The baseline risk for perioperative infection is highly dependent on factors that require risk adjustment in clinical trials and consideration in clinical care. Patient-related risk factors for surgical site infection include extremes of age (younger than 5 and older than 65 years), poor nutritional status, obesity, diabetes mellitus and perioperative glycemic control, peripheral vascular disease, tobacco use, coexistent infections, altered immune response, corticosteroid therapy, preoperative skin preparation (surgical scrub and hair removal), and length of preoperative hospitalization. Institutional variables include surgical experience and technique (i.e., open vs. laparoscopic), duration of procedure, hospital environments including sterilization of instruments, and maintenance of perioperative normothermia.5,6
Of the aforementioned variables, few are modifiable at the time of surgery. Good perioperative glucose control can reduce infection risk. Perioperative glucose control has been studied predominantly in the cardiothoracic surgery population where it is associated with about a 50% decrease in deep sternal infection.7 Continuous insulin infusion was associated with an additional reduction in surgical site infection compared to intermittent subcutaneous injection.8 These trials are the basis of SCIP measure 4. These findings have been generalized to bowel surgery where patients whose glucose was maintained below 200 mg/dL for 48 hours after surgery compared with those having concentrations greater than 200 mg/dL had significantly fewer surgical site infections (29.7% vs. 14.3%).9 However, intensive insulin regimens designed to keep blood sugar ultralow have shown higher hypoglycemia and mortality compared to conventional treatment.10
Although more difficult to achieve, smoking cessation is a perioperative goal. Perioperative education on smoking cessation by surgeons and anesthesiologists in preoperative evaluation is important. The preoperative period has been called a “teachable moment” and even brief smoking cessation can reduce infection risk. A meta-analysis of four studies that have assessed the effect of 4 to 8 weeks of preoperative smoking cessation demonstrates a risk reduction of approximately 50%.11
The anesthesiologist should contribute to the maintenance of perioperative normothermia. It is logical that hypothermia will result in peripheral vasoconstriction, decreased wound oxygen tension and recruitment of leukocytes, favoring infection and impaired healing. In a meta-analysis of trials comparing intraoperative warming to control, warming was associated with a 64% decrease in surgical site infections.12 Prewarming patients before surgery reduces the peripheral to core temperature gradient and has the added advantage of making placement of intravenous lines easier because of peripheral vasodilation. Active prewarming of volunteers for 2 hours resulted in maintenance of core temperatures above 36°C for 60 minutes of general anesthesia at ambient temperature, whereas core temperatures in unwarmed subjects dropped an average of 1.9°C to below 35°C.
Immunosuppression on the basis of long-term use of corticosteroids has been considered a risk factor for surgical site infection. However, there are surprisingly few studies to support this supposition. In a study of infection after mastectomy, steroid use was not found to be associated with surgical site infection. In contrast, long-term steroid treatment was associated with anastomotic leaks in bowel surgery.13 There is clear evidence that a single dose of corticosteroid given to prevent nausea and vomiting and reduce pain does not promote infection. For example, in a study of open abdominal surgery for gynecologic cancer, there were no excess wound infections in patients treated with a single dose of dexamethasone for nausea and vomiting prophylaxis.14
Antimicrobial Prophylaxis for Surgical Procedures
The use of antimicrobial prophylaxis in surgery involves a risk-to-benefit evaluation, which varies depending on the nature of the operative procedure. SCIP measure 1 recommends that prophylactic antimicrobials should be administered intravenously (IV) within 1 hour of surgical incision. The general concept is that tissue concentration of the antibiotic should exceed the minimum inhibitory concentration (MIC) associated with the procedure and or patient characteristics from the time of incision to the completion of surgery. For short-acting antibiotics, this may require redosing (Table 41-2). Antibiotic treatment is not recommended for no longer than 24 hours. This recommendation is based on findings of no benefit to prolonged dosing but rather an increased incidence of drug-resistant organisms.
