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Prophylactic Perioperative Antibiotic Administration: Is It Time to Infuse Our Practices with New Approaches?

Gravenstein, Nikolaus MD*; Fish, Jeffrey T. PharmD; Klinker, Kenneth P. PharmD; Coursin, Douglas B. MD§

doi: 10.1213/ANE.0000000000000541
Editorials: Editorial

From the *Department of Anesthesiology, University of Florida, Gainesville, Florida; Department of Critical Care, University of Wisconsin Hospitals, Madison, Wisconsin; UF Health Shands Hospital, Gainesville, Florida; and §University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.

Accepted for publication September 28, 2014.

Funding: None.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Nikolaus Gravenstein, MD, Department of Anesthesiology, University of Florida College of Medicine, PO Box 100254, Gainesville, FL 32610. Address e-mail to

We hope many are inspired, as were we, by Gordon’s provocative Review Article in this issue titled “Administration of Prophylactic Beta-Lactam Antibiotics in 2014: Review.”1 Given that nearly a century ago, Lord Moynihan already considered every operation an experiment in bacteriology, it is encouraging that our specialty has, over the past decade, accepted ownership of timely perioperative prophylactic antibiotic administration.2 In some institutions, this has decreased the surgical site infection (SSI) rate, but several large, well-done prospective studies have not been able to establish a clear benefit of strict adherence to the Surgical Care Improvement Project Measure 1 that calls for administration of the appropriate prophylactic antibiotic in a window that precedes surgical incision, but not by >60 minutes (120 minutes in the case of vancomycin or fluoroquinolones).3,4 Despite the concerns over the efficacy of current perioperative antibiotic prophylaxis guidelines, the timing of prophylactic antibiotic administration remains an institutional quality marker throughout American hospitals. This begs the question of why there seems to be a disconnect between consistent timely antibiotic administration and a measurable reduction in the SSI rate. Could it be that we have satisfied the administrative requirement without sufficient thought given to the process of preventing these infections? Gordon politely suggests that this is indeed the case and calls on us to be clinicians and not simply technicians as it relates to prophylactic antibiotic administration in the acute perioperative period.

The time surrounding incision and the early postoperative recovery period has been coined the “decisive period” for an infection establishing a foothold or being prevented.5 It is during this period that host defenses and prophylactic antibiotics play a key role in the prevention of SSIs.

Based on the classic work of Miles et al.,5 SSIs may be amplified by low skin blood flow—his team used epinephrine-induced vasoconstriction. A wound edge retractor or cold air and evaporation might create a locally similar effect during surgery. Miles et al. also found that antibiotics concurrently administered during the induced vasoconstriction were effective in preventing infection, but this benefit waned as the interval between antibiotic administration and inoculation grew.

The decisive period is our time. It is our opportunity to make another difference in patient outcomes. The practice of anesthesiology is one of the applied pharmacology and we should practice accordingly as it relates to antibiotics. Gordon reviews antibiotic choice, timing of initial dose, dosing, redosing, patient size, penicillin allergy, and use of tourniquet considerations. The entire review is worth considering, but the concepts of intelligent pharmacodynamic and pharmacokinetic dosing and redosing in operative patients are perhaps the most provocative and important ones. They are also conceptually familiar.

Very simply, most antibiotics, including the β-lactams, for example, cefazolin, cefuroxime, and cefoxitin, used for SSI prophylaxis exert their bactericidal effect through a mechanism referred to as time-dependent killing with little postantibiotic effect.6 For time-dependent kill antibiotics with short half-lives, the best strategy may be frequent administration of smaller doses to ensure that tissue concentrations remain above the minimal inhibitory concentration (MIC) (usually 4 times the MIC for the β-lactams) required to ensure efficacy. The β-lactam class of antibiotics is most effective if its concentration is maintained above the target MIC for a sufficient time, that is, the decisive period.7,8 Unlike the quinolones, metronidazole, and aminoglycosides, which manifest a concentration-dependent killing and have a significant postantibiotic effect, the β-lactams have little-to-no postantibiotic effect. In other words, when β-lactam concentrations fall below the MIC, they no longer have a meaningful antibiotic effect. That is a pharmacodynamic reality. Put this in context with the typical bolus administration of 2 g of cefazolin (3 g if the patient weighs >120 kg). The very high initial peak plasma level rapidly redistributes into the tissue (which Gordon reminds us is crucial to appropriate timing of the first bolus administration) and interstitial compartments and is for a time higher than the MIC. All is good if the operation is short enough that tissue levels sufficiently exceed the MIC for the decisive period (Fig. 1). The typical operation in community surgery centers is <1 hour and is approximately 1.5 hours in inpatient facilities. By comparison, in academic centers, the duration of the same surgeries is roughly twice as long.

