Brifirh Journalof Urology (1980). 52, 311-315 0 1980 British Association of Urological Surgeons

0007-133 1 /80/028003 1 1Un.00

4 8 -Hour Ce p h r ad i n e and Post - p rost a tecto my Bacteriuria

MELANIE WILLIAMS, D. J. HOLE, R. W. G. MURDOCH, A. C. OGDEN and T. B. HARGREAVE Departments of Urology, Bacteriology and lmmunolog y, Western Infirmary, Glasgo w; West of Scotland Cancer Surveillance Unit, Glasgo w

Summary-In a randomised, controlled trial of intramuscular cephradine given in a dose of 1 g 6-hourly for 48 h, there was a significant reduction in the incidence of significant bacteriuria after transurethral resection. In contrast, the incidence of significant bacteriuria after open prostatectomy was unchanged. Post-operative complications were reduced in patients who received cephradine. The use of short-term cephradine would appear to be justified.

It is known that up to 24% of patients may have bacteriuria before prostatectomy and this per- centage is greater in catheterised patients (Jack- aman and Chisholm, 1975). Infected urine may lead to serious and sometimes fatal complications such as secondary haemorrhage, pyelonephritis and septicaemia (Miller et al., 1958). The inci- dence of infection has been reduced by the use of a closed system drainage (Gillespie et al., 1967) and also by the use of frusemide (Essenhigh et al., 1970) and prophylactic antibiotics (Hills et al., 1976). In our unit at the Western Infirmary, Glasgow, we found that either co-trimoxazole or cephradine was the most useful antibiotic as judged by analysis of all urine sensitivities from the unit over a 6-month period. It was decided to evaluate a 48:h course of intramuscular cephra- dine by means of a prospective controlled trial in all men undergoing prostatic surgery. We chose cephradine because of the ease of administration parenterally compared with cotrimoxazole.

Patients and Methods All patients undergoing open or transurethral prostatectomy were included in this study. Patients known to have significant pre-operative infection and patients on antibiotics were excluded. In many cases, however, a patient had infection at the time of operation but this was not known until afterwards. Such patients are included in the analysis because it is important to know the

Received 9 October 1978. Accepted for publication 3 October 1979.

effect of an antibiotic regime in these cases. Patients allergic to penicillin or cephalosporins were excluded. Patients with a serum creatinine greater than 140 mmol/l were also excluded.

Randomisation was stratified to give equal numbers of patients in 4 groups: (1) patients with pre-operative catheter drainage undergoing open prostatectomy (OP); (2) patients without a catheter undergoing open prostatectomy; (3) patients with a pre-operative catheter undergoing transurethral resection (TUR); (4) patients without a pre- operative catheter undergoing transurethral resec- tion.

Cephradine 1 g was given intravenously with the induction of anaesthesia and then intramus- cularly every 6 h for 48 h to a total of 8 g. Al- though the technique of operation was standard- ised, the operations were performed by different surgeons. Two 20 mg injections of frusemide were given in the first 24 h to promote diuresis. Ure- thral catheters were allowed to drain into a closed collecting system. Irrigation was undertaken only when required and sterile water used. No local antibacterial agents were used. The catheters were removed as soon as signs of fresh bleeding ceased.

Data on the patients' clinical progress were recorded daily. Urine samples were examined daily from the day of admission until discharge or 9 days post-operatively. Either a midstream speci- men or, in the presence of a catheter, a specimen aspirated from the catheter tubing, was examined. All of the samples were collected at 7 a.m. and refrigerated at 4" centrigrade within minutes of collection. They were all cultured within 3 hours of collection and examined by the same indepen-

311

312

Prostatectomies 248

BRITISH JOURNAL OF UROLOGY

group 2 group ++ 3 group 4 group 4% I

no with no pre-op. pre-op.

with pre-op. pre-op. catheter catheter catheter catheter , 3,3 , , 6,7 ,

cephradine control cephradine controlcephradine control cephradine control , 2; ,

10 14 15 18 32

, 1124 , 35 58 66

Fig. Distribution of patients by operation and presence of pre-operative catheter drainage.

dent examiner. Significant bacteriuria (SB) was defined as 105 or more organisms per ml of urine. Pyuria was not included in the criteria for diag- nosis of infection because of the inevitable pre- sence of white cells in the urine following surgery.

