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Antibiotic prophylaxis for coronary bypass grafting
J
THORAC CARDIOVASC SURG
86:217-221, 1983
Antibiotic prophylaxis for coronary bypass grafting Comparison of a five-day and a two-day course A trial was conducted to compare the effectiveness of a 2 day and a 5 day course of antibiotic prophylaxis after coronary bypass grafting. One hundred sixty patients were randomized to one of the two courses. The 2 day course comprised 48 hours of intramuscular kanamycin and intravenous cephalothin. The 5 day course comprised 48 hours of intramuscular kanamycin and intravenous cephalothin followed by 3 days of oral cephalexin. After the 2 day course, there were two wound infections and two respiratory tract infections in 79 patients (5.1 %), and after the 5 day course, one wound infection and two respiratory tract infections in 81 patients (3.7%). Subsequently, in 171 patients undergoing coronary bypass grafting and given the 2 day course, the infection rate was 3.5%. There was no significant difference in infection rates among the three groups (p > 0.05). We conclude that no more than 2 days of antibiotic prophylaxis are necessaryfor patients undergoing coronary bypass grafting.
D. J. Hillis, M.B., B.S., F. L. Rosenfeldt, M.D., F.R.C.S.E., W. J. Spicer, F.R.A.C.P., F.R.C.P.A., and G. R. Stirling, F.R.A.C.S., F.A.C.S., Melbourne, Australia
Rients undergoing cardiac operations with cardiopulmonary bypass may be at greater risk from infection than patients undergoing other noncontaminated major surgical procedures.t' Factors that may predispose to infectionduring and after heart surgery include contamination of blood in the heart-lung machine, long operating times, and routine use in the postoperative period of intravascular cannulas, urinary catheters, and positivepressure ventilation. Infection of an implanted prosthetic heart valve is difficult to eradicate and is associated with a high mortality. Hence antibiotic -prophylaxis during cardiac valve replacement is virtually universal, although its value is unproven.' When the coronary bypass operation
From the Cardiovascular Surgical Research Unit of the Baker Medical Research Institute and the C. J. Officer Brown Cardiothoracic Surgery Unit and the Department of Bacteriology, Alfred Hospital, Melbourne, Australia. Dr. Hillis was the recipient of a National Heart Foundation Scholarship. Received for publication May 10, 1982. Accepted for publication Dec. 14, 1982. Address for reprints: Dr. F. Rosenfeldt, Baker Medical Research Institute, Commercial Road, Prahran, 3181, Victoria, Australia.
was introduced, a similar practice of antibiotic prophylaxis was adopted. However, there is little published evidence to support this. In one trial in which 1".... systemic prophylactic antibiotics were used during coronary bypass, a wound infection rate of less than 1% was observed.t' Conte and associates" reported that a single intraoperative dose of cephalothin was as effective in preventing infection as a 4 day course. However, most cardiac units continue to use a 5 or a 7 day course of prophylaxis. The aim of the present study was to compare a course of antibiotic therapy given only until the removal of central venous lines and drainage tubes (usually 2 days after operation) with a standard 5 day course. The study was carried out in two parts. In 1980, a prospective, randomized study was done to compare the two regimens. In 1981, in a nonrandomized study, all patients having coronary bypass were given the short course of prophylaxis and the infection rate was compared with that experienced previously. Methods Randomized study. One hundred eighty-two patients undergoing coronary bypass grafting without additional procedures from April to December, 1980, were ran217
The Journal of Thoracic and Cardiovascular Surgery
2 1 8 Hillis et al.
