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65—4235（ 15 ）Compatibility of carbapenem antibiotics withnafamostat mesilate in arterial infusion therapyfor severe acute pancreatitis:
Stabilities of carbapenem antibiotics
YUKIHIRO HAMADA1, HIROSHI IMAIZUMI2, SHIROU MIYAZAWA2,MITSUHIRO KIDA2, KAZUI SOUMA3, WASABUROU KOIZUMI2,KEISUKE SUNAKAWA4 and MASAKAZU KUROYAMA1
1

2

Department of Pharmacy Kitasato University East Hospital
Department of Gastroenterology Kitasato University Hospital
3Department of Emergency and Critical Care Medicine,Kitasato University School of Medicine
4Infectious Disease Science, Kitasato University,
Kitasato Institute for Life Sciences(Received for publication May 9, 2012)

The effectiveness of continuous regional arterial infusion therapy using proteaseinhibitors and antibiotics for severe acute pancreatitis has been previously reported.
Carbapenem antibiotics, which have a broad antibacterial spectrum, and nafamostat
mesilate are often used for this therapeutic approach. We investigated the compatibilityof various carbapenem antibiotics with nafamostat mesilate.
Carbapenem antibiotics were dissolved in 30 mL of saline or 5% glucose and theappearance, pH, and stability of the solutions were determined. The changes in eachcarbapenem antibiotic solution after mixing with nafamostat mesilate were theninvestigated.
Biapenem and doripenem showed a residual rate of 侒90% at 8 hours after
dissolution in saline or 5% glucose and exhibited an appropriate appearance andresidual rate (侒90%). After mixing with nafamostat mesilate, biapenem maintained aresidual rate of 侒90% for the longest time period (8 hours) and exhibited a slightcoloration, followed by doripenem (6 hours) and meropenem dissolved in saline.
The other carbapenem antibiotics that were tested exhibited changes in appearance
or their residual rate.
Biapenem and doripenem, which exert their effects in a time-dependent manner,
can be infused for prolonged periods for the treatment of not only severe acutepancreatitis, but also other severe infections.

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Introduction
In severe acute pancreatitis (SAP), pancreatic infectious complications are a critical factor
causing poor prognosis, and preventive antibiotic administration has been reported to reduce thefrequency of pancreatic infectious complications and the incidence of infectious pancreatic necrosis, signi¿cantly improving mortality1–4). As a speci¿c therapy to prevent this, the effectiveness ofcontinuous regional arterial infusion therapy (CRAI) with protease inhibitors and antibiotics has
been reported5–9).
Generally, the protease inhibitor, nafamostat mesilate is combined with a carbapenem antibiotic when performing CRAI for SAP6–10). This procedure results in the distribution of these drugs
to the pancreatic tissue at high concentrations11–13).
We previously prepared a manual for performing CRAI for SAP14) using biapenem, which is
physically and chemically more stable against nafamostat mesilate than other carbapenem antibiotics, and favorable treatment results have been obtained using this manual15). In the present
study, we measured the in vitro stability of all the carbapenem antibiotics presently available on
the Japanese market that are generally used after mixing with nafamostat mesilate.

