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Hepatic gas gangrene caused by Clostridium novyi
Anaerobe 57 (2019) 90e92
Contents lists available at ScienceDirect
Anaerobe journal homepage: www.elsevier.com/locate/anaerobe
Case report
Hepatic gas gangrene caused by Clostridium novyi Noriyuki Watanabe a, Kiyoko Kobayashi b, Giichi Hashikita a, Yoshitada Taji a, Noriomi Ishibashi c, Shinichi Sakuramoto d, Kotaro Mitsutake c, Kenji Ikebuchi b, e, Yasuhiro Ebihara b, * a
Clinical Laboratory, Saitama Medical University International Medical Center, Saitama, Japan Department of Laboratory Medicine, Saitama Medical University International Medical Center, Saitama, Japan c Department of Infectious Diseases and Infection Control, Saitama Medical University International Medical Center, Saitama, Japan d Department of Gastroenterological Surgery, Saitama Medical University International Medical Center, Saitama, Japan e Department of Laboratory Medicine, University Hospital, Saitama Medical University, Saitama, Japan b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 November 2018 Received in revised form 26 March 2019 Accepted 26 March 2019 Available online 4 April 2019
We report the case of a patient with advanced gastric cancer and multiple liver metastases, who presented with bacteremia and hepatic gas gangrene caused by Clostridium novyi (C. novyi). The gas gangrene caused abscesses to form within metastatic lesions. This case highlights the antitumor effects of C. novyi in human. © 2019 Published by Elsevier Ltd.
Handling Editor: Hanna Pituch Keywords: Clostridium novyi Gas gangrene Liver metastasis Matrix assisted laser desorption/ionization time of flight mass spectrometry Sulbactam/ampicillin (SBT/ABPC)
1. Introduction
2. Case report
Clostridium novyi (C. novyi) is a gram-positive, endosporeforming, obligate anaerobic microorganism. It is found in soil and feces and is pathogenic to human and animals. There are 3 subtypes (type A-C) of C. novyi [1]. Type A causes gas gangrene in human and animals. Although it is rare, gas gangrene caused by C. novyi is often fatal, particularly due to the lethal a-toxin secreted by C. novyi [2e4]. Herein we report the case of a patient with gastric cancer, who suffered from bacteremia and hepatic gas gangrene caused by C. novyi, which induced peritonitis due to the rapturing of abscesses.
An 81-year-old male was admitted with severe abdominal pain and hepatic dysfunction (aspatate amonotransferase 1694 U/L, alanine aminotransferase 425 U/L). He had been diagnosed with advanced gastric cancer (T3N2M1: stage IV) with multiple liver metastases (Fig. 1a) three months ago. A staging of his cancer revealed that his cancer was inoperable. Thus, palliative treatment has been started one month ago, and oral anticancer drug treatment (TS-1: Tegafur/Gimeracil/Oteracil) for 18 days before this episode. He has also had diabetes mellitus (DM type II) for six years. DM is controlled with insulin and oral diabetes drugs. During the examination performed at admission, he was alert. His temperature was 39.5oC, blood pressure 171/80 mmHg, and pulse rate 100 beats per minute, respectively. And he exhibited SpO2 value of 97%. Laboratory studies showed hepatic dysfunction with hyperbilirubinemia, leukocytosis (neutrophils: 93.3%), a markedly increased C-reactive protein (CRP) level (35.7 mg/dL), and renal dysfunction. An abdominal computed tomography (CT) scan
* Corresponding author. Department of Laboratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka-shi, Saitama, 3501298, Japan. E-mail address: [email protected] (Y. Ebihara). https://doi.org/10.1016/j.anaerobe.2019.03.018 1075-9964/© 2019 Published by Elsevier Ltd.
