Br. J. Surg. Vol. 66 (1979) 188-190

Randomized controlled trial of cefuroxime for established postoperative respiratory infection J. C. L I T C H F I E L D . M. R. B. K E I G H L E Y . I. W. M Y A T T A N D M. C. E D W A R D S * SUMMARY

A randomized controlled trial has investigated the

value of cejbroxime (a new antibiotic resistant to plactamase) in 80 patients with established postoperative respiratory injection. Although the majority of respiratory isolates were sensitive to cefuroxime, there was no significant advantage in the antibiotic group compared with the controls with respect to duration of' fever, rudiological abnormality or infected sputum. We conclude that antibiotics m e rarely necessary .for the majority of patients who develop postoperative respirutory injections.

POSTOPERATIVE respiratory sepsis and atelectasis are frequent complications of upper abdominal operations, particularly in the elderly, heavy smokers and patients with chronic bronchitis (Cahill, 1968;Weightman, 1968; Munro, 1970). It has been suggested that antibiotics might be useful in preventing these complications, but they only occur in a minority of patients. Little is known of the value of deferring antibiotic therapy until respiratory complications have become established (British Medical Journal, 1977). Haemophilus influenza and Streptococcus pneumoniae are the pathogens most frequently isolated from the respiratory tract after operation and they are usually sensitive to the broad spectrum penicillins and the cephalosporins (Cavanagh et al., 1976; O'Callaghan et al., 1976). The aim of this study has been to investigate whether antibiotics are of any value for the management of established postoperative respiratory infection. On account of the emergence of bacteria that destroy antibiotics by the production of p-lactamase (Howard et al., 1978), the antibiotic chosen for this trial was cefuroxime, which is resistant to destruction by p-Iactamases (Gomnie, 1977). Patients and methods Eighty consecutive patients who developed postoperative respiratory sepsis were studied. T wo of the following three criteria were necessary for admission into the trial: fever greater than 38°C. purulent sputum or evidence of a new radiographic abnormality compared with the preoperative chest radiograph. All patients received twice-daily chest physiotherapy (breathing exercises, frappage, postural drainage), but nebulizers, ventilators or oropharyngeal suction were not used. In addition to the physiotherapy regimen, 41 patients received cefuroxime while the remaining 39 were given no antibiotic (controls). The allocation of patients to cefuroxime o r 110 antibiotic was based upon random numbers. Cefuroxime was given by intramuscular injection in a dose of 750 mg three times a day. Response to therapy was evaluated by duration of fever, persistence of infected sputum and duration of radiographic abnormality. Sputum samples were cultured on the third and fifth day. Chest radiographs were repeated on the third and fifth day and were reported by a single radiologist who was unaware whether o r not the patiznt was receiving cefuroxime. Assessment of respiratory function by vitalograph was abandoned because results were not reproducible after recent major surgery. A subjective assessment of response to therapy was also recorded by one of the physiotherapists who did not

know into which group the patient had been allocated. Sputum was collected iri sterile .jars during physiotherapy. The mucus was digested by adding an equal volume of trypurepancreatin mixture and cultured a t 37 "C on blood agar. MacConkey's agar and chocolate agar under aerobic conditions only. Organisms were identified by Gram-stain, appearance of colonies and biochemical reactions. Samples of sputum were stored a t 4 "C for batch antibiotic assay using the plate diffusion method. Patients were excluded if any therapeutic antibiotic had been given before entry into the trial or if prophylactic antimicrobials had been used before or during operation.

Results The treatment and control groups were similar with respect to criteria for entry into the trial-age, sex, cigarette consumption, nature of operation and previous history of respiratory disease (Table I ) . Despite strict clinical criteria for diagnosis of respiratory infection and evidence of radiographic abnormality in 72 patients (90 per cent), only 47 patients (59 per cent) had respiratory pathogens identified on sputum culture. The predominant organisms in both groups were Haemophibs influenzae and Streptococcus pneumoniae (Table II). Table I: COMPARISON OF GROUPS Cefuroxime ( n = 41)

N o antibiotic ( n = 39)

Fever more than 38 "C Purulent sputum Radiographic signs

39 (95%) 41 (100%) 37 (90%)

37 (95%) 37 (92%) 35 (907;)

Mean age (yr) Male More than 20 cigarettes per day Previous chronic respiratory disease Operation Gastric Biliary Colorectal Others

26 3 6 5

22 8 4 3

Table 11: MICRO-ORGANISMS ISOLATED FROM SPU TU M Cefuroxinie No antibiotic

26 24 2 2 5

2 3 7

Hueniophilus influenzae Streptococcus pneumoniae Klehsiellu aerogenes Klebsiellr pneirnionicre Escherichiu coli Proteirs spp. Pseir~ionionnsaeruginom Sruphylococws nureus

16 10

__

I0 14 2

1 1

4

2 3 4

1

1 -

3

-

The numbers of patients with persisting pyrexia after 3 and 5 days were similar in both groups. Radiographic changes were still present at the end of therapy ( 5 days) in 38 per cent of the treated group -

* The General Hospital, Birmingham.

