.1

Classification of Surgical Wounds According to Bacterial Contamination

Adapted from Ortega G et al. An evaluation of surgical site infections by wound classification system using the ACS-NSQIP. J Surg Res . 2012;174(1):33–38.

Classification	Description
1 Clean (Class I)	Uninfected operative wounds in which no inflammation is encountered and the wound is closed primarily. A systemic tract (respiratory, alimentary, genital, or urinary tract) is not entered.
2 Clean-Contaminated (Class II):	Operative wounds in which any of the systemic tracts (respiratory, alimentary, genital, or urinary tract) is entered under controlled conditions and without unusual contamination.
3 Contaminated (Class III):	Open, fresh, traumatic wounds. Operations with major breaks in sterile technique (open cardiac massage, spillage from the gastrointestinal tract, and so on) Incisions with acute, nonpurulent inflammation (dry gangrene)
4 Dirty or Infected (Class IV):	Old infected/traumatic wounds with retained devitalized tissue, foreign bodies, or perforated viscera, or abscesses.

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 ).

TABLE 39.2

General Recommendations for Antibiotic Prophylaxis

Modified with permission from University of Utah Health.

Administer preoperative, prophylactic antimicrobial agents only when indicated based on published clinical practice guidelines and timed such that an effective concentration of the agent is established in the serum and tissues at the time of surgical incision.
Antibiotic prophylaxis choice, dose, and timing should be determined by a hospital committee based on national guidelines, local patterns of antibiotic sensitivity, and other considerations.
Always confirm the antibiotic selection with surgeons at the time-out or earlier.
- The surgeon may wish to delay antibiotics until after culture.
- Antibiotics may not be indicated (e.g., low risk, elective procedures such as laparoscopic cholecystectomy or breast biopsy in which implants will not be used).
- Make sure to record the reason for not giving antibiotics on the record.
Beta-Lactam Allergies
- Penicillin allergy is almost never a contraindication to cefazolin or other cephalosporin administration. A documented history of anaphylaxis or other serious reaction (angioedema, bronchospasm, Stevens-Johnson syndrome, or toxic epidermal necrolysis) is the exception. Determine the severity of a patient's beta-lactam allergy prior to choosing an alternative antimicrobial.
- Lack of understanding of a true allergic reaction can lead to choosing an antimicrobial with reduced efficacy, increased cost, and greater risk of side effects.
Ideally, an antibiotic infusion should be completed before incision, but Centers for Medicare and Medicaid guidelines consider starting the infusion before incision adequate. When possible, for drugs requiring slow (> 30 minutes) infusion, the infusion should be initiated in the preoperative holding area.
Administer the appropriate parenteral prophylactic antimicrobial agents before skin incision for cesarean section, as this reduces the risk of SSI compared to the previous practice of administering the antibiotic after delivery of the baby and clamping of the umbilical cord.
When a tourniquet is used, the dose should be completed at least 5 minutes before the tourniquet is inflated.
Dosing schedules for prophylactic antibiotics are more frequent than for therapeutic use to maintain wound tissue levels throughout surgery and ongoing contamination; usually, re-dosing is recommended after 2 half-lives. For cefazolin, 1 g is the recommended re-dose, regardless of initial dose. Renal insufficiency may delay re-dosing, although the initial dose is usually not affected.
Additional intraoperative doses should be given when there is significant blood loss (~half to 1 blood volume). Use the recommended second dose for this purpose.
In clean and clean-contaminated procedures, do not administer additional prophylactic antimicrobial agent doses after the surgical incision is closed in the operating room, even in the presence of a drain. The duration of antimicrobial prophylaxis should be less than 24 hours for most procedures
When therapeutic antibiotics are given preoperatively for an infection or presumed infection (e.g., acute appendicitis), prophylactic antibiotics are not required. Each situation should be examined individually. In some cases, coverage of skin flora may be appropriate prior to skin incision; often, however, continuation of the therapeutic antibiotics is all that is required.
Patients should be treated on a case-by-case basis. While local guidelines are the starting point, other factors, such as colonization with resistant organisms, should inform the decision.