The antibiotic chosen should be appropriate for the most likely microorganism related to the procedure and patient characteristics (SCIP measure 2). For clean elective surgical procedures such as mastectomy and thyroidectomy in which no tissue (other than the skin) carrying an indigenous flora is penetrated, the risks of routine antimicrobial prophylaxis outweigh the possible benefits. The predominant organisms causing surgical site infections after clean procedures are skin flora (Staphylococcus aureus and Staphylococcus epidermidis). In clean-contaminated procedures, including abdominal procedures and solid organ transplantation, the most common organisms include gram-negative rods and enterococci in addition to skin flora.15 Antibiotic recommendations for specific procedure prophylaxis can be found in Table 41-3.16
Because of their wide therapeutic index and low incidence of side effects, cephalosporins (most often a cost-effective first-generation cephalosporin such as cefazolin) are the antimicrobials of choice for surgical procedures in which skin flora and normal flora of the gastrointestinal and genitourinary tracts are the most likely pathogens. Patients with documented immunoglobulin E (IgE) reaction to cephalosporins are rare and often mistaken for more common intolerances such as nausea or yeast infection. IgE-mediated anaphylactic reactions to antimicrobials usually occur 30 to 60 minutes after dosing and often include urticaria, bronchospasm, and hemodynamic collapse. This reaction is a life-threatening emergency that precludes subsequent use of the drug. Cephalosporins can safely be used in patients with an allergic reaction to penicillins that is not an IgE-mediated reaction (e.g., anaphylaxis, urticaria, bronchospasm) or exfoliative dermatitis (Stevens-Johnson syndrome, toxic epidermal necrolysis).17 Although early reports of cross-reactivity were high due to contaminated drug lots, the actual rate of cross-reactivity is only 1%.17 However, the consequences of true anaphylaxis are severe. Patients should be carefully questioned about the nature of any drug allergy.
In patients with documented IgE-mediated anaphylactic reactions, β-lactam antibiotics can usually be substituted with clindamycin or vancomycin.16 Vancomycin may also be considered when methicillin-resistant S. aureus (MRSA) is considered likely, for example in children or elderly patients known to be colonized with MRSA. Nasal application of mupirocin has been considered as an alternative and has been found to be effective in eliminating MRSA colonization in adults and children. It is U.S. Food and Drug Administration approved for eradication of colonization in adults and health care workers. Treatment with mupirocin is effective in reducing S. aureus infection in documented carriers. Preoperative screening is recommended to identify high-risk patients who would benefit from decolonization and to guide appropriate preoperative antibiotic selection for those with resistant organisms. Routine prophylaxis with vancomycin is not recommended for any patient population in the absence of documented or highly suspected colonization or infection with MRSA (recent hospitalization of nursing home stay and hemodialysis patients) or known IgE-mediated response to β-lactam antibiotics.18 The recommendation against routine prophylaxis with vancomycin is due to concerns about selection of resistant organisms, its risk of inducing hemodynamic instability due to histamine release (red man syndrome; Fig. 41-1) if given rapidly, and evidence that vancomycin is less effective than cephazolin in methicillin-susceptible S. aureus.19,20
Clean-contaminated procedures such as colorectal and abdominal surgeries require additional coverage for gram-negative rods and anaerobes in addition to skin flora. Metronidazole can be added to cefazolin or cefoxitin, cefotetan, ampicillin-sulbactam, ertapenem, or ceftriaxone.
Bowel preparation with oral antimicrobials has been studied as a potentially less costly alternative. Mechanical bowel preparation alone does not reduce infection, but selective decontamination of the digestive tract with oral topical polymyxin, tobramycin, and amphotericin eradicates the colonization gram-negative microorganisms, S. aureus, and yeasts from oral cavity to rectum. Vancomycin would be active against MRSA but is not recommended because gram-positive flora plays an important role in the resistance to colonization.21 In a meta-analysis of eight studies, the combination of oral treatment and perioperative venous prophylaxis was found to be superior to IV prophylaxis alone in preventing surgical site infection and anastomotic leak. However, older studies found that oral antibiotics alone are not a solution. A randomized controlled study was stopped because of higher rate of infection in the oral neomycin and erythromycin group (41%) compared with the single-dose IV metronidazole and ceftriaxone group.22 Another trial of oral metronidazole and kanamycin compared with the same medications given IV found an increased rate of postoperative sepsis and pseudomembranous colitis in the oral group.23 Pseudomembranous colitis is the most frequent complication of prophylactic antimicrobials, including the IV cephalosporins. Additional toxicities are covered in Table 41-4.