Open prostatectomy wounds were examined by the same independent examiner on post-operative days 5 and 8. The wounds were classified into 4 grades on the basis of clinical assessment and the results of cultures: (1) severe wound infection: purulent discharge, culture positive for potential pathogens; (2) mild wound infection: erythema, scanty pus, cultures positive; (3) colonised wound: not clinically infected, cultures positive; (4) healed wound: cultures negative (Griffiths et al., 1976).

Results Two hundred and forty-eight patients entered the trial (Fig.). The median age of the patients was 69 years (range 46 to 93 years). A similar age dis- tribution was attained in all groups, indicating that there was satisfactory randomisation. No patient who received cephradine developed a hypersensitivity reaction. At the time of operation all of the patients in the trial were thought by the

urologist to have sterile urine. However, over- night cultures of the pre-operative sample often showed the patient to have had significant bac- teriuria at the time of the operation (Table 1) and this was more often the case in the presence of a pre-operative catheter (x * = 17.4; P<O.OOl).

Two distinct groups of patients were considered: Group A patients, who had pre-operative sterile urine and in whom the use of cephradine was prophylactic, and Group B patients, who had pre- operative significant bacteriuria (Table 3).

There was no significant reduction in post- operative significant bacteriuria in patients who underwent open prostatectomy and who received cephradine. In patients who underwent trans- urethral resection the overall incidence of post- operative significant bacteriuria was significantly reduced in patients receiving cephradine (Table 2). There was a reduction even in the presence of pre-operative significant bacteriuria in whom the use of cephradine must be considered therapeutic although not guided by sensitivity studies (Table 3).

A measure of the strength of the effect of an antibiotic in reducing the incidence of post- operative significant bacteriuria is given by the

Table 1 Incidence of Pre-operative Significant Bacteriuria in Relation to Pre-operative Catheter Drainage

Number of patients Number (%) with pre- Number with pre-operative operative significant sterile urine bacteriuria

Open prostatectomy and transurethral resection

With pre-operative catheter 91 40 (44) 51 Without pre-operative catheter 157 29 (18) 128

Total 248 69 (28) 179 (Group B) (Group A)

48-HOUR CEPHRADINE AND POST-PROSTATECTOMY BACTERIURIA 313

Table 2 Incidence of Post-operative Significant Bacteriuria According to Type of Prostatectomy

Number of patients Number (Yo) developing Number with post-operative post-operative significant sterile urine bacteriuria

Open prostatectomy Cephradine 25 Control 32

;; } P = 0.8

Transurethral resection 71 } P = <0.001 Cephradine 90 19 (21)

Control 101 49 (49) 52

relative risk. For Group A patients the risk of developing post-operative significant bacteriuria when no antibiotic is given is 5.7 times greater than when cephradine is given. For Group B patients this figure is 2.8. This would indicate that the antibiotic is more effective in preventing sig- nificant bacteriuria in the group receiving it pro- phylactically.

The genera of organisms appeared to be the same whether open prostatectomy or transurethral resection had been performed, and whether or not cephradine had been administered (Table 4). Further details of the organisms and their anti- biotic sensitivities will be published elsewhere (Williams, in preparation).

The overall incidence of complications is shown in Table 5 . No patient receiving cephradine deve- loped either bacteriaemic shock or orchitis.

In patients with no post-operative significant bacteriuria, the incidence of other post-operative complications was reduced from 13 to 5% by

the administration of cephradine (P = 0.06), as shown in Table 6. In addition, patients developing post-operative significant bacteriuria, despite cephradine administration, still had a reduced incidence of other immediate post-operative com- plications (P = 0.04).

“Incontinence” was defined as incontinence lasting more than 24 h after removal of the catheter and in most cases this resolved after a few days. Seven patients died, 5 in the control group and 2 in the cephradine group. The deaths were due to myocardial infarction (4), cerebrovascular acci- dent (2) and one unrelated malignancy.