Table I. Diagnostic criteria for infection Infection Wound In hospital Out of hospital Respiratory tract
Urinary tract
Septicemia Oral candidiasis
Criteria Macroscopic pus Macroscopic pus and culture of specific pathogens Three of the following: I. Purulent sputum 2. Culture of specific pathogen 3. Fever: 37.8° C or above on two of more occasions beyond postop. day 6 4. Significant leukocytosis (> 12,000/mmJ ) Two of the following: 1. Greater than 100,000 organisms per milliliter 2. Dysuria and/or renal angle tenderness 3. Pyuria: more than 5 white blood cells per cubic millimeter Positive blood culture and fever Clinical diagnosis and/or positive culture (1980 only)
domized by hospital unit record number to receive one of two courses of antibiotics. The standardcourse was as follows: cephalothin 12 mg/kg intravenously and kanamycin 7 mg/kg intramuscularly given immediately preoperatively and into the bypass priming fluid intraoperatively. Postoperatively, the patient received the same dose of cephalothin intravenously 4 hourly and kanamycin intramuscularly 12 hourly until removal of central cannulas and drainage tubes (usually 48 hours after operation). Oral cephalexin 1 gm 6 hourly was then given to make a total of 5 days of prophylaxis. The short course comprised parenteral cephalothin and kanamycin given as in the standard course preoperatively, intraoperatively, and postoperatively until removal of central cannulas and drainage tubes. The patients in the short course group received no oral antibiotic therapy. Nonrandomized study. This study included 188 consecutive patients undergoing coronary bypass grafting from January to September, 1981. These patients were given only the short course of antibiotic prophylaxis used in the randomized study. Approval for the protocol was obtained from the Alfred Hospital Ethics Committee. Exclusions. Patients were excluded from the study for the following reasons: (1) The patient died of causes unrelated to sepsis in the postoperative period; (2) the patient did not receive the therapy to which he was randomized; (3) drug allergy necessitated a change of therapy. In the randomized study, 22 of the 182 patients were excluded from the main analysis because they did not receive the therapy allocated. In six of the 22 patients
this was due to drug allergy. In the other 16 patients, development of a low cardiac output state necessitated inotropic support via a central venous cannula beyond the third postoperative day. In these patients the previous practice of the unit was followed of continuing antibiotic prophylaxis to prevent infection from indwelling central venous cannulas. The infections in this group in low cardiac output were analyzed separately. In the nonrandomized group, 17 of the 188 patients required prolonged inotropic support via a central cannula and were given prophylaxis throughout this period. The infections in this group were also analyzed separately. Cultures. Preoperatively, nose and throat swabs and specimens of sputum and midstream urine were obtained. On the first postoperative day, sputum and catheter urine samples were collected. On the seventh postoperative day a midstream urine specimen and a throat swab were obtained. The antibiotic sensitivities of any pathogenic bacteria cultured were determined by the agar dilution method. In the nonrandomized study, the same bacteriologic tests were done, with the exception of the midstream urine specimen and throat swab on the seventh day. Routine patient care. Antibacterial preparation of all patients began soon after admission with the use of framycetin nasal spray and bathing with hexachlorophene soap. On the day before operation, the patient was shaved and then washed with hexachlorophene soap. On the morning of the operation, the skin was washed with hexachlorophene and chlorhexidine. In the operating room, the skin was prepared with alcoholic chlorhexidine and then by 1% alcoholic iodine. Sterile adhesive drapes were applied to the skin. An arterial cannula, central and peripheral venous cannulas, a urinary catheter, chest drainage tubes, and pacing wires were routinely inserted. Postoperatively all patients were mechanically ventilated, the majority being extubated within 4 hours. Wounds and drainage tube sites were washed daily with cetrimide (cetyltrimethylammonium bromide) and chlorhexidine. Merbromin (Mercurochrome) was applied to the incisions. Entry sites of arterial and venous cannulas and pacing wires were washed daily with povidone-iodine complex. If an infection developed, treatment was prescribed in accordance with the clinical signs and bacteriologic fmdings. Definitions of infection. The criteria used for the diagnosis of infection are shown in Table I. While in the hospital, the patients were reviewed daily for infection by medical staff. In the hospital, the diagnosis of wound infection was made if macroscopic pus was observed. The medical staff involved in follow-up after discharge
Volume 86 Number 2 August, 1983
Table
Antibiotic prophylaxis for bypass grafting
2 19
n. Comparison of the randomized groups Standard group No. of patients randomized Completed study Male Female Age (yr, mean and range) Cardiac operation" No. of vessels grafted Duration of cardiopulmonary bypass (min) Antibiotic coverage" Total doses of cephalothin Total doses of kanamycin Total doses of cephalexin
Short course group
93 81 61 20 54 (32-68)
89
3.0 ± 0.8 103 ± 29
2.9 ± 1.0 103 ± 34
11.7 ± 2.6 4.0 ± 0.5 12.5 ± 4.2
12.0 ± 3.0 4.1 ± 0.5
79 66 13 55 (33-68)
·Values given are mean ± standard deviation.
were requested to notify the study team of any late wound infections. The difficulty of verifying clinical data after the patient's discharge necessitated the use of more stringent criteria for the diagnosis of a late wound infection. Late wound infections were diagnosed only if macroscopic pus was seen and a pathogen cultured. After cardiac operations, left lower lobe collapse is common, and even in the absence of demonstrable infection, the patient is commonly febrile up to the sixth postoperative day. Consequently, the diagnosis of a respiratory tract infection was made only if at least three of the following four criteria were fulfilled: purulent sputum, culture of a specific pathogen, a fever beyond the sixth postoperative day, and significant leukocytosis (greater than 12,000 leukocytes per cubic millimeter). Data analysis. The chi square test and Fisher's exact test were used to detect significant differences in proportions. Results In the randomized study, the standard and short course groups were comparable with respect to age, sex distribution, and type of operation (Table 11). Postoperative infection developed in four of '79 patients (5.1%) in the short course group and in three of 81 patients (3.7%) in the standard course group. In the nonrandomized short course group, six of 171 patients (3.5%) had ihfections (Table III). There was no significant difference in the infection rates between any of the groups (p > 0.05). A detailed analysis of the infections is given in Table IV. There were no instances of endocarditis, mediastinitis, bacteremia, or urinary tract infection in any of these groups. Wound infection. In the randomized study, there was one superficial sternotomy wound infection, secondary to a hematoma, in the standard course group, and there
m.