N. Watanabe et al. / Anaerobe 57 (2019) 90e92
a
b
Fig. 1. Abdominal computed tomography (CT) images. a) A contrast-enhanced CT scan showed multiple metastases due to gastric cancer. The metastatic lesions were detected in the liver before the C. novyi infection. b) A plain CT scan showed that multiple abscesses had formed at the locations of the liver metastases (arrow) due to a C. novyi infection. Free air formation, which was probably caused by the rupturing of a liver abscess, was also seen (asterisk).
at admission (Fig. 1b) showed multiple regions of air density, indicating the existence of a gas-producing microorganism, and free air formation in the abdomen, which was probably caused by the rupturing of a liver abscess (Fig. 1b asterisk). Interestingly, the abscesses arise at the same locations as the liver metastases (Fig. 1a; arrow), and the metastases had reduced in size, resulting in cavity formation (Fig. 1b). It seemed that the metastatic tissues were being eradicated by the infection. Some of these abscesses were hard to approach for drainage. And his peritonitis was judged to be local. After the interdisciplinary tumor board conference, we chose to employ conservative treatment, involving the administration of 2 g of wide-spectrum meropenem (MEPM) every 12 hours for the infection. The two sets of blood culture samples taken at admission produced positive results in anaerobic culture bottles within 24 hours, and gram-positive rods of various sizes emerged after 48 hours of culturing. Gray colonies with irregular margins grew during subcultures on Brucella HK (hemin, vitamin K1) agar medium (Kyokuto Pharmaceutical, Tokyo, Japan). C. novyi was identified as the pathogenic microorganism by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI Biotyper, Bruker Daltonics; score: 1.812) and 16S rRNA gene analysis (identity 99.9%). Based on these findings, we diagnosed bacteremia and hepatic gas gangrene caused by C. novyi, accompanied by the rupturing of a liver abscess. Although the gas production by the liver abscesses decreased, a high temperature and elevated CRP levels persisted for one week after the administration of MEPM, which had been demonstrated to be effective against C. novyi. Then, we discontinued the administration of MEPM and re-introduced 3 g of sulbactam/ampicillin (SBT/ABPC) every 12 hours. The administration of SBT/ABPC ameliorated the patient's clinical symptoms. Hepatic abscesses were reduced in size and free air disappeared. During this episode, his primary gastric cancer did not progress. One month later, he was transferred to another hospital to continue receiving palliative treatment and terminal care.
91
[8]. Gas-producing bacteria ferment more glucose and produce more carbon dioxide gas in hyperglycemic conditions. Cancer patients have a risk factor for bacterial infections. Our patient suffered from advanced gastric cancer and DM, indicating that he had risk factors for the onset of gas gangrene. C. novyi has been implicated in wound-associated gas gangrene or severe soft tissue infection in injecting drug users [9]. In addition to cases involving injecting drug users, some spontaneous cases of wound-associated gas gangrene have been reported [2e4]. In one case, a C. novyi-related liver abscess arises spontaneously after an abdominal trauma [10]. The following treatments are recommended for Clostridium infections: immediate debridement and antibiotic treatment with penicillin G coupled with clindamycin, which inhibits toxin synthesis, and supportive care [9]. Mixed infection with aerobic bacteria was often seen when anaerobic infection are found. In the present case, we switched the antibiotics from MEPM to SBT/ABPC based on the patient's clinical response, and his condition improved. C. novyi infections are associated with high mortality rates. In intravenous drug users, the mortality rate of such infections was reported to be 32% [2]. Interestingly, in the current case the abscesses caused by C. novyi arise at the same locations as the liver metastases (Fig. 1a), and the metastatic tumors reduced in size and became cavities (Fig. 1b). This patient received TS-1 for gastric cancer and their metastasis. Although TS-1 had the possibility to eradicate the metastases, 18 days administration of TS-1 might be too short to downsize the tumors. And CT scan showed that TS-1 was not effective for primary gastric cancer during this period. Thus, it seemed that the metastatic tumors were being eradicated by the C. novyi infection. Clostridium species prefer anaerobic conditions. It has been reported that metastatic cancer cells were destroyed and gas was produced when C. septicum proliferated in hypoxic tissue [11]. In experimental studies, the adjacent cancer cells were destroyed and inflammatory cells were attracted by the secretion of soluble host factors when C. novyi was allowed to proliferate in tumors [12,13]. It was reported that the postoperative bacterial infections induced remission and cure of tumor in some of cancer patients [14]. Some experimental studies used a derivative of the wild-type strain, called C. novyi-NT, which was generated by removing the a-toxin gene [12,13,15]. In previous report, a patient with leiomyosarcoma was treated with C. novyi-NT. The treatment reduced the size of tumor [15]. The present case highlights the antitumor effects of C. novyi in humans. In summary, we experienced a rare case of hepatic gas gangrene caused by C. novyi. Clinicians need to be aware that hepatic gas gangrene can be caused by C. novyi. Conflicts of interest The authors declare no conflict of interest relevant to this article. Acknowledgments The authors would like to thank medical technicians Masahiro Kodana, Sachie Koyama, Mayu Tabira, and Junpei Matsuno for their technical supports, and the physicians, and nurses who cared for the patient.
