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Perioperative antibiotics and practice Little things that make a big difference Mark T. Keegan, MB, MRCPI, Daniel R. Brown, PhD, MD* Division of Critical Care Medicine, Department of Anesthesiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

Postoperative surgical site infections (SSIs) number approximately 500,000 per year [1] and are the most common nosocomial infection in surgical patients [2]. Contemporary anesthetic practice has a great influence on the prevention of SSIs and other aspects of infectious risk. The purpose of this article is to review concepts involved in prophylaxis against SSI and to discuss aspects of perioperative care in which the anesthetic team may alter the risk of infection and thus influence patient outcomes.

Perioperative prophylactic antibiotics Benefits of perioperative antimicrobial prophylaxis need to be balanced against risks. Before the understanding of surgical asepsis and the study and acceptance of the principles of antibiotic prophylaxis, postoperative infections were nearly universal. The benefits of decreased infection rate, length of hospital stay, mortality, and costs have been shown in various populations [2]. The risk of a SSI, however, is dependent on many factors including the surgical procedure, underlying health of the patient, and setting of the procedure (elective or emergent, clean or contaminated, and others). Certain procedures are associated with low risk for a SSI, and the risks of antimicrobial prophylaxis may outweigh the benefits. Risks include allergic reactions, toxic side effects of antimicrobials, adverse interactions with other drugs, and development of resistant organisms. The cost of therapy must also be appreciated; costs include not only the antibiotic itself but also pharmacy charges for preparation, transportation, and administration of multiple doses. In major surgical centers the perioperative use of antibiotics may represent nearly half of the hospital’s expenditure for antibiotics [3]. Although the benefits of prophylactic antibiotics in certain settings have been * Corresponding author. E-mail address: [email protected] (D.R. Brown). 0889-8537/04/$ – see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.atc.2004.04.007

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generalized to all surgical procedures, there are some cases in which benefits have not been shown. Some have advocated withholding prophylactic antibiotics in certain settings. When administering prophylactic antibiotics, several principles should guide therapy. The procedure should pose a significant risk for post-procedure site infection or result in significant bacterial contamination. This implies that different procedures have different inherent risks and that these risks are predictable. In addition, factors such as underlying patient characteristics may influence the need for prophylactic antibiotics. Patient risk factors thought to increase the chance of SSI include advanced age, poor nutritional status, obesity, smoking, diabetes, altered immune response, length of preoperative stay, colonization with microorganisms, and coexisting infections remote from the operative site [2]. Once it is determined that prophylactic antibiotics are indicated, antimicrobial drugs effective against the pathogens most commonly associated with SSI for the procedure should be administered. It is important to stress that antimicrobial selection needs to incorporate the resistance patterns determined by local microbiology or infectious disease surveillance. Once the appropriate drug has been selected, it should be administered in a way that achieves tissue and blood concentrations higher than the minimal inhibitory concentration of the pathogens of interest. The idea is not to sterilize tissues but to reduce the microbial burden of intraoperative contamination to a level that cannot overwhelm host defenses. Intravenous administration of the antimicrobial agent is the usual route. Inhibitory concentrations should be present at the start and maintained throughout the duration of the procedure. The optimal duration of postoperative therapy is not clear. Finally, newer or broad-spectrum antimicrobial agents with novel mechanisms of action should not be used for routine prophylactic use but reserved for treatment of resistant organisms.

Which procedures and patients need prophylactic antibiotics? The Centers for Disease Control and Prevention have developed guidelines for prevention of SSIs [2]. Surgical wounds are stratified into four classes: Class I (clean) is an uninfected operative wound in which no inflammation is encountered, and the respiratory, alimentary, genital and urinary tracts are not entered as part of the surgical procedure. Class II (clean-contaminated) are operative wounds in which the respiratory, alimentary, genital, or urinary tracts are entered under controlled, uncomplicated conditions. Class III (contaminated) wounds are open, fresh accidental wounds, or incisions made as part of operation, during which major breaks in sterile technique or gross spillage of gastrointestinal contents have occurred. Class IV (dirty-infected) wounds are old traumatic wounds or those that involve existing clinical infection or perforated viscera. Patients undergoing procedures that entail entry into a hollow viscus under controlled conditions should undergo antimicrobial prophylaxis. Bowel preparation to decrease the number of bacteria in the gastrointestinal tract is also