Table Infection rates in the randomized and the nonrandomized groups Randomized (1980) Types of infection Wound: In hospital Sternotomy Wound: Out of hospital Sternotomy Leg wound Respiratory tract Total No. of patients with infections
Standard group (n=81)
Short course group (n= 79)
0
o
I
o
o 2 3 (3.7%)
2
Nonrandomized (1981) Short course group (n=171)
o 3
2
2
4 (5.1%)
6 (3.5%)
were two leg wound infections in the short course group. In the nonrandomized study there was one sternotomy wound infection following mechanical dehiscence. This cleared in 14 days after repair of the dehiscence and appropriate antibiotic therapy. Also in the nonrandomized study there were three leg wound infections, one of which developed in a groin wound after the use of the intra-aortic balloon pump. In all cases, antibiotic therapy was given and resolution was prompt without surgical intervention. The overall rate of wound infection in patients receiving the short course of prophylaxis was 2.4%. Respiratory tract infection. In the randomized study, two patients in the standard course group and two patients in the short course group had respiratory tract infections. One of these infections developed soon after discharge. The patient was readmitted and after a further 5 days of antibiotic therapy the infection resolved. The remaining infections were mild and resolved within 5 days. In the nonrandomized study
220
The Journal of Thoracic and Cardiovascular Surgery
Hillis et al.
Table IV. Infections Group
Standard, 1980
Short course, 1980
Short course, 1981
Type of infection
Sternotomy Respiratory Respiratory Leg incision Leg incision Respiratory Respiratory Sternotomy Leg incision Leg incision Leg incision Respiratory Respiratory
Duration (days)
Organism Staphylococcus albus
K1ebsieUa Escherichia coli Staphylococcus aureus Staphylococcus aureus Escherichia coli Not isolated Serratia marcescens Staphylococcus aureus Staphylococcus aureus
Proteus Streptococcus pneumoniae, Escherichia coli Streptococcus pneumoniae
there were two respiratory tract infections. In one patient, the respiratory tract infection began preoperatively and intensive antibiotic therapy was required after operation. Another patient with paralysis of the left hemidiaphragm had mild pneumonia of the left lower lobe. Oral Candida infection. There were six cases of oral candidiasis in the standard group compared with three in the short course group. Low cardiac output group. Thirty-three patients (I6 from the randomized study and 17 from the nonrandomized study) were withdrawn from the primary analysis because of the prolonged administration of antibiotics to prevent infection from central venous cannulas used for inotropic drug infusions. There were nine infections in this group. Three were wound infections, one at the site of insertion of an intra-aortic balloon pump and two in the abdominal wound following laparotomy for intra-abdominal complications. Two were respiratory tract infections, two urinary tract infections, and two cases of septicemia. With antibiotic therapy, all infections resolved within 2 weeks, except for one resulting from a multidrug-resistant Staphylococcus aureus. Despite intensive antibiotic treatment this patient died on the tenth postoperative day. The overall incidence of infection in this low cardiac output group was 27%, despite the prolonged course of antibiotic prophylaxis (average 6 days). Preoperative positive cultures. From the total of 331 patients studied, pathogens were isolated in 12 preoperative cultures: five from urine and seven from sputum. All organisms isolated were sensitive to one or both of the prophylactic antibiotics. In all cases the postoperative specimens were clear of the organism.