Cefuroxime for postoperative respiratory infection Table 111: RESULTS OF THE TRIAL Cefuroxime No. X Persisting fever 3d 5d Persisting radiographic signs 3d 5d Persisting infective sputum 3d 5d Subjective assessment of response Excellent Fair Poor

No. antibiotics No.

%

37 9

90 22

35 13

90 33

21 15

67 38

26 19

67 48

20 9

50 23

31 13

80 33

26 8

63 19 17

22 9 8

56 23 20

1

compared with 48 per cent of the controls. The sputum remained infected 5 days after starting treatment in 23 per cent of the antibiotic group compared with 33 per cent of the controls. A subjective assessment of response t o therapy indicated that the clinical response was similar in both groups (Table ZU). The results were also analysed in the 13 patients with severe pre-existing respiratory sepsis. Persistent fever was recorded at the end of treatment in 2 of the 7 patients receiving cefuroxime compared with 1 of the 6 controls. Persistent infected sputum a t 5 days was also recorded in 2 of the 7 treated patients compared with 2 of the 6 controls. Additional antibiotic therapy was used in 8 patients because of failure to respond to the trial regimen; 3 were patients receiving cefuroxime, the remaining 5 patients were in the control group. Three patients in the trial died; in 2 death was due to advanced malignancy but 1 patient not receiving antibiotics developed overwhelming respiratory failure requiring ventilation and died despite subsequent antibiotic therapy. All of the respiratory isolates with the exception of Pseudornonas aeruginosa and one strain of P. mirabilis were sensitive t o 30 mg discs of cefuroxime. The concentration of cefuroxime in the s m t u m in patients receiving therapy ranged from 0 tb 4.7 pg/mi (mean 0.74 p.g/ml). Discussion This trial has indicated that most patients who develop respiratory complications after abdominal operations respond satisfactorily to physiotherapy alone. The addition of cefuroxime, an antibiotic shown to be effective against almost all respiratory pathogens, rarely gave any additional benefit to patients. However, the general trend of these results suggests that the patients receiving cefuroxime fared slightly better than the controls, even though statistical analysis failed to demonstrate any significant advantage in the antibiotic group. Analysis of the results, even amongst patients with severe pre-existing respiratory infection, in whom prophylactic antibiotics would normally be advised (Dudley et al., 1962), showed that patients receiving antibiotics did not appear t o show any improvement over those treated with physiotherapy alone. With the exception of P . aeruginosa and Proteus spp., all other respiratory isolates were sensitive to cefuroxime. Even after 5 days’ treatment, however, 5 patients still had sensitive bacteria isolated from the

189

sputum. Cefuroxime levels in sputum rarely exceeded the minimal inhibitory concentration for most respiratory pathogens, which is in accordance with the results of other studies (Pines et al., 1977). These results suggest, therefore, that systemic therapy may not always be appropriate in patients with postoperative respiratory sepsis. Although there were no drug-induced complications with cefuroxime, a course of injections lasting 5 days was frequently reported by patients to be painful. F o r this reason we would not recommend antibiotics routinely for established postoperative respiratory sepsis since improvement can be expected with physiotherapy alone in most patients. I t could be argued that with greater numbers a significant difference between the groups might have been achieved. An earlier analysis of the results suggested that cefuroxime might prove to be effective therapy, but at that stage the groups were poorly matched for age and type of operation (Keighley and Litchfield, 1978). It was felt that a total of 80 patients would probably demonstrate an important difference if one was present. The analysis of the present data does not support the earlier findings a n d indicates that antibiotics have little place in the management of postoperative chest infection. There is also very little evidence that preoperative prophylactic antibiotics reduce the incidence of postoperative respiratory sepsis (Laszlo et al., 1973; Presley and Alexander-Williams, 1974). Furthermore, this study and others indicate that respiratory complications are frequently transient and respond to physiotherapy (Collins et al., 1968) and that many patients with postoperative respiratory complications have atelectasis without bacterial infection in the sputum. Because of the dangers of unnecessary antibiotic therapy (Garrod, 1972), we would not recommend routine prophylaxis for all patients and would advise that antibiotic prophylaxis be reserved for patients with pre-existing respiratory sepsis or cardiorespiratory failure. References BRITISH MEDICAL J O U R N A L (1977)

