- Email: [email protected]
Perioperative Antibiotics: When, Why?
Thorac Surg Clin 15 (2005) 229 – 235
Perioperative Antibiotics: When, Why? Mark S. Allen, MDa,b,* a
Division of General Thoracic Surgery, Mayo Clinic, 200 First Street, SW Rochester, MN 55905, USA b Department of Surgery, Mayo Medical School, Rochester, MN 55905, USA
Before Joseph Lister’s principle of antisepsis, surgery commonly led to postoperative fevers, commonly known as ‘‘irrative fever,’’ followed by infection, drainage, ‘‘laudable pus,’’ sepsis, and death. Since the introduction of antisepsis, surgery has progressed to an endeavor that prolongs and improves life. About 27 million operations are performed each year in the United States. Surgical site infections (SSI) are the third most common nosocomial infection [1]. About two thirds of SSI develop in the surgical incision. In 1980, Cruse and Foord [2] estimated that SSI increased hospital stay by 10 days and increased costs by $2000, and a 1992 analysis revealed each SSI increased costs more than $3000 and hospital stay by 7.3 days [3]. Prevention of life-threatening and costly SSI is important. A variety of techniques should be considered to decrease SSI, including recommendations for preoperative, intraoperative, and postoperative practices that may reduce the risk of an infection. Careful surgical technique with avoidance of unnecessary tissue destruction is probably the most important factor in decreasing the incidence of postoperative infections. The use of perioperative antibiotics should be seen as an adjunct to meticulous technique and proper procedures. Perioperative antibiotics are thought to decrease wound infections and may decrease other SSI in general thoracic surgery, such as empyema and postoperative pneumonias.
* Division of General Thoracic Surgery, Mayo Clinic, 200 First Street, SW Rochester, MN 55905. E-mail address: [email protected]
The use of prophylactic antibiotics in general thoracic surgery is well established. This article explains the rationale for modern-day surgical wound infection prophylaxis, the why and the when. Various arguments about the use of antibiotics to prevent empyema and pneumonia after a thoracic operation also are presented. The evidence supporting the use of antibiotic prophylaxis for general thoracic surgical procedures is overwhelming; however, despite numerous well-done randomized trials, controversy still exists as to when to stop the antibiotics, which agent to use, and whether or not the use of antibiotics decreases wound infections only or wound infections and deeper infections, such as pneumonia or empyema (Table 1). Prophylactic antibiotics were proposed by Eriksen et al [4,5] in 1954, before any randomized study had proven their efficacy. Kvale et al [6] reported the first randomized study to examine the question in 1977. At that time, there was disagreement between surgeons, who believed perioperative antibiotics decreased infectious complications, and internists, who believed perioperative antibiotics did not decrease infectious complications but increased resistant organisms. The study by Kvale et al [6] was the first randomized study on perioperative antibiotics for lung surgery since the introduction of perioperative antibiotics. At Kvale’s institution, the infection rate was 25% for all thoracic surgery procedures, which the authors found unacceptable. They conducted a randomized, prospective, doubleblind study from March 1974 to December 1975. They gave cefazolin (Kefzol), 500 mg intramuscularly on call and every 6 hours postoperatively until orally tolerated, then cephalexin (Keflex), 500 mg
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Table 1 Randomized studies concerning prophylactic antibiotics Wound infection
Pneumonia
Empyema
77
Significant reduction
Significant reduction
Significant reduction
57
NSD
NSD
NSD
Cephalothin vs placebo
171
NSD
NSD
NSD
Cephalothin vs placebo
211
Significant reduction
NSD
NSD
Penicillin G vs placebo
101
Significant reduction
NSD
NSD
Doxycycline vs cefuroxime Cefazolin vs placebo
120
NSD
NSD
NSD
127
Significant reduction
NSD
Significant reduction
Cefazolin 1 vs 6 doses
199
NSD
NSD
NSD
Penicillin G vs Cefuroxime
94
NSD
NSD
NSD
Ampicillin/sulbactam 1 vs 3 doses
60
NSD
NSD
NSD
Cefuroxime vs placebo
200
NSD
NSD
NSD
Cefuroxime vs placebo
203
NSD
Significant reduction
Ampicillin/sulbactam vs cefazolin Cefuroxime vs cefepime
120
Not stated
102
NSD
Chest x-ray more often normal Significant reduction NSD
Primary author
Year
Type of trial
Agent(s) used
Kvale [6]
1977
Cefazolin vs placebo
Truesdale [7]
1979
Cefazolin vs placebo
Cameron [8]
1981
Ilves [9]
1981
FrimodtMoller [10]
1982
Tarkka [13]
1987
Aznar [14]
1991
Olak [11]
1991
Krasnik [15]
1991
Wertzel [12]
1992
Frey [16]
1993
Bernard [17]
1994
Boldt [18]
1999
Turna [19]
2003
Prospective, randomized, double-blind Prospective, randomized, double-blind Prospective, randomized Prospective, randomized, double-blind Prospective, randomized, double-blind Prospective, randomized Prospective, randomized, double-blind Prospective, randomized, double-blind Prospective, randomized, double-blind Prospective, randomized, double-blind Prospective, randomized Prospective, randomized, double-blind Prospective, randomized Prospective, randomized, double-blind
No. patients
Not stated NSD
Abbreviation: NSD, no significant difference.
