Comparative Study of Cefamandole versus Ampicillin plus Cloxacillin: Prophylactic Antibiotics in Cardiac Surgery

Comparative Study of Cefamandole versus Ampicillin plus Cloxacillin: Prophylactic Antibiotics in Cardiac Surgery Adeeb T. M. Ghoneim, M.R.C. Path., Anand P. Tandon, M.R.C.P., and Marian I. Ionescu, M.D. ABSTRACT A randomized, prospective study of the efficacy of cefamandole naftate versus a combination of ampicillin and cloxacillin was undertaken in 109 adult patients operated on in Leeds during 1979. Sixty patients underwent valve replacement, and 49 had either aortocoronary bypass grafts or other forms of open-heart operation. The two groups matched well in age, sex, and type of operation. One gram of either antibiotic was given intravenously during the induction of anesthesia and every 6 hours thereafter for 48 hours. Two additional grams of antibiotic were placed in the prime of the heartlung machine. The overall rate of infection was 7.5% for the entire series, with 1.7% for the group given cefamandole and 13.7% for the group given ampicillin plus cloxacillin ( p < 0.05). The only patient with infection in the former group (1.7%) had sternal wound involvement. Major sternal wound infection occurred in 3 (5.9%) patients in the latter group. All wound infections were caused by Staphylococcus aureus. In 2 of these patients (ampicillin plus cloxacillin group) the infection proceeded to endocarditis. Urinary and respiratory tract infections occurred in 1.9% and 5.9'/0, respectively, of patients given ampicillin plus cloxacillin. The duration of hospital stay was shorter in the cefamandole group. The results of this study demonstrated that cefamandole confers effective prophylaxis in cardiac operations.

Following cardiac operation, sepsis and early endocarditis can be caused by organisms introduced into the bloodstream either during the operation or as a result of postoperative complications, i.e., infected intravascular catheter site,

wound infection, pneumonia, or urinary tract infection. Because of the high mortality associated with such complications, it is accepted, in general, that patients undergoing open-heart operation should receive prophylactic antibiotics throughout the operation and during the early postoperative period [l-51. However, the choice of antibiotic, route of administration, and length of prophylaxis have yet to be defined. Considering that staphylococci are the commonest cause of infection after cardiac operation, the use of antistaphylococcal antibiotics is now accepted for prophylaxis in those operations [l, 2, 61. At our institution, we used a combination of ampicillin and cloxacillin in addition to antifungal prophylaxis [7] to cover cardiac operations. This eliminated fungal infections and markedly reduced staphylococcal infections. However, a small number of serious infections caused by methicillin-resistant Staphylococcus epidermidis, and a few cases of methicillin-sensitive S. uureus and, to a lesser extent, gram-negative bacteria continued to occur. The objective of this study was to assess the efficacy of cefamandole, which is a new cephalosporin active against S. uureus, S. epidermidis, and many gram-negative bacteria, as a prophylactic agent during cardiac operation. In a randomized prospective study we compared the results of cefamandole with those of ampicillin plus cloxacillin.

Material and Methods The study included all patients who had cardiac From the Department of Microbiology, The University of operations performed by one of us (M. I. I.) at Leeds, and the Department of Cardiovascular Surgery, The the General Infirmary at Leeds from February, General Infirmary at Leeds, Leeds, England. 1979, to January, 1980. Patients who had a hisAccepted for publication Mar 23, 1981. tory of allergy to penicillin or cephalosporins Address reprint requests to Dr. Ghoneim, Department of and those who were operated on while they had Microbiology, The University of Leeds, Leeds, LS2 9JT, Enan active infection were not included in the gland.

