REPORT FROM THE WORKFORCE ON EVIDENCE-BASED MEDICINE The Society of Thoracic Surgeons Practice Guideline Series: Antibiotic Prophylaxis in Cardiac Surgery, Part II: Antibiotic Choice* Richard Engelman, MD, David Shahian, MD, Richard Shemin, MD, T. Sloane Guy, MD, Dale Bratzler, DO, MPH, Fred Edwards, MD, Marshall Jacobs, MD, Hiran Fernando, MD, and Charles Bridges, MD, ScD Baystate Medical Center, Springfield, Massachusetts; Tufts University School of Medicine, Boston, Massachusetts; Boston Medical Center, Boston, Massachusetts; University of California, San Francisco, California; Oklahoma Foundation for Medical Quality, Oklahoma City, Oklahoma; University of Florida, Shands Jacksonville, Jacksonville, Florida; St. Christopher’s Hospital for Children, Philadelphia, Pennsylvania; and University of Pennsylvania Medical Center, Philadelphia, Pennsylvania I. Overview tional publications in so far as they compare different antibiotic regimens involving comparable duration of The importance of prophylactic antibiotics for cardiac multidose antibiotic administration. surgery has been clearly demonstrated in a number of The most pertinent report appeared in 2004 and was placebo-controlled studies completed nearly 30 years ago a very complete meta-analysis of seven randomized Surgical site infections (SSIs) and particularly ster- nal and mediastinal infections have implications for trials, comparing the incidence of SSIs in patients receiv- significantly increasing both morbidity and mortality, as ing either glycopeptide prophylaxis (vancomycin or well as their associated costs in both man-hours and teicoplanin) or a ␤-lactam. Five of the seven trials used a dollars spent multidose regimen and two invoked, in one of their trial Part I of this evidence-based guideline series (The groups, the single preoperative administration of a long- Society of Thoracic Surgeons Practice Guideline Series: Anti- acting agent. In both of these latter reports, the single- biotic Prophylaxis in Cardiac Surgery, Part I: Duration, pub- dose agent was either less effective or not significantly lished in the January 2006 issue of the Annals of Thoracic different from the multidose antibiotic In this Surgery) recommended that the duration for routine post- international, multi-institutional meta-analysis involving operative administration of prophylactic antibiotics be no 5,761 patients, ␤-lactams were at least as effective as longer than 48 hours This initial Guideline did not glycopeptides for the overall prevention of SSIs. How- define the choice of antibiotic to be recommended, its ever, only one institution defined their site as having a dose, or frequency of administration. Those subjects are high incidence of MRSA (more than 2.5 new cases of MISCELLANEOUS the basis for this report. MRSA infection or colonization per 100 admissions) and that may limit the degree to which these findings can be generalized to current practice in which MRSA is II. Choice of Primary Prophylactic Antibiotic much more prevalent. Notwithstanding this caveat, it Cephalosporin or Glycopeptide appeared that prophylaxis with glycopeptides such as vancomycin was less effective in preventing infection by CLASS I RECOMMENDATION. A ␤-lactam antibiotic is indicated methicillin-sensitive organisms, while such prophylaxis as a single antibiotic of choice for standard cardiac was more effective in preventing infection by methicillin- surgical prophylaxis in populations that do not have a resistant organisms high incidence of methicillin-resistant Staphylococcus aureus (MRSA [Level of Evidence A; see Appendix]). Distinguishing Between Cephalosporins There are numerous publications concerned with the CLASS IIA RECOMMENDATION. Based on availability and cost, optimal prophylactic antibiotic recommended for cardiac it is reasonable to use cefazolin (a first-generation agent) surgery, but many of these protocols are comparing not as the cephalosporin for standard cardiac surgical pro- only two or more antibiotic regimens but also two differ- phylaxis in view of the fact that most randomized trials ent dosing programs, for example, single dose versus could not discriminate between cephalosporins (Level of multidose, which was addressed in the previous Guide- Evidence B). line. This second published Guideline will address addi- The next issue to be addressed concerns the choice of a ␤-lactam, remembering that there are first- through *For the full text of the STS Guideline on Antibiotic Prophylaxis in fourth-generation agents presently available, which have Cardiac Surgery, as well as other titles in the STS Practice Guideline differing half-lives, pharmacodynamics, and pharmaco- S