orally every 6 hours for a total of 5 days, or placebo. The vials were identical, so neither the staff nor the patient knew who received antibiotics versus placebo. Patients with prior chest infections, patients with known allergies, patients who had received antibiotics within 1 week of surgery, and patients who had refused informed consent were not eligible. Specific protocols for postoperative management and definitions of wound infection, pneumonia, and empyema were established prospectively. The investigators randomized 77 patients undergoing pulmo-
nary surgery. Of the control group, 17 of 34 (50%) developed ‘‘infection,’’ although 50% of these received no further treatment. Only 8 of 43 (19%) of the treated group developed infection (P = .005). Kvale et al [6] concluded that ‘‘the routine use of perioperative antibiotics is indicated to prevent postoperative infections in pulmonary resection.’’ The results of the Kvale trial were challenged by a subsequent randomized, prospective, double-blind trial by Truesdale et al [7] in 1979. This group randomized 57 patients undergoing pulmonary resec-
perioperative antibiotics
tion. They used cefazolin, 1 g intramuscularly on admittance to the operating room, followed by cephalothin (Keflin), 2 g intravenously every 6 hours for 48 hours, starting immediately after surgery, versus placebo. The vials of antibiotic and placebo were identical so that patients and physicians did not know which patients were receiving antibiotics and which were receiving placebo. In this study, 5 of 29 (17.2%) placebo patients and 5 of 28 (17.8%) treated patients developed a postoperative infection (P = not significant). Complications of prophylaxis occurred in 17.2% (31 of 57) of placebo patients and 64.4% of treated patients and included hypersensitivity reactions in 2, drug fever in 9, phlebitis in 14, and increased blood urea nitrogen and liver function tests in 8. Truesdale et al [7] concluded that prophylactic antibiotics for pulmonary resection did not outweigh the benefits and should not be employed. This view was supported further by a larger randomized trial by Cameron et al [8] from Johns Hopkins Medical Center. They randomized 171 patients undergoing pulmonary resection to cephalothin, 2 g intravenously the evening before surgery, at 6:00 a.m. the morning of surgery, during the operation, and 6 hours after surgery, or placebo (no antibiotics). The hospital stay was 15.5 days for the antibiotic group and 15.7 days for the placebo group. There was no difference in the number of postoperative fevers. The number of ‘‘septic complications’’ in the antibiotic group was 22 versus 26 in the nonantibiotic group. Even when infections were broken down into pneumonia, empyema, and wound infection, there were no differences. The authors did not give the actual numbers of wound infections, so it is unknown if a trend was evident. They did find that when postoperative infections occurred in the antibiotic group, they were often from gram-negative organisms that were resistant to cephalothin. They recommended that patients not receive prophylactic antibiotics before pulmonary surgery. Several months after Cameron’s study, the results from an even larger study from the Toronto general thoracic surgical group was published [9]. Ilves et al [9] randomized 211 patients undergoing a pulmonary or esophageal operation to receive either placebo or cephalothin, 2 g intravenously at the induction of anesthesia and 2 g intravenously 4 hours later. During the study, neither the patients nor the staff knew which group the patients were in. The surgical preparation, procedure, and postoperative care were standardized. The investigators found that 7 patients of 118 (5.9%) in the treatment group developed a wound infection versus 22 of 93 (23.7%) in the placebo group (P < .05). There also was a reduction in the
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incidence of postoperative pulmonary infections and empyemas, but the difference did not reach statistical significance. The investigators were unable to detect a difference in the bacteriology of the infections between the two groups. Ilves et al [9] stated their policy is to ‘‘employ prophylactic perioperative antibiotic coverage in clean-contaminated major thoracic cases.’’ A similar result was reported from Denmark by Frimodt-Moller et al [10] in 1982. They compared penicillin G prophylaxis with placebo in a randomized, double-blind, controlled prospective trial. The investigators used penicillin G at a dose of 5 million IU intravenously immediately before surgery and every 6 hours after surgery for five doses. They randomized 94 patients: 45 in the penicillin G group and 47 in the placebo group. There were nine (19.1%) wound infections in the placebo group versus two (4.4%) in the prophylactic group (P = .03). There was no difference in the number of empyemas or lower respiratory tract infections between the two groups. Frimodt-Moller et al [10] also showed a significant reduction in the length of hospitalization (3 days) with penicillin G prophylaxis, a highly costefficient finding. These two major positive studies seem to contradict the study done by Cameron et al [8]. Perhaps the wound infection rate was already so low at Johns Hopkins that the study was underpowered to show a significant difference. Whatever the reason, most surgeons believed the positive findings of the Ilves and Frimoldt-Moller studies and discounted the negative findings of the Cameron study. Even though most surgeons had been using prophylactic antibiotics for general thoracic surgical operations before the publication of these studies, these findings confirmed what they empirically thought to be fact. The question of whether to give a single dose or prolonged postoperative prophylaxis was examined in a randomized study by Olak et al [11], in which they randomized 208 patients to one dose of cefazolin (1 g intravenously at the induction of anesthesia) or the induction dose of cefazolin plus five doses every 8 hours after surgery. They found no difference in the number of wound infections, pneumonias, or empyemas between the two groups and concluded that there was no benefit to prolonging the antibiotic prophylaxis after the operation concluded. Additional confirmation for use of only a single dose comes from a randomized study done in Germany by Wertzel et al [12]. This group randomized 60 patients undergoing pulmonary resection to receive ampicillin/sulbactam (Unasyn), either 3 g at induction or 3 g at induction and two further doses at
232