3. Discussion References Clostridium species cursive were reported to cause about 7e24% of pyogenic liver abscess [5], and only 5.4% of gas-forming abscesses rupture [6]. Most cases (82.4%) of Clostridial liver abscesses are caused by C. perfringens or C. septicum [7]. It has been suggested that an association exists between Clostridium infections and DM
[1] Y. Sasaki, N. Takikawa, A. Kojima, M. Norimatsu, S. Suzuki, Y. Tamura, Phylogenetic positions of Clostridium novyi and Clostridium haemolyticum based on 16S rDNA sequences, Int. J. Syst. Evol. Microbiol. 51 (2001) 901e904. [2] C.C. Mcguigan, G.M. Penrice, L. Gruer, S. Ahmed, D. Goldberg, M. Black, et al., Lethal outbreak of infection with Clostridium novyi type A and other spore-
92
[3]
[4] [5]
[6] [7]
[8]
[9]
N. Watanabe et al. / Anaerobe 57 (2019) 90e92 forming organisms in Scottish injecting drug users, J. Med. Microbiol. 51 (2002) 971e977. C. Herrera, R. Meehan, V. Podduturi, A.L. Eastman, D.B. Nelson, Maternal death due to Clostridium novyi in an injection drug user, Obstet. Gynecol. 128 (2016) 876e879. C. McGuigan, M. Roworth, Clostridium novyi type A infection: a sporadic fatal case, Scand. J. Infect. Dis. 34 (2009) 209e211. H.-L. Lee, H.-C. Lee, H.-R. Guo, W.-C. Ko, K.-W. Chen, Clinical significance and mechanism of gas formation of pyogenic liver abscess due to Klebsiella pneumoniae
infections due to Clostridium novyi, Anaerobe 50 (2018) 80e84. [10] N.M. Abdel-Haq, P. Chearskul, H. Salimnia, B.I. Asmar, Clostridial liver abscess following blunt abdominal trauma: case report and review of the literature, Scand. J. Infect. Dis. 39 (2007) 734e737. [11] B.A. Urban, R. McCormick, E.K. Fishman, K.D. Lillemoe, B.G. Petty, Fulminant Clostridium septicum infection of hepatic metastases presenting as pneumoperitoneum, Am. J. Roentgenol. 174 (2000) 962e964. [12] L.H. Dang, C. Bettegowda, D.L. Huso, K.W. Kinzler, B. Vogelstein, Combination bacteriolytic therapy for the treatment of experimental tumors, Proc. Natl. Acad. Sci. Unit. States Am. 98 (2001) 15155. [13] N. Agrawal, C. Bettegowda, I. Cheong, J.-F. Geschwind, C.G. Drake, E.L. Hipkiss, et al., Bacteriolytic therapy can generate a potent immune response against experimental tumors, Proc. Natl. Acad. Sci. U.S.A. 101 (2004) 15172. [14] B. Wiemann, C.O. Starnes, Coley's toxins, tumor necrosis factor and cancer research: a historical perspective, Pharmacol. Ther. 64 (1994) 529e564. [15] N.J. Roberts, L. Zhang, F. Janku, A. Collins, R.Y. Bai, V. Staedtke, et al., Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses, Sci. Transl. Med. 6 (2014) 249ra111.
