KAWAMURA, MASAO

KUYAMA, TAKESHI

MIYAMOTO, MASAAKI

SUDO, TAKAAKI

Kyoto University Research Information Repository

TitleAssesment of Antimicrobial Penetration into the PancreaticJuice in DogsAuthor(s)MIYAMOTO, MASAAKI; SUDO, TAKAAKI; KUYAMA,TAKESHI; KAWAMURA, MASAOCitation日本外科宝函 (1990), 59(3): 205-210Issue Date1990-05-01URL http://hdl.handle.net/2433/204451RightType Departmental Bulletin PaperTextversionpublisherKyoto UniversityArch Jpn Chir 59(3), 205～210, Mai, 1990 Assesment of Antimicrobial Penetration into the Pancreatic Juice in Dogs MASAAKI MIYAMOTO, TAKAAKI Suoo, TAKESHI KuvAMA and MAsAo KAWAMURA Second Department of Surgery, Kinki University School of Medicine, Osaka, Japan. (Director: Prof. Tak白 hiKuyama M. D. Ph. D) R氏自vedfor Publication, Jan. 29, 1990 Summary The pancreatic ductal penetration of piperacillin, cefuzonam, fosfomycin and netilmicin, in-jected intravenously, was studied in four dogs with chronic pancreatic fistula. Serum and pancreatic juice were collected simultaneously, frozen, and later assayed for antibiotic concentration. Each an-tibiotic achieved its therapeutic serum level. The pancreatic ductal levels of piperacillin and cefuzonam were therapeutic, in contrast, the fosfomycin and netilmicin levels were subtherapeutic. These results are considered to be of interest in prevention and treatment of pancreatic infections. Introduction In a review of 10,435 cases of endoscopic retrograde cholangiopancreatography (ERCP) Bilbao et al. 1), demonstrated that ERCP can induce pancreatic sepsis in patients with pancreatitis or pan-creatic duct obstruction and that retention of contrast medium readily leads to abscess formation in those with pseudocysts of the pancreas. Considering the risk of infectious complications ofERCP, Davis et al.2l, emphasized the necessi-ty of prophylactic parenteral administration or the incorporation of antibiotics in a contrast medium. There is, furthermore, a consensus about the necessity for systemic administration of an-tibiotics to prevent secondary following acute pancreatitis. Although systemic antibiotic therapy, targeted at the organisms associated with diseases of the pancreas, is required in various situations, the penetrance of antibiotics into pancreatic juice has not been sufficiently investigated. Moreover, only a small number of antibiotics have been included in the evaluations to date, and pancreatic ductal penetration of new antibiotics, which have been developed, remains unknown. In this study, we prepared a dog model with chronic pancreatic fistula and studied the antibiotic concentrations in the pure pancreatic juice. Key words: Pancreatic ductal penetration, Antibiotic concentrations in the pancreatic juice, Minimum inhibitory con-centration80 (MIC80), Antibiotic therapy, Dog with chronic pancreatic fistula. 索引語 抗生剤牌液移行性， F草液抗生剤濃度， 80%発育阻止濃度（MIC80）， 抗生剤療法，慢性解痩犬．Present address: Second Department of Surgery, Kinki University School of Medicine, 377-2 Ohnohigasht, Osakasayama-City, Osaka 589, Japan 206 日外宝第59巻第3号（平成2年5月）STOMACH PANCREATIC FISTULA (modified Herrera cannula) Fig. 1 Operative schema for experimental model. Materials and Methods The experimental model is described first. Taking advantage of the anatomical characteristic of the dog that the pancreatic duct and bile duct open in separate duodenal papillae, a chronic pan-creatic fistula was constructed using a modified Herrera cannula in 4 adult mongrel dogs of either sex