8-hour intervals. They found no difference in the incidence of wound infection or any other infections. They did report about a 30% incidence of bronchitis and pneumonia, but stated that, ‘‘whether PX [prophylactic antibiotics] is reducing these complications cannot be answered by our study’’ [12]. With confirmation that prophylactic antibiotics reduce wound infection rates and that a short course is effective, interest was turned to studying ways of decreasing the rate of pneumonia and empyema after general thoracic surgical operations by employing prophylactic antibiotics directed at respiratory flora. In 1987, Tarkka et al [13] published a prospective, randomized trial from Finland to determine if cefuroxime (Zinacef), an agent effective against the common skin flora Staphylococcus aureus and the respiratory pathogen Haemophilus influenzae, would reduce the rates of wound infection and pneumonia and empyema. They randomized 120 patients to receive either their usual prophylactic antibiotic, doximycin, 200 mg orally the day before surgery, 100 mg intravenously during the operation, and 100 mg orally every day for 3 days, or cefuroxime, 1.5 g during anesthesia induction and 0.75 g every 8 hours times three after surgery. The two groups were comparable in all categories. They found a significantly lower rate of minor lower respiratory tract infections in the cefuroxime group, but no difference in the rate of pneumonia or empyema. Tarkka et al [13] hypothesized that the bactericidal effects of cefuroxime may account for the difference. Aznar et al [14] tried to determine if cefazolin alone would decrease the rates of empyema and pneumonia. They randomized 143 patients and, after excluding 16 patients, were left with 127 patients (57 in the placebo group and 70 in the cefazolin group). Cefazolin, 1 g intravenously one half hour before surgery, was used. There was no significant difference in the demographics or operations performed between the two groups. A marked difference in wound infection (14% versus 1.5%) was shown, but no statistically significant benefit for empyema (14% versus 7%) or pneumonia (8.8% versus 4.3%) in the placebo versus cefazolin group. Aznar et al [14] concluded, as others had, that a preoperative dose of prophylactic antibiotics decreased wound infection rates but not the risk of pneumonia or empyema. In the same year as Aznar’s study, 1991, Krasnik et al [15] reported a randomized double-blind study to examine if cefuroxime was better than penicillin G in preventing empyema and pneumonia as the study by Tarkka et al [13] had done. The medications were started just before surgery and repeated every 8 hours after surgery. Krasnik et al [15] analyzed 94 patients
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(48 in the penicillin G group and 46 in the cefuroxime group). They also found no difference in the rate of pneumonia or empyema between the two groups and concluded they still prefer penicillin G for prophylactic antibiotics for pulmonary surgery. A positive finding from the use of cefuroxime was reported in a German trial [16]. Frey et al [16] compared no antibiotics with one dose of cefuroxime, 1.5 g intravenously at the induction of anesthesia. They found fewer wound infections and fewer patients with ‘‘pronounced infiltration’’ on daily chest x-rays in the cefuroxime group. Also, the number of patients requiring additional antibiotics was less in the treated group compared with the placebo group. The use of a control group with no antibiotics makes interpretation of this study difficult. Another positive study using cefuroxime was published in 1994 [17]. Bernard et al [17] randomized 203 patients undergoing a general thoracic surgical procedure. All patients received an induction dose of cefuroxime, 1.5 g intravenously, and a second dose 2 hours later. Patients were then randomized to cefuroxime, 1.5 g intravenously every 6 hours for 48 hours, or placebo. The investigators found a marked reduction in the incidence of empyema: 6% in the treatment group versus 15.6% in the placebo group (P = .03). This finding is undoubtedly related to the fact that seven patients in the placebo group developed bronchial fistulas, whereas only two in the treatment group developed fistulas. The development of fistulas is thought to be unrelated to an infection, but rather related to local factors at the bronchial closure. Postoperative chest x-rays were more often normal in the treatment group, but there was no difference in the number of patients who developed purulent expectorations and atelectasis associated with a temperature greater than 38°C. No information is given about length of stay for these patients. Bernard et al [17] concluded, perhaps mistakenly, that ‘‘48-hour antibiotic prophylaxis regime decreases the rate of deep infectious complications.’’ In another randomized trial that showed effectiveness in reducing pneumonia, Boldt et al [18] compared a single injection of cefazolin, 2 g intravenously, with ampicillin/sulbactam, 1.5 g intravenously. They also studied the microbiologic tracheal aspirates of the two groups and found all the bacteria were susceptible to the prophylaxis in the ampicillin/ sulbactam group, whereas 8 of 25 patients in the cefazolin-only group had resistant organisms. They found fewer bronchopulmonary infections in the ampicillin/sulbactam group. The group given cefazolin stayed in the ICU longer and incurred higher costs than the ampicillin/sulbactam group.
perioperative antibiotics
Box 1. Centers for Disease Control and Prevention recommendations to reduce surgical site infections Preoperative 1. When possible, identify and treat all existing infections 2. Do not remove hair preoperatively at or around the incision, unless it interferes with the operation 3. If hair is removed, remove it immediately before the operation, preferably with electric clippers 4. Control serum blood glucose levels in all diabetic patients 5. Encourage tobacco cessation 6. Do not withhold necessary blood products 7. Require patients to shower or bathe with an antiseptic agent on at least the night before surgery 8. Thoroughly wash and clean at and around the incision site to remove gross contamination before performing antiseptic skin preparation 9. Use an appropriate antiseptic agent for skin preparation 10. Apply preoperative antiseptic skin preparation in concentric circles moving toward the periphery 11. Keep preoperative hospital stay as short as possible 12. No recommendation to wean steroids, enhance nutrition, apply mupirocin to nares, or enhance wound space oxygenation
Intraoperative Surgical team 1. Keep nails short and do not wear artificial nails 2. Perform preoperative surgical scrub for 2 – 5 minutes 3. Obtain appropriate cultures from, and exclude from duty, surgical personnel who have draining skin lesions until infection has been ruled out or personnel have received adequate therapy and infection has resolved
233
4. Wear a surgical mask that covers the mouth and nose 5. Wear a cap or hood to cover fully hair on the head and face 6. Use surgical gowns and drapes that are effective barriers when wet
Ventilation 1. Maintain positive-pressure ventilation in the operating room with respect to the corridors and adjacent areas 2. Maintain a minimum of 15 air changes per hour, of which at least 3 should be fresh air 3. Filter all air through the appropriate filters 4. Introduce all air at the ceiling and exhaust near the floor 5. Do not use UV radiation in the operating room to prevent SSI 6. Keep operating doors closed except as needed 7. Limit the number of personnel entering the operating room to necessary personnel
Postoperative 1. Protect incision with a sterile dressing for 24 – 48 hours 2. Wash hands before and after dressing changes and any contact with the surgical site 3. When an incision’s dressing must be changed, use sterile technique 4. Educate the patient and family regarding proper incision care, symptoms of SSI, and the need to report such symptoms 5. No recommendation on the need to keep incision covered after 48 hours or on the appropriate time to shower or bathe with an uncovered incision Adapted from Mangram A, Horan T, Peason M, Silver L, Jarvis W. Guideline for prevention of surgical site infection, 1999. Infect Control Hosp Epidemiol 1999;20:247 – 78; with permission.
