Brief report: Antibiotic prophylaxis in biliary tract surgery

Brief Report: Antibiotic Tract Surgery Ciprofoxacin PETER KUJATH,

Prophylaxis

in Biliary

versus Ceftriaxone

M.D. Wtirzburg,

federal Repubiic of Germany

epending on its duration and symptoms, choleliD thiasis is associated with bacterial colonization. Accordingly, surgeons must regard the biliary tract as being contaminated at the time of surgery and requiring perioperative antibiotic prophylaxis. The antibiotic of choice should be active against all major intestinal bacteria that are also encountered in the biliary tract. Following preoperative administration, adequate serum and tissue levels in the region of the operation, including the abdominal wall, should be quickly attained. The present study evaluated the efficacy of ciprofloxacin in biliary tract surgery as compared with that of a third-generation cephalosporin, ceftriaxone, which has been regarded as a standard preparation for biliary tract surgery in my hospital

phy at the Institute of Pharmacology, University of Erlangen (Dr. Hopf). Postoperative evaluation of the wound was carried out daily during the dressing change. Laboratory tests (serum bilirubin, serum glutamic oxaloacetic transaminase levels, gamma glutamyl transferase, alkaline phosphatase, lactate dehydrogenase) were evaluated on the first, third, fifth, and seventh postoperative days. After surgical opening of the choledochal duct, cholangiography was carried out on the fifth postoperative day by a T tube; the T tube was removed when there was free outflow of the contrast medium.

RESULTS The 200 patients who were enrolled into the study (100 patients in the ciprofloxacin group and 100 paPATIENTS AND METHODS tients in the ceftriaxone group) were comparable with After giving informed consent, 200 patients underregard to sex distribution, age, and weight (Table I). going biliary tract surgery were enrolled into the There were also no appreciable differences with restudy. All patients had at least one of the following gard to the indications and surgical risk factors. Altorisk factors for developing cholangitis [ 11: (1) an emer- gether, 161 risk factors were calculated for the ciprogency operation for acute cholecystitis; (2) concomi- floxacin group and 179 risk factors were calculated for tant cholangitis; (3) obesity .amounting to more than 30 the ceftriaxone group. Tumors of the biliary tract percent of normal body weight; (4) age over 70 years; were surgically removed from three patients. The (5) perforation or penetration of gallstones; (6) tumors tumors were malignant in two cases, and there was a of the biliary tract; (7) choledocholithiasis; (8) repeat papillary cystadenoma in the third. surgery. The bacteria isolated corresponded to the typical A total of 100 patients were randomly assigned to intestinal flora known to be present in the contamireceive ciprofloxacin and 100 patients to receive cef- nated biliary tract [2-41. There were no differences in triaxone. Exclusion criteria were: history of hyperthe bacterial population in the two treatment groups sensitivity to cephalosporins or quinolones, preg- (Table II). Antibiotic therapy was prolonged for more nancy, and previous treatment with another antibithan four days in 12 and 15 patients, respectively. otic. These were patients with a cholangitis and a septic Upon introduction of the anesthesia, 200 mg cipro- component (temperature over 38.5% and leukocytosis floxacin or 2 g ceftriaxone dissolved in 50 ml of intraover 15,000 X 10’1~1). venous fluid was administered as an infusion over 15 The most frequent operation performed was a choto 20 minutes. The administration was completed be- lecystectomy, which was performed 95 and 98 times, fore the surgical incision was made. respectively, in the ciprofloxacin and ceftriaxone Intraoperatively, a tissue specimen was obtained groups. Additional operations performed were cholefrom the region of the operation for culture and sensi- dochal revisions (27 and 32 times) and transduodenal tivity tests. Native bile was obtained from all patients papillotomies (five and five times). Eleven and 14 opand investigated for aerobic and anaerobic bacteria. erations in the ciprofloxacin and ceftriaxone groups, Serum and tissue levels were also determined in 20 respectively, were emergency operations. Four and patients who received ciprofloxacin. Tissue samples two reoperations, respectively, were performed. were taken from the gallbladder, and bile was taken Average duration of surgery was 104 minutes in the from the gallbladder and the choledochal duct, accord- ciprofloxacin group and 110 minutes in the ceftriaxone ing to the protocol, and frozen immediately at -70°C. group. Three postoperative wound infections occurred The choledochal bile was taken via a centesis of the during the study, two in the ciprofloxacin group, and choledochal duct. The serum and tissue levels were one in the ceftriaxone group. In the ciprofloxacin determined by high-performance liquid chromatogragroup, these involved a small fistula after removal of the T tube in two cases. These fistulas closed spontaneously. The causative bacteria were Escherichia coli I I and enterococci, both of which are sensitive to ciproFrom the Surgical Clinic and Policlinic of the University of Wtirzburg, Wurzburg, Federal Republic of Germany. Requests for reprints should be addressed to Dr. Peter floxacin. In one patient in the ceftriaxone group, there Kujath, Chlrurgische UniversitBtsklinik, Josef-Schneider-Strasse 2 D.8700 W&burg, was leakage from the choledochal duct with a fistula to Federal Republic of Germany. the abdominal walls after a biliobiliary perforation.