weighing 18-29 Kg according to出Emethod of Hosotani et al. 3) (Fig. 1). A median laparotomy was performed under sodium pentobarbital anesthesia. First, the accessory pancreatic duct was incised and ligated, and a duodenal pouch about 5 cm in lenght constructed at the intact papillary opening of the main pancreatic duct. Reconstruction was made by end-to-end duodenoduodenostomy, and an external pancreatic fistula was created by inserting a modified Herrera cannula between the duodenal pouch and the duodenum. This cannula, which prevented entry of intestinal juice, allow-ed collection of the pure pancreatic juice through the duodenal pouch for experiments and preserved the physiologic flow of the pancreatic juice into the duodenum during non-study periods. Food and water intake was suspended for 5 days after operation, during which time the animals were maintain-ed by total parenteral nutrition via the external jugular vein. The animals were used for the ex-periments when the oral dietary intake was returned to the preoperative level or above after a recovery period of at least 3 weeks. Table 1 Assayed drug combination and dosage Group n Drugs Dosage 4 Cefuzonam (CZON) 1 g Fosfomycin (FOM) 1 g n 4 Piperacillin (PIPC) 1 g Netilmicin (NTし） 100mg ANTIMICROBIAL PENETRATION INTO THE PANCREATIC JUICE 207 Table 2 Antibiotic levels in serum and pancreatic jmce (μg/ml) Drug Serum Panceatoc JU•ce 5’ 60’ 5' 60’ ·~~~：~· ：：~；；~~ FOM 171.8±2.7 60.9±6.3 4.8±1.9 , 28±1.0 * PIPC 184.8±13.1 38.8±3.8 10.6±3.7 147±5.6 NTL 24.0全I.I 1.0±0.5 0.2土日17 0.95±0.3 M:SEM.事P<O.回（師団m帥 'Odto NTL) Four antibiotics, namely piperacillin (PIPC) of penicillin group, cefuzonam (CZON) of the cephalosporin group, netilmicin (NTL) of the aminoglycoside group, and fosfomycin (FOM), were examined. According to the method of Sugawa et al.8l, two of these drugs were dissolved in 20 ml physiologic saline and administered simultaneously9l by intravenous injection in the combinations and doses, (shown in Table 1 ),over 2 minutes exactly. Peripheral blood and pancreatic juice were collected 5 and 60 minutes after the beginning of the intravenous injection. The season for this is that al of these antibiotics show a peak blood concentration about 5 minutes after intravenous i吋ec-tion and have a half-life in the serum of about 60 minutes5l, and also because a peak biliary concentra-tion can be observed about 60 minutes after i吋ection川. Secretin (50 units), was then administered before the antibiotics in order to stimulate external pancreatic secretion. After cold centrifugation, the samples were stored at -20°C until assays. PIPC and CZON were assayed by high perfor-mance liquid chromatography9l, NTL by fluorescence immunoassay, and FOM by the test-standard curve method after alkali degradation. Results Table 2 shows the serum concentrations of CZON and FOM in group 1 at 5 and 60 minutes. In the pure pancreatic juice, the CZON and FOM concentrations were 4.4± 1.0 (M±SEM) and 4.8士1.9μg/ml, respectively at 5 minutes and 9.6±4.7 and 2.8±1.0 μg/ml, respectively at 5 minutes and 9.6±4.7 and 2.8±1.0 μg/ml, respectively, at 60 minutes. In group I, the serum concentrations of PIPC and NTL at 5 and 60 minutes are as shown m Table 2. The concentrations in pancreatic juice were 10.6± 3.0 and 0.2±0.17 μg/ml for PIPC and NTL at 5 minutes and 14.7±5.6 and 0.95±0.34 μg/ml, respectively, at 60 minutes. Significant di-fferences in the concentrations in pancreatic juice could be