7 6 6 10 7 6 7 14 5 5 7 5 6
Antibiotic therapy
Cephalexin Nil Nil FlucloxaciUin Cephalexin Nil Cephalexin Cephalexin, co-trimoxazole, and gentamicin Cephalexin Cephalexin . Cephalexin Co-trimoxazole Nil·
Discussion In the trial, 81 patients were given the standard course of antibiotic prophylaxis and 250 patients were given the short course. There was a low infection rate associated with both courses of therapy, and no statistically significant difference was found between the two. The possibility exists that there was a small but definite difference in the infection rate associated with the two courses of therapy but that the number of patients in this trial was insufficient for this difference to reach statistical significance. Using the formula of Kramer and Greenhouse? for "type II error," we calculated that to exclude, with 80% confidence, an increase in wound infection rate from 1% to 2% would require 2,717 patients per group. Similarly, to exclude an increase in the overall infection rate (wound plus respiratory) from 5% to 10% would require 513 per group. The present trial obviously fell short of satisfying these requirements. To obtain such large numbers would require a trial lasting many years or a multicenter trial. To avoid bias owing to exclusion of patients after randomization,' the results were also analyzed with the 16 patients in low cardiac output retained in the groups to which they were originally randomized. The infection rates then were as follows: short course, six of88 (6.8%); standard course, five of 88 (5.7%), again with no significant difference (p> 0.05). The theoretical goal of antibiotic prophylaxis is to have appropriate antibacterial activity present at the site of and over the period of potential contamination in sufficient concentration to prevent bacterial implantation and subsequent infection." Cephalothin is a relatively safe and effective prophylactic antibiotic during operations.'? II Combination with an aminoglycoside
Volume 86
Antibiotic prophylaxis for bypass grafting 2 2 1
Number 2 August, 1983
counters the relative susceptibility of cephalothin to gram-negative beta lactamases." Adverse effects of antibiotics include a significant morbidity and mortality from allergic reactions" and the appearance of resistant microorganisms which may actually increase the incidence of infection.v": 15 The combination of cephalothin with an aminoglycoside and a diuretic, as is often used in cardiac operations, is particularly nephrotoxic." Oral and esophageal candidiasis is increasingly recognized as a complication of antibiotic prophylaxis following cardiac operations." In the present study, there were more cases of oral candidiasis in the standard course (six of 81) than in the short course (three of 79), though this difference was not statistically significant. These complications of antibiotic prophylaxis become more frequent when the time of administration is prolonged. With the need for cost containment in health care, the cost of antibiotics is assuming great importance. Antimicrobial drugs account for 20% to 35% of total pharmacy costs in many general hospitals," with prophylactic antibiotics responsible for 10% of this total." Shapiro and Associates" have pointed out that, in the United States, 80% of drugs used in antibiotic prophylaxis are administered for 48 hours or more after operation. If such prolonged prophylaxis is without value, it follows there is a large potential saving in the cost of antimicrobial agents. The present study did not attempt to determine whether or not any antibiotic prophylaxis should be given after coronary bypass grafting. It demonstrated, however, that if antibiotic prophylaxis is used, the infection rates for a 2 day course or a 5 day course are similarly low. The fmdings of this study agree with the increasing trend in surgery toward shorter prophylactic antibiotic regimens. We express our appreciation to Dr. B. Davis, Janet Ness, Margaret Sutcliffe, Sister Rigg, and other nursing staff for their help with the study and to Dr. G. Shardey and Professor 1. Ludbrook for reviewing the manuscript, REFERENCES Kluge RM, Calia FM, Mclaughlin JS, Hornick RB: Sources of contamination in open heart surgery. JAMA 230:1415-1418, 1974 2 Freeman R, Hjersing N: Bacterial culture of perfusion blood after open-heart surgery. Thorax 35:754-785, 1980 3 Hirschmann JV, Inui TS: Antimicrobial prophylaxis. A critique of recent trials. Rev Infect Dis 2:1-23, 1980 4 Sutherland RD, Martinez HE, Guynes WA, Miller L: Postoperative chest wound infections in patients requiring
5
6
7
8
9
10
11
12
13
14
15 16
17
18
19
20
coronary bypass. A controlled study evaluating prophylactic antibiotics. J THORAC CARDIOVASC SURG 73:944-946, 1977 Sutherland RD, Miller OL, Martinez HE, Guynes WA, Fyfe T, Harkrider W: Coronary arterial bypass operations without antibiotic coverage. Chest 76: 174-175, 1979 Conte JE, Cohen SN, Roe BB, Elashoff RM: Antibiotic prophylaxis and cardiac surgery. A prospective doubleblind comparison of single-dose versus multiple-dose regimens. Ann Intern Med 76:943-949, 1972 Kramer M, Greenhouse SW: Determination of sample sizes and selection of cases, Psychopharmacology: Problems in Evaluation, Washington, D. c., 1959, National Academy of Sciences, Publication No. 583 May GD, De Mets DL, Friedman LM, Funberg C, Passarnani E: The randomised clinical trial. Bias in analysis. Circulation 64:669-673, 1981 Lindenauer SM, Fry