152 0003-49751821020152-07$01.25 @ 1981 by The Society of Thoracic Surgeons

153 Ghoneim, Tandon, and Ionescu: Cefamandole vs AmpicilliniCloxacillin

study. All other patients were randomly assigned into one of the two regimens: cefamandole or ampicillin plus cloxacillin. Each patient gave a complete history and underwent physical examination. The preoperative laboratory tests included complete blood cell count, measurement of blood urea nitrogen, serum creatinine, serum transaminases, and bilirubin. The preoperative bacteriological screen included midstream urine and swabs from nose, axilla, and groin. All patients undergoing valve operation received antifungal prophylaxis in the form of nystatin tablets and amphotericin lozenges 3 days before and 3 days after operation. One gram of either cefamandole or ampicillin plus cloxacillin was given intravenously during the induction phase of anesthesia as a bolus injection and repeated every 6 hours postoperatively for 48 hours, with a 2 gm supplement injected into the heart-lung machine during cardiopulmonary bypass. All patients had indwelling venous, arterial, and urinary catheters, which were removed within 24 to 48 hours of the operation. The patients were examined clinically at least once daily for evidence of infection. Temperature was recorded hourly for the first 48 hours and twice hourly thereafter. Four types of infection were defined for this study. 1. Wound infection was characterized by purulent discharge with signs of inflammation plus bacterial growth. Localized, minor stitch abscesses were not included. 2. Urinary tract infection was considered present if a colony count of 2105 organisms per milliliter was obtained on two separate occasions from midstream or catheter specimen. 3. Respiratory tract infection was defined by the presence of purulent sputum, pyrexia, and radiological or clinical signs of pneumonia with or without the isolation of recognized pathogens from sputum cultures. 4. Bacteremia was defined as growth of organisms from one or more blood cultures in the presence of pyrexia or other signs of sepsis. Endocarditis was considered to occur in patients with persistent bacteremia showing clinical signs of valve involvement or if de-

tected during operation or postmortem examination. Postoperative laboratory tests included complete blood cell count, blood urea nitrogen, serum creatinine, serum transaminases, and bilirubin as well as urinalysis. The patients were followed-up for at least three months postoperatively for signs of infection, which were thoroughly investigated by the clinical microbiologist and the surgical team. Statistical analysis of the data was performed by the Student’s test. The p value of <0.05 was considered significant.

Results After the exclusion of patients who died at operation or during the immediate postoperative period (2 patients given cefamandole and 5 patients given ampicillin plus cloxacillin) and those who required prolonged stay in the intensive care unit for noninfective causes and were given different antibiotics (3 patients given cefamandole and 4, ampicillin plus cloxacillin), there remained 109 patients. Of these, 58 patients received cefamandole and 51, ampicillin plus cloxacillin. Sixty patients underwent valve replacement, and 49 had aortocoronary bypass grafts or other forms of nonvalvular open-heart operation. No significant differences were noted in sex, age, type of operation, duration of operation, duration of stay in the intensive care unit, and number of days during which these patients had an endotracheal tube, or intravascular or indwelling urinary catheters (Table 1). More patients in the cefamandole group (12 patients) had nasal colonization by S. aweus than those in the group given ampicillin plus cloxacillin (6 patients). However, the difference was not statistically significant. The overall infection rate was 7.5% for the entire series, with 1.7% (1out of 58 patients) in the cefamandole group and 13.7% (7 out of 51 patients) in the ampicillin plus cloxacillin group (p < 0.05). The only patient with infection in the cefamandole group had sternal wound involvement, which occurred on postoperative day 32. Major sternal wound infection occurred in 3 patients (5.9%) in the group given ampicil-

154 The Annals of Thoracic Surgery Vol 33 No 2 February 1982

Table 1 . Comparison of the Two Groups of Patients Variable

Cefamandole

AmpicillinlCloxacillin

No. of patients enrolled in study No. of patients completing study Mean age (yr) SD Sex (maleifemale) Type of cardiac operation Aortic valve replacement Mitral valve replacement Double- or triple-valve replacement Aortocoronary bypass graft Atrial septa1 defect Closure of perivalvular leak Other Mean duration of operation (hr) Mean duration of stay in ICU (d)

63 58 48.6 k 11 32/26

60 51 48.6 k 12 28123

10 14 8 15 7 1 3 5.4 1.52

7 9 12 17 2 2 2 5.6 1.42

*

SD = standard deviation; ICU

=

intensive care unit.