Contents lists available at ScienceDirect
Anaerobe journal homepage: www.elsevier.com/locate/anaerobe
Case report
Hepatic gas gangrene caused by Clostridium novyi Noriyuki Watanabe a, Kiyoko Kobayashi b, Giichi Hashikita a, Yoshitada Taji a, Noriomi Ishibashi c, Shinichi Sakuramoto d, Kotaro Mitsutake c, Kenji Ikebuchi b, e, Yasuhiro Ebihara b, * a
Clinical Laboratory, Saitama Medical University International Medical Center, Saitama, Japan Department of Laboratory Medicine, Saitama Medical University International Medical Center, Saitama, Japan c Department of Infectious Diseases and Infection Control, Saitama Medical University International Medical Center, Saitama, Japan d Department of Gastroenterological Surgery, Saitama Medical University International Medical Center, Saitama, Japan e Department of Laboratory Medicine, University Hospital, Saitama Medical University, Saitama, Japan b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 November 2018 Received in revised form 26 March 2019 Accepted 26 March 2019 Available online 4 April 2019
We report the case of a patient with advanced gastric cancer and multiple liver metastases, who presented with bacteremia and hepatic gas gangrene caused by Clostridium novyi (C. novyi). The gas gangrene caused abscesses to form within metastatic lesions. This case highlights the antitumor effects of C. novyi in human. © 2019 Published by Elsevier Ltd.
Handling Editor: Hanna Pituch Keywords: Clostridium novyi Gas gangrene Liver metastasis Matrix assisted laser desorption/ionization time of flight mass spectrometry Sulbactam/ampicillin (SBT/ABPC)
1. Introduction
2. Case report
Clostridium novyi (C. novyi) is a gram-positive, endosporeforming, obligate anaerobic microorganism. It is found in soil and feces and is pathogenic to human and animals. There are 3 subtypes (type A-C) of C. novyi [1]. Type A causes gas gangrene in human and animals. Although it is rare, gas gangrene caused by C. novyi is often fatal, particularly due to the lethal a-toxin secreted by C. novyi [2e4]. Herein we report the case of a patient with gastric cancer, who suffered from bacteremia and hepatic gas gangrene caused by C. novyi, which induced peritonitis due to the rapturing of abscesses.
An 81-year-old male was admitted with severe abdominal pain and hepatic dysfunction (aspatate amonotransferase 1694 U/L, alanine aminotransferase 425 U/L). He had been diagnosed with advanced gastric cancer (T3N2M1: stage IV) with multiple liver metastases (Fig. 1a) three months ago. A staging of his cancer revealed that his cancer was inoperable. Thus, palliative treatment has been started one month ago, and oral anticancer drug treatment (TS-1: Tegafur/Gimeracil/Oteracil) for 18 days before this episode. He has also had diabetes mellitus (DM type II) for six years. DM is controlled with insulin and oral diabetes drugs. During the examination performed at admission, he was alert. His temperature was 39.5oC, blood pressure 171/80 mmHg, and pulse rate 100 beats per minute, respectively. And he exhibited SpO2 value of 97%. Laboratory studies showed hepatic dysfunction with hyperbilirubinemia, leukocytosis (neutrophils: 93.3%), a markedly increased C-reactive protein (CRP) level (35.7 mg/dL), and renal dysfunction. An abdominal computed tomography (CT) scan
* Corresponding author. Department of Laboratory Medicine, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka-shi, Saitama, 3501298, Japan. E-mail address: [email protected] (Y. Ebihara). https://doi.org/10.1016/j.anaerobe.2019.03.018 1075-9964/© 2019 Published by Elsevier Ltd.