e r i e s , v i s i t at the official STS website kinetics. It can be stated as fact that the later generation cephalosporins have better gram-negative and less Address correspondence to Dr Engelman, Baystate Medical Center, gram-positive coverage. In that our predominant organ- Division of Cardiac Surgery, 759 Chestnut St, Springfield, MA 01199; e-mail: firstname.lastname@example.org. ism for cardiac surgical infections is a Staphylococcus sp, 2007 by The Society of Thoracic Surgeons Ann Thorac Surg 2007;83:1569 –76 • 0003-4975/07/$32.00 Published by Elsevier Inc doi:10.1016/j.athoracsur.2006.09.046 WORKFORCE REPORT ENGELMAN ET AL Ann Thorac Surg ANTIBIOTIC PROPHYLAXIS IN CARDIAC SURGERY 2007;83:1569 –76 the earlier generation cephalosporins are likely to be 65% It has been estimated that colonization with preferred for prophylaxis. In fact, published data would methicillin-resistant organisms, often asymptomatic, oc- support that conclusion curs in 4% to 8% of ICU patients, 0.18% to 7.2% of In 1987, a randomized trial of more than 1,000 cardiac inpatients, and 1.3% to 2% of persons in the community surgical patients was reported comparing multidose ce- In one urban hospital, the incidence of MRSA fazolin, a first-generation cephalosporin, with multidose among newly admitted patients was 7.3%, which is cefamandole, a second-generation cephalosporin, and higher than the 1.3% to 5.3% prevalence in previous found cefamandole to have a lower sternal infection rate reports This alarming incidence of colonization has This study, however, introduced a second agent, led to a strong recommendation for active surveillance at gentamicin, as an additional single-dose prophylactic the time of hospital admission At least one third drug, in half the patients in each cephalosporin group. of MRSA-colonized patients will have a healthcare- That led to the comparative analysis being less than clear related MRSA infection, which is nearly 10 times the risk cut in defining an optimal cephalosporin. A more defin- of noncolonized patients In a study by Lin and itive randomized double-blind study comparing individ- associates at a hospital with a high incidence of ual cephalosporins in 1,641 patients from Johns Hopkins MRSA, 65% of post-sternotomy staphylococcal infections Hospital between 1987 and 1990 was reported in 1993 were due to methicillin-resistant organisms The incidence of all surgical site infections was 8.4% Some studies suggest that patients with post- with cefamandole prophylaxis, 8.4% cefazolin, and 9.0% sternotomy MRSA/MRCNS infections have a less favor- with cefuroxime (clearly not significant). The relative able prognosis compared with those having methicillin- incidence comparing cephalosporins and differentiating sensitive (MSSA) organisms. For example, in the study of between deep and superficial infection was also not Mekontso-Dessap and colleagues overall mortality significantly different between the groups (specifically, was 53.3% for MRSA post-sternotomy infections versus deep sternal infection ϭ 0.6% cefamandole, 1% cefazolin, 19.2% for MSSA infections, with corresponding 3-year and 1.5% cefuroxime). A 1992 meta-analysis cited in actuarial survival rates of 26% versus 79%. Methicillin- the Hopkins report includes some with inherent flaws resistant S aureus was the only independent predictor of but still supports the conclusion that there is no cepha- overall mortality, and MRSA infections had a higher losporin regimen that is clearly superior in affecting a incidence of mediastinitis-related death and treatment lower infection rate. failure compared with MSSA. In a study of SSIs composed MISCELLANEOUS of largely cardiac and orthopedic procedures, Engemann and associates found a mortality rate of 20.7% for MRSA III. Issues Surrounding Staphylococcal Infection versus 6.7% for MSSA, and most deaths in the cardiac Reasons for Concern in Cardiac Surgical Patients group were due to post-sternotomy mediastinitis. The costs directly attributable to methicillin resistance were $13,901 Surgical site infections of the sternal wound and under- per case of staphylococcal infection. lying mediastinum occur in 0.4% to 4% of cardiac surgical procedures, with more than 50% due to S aureus or Potential (Nonallergic) Indications for Primary or coagulase-negative S epidermidis These infections Adjuvant Glycopeptide (Vancomycin) Prophylaxis have profound short- and long-term implications. In- CLASS IIB RECOMMENDATION. In the setting of either a pre- hospital mortality rates of 10% to more than 20% have sumed or known staphylococcal colonization, the institu- commonly been reported, and a 10-year follow-up study tional presence