| 1A. No recommendation can be made regarding the optimal timing of preoperative parenteral prophylactic antimicrobial agent administration for the prevention of surgical site infection. (No recommendation/unresolved issue) |
| Clinical practice guidelines recommend administering by the intravenous route a single dose of prophylactic antimicrobial agent. For most prophylactic agents, administration should be within 60 minutes prior to incision. Administer vancomycin and fluoroquinolones within 60–120 minutes prior to incision.12,22-27 |
| 1B. Administer the appropriate parenteral prophylactic antimicrobial agent prior to skin incision in all cesarean sections. (Category IA)28-31 |
| 1C. No recommendation can be made regarding the safety and effectiveness of weight-adjusted dosing of parenteral prophylactic antimicrobial agents for the prevention of surgical site infection. (No recommendation/unresolved issue) |
| Clinical practice guidelines recommend that for obese and morbidly obese patients, the prophylactic antimicrobial agent dose should be based on the patient’s weight where pharmacokinetic data support it (e.g., cefazolin, vancomycin, and aminoglycosides).22-26 |
| 1D. No recommendation can be made regarding the safety and effectiveness of intraoperative redosing of parenteral prophylactic antimicrobial agents for the prevention of surgical site infection. (No recommendation/unresolved issue)32 |
| Clinical practice guidelines recommend maintaining therapeutic levels of the prophylactic antimicrobial agent in serum and tissues throughout the operation based on individual agent pharmacokinetics.12 Redose intraoperatively at intervals 1–2 times the prophylactic antimicrobial agent half-life (measured starting at the beginning of the single preoperative dose) or when there is excessive blood loss.23-26,33 |
| 1E. In clean and clean-contaminated procedures, do not administer additional prophylactic antimicrobial agent doses after the surgical incision is closed in the operating room, even in the presence of a drain. (Category IA)34-72 |
The recent guidelines developed by the American Society of Health-System Pharmacists (ASHP), and endorsed by the Infectious Diseases Society of America (IDSA), the Surgical Infection Society (SIS), and the Society for Healthcare Epidemiology of America (SHEA) are an update to the previously published ASHP Therapeutic Guidelines on Antimicrobial Prophylaxis in Surgery. Because they are referenced by the CDC update, these ASHP guidelines will become a de facto standard for antibiotic usage for prophylaxis.
One goal of this chapter is to review these guidelines in depth, and to provide a contrarian critique. In certain cases, where we believe recommendations to be not justified by recent data, we provide alternatives. We also note that administration of systemic anti-infectives is part of a broad program of infection control involving adequate operating room ventilation, sterilization, site preparation, barrier usage, and delicate surgical technique.
We also believe that surgical prophylaxis administered per current guidelines has little if any impact on bacterial resistance patterns. In comparison to the substantial quantity of antibiotics prescribed in the community for upper respiratory infections, which affects gram-positive resistance (consider community-associated Staphylococcus aureus), and the 4-fold greater amount of antibiotics used as growth promoters in agriculture (consider quinolone resistance and extended-spectrum β-lactamase-producing Enterobacteriaceae) the volume of antimicrobials provided to surgical patients for prophylaxis is quite small and very brief (typically one dose). Conversely, this is not an argument for use of important therapeutic classes (e.g., carbapenems) for prophylaxis when equivalent results are obtained by agents (cefazolin/cefuroxime) not used for treatment of gram-negative infections.
Pharmacokinetic/pharmacodynamic (PK-PD) correlates of effective antibiotic prophylaxis
β-lactam antibiotics exhibit time-dependent bactericidal action, with therapeutic efficacy maximized when concentrations exceed a threshold value for prolonged portions of the dosing interval. This threshold value is typically assumed to be the minimum inhibitory concentration for targeted pathogens (MIC), although other work suggests a multiple of four times the MIC may be more effective. Because intraoperative contamination may occur at any time during the procedure, the theoretical goal of antimicrobial prophylaxis is to maintain serum and tissue drug concentrations that exceed the MIC for the duration of the operative procedure.