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The American Journal of Medune

Volume 87 (suppl 5A)

5A-255s

SYMPOSIUM

ON CIPROFLOXACIN

Demographic

/ KUJATH

The results of the determination of the serum and tissue concentrations can be seen in Table V. The high concentrations of ciprofloxacin in the hepatic bile that had been punctated from the choledochal duct during the operation were striking. The values were roughly 10 times higher than the values in the bile removed from the gallbladder.

Data Ciprofloxacin

Ceftriaxone

100 73127 59.1 72.0 a2

6832 57.2 71.3

Number of patients Female:male Average age (years) Average weight [kg] Oldest patient (years) Risk factors Choledocholithiasis Acute cholecystitis Cholangitis Jaundice Obesity >30% Age >70 years

100

TABLE II Bacteriologic

Findings of lntraoperative

Bacteria

Samples

Ciprofloxacin

Ceftriaxone

30

Negative cultures

Enferococcus E co/i Streptococcus sp. Staphylococcus aures Proteus sp. Mebsiella sp. Pseudomonas sp. Otrobacter sp.

fi

9

1:

ii

Anaerobes Polymrcrobial

2: 33

6 i : i i

16 27

TABLE Ill Clinical Laboratory Values Ciprofloxacin

Mean SGOT before therapy (umts/liter) Mean SGOTduring therapy (units/liter) Mean SGOTafter therapy (units/liter) Mean bilirubin before therapy (mgldl) Mean bilirubin during therapy (mg/dl) Mean bilirubin after therapy (mg/dl)

Ceftriaxone

Mean

Range

5-376

110

;:

6-286 6-290 0.3-15.7 OMl ;

117

2; ::$

Mean

Rang6

4; 3.4

6-842 7-665 8-641 0.2-18.1 0.4-15.9

1.2

0.3-9.7

SOT = serum glutamic oxaloacetic transaminase.

TABLE IV Postoperative Recovery

Prolongationof antibiotic therapy Fever 38.5”c Wound infection

Ciproffoxacin

Ceftriaxone

Number of Patients

Number of Patients

ii

1

I

This involved a polymicrobial wound infection (E. coli, Pseudomonas, Bacteroides sp), which healed after endoscopic placement of an internal drain. Side effects did not occur in either treatment group during therapy. The markedly raised preoperative laboratory values were attributed to the underlying gallbladder disease and normalized rapidly during therapy (Tables III and IV). 5A-256s

November

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The American Journal of Medicine

COMMENTS The patients in this study were primarily those characterized by biliary tract disease complicated-by the presence of gallstones and thus at high risk for developing postoperative infections; the percentage of patients with choledochal gallstones was 29 percent. The high ,proportion of patients with cholangitis was also striking; this percentage was higher than that of previously published reports 5-71. Although other authors do not mention cholangitis as a severe complication of gallbladder disease [8,9], this should be considered, since it can result in a mortality rate of up to 100 percent if left untreated [lO,ll]. The need for reoperation in patients with biliary tract disease is also rarely mentioned in other studies, although it is exactly this operation of relatively long length that can put the patient in great danger of wound infection [12] and at, high surgical risk [13]. Bacterial colonization of the biliary tract occurs with micro-organisms typical to the intestinal tract [2,14]. However, the large number of culture-negative specimens reported, even in complicated gallstone conditions, suggests that the high concentration of the antibiotic achieved in the gallbladder leads to rapid elimination of the bacteria, even when microbiologic diagnostics are carried out immediately. In this study,‘a total of three wound infections occurred. These were related to the formation of fistulas from the biliary tract and thus were endogenously induced. Accordingly, their development cannot be considered to be related in any way to the use of perioperative antibiotic prophylaxis. The high concentrations of ciprofloxacin attained in the hepatic bile (which are in some cases about 10 times higher than in the bile from the gallbladder) are striking. It is clear, therefore, that ciprofloxacin is also excreted via the liver. Sorgel et al [15] report that the biliary excretion of ciprofloxacin is 5 percent. The concentrations in the serum found after a bolus of 200 mg intravenously correspond with the data in the literature [16,17]. The values found in the choledochal bile, however, are four times higher than the values reported by Brogard et al [X3]. Silverman et al [191 also found lower concentrations in the common bile duct; their findings in the gallbladder wall are in accord with ours. An explanation for this could be that in our study the choledochal bile was removed via centesis. Brogard and Silverman obtained the bile via a T tube. Thus, there might have been a considerable loss of bile and therefore a loss of ciprofloxacin in the enterohepatic circulation. Because of its high concentration in the hepatic bile, ciprofloxacin is also suitable for therapy of cholangitis. CONCLUSIONS Intravenous ciprofloxacin appears to be as effective as ceftriaxone, a third-generation cephalosporin, in antibiotic prophylaxis for biliary tract infection. Gallbladder tissue and bile concentrations of ciprofloxacin were well above the minimal inhibitory concentration