of a “high incidence” of MRSA, patients of such patients by the Northern New England Cardio- susceptible to colonization (hospitalized longer than 3 vascular Disease Study Group demonstrated a marked days, transfer from other inpatient facility, already re- negative impact not only on acute but also on long-term ceiving antibiotics), or an operation for a patient having survival Hollenbeak and colleagues found a prosthetic valve or vascular graft insertion, it would be 1-year mortality rate of 22% for coronary artery bypass reasonable to combine the ␤-lactam (cefazolin) with a graft surgery (CABG) patients with deep chest surgical glycopeptide (vancomycin) for prophylaxis, with the re- site infections versus 0.6% for uninfected patients (p ϭ striction to limit vancomycin to only one or two doses 0.0001). Deep chest infection resulted in 20 additional (Level of Evidence C). hospital days per patient (p ϭ 0.0001) and added an The progressive emergence of methicillin-resistant average of $18,938 in hospital costs. Patients who died as staphylococcal organisms within hospitals and the com- a result of their infection incurred average costs that were munity, as well as the possibly more serious course of $60,547 more than infected patients who lived. such infections in the cardiac surgery patient, has led The choice of a prophylactic antibiotic has become some to recommend more aggressive use of prophylactic increasingly controversial with the emergence of MRSA vancomycin, even for patients with no history of penicil- and methicillin-resistant coagulase-negative Staphylococcus lin or cephalosporin allergy For example, it is argued (MRCNS). According to the National Nosocomial Infec- that patients having surgery in institutions with a high tion Surveillance System Report, the median percentage incidence of methicillin resistance would be better of MRSA isolates from intensive care unit (ICU) and served by receiving vancomycin, although it is unclear as non-ICU patients in hospitals surveyed exceeded 40%, to what constitutes a high incidence Other poten- and the median percentage of MRCNS isolates exceeded tial candidates for vancomycin prophylaxis might include Ann Thorac Surg WORKFORCE REPORT ENGELMAN ET AL 2007;83:1569 –76 ANTIBIOTIC PROPHYLAXIS IN CARDIAC SURGERY patients who are at higher risk for preoperative MRSA appear most reasonable to employ a cephalosporin as the colonization, patients at higher risk for post-sternotomy primary prophylactic agent for the usual 24 to 48 hours, infection in general, and patients with specific risk factors and only to use vancomycin selectively as an adjuvant for MRSA post-sternotomy infection Active surveil- agent, typically a single dose preoperatively (together lance of admitted patients for staphylococcal colonization with the first dose of cephalosporin) with at most one is desirable but results for cardiac surgery additional dose in valve or vascular implant patients or in patients would generally not be available at the time of all patients in highly selected environments (eg, where surgery except in those institutions where rapid polymer- MRSA colonization is likely or documented or where ase chain reaction (PCR) testing is available. Finally, it there is a high prevalence of MRSA isolates from infec- has been suggested, but not generally accepted, that tions). This should provide a reasonable compromise because of the devastating consequences of prosthetic between the goal of providing the broadest spectrum valve or vascular graft infection with methicillin-resistant prophylaxis at the time when it is likely to be most organisms, these patients should also routinely receive effective, and the competing desire to restrict usage of vancomycin vancomycin in order to minimize the emergence of There are observational and randomized trial data resistant organisms. supporting the use of vancomycin prophylaxis for Vancomycin as the Sole Prophylactic Antibiotic cardiac surgery, as well as the results of a sophisticated decision analytic model Using the best available CLASS IIB RECOMMENDATION. Because vancomycin is an clinical and microbiological data from the literature, agent that has no effect on gram-negative flora, its use- Zanetti and colleagues estimated that routine fulness as an exclusive agent in cardiac surgical prophy- vancomycin use in a cohort of 10,000 CABG patients laxis is not recommended (Level of Evidence C). would result in 29 fewer deep chest infections, 58 fewer DISCUSSION. For situations in which vancomycin is be- superficial infections, 3 fewer deaths, lower direct medi- lieved to be indicated as prophylaxis for cardiac surgery, cal costs over 3 months, and