Antibiotic Treatment of Biliary Sepsis

Symposium on Surgical Infections and Antibiotics

Antibiotic Treatment of Biliary Sepsis

M. R. B. Keighley, MB., B.8.,F.R.C.S.,*' R. B. Drysdale, M.A., Ph.D., t A. H. Quoraishi, MB., ChB.,! D. W. Burdon, M.B., B.S., M.R.C.Path.,** and J. Alexander-Williams, M.B., Ch.M., F.R.C.S.tt

Large numbers of pathogenic bacteria can be isolated from the bile in 20 to 50 per cent of patients requiring surgery on the biliary tract.4. 14. 34 The number of patients with bacteria in the bile is much greater if emergency operation is required for suspected perforation of the gall bladder or unresolving cholangitis and in patients who are jaundiced.3. 15. 16.24.26. 46. 50 It has been suggested that there might be an association between the presence and type of bacteria in the bile and the development of wound sepsis.34 A multicenter study in Britain reported that wound sepsis after cholecystectomy (20.6 per cent) was similar to the incidence of wound infection in patients requiring emergency surgery for peritonitis.39 Davidson and othersl l undertook a multi variant analysis of prospective data from 1000 patients to investigate the factors responsible for the genesis of wound sepsis after gastrointestinal surgery. By far the most important factor was the presence of intestinal organisms in the incision during wound closure. It could be argued that patients with infected bile are particularly liable to develop wound sepsis, due to contamination of the incision at the time of operation. Patients with biliary sepsis may develop clinical septicemia before or after operation. Transient bacteremia is an essential component of the triad of symptoms described by Charcot7 in patients with acute obstructive cholangitis. There are some who become extremely ill with increasing jaundice, rigors and gram-negative bacteremia,13· 37. 41 This condition is a surgical emergency and improvement is unlikely to occur until free biliary drainage is established.8 • 22 Bacteremia is probably due "Lecturer, Department of Surgery, University of Birmingham, Birmingham, England tSenior Lecturer in Microbiology, University of Birmingham, Birmingham, England !Senior Registrar, Department of Microbiology, General Hospital, Birmingham, England "Consultant in Microbiology, General Hospital, Birmingham, England ttConsultant Surgeon, General Hospital. Birmingham, England

Surgical Clinics of North America- Vol. 55, No.6, December 1975

1379

1380

M. R. B.

KEIGHLEY ET AL.

to a pressure gradient from the intrahepatic biliary radicles to the liver sinusoids.21 Particles of size comparable to gram-negative bacteria are capable of entering the bloodstream by this route. 23 This syndrome also may be a complication of diagnostic x-ray procedures when contrast medium is injected directly into the biliary system. Bacteremia has been recorded after transhepatic cholangiography.6, 12, 16, 27 Septicemia has been reported after operative and postoperative T-tube cholangiography and has usually occurred when contrast medium has failed to enter the duodenum because of edema, spasm or calculus obstruction of the duct. 37, 42, 44 The principal danger of this complication is the development of endotoxemia which carries a high mortality.36,48 This article is concerned with the value of antibiotic therapy for the control of established biliary sepsis and the prevention of postoperative complications among patients in whom the bile is infected at the time of operation.

BILIARY INFECTION Incidence The number of patients with bacteria in the bile at the time of operation was recorded by the authors in 181 consecutive biliary operations. None received preoperative antibiotics. Microorganisms were isolated in 57 patients (31.5 per cent). Where emergency operation was performed for suspected perforation of the gall bladder or in unresolving cholangitis, 16 out of 17 cases had evidence of biliary sepsis (Table 1). In comparison, the incidence of infected bile among patients un-

Table 1.