234
A more recent randomized trial comes from Turkey, where Turna et al [19] hypothesized that using a third-generation cephalosporin may have greater activity against gram-negative pathogens and reduce the rate of postoperative pneumonias. They randomized 104 patients to receive either cephalexin, 1.5 g intravenously 1 hour before surgery and every 12 hours for 48 hours postoperatively, or cefepime (Maxipime), 1 g intravenously for 24 hours after surgery. The study was powered to find a 30% difference in the 40% infection rate in the investigators’ department. In contrast to the prior studies, these investigators found no difference in the infection rates between the two groups, and the third-generation cephalosporin was more expensive. Even with these well-done randomized, doubleblind control trials, the use of prophylactic antibiotics to reduce the rate of pneumonia or empyema remains controversial. At present, there are conflicting results in the literature, and the use of prophylactic antibiotics is nonuniform throughout thoracic surgery. Highlighting the consequence of these conflicting data is a 1990 study by LoCicero [20], in which he surveyed 408 thoracic surgeons about their practice of prophylactic antibiotic usage. A quarter of the surgeons were from a university practice, and almost three quarters were in a private practice. About half of the respondents had been in practice for 5 to 15 years. Prophylactic antibiotics were given in only 80.9% of patients undergoing pulmonary resection, despite the overwhelming evidence of effectiveness presented earlier in this article. The percentage of use was worse for esophageal operations (77.7%), open lung biopsies (51%), or other thoracic procedures (52%). The most commonly used drugs were cephalosporin (54.4%) and late-generation cephalosporin (30.1%). Almost all surgeons who gave prophylactic antibiotics gave them before the skin incision. The length of administration also varied. In pulmonary resections, antibiotics were given for 1 day in 17%, 2 days in 40.3%, 3 days in 21%, and greater than 3 days in 15.9%. For esophageal operations, the use tended to be longer—for 2 days in 30%, 3 days in 18.9%, and greater than 3 days in 38.3%. The current guidelines for prevention of SSI are available online (http://www.cdc.gov/ncidod/hip/ssi/ ssi.pdf). This document is a comprehensive description of procedures and techniques to minimize SSI. Included is an excellent description about antimicrobial prophylaxis for all surgical procedures. It emphasizes that prophylactic antibiotics are not an attempt to sterilize tissues, but rather to reduce the burden ‘‘to a level that cannot overwhelm host de-
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fenses.’’ Four principles are outlined to maximize the effectiveness of antimicrobial prophylaxis: 1. Use prophylaxis based on clinical trials. 2. Use a safe, inexpensive agent that is bactericidal for most contaminants (S. aureus for general thoracic surgery). 3. Establish serum levels at the time of incision (give on call to operating room). 4. Maintain levels during operation, and discontinue ‘‘at most’’ a few hours after incision closure. Also included in this document is a variety of procedures and techniques related to skin preparation, operating room environment, and medical personnel hygiene to reduce SSI (Box 1). Given all the recommendations, the best method of reducing infection remains meticulous technique and attention to detail.
References [1] Mangram A, Horan T, Peason M, Silver L, Jarvis W. Guideline for prevention of surgical site infection, 1999. Infect Control Hosp Epidemiol 1999;20:247 – 78. [2] Cruse P, Foord R. The epidemiology of wound infection: a 10-year prospective study of 62,939 wounds. Surg Clin North Am 1980;60:27 – 40. [3] Poulsen KB, Bremmelgaard A, Sorenson AI, et al. Estimated costs of postoperative wound infections. A case-control study marginal hospital and social security costs. Epidemiol Infect 1994;113:283 – 95. [4] Eriksen K, Hansen J, Lund F. Postoperative infection in surgery of the lung: prophylaxis with high level systemic penicillin therapy. Acta Chir Scand 1954;107: 460 – 5. [5] Eriksen K, Hansen J. Prophylactic use of antibiotics in surgery of the lung. Acta Chir Scand 1964;128:651 – 8. [6] Kvale P, Ranga V, Kopacz M, Cox F, Magalligan D, Davila J. Pulmonary resection. South Med J 1977; 70(Suppl 1):64 – 9. [7] Truesdale R, D’Alessandri R, Manuel V, Diacoff G, Kluge R. Antimicrobial vs placebo prophylaxis in noncardiac thoracic surgery. JAMA 1979;241:1254 – 6. [8] Cameron J, Imbembo A, Keiffer R, Spray S, Baker R. Prospective clinical trial of antibiotics for pulmonary resection. Surg Gynecol Obstet 1981;152:156 – 8. [9] Ilves R, Cooper J, Todd T, Pearson F. Prospective, randomized, double-blind study using prophylactic cephalothin for major, elective, general thoracic operations. J Thorac Cardiovasc Surg 1981;81:813 – 7. [10] Frimodt-Moller N, Ostri P, Pedersen I, Poulsen S. Antibiotic prophylaxis in pulmonary surgery: a doubleblind study of penicillin versus placebo. Ann Surg 1982;195:444 – 50.
perioperative antibiotics [11] Olak J, Jeyasingham K, Forrester-Wood C, Hutter J, Al-Seerah M, Brown E. Randomized trial of one-dose versus six-dose cefazolin prophylaxis in elective general thoracic surgery. Ann Thorac Surg 1991;51:956 – 8. [12] Wertzel H, Swoboda L, Joos-Wurtemberger A, Frank U, Hasse J. Perioperative antibiotic prophylaxis in general thoracic surgery. Thorac Cardiovasc Surg 1992;40: 326 – 9. [13] Tarkka M, Pokela R, Lepojarvi M, Nissinen J, Karkola P. Infection prophylaxis in pulmonary surgery: a randomized prospective study. Ann Thorac Surg 1987;44: 508 – 13. [14] Aznar R, Mateu M, Miro J, et al. Antibiotic prophylaxis in non-cardiac thoracic surgery: cefazolin versus placebo. Eur J Cardiothorac Surg 1991;5:515 – 8. [15] Krasnik M, Thiss J, Frimodt-Moller N. Antibiotic prophylaxis in non-cardiac thoracic surgery: a double blind study of penicillin vs. cefuroxime. Scand J Thorac Cardiovasc Surg 1991;25:73 – 6.
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[16] Frey D, Reichmann A-K, Mauch H, Kaiser D. ‘‘Singleshot’’ antibiotikaprophylaxe in der thoraxchirurgie: Senkung der postopertiven infektionstrate. Infection 1993;21(Suppl):35 – 44. [17] Bernard A, Pillett M, Goudet P, Viard H. Antibiotic prophylaxis in pulmonary surgery a prospective randomized double-blind trial of flash cefuroxime versus forty-eight-hour cefuroxime. J Thorac Cardiovasc Surg 1994;107:896 – 900. [18] Bolt J, Piper S, Uphus D, Fussle R, Hempelmann G. Preoperative microbiologic screening and antibiotic prophylaxis in pulmonary resection operations. Ann Thorac Surg 1999;68:208 – 11. [19] Turna A, Kutlu C, Ozalp T, Karamustafaoglu A, Mulazimoglu L, Bedirhan M. Antibiotic prophylaxis in elective thoracic surgery: cefuroxime versus cefepime. Thorac Cardiovasc Surg 2003;51:84 – 8. [20] LoCicero J. Prophylactic antibiotic usage in cardiothoracic surgery. Chest 1990;98:719 – 23.