Material and Methods
The test substances were comprised of the protease inhibitor nafamostat mesilate (Futhan 50,for injection; Torii Pharmaceutical Co., Ltd.) and all the carbapenem antibiotics presently available on the Japanese market: biapenem (Omegacin, for infusion [0.3 g]; Meiji Seika Pharma Co.,Ltd.), imipenem/cilastatin sodium (Tienam, for intravenous infusion [0.25 g]; MSD K.K.), panipenem/betamipron (Carbenin, for infusion [0.5 g]; Daiichi Sankyo Co., Ltd.), meropenem (Meropen, vial for infusion [0.5 g]; Dainippon Sumitomo Pharma Co., Ltd.) and doripenem (Finibax,for infusion [0.25 g]; Shionogi & Co., Ltd.). Physiological saline (Otsuka normal saline; Otsuka
Pharmaceutical Factory, Inc.) or a 5% glucose injection (Otsuka Glucose Injection 5%; Otsuka
Pharmaceutical Factory, Inc.) was used as the solution.
To prepare the test solutions, 1 vial of each carbapenem antibiotic was dissolved in 30 mL ofsolution based on the doses used in clinical practice15) to yield solutions containing 10 or 20 mg/mL of biapenem, 16.7 mg/mL of imipenem, 16.7 mg/mL of panipenem, 16.7 mg/mL of meropenem, or 8.3 mg/mL of doripenem. Ten milliliters of each solution was used to determine theappearance, pH and residual rate as the control solution, and was compared with test solutions
prepared by adding 2 mL of 5 mg/mL nafamostat mesilate to the solutions containing each carbapenem antibiotic. As a dose of 0.6 g of biapenem is sometimes used for the treatment of SAP at
our institution, 2 vials of biapenem were dissolved in 30 mL of solution as an additional test. Thesolutions were kept at 25°C and 1000 lx (in a light-exposed chamber). Samplings were performed

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65—4237（ 17 ）at 0 (immediately after mixing), 1, 3, 6, 8, 12 and 24 hours after mixing.
Regarding the compatibility tests and the evaluation methods, the test and control solutions
were visually observed and their pH levels were measured. Then, the solutions were ¿ltered witha 0.22 ȝm pore-size membrane ¿lter and puri¿ed water was added to the ¿ltrates for dilution, so
as to prepare the sample solutions for high-performance liquid chromatography (HPLC). Referring to the measurement method of KURIHARA et al.,16) these sample solutions were then used for
HPLC under the following conditions to measure the peak area of each carbapenem antibiotic
and to calculate the peak area ratio for the solution immediately after mixing, enabling the residual titer rate to be obtained: detector, ultraviolet absorption photometer; measurement wavelength, 300 nm; column, Luna 5u C18(2) 100A (250×4.6 mm; Phenomenex); column temperature, constant temperature around 30°C; sample cooler temperature, 5°C; mobile phase (0.1 M
phosphate buffer [pH 7.8]: methanol), 92 : 8 for biapenem and imipenem, 87 : 13 for panipenem,
and 78 : 22 for meropenem and doripenem; mobile phase Àow rate, 1 mL/min; and analysis times,
6 min. for biapenem and imipenem test and control solutions, 10 min. for panipenem test solution,
6 min. for panipenem control solution, 25 min. for meropenem and doripenem test solutions,
11 min. for meropenem control solution, and 7 min. for doripenem control solution.

Results
Table 1-1 shows the sequential residual rates of each carbapenem antibiotic dissolved in saline in the control solutions. Panipenem and meropenem were reduced to less than 90% at 8hours. When dissolved in 5% glucose, meropenem was reduced to less than 90% at 6 hours, andimipenem and panipenem were reduced to less than 90% at 8 hours, as shown in Table 1-2.
In the compatibility test of each carbapenem antibiotic dissolved in saline with nafamostat
mesilate, panipenem precipitated immediately after mixing and imipenem also precipitated 3hours after mixing. Regarding the residual rates, panipenem was reduced to less than 90% at 3hours after mixing, and meropenem and doripenem were reduced to less than 90% at 8 hours
after mixing, as shown in Table 2-1. Likewise, when dissolved in 5% glucose, panipenem precipitated immediately after mixing and imipenem also precipitated 1 hour after mixing (Table 2-2).
As for the residual rate, panipenem was reduced to less than 90% at 3 hours after mixing, meropenem was reduced to less than 90% at 6 hours after mixing, and doripenem was reduced toless than 90% at 8 hours after mixing, as shown in Table 2-2. Biapenem (10 and 20 mg/mL)
showed a residual rate of 90% or more, with slight coloration, at 8 hours after mixing (Table 2-2).

1-1. Sequential changes in control solutions using saline (25°C, 1000 lx).

Table 1. Compatibility tests of each carbapenem antibiotic in solution.

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1-1. Sequential changes in control solutions using saline (25°C, 1000 lx). (Continued)

Table 1. Compatibility tests of each carbapenem antibiotic in solution. (Continued)

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239（ 19 ）1-2. Sequential changes in control solutions using 5% glucose injection (25°C, 1000 lx).