Incidence of Bacteria in the Bile at Operation (181 Patients)

Overall Incidence EMERGENCY OPERATION Suspected perforation Unresolving cholangitis ELECTIVE OPERATION Jaundiced Biliary calculi Malignant obstruction Nonjaundiced Acalculous cholecystitis Stones confined to the gall bladder Choldocholithiasis Malignant periampullary lesions Choledochal cyst

BACTERIA IN

TOTAL

THE BILE

NUMBER

57 16 10 6

181 17 10 7

41 14 10 4

PERCENTAGE

31.5 94 100 86

164 25 14 11

27

25 56 72 36

139

0

13

18 5

114 8

2 2

2 2

20

16 62.5

1381

ANTIBIOTIC TREATMENT OF BILIARY SEPSIS

dergoing elective operation was only 25 per cent. This is a highly significant difference (p <0.001). Patients requiring elective operation were subdivided according to whether or not they were jaundiced at operation. The incidence of biliary sepsis in these cases was 56 per cent and 20 per cent respectively (p <0.001). The number of positi ve bile cultures in the jaundiced patients was 72 per cent when this was due to calculi, as compared with 36 per cent among patients with malignant obstructive jaundice. Further analysis was undertaken among patients undergoing elective operation only. There was a significantly increased incidence of biliary sepsis in patients who admitted to having had rigors within one month of operation (p <0.001), and those who gave a history of being jaundiced in the past (p <0.001). With each decade there was an increasing incidence of biliary sepsis. The bile contained pathogenic organisms in over half the patients over 70 years (54 per cent), compared with only 20 per cent of those who were younger (p <0.01). When the cystic duct was obstructed, the number of patients with infected gall bladder bile was only slightly increased from 24 per cent to 31 per cent. This was largely because organisms were isolated in only 10 per cent of patients with a mucocele of the gall bladder. Nevertheless there was a significantly increased incidence of biliary sepsis when stones were found in the common bile duct at operation compared with patients who had a stone free duct (71 per cent and 16 per cent respectively p <0.001). Organisms Responsible for Biliary Sepsis The microorganisms isolated from the bile in 231 patients undergoing biliary operations are shown on Table 2. Escherichia coli were identified in 65 patients (31 per cent), and were the commonest biliary

Table 2.

Bacteria in the Bile (231 Patients)

Escherichia coli Klebsiella aero genes/ Aerobacter spp. Streptococcus faecalis Proteus spp. Enterobacter cloacae Streptococcus viridens Pseudomonas aeruginosa Serratia spp. Aeromonas spp. Lactobacillus spp. Staphylococcus aureus Staphylococcus albus Paracolon spp. Others Anaerobic streptococci Clostridium welchii Bacteroides spp. Total Figures in parentheses refer to mixed cultures. i

II

65 20 22 13

8 3 3 2

2 3

(36) (12) (15) (12) (6) (1) (2) (0) (0) (0) (1) (2) (1)

2

7 11 2 166

(3) (11) (2) (104)

1382

M. R. B.

KEIGHLEY ET AL.

pathogen. The other frequently encountered aerobes were Klebsiella aero genes and Streptococcus faecalis. These three organisms accounted for 75 per cent of the aerobic microflora. Even though bile was innoculated immediately into cooked meat broth or plated out and incubated under anaerobic conditions within 1 hour of collection, anaerobic bacteria were isolated in only 13 per cent of the cultures (anaerobic streptococci and Clostridium welchii) and Bacteroides spp. were found in only one patient, throughout the entire study. Fresh bile samples were collected and colony counts were carried out from the gall bladder, common bile duct and T-tube. In 91 per cent of samples counts were greater than 105 organisms per ml. Relationship Between Infected Bile and Postoperative Sepsis Wound sepsis was defined as the presence of pus which spontaneously discharged or required drainage and was recorded by an independent observer. Stitch abscess was not included. In the prospective study of 181 patients undergoing biliary surgery, wound infections occurred in 36 cases (20 per cent). The incidence of wound sepsis in patients in whom the bile was sterile or infected at operation was 13 per cent and 35 per cent respectively (p <0.001). In the latter, 14 of 21 wound infections were caused by an organism which had been previously cultured from the bile. Bacteremia was assessed by blood cultures taken on three separate occasions following surgery and in any patient with clinical septicemia or an unexplained pyrexia. In a group of 436 consecutive patients, none of whom were receiving prophylactic chemotherapy, positive blood cultures were identified in 45. Of these, 18 were asymptomatic and 27 had clinical evidence of septicemia. In the latter, endotoxemia occurred in 9, and despite vigorous resuscitative measures was fatal in 5 cases. Of the 45 patients with positive blood cultures, all had evidence of microorganisms in the bile (either during or after operation) and in 42 of them the organisms were identical at both sites. Bacteria in the Bile during T-tube Drainage Recent observations have demonstrated a high incidence of organisms in the bile during T-tube drainage. 25 ,30 In this survey, 50 patients had the bile duct drained by a T-tube after choledochotomy. Bile cultures obtained 5 days after operation demonstrated the presence of organisms in 40 (80 per cent). In these individuals there was a very high incidence of wound infection and clinical septicemia (33 per cent and 15 per cent respectively). There was also a close correlation between the presence and type of bacteria in the T-tube and the incidence of these particular complications. It must be concluded therefore that organisms in the bile are responsible for the majority of infections in the wound and in the bloodstream after biliary surgery.