Volume 87 (suppl 5A)

SYMPOSIUM

ON CIPROFLOXACIN

/ KUJATH

TABLE V Pharmacokinetic

Results: Concentration of Ciprofloxacin Serum

Time of Specimen Collection after Dosing 65-70 minutes 80-95 minutes

Mm0

in Serum, Bile, and Gallbladder Wall Liver Bile t&d

Bile from Gallbladder &ml)

Wall of Gallbladder il.&)

1.26 c 0.99

56.77k 21.60

2.43 1 1.86

4.47 f 2.35

1.10 ? 0.45

41.52 2 18.42

1.48 t 0.92

2.10 IO.43

for organisms known to cause biliary tract infection. Although the concentrations of ciprofloxacin in biliary tract tissue and bile were not as high as those of ceftriaxone, the excellent activity of the drug against a wide range of gram-negative bacilli and enterococci makes ciprofloxacin a potentially useful prophylactic agent in biliary tract surgery. REFERENCES 1. Kujath P, Arbogast R, Trenkel D: Die perroperative antrbiotische prophylaxe rn der Gallen-chrrurgie mit ceftriaxon. Klinrkarrt 1984; 13: U4-777. 2. Anderson RE, Prrestley JT: Observations on the bacterrology of choledochal bile. Ann Surg 1951; 133: 456-489. 3. Eggeri A, Wittmann DH, Schroder HJ, Schrmmel G: Die Bedeutung tntraoperabver bacterieller Befunde her Gallenblasen- und Gallenwegsoperat~onen. Miincfr Med Wochenschr 1977 119: 9555958. 4. Blenkhorn JI, Blumgart LH: Streptococcal bacteremla in hepatobiliary operairons. Surg Gynecal Obstet 1985; 160: 139-141. 5. Kujath P, Arbogast R, Horl M: Die perioperative antibiotikaprophylaxe rn der gallenwegschirurgie. In: Hengstmann JH, Kolb R, Linrenmerer G, Schonfeld H, eds. Ceftriaxon (Rocphin). Basel: Editiones Roche, 1985; 279-283. 6. Kellum JM, Gargano S, Talcof E, ei a/: Antrbiobc prophylaxis rn high-rusk bilrary operations: multrcenter trial of single preoperative ceftriaxone versus multrdose cefazolin. Am J Surg 1984; 148 (Suppl 4A): 15-18. 7. Glenn F: Surgical management of acute cholecystitrs in patients 65 years of age and

November

Ratio 1:45:1.8:3.9 1:38:1.3:1.9

older. Ann Surg 1981; 193: 56-59. 8. Jarvinen JH, Hastbacka J: Early cholecystectomy for acute cholecystrtrs Ann Surg 1980; 191: 501-505. 9. Kerghley MRB, Flrnn R, Alexander-Williams J. Multrvariate analysis of clrnrcal and operative findings assocrated with bilrary sepsrs. Br J Surg 1970; 63: 528-531. 10. Reynolds BM, Dargan EL: Acute obstructive cholangrtis. Ann Surg 1959; 150: 299303. 11. Dow RW, Lrndenauer SM: Acute obstructrve suppuratrve choiangrtrs. Ann Surg 1969: 169: 272-276. 12. Cruse DJE, Foord R: The eprdemrology of wound Infection. Surg Clrn North Am 1980; 60: 27-39. 13. Gerard RM, Legros G: Stones rn the common brie duct-surgrcal approaches. In: Blumgart LH, ed. Surgery of the liver and brlrary tract. Vol. 1. Edrnburgh, London: Church111 Lrvrngstone. 1988; 5%585 14. Robson MC, Bogart JN, Heggers JP: An endogenous source for wound Infections based on quantitative bacteriology of the brlrary tract. Surgery 1970; 86: 471-476. 15. Sorgel F, Naber KG, Stephan U: Pharmakokrnitik und Analybk von Gyrase-Hemmern. FAC Fortschr Antimlkr Antineoolast Chemother 1987: 6-10: 1907-1961. 16. Dalhoff A, Weuta H: Penetratron of crprofloxacrn into gynecologrc tissues. Am J Med 1987; 82 (suppl 4A): 133-138. 17. Bergan T, Dalhoff A, Rohwedder R: Pharmacokrnetrcs of crprofloxacrn. Infection 1988; 16 (suppl 1): 3-13. 18. Brogard JM, Arnaud JP, Jehl F, Blickle JF, Monteii H: Crprofloxacrn: evaluation of its brlrary excretion In man. In: Neu HC, Weuta H, eds. Proceedings of the 1st International Crprofloxacrn Workshop. Amsterdam: Experta Medica, 1986; 130-135. 19. Silverman SH, Johnson M, Burden DW, Kerghley MRB: Pharmacokinetrcs of single dose intravenous ciprofloxacrn in patients undergoing gastrorntestinal surgery J An. trmlcrob Chemother 1986; 18: 107-112.

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The Amerrcan Journal of Medtcrne

Volume 87 (suppl 5A)

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