Table 1. Compatibility tests of each carbapenem antibiotic in solution. (Continued)

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1-2. Sequential changes in control solutions using 5% glucose injection (25°C, 1000 lx). (Continued)

Table 1. Compatibility tests of each carbapenem antibiotic in solution. (Continued)

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241（ 21 ）2-1. Sequential changes in mixed solutions using saline (25°C, 1000 lx).

Table 2. Compatibility tests of each carbapenem antibiotic mixed with nafamostat mesilate.

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2-1. Sequential changes in mixed solutions using saline (25°C, 1000 lx). (Continued)

Table 2. Compatibility tests of each carbapenem antibiotic mixed with nafamostat mesilate. (Continued)

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243（ 23 ）2-2. Sequential changes in mixed solutions using 5% glucose injection (25°C, 1000 lx).

Table 2. Compatibility tests of each carbapenem antibiotic mixed with nafamostat mesilate. (Continued)244（ 24 ）THE JAPANESE JOURNAL OF ANTIBIOTICS
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2-2. Sequential changes in mixed solutions using 5% glucose injection (25°C, 1000 lx). (Continued)

Table 2. Compatibility tests of each carbapenem antibiotic mixed with nafamostat mesilate. (Continued)

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Discussion
The prevention of pancreatic infectious complications is important in patients with SAP, andinfectious pancreatic necrosis caused by the translocation of enteric bacteria, which are often thecauses of such infections, has an extremely poor prognosis17,18). In recent years, the usefulness ofCRAI for SAP has been reported9,10,19,20), and the indication for CRAI is generally considered tobe necrotizing pancreatitis. However, pancreatic infection and pancreatic necrosis are dif¿cult topredict, and CRAI may be applicable to patients diagnosed as having SAP. By starting CRAI
early, we think that pancreatic necrosis may be preventable.
Enteric Gram-negative bacilli, such as Escherichia coli 21,22) and Enterobacter 22), Pseudomonas aeruginosa and MRSA have been separately identi¿ed in lesions of infectious pancreatic necrosis16–23). Carbapenem antibiotics, which have a broad antibacterial spectrum, show excellent
antimicrobial activity against these causative bacteria, with the exception of MRSA, and are considered to be bacteriologically useful. When using carbapenem antibiotics, it is important to prolong the duration of the drug concentration above the minimum inhibitory concentration (MIC)from the standpoint of the pharmacokinetics-pharmacodynamics (PK-PD)24,25), and excellent effects can be expected by prolonging the administration time and increasing the number of doses.
In CRAI, a syringe pump is used to infuse carbapenem antibiotics at higher concentrations thanusual. Therefore, when considering which antibiotics should be used, the selection of an antibiotic that is stable against nafamostat mesilate for a long period of time and that can be infused in
combination with nafamostat mesilate is desirable. Regarding biapenem, higher residual rates atconcentrations of both 10 and 20 mg/mL were observed, compared with the residual rates forother carbapenem antibiotics (Tables 2-1, 2-2), supporting our choice of this drug for CRAI. The
reason for the lower residual rates in this study, compared with those in previous reports15), wasthought to be that higher concentrations of each carbapenem antibiotic were used. For general
CRAI, the combination of nafamostat mesilate and imipenem/cilastatin or meropenem has often
been used5,6,9,10,20). However, when the number of infusion routes is limited, the infusion of nafamostat mesilate is often temporarily discontinued; instead, only imipenem/cilastatin or meropenem is infused. With the use of biapenem and doripenem, the techniques required for the infusionof imipenem/cilastatin, such as catheter irrigation and catheter air removal, become unnecessary,reducing catheter dif¿culties. We have experienced crystal precipitation when using panipenem/betamipron and imipenem/cilastatin in clinical practice, and crystal precipitation was also seen in
the present study immediately or at 1 hour after mixing. Therefore, these drugs should be usedwith caution. The usefulness of biapenem and doripenem was also suggested from the viewpointof risk management.
As biapenem has been reported to be more effectively distributed to the pancreas than imipenem/cilastatin in an animal model for SAP26), these results suggest that biapenem may have aAug. 2012

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65—4247（ 27 ）bene¿cial effect on CRAI for SAP. It may be needed to evaluate the bacteriological ef¿cacy inthe future.