Perioperative Antibiotics: When, Why? Mark S. Allen, MDa,b,* a
Division of General Thoracic Surgery, Mayo Clinic, 200 First Street, SW Rochester, MN 55905, USA b Department of Surgery, Mayo Medical School, Rochester, MN 55905, USA
Before Joseph Lister’s principle of antisepsis, surgery commonly led to postoperative fevers, commonly known as ‘‘irrative fever,’’ followed by infection, drainage, ‘‘laudable pus,’’ sepsis, and death. Since the introduction of antisepsis, surgery has progressed to an endeavor that prolongs and improves life. About 27 million operations are performed each year in the United States. Surgical site infections (SSI) are the third most common nosocomial infection [1]. About two thirds of SSI develop in the surgical incision. In 1980, Cruse and Foord [2] estimated that SSI increased hospital stay by 10 days and increased costs by $2000, and a 1992 analysis revealed each SSI increased costs more than $3000 and hospital stay by 7.3 days [3]. Prevention of life-threatening and costly SSI is important. A variety of techniques should be considered to decrease SSI, including recommendations for preoperative, intraoperative, and postoperative practices that may reduce the risk of an infection. Careful surgical technique with avoidance of unnecessary tissue destruction is probably the most important factor in decreasing the incidence of postoperative infections. The use of perioperative antibiotics should be seen as an adjunct to meticulous technique and proper procedures. Perioperative antibiotics are thought to decrease wound infections and may decrease other SSI in general thoracic surgery, such as empyema and postoperative pneumonias.
* Division of General Thoracic Surgery, Mayo Clinic, 200 First Street, SW Rochester, MN 55905. E-mail address: [email protected]
The use of prophylactic antibiotics in general thoracic surgery is well established. This article explains the rationale for modern-day surgical wound infection prophylaxis, the why and the when. Various arguments about the use of antibiotics to prevent empyema and pneumonia after a thoracic operation also are presented. The evidence supporting the use of antibiotic prophylaxis for general thoracic surgical procedures is overwhelming; however, despite numerous well-done randomized trials, controversy still exists as to when to stop the antibiotics, which agent to use, and whether or not the use of antibiotics decreases wound infections only or wound infections and deeper infections, such as pneumonia or empyema (Table 1). Prophylactic antibiotics were proposed by Eriksen et al [4,5] in 1954, before any randomized study had proven their efficacy. Kvale et al [6] reported the first randomized study to examine the question in 1977. At that time, there was disagreement between surgeons, who believed perioperative antibiotics decreased infectious complications, and internists, who believed perioperative antibiotics did not decrease infectious complications but increased resistant organisms. The study by Kvale et al [6] was the first randomized study on perioperative antibiotics for lung surgery since the introduction of perioperative antibiotics. At Kvale’s institution, the infection rate was 25% for all thoracic surgery procedures, which the authors found unacceptable. They conducted a randomized, prospective, doubleblind study from March 1974 to December 1975. They gave cefazolin (Kefzol), 500 mg intramuscularly on call and every 6 hours postoperatively until orally tolerated, then cephalexin (Keflex), 500 mg
1547-4127/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.thorsurg.2005.01.005
thoracic.theclinics.com
230
allen
Table 1 Randomized studies concerning prophylactic antibiotics Wound infection
Pneumonia
Empyema
77
Significant reduction
Significant reduction
Significant reduction
57
NSD
NSD
NSD
Cephalothin vs placebo
171
NSD
NSD
NSD
Cephalothin vs placebo
211
Significant reduction
NSD
NSD
Penicillin G vs placebo
101
Significant reduction
NSD
NSD
Doxycycline vs cefuroxime Cefazolin vs placebo
120
NSD
NSD
NSD
127
Significant reduction
NSD
Significant reduction
Cefazolin 1 vs 6 doses
199
NSD
NSD
NSD
Penicillin G vs Cefuroxime
94
NSD
NSD
NSD
Ampicillin/sulbactam 1 vs 3 doses
60
NSD
NSD
NSD
Cefuroxime vs placebo
200
NSD
NSD
NSD
Cefuroxime vs placebo
203
NSD
Significant reduction
Ampicillin/sulbactam vs cefazolin Cefuroxime vs cefepime
120
Not stated
102
NSD
Chest x-ray more often normal Significant reduction NSD
Primary author
Year
Type of trial
Agent(s) used
Kvale [6]
1977
Cefazolin vs placebo
Truesdale [7]
1979
Cefazolin vs placebo
Cameron [8]
1981
Ilves [9]
1981
FrimodtMoller [10]
1982
Tarkka [13]
1987
Aznar [14]
1991
Olak [11]
1991
Krasnik [15]
1991
Wertzel [12]
1992
Frey [16]
1993
Bernard [17]
1994
Boldt [18]
1999
Turna [19]
2003
Prospective, randomized, double-blind Prospective, randomized, double-blind Prospective, randomized Prospective, randomized, double-blind Prospective, randomized, double-blind Prospective, randomized Prospective, randomized, double-blind Prospective, randomized, double-blind Prospective, randomized, double-blind Prospective, randomized, double-blind Prospective, randomized Prospective, randomized, double-blind Prospective, randomized Prospective, randomized, double-blind
No. patients
Not stated NSD
Abbreviation: NSD, no significant difference.
