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Administration of Parenteral Prophylactic Beta-Lactam Antibiotics in 2014: A Review

Gordon, Ronald J. MD, PhD

doi: 10.1213/ANE.0000000000000468
Patient Safety: Review Article
Continuing Medical Education

The role of the anesthesiologist in reducing the incidence of surgical-site infections by the administration of prophylactic parenteral beta-lactam antibiotics is reviewed. Suggestions are made with regard to timing, dosing, and method of administration of these drugs to potentially reduce the risk of surgical-site infection.

From the Department of Anesthesia, Naval Medical Center San Diego, San Diego, California; Department of Anesthesia, the Veteran’s Administration Hospital San Diego, San Diego, California; and Department of Anesthesia, the University of California Medical Center, San Diego, San Diego, California.

Accepted for publication August 13, 2014.

Funding: None.

The author declares no conflicts of interest.

Reprints will not be available from the author.

The views expressed in this article are those of the author and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the US Government.

Address correspondence to Ronald J. Gordon, MD, PhD, Clinical Investigation Department (KCA), Naval Medical Center San Diego, 34800 Bob Wilson Dr., Suite 5, San Diego, CA 92134. Address e-mail to rjgordonmd@gmail.com.

As of 2014, the administration of prophylactic parenteral antibiotics in the perioperative period is well embedded into the practice of anesthesia. In popular jargon, we “own it,” and are responsible for assuring perioperative prophylactic parenteral antibiotics are given so as to optimize their effectiveness, thereby minimizing the incidence of surgical-site infections (SSIs). It is proper and fitting that this should be so, both because of our role as perioperative physicians and by virtue of our central position within the flow of the surgical patient’s care. Before 2006, this was not the case. Prophylactic antibiotics often were given by the nursing staff, either on the hospital floor or in the preoperative holding area. However, the aggressive and comprehensive efforts of major figures in the health care establishment, such as Donald Berwick through the Institute for Healthcare Improvement and the “100,000 lives campaign,”1 as well as the Centers for Medicare and Medicaid’s (CMS) efforts to improve medical quality via the physician’s quality reporting initiative, rapidly moved this responsibility to the anesthesia health care team. For us to be more than just technicians, administering medications ordered by the surgical resident or attending without having any input, we require an understanding of the pharmacokinetics and pharmacodynamics of prophylactic parenteral antibiotics. It is imperative that we act in a manner befitting our dual roles as the surgical team member responsible for providing safe and optimal operating conditions, as well as being a significant contributor to efforts to reduce longer-term perioperative complications.2,3 Such complications include SSIs, chronic pain, perioperative myocardial and pulmonary events, and venous thromboembolic phenomena. To effectively provide such benefits to our patients, there must also be a mutually respectful symbiotic relationship between surgeon and anesthesiologist.2

The following discussion focuses on the problem of hospital-acquired infections (HAIs) after surgery. The proper administration of prophylactic beta-lactam antibiotics is then reviewed. It is common knowledge among medical providers that HAIs (or as they are more commonly known, SSIs) are a major perioperative complication and add markedly to the cost of health care for the American public. A recent study indicated that the annual cost associated with HAIs in the United States is approximately 9.8 billion dollars.4 A significant component of these HAIs and costs occurs after surgical procedures.4 For example, a SSI in a routine ventral hernia repair with mesh can add more than $100,000 to the patient’s total cost of care.a

SSIs are the most common reason for hospital readmission after surgery.b In elderly patients, the complication of a deep incisional or organ space infection increases mortality by a factor of 4 and average hospital stay by 15.7 days.5 The US Department of Health and Human Services’ Administration on Aging website projects the number of elderly Americans will grow from 39.6 million in 2009 to 72.1 million in 2030. Hence, the importance of this issue with regard to patient morbidity, mortality, and health care costs will continue to increase. Historically, prevention and treatment of SSIs has been within the purview of the operating surgeon, but recently the complementary role of the anesthesia provider has received attention.6–16 Our specialty has much to contribute in the battle against this major health care issue. Efforts to broaden the scope of anesthesia care, for example, with the development of the perioperative surgical home17 or protocols for enhanced recovery after surgery,18 increasingly focus on the role of the anesthesiologist in influencing long-term patient outcomes.3,11,16

Anesthetic interventions potentially effective in decreasing SSIs derive from 5 fundamental pathophysiologic principles:

  1. SSIs develop after inoculation of bacteria of sufficient dose and virulence into tissue to overcome local host defenses, which in turn may be weakened by such factors as hypoxia, surgical stress, blood transfusion, pain, and hyperglycemia.
  2. The primary host defense is oxidative killing by neutrophils.
  3. Neutrophils must be delivered in sufficient number to be effective, dependent in part on local capillary blood flow. Hypothermia, hypovolemia, and increased sympathetic tone decrease capillary blood flow whereas interventions that reduce sympathetic tone, such as neuraxial anesthesia, increase capillary blood flow.
  4. The time from skin incision to a few hours after skin closure is a decisive period6,19,20 during which infection is established. Modifications in anesthetic management to decrease SSIs are most effective when implemented during this decisive period.
  5. To optimize effectiveness, prophylactic antibiotics must be administered at a proper time in sufficient dose and with sufficient frequency such that the maximum tissue concentration occurs at the time of incision21–23 and tissue concentrations exceed the minimum inhibitory concentration (MIC) of potential microbial pathogens for the duration of the decisive period.24

It follows that anesthesiologists potentially may contribute to a reduction in the frequency of SSIs in many ways. Interventions suggested (but not necessarily proven) to be beneficial include frequent handwashing,1214 maintenance of intraoperative normothermia,6,8,15,16 neuraxial anesthesia,9 modest glucose control (maintaining blood levels <200 mg%),25 induced hypercarbia,6,7 increased inspired oxygen concentrations,6,8,11 timely administration of prophylactic antibiotics,15,24 minimization of operating theater traffic,26 avoidance of blood transfusions,8,26 and effective postoperative pain control.6,11 Of these, perioperative temperature management and timely administration of prophylactic parenteral antibiotics have become accepted universally and are integrated widely into clinical practice in the United States. These latter 2 interventions also are included in the Surgical Care Improvement Project (SCIP) Module 1 on prevention of SSIs and in the CMS Physician Quality Reporting System (PQRS) measures 193 and 30:

PQRS Measure 193. Perioperative Temperature Manage ment: Percentage of patients, regardless of age, undergoing surgical or therapeutic procedures under general or neuraxial anesthesia of 60 minutes’ duration or longer, except patients undergoing cardiopulmonary bypass, for whom either active warming was used intraoperatively for the purpose of maintaining normothermia, or at least one body temperature ≥36°C (or 96.8°F) was recorded within the 30 minutes immediately before or the 15 minutes immediately after anesthesia end time.

PQRS Measure 30. Perioperative Care: Timely Adminis tration of Prophylactic Parenteral Antibiotics: Percentage of surgical patients aged 18 years and older who receive an anesthetic when undergoing procedures with the indications for prophylactic parenteral antibiotics for whom administration of the prophylactic antibiotic ordered has been initiated within 1 hour (if fluoroquinolone or vancomycin, 2 hours) before the surgical incision (or start of procedure when no incision is required).

Most medical centers in the United States require anesthesia providers to be in compliance with these CMS measures, and within the realm of publicly reported quality yardsticks, they represent (along with the central line placement, PQRS Measure 76) the only publicly available means of assessing anesthesia care.27 Current efforts by such organizations as the Anesthesia Quality Institute certainly will lead to much more comprehensive and useful assessments of anesthesia quality of care,2,27 but at present, the CMS measures are all that is available. To be sure we “tow the mark” regarding compliance with these measures, starting in 2013 CMS imposed penalties (assessed in 2015) on anesthesia providers for noncompliance. It is disconcerting then, with so much riding on compliance with measure 30, that a number of editorials and studies by prominent authorities in the field call into question the clinical benefit of its enforcement. We are troubled by missives such as “Surgical Care Improvement: Should Performance Measures Have Performance Measures,”28 “SCIP to the Loo,”29 “Reducing the Risk of Surgical Site Infections: Did We Really Think SCIP was Going to Lead Us to the Promised Land?”21 and “Is it time to refine? An exploration and simulation of optimal antibiotic timing in general surgery,”30 all of which question the clinical benefit of enforcement of performance measure 30. A major goal of the SCIP project was the reduction of SSIs by 25%.21 To date, despite the almost universal implementation of measure 30, very little if any reduction has occurred.31 It is therefore a most appropriate time to revisit and reevaluate current literature on this topic.