a net $1,170,000 cost saving for example, ␤-lactam allergy, should it be used as a compared with routine cefazolin. Sensitivity analysis single agent or combined with another antimicrobial? indicated that cephazolin was more effective or less costly Overall, vancomycin has a narrower antimicrobial spec- only when MRSA represented fewer than 3% of all trum, inferior tissue and bone penetration, less desirable staphylococcal isolates in a hospital, which would be pharmacokinetics, and slower bactericidal killing com- unusual in contemporary practice. Based on 366,000 pared with cephalosporins and the CABG procedures annually in the United States, this incidence of SSI due to methicillin-sensitive organisms model predicts that vancomycin use would result in 110 has been higher when only vancomycin has been em- fewer deaths, prevent 3,184 SSIs, and potentially save $43 ployed for prophylaxis Additionally, since some million. hospitals report both deep surgical site infections and One of the most serious objections to increased use of blood stream infections after cardiac surgery from gram- vancomycin prophylaxis is concern about the emergence negative organisms it is recommended that an MISCELLANEOUS of resistant strains of Staphylococcus and Enterococcus aminoglycoside be added for one preoperative and at organisms This consideration has prompted the most one additional postoperative dose to act as a spe- publication of restrictive guidelines for the use of vanco- cific gram-negative agent when vancomycin is indicated mycin or teicoplanin (both glycopeptides), which include to be the primary prophylactic agent. a specific recommendation by the CDC against the rou- Mupirocin for Preoperative Therapy to Eliminate tine use of vancomycin for prophylaxis However, it Staphylococcal Nasal Colonization should be noted that antibiotic resistance may also de- velop with ␤-lactam antimicrobials. Furthermore, the CLASS I RECOMMENDATION. Routine mupirocin administra- duration of vancomycin administration as a primary or tion is recommended for all patients undergoing cardiac adjuvant prophylactic agent, as opposed to its use for surgical procedures in the absence of a documented established post-sternotomy infections, must also be con- negative testing for staphylococcal colonization (Level of sidered. In terms of the emergence of drug-resistant Evidence A). organisms, which is worse— using short-duration pro- DISCUSSION. Mupirocin is a patient self-administered top- phylactic vancomycin in a larger number of patients, ical antibiotic that is highly effective in eradicating nasal possibly preventing some clinical infections due to me- S aureus, including methicillin-resistant strains of Staphy- thicillin-resistant organisms; or using a cephalosporin loccocus. It is a naturally occurring antibiotic produced by after which a serious SSI is more likely to involve MRSA a fermentation of Pseudomonas bacteria mixed in a non- or MRCNS, thus committing such patients to weeks or irritating paraffin composition. Its specific mechanism of months of continuous vancomycin therapy action is to bind to isoleucyl-transfer RNA synthetase This is a central question that as yet has not been and disrupt cell function It is reportedly more than resolved and would require research not likely to be 90% effective in eradicating nasal colonization of Staphy- performed. Thus, this particular question cannot be ad- lococcus for as long as 1 year Short-term therapy (a dressed by randomized trials. 5-day course) has been shown to be highly effective Unless there is demonstrated penicillin or ␤-lactam Correlation of nasal or hand colonization and infection in allergy (see Section V, “Allergy to Penicillin”), it would the same patient by the same phage type of Staphyloccocus WORKFORCE REPORT ENGELMAN ET AL Ann Thorac Surg ANTIBIOTIC PROPHYLAXIS IN CARDIAC SURGERY 2007;83:1569 –76 has been shown to be near 90% Recent reports of 2. When the surgical incision remains open in the both randomized and nonrandomized trials in cardiac operating room, to patients with normal renal func- surgical patients, one a meta-analysis, supports its rou- tion, a second dose of 1 g should be administered tine use in prophylaxis every 3 to 4 hours. If it is apparent that cardiopul- Resistance to mupirocin ointment has become a con- monary bypass will be discontinued within 4 hours, cern for infectious disease specialists, but such resistance it is appropriate to delay until perfusion is complete is largely found after prolonged treatment periods when to maximize effective blood levels (Class I, Level of used to treat either large open wounds or dermatitis. Evidence B). There