orally every 6 hours for a total of 5 days, or placebo. The vials were identical, so neither the staff nor the patient knew who received antibiotics versus placebo. Patients with prior chest infections, patients with known allergies, patients who had received antibiotics within 1 week of surgery, and patients who had refused informed consent were not eligible. Specific protocols for postoperative management and definitions of wound infection, pneumonia, and empyema were established prospectively. The investigators randomized 77 patients undergoing pulmo-
nary surgery. Of the control group, 17 of 34 (50%) developed ‘‘infection,’’ although 50% of these received no further treatment. Only 8 of 43 (19%) of the treated group developed infection (P = .005). Kvale et al [6] concluded that ‘‘the routine use of perioperative antibiotics is indicated to prevent postoperative infections in pulmonary resection.’’ The results of the Kvale trial were challenged by a subsequent randomized, prospective, double-blind trial by Truesdale et al [7] in 1979. This group randomized 57 patients undergoing pulmonary resec-
perioperative antibiotics
tion. They used cefazolin, 1 g intramuscularly on admittance to the operating room, followed by cephalothin (Keflin), 2 g intravenously every 6 hours for 48 hours, starting immediately after surgery, versus placebo. The vials of antibiotic and placebo were identical so that patients and physicians did not know which patients were receiving antibiotics and which were receiving placebo. In this study, 5 of 29 (17.2%) placebo patients and 5 of 28 (17.8%) treated patients developed a postoperative infection (P = not significant). Complications of prophylaxis occurred in 17.2% (31 of 57) of placebo patients and 64.4% of treated patients and included hypersensitivity reactions in 2, drug fever in 9, phlebitis in 14, and increased blood urea nitrogen and liver function tests in 8. Truesdale et al [7] concluded that prophylactic antibiotics for pulmonary resection did not outweigh the benefits and should not be employed. This view was supported further by a larger randomized trial by Cameron et al [8] from Johns Hopkins Medical Center. They randomized 171 patients undergoing pulmonary resection to cephalothin, 2 g intravenously the evening before surgery, at 6:00 a.m. the morning of surgery, during the operation, and 6 hours after surgery, or placebo (no antibiotics). The hospital stay was 15.5 days for the antibiotic group and 15.7 days for the placebo group. There was no difference in the number of postoperative fevers. The number of ‘‘septic complications’’ in the antibiotic group was 22 versus 26 in the nonantibiotic group. Even when infections were broken down into pneumonia, empyema, and wound infection, there were no differences. The authors did not give the actual numbers of wound infections, so it is unknown if a trend was evident. They did find that when postoperative infections occurred in the antibiotic group, they were often from gram-negative organisms that were resistant to cephalothin. They recommended that patients not receive prophylactic antibiotics before pulmonary surgery. Several months after Cameron’s study, the results from an even larger study from the Toronto general thoracic surgical group was published [9]. Ilves et al [9] randomized 211 patients undergoing a pulmonary or esophageal operation to receive either placebo or cephalothin, 2 g intravenously at the induction of anesthesia and 2 g intravenously 4 hours later. During the study, neither the patients nor the staff knew which group the patients were in. The surgical preparation, procedure, and postoperative care were standardized. The investigators found that 7 patients of 118 (5.9%) in the treatment group developed a wound infection versus 22 of 93 (23.7%) in the placebo group (P < .05). There also was a reduction in the
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incidence of postoperative pulmonary infections and empyemas, but the difference did not reach statistical significance. The investigators were unable to detect a difference in the bacteriology of the infections between the two groups. Ilves et al [9] stated their policy is to ‘‘employ prophylactic perioperative antibiotic coverage in clean-contaminated major thoracic cases.’’ A similar result was reported from Denmark by Frimodt-Moller et al [10] in 1982. They compared penicillin G prophylaxis with placebo in a randomized, double-blind, controlled prospective trial. The investigators used penicillin G at a dose of 5 million IU intravenously immediately before surgery and every 6 hours after surgery for five doses. They randomized 94 patients: 45 in the penicillin G group and 47 in the placebo group. There were nine (19.1%) wound infections in the placebo group versus two (4.4%) in the prophylactic group (P = .03). There was no difference in the number of empyemas or lower respiratory tract infections between the two groups. Frimodt-Moller et al [10] also showed a significant reduction in the length of hospitalization (3 days) with penicillin G prophylaxis, a highly costefficient finding. These two major positive studies seem to contradict the study done by Cameron et al [8]. Perhaps the wound infection rate was already so low at Johns Hopkins that the study was underpowered to show a significant difference. Whatever the reason, most surgeons believed the positive findings of the Ilves and Frimoldt-Moller studies and discounted the negative findings of the Cameron study. Even though most surgeons had been using prophylactic antibiotics for general thoracic surgical operations before the publication of these studies, these findings confirmed what they empirically thought to be fact. The question of whether to give a single dose or prolonged postoperative prophylaxis was examined in a randomized study by Olak et al [11], in which they randomized 208 patients to one dose of cefazolin (1 g intravenously at the induction of anesthesia) or the induction dose of cefazolin plus five doses every 8 hours after surgery. They found no difference in the number of wound infections, pneumonias, or empyemas between the two groups and concluded that there was no benefit to prolonging the antibiotic prophylaxis after the operation concluded. Additional confirmation for use of only a single dose comes from a randomized study done in Germany by Wertzel et al [12]. This group randomized 60 patients undergoing pulmonary resection to receive ampicillin/sulbactam (Unasyn), either 3 g at induction or 3 g at induction and two further doses at