The remarks that follow relate primarily to the beta-lactam class of antibiotics. This group includes the penicillins, cephalosporins, and carbapenems and is widely used in clinical practice. The beta-lactams exhibit pharmacodynamic behavior suggesting the possibility of more effective utilization. In contrast to the fluoroquinolones and aminoglycosides, the beta-lactams (as well as clindamycin) work primarily via a process termed “time-dependent killing.”32 In time-dependent killing, the fraction of time the drug concentration exceeds MIC is the primary determinant of effectiveness.32–40 The beta-lactams also demonstrate a limited postantibiotic effect (the ability to continue bacterial killing after the concentration of the drug is below MIC), whereas the fluoroquinolones and aminoglycosides exhibit primarily concentration-dependent killing and a pronounced postantibiotic effect.32 For these latter drugs, the maximum concentration achieved and the area under the concentration-time curve are the most important variables. Drugs such as vancomycin exhibit both time-dependent killing and a moderate postantibiotic effect. Examples of the different drug classes are listed in Table 1. Beta-lactams such as cefazolin are also highly protein bound, and only the free or unbound drug has antibacterial activity.42 To influence bacterial virulence by virtue of the inhibition of bacterial cell wall synthesis (the primary mechanism of action of the beta-lactams), the unbound drug must first achieve an effective concentration throughout the interstitial fluid.40 In most literature on the subject, the terms “tissue concentration” and “interstitial fluid concentration” are used interchangeably, and that convention will be followed here. Thus, to be effective, the unbound drug must pass though the capillary membrane, diffuse throughout the interstitial fluid to reach the offending pathogens, and finally bind to the penicillin-binding proteins on the bacterial wall. This process by necessity takes time, dependent on such factors as the free drug’s diffusion coefficient and the average distance from blood vessel to tissue. For the obese patient, this average distance is increased,43,44 and the antibiotic transport time is by necessity also increased. Finally, all things being equal, prophylactic antibiotic administration should be timed such that maximum tissue concentrations are achieved immediately before times of known bacterial seeding, for example, during skin incision or bowel entry in clean-contaminated cases.21–23 Because it is well known that tissue concentrations of antibiotics vary significantly between skin, adipose tissue, muscle, and omentum secondary to variations in capillary perfusion,45–48 striving for a maximum average tissue concentration at incision is most likely to ensure adequate antibiotic coverage at all sites of potential contamination.21–23

Table 1

Table 1

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TIMING OF INITIAL DOSE OF PROPHYLACTIC PARENTERAL ANTIBIOTICS

As measure 30 is currently written, we are free to administer the selected antibiotic 60 minutes before skin incision, 30 minutes before skin incision, or 30 seconds before skin incision. We are free to administer the drug after tourniquet inflation in an orthopedic procedure, as long as that occurs before skin incision. Most authorities would consider administration of prophylactic parenteral antibiotics 30 seconds before skin incision or after tourniquet inflation (often during the surgical “time out”) suboptimal care because the tissue levels of the drug at the commencement of surgery would be expected to be quite low. Deiner and Silverstein16 stated it well when they noted, “if prophylaxis is started as soon as 1 minute before incision, the OR team is still in compliance from a regulatory perspective. Although this practice may follow the strict definition of the criteria, it certainly does not follow our understanding of the science and therefore the spirit of the criteria.”

With these remarks as background, it is helpful to review in simple terms the science in question. Starting with the fundamental studies of Burke,19,20 it has been demonstrated that for antibiotics to be effective in reducing the incidence of SSIs, they must be present at sufficient levels within the at-risk tissues at the time of bacterial inoculation and throughout the surgical procedure (principle 5 above).24 The 2013 revised policy paper on prophylactic antibiotics developed jointly by the American Society of Health-System Pharmacists (ASHP), the Infectious Disease Society of America, the Surgical Infection Society, and the Society for Healthcare Epidemiology of America24 (which P. S. Barie49 refers to as a “must read must heed” for every surgeon) states:

“Successful prophylaxis requires the delivery of the antimicrobial to the operative site before contamination occurs. Thus, the antimicrobial agent should be administered at such a time to provide serum and tissue concentrations exceeding the minimum inhibitory concentration (MIC) for the probable organisms associated with the procedure, at the time of incision, and for the duration of the procedure.”

Because it is also desirous that antibiotic tissue concentrations be maximal at times of greatest risk, it follows that sufficient time must elapse after IV infusion for peak tissue and interstitial fluid concentrations to be achieved at incision. Weber et al.50 note that for cefuroxime, drug administration less than 30 minutes before skin incision may provide insufficient time to achieve adequate tissue concentrations. Andersson et al.,23 in discussing the strategy for antibiotic infusion, state “current knowledge suggests that this is approximately 30 minutes before incision in relation to the type of antibiotics with a half-life of 30 minutes.” The authors then go on to suggest 15 to 45 minutes before incision or tourniquet application as an acceptable time span for infusion. Edmiston et al.21 note that “pragmatically, the likelihood of achieving the maximum tissue concentration at 30–45 minutes before incision is greater than if the drug is bolused 5–10 minutes before incision.” Stefánsdóttir et al.51 also advocate administering the antibiotic 30 minutes before incision, again with a range of 15 to 45 minutes considered acceptable. Indeed, the overwhelming majority of available studies are consistent with an optimal preincision infusion time window between 15 and 45 minutes. Consistent with these empirical guidelines, the careful microdialysis studies of Toma et al.45 demonstrate that for cefoxitin, the peak tissue concentration in adipose tissue is reached at an average time of 29 ± 11 minutes after rapid IV infusion.

