177
DIAG. MICROBIOL.INFECT. DIS. 1990;13:177-179
Ciprofloxacin Prior to Colon Surgery Arnulf D6rner, Andreas Witthohn, and Ernst Kraas
INTRODUCTION The prophylactic use of antibiotics and improved bowel preparation procedures have dramatically decreased the infectious complications of colorectal surgery. The broad antimicrobial spectrum of ciprofloxacin and its high penetration into the intestinal mucosa have focused our interest on the use of ciprofloxacin in this setting. In a preliminary study, we were able to see a rapid accumulation of the drug in the colon wall, especially in the colon mucosa. The goal of this study was to determine the concentrations of ciprofloxacin in different layers of the colon wall (tunica muscularis-tunica mucosa/submucosa) after various preoperative or perioperative administration times. These values were correlated to the concentrations in the serum and in the feces.
MATERIALS A N D METHODS Resection of the colorectum was performed in a consecutive series of patients. All patients had either a colonic neoplasm or inflammatory bowel disease. Intravenous (IV) ciprofloxacin (200 mg) was administered pre- or perioperatively over a period of 30 min by means of an infusion pump. The time between the end of the dosing and the moment of resection was designated t (rain). Any adhering feces were thoroughly wiped off the specimens, and the mucosa/submucosa was separated from the muscularis. At the same time, 10 ml of blood was drawn. When available, feces were collected from the specFrom the Department of Surgery, KrakenhausAlten Eichen (E.K.), Hamburg; and the Department of ClinicalChemistry, University of L~ibeck(A.D., A.W.), Lubeck, FRG. Address reprint requests to: Dr. A. D6rner, Department of Surgery, KrakenhausAlten Eichen, D-2000 Hamburg 54, FRG. Received January 10, 1990; revised and accepted January 12, 1990. © 1990 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732°8893/90/$03.50
imens. All the tissue and serum samples (collected from blood) were stored at 20°C. The tissues were homogenized and diluted prior to assay. The concentrations of ciprofloxacin were determined by the high-performance liquid chromatography (HPLC) assay method: the values are referred to as milliliters of serum or grams of wet weight.
RESULTS A total of 29 patients participated in the study. The mean age of the patients was 63.4 years (range, 3988). Five groups of patients were formed according to the interval between the time of drug administration and the resection: group 1, t = 0-15 min; group 2, t = 16-30 rain, group 3, t = 31-60 min; group 4, t = 61-90 min; and group 5, t = 91-162 min. The results are listed in Tables 1-5. The highest mean serum level occurred in group 1 (mean = 1.7; SD = 0.45). An increasing gradient of concentrations from the serum to the muscularis and the mucosa was found in each group (p = 0.05 in groups 1, 2, 3, and 5; p = 0.01 in group 4). If the values of all the patients in all groups are averaged, the concentrations differ by a high level of significance according to the Wilcoxon test (p = 0.001). The concentration of ciprofloxacin in the feces increased up to 5.9 p,g/g. This high value was found in a specimen that was excluded from the passage of feces by a loop colostomy.
DISCUSSION The concentration of ciprofloxacin in the feces and the tunica mucosa was found to be higher than the corresponding serum levels. After IV administration, ciprofloxacin may reach the colonic mucosa either by bile excretion and reabsorption from the colonic
178
T A B L E 1.
A. D 6 r n e r et al.
Groupl(t
= 0-15min;n
= 6)
T A B L E 4.
Group4(t
Level of Ciprofloxacin Time (min)
Muscularis (p,g/g)
Mucosa (lag/g)
7 7 11 11 13 15
1.90 2.30 1.01 1.90 1.80 1.40
9.18 5.07 3.18 1.83 13.30 4.14
10.40 7.66 4.78 5.07 13.20 6.04
Mean SD SEM
1.718 0.450 0.184
7.858 3.334 1.361
Level of significance (Wilcoxon text) for muscularis/serum, mucosa/serum, and mucosWmuscalaris is p = 0.05.
T A B L E 2.