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indicated for certain clean-contaminated procedures such as elective bowel resection. In some circumstances, antimicrobial prophylaxis is given for surgical procedures in which only Class I wounds are anticipated. These include operations in which prosthetic material is placed intravascularly (eg, aortic aneurysm repair with graft placement) or into a joint (eg, total hip arthroplasty), or for any surgery after which an incisional or organ or space in which SSI would be catastrophic (eg, cardiac surgery and neurosurgical procedures). Patients undergoing Class IV (dirty-infected) operations should not receive antimicrobial prophylaxis. They should receive therapeutic antimicrobials directed at anticipated organisms based on the anatomic location and clinical situation surrounding the injury. In such scenarios, therapeutic agents are started at the time of injury or suspected infection, often before the patient presenting to the operating room.

Which antimicrobial agents should be administered? Antimicrobial prophylaxis is directed against the most likely infecting organism. Prophylaxis does not have to cover every potential pathogen [4]. Skin organisms such as Staphylococci and Streptococci are the most likely pathogens in surgeries that do not enter a chronically colonized body cavity. Cephalosporins are effective against many gram-positive and gram-negative bacteria, and they are the most widely prescribed agents for perioperative surgical wound prophylaxis [5]. Cephalosporins are safe, relatively inexpensive, and have acceptable pharmacokinetics. Cefazolin is generally viewed as the antimicrobial of first choice in clean operations. A full therapeutic dose of cefazolin (1 –2 g depending on volume of distribution) should be given to adult patients no more than 30 min before skin incision [2,6]. The more expensive third and fourth generation cephalosporins are not ideal for prophylaxis. Most are less efficacious than cefazolin against Staphylococci and are more active against organisms that are unlikely to cause perioperative infection [7]. Additionally, the emergence of resistant organisms (especially Enterococci) is promoted by their use. Prophylaxis for operations involving the lower gastrointestinal tract should include coverage against gram-negative enteric bacteria and bowel anaerobes, especially Bacteroides fragilis. Vancomycin should not be routinely used for antimicrobial prophylaxis for any type of surgical procedure, except possibly when a cluster of methicillinresistant Staphylococci has been detected. Even in this setting, one randomized trial [8] of vancomycin in a cardiac surgical setting with a high risk of methicillinresistant S. aureus failed to show a benefit over cefazolin. If vancomycin is used because of allergy to the drug of choice or because of the circumstances described above, it must be given over a period of time to avoid potential side effects (see discussion below). Commencing a vancomycin infusion after induction of anesthesia will not, in most cases, allow sufficient time to complete drug administration before skin incision. Thus, arrangements should be made to initiate

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administration of vancomycin before the patient arrives in the operating room so that the infusion is complete before beginning the procedure.

Procedure-specific recommendations Procedure-specific recommendations for antimicrobial selection and dosing have recently been published [7,9]. Table 1 presents a summary of current prophylactic antimicrobial recommendations. Considerations for specific types of procedures are discussed below. Prosthetic joint replacement Infection of a prosthetic joint is a feared complication in orthopedic surgery that requires a prolonged therapeutic course of antibiotics and, potentially, removal of the infected joint. Preoperative antibiotic prophylaxis is standard of care for all patients undergoing joint replacement [10]. The most commonly used antibiotic is cefazolin. The drug is usually given as a dose of 1 to 2 g at induction of anesthesia and is typically repeated for a total of three doses in the perioperative period. If a patient is allergic to penicillin, vancomycin is administered instead, bearing in mind the need for prolonged administration time. Additional measures may be used in an effort to prevent prosthetic joint infections, such as the use of laminar flow in the operating room, body exhaust surgical suits, and antibiotic-impregnated bone cement. The value and cost effectiveness of these additional measures are controversial [11]. There is no evidence to support the practice of ‘‘routine’’ antibiotic administration to patients with prosthetic joints undergoing surgical or dental procedures. Antibiotics should be administered only if the nature of the surgical procedure indicates they are required for prophylaxis against a surgical site infection or if the patient has an indication for the use of prophylaxis against infective endocarditis. If there is suspicion for infection in a prosthetic joint and surgical debridement is planned, the anesthesia provider should discuss with the surgeon whether or not antibiotics should be given before cultures are taken. Identification of the infecting microorganism and assessment of its sensitivity to antibiotics may be hindered by inappropriate administration of routine antibiotics. Ophthalmic procedures There are no well-controlled trials of antibiotic administration for prophylaxis in ophthalmic surgery, and opinion and practice among eye surgeons vary. Postoperative endophthalmitis, however, is a severe complication, and antimicrobial eye drops are reasonable for procedures that invade the globe. Subconjunctival antibiotics may be appropriate for high-risk patients and are administered by some practitioners for 1 to 3 days before surgery to decrease the conjunctival bacterial count [12].