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8-hour intervals. They found no difference in the incidence of wound infection or any other infections. They did report about a 30% incidence of bronchitis and pneumonia, but stated that, ‘‘whether PX [prophylactic antibiotics] is reducing these complications cannot be answered by our study’’ [12]. With confirmation that prophylactic antibiotics reduce wound infection rates and that a short course is effective, interest was turned to studying ways of decreasing the rate of pneumonia and empyema after general thoracic surgical operations by employing prophylactic antibiotics directed at respiratory flora. In 1987, Tarkka et al [13] published a prospective, randomized trial from Finland to determine if cefuroxime (Zinacef), an agent effective against the common skin flora Staphylococcus aureus and the respiratory pathogen Haemophilus influenzae, would reduce the rates of wound infection and pneumonia and empyema. They randomized 120 patients to receive either their usual prophylactic antibiotic, doximycin, 200 mg orally the day before surgery, 100 mg intravenously during the operation, and 100 mg orally every day for 3 days, or cefuroxime, 1.5 g during anesthesia induction and 0.75 g every 8 hours times three after surgery. The two groups were comparable in all categories. They found a significantly lower rate of minor lower respiratory tract infections in the cefuroxime group, but no difference in the rate of pneumonia or empyema. Tarkka et al [13] hypothesized that the bactericidal effects of cefuroxime may account for the difference. Aznar et al [14] tried to determine if cefazolin alone would decrease the rates of empyema and pneumonia. They randomized 143 patients and, after excluding 16 patients, were left with 127 patients (57 in the placebo group and 70 in the cefazolin group). Cefazolin, 1 g intravenously one half hour before surgery, was used. There was no significant difference in the demographics or operations performed between the two groups. A marked difference in wound infection (14% versus 1.5%) was shown, but no statistically significant benefit for empyema (14% versus 7%) or pneumonia (8.8% versus 4.3%) in the placebo versus cefazolin group. Aznar et al [14] concluded, as others had, that a preoperative dose of prophylactic antibiotics decreased wound infection rates but not the risk of pneumonia or empyema. In the same year as Aznar’s study, 1991, Krasnik et al [15] reported a randomized double-blind study to examine if cefuroxime was better than penicillin G in preventing empyema and pneumonia as the study by Tarkka et al [13] had done. The medications were started just before surgery and repeated every 8 hours after surgery. Krasnik et al [15] analyzed 94 patients
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(48 in the penicillin G group and 46 in the cefuroxime group). They also found no difference in the rate of pneumonia or empyema between the two groups and concluded they still prefer penicillin G for prophylactic antibiotics for pulmonary surgery. A positive finding from the use of cefuroxime was reported in a German trial [16]. Frey et al [16] compared no antibiotics with one dose of cefuroxime, 1.5 g intravenously at the induction of anesthesia. They found fewer wound infections and fewer patients with ‘‘pronounced infiltration’’ on daily chest x-rays in the cefuroxime group. Also, the number of patients requiring additional antibiotics was less in the treated group compared with the placebo group. The use of a control group with no antibiotics makes interpretation of this study difficult. Another positive study using cefuroxime was published in 1994 [17]. Bernard et al [17] randomized 203 patients undergoing a general thoracic surgical procedure. All patients received an induction dose of cefuroxime, 1.5 g intravenously, and a second dose 2 hours later. Patients were then randomized to cefuroxime, 1.5 g intravenously every 6 hours for 48 hours, or placebo. The investigators found a marked reduction in the incidence of empyema: 6% in the treatment group versus 15.6% in the placebo group (P = .03). This finding is undoubtedly related to the fact that seven patients in the placebo group developed bronchial fistulas, whereas only two in the treatment group developed fistulas. The development of fistulas is thought to be unrelated to an infection, but rather related to local factors at the bronchial closure. Postoperative chest x-rays were more often normal in the treatment group, but there was no difference in the number of patients who developed purulent expectorations and atelectasis associated with a temperature greater than 38°C. No information is given about length of stay for these patients. Bernard et al [17] concluded, perhaps mistakenly, that ‘‘48-hour antibiotic prophylaxis regime decreases the rate of deep infectious complications.’’ In another randomized trial that showed effectiveness in reducing pneumonia, Boldt et al [18] compared a single injection of cefazolin, 2 g intravenously, with ampicillin/sulbactam, 1.5 g intravenously. They also studied the microbiologic tracheal aspirates of the two groups and found all the bacteria were susceptible to the prophylaxis in the ampicillin/ sulbactam group, whereas 8 of 25 patients in the cefazolin-only group had resistant organisms. They found fewer bronchopulmonary infections in the ampicillin/sulbactam group. The group given cefazolin stayed in the ICU longer and incurred higher costs than the ampicillin/sulbactam group.
perioperative antibiotics
Box 1. Centers for Disease Control and Prevention recommendations to reduce surgical site infections Preoperative 1. When possible, identify and treat all existing infections 2. Do not remove hair preoperatively at or around the incision, unless it interferes with the operation 3. If hair is removed, remove it immediately before the operation, preferably with electric clippers 4. Control serum blood glucose levels in all diabetic patients 5. Encourage tobacco cessation 6. Do not withhold necessary blood products 7. Require patients to shower or bathe with an antiseptic agent on at least the night before surgery 8. Thoroughly wash and clean at and around the incision site to remove gross contamination before performing antiseptic skin preparation 9. Use an appropriate antiseptic agent for skin preparation 10. Apply preoperative antiseptic skin preparation in concentric circles moving toward the periphery 11. Keep preoperative hospital stay as short as possible 12. No recommendation to wean steroids, enhance nutrition, apply mupirocin to nares, or enhance wound space oxygenation
Intraoperative Surgical team 1. Keep nails short and do not wear artificial nails 2. Perform preoperative surgical scrub for 2 – 5 minutes 3. Obtain appropriate cultures from, and exclude from duty, surgical personnel who have draining skin lesions until infection has been ruled out or personnel have received adequate therapy and infection has resolved
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4. Wear a surgical mask that covers the mouth and nose 5. Wear a cap or hood to cover fully hair on the head and face 6. Use surgical gowns and drapes that are effective barriers when wet
Ventilation 1. Maintain positive-pressure ventilation in the operating room with respect to the corridors and adjacent areas 2. Maintain a minimum of 15 air changes per hour, of which at least 3 should be fresh air 3. Filter all air through the appropriate filters 4. Introduce all air at the ceiling and exhaust near the floor 5. Do not use UV radiation in the operating room to prevent SSI 6. Keep operating doors closed except as needed 7. Limit the number of personnel entering the operating room to necessary personnel
Postoperative 1. Protect incision with a sterile dressing for 24 – 48 hours 2. Wash hands before and after dressing changes and any contact with the surgical site 3. When an incision’s dressing must be changed, use sterile technique 4. Educate the patient and family regarding proper incision care, symptoms of SSI, and the need to report such symptoms 5. No recommendation on the need to keep incision covered after 48 hours or on the appropriate time to shower or bathe with an uncovered incision Adapted from Mangram A, Horan T, Peason M, Silver L, Jarvis W. Guideline for prevention of surgical site infection, 1999. Infect Control Hosp Epidemiol 1999;20:247 – 78; with permission.