Group2(t
= 16-30min;n
= 5)
Level of Ciprofloxacin Time
Serum
Muscularis
Mucosa
(min)
(~g/ml)
(~g/g)
(~g/g)
16 20 23 27 30
1.43 1.40 1.06 1.54 1.19
5.88 5.22 2.96 5.02 3.61
9.91 5.66 3.53 6.97 3.97
Mean SD SEM
1.324 0.194 0.087
4.538 1.209 0.541
6.008 2.577 1.153
Level of significance (Wilcoxon text) for muscularis/serum, mucosa/serum, and mucosa/muscalaris is p = 0.05.
Time (min)
Serum (~g/ml)
Muscularis (ixg/g)
Mucosa (~xg/g)
61 62 69 75 75 75 83
0.91 0.45 0.62 0.59 0.34 0.90 0.48
4.13 1.54 1.90 2.64 0.94 2.90 1.36
4.40 2.40 2.68 3.35 1.03 4.13 1.72
Mean SD SEM
0.613 0.220 0.083
2.201 1.098 0.415
2.816 1.232 0.466
Level of significance (Wilcoxon text) for muscularis/serum, mucosa/serum, and mucosa/muscalaris is p = 0.01.
l u m e n or b y h e m a t o g e n i c a c c u m u l a t i o n in the b o w e l wall a n d s e c r e t i o n into t h e l u m e n . B r o g a r d et al. (1986) f o u n d t h a t the e l i m i n a t i o n of ciprofloxacin b y bile w a s ~ 0.32 _+ 0.04% of a g i v e n d o s e . Siefert a n d S u w e l a c k (1983) f o u n d t h a t 11% of a n IV d o s e of ciprofloxacin w a s e x c r e t e d b y t h e feces. T h a d e p a l l i a n d c o - w o r k e r s (1984) r e p o r t e d t h a t in a n isolated l o o p of intestine, the levels of ciprofloxacin in the intestinal m u c o s a w e r e t e n f o l d h i g h e r t h a n in t h e serum. The data from our patients support the conc e p t of a h e m a t o g e n i c a c c u m u l a t i o n of the d r u g in the b o w e l wall a n d a c o n s e c u t i v e excretion into the colonic l u m e n . T h e h i g h levels of ciprofloxacin in the tunica m u c o s a shortly after administration ( g r o u p 1) r u n parallel to the s e r u m levels. A r e a b s o r p t i o n f r o m t h e l u m e n after s u c h a s h o r t i n t e r v a l is unlikely. I n a p a t i e n t of g r o u p 3 (t = 40 min), t h e c o n c e n t r a tion of ciprofloxacin w a s s e v e n f o l d h i g h e r in m u c o s a T A B L E 5.
T A B L E 3.
Group3(t
= 31-60min;n
= 7)
Level of Ciprofloxacin
Serum (~g/ml)
6.117 4.312 1.761
= 61-90min;n
Group5(t
= 91-162min;n
= 6)
= 5) Level of Ciprofloxacin
Level of Ciprofloxacin Time (min)
Serum (~g/ml)
Muscularis (lag/g)
Mucosa (lag/g)
35 40 44 53 53
0.98 0.84 1.21 0.70 1.26
4.48 5.86 1.67 1.69 3.26
6.87 6.12 3.91 2.31 3.47
Mean SD SEM
0.998 0.239 0.107
3.392 1.813 0.811
4.536 1.900 1.850
Level of significance (Wilcoxon text) for muscularis/serum, mucosa/serum, and mucosa/muscalaris is p = 0.05.
Time (min)
Serum (lag/ml)
Muscularis (p~g/g)
Mucosa (lag/g)
93 107 124 147 150 162
0.56 0.60 0.47 0.35 1.21 0.35
2.81 1.88 1.02 0.69 1.96 0.92
4.72 2.78 1.44 1.29 4.56 1.67
Mean SD SEM
0.590 0.321 0.131
1.547 0.810 0.331
2.743 1.560 0.637
Level of significance (Wilcoxon text) for muscularis/serum, mucosa/serum, and mucosa/muscalaris is p = 0.05.