It would be surprising indeed if antibiotic infusion 15 to 45 minutes before incision ensured optimal tissue and serum concentrations for every beta-lactam, but because the molecular size of most of these drugs are similar, it is not an unreasonable assumption. Clinical studies by Davies et al.52 in which they compare cefamandole, cefuroxime, and cephradine in 60 patients with hip replacement are consistent with the premise. These authors note “we feel that the three agents when given at the same dose showed a similar pharmacokinetic profile; the choice of antibiotic for chemoprophylaxis for total hip replacement should be influenced by the likely pathogens and the cost of the drug.”52 As noted previously, for the morbidly obese patient, the average distance from capillary to tissue is increased,43,44 suggesting that a longer diffusion time may be required for the antibiotic to reach maximum tissue levels. It would seem prudent therefore, based on the recommendations and clinical studies noted, to further tighten our antibiotic infusion time to 30 to 45 minutes when possible (the pragmatic suggestion of Edmiston et al.)21 for the obese patient. In such a manner, we are more likely to achieve the goal of maximum tissue concentrations at the initiation of surgery. Before we can make this universal recommendation, however, the ASHP admonition that tissue concentrations should exceed MIC for the “duration of the procedure” also must be considered.

For those antibiotics with relatively short half-lives (e.g., cefoxitin 0.7–1.1 hours) or for lengthy procedures, the tissue concentrations may be inadequate in the latter stages of the operation (particularly for the morbidly obese patient, whose tissue concentrations may never achieve effective levels).45–47 Hence, administering the antibiotic closer to incision (for example, 0–10 minutes) may provide an insufficient interval to maximize tissue concentrations at incision but may have the alternative benefit of increasing the portion of the decisive period for which the antibiotic concentration exceeds MIC. This trade-off between assuring tissue concentrations are maximum at incision and maintaining tissue concentrations above MIC for the majority of the operative procedure suggests clinical studies may show conflicting results in terms of when to administer the initial antibiotic dose. For example, according to Dellinger53:

“Some have questioned whether giving the antibiotic too close to the time of incision might have less efficacy, but the data of van Kasteren et al. and others are reassuring in this regard. It is important to observe that, although there was no statistically significant difference between the results of administration of prophylaxis during the intervals of 30 to 60 minutes and 0 to 30 minutes before incision, the results during the 0- to 30-minute interval actually showed a lower rate of SSI, which lends no credence to the concern that administration of prophylaxis close to the time of incision might be less effective. However, for total hip arthroplasty, administration of prophylaxis during the 60 minutes before incision had equally good results. This may be because the average duration of operation was only 79 minutes, and thus, administration of prophylaxis even 1 hour before incision would be expected to achieve therapeutic levels of antibiotics throughout the duration of operation. The longer the operation, the more benefit is achieved by administration of prophylaxis as close as possible to the time of incision.” Steinberg et al.54 also argues against the concern over giving antibiotics too close in time to incision. We see 2 different factors at play with respect to antibiotic timing: (1) high tissue levels are desired at skin incision, which is more likely to occur when antibiotics are given approximately 15 to 45 minutes out; and (2) tissue levels above MIC are desired for the duration of the operative procedure, which is more likely to occur when the antibiotic is given immediately before incision. These concepts are illustrated in Figs. 1 and 2, wherein the stippled areas represent the time periods for which tissue concentrations are below MIC.

Figure 1

Figure 1

Figure 2

Figure 2

In other studies, in an analysis of 3836 patients using a single dose of cefuroxime, Weber et al.50 found that administration of the antibiotic 30 to 60 minutes before incision more effective than administration 0 to 30 minutes before incision. Here again, these data are not inconsistent with the benefits of using the 15- to 45-minute time interval, but rather that time interval was not examined. Steinberg et al.54 studied data from 4472 cardiac, hip/knee, and hysterectomy cases and found the lowest rate of infection when antibiotics were given within 30 minutes of incision. An examination of their data demonstrates once again consistency with the 15- to 45-minute interval. In contrast, in a recent analysis of 32,459 Veterans Affairs surgeries, Hawn et al.55 found greater rates of SSI for procedures during which the antibiotic was started more than 60 minutes before incision but not for antibiotics administered after incision. The authors concluded, “while adherence to (measure 30) is not bad care, there is little evidence to suggest it is better care.” In Hawn et al.’s study, there was no limitation on the length of surgery, and redosing of antibiotics was not examined. Koch et al.30 examined rates of SSIs in 6731 patients who underwent 7095 procedures. Their results were limited to procedures of less than 4 hours in duration. Four hundred forty-four patients developed a SSI. The authors found a continuous decrease in rates of SSI as the time between administration of antibiotics and surgical incision was shortened, with 4 minutes before incision as the optimal time for infusion. They concluded that antibiotic administration should be moved closer to incision time, in particular within 18 minutes of incision with a 95% confidence limit.30