have been no reports of high-level drug resistant 3. In patients for whom vancomycin is an appropriate strains developing after a short course of treatment such prophylactic antibiotic for cardiac surgery, a dose of as proposed for preoperative prophylaxis despite 4 years 1 to 1.5 g or a weight-adjusted dose of 15 mg/kg of surveillance in one hospital using this approach rou- administered intravenously slowly over 1 hour, tinely in both orthopedic and vascular surgery In with completion within 1 hour of the skin incision, fact, many, if not most, cardiac surgical programs have is recommended (Class I, Level of Evidence A). A instituted a routine protocol for intranasal mupirocin second dose of vancomycin of 7.5 mg/kg may be beginning at least the day before operation (sooner, if considered during cardiopulmonary bypass, al- elective operation) and continuing for 2 to 5 days after though its usefulness is not well established (Class surgery. Recently, a PCR rapid analysis for Staphyloccocus IIb, Level of Evidence C). sp has become available in some hospitals, with addi- 4. For patients who receive an aminoglycoside (usu- tional institutions gaining access to the technology on a ally gentamicin, 4 mg/kg) in addition to vancomy- regular basis. A report has just been published for a cin before cardiac surgery, the initial dose should PCR-based mupirocin study performed at the Cleveland be administered within 1 hour of the skin incision Clinic. In this study, screening for nasal carriage of S (Class I, Level of Evidence C). Redosing an amino- aureus (both MRSA and MSSA) was routinely performed glycoside during cardiopulmonary bypass is not before cardiac surgery. There were 6,334 patients indicated and may be harmful (Class III, Level of screened over 21 months, and 1,342 were found to have Evidence C). colonization (21%), which is the identical incidence re- There is a considerable body of evidence supporting ported in a second study as well The administration MISCELLANEOUS the need for the timely administration of preoperative of mupirocin was reserved for these colonized patients, antibiotics, which means administration within 1 hour of and while the mupirocin use in the cardiac surgical the skin incision These data accrue from numer- population declined significantly (by nearly 80%), there ous animal and clinical studies and are broadly applica- was no demonstrable difference between carriers and ble to all procedures for which prophylactic antibiotics noncarriers in the overall incidence of infection or in the are administered In spite of the relative paucity incidence of infection caused by S aureus. It was con- of controlled randomized or large-scale retrospective cluded that the effect of mupirocin on colonized patients resulted in appropriately reducing the Staphyloccal in- studies to address this issue specifically in cardiac sur- fection incidence to nullify the influence of colonization. gery, the timing of the administration of the prophylactic Because, inherently, one would not recommend use of antibiotic is quite important to the cardiac surgical com- any agent that is not useful for treatment, limiting mupi- munity. Cardiopulmonary bypass (CPB) is a technique rocin prophylaxis to colonized patients would appear to that is nearly exclusively used by cardiac surgeons, and it be a sensible approach. However, access to the PCR test has profound effects on the volume of distribution, and is required. Because mupirocin is self-administered, the elimination kinetics of a variety of drugs including the patient must be informed about the need for the treat- commonly used prophylactic antibiotics such as cepha- ment and the technique of insertion. In the absence of losporins, vancomycin, and aminoglycosides access to PCR testing, routine prophylaxis with mupiro- Certain drugs, including opiates, nitrates and vancomy- cin is recommended. cin also have been shown to be sequestered in the components of the heart lung machine, decreasing bio- logical availability both during and after the completion IV. Guidelines for Appropriate Dosing of of CPB Therefore, appropriate perioperative Prophylactic Antibiotics dosing of antibiotics during cardiac surgery presents RECOMMENDATIONS unique challenges, particularly since tissue levels, specif- ically in bone and sternal fat, are likely more relevant 1. In patients for whom cefazolin is the appropriate than the more commonly measured serum concentra- prophylactic antibiotic for cardiac surgery, admin- tions. In fact, cefazolin tissue concentrations during sur- istration within 60 minutes of the skin incision is gery are clearly correlated with body weight (increased indicated (Class I, Level of Evidence A). The pre- body mass index correlates with decreased tissue levels) operative prophylactic dose of cefazolin for a pa- such that therapeutic tissue levels may not be achieved in tient of greater than 60 kg body weight is recom- the morbidly obese patient even with 2 g administered mended to be 2 g (Class I, Level of Evidence B). for prophylaxis Ann Thorac Surg WORKFORCE REPORT ENGELMAN ET AL 2007;83:1569 –76 ANTIBIOTIC PROPHYLAXIS IN CARDIAC SURGERY Several studies have investigated intraoperative van- V. Guidelines for Prophylactic Antibiotics in comycin cephalosporin and aminoglyco- Special Circumstances side pharmacokinetics. After a single preopera- Allergy to Penicillin tive dose of vancomycin, typically administered over 1 RECOMMENDATIONS hour, immediately before the skin incision serum con- centrations averaged 18 to 66 mg/L after a dose of either 1. In patients with a history of an immunoglobulin-E 1 g or a weight-adjusted dose of 15 mg/kg All of (IgE)–mediated reaction to penicillin or cephalo- these studies also documented an 11% to 41% abrupt sporin (anaphylaxis, hives, or angioedema), vanco- decrease in serum vancomycin concentration after the mycin should be given preoperatively and for no initiation of cardiopulmonary bypass due primarily to more than 48 hours. Alternatively, skin testing may dilution in direct proportion to the pump prime volume. be performed in these patients and, if negative, a During cardiopulmonary bypass, there is a progressive cephalosporin regimen administered (Class I, Level decline in serum concentrations due to a combination of of Evidence A). renal clearance and sequestration in the heart lung 2. For patients with a history of a non-IgE mediated machine After a single preoperative dose, the reaction to penicillin (such as a simple rash) or an serum level in each of the reported studies remains unclear history either vancomycin or a cephalosporin above the minimal inhibitory concentration (MIC) for is recommended for prophylaxis with the under- 90% of both methicillin-sensitive and methicillin- standing that these patients have a low incidence of resistant S aureus (1 mg/L) and coagulase-negative Staph- significant allergic reactions to cephalosporins (Class ylococcus (2 mg/L) throughout the procedure with an I, Level of Evidence B). average bypass time of approximately 1 to 2 hours 3. The addition of an aminoglycoside or other gram- There is incomplete recovery of serum levels negative bacterial coverage to a vancomycin antibi- after bypass, however, owing to vancomycin sequestra- otic regimen may be reasonable, but its efficacy is not tion in the heart-lung machine, alterations in protein well established (Class IIb, Level of Evidence C). binding, and persistent changes in the volume of distri- In patients with a history suggestive of an IgE- bution after bypass. Similarly, studies have shown that mediated reaction to penicillin (anaphylaxis, hives, or aminoglycosides first- and second-generation ceph- angioedema), indiscriminate use of a cephalosporin for alosporins have a similar (as much as 50%) surgical prophylaxis in cardiovascular surgery is not reduction in serum concentration after the initiation of advised Early studies established a cross-reactivity rate between penicillin and cephalosporins at approxi- As a result of the reduction in the levels of cefazolin mately 20% More recent data including those ceph- and vancomycin immediately after and during CPB, two alosporins in current clinical use suggests a cross- studies evaluated the efficacy of administering a second reactivity rate of less than 2% dose of cefazolin or a second dose of vancomycin after As many as 20% of the general population are labeled MISCELLANEOUS the initiation of cardiopulmonary bypass Both penicillin-allergic. Fewer than half of these will have a studies found that with the second dosing regimen, the history suggesting an IgE-mediated reaction to penicillin. serum levels were above the MIC for both S aureus and Of these, fewer than 20% will have a positive penicillin coagulase-negative Staphylococci throughout the proce- skin-test Those patients with nonsuggestive or un- dure. The two-dose regimen of vancomycin resulted in known histories have a penicillin skin-test positivity rate higher serum levels but no significant difference in ster- of less than 2% Among all patients labeled penicil- nal bone, fat, myocardial, or pericardial tissue levels lin-allergic, the frequency of serious reactions to cepha- losporin administration is less than 1% It is now firmly established with good documentation With regard to choice of alternative prophylaxis in the