Antimicrobial Selection
Prompt identification of the causative organism is essential for the selection of appropriate antimicrobial drugs to treat ongoing infection. The efficacy of antimicrobial therapy depends on drug delivery to the site of infection. Transport across the blood–brain barrier varies greatly among antimicrobials. Antimicrobial therapy is more likely to be effective if the infected material (foreign body, prosthesis) is removed. Infections behind obstructing lesions such as pneumonia behind a blocked bronchus will not respond to antimicrobials until the obstruction is relieved.
Nosocomial Infections
Nearly 80% of nosocomial infections occur in three sites (urinary tract, respiratory system, and bloodstream). The incidence of nosocomial infections is highly associated with the use of devices such as ventilators, vascular access catheters, and urinary catheters. Intravascular access catheters are the most common causes of bacteremia or fungemia in hospitalized patients.24 The organism infecting access catheters most commonly comes from the colonized hub or lumen and reflect skin flora (S. aureus and S. epidermidis). Initial therapy of suspected intravascular catheter infection usually includes vancomycin because of the high incidence of MRSA and methicillin-resistant S. epidermidis in the nosocomial environment.
Special Patient Groups
Parturients
Administration of antimicrobials during pregnancy introduces the question of safety for the mother and fetus (Table 41-5). Most antimicrobials cross the placenta and enter maternal milk. The immature fetal liver may lack enzymes necessary to metabolize certain drugs such that pharmacokinetics and toxicities in the fetus are often different from those in older children and adults. Teratogenicity is a concern when any drug is administered during early pregnancy. Increases in maternal blood volume, glomerular filtration rate, and hepatic metabolic activity may decrease plasma antimicrobial concentrations (10% to 50%), especially late in pregnancy and in the early postpartum period. In some parturients, delayed gastric emptying may decrease absorption of orally administered antimicrobials.
Elderly Patients
Physiologic changes that occur with increasing age can alter oral absorption (decreased gastric acidity, reduced gastrointestinal motility), distribution (increased total body fat, decreased plasma albumin concentrations), metabolism (decreased hepatic blood flow), and excretion (decreased glomerular filtration rate) of antimicrobials. Penicillins and cephalosporins, because of their large therapeutic index, obviate the need for significant changes in dosage schedules in elderly patients who have normal serum creatinine concentrations. Conversely, administration of aminoglycosides and vancomycin to elderly patients may require adjustments in dosing regimens. Measurement of plasma concentrations of antimicrobials and monitoring of renal function may be indicated when administering certain antimicrobials to elderly patients.
HIV-Infected Patients
There has been concern about increased risk of postoperative infection in HIV-infected patients based on their increased risk for opportunistic infection in the setting of reduced T4 cell counts. Several recent studies have addressed this issue and produced conflicting results.25–27 Favorable results appear to be related to good preoperative control on an antiretroviral regimen with preserved T4 cell counts.28
Antibacterial Drugs Commonly Used in the Perioperative Period
Penicillins
The basic structure of penicillins is a dicyclic nucleus (aminopenicillanic acid) that consists of a thiazolidine ring connected to a β-lactam ring. The penicillins may be classified into subgroups because of their structure, β-lactamase susceptibility, and spectrum of activity. The bactericidal action of penicillins reflects the ability of these antimicrobials to interfere with the synthesis of peptidoglycan, which is an essential component of cell walls of susceptible bacteria. Penicillins also decrease the availability of an inhibitor of murein hydrolase such that the uninhibited enzyme can then destroy (lyse) the structural integrity of bacterial cell walls. Cell membranes of resistant gram-negative bacteria are in general resistant to penicillins because they prevent access to sites where synthesis of peptidoglycan is taking place.
Clinical Indications
Penicillin is the drug of choice for treatment of pneumococcal, streptococcal, and meningococcal infections. Gonococci have gradually become more resistant to penicillin, requiring higher doses for adequate treatment. Treatment of syphilis with penicillin is highly effective. Penicillin is the drug of choice for treating all forms of actinomycosis and clostridial infections causing gas gangrene.
Prophylactic administration of penicillin is highly effective against streptococcal infections, accounting for its value in patients with rheumatic fever. Transient bacteremia occurs in the majority of patients undergoing dental extractions, emphasizing the importance of prophylactic penicillin in patients with congenital or acquired heart disease or tissue implants undergoing dental procedures. Transient bacteremia may also accompany surgical procedures, such as tonsillectomy and operations on the genitourinary and gastrointestinal tracts, and vaginal delivery.