In another study of 28,250 cardiac surgery patients, Koch et al. found that for cefuroxime initiation of administration of the antibiotic 15 minutes before incision resulted in the lowest SSI rate, whereas for vancomycin the optimal time to initiate infusion was 32 minutes before incision.56 Here yet again the data are consistent with a range of 15 to 45 minutes leading to the lowest rate of SSIs. It is notable that available studies demonstrate that it does not take long for many antibiotics to achieve adequate tissue levels after bolus IV administration (in studies by DiPiro et al.57 and Wong-Beringer et al.,58 measurable tissue levels of cefoxitin and cefazolin and cefmetazole, respectively, were found within a few moments of infusion), but it does seem to require approximately 15 to 30 minutes for most cephalosporins to reach maximum tissue levels. Even in the study by DiPiro et al.,57 not all patients had measurable tissue levels in muscle at 20 minutes. van Kasteren et al.59 noted that for total hip arthroplasty procedures, optimal antibiotic administration times clustered around 30 minutes before incision, although the data did not reach statistical significance. A summary of some of the recent major studies on timing in the “SCIP era” primarily for the beta-lactams is listed in Table 2.

Table 2

Table 2

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REDOSING OF PROPHYLACTIC PARENTERAL ANTIBIOTICS AND CONTINUOUS INFUSION

The plasma half-life of cefazolin is estimated at 1.2 to 2.2 hours.24 As the plasma concentration decreases, so ultimately does the tissue concentration. Administering cefazolin 30 minutes before skin incision may lead to peak tissue levels at incision, but rapidly decreasing plasma and tissue levels thereafter. Giving cefazolin closer to the time of incision results in lower tissue concentrations at incision but greater tissue concentrations at closure. As emphasized previously, because cephalosporins work via time-dependent killing, it is the time above MIC rather that the maximum concentration reached, which determines effectiveness. The ASHP recommends redosing at intervals of approximately 2 half lives.24 Hence, for cefazolin, a redosing interval of 4 hours is suggested, whereas for ampicillin-sulbactam, a redosing interval of 2 hours is suggested. Ho et al.60 and Goede et al.61 have also emphasized the importance of redosing. In Goede et al.’s study, the lack of redosing had the greatest noncompliance (45.1%) among the various SSI prevention measures analyzed. Those studies in which redosing was used indicate this in turn results in a sinusoidal or sawtooth type of concentration profile, with drug levels alternatively peaking and decreasing.22 Many authors have suggested that a continuous infusion after the initial prophylactic bolus injection so that the total amount of drug infused stays the same for lengthy cases is much more in keeping with the pharmacokinetics and pharmacodynamics of the beta-lactams.22,33–40 For example, if cefazolin is given at an initial dose of 2 g in a 100-kg individual and 3 hours later is redosed with an additional 2 g, with continuous infusion the drug is immediately started at a rate of 2 g over 3 hours after the initial bolus, so that at the end of 3 hours of surgery a total of 4 g has been given. In this manner, assuming the drug reaches a steady-state concentration, we conform to the optimal time-dependent killing concentration profile. Although clinical studies demonstrating a reduced rate of SSIs are not available, numerous authors have suggested such an approach to be beneficial.22,33–40 Available data by Adembri et al.22 measuring tissue levels in cardiac surgery patients shows a clearly beneficial effect on antibiotic concentrations in atrial tissue with continuous administration at the same total dose of cefazolin. In their study, plasma concentrations of cefazolin remained above MIC for >90% of the surgical procedure in 9 of 10 patients for continuous infusion, whereas only 3 of 10 patients in the bolus dosing group achieved plasma concentrations above MIC for >90% of the procedure at the same total dose. In addition to the pharmacokinetically calculated and expected decrease in antibiotic concentrations with time due to physiologic clearance, some surgeries also are associated with significant blood loss and fluid requirements. Both factors result in additional decreases in antibiotic tissue concentrations, either as a result of dilution or elimination. Current recommendations in this area are limited, but some authors recommend redosing for >1500 cm3 of estimated blood loss.24 Assuming an average blood volume of 5000 cm3, 1500 cm3 of blood loss would reduce plasma levels of antibiotics (assuming euvolemia) by 30%. Because blood volume varies significantly in the adult patient population, a better approach would be to calculate the total blood volume using the Lemmens formula (see next section) and redose at a 30% estimated blood loss.