Serum creatinine and urea were measured pre- operatively and on the fifth post-operative day. There was no evidence in this trial that cephradine added to impaired renal function. Cephradine made no difference to the duration of hospital stay except in open prostatectomy patients with pre-operative catheter drainage. These patients had the highest incidence of post-operative wound

Table 3 (Pre-operative Significant Bacteriuria) Patients According to the Type of Prostatectomy

Incidence of Post-operative Significant Bacteriuria in Group A (Pre-operative Sterile Urine) and Group B

Number with post-operative

sterile urine

Number of patients Number (%) developing post-operative significant bacteriuria

Open prostatectomy Group A

12} P = 0 . 6 15

Cephradine I S 6 (33) Control 26 11 (42)

Group B Cephradine I 5 (71) i} P = 0.9 Control 6 4 (67)

Transurethral resection Group A Cephradine 59 7 (12) 52 ) P = <0.001 Control 76 33 (43) 43

Groun B Ce&iine 31 12 (39) Control 25 16 (64)

314 BRITISH JOURNAL OF UROLOGY

Table 4 Genera of Organisms Isolated from Patients with Post-prostatectomy SB According to Type of Opera- tion

~

Open prostatectomy Transurethral resection

Total Cephradine Control Total Cephradine Control

No. f%) No. f%) No. No. No. No.

Genus Enterococci 10 30 6 4 25 28 5 20 Esch. coli 5 15 3 2 21 24 8 13 Proteus species 5 15 2 3 I5 17 5 10 Coagulase-negative Staphylococci 5 15 2 3 8 9 0 8 Klebsiella-Enterobacter species 4 12 2 2 1 1 12 3 8 Staph. aureus 3 0 3 2 0 2 Others 1 1 0 7 3 4

Number of isolates 33 89 Number of mixed infections 7 15 Number of patients with

post-operative SB 26 68

Table 5 Immediate Post-operative Complications

Control Ceohradine

After OP and TUR Significant bacteriuria Bacteriaemic shock Orchitis Re-catheterisation Incontinent Re-operation

Wound infection After open prostatectomy

(grades I and 11)

(N = 133) 64 2 3 8 6 2

(N = 32)

6

~~ ~

(N = 115) 30 0 0 1 1 1

(N = 25)

3

infection and consequently administration of cephradine shortened their post-operative in- patient stay.

Discussion In this study the normal admission and handling of patients was not altered to suit a trial protocol. This is important as it means that the results are applicable to a general urology unit. Randomisa-

tion was stratified to allow for the higher pre- operative infection rate accompanying pre- operative catheterisation. When evaluating the results, distinction was made between the patients with sterile urine pre-operatively and those with an unknown infection. Previous trials have either excluded infected cases (Hills et al., 1976) or failed to distinguish between the 2 groups (Genster and Madsen, 1970).

The risk of infection begins at the moment the catheter is inserted into the bladder and ends at a much less well defined time after the catheter is removed (O’Grady, 1972). We decided to ad- minister cephradine for 48 h beginning at the time of operation. This is prophylaxis in Group A patients and a short course of therapy in Group B pafients. Charlton et al. (1970) have shown that an antibiotic effective against the organism res- ponsible for urinary infection sterilised the urine in 48 h and that, in general practice, a short course of antibiotics was as successful as a 10-day course (Charlton et al., 1976). Previous trials of antimicrobial prophylaxis in prostatectomy patients have used longer periods of cover; for

Table 6 Incidence of Post-operative Complications According to the Presence of Post-ouerative SB

Patients with post-operative SB

No. No. f 9%) with at least one No. No. (Yo) with at least one other immediate post- immediate post-operative operative complication complication

Patients without post-operative SB

Cephradine 30 2 (7) 85 4 ( 5 )

Control 64 13 (20) 69 9 (13)

48-HOUR CEPHRADINE AND POST-PROSTATECTOMY BACTERIURIA 315

example, Hills et al. (1976) used a 10-day course of co-trimoxazole, Gonzalez et al. (1976) a 10-day course of cephalothin and Lacy et al. (1971) a 3-24 day course of cephaloridine.

Strachan et al. (1977) found that cephazolin given as a single pre-operative dose reduced the incidence of post-operative wound sepsis in patients undergoing routine cholecystectomy. We found that the number of wound infections was reduced in patients receiving cephradine.

There were no serious side effects from cephra- dine. We found no cases of allergic rash. Cepha- loridine has been shown to cause nephrotoxicity and this is enhanced by frusemide (Lawson et al., 1970). We found no case of deteriorating renal function in patients given cephradine despite the concurrent use of frusemide. This was true even when pre-operative creatinine was elevated.