N. Watanabe et al. / Anaerobe 57 (2019) 90e92
a
b
Fig. 1. Abdominal computed tomography (CT) images. a) A contrast-enhanced CT scan showed multiple metastases due to gastric cancer. The metastatic lesions were detected in the liver before the C. novyi infection. b) A plain CT scan showed that multiple abscesses had formed at the locations of the liver metastases (arrow) due to a C. novyi infection. Free air formation, which was probably caused by the rupturing of a liver abscess, was also seen (asterisk).
at admission (Fig. 1b) showed multiple regions of air density, indicating the existence of a gas-producing microorganism, and free air formation in the abdomen, which was probably caused by the rupturing of a liver abscess (Fig. 1b asterisk). Interestingly, the abscesses arise at the same locations as the liver metastases (Fig. 1a; arrow), and the metastases had reduced in size, resulting in cavity formation (Fig. 1b). It seemed that the metastatic tissues were being eradicated by the infection. Some of these abscesses were hard to approach for drainage. And his peritonitis was judged to be local. After the interdisciplinary tumor board conference, we chose to employ conservative treatment, involving the administration of 2 g of wide-spectrum meropenem (MEPM) every 12 hours for the infection. The two sets of blood culture samples taken at admission produced positive results in anaerobic culture bottles within 24 hours, and gram-positive rods of various sizes emerged after 48 hours of culturing. Gray colonies with irregular margins grew during subcultures on Brucella HK (hemin, vitamin K1) agar medium (Kyokuto Pharmaceutical, Tokyo, Japan). C. novyi was identified as the pathogenic microorganism by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI Biotyper, Bruker Daltonics; score: 1.812) and 16S rRNA gene analysis (identity 99.9%). Based on these findings, we diagnosed bacteremia and hepatic gas gangrene caused by C. novyi, accompanied by the rupturing of a liver abscess. Although the gas production by the liver abscesses decreased, a high temperature and elevated CRP levels persisted for one week after the administration of MEPM, which had been demonstrated to be effective against C. novyi. Then, we discontinued the administration of MEPM and re-introduced 3 g of sulbactam/ampicillin (SBT/ABPC) every 12 hours. The administration of SBT/ABPC ameliorated the patient's clinical symptoms. Hepatic abscesses were reduced in size and free air disappeared. During this episode, his primary gastric cancer did not progress. One month later, he was transferred to another hospital to continue receiving palliative treatment and terminal care.
91
[8]. Gas-producing bacteria ferment more glucose and produce more carbon dioxide gas in hyperglycemic conditions. Cancer patients have a risk factor for bacterial infections. Our patient suffered from advanced gastric cancer and DM, indicating that he had risk factors for the onset of gas gangrene. C. novyi has been implicated in wound-associated gas gangrene or severe soft tissue infection in injecting drug users [9]. In addition to cases involving injecting drug users, some spontaneous cases of wound-associated gas gangrene have been reported [2e4]. In one case, a C. novyi-related liver abscess arises spontaneously after an abdominal trauma [10]. The following treatments are recommended for Clostridium infections: immediate debridement and antibiotic treatment with penicillin G coupled with clindamycin, which inhibits toxin synthesis, and supportive care [9]. Mixed infection with aerobic bacteria was often seen when anaerobic infection are found. In the present case, we switched the antibiotics from MEPM to SBT/ABPC based on the patient's clinical response, and his condition improved. C. novyi infections are associated with high mortality rates. In intravenous drug users, the mortality rate of such infections was reported to be 32% [2]. Interestingly, in the current case the abscesses caused by C. novyi arise at the same locations as the liver metastases (Fig. 1a), and the metastatic tumors reduced in size and became cavities (Fig. 1b). This patient received TS-1 for gastric cancer and their metastasis. Although TS-1 had the possibility to eradicate the metastases, 18 days administration of TS-1 might be too short to downsize the tumors. And CT scan showed that TS-1 was not effective for primary gastric cancer during this period. Thus, it seemed that the metastatic tumors were being eradicated by the C. novyi infection. Clostridium species prefer anaerobic conditions. It has been reported that metastatic cancer cells were destroyed and gas was produced when C. septicum proliferated in hypoxic tissue [11]. In experimental studies, the adjacent cancer cells were destroyed and inflammatory cells were attracted by the secretion of soluble host factors when C. novyi was allowed to proliferate in tumors [12,13]. It was reported that the postoperative bacterial infections induced remission and cure of tumor in some of cancer patients [14]. Some experimental studies used a derivative of the wild-type strain, called C. novyi-NT, which was generated by removing the a-toxin gene [12,13,15]. In previous report, a patient with leiomyosarcoma was treated with C. novyi-NT. The treatment reduced the size of tumor [15]. The present case highlights the antitumor effects of C. novyi in humans. In summary, we experienced a rare case of hepatic gas gangrene caused by C. novyi. Clinicians need to be aware that hepatic gas gangrene can be caused by C. novyi. Conflicts of interest The authors declare no conflict of interest relevant to this article. Acknowledgments The authors would like to thank medical technicians Masahiro Kodana, Sachie Koyama, Mayu Tabira, and Junpei Matsuno for their technical supports, and the physicians, and nurses who cared for the patient.