ANTIBIOTIC TREATMENT OF BILIARY SEPSIS

1383

ANTIBIOTIC TREATMENT General Considerations It has previously been suggested that the choice of an antibiotic in patients with biliary sepsis will depend upon two important considerations. The first is the sensitivity of biliary organisms to various agents and the second is the concentration of these antibiotics in the bile. Mason34 found that most of the organisms belonging to the genera of Escherichia, Klebsiella and Clostridia (which accounted for 34 of the 42 bacteria in the bile) were extremely sensitive to chloramphenicol and tetracycline. Because Streptococcus faecalis is often resistant to the antibiotics mentioned so far, infections caused by this organism should probably be treated with ampicillin or one of the sulfonamides.3! Maddocks and others32 reviewed the results of bile cultures from 100 jaundiced patients requiring surgery for strictures or common bile duct calculi. The antibiotics to which these organisms were most frequently sensitive were gentamicin, colistimethate, chloramphenicol, and kanamycin in that order. Less than 50 per cent of these organisms are sensitive to ampicillin or tetracycline.26 It has been assumed that high bile concentrations of an antibiotic are desirable in patients with biliary sepsis.! Biliary antibiotic levels in man have been determined in three ways: collections of duodenal juice, assay from T-tube drainage and preoperative collections of bile. Duodenal samples have been used to study the excretion of penicillin, novobiocin and tetracycline in bile.9 • !O, 40 This method of collection is unsatisfactory because of the presence of gastrointestinal secretions and the periodic emission of concentrated bile.5! Collections of T-tube bile have been used for the majority of studies. Using a plate assay method, the following antibiotics have been shown to attain biliary concentrations which greatly exceed their peak serum level: penicillin,53 tetracycline,48 rifamycin,!7 novobiocin,33 and erythromycin. 20 There are however, certain serious objections to the use of Ttube drainage for bile collection. Hepatic function may be impaired by recent anesthesia and the measurement of any antibiotic which is reexcreted through the liver is liable. to be erroneous because the enterohepatic circulation is disturbed. The most serious objection however is that free biliary drainage has already been established. It is impossible therefore to obtain any indication of the concentration of an antibiotic in a patient with biliary tract obstruction. As far as therapy for cholecystitis or cholangitis is concerned, free drainage is the exception rather than the rule. A number of antibiotics have now been assayed in bile during operations among patients with biliary disease. Sulfathiazole, although achieving satisfactory biliary concentrations in the nonobstructed biliary system, could not be detected in the gall bladder when the cystic duct was obstructed.52 SiInilar findings were reported with respect to bile levels of penicillin53 and chlortetracycline.54 Mortimore and others35 measured ampicillin levels one hour after intramuscular injection in 23

....

~

00

,j:I.

Table 3.