from both clinical and experimental studies that read- presence of allergy, vancomycin appears to be best owing to ministration of a prophylactic antibiotic during surgery its gram-positive coverage and, particularly, coverage of should be within two half-lives of the antibiotic, exclusive methicillin-resistant S aureus. There are concerns over lack of any influence of the effects of cardiopulmonary bypass of gram-negative coverage with vancomycin relative to Cefazolin has a half-life of approximately 1.8 cephalosporins. For this reason, an aminoglycoside, usually hours, and therefore it is recommended that there should gentamicin, should be added. It must be recognized, how- be additional dosing during surgery every 3 to 4 hours ever, that gentamicin is associated with nephrotoxicity and when an operation is proceeding with an open wound ototoxicity, and excretion is delayed after cardiopulmonary beyond that period. The major consideration for defining bypass Therefore, a single dose, or at most two doses, the appropriate pharmacodynamics of antimicrobials is of no more than 4 mg/kg is recommended There is no to maintain the serum level of any antibiotic used above study directly comparing vancomycin and vancomycin plus the MIC for the infecting pathogens, presumed in cardiac an aminoglycoside. A single study from 1987 compared surgery to be Staphylococcus sp, while the operative gentamicin plus a ␤-lactam with the latter alone and found wound remains open. This typically dictates readminis- no benefit to the combination therapy, compounded by the tration approximately every two serum half-lives of each appearance of resistant gram-negative organisms only in antibiotic considered appropriate patients receiving gentamicin WORKFORCE REPORT ENGELMAN ET AL Ann Thorac Surg ANTIBIOTIC PROPHYLAXIS IN CARDIAC SURGERY 2007;83:1569 –76 The use of vancomycin as an alternative to cephalo- concerns over antibiotic penetration into this area and sporins is not entirely benign. Vancomycin commonly resultant infection with S aureus. As in the case of causes histamine release and cutaneous reactions when intravenous vancomycin, there is concern over the pro- administered too rapidly. It is also associated with nephro- motion of resistant organisms. toxicity when used in combination with other nephrotoxins A review of the literature on the use of topical vanco- and can rarely case anaphylaxis In one study mycin revealed a single randomized controlled trial from 116 patients (106 adults and 10 children) undergoing cardiac 1989 comparing patients treated with either vancomycin- surgery procedures were given vancomycin. Thirty-one thrombin–powdered gelatin paste (223 patients) versus patients (27%) had an adverse reaction including hypoten- treatment with thrombin-powdered gelatin paste alone sion (25%). Maculopapular edema was seen in 6% and was (193 patients) This group from the University of associated with hypotension (Red Man’s syndrome) in 5 Massachusetts reported a sternal infection rate of 0.45% patients and bronchospasm in 1 patient. (1 patient) in the treatment group and 3.5% (7 patients) in One group used mathematical modeling to predict the the control group (p ϭ 0.02). Multivariate testing was most cost-effective strategy for antimicrobial prophylaxis performed. The use of topical vancomycin and shorter of cardiovascular surgery patients labeled penicillin- operative times predicted reduced infection rates. An- allergic The strategy of giving vancomycin to all other reported study of 4 patients in whom serum levels patients labeled with a penicillin allergy was found to be were measured after topical application without systemic the most expensive but was associated with the lowest administration found levels of vancomycin in 1 patient as rate of serious allergic reaction. Giving cefazolin to all high as 4.4 mg/L 3 to 4 hours after topical application of such patients was the cheapest, but it was associated with 1 g vancomycin powder to the sternum, which is signif- the highest rate of allergic reaction. While giving vanco- icantly lower than would be seen with systemic admin- mycin to patients with positive skin tests improved cost istration (18 to 66 mg/L) effectiveness, it was thought to be impractical on a The topical application of gentamicin has also been routine preoperative basis. Therefore, this group adopted studied. In a randomized trial of 2,000 cardiac surgery a policy of using vancomycin in place of cephalosporins patients, Friberg and coworkers compared prophy- in patients with a history suggesting a previous IgE- laxis with intravenous isoxazolyl-penicillin alone versus mediated reaction to penicillin. this