Administration of high doses of penicillin G IV to patients with renal dysfunction may result in neurotoxicity and hyperkalemia (10 million U of penicillin G contains 16 mEq of potassium). If this amount of potassium introduces a risk to the patient, a sodium salt of penicillin G or a sodium salt of a similar penicillin, such as ampicillin or carbenicillin, can be substituted for the aqueous penicillin G.
Other drugs should not be mixed with penicillin as the combination may inactivate the antimicrobial. Intrathecal administration of penicillins is not recommended because these drugs are potent convulsants when administered by this route. Furthermore, arachnoiditis and encephalopathy may follow intrathecal penicillin administration.
Excretion
Renal excretion of penicillin is rapid (60% to 90% of an intramuscular [IM] dose is excreted in the first hour), such that the plasma concentration decreases to 50% of its peak value within 1 hour after injection. Approximately 10% is eliminated by glomerular filtration, and 90% is eliminated by renal tubular secretion. Anuria increases the elimination half-time of penicillin G approximately 10-fold.
Duration of Action
Methods to prolong the duration of action of penicillin include the simultaneous administration of probenecid, which blocks the renal tubular secretion of penicillin. Alternatively, the IM injection of poorly soluble salts of penicillin, such as procaine or benzathine, delays absorption and thus prolongs the duration of action. Procaine penicillin contains 120 mg of the local anesthetic for every 300,000 U of the antimicrobial. Possible hypersensitivity to procaine must be considered when selecting this form of the antimicrobial for administration.
Penicillinase-Resistant Penicillins
The major mechanism of resistance to the penicillins is bacterial production of β-lactamase enzymes that hydrolyze the β-lactam ring, rendering the antimicrobial molecule inactive. Methicillin (dimethoxybenzylpenicillin), oxacillin, nafcillin, cloxacillin, and dicloxacillin are not susceptible to hydrolysis by staphylococcal penicillinases that would otherwise hydrolyze the cyclic amide bond of the β-lactam ring and render the antimicrobial inactive. Specific indications for these drugs are infections caused by staphylococci known to produce this enzyme. Penetration of nafcillin into the central nervous system (CNS) is sufficient to treat staphylococcal meningitis. Parenteral methicillin has largely been superseded by oxacillin and nafcillin. Hemorrhagic cystitis and an allergic interstitial nephritis (hematuria, proteinuria) may accompany administration of methicillin. Hepatitis has been associated with high-dose oxacillin therapy. Renal excretion of methicillin, oxacillin, and cloxacillin is extensive. More than 80% of an IV dose of nafcillin is excreted in the bile, which may be an advantage when high-dose therapy is necessary in a patient with impaired renal function.
Oxacillin and nafcillin, unlike methicillin, are relatively stable in an acidic medium, resulting in adequate systemic absorption after oral administration. Nevertheless, variable absorption from the gastrointestinal tract often dictates a parenteral route of administration for treatment of serious infections caused by penicillinase-producing staphylococci. Cloxacillin and dicloxacillin are available only as oral preparations and may be preferable because they produce higher blood levels than do oxacillin and nafcillin.
Penicillinase-Susceptible Broad-Spectrum Penicillins (Second-Generation Penicillins)
Broad-spectrum penicillins, such as ampicillin, amoxicillin, and carbenicillin, have a wider range of activity than other penicillins, being bactericidal against gram-positive and gram-negative bacteria. They are, nevertheless, all inactivated by penicillinase produced by certain gram-negative and gram-positive bacteria. Therefore, these drugs are not effective against most staphylococcal infections.
Ampicillin
Ampicillin (α-aminobenzylpenicillin) has a broader range of activity than penicillin G. Its spectrum encompasses not only pneumococci, meningococci, gonococci, and various streptococci but also a number of gram-negative bacilli, such as Haemophilus influenzae and Escherichia coli. Ampicillin is stable in acid and thus is well absorbed after oral administration, although peak plasma concentrations are lower than those achieved after administration of penicillin V. Approximately 50% of an oral dose of ampicillin is excreted unchanged by the kidneys in the first 6 hours, emphasizing that renal function greatly influences the duration of action of this antimicrobial. Ampicillin also appears in the bile and undergoes enterohepatic circulation. Among the penicillins, ampicillin is associated with the highest incidence of skin rash (9%), which typically appears 7 to 10 days after initiation of therapy. Many of these rashes are due to protein impurities in the commercial preparation of the drug and do not represent true allergic reactions.