Sensitivity of Individual Organisms in the Bile

CONCENTRATION OF ANTIBIOTIC

Gentamicin Ampicillin Cephaloridine Chloramphenicol Tetracycline Rifamide

KLEB-

STREPTO-

ENTERO-

ANAEROBIC STREP. 6

IN THE DISC

ESCHERI-

SIELLA 17

COCCUS 24

BACTER 14

PROTEUS

PSEUDOMONAS 6

"ANAER-

CLOSTRIDIUM 9

(/-tG'/ML.)

CHIA COLI 65

AEROGENES

FAECALIS

SP.

SP.9

AEROGINOSA

OBES"15

WELCHII

10 10 10 25 10 25

65 100% 23 36% 59 90% 57 88% 37 57% 8 12%

17 100% 2 10% 17 100% 13 75% 13 75% 0

1356% 2293% 1773% 2293% 1458% 1253%

14 100% 1 10% 8 55% 13 93% 12 86% 8 54%

6 100% 1 17%

3 13

24% 87%

4

11

74%

9 9 9 9

100% 100% 100% 100% 11% 2 22%

66%

~ ;:0 t:d

~

~

l'j

>< l'j

>-3

:.!:"

ANTIBIOTIC TREATMENT OF BILIARY SEPSIS

1385

cases. In patients with nonobstructive cholelithiasis, mean concentrations in the gall bladder and common bile duct were 13.1 and 22.3 ILg/ml. respectively. When the cystic duct was obstructed the mean gall bladder concentration was only 1.45 ILg./ml. In jaundiced patients, levels were too low to be satisfactorily measured. Khan and Scotf9 assayed rifamycin levels in jaundiced and nonjaundiced patients, and although extremely high bile levels were found in patients with a normal bilirubin, levels were too low to be of therapeutic value when the bile duct was completely obstructed. These studies show that whatever the potential biliary excretion of an antibiotic, the concentration of all agents studied so far has been well below the desired therapeutic level when the biliary tract was obstructed. Despite these theoretical objections Scioli45 reported a satisfactory response in all 21 patients with cholangitis or acute cholecystitis who were treated with intravenous ampicillin even though eight were jaundiced. Similar findings were observed in patients with cholangitis treated with cephaloridine. 13 The therapeutic value of rifamide has been established also, both in the treatment of acute cholecystitis and as a means of controlling wound sepsis after biliary surgery.5.47 Sensitivity of Biliary Organisms to Various Antibiotics Antibiotic sensitivity patterns have already been reported from this unit in 150 patients.These have indicated that gentamicin was more likely to be effective against organisms isolated in the bile than any other antibiotic currently available.28 Further data have been obtained from 310 patients to determine the sensitivity of individual biliary isolates to 6 specific antibiotics (Table 3). The results indicate that gentamicin is effective against all biliary organisms apart from certain fecal streptococci and the majority of the anaerobes. However both of these groups of resistant bacteria were extremely sensitive to ampicillin. Influence of Prophylactic Chemotherapy on Postoperative Sepsis A randomized controlled trial was designed to determine the value of parenteral prophylactic gentamicin in 100 patients requiring biliary surgery. The dose used was 80 mg. given by intramuscular injection at 6 a.m. on the morning of operation and repeated in the anesthetic room immediately prior to the induction of anesthesia. The same dose was continued at 8 hour intervals for 5 days after operation. Bile and serum were collected during operation for antibiotic assay. Three patients were withdrawn from the trial, leaving 49 in the treated group and 48 controls. Eighty five per cent of biliary microorganisms were inhibited by 2 ILg./ml. of gentamicin. Twice this concentration was found in the gall bladder and common bile duct bile at the time of operation in only 9 per cent and 2 per cent respectively. However, serum concentrations exceeded 4 ILg./ml. in 86 per cent of patients. Although gentamicin reduced the incidence of bacteria in the bile from 39 per cent to only 24 per cent, this is not a significant difference. Nevertheless there was a

1386

M. R. B.

KEIGHLEY ET AL.