One difficulty in identifying the correct dose and timing of antimicrobial prophylaxis has to do with the role of extracellular fluid concentrations versus serum concentrations in determining success or failure of antimicrobial prophylaxis. There is a general consensus that extracellular fluid concentrations are most accurate as an efficacy parameter, and that studies done using tissue homogenates provide highly inaccurate information. More recently, information generated by Monte Carlo simulations has been proposed and in some cases accepted as surrogates for in vivo data. This seems preferable to the extrapolation of inconsistent data obtained from relatively small clinical trials. Further, these simulations have, at least in retrospect, explained failure of prophylaxis in high-risk procedures including those performed in the colon and rectum.
An additional problem is that antibiotic susceptibilities of clinically isolated anaerobes and enteric gram-negative facultatives and aerobes have substantially changed over the past two decades. Before 2010, the breakpoints for parenteral cephalosporins and Enterobacteriaceae had been those that were set several decades ago. In the case of the first-generation cephalosporins cephalothin and cefazolin, the breakpoints had been in existence for >30 years. Since first publication of these breakpoints, the science of antimicrobial PK-PD emerged, and matured to the point that it became an essential tool to assist breakpoint setting and revision, and PK-PD analyses were included in the essential data requirements by the Clinical and Laboratory Standards Institute (CLSI) Subcommittee.
Wound classification systems for identifying risk of infection
To understand the potential risk elements for SSI, accurate risk models are required to identify modifiable variables. It is assumed that at least three categories of variables serve as predictors of SSI risk: (1) those that estimate the intrinsic degree of microbial contamination of the surgical site; (2) those that measure the duration of the operation and other less easily quantifiable elements of the procedure, a presumptive surrogate for a range of variables including surgeon skill, anatomic difficulties, and a concomitant requirement for extensive dissection; and (3) those that serve as markers for host susceptibility.
The CDC, through the National Nosocomial Infection Survey (NNIS), tested a risk index for acquiring an SSI. The risk index score, ranging from 0 to 3, is the number of risk factors present among the following: (1) an operation classified as contaminated or dirty-infected (Table 114.2); (2) a patient with an American Society of Anesthesiologists preoperative assessment score of 3, 4, or 5 (Table 114.2); and (3) an operation lasting over T hours, where T depends on the operative procedure being performed (Table 114.2). The SSI rates for patients with scores of 0, 1, 2, and 3 were 1.5, 2.9, 6.8, and 13.0, respectively.
| Class I/Clean: An uninfected operative wound in which no inflammation is encountered and the respiratory, alimentary, genital, or uninfected urinary tract is not entered. In addition, clean wounds are primarily closed and, if necessary, drained with closed drainage. Operative incisional wounds that follow nonpenetrating (blunt) trauma should be included in this category if they meet the criteria. |
| Class II/Clean-Contaminated: An operative wound in which the respiratory, alimentary, genital, or urinary tracts are entered under controlled conditions and without unusual contamination. Specifically, operations involving the biliary tract, appendix, vagina, and oropharynx are included in this category, provided no evidence of infection or major break in technique is encountered. |
| Class III/Contaminated: Open, fresh, accidental wounds. In addition, operations with major breaks in sterile technique (e.g., open cardiac massage) or gross spillage from the gastrointestinal tract, and incisions in which acute, nonpurulent inflammation is encountered are included in this category. |
| Class IV/Dirty-Infected: Old traumatic wounds with retained devitalized tissue and those that involve existing clinical infection or perforated viscera. This definition suggests that the organisms causing postoperative infection were present in the operative field before the operation. |
| ASA PS Category | Preoperative Health Status Comments | Examples |
|---|---|---|
| ASA PS 1 | Normal healthy patient | |
| ASA PS 2 | Patients with mild systemic disease | No functional limitations; has a well-controlled disease of one body system |
| ASA PS 3 | Patients with severe systemic disease | Some functional limitation; has a controlled disease of more than one body system or one major system |
| ASA PS 4 | Patients with severe systemic disease that is a constant threat to life | Has at least one severe disease that is poorly controlled or at end stage |
| ASA PS 5 | Moribund patients who are not expected to survive without operation |
| Procedure | 75% Percentile for Time (hours) |
|---|---|
| CABG – chest and donor site | 5 |
| Liver and pancreas | 4 |
| Other GI | 3 |
| Herniorraphy | 2 |
| Mastectomy | 3 |
| Abdominal hysterectomy | 2 |
The yes or no single-point award obviously provides no gradation particularly for the “host” resistance wherein patients with mild chronic diseases (ASA 3) are considered at the same risk as moribund patients. Similarly, there is no grading discriminating a procedure 1 minute over the T time from that several hours beyond.