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Obstetrics and Gynecology Prophylactic antibiotics decrease the incidence of infection after abdominal and vaginal hysterectomy [13]. Antibiotics are also indicated during Cesarean section [14] and may decrease the risk of infection in women undergoing therapeutic abortion [15]. In patients undergoing Cesarean section, the initial dose of prophylactic antibiotic should be administered after the umbilical cord has been clamped [16]. Head and neck procedures Prophylactic antimicrobials are indicated in head and neck surgeries that involve an incision through the oral or pharyngeal mucosa [17]. Aerobic grampositive and gram-negative and anaerobic bacteria found in the oropharynx should be targeted. Endoscopic sinus surgery does not warrant prophylaxis unless nasal packing is used [18]. Neurologic surgery Although infection rates in neurosurgery vary widely, antibiotics are usually administered to patients undergoing craniotomy and have been shown to decrease infection rates [19]. Antibiotic therapy is indicated in operations after penetrating cranial trauma [20] and in spinal surgery procedures in which hardware is placed. Cardiac, vascular and thoracic surgery A large meta-analysis [21] has demonstrated that prophylactic antibiotics are indicated in cardiac surgery. Sternal wound infections are associated with significant morbidity and mortality. Cefazolin is commonly used, but, as mentioned earlier, in some institutions vancomycin may be preferred if S. aureus wound infections continue to occur despite cefazolin prophylaxis. The value of prophylactic antibiotics in carotid surgery without prosthetic material has not been demonstrated. Prophylaxis is indicated in patients undergoing aortic surgery, vascular surgery involving a groin incision, and procedures involving implantation of any vascular prosthetic material [22]. Prophylactic cefazolin is indicated in patients undergoing non-cardiac thoracic surgical procedures, including lobectomy and pneumonectomy. The optimal duration of prophylaxis has not been established, but the practice of continuing antibiotics until chest tubes are removed is questionable. Urologic procedures In the presence of sterile urine, antimicrobial prophylaxis is not indicated before most urologic procedures, although administration of antibiotics (cipro-

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Nature of operation Cardiac Prosthetic valve, coronary artery bypass, other open-heart surgery, pacemaker or defibrillator implant Gastrointestinal Esophageal gastroduodenal Biliary tract Colorectal

Appendectomy non-perforated Genitourinary Gynecologic and Obstetric Vaginal or abdominal hysterectomy

Cesarian section

Likely pathogens

Recommended drugs

Adult dosage before surgery

Staphylococcus epidermidis, S. aureus, Corynebacterium, enteric gram-negative bacilli

Cefazolin cefuroxime OR vancomycinb

1 – 2 g IVa 1 – 2 g IVa 1 g IV

Enteric gram-negative bacilli, gram-positive cocci Enteric gram-negative bacilli, Enterococci, Clostridia Enteric gram-negative bacilli, anaerobes, enterococci

High-riskc only: cefazolind

1 – 2 g IV

High riske only: cefazolind

1 – 2 g IV

Oral: neomycin + erythromycin basef Parental: cefoxitin or cefotetan OR cefazolin + metronidazole Cefoxitin or cefotetan High riskg only: ciprofloxacin

1 – 2 g IV 1 – 2 g IV 1 – 2 g IV 0.5 g IV 1 – 2 g IV 1 – 2 g IV 500 mg PO or 400 mg IV

cefazolin or cefotetan or cefoxitin High riskh only: cefazolin

1 – 2 g IV 1 – 2 g IV 1 g IV 1 g IV after cordclamping

Enteric gram-negative bacilli, anaerobes, Enterococci Enteric gram-negative bacilli, Enterococci Enteric gram-negative, anaerobes, Gp B strep, Enterococci Same as for hysterectomy

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Table 1 Prevention of wound infection and sepsis in surgical patients