significant reduction in number of patients who developed wound sepsis, from 10 to 3 (p <0.05). Bacteremia occurred in only one patient receiving gentamicin compared with five controls. The results were also analysed depending on the presence or absence of biliary sepsis at operation. The only significant difference was in the incidence of wound sepsis which fell from 39 per cent to 12 per cent (p <0.05) in patients with evidence of biliary sepsis at the time of surgery. Because gentamicin prophylaxis is entirely dependent upon high serum concentrations, it could be argued that results might be improved by an agent which is entirely excreted in the bile. To examine this hypothesis, rifamide, a synthetic derivative of rifamycin B, was chosen. This antibiotic is excreted almost entirely in bile, and serum concentrations even in patients with liver disease or obstructive jaundice are too low to be of therapeutic value.29 To compare rifamide with an antibiotic which achieves satisfactory serum levels but is inadequately excreted in bile a trial was conducted in 150 patients who were randomly allocated to receive rifamide, gentamicin or no antibiotic. To provide an equal number of jaundiced patients in each group, cases were separately randomized depending on whether or not they were clinically jaundiced at operation. In each group of 50 patients, 11 were jaundiced and 37 were not. The concentration of rifamide required to inhibit 85 per cent of biliary organisms was 30 JLg./ml. In the nonobstructed biliary tract biliary rifamide concentrations ranged from 300 to 10,000 JLg./ml. In jaundiced patients levels ranged from only 1. 7 to 60 JLg./ml. and gall bladder bile concentrations in patients with cystic duct occlusion were even lower (1.4 to 4.5 JLg./ml.). In the presence of biliary occlusion, levels of rifamide in bile exceeded 60 JLg./ml. (2 x minimum inhibitory concentration for 85 per cent of biliary organism) in only one patient. The number of patients with positive bile cultures in the rifamide, gentamicin and control groups was 10, 12 and 19 respectively. The only significant difference in the incidence of biliary sepsis between the treated and the controls was among the nonjaundiced patients receiving rifamide (p <0.05). Although wound sepsis was reduced in both of the treated groups, in neither case (because of the small numbers) was the difference significant. Bacteria were isolated from postoperative blood cultures in seven of the control subjects, five of whom had clinical evidence of septicemia. In patients receiving rifamide, four had positive blood cultures in association with rigors or an intermittent fever. It is interesting that the incidence of bacteremia in jaundiced patients (in whom rifamide was inadequately excreted in bile) was the same in both groups. In contrast only one patient receiving gentamicin developed bacteremia (p <0.05). The combined results of both trials have confirmed that gentamicin will reduce both wound sepsis and bacteremia after biliary surgery. We have also shown that an antibiotic which achieves satisfactory serum levels is of more value than one having potentially high biliary concentrations. This is largely because therapeutic bile levels cannot be

ANTIBIOTIC TREATMENT OF BILIARY SEPSIS

1387

achieved in the presence of biliary obstruction. These results have also shown that prophylaxis is justified only in patients in whom the bile is infected at the time of operation.

PRACTICAL MANAGEMENT OF PATIENTS WITH BILIARY SEPSIS The management of patients with biliary sepsis falls into two categories. First, there is the use of prophylactic chemotherapy for patients requiring biliary operations and second, the choice of an antibiotic in patients with acute cholecystitis or unresolving cholangitis. These aspects of therapy will be considered separately. It is clearly desirable in both of these circumstances to identify the presence and type of infecting organism either before or at the time of operation, and certainly before the results of operative bile cultures eventually become available.

Detection of Biliary Microorganism It is possible to identify the presence of biliary microorganisms from duodenal fluid provided that the size of the bacterial population is known. Although duodenal juice frequently contains its own flora, these organisms are usually present in concentrations which are less than 10.3 In a series of 41 collections of duodenal fluid obtained within six hours of operation, the bile was infected in 12. In 10 of these patients, duodenal juice contained organisms with viable counts which were in excess of 10.5 In the remainder with sterile bile (29 cases), although organisms were identified in the duodenum in 15, counts were less than 105 in all except two cases. Because the results of operative bile samples may not be available for up to 72 hours after operation, the value of Gram stain films of bile was evaluated in 50 patients. The findings were subsequently compared with the results of the bile cultures. Gram stained films of bile demonstrated organisms in 18 patients and their presence was subsequently confirmed by culture in 17. Apart from a single false positive result, there were only two further errors due to inaccuracies in the morphology of the organisms seen during Gram staining.