References
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2) PEDERZOLI, P.; C. BASSI, S. VESENTINI, et al.: A randomized multicenter clinical trial of antibiotic
prophylaxis of septic complications in acute necrotizing pancreatitis with imipenem. Surg. Gynecol. Obstet. 176: 480〜483, 1993
3) BASSI, C.; G. MANGIANTE, M. FALCONI, et al.: Prophylaxis for septic complications in acute necrotizing pancreatitis. J. Hepatobiliary Pancreat. Surg. 8: 211〜215, 2001
4) BASSI, C.; M. FALCONI, G. TALAMINI, et al.: Controlled clinical trial of peÀoxacin versus imipenemin severe acute pancreatitis. Gastroenterol. 115: 1513〜1517, 1998
5) TAKEDA, K.; S. MATSUNO, M. SUNAMURA, et al.: Continuous regional arterial infusion of proteaseinhibitor and antibiotics in acute necrotizing pancreatitis. Am. J. Surg. 171: 394〜398, 1996
6) TAKEDA, K.; S. MATSUNO, M. OGAWA, et al.: Continuous regional arterial infusion (CRAI) therapy
reduces the mortality rate of acute necrotizing pancreatitis: results of a cooperative survey inJapan. J. Hepatobiliary Pancreat. Surg. 8: 216〜220, 2001
7) ANAI, H.; H. SAKAGUCHI, H. UCHIDA, et al.: Continuous arterial infusion therapy for severe acutepancreatitis: correlation between CT arteriography and therapeutic effect. J. Vasc. Interv. Radiol.
10: 1335〜1342, 1999
8) OKADA, T.; H. KOMORIYAMA & H. UCHIDA: Continuous arterial infusion of protease inhibitor in intensive care acute pancreatitis [in Japanese]. Shuchu Chiryo 9: 555〜562, 1997
9) PIA㵼CIK, M.; G. RYDZEWSKA, J. MILEWSKI, et al.: The results of severe acute pancreatitis treatment
with continuous regional arterial infusion of protease inhibitor and antibiotic: a randomized controlled study. Pancreas 39: 863〜867, 201010) SHIRAI, K.; K. TANJOU, K. SHINOHARA, et al.: The effectiveness of continuous regional arterial infusion therapy with meropenem in severe acute pancreatitis compared with imipenem: A prospective, randomized study [in Japanese]. Jpn. J. Gastroenterol. Surg. 41: 1〜11, 200811) MIKAMI, Y.; K. TAKEDA, K. MATSUDA, et al.: Rat experimental model of continuous regional arterial infusion of protease inhibitor and its effects on severe acute pancreatitis. Pancreas 30: 248〜253, 2005
12) KAKUGAWA, Y.; K. TAKEDA, M. SUNAMURA, et al.: Effect of continuous arterial infusion of proteaseinhibitor on experimental acute pancreatitis induced by closed duodenal loop obstruction. Nihon
Shokakibyo Gakkai Zasshi 87: 1444〜1450, 1990
13) SATOH, H.; M. HARADA, S. TASHIRO, et al.: The effect of continuous arterial infusion of gabexate
mesilate (FOY-007) on experimental acute pancreatitis. J. Med. Invest. 51: 186〜193, 2004
14) HAMADA, Y.; H. IMAIZUMI, H. NAITO, et al.: Development of a guideline for continuous regional
arterial infusion of biapenem in a patient with severe acute pancreatitis [in Japanese]. J. Jpn. Soc.
Hosp. Pharm. 43: 187〜190, 200715) HAMADA, Y.; H. IMAIZUMI, M. WATANABE, et al.: Continuous regional arterial infusion therapy withbiapenem and nafamostat mesilate for severe acute pancreatitis [in Japanese]. J. Jpn. Pancreas
Soc. 23: 578〜586, 2008