observed only between NTL and the other 3 drugs at 5 and 60 minutes (P<0.05, Table 2). Discussion Study of the penetrance of antibiotics into the pancreatic juice was first done by Howard et al. 4l, m 1951. They examined the concentrations of penicillin, sulfadiazine, streptomycin, the aureomycin in a 32・year-oldpatient with an external pancreatic fistula after a gunshot wound and reported good tr如 sportof penicillin and sulfadiazine to pancreatic juice. In the pancreatic juice col-208 日外宝第59巻第3号（平成2年5月）MIC80 MI C凹（μg/ml)Bae illよ~ 0・05 0・1 0.2 0・39 0・78 1.56 3.13 6.25 12.5 25 50 100 Escherichia coli Klebsoella pneu肉、。noaeBacteroodes fragilis PIPC Ant1b1ot1c levels 1n pancreatic juice ( 60min.) }Lg/ml CZON ... 一一・PIPC←ー －FO M 酔ー－Fig. 2 Correlation of antibiotic levels in pan口eaticjuice and MIC加・lected by ERCP, W allance et al. 12, examined pancreatic ductal penetration of mezlocillin, metronidazole, trimethoprim-sulfamethoxazole concentrations reached therapeutic levels but the penetration of mezlocillin was unsatisfactory. They also stated that the penetrance into pancreatic juice was good for lipophilic drugs such as chloramphenicol, metronidazole, and trimethoprim but poor in water soluble dnゅ suchas tl-lactams and aminoglycosides. Furthermore, they suggested that weakly acidic drugs may better penetrate the alkaline pancreas. Sugawa et aJ.Bl, also showed good pancratic penetration of penetration of ampicillin, mezlocillin, cefamandole, gentamicin, and amikacin in ERCP specimens. Among animal experiments, Rubinstein et al. 7l,produced a duodenal fistula in adult mongrel dogs using a modified Thomas cannula and examined penetration of clindamycin into pancreatic secretion. The concentration of this antibiotics in pancreatic juice was 1.32 ± 5.5 μg/ml, which was 今ー6%of its serum concentration. Trudel et al.1l, produced hemorrhagic pancreatitis by infusing trypsin and bile into the pancreatic duct of adult mongrel dogs and then studied the tissue concentra-tions of antibiotics in the normal pancreas and pancreas during pancreatitis. According to their results, the concentrations of clindamycin, metronidazole, and chloramphenicol reached the therapeutic levels in both the normal pancreas and inflammed pancreas while those of gentamicin, cefazolin, and tetracycline did not. On the basis of these findings, they recommended the first drugs in pancreatic infections. ANTIMICROBIAL PENETRATION INTO THE PANCREATIC JUICE 209 The history of the study of pancreatic ductal penetration of antibiotics has been summarized above. According to our results, the concentration in the pancreatic juice was highest for PIPC at 14.7±5.6 μg/ml, followed by CZON at 9.6土4.7 μg/ml, and FOM at 2.8土1.0μg/ml. These results were comparable to those of Howard et al. 4) As for aminoglycosides, their penetration into the pancreatic juice was poor as reported by Sugawa et al. 8), as well as Trudel et al.11) We studied minimum inhibitory concentration (MIC), especiallyお1IC80against clinically isolated bacteria, of PIPC, CZON, and FOM in consideration of their clinical use. MIC80 against Escherichia coli, which is frequently responsible for intraperitoneal infections, was 6.25, 0.1 and 12.5 μg/ml for PIPC, CZON, and FOM, respectively; that against Klebsiella pneumoniae was 12.5, 0.1, and 50.0 μg/ml, respectively; that against Bacteroides jト・agiliswas 12.5, 6.25 and 25.0 μg/ml, respectively. Also, in light of the antibacterial potency of each