Prophylaxis It is clearly undesirable to prescribe an antibiotic like gentamicin to every patient undergoing operations on the biliary tract. Altemeier and others2 have condemned the use of unnecessary prophylaxis. Apart from the risk of tOxicity, hypersensitivity and the selective encouragement of resistant bacteria, there is always a danger of superinfection.19 Furthermore gentamicin is not always the antibiotic of choice, particularly if anaerobic organisms or fecal streptococci are found in the bile. The antibiotic studies reported here have shown that prophylactic chemotherapy is justified only in patients in whom the bile is infected at the time of operation. It is our current practice to withhold preoperative

1388

M. R. B.

KEIGHLEY ET AL.

prophylactic antibiotics unless the patient requires an emergency operation. As soon as the abdomen is opened, bile is aspirated from the gall bladder and sent to the laboratory for Gram stain and culture. The result of the Gram stain is telephoned to the operating theatre before the abdomen is closed. If gram-positive organisms are identified, 500 mg. of ampicillin is given, initially by bolus intravenous injection and continued at 6 hour intervals for 5 days. If gram-negative bacteria are seen, a stat dose of gentamicin is administered (160 mg.), thereafter 80 mg. is given at 8 hour intervals for a similar period. If both gram-negative and gram-positive organisms are reported, both antibiotics are given. In patients on T-tube drainage, chemotherapy is continued until the tube is removed. This regimen is modified only if resistant organisms are subsequently isolated from the bile cultures. So far 60 patients have been treated using this method of prophylaxis; wound infections have occurred in only three patients, and none have developed bacteremia. Management of Cholangitis Patients with unresolving cholangitis certainly require antibiotic therapy, and if improvement has not occurred over a period of 48 hours surgical decompression is to be recommended, particularly in the elderly. It is our practice to obtain blood cultures and a single collection of duodenal fluid before antibiotic therapy is started. Provided there is no contraindication, because of penicillin hypersensitivity or severe renal impairment, high doses of ampicillin and gentamicin are given by the intravenous route. Serum gentamicin assays are repeated on alternate days. If operation is indicated, the antibiotic treatment is continued and modified only if operative bile cultures indicate the presence of a resistant organism.

CONCLUSIONS Biliary sepsis is almost always associated with some degree of obstruction in the biliary tract. Hitherto the choice of a suitable antibiotic has been based on its excretion in bile rather than the susceptibility of biliary microorganisms to adequate serum concentrations. The most serious sequelae of biliary sepsis is septicemia, which if associated with endotoxemia may be fatal. It has been shown that whatever the potential biliary excretion of an antibiotic, whenever there is obstruction, therapeutic levels cannot be achieved in the bile. It is concluded that serum concentrations of a suitable antimicrobial are required to prevent and control the systemic manifestations of biliary sepsis. REFERENCES 1. Acocella, G., Matiussi, R., Pallanza, R., Tenconi, L. T., and Nicolis, F. B.: Biliary excretion

of antibiotics in man. Gut, 9:536-545, 1968. 2. Altemeier, W. A., Culbertson, W. R., and Velto, M.: Prophylactic antibiotic therapy. Arch. Surg., 71 :2-6, 1956.