Ciprofloxacin Prior to Colon Surgery
than in the serum (feces, 5.0 ~g/g; serum, 0.84 ~g/ml). The passage of feces was excluded by a loop colostomy that was established some months before. The excretion of large molecules, including drugs, by the colonic mucosa is an uncommon phenomenon and its mechanism is not yet understood. Selden et al. (1974) described the excretion of the glycoside ouabain in the feces after ligation of the common bile duct. The importance of an accumulation of ciprofloxacin in the colonic wall and its excretion through the mucosa into the feces is evident. The high concen-
179
trations of ciprofloxacin obtained in the intestine exceeds the minimal inhibitory concentrations (MICs) of a wide variety of aerobic bacteria, even those that are resistant to the drug at usual serum levels. This is the rationale for a prophylactic use in colorectal surgery. Furthermore, the therapeutic safety of ciprofloxacin is expanded in a case of renal failure. Bergan et al. (1990) and Rohwedder et al. (1990) found that the transintestinal elimination became the major route of elimination in patients with renal impairment. Thus, excessive increases in drug concentration in these patients is avoided.
REFERENCES Bergan T, Dalhoff A, Rohwedder R (1990) Pharmacokinetics of ciprofloxacin. Infection (in press). Brogard JM, Arnaud JP, Jehl F, BlickleJF, Monteil H (1986) Ciprofloxacin: evaluation of its biliary excretion in man. In Proceedings of the First International Ciprofloxacin Workshop. Leverkusen, 6-8, 1985. Eds., HC Neu and H. Weuta. Amsterdam: Excerpta Medica. Rohwedder RW, Bergan T, Thornsteinsson SB, Scholl H (1990) The transintestinal elimination of ciprofloxacin. Diagn Microbiol Infect Dis (in press).
Selden R, Margolies MN, Smith TW (1974) Renal and gastrointestinal excretion of ouabain in dog and man. J Pharmacol Exp Ther 188:615-623. Siefert HM, Suwelack D (1983) 14C Bay o 9687: Pharmacokinetic study in rats. Pharma-Bericht No. 11783 (P) Bayer AG. Thadepalli H, Mandal AK, Dausal MD (1984) Ciprofloxacin IV in microflora of colon and experimentally isolated jejunal segment (Abstr). Fifteenth International
Congress of Chemotherapy, Istanbul.
DIAG. MICROBIOL.INFECT. DIS. 1990;13:177-179
Ciprofloxacin Prior to Colon Surgery Arnulf D6rner, Andreas Witthohn, and Ernst Kraas
INTRODUCTION The prophylactic use of antibiotics and improved bowel preparation procedures have dramatically decreased the infectious complications of colorectal surgery. The broad antimicrobial spectrum of ciprofloxacin and its high penetration into the intestinal mucosa have focused our interest on the use of ciprofloxacin in this setting. In a preliminary study, we were able to see a rapid accumulation of the drug in the colon wall, especially in the colon mucosa. The goal of this study was to determine the concentrations of ciprofloxacin in different layers of the colon wall (tunica muscularis-tunica mucosa/submucosa) after various preoperative or perioperative administration times. These values were correlated to the concentrations in the serum and in the feces.
MATERIALS A N D METHODS Resection of the colorectum was performed in a consecutive series of patients. All patients had either a colonic neoplasm or inflammatory bowel disease. Intravenous (IV) ciprofloxacin (200 mg) was administered pre- or perioperatively over a period of 30 min by means of an infusion pump. The time between the end of the dosing and the moment of resection was designated t (rain). Any adhering feces were thoroughly wiped off the specimens, and the mucosa/submucosa was separated from the muscularis. At the same time, 10 ml of blood was drawn. When available, feces were collected from the specFrom the Department of Surgery, KrakenhausAlten Eichen (E.K.), Hamburg; and the Department of ClinicalChemistry, University of L~ibeck(A.D., A.W.), Lubeck, FRG. Address reprint requests to: Dr. A. D6rner, Department of Surgery, KrakenhausAlten Eichen, D-2000 Hamburg 54, FRG. Received January 10, 1990; revised and accepted January 12, 1990. © 1990 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732°8893/90/$03.50
imens. All the tissue and serum samples (collected from blood) were stored at 20°C. The tissues were homogenized and diluted prior to assay. The concentrations of ciprofloxacin were determined by the high-performance liquid chromatography (HPLC) assay method: the values are referred to as milliliters of serum or grams of wet weight.