drug, PIPC and CZON are considered to have therapeutic E百ects(Fig. 2). No significant di釘erences,however, were observed in the concentration of PIPC, CZON, and FOM in the pancreatic juice, and the concentration of NTL alone was significantly di-fferent from those of the other three drugs. From these observations, PIPC and CZON appear to be comparable with respect to the penetrance into the pancreatic juice, but further studies with a larger number of samples are needed. Studies with other antibiotics are also in progress. At any rate, the present results hopefully may seive as a future reference in the treatment of pancreatic infections as well as in the development of new drugs. Acknowledge皿ents The author expresses sincere thanks to K Inoue., First Department of Surgerγ，Kyoto University School of Medicine, for his instructions in the preparation of the chronic pancreatic fistula in the dog. References 1) Bilbao MK, Dotter CT, Lee TH, Katon RM: Complications of endoscopic retrograde cholangiopancreatography (ERCP); a study of 10,000 cases. Gastroenterology 70: 31十 320,1976. 2) Davis JL, Milligan FD, Cameron JL: Septic complications following endoscopic retrograde cholangiopan-creatography. Surg. Gynecol, Obstet. 140: 365-367, 1975 3) Hosotani R, Inoue K, Okuno T, Miyata S, Tobe T: E百ectof gastrin releasing peptide on exocrine pancreatic secretion and plasma levels ofCCK and PP in conscious dogs. Jpn. J.Gastroenterol. 82: 66←672, 1985. 5) Nakashima M, Hashimoto H, Takiguchi Y: Phase I study of L-105. Chemotherapy 34: 133-148, 1986. 6) Nielsen SW, Bishop EJ: The duct system of the canine pancreas. Am J Vet Res 15：・ 266-271,1954 7) Rubinstein E, Haspel J, Tadmor A, Ben-Ari G: Clindamycin excretion in the pancreatic fluid of dogs. Scand J Infect Dis 11: 147-149, 1979. 8) Sugawa C, Kon Y, Lucas CE, Ledgerwood AM: Assessment of antimicrobial penetrance into the pancreatic juice. Gastroenterol. Endosc. 30: 678--682, 1988 9) Tanimura H, Kobayashi N, Saito T: Chemotherapy of biliary tract infection (XXIV): Tissue concentration in gallbladder, biliary excretion and clinical e仔ectsunder 6315-s (FlomoxeηChemotherapy 35: 852 873, 1987 10) Tanimura H, Kobayashi N, Saito T: Chemotherapy in biliary tract infection (XXVIII) Biliary excretion, tissue concentration in gallbladder and dini日 leffects in patients treated with L-105- Chemotmerapy 34: 601-617, 1986. 1) Trudel JL, Mutch DO, Broun PR, Richards GK, Brown RA: Antibiotic therapy for p四 creaticsepsis: Di-百erencesin bioactive blood and tissue level. Surg Forum 33: 26-27, 1982 12) Wallace JR, Cushing RD, Bawdon RE, Sugawa C, Lucas CE, Ledgerwood AM: Assessment of antimicrobial penetrance into the pancreatic juice in humans. Surg. Gynecol. Obstet. 162: 313-316, 1986. 210 日外宝第59巻第3号（平成2年5月）和文抄録抗生剤醇液移行性に関する実験的評価近畿大学医学部第2外科学教室（主任久山 健教授）宮本正章，須藤峻章，久山 健，河村正生勝臓を標的臓器として抗生剤の全身投与を必要とす 度は， PIPC: 14.7±5.6 μglml であり， CZON:9.6 る機会が多々 あるにもかかわらず，抗生剤の勝液移行 ±4.7 μglml, FOM: 2.8±1.0 μg/ml, NTL: 0.2±0.17 性については，いまだ充分には検索されていなレ．そ μglmlであった．そして，血清濃度との比較，各種薬こで著者らは， t峰雄雑種成犬4頭を用いて慢性降痩 剤の MIC80との検討により， piperacillin,cefuzonam 犬を作製し，各種抗生剤の勝液移行性について実験的 の醇管内への移行性は優れており， fosfomycin,に検討した．検討した薬剤は， piperacillin(PIPC). netilmicinて‘は治療域に達していないと考えられたcefuzonam (CZON), netilmicin (NTL), fosfomycin これらの結果は，騨織に関連する感染症の予防および(FOM）の4種の抗生剤である．静注60分後の醇液獲 治療に関して興味深いものであると思われた．

抗生剤膵液移行性に関する実験的評価

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抗生剤膵液移行性に関する実験的評価

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