WJ, Schaub G, Wild D: The use of antibiotics in the prevention of vascular graft infections. Surgery 62:487-492, 1967 Gonzalez-Lavin L, Blanco G, Nichols HT: Sodium cephalothin in open-heart surgery. A preliminary report. Clin Med, December, 1970, pp 31-33 Myerowitz PD, Caswell K, Lindsay WG, Nicoloff DM: Antibiotic prophylaxis for open-heart surgery. J THORAC CARDIOVASC SURG 73:625-629, 1977 Bulger RJ: In-vitro activity of cephalothin/kanamycin and methicillin/kanamycin combinations against methicillinresistant Staphylococcus aureus. Lancet 1:17-19, 1967 Spruilli FG, Minette LJ, Sterner WQ: Two surgical deaths associated with cephalothin. JAMA 229:440-441, 1974 Freeman R: Short-term adverse effects of antibiotic prophylaxis for open-heart surgery. Thorax 35:941-944, 1980 Weinstein L, Musher DM: Antibiotic-induced suprainfection. J Infect Dis 119:662-665, 1969 Wade JC, Smith CR, Petty BG, Lipsky JJ, Conrad G, Ellner J, Lietman PS: Cephalothin plus an aminoglycoside is more nephrotoxic than methicillin plus an aminoglycoside. Lancet 2:604-696, 1978 Gundry SR, Borkon AM, McIntosh CL, Morrow AG: Candida esophagitis followingcardiac operation and shortterm antibiotic prophylaxis. J THORAC CARDIOVASC SURG 80:661-668, 1980 Craig WA, Uman SJ, Shaw WR, Ramgopal V, Egan LL, Leopold ET: Hospital use of antimicrobial drugs. Survey at 19 hospitals and results of antimicrobial control program. Ann Intern Med 89:793-795, 1978 Mashford ML, Robertson MB: Surveying antibiotic use in a general teaching hospital. Med J Aust 2:515-518, 1979 Shapiro M, Townsend TR, Rosner B, Kass EH: Use of antimicrobial drugs in general hospitals. Patterns of prophylaxis. N Eng! J Med 301:351-355, 1979
THORAC CARDIOVASC SURG
86:217-221, 1983
Antibiotic prophylaxis for coronary bypass grafting Comparison of a five-day and a two-day course A trial was conducted to compare the effectiveness of a 2 day and a 5 day course of antibiotic prophylaxis after coronary bypass grafting. One hundred sixty patients were randomized to one of the two courses. The 2 day course comprised 48 hours of intramuscular kanamycin and intravenous cephalothin. The 5 day course comprised 48 hours of intramuscular kanamycin and intravenous cephalothin followed by 3 days of oral cephalexin. After the 2 day course, there were two wound infections and two respiratory tract infections in 79 patients (5.1 %), and after the 5 day course, one wound infection and two respiratory tract infections in 81 patients (3.7%). Subsequently, in 171 patients undergoing coronary bypass grafting and given the 2 day course, the infection rate was 3.5%. There was no significant difference in infection rates among the three groups (p > 0.05). We conclude that no more than 2 days of antibiotic prophylaxis are necessaryfor patients undergoing coronary bypass grafting.
D. J. Hillis, M.B., B.S., F. L. Rosenfeldt, M.D., F.R.C.S.E., W. J. Spicer, F.R.A.C.P., F.R.C.P.A., and G. R. Stirling, F.R.A.C.S., F.A.C.S., Melbourne, Australia
Rients undergoing cardiac operations with cardiopulmonary bypass may be at greater risk from infection than patients undergoing other noncontaminated major surgical procedures.t' Factors that may predispose to infectionduring and after heart surgery include contamination of blood in the heart-lung machine, long operating times, and routine use in the postoperative period of intravascular cannulas, urinary catheters, and positivepressure ventilation. Infection of an implanted prosthetic heart valve is difficult to eradicate and is associated with a high mortality. Hence antibiotic -prophylaxis during cardiac valve replacement is virtually universal, although its value is unproven.' When the coronary bypass operation
From the Cardiovascular Surgical Research Unit of the Baker Medical Research Institute and the C. J. Officer Brown Cardiothoracic Surgery Unit and the Department of Bacteriology, Alfred Hospital, Melbourne, Australia. Dr. Hillis was the recipient of a National Heart Foundation Scholarship. Received for publication May 10, 1982. Accepted for publication Dec. 14, 1982. Address for reprints: Dr. F. Rosenfeldt, Baker Medical Research Institute, Commercial Road, Prahran, 3181, Victoria, Australia.
was introduced, a similar practice of antibiotic prophylaxis was adopted. However, there is little published evidence to support this. In one trial in which 1".... systemic prophylactic antibiotics were used during coronary bypass, a wound infection rate of less than 1% was observed.t' Conte and associates" reported that a single intraoperative dose of cephalothin was as effective in preventing infection as a 4 day course. However, most cardiac units continue to use a 5 or a 7 day course of prophylaxis. The aim of the present study was to compare a course of antibiotic therapy given only until the removal of central venous lines and drainage tubes (usually 2 days after operation) with a standard 5 day course. The study was carried out in two parts. In 1980, a prospective, randomized study was done to compare the two regimens. In 1981, in a nonrandomized study, all patients having coronary bypass were given the short course of prophylaxis and the infection rate was compared with that experienced previously. Methods Randomized study. One hundred eighty-two patients undergoing coronary bypass grafting without additional procedures from April to December, 1980, were ran217
The Journal of Thoracic and Cardiovascular Surgery
2 1 8 Hillis et al.