Abortion

Ophthalmic

Orthopedic Total joint replacement internal fixation of fractures Thoracic (Non-Cardiac)

Vascular Arterial surgery involving a prosthesis, the abdominal aorta, or a groin incision Lower extrenity amputation for ischemia

2 million units IV 300 mg POj 1 g IV

Anaerobes, enteric gram-negative bacilli, S. aureus

clyndamycin + gentamicin

600 – 900 mg IV 1.5 mg/kg IV

S. aureus, S. epidermidis

cefazolin OR vancomycinb gentamicin, tobramycin, ciprofloxacin, ofloxacin or neomycin-gramicidin-polymyxin B cefazolin

1 – 2 g IV 1 g IV Multiple drops topically over 2 – 24 hours

cefazolin OR vancomycinb cefazolin or cefuroxime OR vancomycinb

1 – 2 g IV 1 g IV 1 – 2 g IV 1 – 2 g IV 1 g IV

cefazolin OR vancomycinb cefazolind OR vancomycinb

1 – 2 g IV 1 g IV 1 – 2 g IV 1 g IV

S. epidermidis, S. aureus, Streptococci, enteric gram-negative bacilli, Pseudomonas

S. aureus, S. epiderdimis S. aureus, S. epiderdimis, Streptococci, enteric gram-negative bacilli S. aureus, S. epidermidis, enteric gram-negative bacilli S. aureus, S epidermidis, enteric gram-negative bacilli, Clostridia

100 mg subconjunctivally

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Head and neck surgery Incisions through oral or pharyngeal mucosa Neurosurgery Craniotomy

First trimester, high riski: aqeous penicillin G OR doxycycline Second trimester: cefazolin

Same as for hysterectomy

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Nature of operation Contaminated Surgeryk Ruptured viscus

Traumatic wound a

Likely pathogens

Recommended drugs

Adult dosage before surgery

Enteric gram-negative bacilli, anaerobes, Enterococci

Cefoxitin or cefotetan ± gentamicin OR clindamycin + gentamicin Cefazolinl

1 – 2 g IV q6h 1 – 2 g IV q12h 1.5 mg/kg IV q8h 600 mg IV q6h 1.5 mg/kg IV q8h 1 – 2 g IV q8h

S. aureus, Gp A strep, Clostridia

Some sources recommend an additional dose when patients are removed from bypass during open-heart surgery. For hospitals in which methicillin-resistant S. aureus and S. epidermidis are a frequent cause of postoperative wound infection, or for patients allergic to penicillins or cephalosporins. For procedures in which enteric gram-negative bacilli are likely pathogens, such as vascular surgery involving a groin incision, cefazolin should be included in the prophylaxis regimen for patients not allergic to cephalosporins. c Morbid obesity, esophageal obstruction, decreased gastric-acidity or gastrointestinal motility. d Some sources favor cefoxitin for better anaerobic coverage in this setting. e Age 70 years, acute cholecystitis, non-functioning gall bladder, obstructive jaundice or common duct stones. f After appropriate diet and catharsis, 15 gram of each at 1 PM, 2 PM, and 11 PM the day before an 8-AM operation. g Urine culture positive and unavailable, preoperative catheter, transrectal prostatic biopsy. h Active labor or premature rupture of membranes. i Patients with previous pelvic inflammatory disease, previous gonorrhea, or multiple sex partners. j Divided into 100 mg 1 h before the abortion and 200 mg one half h after. k Ruptured viscus in postoperative setting (dehiscence) requires antibacterials to include coverage of nosocomial pathogens. l For bite wounds, in which likely pathogens may also include oral anaerobes, Eikenella corrodens (human), or Pasteurella multocida (dog and cat), some sources recommend use of amoxicillin-clavunic acid (Augmentin) or ampicillin-sulbactam (Unasyn). Adapted from Anonymous. Antimicrobial prophylaxis in surgery. Med Lett Drugs Ther 2001;43:92 – 8. b

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Table 1 (continued)

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floxacin or trimethoprim-sulfamethoxazole) before ultrasound-guided prostate biopsy is common practice [23]. Urologists usually administer antibiotics to sterilize the urine preoperatively if the patient has bacteriuria or an indwelling catheter [7].