Another problem is that the numbers of patients in each of these groups, however, were not provided and it is highly likely that category 3 contains very few patients, while categories 0 and 1 contain the bulk of patients undergoing operation in the USA. This means that infections in the 0 and 1 groups are outside of the current risk model, and that the model does not well apply to the bulk of the patients treated. This is very important in estimating the effects of a process change such as increasing doses and shortening dosing intervals, because the reasons for the infections are not explained.
More recent efforts to utilize CDC/NHSN (National Healthcare Safety Network) administrative data to improve the system have not demonstrated substantial improvement. Creating a more explanatory risk model will be difficult for administrative reasons. Data collection tools would have to be developed, tested, and then sent to every hospital in the United States. Creating software/hardware for this and retraining the surveyors doing this work would be extremely expensive and may not be worth the effort. It is extremely unlikely that mathematically superior models would be useful with current levels of deep/organ space infections, the only ones reported by NHSN, of 0.5% to 2% for clean and most clean-contaminated procedures. Given how infrequently infections occur at an individual hospital with “average” procedure volumes, hospital level risk modeling is and will continue to be enormously inaccurate.
The point is, measuring the outcome effects of changes in process is very difficult and the absence of level 1 data argues that additional complexity not be added to the perioperative care system. We have major concerns for increasing the frequency of redosing of intraoperative antimicrobial prophylactic agents. With infection rates <2% for clean surgery and no evidence that doing so would further lower rates, such a change seems unneeded. Further, the benefits, if any, would be limited. About half of these infections are superficial, and do not cause prolonged hospitalization, reoperation, or risk of mortality. There are a few problem areas, but there is no evidence that high continuous levels of antibiotics will substantially avert these problems. Because of the large size of the population needed to be treated to theoretically protect a small number, toxicity becomes a real risk.
Certainly prolonged procedures (>75% of time for all such procedures) are an independent risk for infection. The risk of this may be partly explained by deficient plasma levels at the end of the procedure. However, prolonged procedures reflect items such as surgeon skill, difficulty of procedure, adhesions and difficult dissection, and other nonpharmaceutical problems, and it is not known that higher antibiotic levels will do much. Three-hourly dosing is too frequent for cefazolin; 4-hour dosing seems a reasonable compromise.
A critique of the ASHP guidelines
We are concerned about the system used for evaluating available evidence and therefore defining the strength and believability of the recommendations. Most guideline development groups have moved to use of the GRADE system. These include IDSA, CDC, the Society for Healthcare Epidemiology of America (SHEA), the World Health Organization (WHO), and a range of other groups detailed on the GRADE working group web site. HICPAC described the rationale for requiring that the 2014 update to the CDC guideline for prevention of surgical site infections was done with GRADE methodology.
Instead, ASHP chose to use a system that is heavily biased towards expert opinion, providing the argument that historically it has been used by those organizations that, in fact, have now moved to GRADE.
Strengths of recommendation are then given as: A: Levels I–III; B: Levels IV–VI; and C: Level VII.
In fact many randomized clinical trials are not well designed or well conducted, and there are serious concerns about the value of cohort or case–control studies, wherein the rationale for providing one therapy versus another is not known but is assumed to be based upon physicians’ beliefs about “optimal” treatment. Effect sizes in these types of trials are notoriously large (Health Technology Assessment Report) and therefore overstate the benefits of a particular therapy. At the other extreme, expert opinion is not data.
The benefit of GRADE evaluations is that the studies are analyzed into predefined tables, and the strength of the individual studies cited as bases for recommendations can therefore be scrutinized by the reader.
The point is that the evidence rating system used in the ASHP guidelines does not provide confidence that the recommendations are robust, nor does it provide any assurance that as a future policy statement change is unlikely.
Choice of anti-infectives for prophylaxis
The anticipated pathogens from various operative sites are detailed in Table 114.3. It is most convenient to discuss antimicrobial prophylaxis in clean and clean-contaminated procedures since contaminated and dirty wounds typically require therapeutic use of antibiotics.
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