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WEIGHT-BASED DOSING AND OTHER ESTIMATES OF ANTIBIOTIC REQUIREMENTS

To simplify dosing schedules for commonly used beta-lactams, often 1 g of cefazolin, cefoxitin, or cefotetan is used for patients ≤70 kg and 2 g for patients ≥70 kg. For cefuroxime, 1.5 g often is used for all patients. In Chopra et al.’s62 study on obese patients, a dose of 3 g of cefazolin was recommended for patients with a body mass index (BMI) >50. It is evident, however, that the 1.5-m tall, obese individual with a BMI of 50 will have a far smaller blood volume than the 2.0-m tall individual with a BMI of 50, and in the former case, the initial plasma concentration of cefazolin will consequently be significantly higher. The ASHP recommends a dose of 3 g of cefazolin for patients who weigh ≥120 kg but does not discuss dosage modifications with increasing weight for many of the other beta-lactams. Once again, the 1.5-m tall individual with a weight of 120 kg will have a far smaller blood volume than the 2.0-m tall individual with the same weight. The matter is far from settled, and the few available studies on antibiotics and morbid obesity indicate current dosing regimens to be inadequate.44–46,62,63

Because serum antibiotic levels often are used as a surrogate for antibiotic tissue concentrations as well as reflecting to some degree the risk of toxicity, a more physiological approach to dosing commonly used beta-lactams would be to strive for the same initial plasma level of antibiotic. With serum concentration as a guide, and with the use of a minimum dose of 2.0 g of cefazolin, cefoxitin, or cefotetan for a 70-kg patient as a “floor,” the calculated antibiotic dose is 0.00041 g/cm3 of blood, using a blood volume of 70 cm3/kg. Similarly, for cefuroxime, with a minimum dose of 1.5 g for a 70-kg patient as a floor,24 the calculated antibiotic dose is 0.00031 g/cm3 of blood.

To estimate blood volume in the obese patient, one useful tool is the Lemmens formula44:

CV

CV

where BMI is the patient’s body mass index in kg/m.2 There fore, the required dose of cefazolin, for example, to achieve the same initial plasma level for patients >70 kg (where W is the actual body weight in kg) is estimated as follows:

CV

CV

For a morbidly obese patient with a height of 1.77 m and a weight of 157 kg (BMI = 50), the required dose would be 3.0 g, identical to the recommendation of Chopra et al.62 For a morbidly obese patient with a height of 1.50 m and a weight of 113 kg (BMI = 50), the required dose would be reduced to 2.15 g, a result of the markedly decreased blood volume. Selecting 3 hours as the redosing interval (approximately 1.5 half-lives) for the former patient, the initial bolus would be followed by a continuous infusion at 1.00 g/h. Maintaining this antibiotic infusion until the patient’s discharge from the postanesthesia care unit is more likely to maintain adequate blood levels in the (obese) patient throughout the entire decisive period than a traditional dosing regimen.21,45,46 Thus, as anesthesia providers, one possible and logical way we can address the troubling issue of ineffective antibiotic tissue levels for obese patients is by (1) calculating antibiotic dose based on the Lemmens formula with floors for cefoxitin, cefotetan, or cefazolin of 2 g and for cefuroxime of 1.5 g for a 70-kg patient and (2) for high-risk patients or patients in whom a SSI would be catastrophic, following the initial bolus dose by a continuous infusion. It is noteworthy that the Lemmens formula gives results in approximate agreement with the dosing weight calculations for aminoglycosides, which is not surprising because the toxicity of these latter drugs is also related to plasma concentration.

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USE OF A TOURNIQUET

The anesthesiologist often is charged with the task of administering prophylactic antibiotics to patients for whom a pneumatic tourniquet is used. Use of a tourniquet creates unique problems with regard to antibiotic dosing. After tourniquet inflation, the affected limb is ischemic for the duration and oxidative neutrophil killing, the body’s primary defense mechanism against pathogens, stops. Hence, pathogens weakened by the initial dose of antibiotics and more susceptible to host defenses remain viable while bacterial seeding from a variety of external sources continues during ischemia. This bacterial load is then integrated into the clot that forms after tourniquet release, making neutrophil killing more difficult.64 Simultaneously, the blood infusing the affected limb after tourniquet release has a much lower antibiotic concentration, affected by the duration of tourniquet use and the half life of the specific antibiotic administered.65,66 The literature on the topic is equivocal, and equal SSI rates are seen whether the antibiotic is given before or after tourniquet inflation.65–67 It has been suggested that a tourniquet release dose is appropriate, as well as an initial dose at least 10 minutes but preferably longer before tourniquet inflation and skin incision.67,68 Although evidenced-based studies are lacking, this approach has the weight of physiologic reasoning behind it, common to many of the anesthesia techniques we use.69 On the other hand, the ASHP monograph makes the point that antibiotic administration before tourniquet inflation seems intuitively correct and does not discuss a tourniquet release dose.24 In summary, it appears prudent to administer the first dose of antibiotic within the 15- to 45-minute time span before tourniquet inflation (being careful to satisfy the 1-hour PQRS requirement for antibiotic to incision time) and add an additional tourniquet release dose for those procedures in which occurrence of a SSI would be catastrophic, such as total knee replacement. Continuous infusions of antibiotics have no logical place in procedures involving a tourniquet.