Table I. Diagnostic criteria for infection Infection Wound In hospital Out of hospital Respiratory tract
Urinary tract
Septicemia Oral candidiasis
Criteria Macroscopic pus Macroscopic pus and culture of specific pathogens Three of the following: I. Purulent sputum 2. Culture of specific pathogen 3. Fever: 37.8° C or above on two of more occasions beyond postop. day 6 4. Significant leukocytosis (> 12,000/mmJ ) Two of the following: 1. Greater than 100,000 organisms per milliliter 2. Dysuria and/or renal angle tenderness 3. Pyuria: more than 5 white blood cells per cubic millimeter Positive blood culture and fever Clinical diagnosis and/or positive culture (1980 only)
domized by hospital unit record number to receive one of two courses of antibiotics. The standardcourse was as follows: cephalothin 12 mg/kg intravenously and kanamycin 7 mg/kg intramuscularly given immediately preoperatively and into the bypass priming fluid intraoperatively. Postoperatively, the patient received the same dose of cephalothin intravenously 4 hourly and kanamycin intramuscularly 12 hourly until removal of central cannulas and drainage tubes (usually 48 hours after operation). Oral cephalexin 1 gm 6 hourly was then given to make a total of 5 days of prophylaxis. The short course comprised parenteral cephalothin and kanamycin given as in the standard course preoperatively, intraoperatively, and postoperatively until removal of central cannulas and drainage tubes. The patients in the short course group received no oral antibiotic therapy. Nonrandomized study. This study included 188 consecutive patients undergoing coronary bypass grafting from January to September, 1981. These patients were given only the short course of antibiotic prophylaxis used in the randomized study. Approval for the protocol was obtained from the Alfred Hospital Ethics Committee. Exclusions. Patients were excluded from the study for the following reasons: (1) The patient died of causes unrelated to sepsis in the postoperative period; (2) the patient did not receive the therapy to which he was randomized; (3) drug allergy necessitated a change of therapy. In the randomized study, 22 of the 182 patients were excluded from the main analysis because they did not receive the therapy allocated. In six of the 22 patients
this was due to drug allergy. In the other 16 patients, development of a low cardiac output state necessitated inotropic support via a central venous cannula beyond the third postoperative day. In these patients the previous practice of the unit was followed of continuing antibiotic prophylaxis to prevent infection from indwelling central venous cannulas. The infections in this group in low cardiac output were analyzed separately. In the nonrandomized group, 17 of the 188 patients required prolonged inotropic support via a central cannula and were given prophylaxis throughout this period. The infections in this group were also analyzed separately. Cultures. Preoperatively, nose and throat swabs and specimens of sputum and midstream urine were obtained. On the first postoperative day, sputum and catheter urine samples were collected. On the seventh postoperative day a midstream urine specimen and a throat swab were obtained. The antibiotic sensitivities of any pathogenic bacteria cultured were determined by the agar dilution method. In the nonrandomized study, the same bacteriologic tests were done, with the exception of the midstream urine specimen and throat swab on the seventh day. Routine patient care. Antibacterial preparation of all patients began soon after admission with the use of framycetin nasal spray and bathing with hexachlorophene soap. On the day before operation, the patient was shaved and then washed with hexachlorophene soap. On the morning of the operation, the skin was washed with hexachlorophene and chlorhexidine. In the operating room, the skin was prepared with alcoholic chlorhexidine and then by 1% alcoholic iodine. Sterile adhesive drapes were applied to the skin. An arterial cannula, central and peripheral venous cannulas, a urinary catheter, chest drainage tubes, and pacing wires were routinely inserted. Postoperatively all patients were mechanically ventilated, the majority being extubated within 4 hours. Wounds and drainage tube sites were washed daily with cetrimide (cetyltrimethylammonium bromide) and chlorhexidine. Merbromin (Mercurochrome) was applied to the incisions. Entry sites of arterial and venous cannulas and pacing wires were washed daily with povidone-iodine complex. If an infection developed, treatment was prescribed in accordance with the clinical signs and bacteriologic fmdings. Definitions of infection. The criteria used for the diagnosis of infection are shown in Table I. While in the hospital, the patients were reviewed daily for infection by medical staff. In the hospital, the diagnosis of wound infection was made if macroscopic pus was observed. The medical staff involved in follow-up after discharge
Volume 86 Number 2 August, 1983
Table
Antibiotic prophylaxis for bypass grafting
2 19
n. Comparison of the randomized groups Standard group No. of patients randomized Completed study Male Female Age (yr, mean and range) Cardiac operation" No. of vessels grafted Duration of cardiopulmonary bypass (min) Antibiotic coverage" Total doses of cephalothin Total doses of kanamycin Total doses of cephalexin
Short course group
93 81 61 20 54 (32-68)
89
3.0 ± 0.8 103 ± 29
2.9 ± 1.0 103 ± 34
11.7 ± 2.6 4.0 ± 0.5 12.5 ± 4.2
12.0 ± 3.0 4.1 ± 0.5
79 66 13 55 (33-68)
·Values given are mean ± standard deviation.