Figure 1

Figure 1

In the case of cefazolin, with a half-life of only 1.2 to 2.2 hours, if you are redosing it at least every 2 half-lives as recommended by the American Society of Hospital Pharmacists, redosing is due every 3 to 4 hours.9 Your patient may well be below the target MIC threshold level before the redose is due.10,11 In the case of cefoxitin, with a 1-hour half-life and a 2-hour redosing strategy, the risk of falling below the target MIC occurs earlier. To put a time-dependent effect antibiotic such as cefazolin into context, think of an anesthetic, or even a sedative, where to ensure an adequate anesthetic we give a bolus dose for induction followed by frequent boluses or a continuous infusion. This same principle can be applied to antibiotic administration. Yes, an infusion. An infusion is simply continuous administration of very small boluses. Is the infusion complicated to calculate or administer? No, not at all. The antibiotic redose infusion is simply set so that at what would have been your next bolus dose time, the redose infusion dose is just in. For a 2 g every 4-hour cefazolin redose interval, the infusion would begin immediately after the first 2 g dose and run at 500 mg/h. If your institution uses a 3-hour cefazolin redosing interval, the redose infusion is run over 3 hours. In the case of cefoxitin, with a 2 g every 2-hour schedule, the infusion would run at 1 g/h for the duration of the procedure. A potentially important benefit of this approach is that in the acute postoperative period, there is still a high plasma/tissue level during the time that is still considered to be within the decisive period window (Fig. 1).

The current antibiotic prophylaxis guidelines are prescriptive and not necessarily based on patient- or operation-specific factors. The existing approach is an all or nothing one; the medication was given, yes or no, within 1 hour of incision, yes or no. Unanswered are factors such as was the right drug and dose administered? Was sufficient time allowed for adequate tissue penetration? Was the drug redosed in a timely manner or would a continuous infusion of a β-lactam provide a better infection prevention of the surgical site milieu?

Dr. Gordon nicely addresses why many patients who receive β-lactam prophylaxis might be better or best served if they received a loading dose and then a continuous infusion. This would result in drug concentrations above the target MIC from incision throughout the surgery and wound closure. We have delivery systems readily available to do so and it does not require greater doses of medication to maintain a sufficient MIC multiple. He bases his discussion on sound pharmacodynamic and kinetic principles; ones we routinely apply daily.

Why should antibiotic use and delivery be different than the routine use of sedatives, amnestics, analgesics, and paralytics, which we administer regularly and confidently, often as continuous infusions based on familiar principles? Antibiotics are not magical, but they are only as effective as our ability to choose the right one(s) and administer them in a manner that results in adequate tissue concentrations for an appropriate time frame. There is a clear analogy between surgical antibiotic prophylaxis and the current Surviving Sepsis recommendations.12 The latter emphasize the need to quickly identify the most likely infectious pathogen (skin, bowel, or bladder flora or pathogen coverage for intraoperative prophylaxis) and select the best option for definitive treatment. We must remember to think beyond just reflexive administration of cefa-“something” and make certain we pick the appropriate drug to prophylax against the most likely bug. Whatever we choose to administer should be for short-term prophylaxis only and dosing should be discontinued within <24 hours. In sepsis, empiric broad-spectrum antibiotics with rapid de-escalation within 48 hours as causative factors are identified and provision of the appropriate dose at the appropriate time, as soon as possible, ideally within 1 hour of diagnosis. Surviving sepsis recommends a <3-hour delay for initiation of definitive broad-spectrum antibiotics. This dramatically impacts survival.13 In septic patients, the incorrect drug or a delay of >12 hours markedly increases mortality. Analogously unsophisticated prophylactic antibiotic administration risks otherwise potentially avoidable SSIs. Of note, some practitioners now advocate continuous infusions of time-dependent antibiotics in septic intensive care unit patients, but the best practice remains unknown.14,15 With regard to achieving target plasma prophylactic β-lactam concentrations, there is a clinical trial scheduled to start in 2014 that will formally address the question as it relates to plasma drug levels of cefazolin in major abdominal surgery patients:

Enhanced understanding of the basic principles of antibiotic administration related, in part, to drug class, patient characteristics, and surgical type and location will be bolstered by this review. Gordon outlines several areas where it would be helpful to have more prospective data. Like so much in our pharmacologic practice, 1 size, 1 time, 1 way does not always result in global benefit or benefit for an individual patient. Now that we have reliably conquered preincision prophylactic antibiotic administration, the next opportunity for our specialty is to tackle the surrounding nuances to optimize β-lactam antibiotic prophylaxis.

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Name: Nikolaus Gravenstein, MD.

Contribution: This author contributed to the editorial review, analysis, and manuscript preparation.

Attestation: Nikolaus Gravenstein approved the final manuscript.

Name: Jeffrey T. Fish, PharmD.

Contribution: This author contributed to the editorial review, analysis, and manuscript preparation.

Attestation: Jeffrey T. Fish approved the final manuscript.

Name: Kenneth P. Klinker, PharmD.

Contribution: This author contributed to the editorial review, analysis, and manuscript preparation.

Attestation: Kenneth P. Klinker approved the final manuscript.

Name: Douglas B. Coursin, MD.

Contribution: This author contributed to the editorial review, analysis, and manuscript preparation.

Attestation: Douglas B. Coursin approved the final manuscript.

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

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