3. Discussion References Clostridium species cursive were reported to cause about 7e24% of pyogenic liver abscess [5], and only 5.4% of gas-forming abscesses rupture [6]. Most cases (82.4%) of Clostridial liver abscesses are caused by C. perfringens or C. septicum [7]. It has been suggested that an association exists between Clostridium infections and DM
[1] Y. Sasaki, N. Takikawa, A. Kojima, M. Norimatsu, S. Suzuki, Y. Tamura, Phylogenetic positions of Clostridium novyi and Clostridium haemolyticum based on 16S rDNA sequences, Int. J. Syst. Evol. Microbiol. 51 (2001) 901e904. [2] C.C. Mcguigan, G.M. Penrice, L. Gruer, S. Ahmed, D. Goldberg, M. Black, et al., Lethal outbreak of infection with Clostridium novyi type A and other spore-
92
[3]
[4] [5]
[6] [7]
[8]
[9]
N. Watanabe et al. / Anaerobe 57 (2019) 90e92 forming organisms in Scottish injecting drug users, J. Med. Microbiol. 51 (2002) 971e977. C. Herrera, R. Meehan, V. Podduturi, A.L. Eastman, D.B. Nelson, Maternal death due to Clostridium novyi in an injection drug user, Obstet. Gynecol. 128 (2016) 876e879. C. McGuigan, M. Roworth, Clostridium novyi type A infection: a sporadic fatal case, Scand. J. Infect. Dis. 34 (2009) 209e211. H.-L. Lee, H.-C. Lee, H.-R. Guo, W.-C. Ko, K.-W. Chen, Clinical significance and mechanism of gas formation of pyogenic liver abscess due to Klebsiella pneumoniae
infections due to Clostridium novyi, Anaerobe 50 (2018) 80e84. [10] N.M. Abdel-Haq, P. Chearskul, H. Salimnia, B.I. Asmar, Clostridial liver abscess following blunt abdominal trauma: case report and review of the literature, Scand. J. Infect. Dis. 39 (2007) 734e737. [11] B.A. Urban, R. McCormick, E.K. Fishman, K.D. Lillemoe, B.G. Petty, Fulminant Clostridium septicum infection of hepatic metastases presenting as pneumoperitoneum, Am. J. Roentgenol. 174 (2000) 962e964. [12] L.H. Dang, C. Bettegowda, D.L. Huso, K.W. Kinzler, B. Vogelstein, Combination bacteriolytic therapy for the treatment of experimental tumors, Proc. Natl. Acad. Sci. Unit. States Am. 98 (2001) 15155. [13] N. Agrawal, C. Bettegowda, I. Cheong, J.-F. Geschwind, C.G. Drake, E.L. Hipkiss, et al., Bacteriolytic therapy can generate a potent immune response against experimental tumors, Proc. Natl. Acad. Sci. U.S.A. 101 (2004) 15172. [14] B. Wiemann, C.O. Starnes, Coley's toxins, tumor necrosis factor and cancer research: a historical perspective, Pharmacol. Ther. 64 (1994) 529e564. [15] N.J. Roberts, L. Zhang, F. Janku, A. Collins, R.Y. Bai, V. Staedtke, et al., Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses, Sci. Transl. Med. 6 (2014) 249ra111.