drug plus topical application of collagen-gentamicin An aminoglycoside is often added to vancomycin for sponges at sternotomy closure. The topical antibiotic MISCELLANEOUS cardiac surgery in penicillin-allergic patients owing to its group had an incidence of wound infection at 4.3% and enhanced gram-negative coverage as well as its coverage the control group, at 9% (p Ͻ 0.001). The same author of methacillin-sensitive S aureus. However, in a 1987 examined serum versus local wound fluid concentrations study from St. Thomas Hospital in Nashville, the only of gentamicin in 101 patients receiving topical gentamicin patients with resistant gram-negative sternal infections during cardiac surgery and found extremely high concen- were those who received gentamicin along with either trations (median 304 mg/L) in local wound fluid but very cefazolin or cefamandole low serum concentrations (peak median 2.05 mg/L) Eklund and associates recently reported a random- Specific Issues Regarding Gram-Negative Infections ized controlled trial comparing topical gentamicin-collagen RECOMMENDATIONS implants (n ϭ 272) and no topical antibiotics (n ϭ 270) during coronary artery bypass graft surgery. Both study 1. For institutions with an outbreak of gram-negative groups received standard intravenous prophylaxis consist- deep wound infections due to a specific pathogen, it ing of cefuroxime (85%) or cefuroxime and vancomycin is reasonable to employ a first-generation cephalo- (14%). The sternal wound infection rate was 4.0% in the sporin for routine prophylaxis (Յ48 hours) supple- topical gentamicin group and 5.9% in the control group. mented with an appropriate antibiotic to which the Deep mediastinal infections were seen in 1.1% of the topical offending organisms are sensitive (Class IIa, Level antibiotic group and 1.9% in the control group. The authors of Evidence C). concluded that a slight reduction in infection was seen but 2. In patients with renal dysfunction requiring gram- that the population was too small to draw a definitive negative prophylaxis to supplement a cephalosporin conclusion. While the use of topical antibiotics is controver- or vancomycin as the primary antibiotic, it is reason- sial and they are not used by most cardiac surgeons, the able to use either one dose of an aminoglycoside or an existing studies demonstrate a reduction in the wound antibiotic such as levofloxacin with a low incidence of infection rate. More study is warranted before topical anti- renal toxicity (Class IIa, Level of Evidence C). biotics can be recommended as standard prophylaxis. Topical Application of Antibiotics Summary Conclusions CLASS IIB RECOMMENDATION. Topical antibiotics may be con- sidered for antibiotic prophylaxis in cardiac surgery The primary prophylactic antibiotic for adult cardiac (Level of Evidence B). surgery is recommended to be a first-generation cepha- Some cardiac surgeons have used topical antibiotics, losporin, which is usually cefazolin. The most frequent usually vancomycin or gentamicin, applied to the cut organism cultured in cardiac SSI is Staphylococcus, and sternal edges. There is some appeal to this concept given colonization is considered the major factor in wound Ann Thorac Surg WORKFORCE REPORT ENGELMAN ET AL 2007;83:1569 –76 ANTIBIOTIC PROPHYLAXIS IN CARDIAC SURGERY contamination. For this reason, until rapid screening tests prophylaxis in cardiac operations. J Thorac Cardiovasc Surg for S aureus colonization are widely available, mupirocin 1993;106:664 –70. is recommended as a routine prophylactic measure. In 15. Kreter B, Woods M. Antibiotic prophylaxis for cardiothoracic operations. J Thorac Cardiovasc Surg 1992;104:590 –9. patients considered at high risk for a staphylococcal 16. Massias L, Dubois C, DeLentdecker P, Brodaty O, Fischler infection, vancomycin (one preoperative with or without M. 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Excellence in Prevention – descriptions of the prevention programs and strategies with the greatest evidence of success Name of Program/Strategy: Peacemakers Report Contents Implementation considerations (if available) Cost effectiveness report (Washington State Institute of Public Policy – if available) Washington State results (from Performance Based Prevention System (P
nausea and vomitingRudolph M. Navari, MD, PhDIndiana University School of Medicine–South Bend, South Bend, INNausea and vomiting associated with cancer chemotherapy are experienced by 70%–80% of patients receiving chemotherapy and can result in signiﬁcant morbidity. Chemotherapy-induced nausea and vomiting (CINV) adversely affects patient quality of life, often leading to poor compliance