Table 2. Summary of the Clinical Findings in 4 Patients with Sternal Wound lnfection with and without Endocarditis AmpicillidCloxacillin (N

=

3)

Variable

Cefamandole (N = 1)

Patient 1

Patient 2

Patient 3

Age (yr), sex Operation

65, M MVR +AVR

57, M MVR

59, F MVR

Stay in ICU (d) Tracheostomy Diagnosed (postop d) Preceding discharge (d)" Endocarditis Organism Treatment Antibiotics and surgery" Antibiotics and valve replacement

1 0 32 10

2 0 17

2 0 10

28, M Repair perivalvular leak 2 0 13

0

0

0

No S. aureus

Yes S. a w e u s

Yes S . aweus

No S. aweus

+ -

+ +

+

+

Hospital stay (d) Outcome

71 Cured

82 Cured

37 Died

87 Cured

-

-

aNumber of days of discharge without infection noticed before the wound became infected. "Local debridement without sternal opening.

MVR = mitral valve replacement; AVR

=

aortic valve replacement; ICU = intensive care unit.

lin plus cloxacillin. The infections were noted Urinary and respiratory tract infections ocon postoperative days 10,13, and 17. All wound curred in 1.96% and 5.9% of patients, respectively, in the ampicillin plus cloxacillin group. infections were caused by S. aweus. In 2 patients with sternal wound infection The causative organisms were Escherichia coli, from the ampicillin plus cloxacillin group, sep- Hemophilus influenzae, Proteus mirabilis, and sis and endocarditis occurred; 1of them died. A Streptococcus pneumoniae. A summary of the summary of the clinical findings in patients clinical findings in these patients is presented with wound infection with or without endocar- in Table 3. Patients with sepsis and endocarditis from the ampicillin plus cloxacillin group ditis is presented in Table 2.

155 Ghoneim, Tandon, and Ionescu: Cefamandole vs AmpicillinlCloxacillin

Table 3 . Sumrnary of the Clinical Findings in 4 Patients with Other lnfections" Respiratory Tract Infection (N = 3) Variable

Patient 1

Patient 2

Patient 3

Age (yr), sex Operation ICU stay (d) Tracheostomy Diagnosed (postop d )

58, M AVR 2 0 9 H . influerizae, S . pneumoniae

38, M MVR + AVR

57, F MVR

Organisms

Urinary Tract Infection (N= 1)

1

L

0 8

0 10

5. prieumoniae

Proteus mirabilis

35, F ASD 1 0 3 E . coli

+ AVR

Treatment Antibiotics only Antibiotics and

+

+

+

-

-

+

-

Hospital stay (d) Outcome

31 Cured

24 Cured

23 Cured

10 Cured

-

operation

"All patients with other infections were administered ampicillin and cloxacillin. AVR = aortic valve replacement; MVR = mitral valve replacement; ASD = atrial septa1 defect; ICU = intensive care unit,

had a longer hospital stay (54.3 f 22.6 days) than the average length for their whole group (22.6 f 9.6 days) and than the cefamandole group (19.6 f 7.7 days) ( p < 0.001). A comparison of the total number of hospital days, mean duration of hospital stay, and number of days with pyrexia (>37.5"C axillary temperature), respectively, between both groups is as follows: cefamandole, 1,135 days and ampicillin plus cloxacillin, 1,132 days; cefamandole, 19.6 f 7.7 days (k standard deviation) and ampicillin plus cloxacillin, 22.6 k 9.6 days; and cefamandole, 39 days (3.4% of total) and ampicillin plus cloxacillin, 108 (9.5%). Because of the lower infection rate, the mean duration of hospital stay for the cefamandole group was shorter than that of the other group. However, the difference was just outside the limit of statistical significance. The relation of axillary temperature with the clinical findings in patients of both groups is presented in Tables 4 and 5. There were neither adverse reactions to the antibiotic regimens nor any obvious evidence of renal impairment associated with cefamandole usage. A comparison of blood urea nitrogen and serum creatinine levels is presented in Figures 1 and 2 , which show no difference between patients in the two groups.