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BIOFILMS

Many surgical procedures involve insertion of a foreign substance into the patient (pacemakers, mesh, prostheses, etc.). This is particularly true in the case of the extensive instrumentation involved in complex orthopedic procedures.70 In all such cases, the development of a bacterial biofilm creates a formidable obstacle to infection control.13,71 The development of a biofilm occurs in as little as 6 hours.71 Hence, procedures involving mesh, instrumentation, and other foreign bodies necessitate more aggressive antibiotic prophylaxis. Until such time as molecules that interfere with biofilm production or facilitate penetration of the film with effective antimicrobials are routinely introduced into clinical practice,72 the use of a beta-lactam bolus followed immediately by a continuous infusion may be justified.73 Clear recommendations in the medical literature on this subject are not available.

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OTHER COMMON CONSIDERATIONS

When to Avoid Prophylactic Antibiotics

Many other questions and issues occur in the course of selecting appropriate prophylactic antibiotic coverage, much of this relevant to the attending anesthesiologist. A significant and often-controversial issue concerns the actual need for antibiotics. The ASHP white paper discusses a number of situations for which antibiotics are not indicated. These include clean orthopedic procedures on the extremities without instrumentation, as well as clean head and neck procedures such as thyroidectomy or lymph node excision in low-risk patients. In addition, both the ASHP policy paper and the Medical Letter suggest that for low risk ASA I or II patients undergoing elective cholecystectomy, antibiotic prophylaxis is usually not indicated.74 Other surgical procedures wherein antibiotics appear to have little or no place for low-risk patients include laparoscopic oophorectomies, tonsillectomies, and cystoscopies. To avoid delays, confrontations, and unpleasantries, all of these issues should of course be discussed in a cooperative and helpful exchange between the surgical and anesthesia teams and general policies and guidelines put in place. In situations in which prophylactic antibiotics may be avoided, their use should be discouraged because none of these medications are without potential harm. For example, Clostridium difficile, a rapidly growing health care problem and major contributor to morbidity and mortality in HAIs, is strongly associated with antibiotic administration75 (as well as with the use of proton pump inhibitors and increased age, both increasingly common in today’s surgical population), even when antibiotic use is restricted solely to prophylactic perioperative antibiotics.76

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The Patient with a Penicillin Allergy

Traditionally, patients for whom cefazolin is the recommended antibiotic often are switched to clindamycin or vancomycin when they present with a history of a penicillin allergy. However, many authorities recommend that only in those situations where the patient’s history is consistent with either an IgE-mediated penicillin allergy (urticaria, angioedema, anaphylaxis, bronchospasm) or a severe non–IgE-mediated reaction (interstitial nephritis, toxic epidermal necrolysis, hemolytic anemia, or Stevens-Johnson syndrome) is it necessary to switch out the cefazolin.77–79 Even in these situations, there is at least some question if cefazolin need be avoided. Cross-sensitivity occurs when the R1 side chains of the penicillins and cephalosporins are similar, which perhaps surprisingly is not the case with cefazolin. Cephalosporins with R1 side chains similar to penicillins include cephalexin, cefaclor, and cefadroxil. According to The Medical Letter, for patients with mild-to-moderate reactions to penicillin G, ampicillin, or amoxicillin, the risk associated with use of first- or second-generation cephalosporins with dissimilar side chains, or third- or fourth-generation cephalosporins, “appears to be very low.”78 Thus, reflexively dismissing cefazolin use with a vague history of any penicillin allergy should be reconsidered. We can certainly make our voices heard in these situations.