ANTIBIOTIC TREATMENT OF BILIARY SEPSIS

1389

3. Anderson, R E., and Priestley, J. T.: Observations on the bacteriology of choledochal bile. Ann. Surg., 133:486-489,1951. 4. Andrews, E., and Henry, L. D.: Bacteriology of the normal and diseased gall bladder. Arch. Int. Med., 56:1171-1188,1935. 5. Bevan, P. G., and Williams, J. D.: Rifamide in acute cholecystitis and biliary surgery. Br. Med. J., 3:284-287,1971. 6. Castiglioni, G. C., and Petronio, R: Percutaneous intrahepatic cholangiography as a diagnostic aid in post hepatic jaundice. Surgery, 56:635-643, 1964. 7. Charcot, J. J.: In Le cours sur Ie maladie du foie des voies biliares et des reins. Fac. Med., Paris, pp. 176-185, 1877. 8. Cole, W. H.: Suppurative cholangitis. SURG. CLIN. N. AM., 27:23-41,1947 9. Conti, F., Cassano, A., Miano, G., Mazzeo, M., and Barletta, R: Un nuovo antibiotico: la tetraciclina. Rif. Med., 68:869-883,1954. 10. Conti, F., Barletta, R, Mazzeo, M., and Miano, G.: Ricerche sull assorbimento, diffusione ed eliminazione della novobiocina nell uomo: attivita in vitro su 50 ceppi di stafi lococco. Min. Med., 48:245-251, 1957. 11. Davidson, A. 1. G., Clark, C., and Smith, G.: Postoperative wound infection: a computer analysis. Br. J. Surg., 58:333-337,1971. 12. Dodd, G. D.: Percutaneous transhepatic cholangiography. SURG. CLIN. N. AM., 47:10951106, 1967. 13. Dow, R W. and Lindenauer, S. M.: Acute obstructed suppurative cholangitis. Ann. Surg., 169:272-276,1969. 14. Edlund, Y., Mollstedt, B. 0., and Ouchterlony, 0.: Bacteriological investigation of the biliary system and liver in biliary tract disease correlated to clinical data and microstructure of the gall bladder and liver. Acta Chir. Scand., 116:461-476, 1958. 15. Elkeles, G., and Mirrizi, P. L.: A study of the bacteriology of the common bile duct in comparison with the other extrahepatic segments of the biliary tract. Ann. Surg., 116:360-366, 1942. 16. Flemma, R J., Flint, L. M., Osterhout, S., and Shingleton, W. W.: Bacteriological studies of biliary tract infection. Ann. Surg., 166:563-572, 1967. 17. Furesz, S., Acocella, G., and Scotti, R: Experimental data for the use of Rifamycin S. V. in biliary infections: in vitro activity against various pathogenic bacteria and bile concentrations in man. Chemotherapia, 7:365-373,1963. 18. Galbraith, H. J. B.: A clinical study of cephaloridine. Br. J. Clin. Pract., 21 :331-336, 1967. 19. Garrod, L. P.: Causes of failure in antibiotic treatment. Br. Med. J., 4:473-476,1972. 20. Hammond, J. B., and Griffith, R S.: Factors affecting the absorption and biliary excretion of erythromycin and two of its derivatives in humans. Clin. Pharm. Exp. Ther., 3:308312, 1960. 21. Hanzon, V.: Liver cell secretion under normal and pathological conditions studied by fluorescence microscopy on living rats. Acta Physiol. Scand., 28, Suppl., 101 :1-168, 1952. 22. Haupert, A. P., Carey, L. C., Evans, W. E., and Ellison, E. H.: Acute suppurative cholangitis. Arch. Surg., 98:629-632,1967. 23. Huang, T., Bass, J. A., and Williams, R D.: The significance of biliary pressure in cholangitis. Arch. Surg., 98:629-632, 1969. 24. Illingworth, C. F. W.: Types of gall bladder infection: a study of 110 operated cases. Br. J. Surg., 15:221-228,1928. 25. Keighley, M. R B., and Graham, N. G.: Infective complications of choledochotomy with T-tube drainage. Br. J. Surg., 58:764-769,1971. 26. Keighley, .M. R B., and Graham, N. G.: Infective cholecystitis. J. R ColI. Surg., Edinb., 18:213-220,1973. 27. Keighley, M. R B., Kelly, J. P., and Wilson, G.: Fatal endotoxic shock of biliary tract origin complicating transhepatic cholangiography. Br. Med. J., 3:147-148,1973. 28. Keighley, M. R B., Lister, D. M., Jacobs, S. 1., and Giles, G. R: Hazards of surgical treatment due to microorganisms in the bile. Surgery, 75:578-583,1974. 29. Khan, G. A., and Scott, A. J.: The place of rifamycin B diethylamide in the treatment of cholangitis complicating biliary obstruction. Br. J. Pharm., 31 :506-512, 1967. 30. Kornfield, H. J., and Allbritten, F. F.: Roles of choledochostomy and antibiotics in gall bladder surgery. Surg. Gynecol. Obstet., 113 :227-282, 1961. 31. Larmi, T. K. I., Fock, G., and Yuopio, C.: Occurrence and antibiotic sensitivity of aerobic bacteria in the bile and their role in post operative inflammatory complications of biliary tract disease. Acta Chir. Scand., 114:379-386, 1957. 32. Maddocks, A. C., Hilson, G. R F., and Taylor, R: The bacteriology of the obstructed biliary tract. Ann. R ColI. Surg. Eng., 52:316-319, 1973. 33. Martin, W. J., Heilman, F. R, Nicholls, D. R, Wellman, W. E., and Geracia, J. E.: Streptounicin: a new antibiotic, a preliminary report. Proc. Mayo Clin., 30:540-551, 1955. 34. Mason, G. R: Bacteriology and antibiotic selection in biliary surgery. Arch. Surg., 97:533-537, 1968.

