Excretion of Metronidazole in Human Bile Investigations of Hepatic Bile, Common Duct Bile, and Gallbladder Bile

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MOGENS LYKKEGAARD NIELSEN & TAGE JUSTESEN Surgical Dept. K, Frederiksberg Hospital, and Dept. of Clinical Microbidogy (Institute of Medical Microbiology), University of Copenhagen, Copenhagen, Denmark

Lykkegaard Nielsen, M. & Justesen, T. Excretion of metronidazole in human bile. Investigations of hepatic bile, common duct bile. and gallbladder bile. Scand. J. Gasfroenf. 1977. 12, 1003-1008. Excretion of metronidazole (MNZ) in the normal and in the diseased biliary tract was investigated in 58 patients after oral or intravenous administration of MNZ. After oral administration MNZ appeared rapidly in hepatic bile, and throughout the period of absorption and elimination almost identical concentrations of MNZ were found in serum and hepatic bile. After intravenous administration no significant differences were found between concentrations of MNZ in common duct bile and serum in the non-obstructed common duct; in common duct obstruction, concentrations of MNZ in common duct bile were 56-99 per cent of corresponding concentrations in serum. MNZ was concentrated in normal gallbladders. In patients with gallbladder stones and preserved function of the gallbladder and in patients with no function of the gallbladder but a patent cystic duct, no significant differences were found between concentrations of MNZ in gallbladder bile, common duct bile, and serum. In most gallbladders with the cystic duct blocked by a stone, no MNZ was found in gallbladder bile. Key-words: Anaerobic bacteria; antibiotics; biliary tract; biliary tract infection; gallstones Mogens Lykkegaard Nielsen, M.D., 31 Sojevej, DK-2900 Hellerup, Denmark

I t has recently been demonstrated that a variety of anaerobic bacteria can be isolated from bile in patients with biliary tract diseases, and that the anaerobic bacterial species isolated from the biliary tract are normal inhabitants of the gut ( 5 ) . The incidence and significance of anaerobic bacteria in biliary tract infections are not yet fully elucidated. although many case-reports of cholecystitis and cholangitis due to anaerobic bacteria have been reported. Metronidazole (Flagyl'R') has been used for many years in the treatment of vaginal trichomonad infections. Since 1972 an increasing number of reports have documented a marked antibacterial activity of metronidazole ( M N Z ) in vitro against most ar,aerobic bacteria (for survey see 3, for later reports see 9, 12). The aim of the present study was to investigate the excretion of M N Z in the normal and diseased human biliary tract in order to determine the pos-

sible value of M N Z in the treatment of biliary tract i n fect io ns. MATERIAL A N D METHODS Par ienis The material comprised 58 patients. Three patients operated on for common duct stones with insertion of a T-drain were investigated in the postoperative period. The diagnosis in the remaining 5 5 patients. all investigated during operation. appears from Table I. Eleven patients. operated on for duodenal ulcer, had no symptoms from the biliary tract and a preoperative cholangiography was normal in all 1 1 ; in 39 patients with gallbladder stones, preop erative cholangiography showed a normal common duct. which was confirmed at operation i n all of them; 5 patients all had common duct stones with elevated values of serum bilirubin, with very severe jaundice in 4.

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M.Lykkegaard Nielsen Br T. Justesen

Table I. Excretion of metronidazole in bile. Age, sex, and diagnosis in 55 patients investigated after intravenous administration of metronidazole

No'

Diagnosis

Of

patients

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Normal biliary tract Gallbladder stones with normal common duct (gallbladder function preserved) Gallbladder stones with normal common duct (gallbladder function lost) Common duct stones with common duct obstruction and jaundice

11

17

Age (median and range) 57 (38-78)

Sex p/b' 417

59

shows dose of MNZ per kg bodyweight and the time from administration of the drug until sampling of bile. Bile was sampled after laparotomy before commencing the biliary tract operation. Gall bladder bile and common duct bile were aspirated in asterile syringe after puncture of the gallbladder wall and common duct wall, respectively, using a thin needle. In patients with a normal biliary tract (cf. Table I ) only gallbladder bile was aspirated. Four samples of blood were obtained from a cubital vein: one sample at the beginning of the laparotomy, one at the time

(2 1-75)

22

66 (3&82)

Table 11. Dose of metronidazole (MNZ)and period elapsing from administration of MNZ until sampling of bile mg MNZ per body-

minutes until

weight

bile (median and range)

kg 5

63 (60-90)

In patients with gallbladder stones but normal common duct without obstruction (39 patients). gallbladder function was recorded as preserved or lost (Table I ) depending on visualization or nonvisualization of the gallbladder during preoperative i.v. cholangiography. All patients included in this study had normal renal function. evaluated from two determinations of serum creatinine.