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Practical Considerations in Drug Selection

It is generally agreed that antibiotic selection should target the most likely pathogens, and that targeting all potential pathogens is unnecessary and potentially harmful. The Medical Letter’s 2012 recommendations for antibiotic selection take this approach. For many surgeries, cefazolin is the drug of choice.74 The ASHP white paper reflects similar sentiment but gives a wider and much more detailed selection of appropriate antibiotics, with specific recommendations for a multitude of operative procedures.24 The predictable culprits for different procedures vary by hospital, but it is common consensus that skin pathogens (Staphylococcus aureus, Staphylococcus epidermidis) are frequent offenders in clean surgeries, whereas enteric gram-negative microbes are found in many clean contaminated surgeries. The Center for Disease Control tracks common pathogens via the National Healthcare Safety Network, the most widely used infection-tracking system in the United States. According to the National Healthcare Safety Network, the top 5 most commonly reported pathogens are (1) Staphylococcus aureus, (2) coagulase-negative staphylococci, (3) Escherichia coli, (4) Enterococcus faecalis, and (5) Pseudomonas aeruginosa.80

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CONCLUSIONS

It would certainly be unusual for an anesthesia provider to administer a medication in the absence of a thorough knowledge of the pharmacology, proper dosing, and indications for that medication, but this is often the case with parenteral prophylactic antibiotics. Glance and Fleisher2 note if we are unwilling to share accountability for surgical outcomes, we run the risk of trivializing the specialty of anesthesiology. SSIs are one such frequent negative outcome, and because antibiotic administration is a cornerstone of prevention efforts, a thorough knowledge of the fundamentals of principles supporting appropriate selection and use is required.

If we consistently use well-understood pathophysiological concepts and current data with respect to the pharmacokinetics and pharmacodynamics of prophylactic antibiotics, it is highly likely we can reduce national rates of SSIs. We do not have the luxury of time to wait for the definitive large-scale clinical studies, so rare in modern anesthesiology.81 Current evidence suggests that for most beta-lactams, a bolus dose at 15 to 45 minutes before incision is ideal and provides maximum interstitial fluid concentrations at the time of initial bacterial seeding. Because diffusion distances from capillary to pathogen are greater in obese patients, for this patient subset initiating antibiotic infusion 30 minutes or longer before incision is warranted on theoretical grounds. Koch et al.’s work is consistent with this premise, and for cefuroxime, patients with a BMI >30 had an optimal time for initiation of infusion of 39 minutes before incision versus 21 minutes for patients with a BMI < 30.56 A current prospective study underway in Switzerland hypothesizes that antibiotics should be administered no earlier than 30 minutes before skin incision to minimize SSIs.82

The initial beat-lactam bolus dose should be followed by additional doses at every 1 to 2 half lives per the ASHP guidelines. For situations for which a SSI would be catastrophic, available literature and pharmacodynamic considerations suggest the initial bolus should be followed immediately by a continuous infusion such that the same total dose of drug is administered as in the case of redosing. Calculation of antibiotic dosing for obese patients is controversial, and although the simple expedient of giving 3 g of cefazolin for the 120-kg patient or alternatively for the patient with a BMI of ≥50 is acceptable, use of the Lemmens formula and blood volume dosing would seem prima facie preferable. Estimation of blood volume and using 30% of blood volume loss as an antibiotic trigger for redosing would also seem preferable to the unqualified recommendation of redosing for every 1500 cm3 of blood loss in all patients. In the case of tourniquet use, a tourniquet release dose appears justified for those procedures in which a SSI would be devastating.

The pharmacokinetics and pharmacodynamics of antibiotics should guide their administration by the anesthesia provider. It is time for us to embrace our role in the overall surgical experience. We can do better.

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DISCLOSURES

Name: Ronald J. Gordon, MD, PhD.

Contribution: This author wrote the manuscript.

Attestation: Ronald J. Gordon approved the final manuscript.

This manuscript was handled by: Sorin J. Brull, MD, FCARCSI (Hon).

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ACKNOWLEDGMENTS

I would like to thank Dr. Charles E. Edmiston, Jr, Department of Surgery, Medical College of Wisconsin, for his interest and very helpful comments and suggestions.

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FOOTNOTES

a Colavita PD, Zemlyak AY, Burton PV, Dacey KT, Walters AL, Lincourt AE, Tsirline VB, Augenstein VA, Kercher KW, Heniford BT. The expansive cost of wound complications following ventral hernia repair. American College of Surgeons Clinical Congress 2013. Walter E. Washington Convention Center, Washington, DC, October 7, 2013. Scientific Sessions. Available at: http://web2.facs.org/cc_program_planner/Detail_Session_2013.cfm?CCYEAR=2013&SESSION=SP04&GROUP=SP. Accessed June 21, 2014.
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b Outpatient Surgery. February 2014. Available at: http://www.outpatientsurgery.net/surgical-facility-administration/infection-control/study-finds-ssis-the-best-predictor-of-surgical-readmissions--02-19-14. Accessed June 21, 2014.
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c Surgical prophylaxis antibiotic guidelines. Rochester General Health System. September 2012. Available at: http://nebula.wsimg.com/9678632ff686d48917fa1a34bc83f4ef?AccessKeyId=FD7CB6ADC6CB16B0172B&disposition=0&alloworigin=1. Accessed June 21, 2014.
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