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.
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:
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.
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.
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.
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
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.
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
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.
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.
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.
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.
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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