(median and range) Normal biliary tract (n= 11) Gallbladder stones (gallbladder function preserved)

sampling of

8.1 (6.3- 10.0)

I40 (85-32 1)

8.6 (5.2- 12.2)

150 (95-3 15)

8.2 (6.1-1 I . 1)

(85-345)

8.2 (5.4-9.1)

I57 (105-345)

(n= 17)

Gallbladder stones (gallbladder function lost) (n=22) Common duct stones with obstruction and jaundice

152

Administration of M N Z and sampling of bile and ( n = 5 ) blood. Three patients, who had a T-drain inserted in the common duct and who were investigated during the gallbladder bile was aspirated. one a t the time compostoperative period, received M N Z orally in a dose mon duct bile was aspirated, and finally one sample of 2g. The T-drain was tubulated with a thin cathe- at the end of the operation. ter, the tip of which was placed proximally in the common duct just below the two hepatic ducts. Microbiological assay of M N Z Hepatic bile was aspirated through this catheter a t The assay of M N Z in bile and blood has been intervals of t o one hour as indicated in Figure 1. described in detail elsewhere (4). M N Z was deterSamples of blood were drawn simultaneously from a mined by an anaerobic modification of an agar catheter in a cubital vein. diffusion technique using filter paper discs. and In 5 5 patients investigated during operation. Fusobacterium necrophorum was employed as test 500mg M N Z was given intravenously one hour bacterium. The ,analytical error of the method apbefore the planned start of the operation. Table 11 pears from Table 111.

+

Metronidazole in Bile Table 111. Analytical error (coefficient of variation) of the microbiological assay of metronidazole in bile. Anaerobic modification of an agar diffusion technique using filter paper discs

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No. of trials

No. of standards used

k h l )

10

I I 1

10

I

8.0 15.7 3 1.6 58.6

10

10

12.4

10 10

S2

Coefficient of variation

0.037 0.353 3.078 13.518

2.4Yo 3.8%

0.37 1

4.9%

5.6% 6.3%

RESULTS Excretion of M N Z in hepatic bile is shown i n Figure I . In all three patients M N Z appeared rapidly in hepatic bile, and throughout the period investigated almost identical concentrations of M N Z were found in serum and hepatic bile. Concentrations of M N Z in serum and bile in patients investigated during operation appear from Table IV. Concentrations of M N Z in serum in the three groups of patients tabulated were fully compa-

rable at the time bile was sampled. In patients with a normal biliary tract, significantly higher concentrations of M N Z were found in gallbladder bile than in serum. In patients with gallbladder stones a)zdpreserved function of the gallbladder, no differences were found between concentrations of M N Z i n serum, common duct bile, and gallbladder bile. i n patients with gallbladder stones but lost function of the gallbladder, no differences were found between concentrations of M N Z in serum and in common duct bile, whereas concentrations of M N Z in gallbladder bile were significantly lower than concentrations of MNZ in both serum and common duct bile. When concentrations of M N Z in gallbladder bile were compared. (Table IV), significant differences were found between all three groups of patients: highest concentrations were found in normal gallbladders and lowest concentrations in non-functioning gallbladders. In Table V pstients with no gallbladder function according to preoperative cholangiography have been divided into two groups according to findings at operation, all patients having normal common ducts. In 14 patients the cystic duct was blocked by a stone and the gallbladder contained colourless o r discoloured bile. In 8 patients the cystic duct was

3

5

9

13

I7

hours

Fig. 1. Metronidazole in serum and hepatic bile in 3 patients after an oral dose of 2g metronidazole. ____ Metronidazole in serum Metronidazole in bile

~

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M. Lykkegaard Nielsen & T . Jusresen

Table IV. Excretion of metronidazole (MNZ) in gallbladder bile and common duct bile in 50 patients investigated during operation. Figures tabulated are median and range. MNZ in bile has for every single patient been calculated as per cent of MNZ in serum at the time bile was sampled. In all patients 500mg MNZ was given intravenously (cf. Table 11) pg MNZ per ml bile pg MNZ per ml serum

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gallbladder bile Normal biliary tract (n= 1 I )

12.4 (8.2- 14.6)

Gallbladder stones (gallbladder function preserved, n = 17)

12.7 (8.7-16.7)

Gallbladder stones (gallbladder function lost, n = 22)

12.3 (7.7- 16.2)

**

ns NS

common duct bile

127% (101-215) 00

104%

NS

106% (87- 150)

**

107% (87- 13 6)

(42-202)

00

ns

**

54%

ns

(C123)

**: Wilcoxon test for pair differences p 0.20. 00: Mann-Whitney ranksum test p 0.20. The signs ( * *. NS, 00, ns) refer to differences between groups on each side of a sign.