Comment A proper evaluation of the efficacy of different prophylactic antibiotic regimens in cardiac operations is complicated by the seriousness of the infections that can follow such operations and that make it unacceptable to include a control group of patients on a placebo only. Most published studies assess a single antibiotic in comparison with data collected retrospectively from the same institution or gathered from the literature [l, 2,8]. Only in a few series were two antibiotics compared [3,4, 9,101. However, because of the low incidence of endocarditis and because only a small number of patients usually was included, many investigators were unable to show significant differences between various regimens. In addition the efficacy of prophylaxis may depend on the type of operation. In closed heart operations where the risk of infection is low, there is no evidence that prophylaxis is of great value. On the other hand, antibiotic prophylaxis has been considered essential in open-heart operations because many studies have shown a reduced incidence of endocarditis [5]. In nonvalvular open-heart operations such as aortocoronary bypass grafting and repairs of congenital defects, where the risk of endocarditis is minimal, comparative studies evaluating the efficacy of different reg-

156 The Annals of Thoracic Surgery Vol33 No 2 February 1982

Table 4. Correlation of Axillary Temperature and Clinical Findings in 51 Patients Who Received Ampicillin plus Cloxacillin Temperature

No. of Patients

No pyrexia (<37.0°C)

39

Intermittent, nonpersistent pyrexia (2-3 spikes 37.5"C)

6

Significant pyrexia (>37.5"C for >4 days)

6

Clinical Outcomea Uncomplicated recovery (30) Viral infection, Cytomegalovirus (2) Postcardiotomy syndrome (1) Inflamed but noninfected wound (5) Urinary tract infection (1) Uncomplicated recovery (1) Inflamed but noninfected wound (1) Respiratory tract infection (2) Cytomegalovirus infection (1) Postcardiotomy syndrome (1) Sternal wound infection and endocarditis (2) Sternal wound infection (1) Respiratory tract infection (1) Phlebitis (1) Postcardiotomy syndrome (1)

"Number of patients in parentheses.

Table 5. Correlation of Axillary Temperature and Clinical Findings in 58 Patients Who Received Cefamandole Naftate Temperature

No. of Patients

No pyrexia (<37.0°C)

54

Intermittent, nonpersistent pyrexia (2-3 spikes > 37.5"C) Significant pyrexia (>37.5"C > 4 days)

Clinical Outcomea

3

Uncomplicated recovery (50) Inflamed but noninfected wound (3) Myocardial infarction (1) Inflamed but noninfected wound (3)

1

Sternal wound infection (1)

"Number of patients in parentheses. 160

13 I21

T

I30

mmollL

8

7 6

I

I

1

2nd 3rd Pre-op

I

71h

I

14th

Post-op

Fig 1. Comparison of serum creatinine levels i n the t w o groups of patients. Fifty-eight patients received cefamandole naftate and 51, ampicillin plus cloxacillin. Data are shown as mean k standard error of the mean. (Broken line = cefamandole group; solid line = ampicillin plus cloxacillin group.)

I

I I 2nd 3rd

1 7th

1 14th

Pro-op Post-op

Fig 2. Comparison of blood urea levels in the t w o groups of patients. Fifty-eight patients received cefarnandole naftate and 52, ampicillin plus cloxacillin. Data are shown as mean 3z standard error of the ineaii. (Broken line = cefamandole group; solid line = ampicillin plus cloxacillin group.)