Large numbers are needed in order to produce statistically significant differences in morbidity and mortality, but the results of this trial indicate that a short-term course of antibiotics-in this case cephradine-does reduce the incidence of immediate post-prostatectomy complications.

Acknowledgements We are most grateful to Mr A. G. Graham, Mr K. F. Kyle and Mr R. F. Deane for allowing us to study patients under their care and for their help and encouragement during this study. We are further indebted to Dr J. D. Sleigh, Department of Bacteriology and Immunology, for his helpful comments.

References Charlton, C. A. C., Crowther, A., Davies, J. G., Dynes, J.,

Haward, M. W. A., Mann, P. G. and Rye, S. (1976). Three-day and ten-day chemotherapy for urinary tract infection in general practice. British Medical Journal, 1,

Charlton, C. A. C., O’Grady, F., MacSherry, A. L. and Sutcliffe, M. (1970). Use of cephalexin for the initial treat- ment of patients with persistent or recurrent urinary tract infection. Postgraduate Medical Journal Supplement, 46,

Essenhigh, D. M., Clayton, C. B. and Taha, M. A. (1970). The use of Lasix (frusemide) in the prevention of urinary infection following prostatectomy. British Journal of

124-1 26.

30-32.

Urology, 42, 450-456.

Genster, H. G. and Madsen, P. 0. (1970). Urinary tract infec- tions following transurethral prostatectomy: with special reference to the use of antimicrobials. Journal of Urology,

Gillespie, W. A., Lennon, G . G. , Linton, K. B. and Phippen, A. (1967). Prevention of urinary infection by means of closed drainage into a sterile plastic bag. British Medical Journal, 3 , 90-92.

Gonzalez, R., Wright, R. and Blackard, C. E. (1976). Pro- phylactic antibodies in transurethral prostatectomy. Journal

Griffiths, D. A., Shorey, B. A., Simpson, R. A., Speller, D. C. E. and Williams, N. B. (1976). Single-dose pre- operative antibiotic prophylaxis in gastro-intestinal surgery. Lancet, 2, 325-328.

Hills, N. H., Bultitude, M. I. and Eykyn, S. (1976). Co- trimoxazole in prevention of bacteriuria after prostatec- tomy. British Medical Journal, 2 , 498-499.

Jackaman, F. R. and Chisholm, G. D. (1975). Urinary infec- tion and prostatectomy. British Journal of Urology, 41, 545-548.

Lacy, S., Drach, G . W. and Cox, G. E. (1971). Incidence of infection after prostatectomy and efficacy of cephaloridine prophylaxis. Journal of Urology, 105, 836-839.

Lawson, D. H., MscAdsm, R. F., Slngh, H., Gavras, H. and Linton, A. L. (1970). The nephrotoxicity of, cephaloridine. Postgraduate Medical Journal Supplement, 46, 36-38.

Miller, A., Gillespie, W. A., Linton, K. B., Slade, N. and Mitchell, J. P. (1958). Post-operative infection in urology. Lancet, 2, 608-612.

O’Grady, F. (1972). Chemoprophylaxis in medicine and sur- gery, Journal of the Royal College of Physicians of London,

Strachan, C. J., Black, J., Powis, S. J. A., Watemorth, T. A., Wise, R., Wilkinson, A. R., Burdon, D. W., Severn, M., Mitra, B. and Norcott, H. (1977). Prophylactic use of cephazolin against wound sepsis after cholecystectomy. British Medical Journal. 1. 1254-1256.

104, 163-168.

Of Urology, 116, 203-205.

6, 203-215.

The Authors Melanie Williams, MB, BS. Formerly Registrar, Department

of Bacteriology and Immunology, Western Infirmary. Now Senior Registrar, Department of Bacteriology, Royal Infirmary, Glasgow.

D. J. Hole, MSc, Statistician, West of Scotland Cancer Sur- veillance Unit.

R. W. G. Murdoch, MB, BS, FRCS, Surgical Registrar, Western Infirmary.

A. C. Ogden, MB, ChB, FRCS, Surgical Registrar, Western Infirmary.

T. B. Hargreave, FRCSE. Formerly Senior Urological Regis- trar, Western Infirmary. Now Senior Lecturer, Department of Surgery/Urology, Western General Hospital, Edinburgh.

Requests for reprints to: Melanie Williams, Department of Bacteriology, Glasgow Royal Infirmary, 86 Castle Street, Glasgow G4 OSF.