were requested to notify the study team of any late wound infections. The difficulty of verifying clinical data after the patient's discharge necessitated the use of more stringent criteria for the diagnosis of a late wound infection. Late wound infections were diagnosed only if macroscopic pus was seen and a pathogen cultured. After cardiac operations, left lower lobe collapse is common, and even in the absence of demonstrable infection, the patient is commonly febrile up to the sixth postoperative day. Consequently, the diagnosis of a respiratory tract infection was made only if at least three of the following four criteria were fulfilled: purulent sputum, culture of a specific pathogen, a fever beyond the sixth postoperative day, and significant leukocytosis (greater than 12,000 leukocytes per cubic millimeter). Data analysis. The chi square test and Fisher's exact test were used to detect significant differences in proportions. Results In the randomized study, the standard and short course groups were comparable with respect to age, sex distribution, and type of operation (Table 11). Postoperative infection developed in four of '79 patients (5.1%) in the short course group and in three of 81 patients (3.7%) in the standard course group. In the nonrandomized short course group, six of 171 patients (3.5%) had ihfections (Table III). There was no significant difference in the infection rates between any of the groups (p > 0.05). A detailed analysis of the infections is given in Table IV. There were no instances of endocarditis, mediastinitis, bacteremia, or urinary tract infection in any of these groups. Wound infection. In the randomized study, there was one superficial sternotomy wound infection, secondary to a hematoma, in the standard course group, and there
m.
Table Infection rates in the randomized and the nonrandomized groups Randomized (1980) Types of infection Wound: In hospital Sternotomy Wound: Out of hospital Sternotomy Leg wound Respiratory tract Total No. of patients with infections
Standard group (n=81)
Short course group (n= 79)
0
o
I
o
o 2 3 (3.7%)
2
Nonrandomized (1981) Short course group (n=171)
o 3
2
2
4 (5.1%)
6 (3.5%)
were two leg wound infections in the short course group. In the nonrandomized study there was one sternotomy wound infection following mechanical dehiscence. This cleared in 14 days after repair of the dehiscence and appropriate antibiotic therapy. Also in the nonrandomized study there were three leg wound infections, one of which developed in a groin wound after the use of the intra-aortic balloon pump. In all cases, antibiotic therapy was given and resolution was prompt without surgical intervention. The overall rate of wound infection in patients receiving the short course of prophylaxis was 2.4%. Respiratory tract infection. In the randomized study, two patients in the standard course group and two patients in the short course group had respiratory tract infections. One of these infections developed soon after discharge. The patient was readmitted and after a further 5 days of antibiotic therapy the infection resolved. The remaining infections were mild and resolved within 5 days. In the nonrandomized study
220
The Journal of Thoracic and Cardiovascular Surgery
Hillis et al.
Table IV. Infections Group
Standard, 1980
Short course, 1980
Short course, 1981
Type of infection
Sternotomy Respiratory Respiratory Leg incision Leg incision Respiratory Respiratory Sternotomy Leg incision Leg incision Leg incision Respiratory Respiratory
Duration (days)
Organism Staphylococcus albus
K1ebsieUa Escherichia coli Staphylococcus aureus Staphylococcus aureus Escherichia coli Not isolated Serratia marcescens Staphylococcus aureus Staphylococcus aureus
Proteus Streptococcus pneumoniae, Escherichia coli Streptococcus pneumoniae
there were two respiratory tract infections. In one patient, the respiratory tract infection began preoperatively and intensive antibiotic therapy was required after operation. Another patient with paralysis of the left hemidiaphragm had mild pneumonia of the left lower lobe. Oral Candida infection. There were six cases of oral candidiasis in the standard group compared with three in the short course group. Low cardiac output group. Thirty-three patients (I6 from the randomized study and 17 from the nonrandomized study) were withdrawn from the primary analysis because of the prolonged administration of antibiotics to prevent infection from central venous cannulas used for inotropic drug infusions. There were nine infections in this group. Three were wound infections, one at the site of insertion of an intra-aortic balloon pump and two in the abdominal wound following laparotomy for intra-abdominal complications. Two were respiratory tract infections, two urinary tract infections, and two cases of septicemia. With antibiotic therapy, all infections resolved within 2 weeks, except for one resulting from a multidrug-resistant Staphylococcus aureus. Despite intensive antibiotic treatment this patient died on the tenth postoperative day. The overall incidence of infection in this low cardiac output group was 27%, despite the prolonged course of antibiotic prophylaxis (average 6 days). Preoperative positive cultures. From the total of 331 patients studied, pathogens were isolated in 12 preoperative cultures: five from urine and seven from sputum. All organisms isolated were sensitive to one or both of the prophylactic antibiotics. In all cases the postoperative specimens were clear of the organism.