157 Ghoneim, Tandon, and Ionescu: Cefamandole vs AmpicillinlCloxacillin

imens are difficult to analyze. However, in a operation. On the other hand, in 1979, Fong study by Fong and colleagues [4], a short course and co-workers [4] found cephalothin and of prophylactic antistaphylococcal penicillin or methicillin to be equally effective in preventing cephalosporins was found to reduce wound and infections after aortocoronary bypass operarespiratory tract infections in patients under- tions. During the past five years, a combination of going aortocoronary bypass. The authors concluded that prophylaxis is justified in those op- ampicillin and cloxacillin has been used as the erations. This agrees with the common practice standard prophylaxis for open-heart operation of many cardiac surgeons who use prophylactic at our institution. Ampicillin was added to antibiotics in all forms of open-heart operation. cloxacillin to improve the action of the latter In a number of early reports, the routine use of against the streptococci, especially fecal strepprophylactic antibiotics in open-heart opera- tococci, and also to improve the efficacy against tions was associated with an increased inci- respiratory pathogens, e.g., S. pneumoniae and dence of infection and with the emergence of H . influenzae. We used 500 mg of each antibiotic resistant organisms [ll-141. Presumably this every 6 hours because larger doses of amwas caused by the prolonged use of prophylaxis picillin produced massive changes in the upper for many days before or after operation, or respiratory tract flora and were associated with during both times. In 1977, Goldman and co- colonization and infections due to resistant workers [2] compared the efficacy of short-term gram-negative bacteria. The combination of and long-term antibiotic prophylaxis in open- ampicillin and cloxacillin was thought to be heart operations. The results of the study less nephrotoxic than cephalothin and other showed that short-term prophylaxis (48 hours) cephalosporins available at that time. with cephalothin was as effective as, if not However, the new cephalosporins are rebetter than, those obtained with long-term ported to be less nephrotoxic than cephalothin, prophylaxis . and they have a wider spectrum of activity In the tissue exposed to the risk of infection, a against H. influenzae and nonenterococcal strepsuccessful prophylactic antibiotic should reach tococci, including S. pneumoniae [17]. These concentrations that are greater than the mini- new cephalosporins were thought to be a better mal inhibitory concentrations against the com- alternative to cephalothin [15, 161. Archer and monest cause of infection and should remain at associates [15] in 1978 compared atrial and Valthose levels for the duration of the operation. It vular tissue levels of cephalothin and cefamanis essential that the antibiotics be administered dole after a dose of 20 mg per kilogram of body shortly before the operative procedure. To en- weight was given intramuscularly during the hance the antibiotic levels during lengthy oper- induction phase of anesthesia prior to cardiac ation, especially when antibiotics with a short operation. The tissue levels of cefamandole half-life are used, an additional intraoperative were higher than those of cephalothin. The dose may be required [15, 161. The antibiotics high levels of cefamandole were not related to used for prophylaxis are usually semisynthetic serum levels or protein binding and were penicillins or cephalosporins. Cephalothin has thought to be due to a high penetration rate. been used frequently because of its superior The results of our investigation have shown effect on S. epideumidis, which is an important that intermittent bolus injections of cefamancause of early onset prosthetic valve endo- dole naftate over 48 hours intraoperatively and carditis, and because of its activity against postoperatively were effective in preventing gram-negative bacteria when compared with surgical infections associated with open-heart methicillin. However, comparative studies of operation. Cefamandole was found superior to the efficacy of cephalosporins and penicillin ampicillin plus cloxacillin, when used in the in this type of operation are few. In 1977, indicated doses, in preventing blood, wound, Myerowitz and associates [31 showed ceph- urinary, and respiratory infections following alothin to be superior to methicillin in pre- cardiac operation. The duration of hospitalizaventing postoperative infections after cardiac tion was shorter in the cefamandole group. The