RESULTS A total of 29 patients participated in the study. The mean age of the patients was 63.4 years (range, 3988). Five groups of patients were formed according to the interval between the time of drug administration and the resection: group 1, t = 0-15 min; group 2, t = 16-30 rain, group 3, t = 31-60 min; group 4, t = 61-90 min; and group 5, t = 91-162 min. The results are listed in Tables 1-5. The highest mean serum level occurred in group 1 (mean = 1.7; SD = 0.45). An increasing gradient of concentrations from the serum to the muscularis and the mucosa was found in each group (p = 0.05 in groups 1, 2, 3, and 5; p = 0.01 in group 4). If the values of all the patients in all groups are averaged, the concentrations differ by a high level of significance according to the Wilcoxon test (p = 0.001). The concentration of ciprofloxacin in the feces increased up to 5.9 p,g/g. This high value was found in a specimen that was excluded from the passage of feces by a loop colostomy.
DISCUSSION The concentration of ciprofloxacin in the feces and the tunica mucosa was found to be higher than the corresponding serum levels. After IV administration, ciprofloxacin may reach the colonic mucosa either by bile excretion and reabsorption from the colonic
178
T A B L E 1.
A. D 6 r n e r et al.
Groupl(t
= 0-15min;n
= 6)
T A B L E 4.
Group4(t
Level of Ciprofloxacin Time (min)
Muscularis (p,g/g)
Mucosa (lag/g)
7 7 11 11 13 15
1.90 2.30 1.01 1.90 1.80 1.40
9.18 5.07 3.18 1.83 13.30 4.14
10.40 7.66 4.78 5.07 13.20 6.04
Mean SD SEM
1.718 0.450 0.184
7.858 3.334 1.361
Level of significance (Wilcoxon text) for muscularis/serum, mucosa/serum, and mucosWmuscalaris is p = 0.05.
T A B L E 2.
Group2(t
= 16-30min;n
= 5)
Level of Ciprofloxacin Time
Serum
Muscularis
Mucosa
(min)
(~g/ml)
(~g/g)
(~g/g)
16 20 23 27 30
1.43 1.40 1.06 1.54 1.19
5.88 5.22 2.96 5.02 3.61
9.91 5.66 3.53 6.97 3.97
Mean SD SEM
1.324 0.194 0.087
4.538 1.209 0.541
6.008 2.577 1.153
Level of significance (Wilcoxon text) for muscularis/serum, mucosa/serum, and mucosa/muscalaris is p = 0.05.
Time (min)
Serum (~g/ml)
Muscularis (ixg/g)
Mucosa (~xg/g)
61 62 69 75 75 75 83
0.91 0.45 0.62 0.59 0.34 0.90 0.48
4.13 1.54 1.90 2.64 0.94 2.90 1.36
4.40 2.40 2.68 3.35 1.03 4.13 1.72
Mean SD SEM
0.613 0.220 0.083
2.201 1.098 0.415
2.816 1.232 0.466
Level of significance (Wilcoxon text) for muscularis/serum, mucosa/serum, and mucosa/muscalaris is p = 0.01.
l u m e n or b y h e m a t o g e n i c a c c u m u l a t i o n in the b o w e l wall a n d s e c r e t i o n into t h e l u m e n . B r o g a r d et al. (1986) f o u n d t h a t the e l i m i n a t i o n of ciprofloxacin b y bile w a s ~ 0.32 _+ 0.04% of a g i v e n d o s e . Siefert a n d S u w e l a c k (1983) f o u n d t h a t 11% of a n IV d o s e of ciprofloxacin w a s e x c r e t e d b y t h e feces. T h a d e p a l l i a n d c o - w o r k e r s (1984) r e p o r t e d t h a t in a n isolated l o o p of intestine, the levels of ciprofloxacin in the intestinal m u c o s a w e r e t e n f o l d h i g h e r t h a n in t h e serum. The data from our patients support the conc e p t of a h e m a t o g e n i c a c c u m u l a t i o n of the d r u g in the b o w e l wall a n d a c o n s e c u t i v e excretion into the colonic l u m e n . T h e h i g h levels of ciprofloxacin in the tunica m u c o s a shortly after administration ( g r o u p 1) r u n parallel to the s e r u m levels. A r e a b s o r p t i o n f r o m t h e l u m e n after s u c h a s h o r t i n t e r v a l is unlikely. I n a p a t i e n t of g r o u p 3 (t = 40 min), t h e c o n c e n t r a tion of ciprofloxacin w a s s e v e n f o l d h i g h e r in m u c o s a T A B L E 5.