1390

M. R. B.

KEIGHLEY ET AL.

35. Mortimore, P. R., Mackie, D. B., and Haynes, S.: Ampicillin levels in human bile in the presence of biliary tract disease. Br. Med. J., 3:88-89, 1969. 36. Murdoch, J. McC., Spiers, C. F., and Pullen, H.: The bacteremic shock syndrome. Br. J. Hosp. Med., 1 :346-353, 1968. 37. Norman, 0., and Milbourn, E.: Erfarenheter avo cholangiografi med lansyn till ternik och resultat. Nord. Med., 42:1645-1649,1949. 38. Ostermiller, W., Thompson, R. J., Carter, R., and Hinshaw, D. B.: Acute obstructive cholangitis. Arch. Surg., 90:392-395, 1965. 39. Public Health Laboratory Service Report. Lancet, 2:659-663, 1960. 40. Rammelkamp, C. H., and Helm, J. D.: Excret,ion of Penicillin in bile. Proc. Soc. Exp. BioI., 54:31-34,1943. 4l. Reynolds, B. M., and Dargan, C.: Acute obstructive cholangitis. Ann. Surg., 150 :299-303, 1959. 42. Rigler, L. 0., and Mixer, H. W.: Biliary reflux after cholangiography. Radiology, 48:463472,1947. 43. Rouillier, C.: Les canilicules biliares: etude en microscope electronique. Acta Anat., 26:94-109, 1956. 44. Schulenburg, C. A.: Operative cholangiography: 1000 cases. Surgery, 65:723-739,1969. 45. Scioli, C.: Intravenous ampicillin treatment in infections of the biliary tract. Br. J. Clin. Pract., 20:191-192,1966. 46. Scott, A. J., and Khan, G. A.: Partial biliary obstruction with cholangitis producing a blind loop syndrome. Gut, 9:187-192,1968. 47. Stratford, B. D.: The treatment of acute cholecystitis and other diseases with rifamycin diethylamide (Rifamide). Med. J. Aust., 1 :7-9, 1966. 48. Turner, F. P.: Fatal Clostridium welchii septicaemia following cholecystectomy. Am. J. Surg., 108:3-7,1964. 49. Twiss, J. R., Gillette, L., Berger, W. V., Aronson, A. R., and Seigel, L.: The role of antibiotics in infections of the biliary tract: studies in sensitivity and biliary tract excretion. Ann. Surg., 144:1008-1012,1956. 50. Watson, J. F.: The role of bacterial infection in acute cholecystitis: a prospective clinical study. Milit. Med., 134:416-426,1969. Department of Surgery Queen Elizabeth Hospital Birmingham, (B15 2TH) England