158 The Annals of Thoracic Surgery Vol33 No 2 February 1982

problem of superinfection w i t h resistant or6. Johnson WD Jr: Prosthetic valve endocarditis. In Kaye D (ed): Infective Endocarditis. Baltimore, ganisms did not arise, presumably because of London, University Park Press, 1976, pp 129-142 the short duration of prophylaxis. The infecting 7. Evans EGV: The incidence of pathogenic yeasts organisms in both groups were mostly sensitive among open heart surgery patients: the value of to the antibiotics used. The use of antifungal prophylaxis. J Thorac Cardiovasc Surg 70:466, prophylaxis might have been responsible for 1975 the absence of fungal infections in our series. A 8. Austin TW, Coles JC, McKechnie P, et al: Cephalothin prophylaxis and valve replacement. recent report on the occurrence of Candida albiAnn Thorac Surg 23:333, 1977 cans esophagitis after open-heart operation [18] 9. Carrizosa J, Kobasa WD, Kaye D: Effectiveness of shows a potential danger of fungi even after a nafcillin, methicillin and cephalothin in experishort-term prophylaxis in patients who were mental Staphylococcus uureus endocarditis. Annot immunosuppressed. timicrob Agents Chemother 15:735, 1979 Although the n u m b e r of infections i n o u r se- 10. Galland RB, Shama DM, Prenger KB, Darrell JH: Preoperative antibiotics in the prevention of ries was small, the seriousness of the infections chest infection following cardiac operations. Br J associated with the use of ampicillin plus Surg 67:97, 1980 cloxacillin led us to a b a n d o n its use for surgi- 11. Firor WB: Infection following open heart surgery cal prophylaxis. During the last six months, with special reference to the role of prophylactic antibiotics. J Thorac Cardiovasc Surg 53:371, cefamandole w a s the standard prophylactic 1967 agent, and among the last 50 patients operated 12. Sallam IA, Mackey WA, Bain WH: Prophylactic on recently, there were no instances of sepsis antibiotics in intensive therapy: experience in a or endocarditis. cardiac surgical unit. Br J Surg 57:722, 1970 13. Sallam IA, Sammon A, McGeachie J, Bain WH: Prophylactic antibiotics in closed heart surgery. Chest 60:252, 1971 References 1. Bain WH, McGeachie J, Underwood J: The use of 14. Sallam IA: Prophylactic antibiotics in open heart surgery. Surg Digest 8:7, 1973 cephalothin sodium (Keflin) as the prophylactic antibiotic for open heart surgery. J Antimicrob 15. Archer GL, Polk RE, Duma RJ, Laver R: Comparison of cephalothin and cefamandole proChemother 3:339, 1977 phylaxis during insertion of prosthetic heart 2. Goldman DA, Hopkins CC, Karchmer AW, et al: valve. Antimicrob Agents Chemother 13:924, Cephalothin prophylaxis in cardiac valve sur1978 gery: a prospective, double-blind comparison of two day and six day regimens. J Thorac Car- 16. Quintiliani R, Klemek J, Nightingale CH: Penetration of cephapirin and cephalothin into the diovasc Surg 73:470, 1977 right atrial appendage and pericardial fluid of 3. Myerowitz PD, Caswell K, Lindsay WG, Nicoloff patients undergoing open heart surgery. J Infect DM: Antibiotic prophylaxis for open heart surDis 139:348, 1979 gery. J Thorac Cardiovasc Surg 73:625, 1977 4. Fong IW, Baker CB, McKee DC: The value of 17. Barry AL, Schoenknect FD, Shadomy S, et al: In-vitro activities of cefamandole and cephaprophylactic antibiotics in aorta-coronary bypass lothin against 1,881 clinical isolates. Am J Clin operations. J Thorac Cardiovasc Surg 78:908, Pathol 725358, 1979 1979 5. Veterans Administration Ad Hoc Interdiscipli- 18. Gundry SR, Borkon AM, McIntosh CL, Morrow AG: Candida esophagitis following cardiac opernary Advisory Committee on Antimicrobial ation and short-term antibiotic prophylaxis. J Drug Usage: Prophylaxis in surgery. JAMA Thorac Cardiovasc Surg 80:661, 1980 237:1003, 1977