Amoxicillin
Amoxicillin is chemically identical to ampicillin except for an −OH substituent instead of an −H on the side chain. Its spectrum of activity is identical to that of ampicillin, but it is more efficiently absorbed from the gastrointestinal tract than ampicillin, and effective concentrations are present in the circulation for twice as long.
Extended-Spectrum Carboxypenicillins (Third-Generation Penicillins)
Carbenicillin
Carbenicillin (α-carboxybenzylpenicillin) results from the change from an amino to carboxy substituent on the side chain of ampicillin. The principal advantage of carbenicillin is its effectiveness in the treatment of infections caused by Pseudomonas aeruginosa and certain Proteus strains that are resistant to ampicillin. This antimicrobial is penicillinase susceptible and therefore ineffective against most strains of S. aureus. Carbenicillin is not absorbed from the gastrointestinal tract; therefore, it must be administered parenterally. The elimination half-time is approximately 1 hour and is prolonged to approximately 2 hours when there is hepatic or renal dysfunction. Approximately 85% of the unchanged drug is recovered in urine over 9 hours. Probenecid, by delaying renal excretion of the drug, increases the plasma concentration of carbenicillin by approximately 50%.
The sodium load administered with a large dose of carbenicillin (30 to 40 g) is considerable because greater than 10% of carbenicillin is sodium (about 5 mEq/g). Congestive heart failure may develop in susceptible patients in response to this acute drug-produced sodium load. Hypokalemia and metabolic alkalosis may occur because of obligatory excretion of potassium with the large amount of nonreabsorbable carbenicillin. Carbenicillin interferes with normal platelet aggregation such that bleeding time is prolonged but platelet count remains normal.
Extended-Spectrum Acylaminopenicillins (Fourth-Generation Penicillins)
The acylaminopenicillins (mezlocillin, piperacillin, azlocillin) have the broadest spectrum of activity of all the penicillins. Like the carboxypenicillins, the acylaminopenicillins are derivatives of ampicillin. These drugs are ineffective against penicillinase-producing strains of S. aureus. The acylaminopenicillins have lower sodium content than the carboxypenicillins but otherwise the side effects are similar. Clinical studies have not demonstrated that these antimicrobials are superior to the carboxypenicillins.
Penicillin β-Lactamase Inhibitor Combinations
Clavulanic acid, sulbactam, and tazobactam are β-lactam compounds that have little intrinsic antimicrobial activity. However, these compounds bind irreversibly to the β-lactamase enzymes, which are produced by many bacteria, thus inactivating these enzymes and rendering the organisms sensitive to β-lactamase–susceptible penicillins. Clavulanic acid is available with oral amoxicillin and parenteral ampicillin preparations have been combined with sulbactam.
Cephalosporins
Cephalosporins, like the penicillins, are bactericidal antimicrobials that inhibit bacterial cell wall synthesis and have a low intrinsic toxicity. These antimicrobials are derived from 7-aminocephalosporanic acid. Resistance to the cephalosporins, as to the penicillins, may be due to an inability of the antimicrobial to penetrate to its site of action. Bacteria can also produce cephalosporinases (β-lactamases), which disrupt the β-lactam structure of cephalosporins and thus inhibit their antimicrobial activity. Like the newer penicillins, the new cephalosporins have an extraordinarily broad spectrum of antimicrobial action but are expensive.
Individual cephalosporins differ significantly with respect to the extent of absorption after oral ingestion, severity of pain produced by IM injection, and protein binding. IV administration of any of the cephalosporins can cause thrombophlebitis. Diacetyl metabolites of cephalosporins can occur and are associated with decreased antimicrobial activity.
A positive Coombs’ reaction frequently occurs in patients who receive large doses of cephalosporins. Hemolysis, however, is rarely associated with this response. Nephrotoxicity owing to cephalosporins, with the exception of cephaloridine, is less frequent than after administration of aminoglycosides or polymyxins.
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