Postoperative chest infections. 2, 1500-1501. C A H I L L J. M. (1968) Respiratory problems in surgery patients. Anz. J . Surg. 116, 362-368. CAVANACH P., KATTAN s. and SYKES R. B. (1976) Antibiotic sensitivity to haemophilus influenza. In : W I L L I A M S J. D. and GEDDES A. M. (ed.) Chemotherapy, vol. 3. New York, Plenum Press, pp. 247-249. COLLINS c. D., D A R K E c. s. and KNOWELDEN F. (1968) Chest complications after upper abdominal surgery, their anticipation and prevention. Br. Med. J. 1, 401-406. D U D L E Y H. A. F., BAKER w. w. and ANDERSON W. A. (1962) The place of bronchoscopy and tracheostomy in general surgical patients. J. R . Cull. SurR. Erlinb. 7, 121-127. C A R R O D L. P. (1972) Causes of failure in antibiotic treatment. Br. Metl. J. 4, 473-416. C O M M E L. (1977) Cefuroxime treatment of patients with lower respiratory and urinary tract infections. Pror. R . Soc. Mecl. 70, SUPPI. 9, pp. 82-85. HOWARD A. J., HINCE c. J. and W I L L I A M S J. D. (1918) Antibiotic resistance in Streptococcus pnerimoniae and Haernophilus influenzae: report of a study group on bacterial resistance. B r . Med. J. 1, 1657-1659. KEICHLEY M. R. B. and LITCHFIELD J. c. (1978) A controlled trial of cefuroxime in the management of established postoperative respiratory infections. The early evaluation of cefuroxime. Greenford, Middlesex, Glaxo Research Ltd, pp. 153-158.

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J. C. Litchfield et al.

DARRELL 1. H. et a]. (1973) The diagnosis and prophybdxis of pulmonary complications of surgical operation. Br. J . Surg. 60, 129-134. MIJNRO u. D. (1970) Practical guides to prophylaxis and treatment of lung complications. Surgery 66, 727-728. O’CALLAGHAN c. H., SYKES R . B., G R ~ F F I T H S A. et al. (1976) Cefuroxime-a new cephalosporin antibiotic: activity in oitro. Antiniicrob. Chemother. 9, 51 1-5 19. PINES A., RAAFAT H., TAYLOR-PEARCE M . et al. (1977) Cefuroxime in lower respiratory infections-a preliminary communication. The early evaluation of cefuroxime. Greenford, Middlesex, Glaxo Research Ltd, pp. 95-101.

LASZLO G., ARCHER G. G.,

and ALEXANDER-WILLIAMS J . (1974) Postoperative chest infection. Br. J . Surg. 61, 448-452. WEIGHTMAN J. A . K . (1968) A prospective survey of the incidence of postoperative pulmonary complications. Br. J . Surg. 55, 86-91. PRESLEY A. P .

Paper accepted 1 1 September 1978.

Some of the important international conferences and meetings of 1979-80 April American College of Surgeons 2 - 5 April 1979: Denver

Association for Thoracic Surgery 30 April-2 May 1979: Boston May International College of Surgeons 13- I9 May 1979: Paris

American U rological Association 14- 17 May 1979: New York International Confederation for Plastic and Reconstructive Surgery 20~-25May 1979: Sac Paulo

June American Society of Colon and Rectal Surgeons 10-14 June 1979: Atlanta 18th Congress of the International Urology Society 24~.29June 1979: Paris

September American Association for Surgery of Trauma 27-29 September 1979: Chicago October Congress of Neurologica! Surgeons 8-12 October 1979: Las Vegas

American College of Gastroenterology 21-27 October 1979: Atlanta American College of Surgeons 22-26 October 1979: Chicago American Cancer Society 5-9 November 1979: New York February 8th International Thyroid Congress 7-9 February 1980: Melbourne

June World Congress of Paediatric Cardiology 2-6 June 1980: London

July 6th European Congress of Neurosurgery 16-20 July 1979: Paris

European Congress on Gastroenterology 8-22 June 1980: Hamburg

Congress of British Association of Paediatric Surgery 18-21 July 1979: Marseille

14th World Congress for Rehabilitation 22-27 June 1980: Winnipeg