T A B L E 3.
Group3(t
= 31-60min;n
= 7)
Level of Ciprofloxacin
Serum (~g/ml)
6.117 4.312 1.761
= 61-90min;n
Group5(t
= 91-162min;n
= 6)
= 5) Level of Ciprofloxacin
Level of Ciprofloxacin Time (min)
Serum (~g/ml)
Muscularis (lag/g)
Mucosa (lag/g)
35 40 44 53 53
0.98 0.84 1.21 0.70 1.26
4.48 5.86 1.67 1.69 3.26
6.87 6.12 3.91 2.31 3.47
Mean SD SEM
0.998 0.239 0.107
3.392 1.813 0.811
4.536 1.900 1.850
Level of significance (Wilcoxon text) for muscularis/serum, mucosa/serum, and mucosa/muscalaris is p = 0.05.
Time (min)
Serum (lag/ml)
Muscularis (p~g/g)
Mucosa (lag/g)
93 107 124 147 150 162
0.56 0.60 0.47 0.35 1.21 0.35
2.81 1.88 1.02 0.69 1.96 0.92
4.72 2.78 1.44 1.29 4.56 1.67
Mean SD SEM
0.590 0.321 0.131
1.547 0.810 0.331
2.743 1.560 0.637
Level of significance (Wilcoxon text) for muscularis/serum, mucosa/serum, and mucosa/muscalaris is p = 0.05.
Ciprofloxacin Prior to Colon Surgery
than in the serum (feces, 5.0 ~g/g; serum, 0.84 ~g/ml). The passage of feces was excluded by a loop colostomy that was established some months before. The excretion of large molecules, including drugs, by the colonic mucosa is an uncommon phenomenon and its mechanism is not yet understood. Selden et al. (1974) described the excretion of the glycoside ouabain in the feces after ligation of the common bile duct. The importance of an accumulation of ciprofloxacin in the colonic wall and its excretion through the mucosa into the feces is evident. The high concen-
179
trations of ciprofloxacin obtained in the intestine exceeds the minimal inhibitory concentrations (MICs) of a wide variety of aerobic bacteria, even those that are resistant to the drug at usual serum levels. This is the rationale for a prophylactic use in colorectal surgery. Furthermore, the therapeutic safety of ciprofloxacin is expanded in a case of renal failure. Bergan et al. (1990) and Rohwedder et al. (1990) found that the transintestinal elimination became the major route of elimination in patients with renal impairment. Thus, excessive increases in drug concentration in these patients is avoided.
REFERENCES Bergan T, Dalhoff A, Rohwedder R (1990) Pharmacokinetics of ciprofloxacin. Infection (in press). Brogard JM, Arnaud JP, Jehl F, BlickleJF, Monteil H (1986) Ciprofloxacin: evaluation of its biliary excretion in man. In Proceedings of the First International Ciprofloxacin Workshop. Leverkusen, 6-8, 1985. Eds., HC Neu and H. Weuta. Amsterdam: Excerpta Medica. Rohwedder RW, Bergan T, Thornsteinsson SB, Scholl H (1990) The transintestinal elimination of ciprofloxacin. Diagn Microbiol Infect Dis (in press).
Selden R, Margolies MN, Smith TW (1974) Renal and gastrointestinal excretion of ouabain in dog and man. J Pharmacol Exp Ther 188:615-623. Siefert HM, Suwelack D (1983) 14C Bay o 9687: Pharmacokinetic study in rats. Pharma-Bericht No. 11783 (P) Bayer AG. Thadepalli H, Mandal AK, Dausal MD (1984) Ciprofloxacin IV in microflora of colon and experimentally isolated jejunal segment (Abstr). Fifteenth International
Congress of Chemotherapy, Istanbul.