Colorectal procedures A review [24] of the value of antimicrobial prophylaxis in colorectal surgery suggests that a single dose or short-term use of a first-generation cephalosporin is appropriate. Other practitioners have advocated the addition of specific anaerobic prophylaxis such as metronidazole to cefazolin or the use of agents with extended gram-negative coverage such as cefoxitin or ampicillin-sulbactam [9].

Perioperative antibiotics for patients receiving solid organ transplants Patients undergoing solid organ transplant procedures will be at risk of lifethreatening infection for the rest of their lives because of the use of immunosuppressant agents. The infections most commonly involve surgical wounds, lungs, the urinary tract, or vascular access devices and are similar to those that occur in surgical patients who are not immunocompromised [25]. Perioperative antibiotic prophylaxis has been shown to be effective in the prevention of wound infections in kidney transplant recipients [26]. This practice has become standard care in other transplant recipients, although there is less published evidence to support this. In the liver transplant population, selective decontamination of the digestive tract, although it is controversial, is advocated [27]. Liver transplant recipients should also receive prophylaxis before and after a transplant cholangiogram, biliary tract manipulation, or liver biopsy. Impairment of mucociliary clearance and the cough reflex in patients who receive lung and heart-lung transplants predisposes such patients to pulmonary infections. Perioperative antibiotics are chosen on the basis of sputum culture results obtained preoperatively, and antibiotics are administered for up to 2 weeks postoperatively [25]. Pneumonia is the most common bacterial infection after orthotopic heart transplantation [28], and short term (less than 3 days) prophylaxis against gram-negative organisms and staphylococcus species is used to decrease the risk of lung and wound infection. Broad-spectrum antibacterial prophylaxis is routinely administered to recipients of pancreas transplants in an effort to decrease the likelihood of wound and intra-abdominal infections. In transplant recipients, perioperative antibacterial prophylaxis should begin on an ‘‘on-call’’ basis in the operating room and should continue for less than 24 hours and less than 3 days in kidney transplant and other solid-organ transplant recipients, respectively [25]. Perioperative prophylaxis is sometimes continued in lung and heart-lung transplant recipients until mediastinal drains and central lines are removed. Perioperative prophylactic antibiotics, however, should not be continued for more than 7 days after surgery in patients who do not have

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cystic fibrosis. The use of ongoing prophylactic antibiotic, antifungal, and antiviral therapy in transplant recipients is beyond the scope of this review.

Dosing of antibiotics Timing of antibiotic administration Theory and evidence from clinical trials would suggest that bactericidal levels of appropriate antimicrobial therapy should be present in the serum and at the surgical site when the skin incision is made [6,29]. Classen et al [6] showed that the administration of antibiotics in the 2 hours before surgery reduces the risk of wound infection, but they also demonstrated that only 60% of their study group received the antibiotics during this period. Antibiotics that are given more than 2 hours before skin incision were measurably less effective. A more recent study [30] of patients undergoing vascular surgery in a community hospital setting examined the results of an educational and intervention policy on antibiotic administration. Originally, only one fourth of the patients received their antibiotics at the appropriate time, but a quality improvement process led to a remarkable improvement in the timing of antibiotic administration. Altered dosing Certain drugs may have altered dosing depending on the severity of disease, volume of distribution, and other factors. For example, piperacillin-tazobactam and levofloxacin require increased dosing to achieve appropriate pulmonary tissue drug levels. No change in loading doses in patients with renal failure for many renally cleared drugs (eg, aminoglycosides) is required, although subsequent dosing frequency may decrease. In the morbidly obese, larger doses of antimicrobials are required for effective prophylaxis. Re-dosing The bactericidal activity of cephalosporins is time-dependent. To be most effective, the levels of the prophylactic antibiotics should continuously exceed the minimum bactericidal concentration for the target pathogens [31]. This requires re-dosing at 3- to 4-hour intervals during the procedure. Re-dosing should also occur if the antibiotic chosen has a very short half-life (eg, cefoxitin) or if the procedure involves major blood loss. The use of long-acting cephalosporins such as ceftriaxone may be advantageous in this regard [32]. Some data suggest that re-dosing should occur after an estimated 1500 mL loss of blood [33]. Although the need for re-dosing is often either unappreciated or forgotten by the health care team, specific recommendations are difficult because of a variety of factors. In general, antimicrobial re-dosing needs to be individualized based on blood loss, volume of distribution, and anticipated drug elimination.