7 6 6 10 7 6 7 14 5 5 7 5 6
Antibiotic therapy
Cephalexin Nil Nil FlucloxaciUin Cephalexin Nil Cephalexin Cephalexin, co-trimoxazole, and gentamicin Cephalexin Cephalexin . Cephalexin Co-trimoxazole Nil·
Discussion In the trial, 81 patients were given the standard course of antibiotic prophylaxis and 250 patients were given the short course. There was a low infection rate associated with both courses of therapy, and no statistically significant difference was found between the two. The possibility exists that there was a small but definite difference in the infection rate associated with the two courses of therapy but that the number of patients in this trial was insufficient for this difference to reach statistical significance. Using the formula of Kramer and Greenhouse? for "type II error," we calculated that to exclude, with 80% confidence, an increase in wound infection rate from 1% to 2% would require 2,717 patients per group. Similarly, to exclude an increase in the overall infection rate (wound plus respiratory) from 5% to 10% would require 513 per group. The present trial obviously fell short of satisfying these requirements. To obtain such large numbers would require a trial lasting many years or a multicenter trial. To avoid bias owing to exclusion of patients after randomization,' the results were also analyzed with the 16 patients in low cardiac output retained in the groups to which they were originally randomized. The infection rates then were as follows: short course, six of88 (6.8%); standard course, five of 88 (5.7%), again with no significant difference (p> 0.05). The theoretical goal of antibiotic prophylaxis is to have appropriate antibacterial activity present at the site of and over the period of potential contamination in sufficient concentration to prevent bacterial implantation and subsequent infection." Cephalothin is a relatively safe and effective prophylactic antibiotic during operations.'? II Combination with an aminoglycoside
Volume 86
Antibiotic prophylaxis for bypass grafting 2 2 1
Number 2 August, 1983
counters the relative susceptibility of cephalothin to gram-negative beta lactamases." Adverse effects of antibiotics include a significant morbidity and mortality from allergic reactions" and the appearance of resistant microorganisms which may actually increase the incidence of infection.v": 15 The combination of cephalothin with an aminoglycoside and a diuretic, as is often used in cardiac operations, is particularly nephrotoxic." Oral and esophageal candidiasis is increasingly recognized as a complication of antibiotic prophylaxis following cardiac operations." In the present study, there were more cases of oral candidiasis in the standard course (six of 81) than in the short course (three of 79), though this difference was not statistically significant. These complications of antibiotic prophylaxis become more frequent when the time of administration is prolonged. With the need for cost containment in health care, the cost of antibiotics is assuming great importance. Antimicrobial drugs account for 20% to 35% of total pharmacy costs in many general hospitals," with prophylactic antibiotics responsible for 10% of this total." Shapiro and Associates" have pointed out that, in the United States, 80% of drugs used in antibiotic prophylaxis are administered for 48 hours or more after operation. If such prolonged prophylaxis is without value, it follows there is a large potential saving in the cost of antimicrobial agents. The present study did not attempt to determine whether or not any antibiotic prophylaxis should be given after coronary bypass grafting. It demonstrated, however, that if antibiotic prophylaxis is used, the infection rates for a 2 day course or a 5 day course are similarly low. The fmdings of this study agree with the increasing trend in surgery toward shorter prophylactic antibiotic regimens. We express our appreciation to Dr. B. Davis, Janet Ness, Margaret Sutcliffe, Sister Rigg, and other nursing staff for their help with the study and to Dr. G. Shardey and Professor 1. Ludbrook for reviewing the manuscript, REFERENCES Kluge RM, Calia FM, Mclaughlin JS, Hornick RB: Sources of contamination in open heart surgery. JAMA 230:1415-1418, 1974 2 Freeman R, Hjersing N: Bacterial culture of perfusion blood after open-heart surgery. Thorax 35:754-785, 1980 3 Hirschmann JV, Inui TS: Antimicrobial prophylaxis. A critique of recent trials. Rev Infect Dis 2:1-23, 1980 4 Sutherland RD, Martinez HE, Guynes WA, Miller L: Postoperative chest wound infections in patients requiring
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