Clinical Pharmacology of Common Perioperative Antimicrobial Agents

Beta-Lactam Antibiotics

Beta-lactam antibiotics, defined by their shared structural β-lactam ring, are among the most common perioperatively prescribed drugs, including penicillin, cephalosporins, carbapenems, monobactams, and β-lactamase inhibitors. Beta-lactam antibiotics inhibit the transpeptidation reaction in sensitive bacteria and inactivate several enzymes known as penicillin-binding proteins (PBPs) that are involved in cross-linking cell wall peptidoglycans. This interferes with osmotic stability of the bacteria. Different β-lactam antibiotics inhibit different PBPs and have varying efficacies in inhibiting bacterial growth or killing the organism. Apart from a few agents, all are excreted renally and require dose adjustment in renal insufficiency.

Resistance to penicillins and other β-lactams can be caused by inactivation of the antibiotic, altered target PBPs, or impaired penetration/efflux. Hydrolysis of the β-lactam ring by certain bacterial β-lactamases yields penicilloic acid, which lacks antibacterial activity. Beta-lactamase inhibitors (clavulanic acid, sulbactam, and tazobactam) resemble β-lactam molecules and extend the spectrum of other β-lactams when combined. Altered target PBPs are the basis of MRSA and the use of an efflux pump or altered drug entry are exhibited by gram-negative species.

Penicillins

Penicillins can be assigned to 1 of 3 groups: penicillins, antistaphylococcal penicillins, or extended-spectrum penicillins. These groups have varying activity against gram-positive organisms and gram-negative organisms.

Serum concentrations of penicillins after intravenous administration is determined by protein binding. Penicillins are widely distributed in body fluids and tissues with the exception of a few formulated to delay absorption, resulting in prolonged blood and tissue concentrations. Doses must be adjusted according to renal function except with nafcillin, oxacillin, and dicloxacillin, which are cleared by biliary excretion as well.

Penicillins are generally well tolerated. The serious adverse effects are due to hypersensitivity or autoimmune reactions to a penicillin–protein complex. Patients with true allergy to penicillins can be treated with alternative drugs, although, as discussed earlier, this increases the risk of SSI and thus should be avoided when the risk of cross-reaction is low, as with a history of rash.

Cephalosporins

Cephalosporins have a broader spectrum of activity than penicillins but are not active against Listeria monocytogenes and strains of E. coli and Klebsiella species expressing extended-spectrum β-lactamases. They are classified into 4 generations according to their spectrum of antimicrobial activity.

First-generation cephalosporins (cephalexin, cefazolin). Cefazolin (half-life, 1.5 hours) is the drug of choice for surgical prophylaxis and many streptococcal and staphylococcal infections.
Second-generation cephalosporins (cefaclor, cefuroxime, cefprozil, and the cephamycins cefoxitin and cefotetan). Members of this group have differences in pharmacokinetics: protein binding and toxicity. In addition to inhibiting organisms covered by first-generation drugs, they have extended gram-negative coverage against organisms such as Haemophilus influenzae and Bacteroides fragilis . Cefoxitin has an approximate 4-hour half-life and must be re-dosed every 2 hours intraoperatively. While cefoxitin is effective for antibiotic prophylaxis for clean-contaminated abdominal colorectal surgery, cefazolin and metronidazole are recommended because cefazolin only requires re-dosing every 4 hours.
Third-generation cephalosporins (including cefotaxime, ceftazidime, and ceftriaxone). Cephalosporins of this group also have extended gram-negative coverage and achieve therapeutic levels in the cerebrospinal fluid when given intravenously. Ceftazidime is the only agent with useful activity against Pseudomonas aeruginosa . Ceftriaxone requires no dose adjustment in renal insufficiency because it is excreted through the biliary tract.
Fourth-generation cephalosporins (cefepime). Cefepime is active against P. aeruginosa , Enterobacteriaceae , methicillin-susceptible S. aureus (MSSA), S. pneumoniae , and Haemophilus and Neisseria sp . It penetrates well into cerebrospinal fluid. It has a half-life of only 2 hours, however.
Cephalosporins active against methicillin-resistant staphylococci. Ceftaroline is a distinct cephalosporin with increased binding to penicillin-binding protein 2a, which mediates methicillin resistance in staphylococci. It is therefore active against methicillin-resistant staphylococci, and gram-negative organisms, excluding P. aeruginosa .

Despite an increased risk of hypersensitivity in patients with documented penicillin anaphylaxis, the frequency of cross-allergenicity between the two drugs is low. Cephalosporins that contain a methylthiotetrazole group, such as cefotetan, may cause hypoprothrombinemia and bleeding disorders as well as disulfiram-like reactions. Administration of vitamin K and the avoidance of alcohol-containing medications is required in patients with such sensitivity.

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