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Adverse effects of perioperative antibiotics Anesthesia providers usually administer antibiotics given in the operating room, although they may lack knowledge of the potential adverse reactions associated with the drugs [34,35]. Interactions between anesthetic agents and antibiotics may be poorly appreciated. Untoward reactions may be idiosyncratic and rare or predictable, common, and preventable. There is often a similar reaction to classes of drugs. The penicillins, cephalosporins, and vancomycin are the antibiotics most implicated in anaphylactic or anaphylactoid reactions, but such a reaction to any antimicrobial is possible. Penicillin, of all parenteral medications, has the highest rate of allergic reactions (1% – 10%) [36]. Usually the allergic response manifests in a delayed maculopapular rash, which may be associated with fever. Immunoglobulin E antibodies may mediate immediate hypersensitivity reactions, which can cause laryngeal edema, bronchospasm, and cardiovascular collapse. Anaphylaxis occurs in 0.01% of patients who have no previous history of penicillin allergy [37]. The intravenous route of administration, which is the most effective route for surgical prophylaxis, is also the most likely to cause severe anaphylaxis. It has been reported that in patients with a true penicillin allergy, there is a 5.4% to 16.5% chance of allergic reaction following cephalosporin administration, depending on the generation of the cephalosporin, because of the structural similarity of penicillins and cephalosporins [38]. Although subsequent reports suggest the frequency to be lower, in patients with a documented immunoglobulin E-mediated hypersensitivity to penicillin, cephalosporins should be avoided [39]. Carbapenems, such as imipenem and meropenem, should not be administered to patients who have had anaphylactic reactions to penicillin or cephalosporins. Although allergy to penicillin is genuinely common, many patients be erroneously labeled ‘‘penicillin allergic.’’ Li et al [40] showed that in elective orthopedic surgery, of the patients thought to be allergic to penicillin, 90% had negative skin testing and safely received cefazolin. The benefits of a negative penicillin skin test extend beyond a single hospitalization and may have positive implications for subsequent hospital visits [41]. Rapid infusion of vancomycin predictably causes hypotension and may even cause cardiac arrest. The facial and truncal flushing of the so-called ‘‘red man syndrome’’ is caused by histamine release. Hypotension and hypoxemia may occur secondary to vasodilation and ventilation-perfusion alterations [42]. Sudden chest pain and spasm of the chest muscles, without evidence of myocardial ischemia, may also be precipitated by rapid administration of the drug [43]. These problems typically do not occur if vancomycin is administered over 30 to 60 minutes [44]. Rapid administration of clindamycin may also cause mast cell degranulation and histamine release [45]. Many perioperative antibiotics can interfere with neuromuscular transmission by interacting at multiple sites at the neuromuscular junction [46]. Some antibiotics may directly cause muscle weakness or they may interact with administered muscle relaxants. Aminoglycosides are most frequently associated with

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weakness. Administration of certain drugs early in the postoperative period may potentiate residual neuromuscular blocking agents. Patients with pre-existing neuromuscular disease such as myasthenia gravis can have extreme muscle weakness after administration of some antibiotics such as aminoglycosides [47]. Penicillin salts contain sodium or potassium, which may cause electrolyte disturbances [48]. Carbenicillin and ticarcillin are associated with a sodium load of 125 to 200 mEq. Rapid intravenous injection of penicillin G has led to cardiac arrest because of the potassium load [49]. The volume required to infuse certain antibiotics (eg, vancomycin or trimethoprim-sulfamethoxazole) may be problematic in some patients with renal or cardiac failure. In addition to frequently causing phlebitis, intravenous administration of erythromycin may cause prolongation of the QT interval [50]. The aminoglycosides may cause nephrotoxicity and oto-toxicity, related to elevated trough levels. Single daily dosing confers some degree of protection [51]. The narrow therapeutic window for aminoglycosides and the availability of suitable alternatives have recently resulted in decreased use.