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A more recent randomized trial comes from Turkey, where Turna et al [19] hypothesized that using a third-generation cephalosporin may have greater activity against gram-negative pathogens and reduce the rate of postoperative pneumonias. They randomized 104 patients to receive either cephalexin, 1.5 g intravenously 1 hour before surgery and every 12 hours for 48 hours postoperatively, or cefepime (Maxipime), 1 g intravenously for 24 hours after surgery. The study was powered to find a 30% difference in the 40% infection rate in the investigators’ department. In contrast to the prior studies, these investigators found no difference in the infection rates between the two groups, and the third-generation cephalosporin was more expensive. Even with these well-done randomized, doubleblind control trials, the use of prophylactic antibiotics to reduce the rate of pneumonia or empyema remains controversial. At present, there are conflicting results in the literature, and the use of prophylactic antibiotics is nonuniform throughout thoracic surgery. Highlighting the consequence of these conflicting data is a 1990 study by LoCicero [20], in which he surveyed 408 thoracic surgeons about their practice of prophylactic antibiotic usage. A quarter of the surgeons were from a university practice, and almost three quarters were in a private practice. About half of the respondents had been in practice for 5 to 15 years. Prophylactic antibiotics were given in only 80.9% of patients undergoing pulmonary resection, despite the overwhelming evidence of effectiveness presented earlier in this article. The percentage of use was worse for esophageal operations (77.7%), open lung biopsies (51%), or other thoracic procedures (52%). The most commonly used drugs were cephalosporin (54.4%) and late-generation cephalosporin (30.1%). Almost all surgeons who gave prophylactic antibiotics gave them before the skin incision. The length of administration also varied. In pulmonary resections, antibiotics were given for 1 day in 17%, 2 days in 40.3%, 3 days in 21%, and greater than 3 days in 15.9%. For esophageal operations, the use tended to be longer—for 2 days in 30%, 3 days in 18.9%, and greater than 3 days in 38.3%. The current guidelines for prevention of SSI are available online (http://www.cdc.gov/ncidod/hip/ssi/ ssi.pdf). This document is a comprehensive description of procedures and techniques to minimize SSI. Included is an excellent description about antimicrobial prophylaxis for all surgical procedures. It emphasizes that prophylactic antibiotics are not an attempt to sterilize tissues, but rather to reduce the burden ‘‘to a level that cannot overwhelm host de-
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fenses.’’ Four principles are outlined to maximize the effectiveness of antimicrobial prophylaxis: 1. Use prophylaxis based on clinical trials. 2. Use a safe, inexpensive agent that is bactericidal for most contaminants (S. aureus for general thoracic surgery). 3. Establish serum levels at the time of incision (give on call to operating room). 4. Maintain levels during operation, and discontinue ‘‘at most’’ a few hours after incision closure. Also included in this document is a variety of procedures and techniques related to skin preparation, operating room environment, and medical personnel hygiene to reduce SSI (Box 1). Given all the recommendations, the best method of reducing infection remains meticulous technique and attention to detail.
References [1] Mangram A, Horan T, Peason M, Silver L, Jarvis W. Guideline for prevention of surgical site infection, 1999. Infect Control Hosp Epidemiol 1999;20:247 – 78. [2] Cruse P, Foord R. The epidemiology of wound infection: a 10-year prospective study of 62,939 wounds. Surg Clin North Am 1980;60:27 – 40. [3] Poulsen KB, Bremmelgaard A, Sorenson AI, et al. Estimated costs of postoperative wound infections. A case-control study marginal hospital and social security costs. Epidemiol Infect 1994;113:283 – 95. [4] Eriksen K, Hansen J, Lund F. Postoperative infection in surgery of the lung: prophylaxis with high level systemic penicillin therapy. Acta Chir Scand 1954;107: 460 – 5. [5] Eriksen K, Hansen J. Prophylactic use of antibiotics in surgery of the lung. Acta Chir Scand 1964;128:651 – 8. [6] Kvale P, Ranga V, Kopacz M, Cox F, Magalligan D, Davila J. Pulmonary resection. South Med J 1977; 70(Suppl 1):64 – 9. [7] Truesdale R, D’Alessandri R, Manuel V, Diacoff G, Kluge R. Antimicrobial vs placebo prophylaxis in noncardiac thoracic surgery. JAMA 1979;241:1254 – 6. [8] Cameron J, Imbembo A, Keiffer R, Spray S, Baker R. Prospective clinical trial of antibiotics for pulmonary resection. Surg Gynecol Obstet 1981;152:156 – 8. [9] Ilves R, Cooper J, Todd T, Pearson F. Prospective, randomized, double-blind study using prophylactic cephalothin for major, elective, general thoracic operations. J Thorac Cardiovasc Surg 1981;81:813 – 7. [10] Frimodt-Moller N, Ostri P, Pedersen I, Poulsen S. Antibiotic prophylaxis in pulmonary surgery: a doubleblind study of penicillin versus placebo. Ann Surg 1982;195:444 – 50.
perioperative antibiotics [11] Olak J, Jeyasingham K, Forrester-Wood C, Hutter J, Al-Seerah M, Brown E. Randomized trial of one-dose versus six-dose cefazolin prophylaxis in elective general thoracic surgery. Ann Thorac Surg 1991;51:956 – 8. [12] Wertzel H, Swoboda L, Joos-Wurtemberger A, Frank U, Hasse J. Perioperative antibiotic prophylaxis in general thoracic surgery. Thorac Cardiovasc Surg 1992;40: 326 – 9. [13] Tarkka M, Pokela R, Lepojarvi M, Nissinen J, Karkola P. Infection prophylaxis in pulmonary surgery: a randomized prospective study. Ann Thorac Surg 1987;44: 508 – 13. [14] Aznar R, Mateu M, Miro J, et al. Antibiotic prophylaxis in non-cardiac thoracic surgery: cefazolin versus placebo. Eur J Cardiothorac Surg 1991;5:515 – 8. [15] Krasnik M, Thiss J, Frimodt-Moller N. Antibiotic prophylaxis in non-cardiac thoracic surgery: a double blind study of penicillin vs. cefuroxime. Scand J Thorac Cardiovasc Surg 1991;25:73 – 6.
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[16] Frey D, Reichmann A-K, Mauch H, Kaiser D. ‘‘Singleshot’’ antibiotikaprophylaxe in der thoraxchirurgie: Senkung der postopertiven infektionstrate. Infection 1993;21(Suppl):35 – 44. [17] Bernard A, Pillett M, Goudet P, Viard H. Antibiotic prophylaxis in pulmonary surgery a prospective randomized double-blind trial of flash cefuroxime versus forty-eight-hour cefuroxime. J Thorac Cardiovasc Surg 1994;107:896 – 900. [18] Bolt J, Piper S, Uphus D, Fussle R, Hempelmann G. Preoperative microbiologic screening and antibiotic prophylaxis in pulmonary resection operations. Ann Thorac Surg 1999;68:208 – 11. [19] Turna A, Kutlu C, Ozalp T, Karamustafaoglu A, Mulazimoglu L, Bedirhan M. Antibiotic prophylaxis in elective thoracic surgery: cefuroxime versus cefepime. Thorac Cardiovasc Surg 2003;51:84 – 8. [20] LoCicero J. Prophylactic antibiotic usage in cardiothoracic surgery. Chest 1990;98:719 – 23.