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Aug. 201216) KURIHARA, Y.; J. KIZU & S. HORI: Simple and rapid determination of serum carbapenem concentrations by high-performance liquid chromatography. J. Infect. Chemother. 14: 30〜34, 2008
17) FURUYA, T.; T. SOENO & M. KOMATSU: Strategy for bacterial translocation in acute pancreatitis.
Nihon Shokakibyo Gakkai Zasshi 101: 502〜509, 200418) ISAJI, S. & S. UEMOTO: Pathophysiology and management of infectious complications in severacute pancreatitis [in Japanese]. Tan to Sui. 23: 825〜830, 2002
19) TAKEDA, K.; J. YAMAUCHI, K. SHIBUYA, et al.: Bene¿t of continuous regional arterial infusion ofprotease inhibitor and antibiotic in the management of acute necrotizing pancreatitis. Pancreatology 1: 668〜673, 200120) IMAIZUMI, H.; M. KIDA, H. NISHIMAKI, et al.: Ef¿cacy of continuous regional arterial infusion of aprotease inhibitor and antibiotic for severe acute pancreatitis in patients admitted to an intensive
care unit. Pancreas 28: 369〜373, 2004
21) ACOSTA, J. M.; O. M. RUBIO GALLI, R. ROSSI, et al.: Effect of duration of ampullary gallstoneobstruction on severity of lesions of acute pancreatitis. J. Am. Coll. Surg. 184: 499〜505, 199722) SENNINGER, N.; F. G. MOODY, J. C. COELHO, et al.: The role of biliary obstruction in the pathogenesis of acute pancreatitis in the opossum. Surgery 99: 688〜693, 198623) TAKEYAMA, N.: Pathophysiology, diagnosis and treatment of severe acute pancreatitis infectious
complication with severe acute pancreatitis. J. Biliary Tract & Pancreas 27: 31〜36, 2006
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65—4249（ 29 ）重症急性膵炎（SAP）動注療法におけるカルバペネム系抗菌薬とnafamostat mesilate（NM）の配合変化試験―カルバペネム系抗菌薬の安定性―
浜田幸宏 1）・今泉弘 2）・宮澤志朗 2）・木田光広 2）・

相馬一亥 3）・小泉和三郎 2）・砂川慶介 4）・黒山政一 1）1）

北里大学東病院薬剤部

2）

北里大学医学部消化器内科学

3）

北里大学医学部救命救急医学4）

北里大学北里生命科学研究所

近年，重症急性膵炎（SAP）に対する蛋白分解酵素阻害薬・抗菌薬持続動注療法（以下，動注療法）の有効性を示す報告が散見される。その動注療法では広域抗菌ス
ペクトルを有するカルバペネム系抗菌薬と nafamostat mesilate（NM）が用いられることが多い。我々は，日本の臨床で上市されている全カルバペネム系抗菌薬と NM との配合後のカルバペネム系抗菌薬の配合変化について検討した。カルバペネム系抗菌薬を生理食塩液または 5% ブドウ糖 30 mL で溶解し，外観，pH および安定性について観察または測定した。また，各カルバペネム系抗菌薬溶液と NM 溶液との配合後の変化について検討した。各カルバペネム系抗菌薬の生理食塩液および 5% ブドウ糖液で溶解後 8 時間まで残存率が 90% 以上を示したのは，Biapenem（BIPM）と Doripenem（DRPM）であり，外観および残存率（90% 以上）とも問題ないと判断された。NMと各カルバペネム系抗菌薬を配合後の変化については，僅かな着色と 90% 以上の残存率を示したのは BIPM の 8 時間が最も長く，次いで，DRPM の 6 時間，生理食塩液で溶解した MEPM であった。他のカルバペネム系抗菌薬では外観および残存率の変化を認めた。時間依存的に効果を発揮するカルバペネム系抗菌薬では SAP のみに限らず他の重症感染症においても BIPM および DRPM は点滴時間を延長した投与が可能と考えられた。