Prophylaxis against infective endocarditis Infective endocarditis (IE) is an uncommon but life-threatening infection that usually occurs in people with abnormal or prosthetic heart valves. Although antimicrobial prophylaxis for IE is the standard of care in most developed countries, the evidence for such therapy is not conclusive [52]. Nonetheless, failure to administer prophylactic antimicrobials in patients at risk for IE could possibly have medicolegal implications for both the surgeon and the anesthesia provider [53]. The American Heart Association convened an expert panel and published recommendations for the prevention of IE [54]. The guidelines for prophylaxis consider both the nature of the valvular lesion and the specific surgical intervention or procedure planned. Patients considered to be at high risk for IE, to whom prophylaxis should be administered, include those with prosthetic heart valves (including bioprosthetics and homografts) [55], complex congenital cyanotic heart disease, surgically constructed systemic or pulmonary shunts, or a history of infective endocarditis. Prophylaxis is usually offered to those with moderate risk of endocarditis, including patients with most other congenital cardiac malformations (except isolated secundum atrial septal defect, or surgical repair of an atrial septal defect, ventricular septal defect, or patent ductus arteriosus). Mitral valve prolapse with regurgitation, hypertrophic cardiomyopathy, and acquired valvular defects are also considered moderate risk lesions. IE prophylaxis is given to appropriate patients when undergoing surgical procedures associated with a risk of bacteremia. Many procedures are not reasons to give prophylaxis (eg, cardiac catheterization, endotracheal intubation, and Cesarean section). The reader is referred to the American Heart Association web site (www.americanheart.org) for further details. Specific IE prophylaxis guidelines for gastrointestinal endoscopy also have been published [56].

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Aspects of perioperative care that affect infection Continuation of existing antibiotic regimens Many patients receive antimicrobial therapy before receiving care by the anesthesia team. Such therapy relies on maintaining therapeutic concentrations of antimicrobial agents. Therapeutic serum concentrations must be maintained during their procedure, and, if indicated, the dosing interval is shortened to reflect the effect of blood loss on drug levels (see section ‘‘Dosing of antibiotics’’). It is important to incorporate the susceptibility of the anticipated organisms for which prophylaxis is indicated for the procedure and the antimicrobial regimen that a patient is receiving before the procedure. Frequently, pre-existing therapy may involve broad-spectrum antimicrobials, and no additional prophylaxis need be given. For example, a patient receiving piperacillin-tazobactam for an intraabdominal process need not receive additional cefazolin prophylaxis before exploratory laparotomy. Intraoperative events prompting altered antimicrobial therapy The intraoperative surgical course may dictate a change in prophylactic antimicrobial therapy. For example, appropriate antimicrobial prophylaxis during open repair of an abdominal aortic aneurysm in a patient who is not allergic to penicillin would consist of cefazolin, but if the bowel were injured during the repair, requiring primary reanastomosis, broadened antimicrobial coverage, to include gram-negative and anaerobic prophylaxis, might be indicated. It is crucial that the anesthesia provider remain engaged in the course of the procedure to allow for prompt, appropriate changes in antimicrobial therapy because the surgical team may be consumed by the operative field and not request alteration in therapy. Operating room environment Many aspects of infection control that are applicable to operating room design [57] have been discussed in the recent Centers for Disease Control and Prevention recommendations for prevention of SSIs [2] and are neither under the influence of anesthesiologists nor the focus of this article; however, anesthesiologists make daily decisions that may influence infectious complications. The microbial burden in operating room air is directly proportional to the number of people moving about in the room [58]. Consequently, efforts should be made to limit nonessential traffic in the operating room. Use of scrub suits and masks have theoretical advantages, although laundering practices and the need for surgical masks have been debated. It is likely that gowns and masks benefit patients from an infection standpoint, but gowns and masks also offer some protection from blood and body fluids to the health care provider and are recommended. Although surgical caps and hoods reduce contamination of the surgical field by organisms shed from the hair and scalp, use of shoe covers has not been