Table V. Excretion of metronidazole (MNZ) in gallbladder bile and common duct bile in 22 patients with gallbladder stones and lost function of the gallbladder determined from preoperative cholangiography. In all patients the common duct was normal without obstruction. Figures tabulated are median and range. MNZ in bile has for every single patient been calculated as per cent of MNZ in serum at the time bile was sampled. Dose of MNZ: cf. Tables I1 and IV pg MNZ per ml bile x 100 pg MNZ per ml serum

gallbladder bile Cystic duct blocked by stone (n = 14) Cystic duct patent (n=8) Total group (n=22)

12.3 (8.3-16.1 ) ns 12.0 (7.7- 16.2) 12.3 (7.7- 16.2)

**

0%

common duct bile

**

(0-63) 00

NS

94% (82-123)

107% (87- 12 3)

ns NS

54%

(9-123)

* *: Wilcoxon test for pair differences p < 0.0 1. NS: Wilcoxon test for pair differences p >0.20. 00:Mann-Whitney ranksum test p (0.0 1. ns: Mann-Whitney ranksum test p >0.20. The signs (**, NS, 00, ns) refer to differences between two groups on each side of the sign.

109% (92- 136) 107% (87- 13 6)

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Metroriidazole in Bile

patent, the gallbladder containing stones and normal coloured bile, but the gallbladder wall was thickened by fibrosis. In 9 out of 14 patients with a blocked cystic duct no M N Z was detected in gallbladder bile, and in the remaining 5 patients a concentration was found of 43-63 per cent of M N Z in serum; thus, concentrations of M N Z in gallbladder bile were significantly lower than concentrations of M N Z in both serum and common duct bile, whereas no significant difference was found between serum and common duct bile. In 8 patients with a patent cystic duct no significant differences were found between concentrations of M N Z in serum, common duct bile, and gallbladder bile. It appears from the table (Table V) that a significant difference was found between the two groups of patients in regard t o M N Z in gallbladder bile, and that the two groups were comparable in regard to concentrations of MNZ in serum and M N Z in common duct bile. Table VI. Excretion of metronidazole (MNZ) in common duct bile in 5 patients with common duct obstruction and jaundice due to common duct stones pg MNZ per ml

Bilirubin in serum

(rnmolh) * 35 257 34 1 315 406

serum

bile

b i l e x 100 serum

12.1 9.9 10.5 10.2 12.3

9.4 9.3 8.8 10.1 6.9

78% 94% 84% 99% 56%

*Normal values for bilirubin in serum are 5-17mrnol/l.

Excretion of MNZ in common duct bile in patients with common duct obstruction appears from Table VI. Four of the five patients had very severe jaundice lasting for at least two weeks before operation was performed. Concentrations of M N Z in common duct bile varied from 5 6 to 9 9 per cent of the corresponding concentration of M N Z in serum. DISCUSSION Excretion of M N Z in humn bile has not previously been investigated. The present study reveals that in the non-obstructed biliary tract M N Z appears in

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hepatic bile in concentrations similar to those found in serum (FIg. I). and that M N Z is concentrated in the normal gallbladder (Table IV). When the sensitivity of anaerobic bacteria to M N Z is expressed by MIC values obtained by the agar dilution method. 95 per cent or more of anaerobic bacteria can roughly be classified into a highly sensitive group, a sensitive group. and a resistant group ( 1 2). The highly sensitive group comprises B. melaninogenicus, Fusobacterium spp., Peptococcus spp. and Closiridium spp., these bacteria being sensitive t o < 2 pg MNZ/ml. The sensitive group comprises B. fragilis spp., Peptostreptococcus spp. and Eubacterium spp., these bacteria being sensitive to 16pg MNZ/ ml. The resistant group comprises Propionibacterium spp., Actinomyces spp., Lactobacillus spp. and Bfidobacferium spp., these bacteria being sensitive only to concentrations 2 256 pg MNZ/ml. In biliary tract infections bacteria from the highly sensitive group and from the sensitive group are often isolated from bile. whereas bacteria from the resistant group are seldom encountered ( 5 ) . Biliary tract infections which are located in the gallbladder and which demand chemotherapy are severe attacks from acute cholecystitis. septic complications arising from acute cholecystitis (bacteremia? liver abscess), and emphyema of the gallbladder. In these conditions the cystic duct is often blocked by a stone, and according to the present investigation it is not t o be expected that therapeutic levels of M N Z can be achieved in gallbladder bile itself, when the cystic duct is blocked. In this respect M N Z does not differ from other antibiotics ( I . 2,6. 7. 8, 10. 1 I , 13), since they all mainly reach the gallbladder contents ductogenously. but in many reports it is not recorded whether the cystic duct is blocked or patent in non-functioning gallbladders. In cholangitis the common duct may be more or less obstructed, frequent kinds of obstruction being common duct stones or common duct strictures after previous biliary tract surgery. I n patients with common duct stones or strictures, common duct bile is infected in 80-90 per cent of all cases, anaerobic bacteria being recovered from bile in 40 per cent of cases with infected bile (5). It appears from Figure I that therapeutic levels of M N Z in common duct bile are dependent on serum levels of MNZ, and that high concentrations can be obtained in common

Excretion of metroindazole in human bile. Investigations of hepatic bile, common duct bile, and gallbladder bile.

Excretion of Metronidazole in Human Bile Investigations of Hepatic Bile, Common Duct Bile, and Gallbladder Bile Scand J Gastroenterol Downloaded from...
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