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shown to decrease SSI risk or to decrease bacterial counts on the operating room floor [59]. Aseptic technique Lack of adherence to aseptic technique during medication preparation may be associated with infectious complications. Medications and delivery systems may be contaminated before administration to the patient and have been shown to subsequently cause infections, including SSI [60]. Recommendations for infection control in anesthetic practice have been published [61]. Central line placement More than 5 million central venous catheters are placed in the United States each year, many by anesthesiologists [62]. Infectious complications occur in up to 26% of these patients [63]. Many of the factors that have been associated with catheter-related infections are directly applicable to anesthetic practice. Antimicrobial-impregnated catheters have been shown in randomized clinical trials to decrease catheter-related bloodstream infections [64,65] and should be considered when the institutional rate of catheter-related blood stream infections is greater than 2%. The site of catheter insertion also influences infection rate. Femoral catheterization has the highest associated infection rate compared with internal jugular and subclavian sites [66]. Available evidence suggests catheterrelated infections are less likely to be associated with subclavian compared with internal jugular catheterization [67]. Although infectious and thrombotic complications may make the subclavian site preferable, mechanical complication risk, as well as underlying patient considerations (poor anatomy, prior cannulations, thrombosed sites) may override such concerns and favor alternative access. Skin preparation with chlorhexidine-based solutions has been shown to decrease the rate of catheter colonization compared with a preparation with povidone-iodine solutions [68]. Maximal sterile barrier precautions should be used, including mask, cap, and sterile gown, gloves, and drapes. Antibiotic ointments have not been shown to decrease catheter-related infections [69] and should be avoided, given concerns of promoting fungi and antibiotic-resistant bacterial growth. Two reviews regarding prevention of central venous catheter-related infections recently have been published [63,70]. Temperature regulation Prospective, randomized controlled trials have shown that mild perioperative hypothermia is associated with adverse outcomes [71], including wound infection, and delayed healing [72]. Hypothermia triggers thermoregulatory vasoconstriction, leading to a decrease in subcutaneous oxygen tension, which may increase risk of infection [73]. Additionally, mild core hypothermia has detrimental effects on neutrophils and other elements of the immune response [74]. A change of only 1.9°C of core hypothermia triples the incidence of surgical wound

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infection after colon resection [75]. Accordingly, perioperative normothermia has been advocated as a means of reducing the incidence of surgical wound infections. Anesthesiologists have considerable influence over efforts to maintain normothermia in the surgical patient. Fluid warmers, airway gas humidifiers, passive and active cutaneous heating, and even room temperature are potentially under anesthesia control and should be used in an effort to avoid even mild hypothermia in most cases [76].

Oxygen therapy Oxygen is intimately involved in the formation of reactive oxygen species that are components of bactericidal host defenses. Increased local tissue oxygen tension has been shown to be associated with reduced infection in certain situations [73]. Greif et al [77] showed that supplemental perioperative oxygen decreases wound infections in patients undergoing elective colon resection. In this study, 500 normothermic patients were randomly assigned to receive 80% or 30% inspired oxygen during the perioperative period. This study reported a 50% reduction in the incidence of surgical wound infection in the group receiving higher inspired oxygen; however, increased oxygen partial pressure may have deleterious effects. Increasing reactive oxygen species may produce tissue injury and inhibit antibacterial mechanisms. Consequently, the results from Greif et al’s study were interpreted with caution, and routine administration of a high perioperative FIO2 for all surgical procedures was not universally adopted [78]. A recent double-blind, randomized controlled trail by Pryor et al [79] in patients undergoing intra-abdominal surgical procedures under general anesthesia reported a 2-fold increased risk of SSIs with higher perioperative FIO2 (FIO2 0.8 versus 0.35). Consequently, it appears that certain subgroups of patients may experience benefit or harm from increased perioperative FIO2. Further investigation is required to elucidate which surgical patients should receive supplemental perioperative oxygen for prevention of SSI.

Glycemic control Perioperative glycemic control is receiving increased attention from clinicians and investigators. Diverse patient populations have shown improved outcomes with tighter glucose control. A prospective randomized trial in critically ill patients with intensive insulin therapy targeting serum glucose concentration less than 110 mg/dL showed a 34% decrease in hospital mortality [80]. Of note, the majority of patients in this trial had undergone cardiac surgery. Retrospective data in another population of post-cardiac surgery patients showed hyperglycemia to be directly associated with increased deep sternal and overall infection rate [81]. Further analysis of this data showed hyperglycemia to be the single most important predictor of serious infectious complications. It would seem that given the association between improved outcomes, including infection rates, in a

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variety of patient populations and settings that tight glucose control during the perioperative period is desirable.

Summary Perioperative antibiotic administration and anesthetic practice have major influences on infectious complications. Anesthesiologists need to place high importance on perioperative antibiotic administration to allow patients to receive optimal benefit from this therapy and to minimize risk. Many aspects of perioperative care ranging from thermoregulation to glycemic control may have a profound long-term impact on infection rate and thereby patient outcome.

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