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Review| Volume 51, P44-46, October 2016

Clostridium tertium in neutropenic patients: case series at a cancer institute

Open AccessPublished:August 27, 2016DOI:https://doi.org/10.1016/j.ijid.2016.08.013
Clostridium tertium in neutropenic patients: case series at a cancer institute
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      Highlights

      • •
        Clostridium tertium is an uncommon pathogen in humans, usually considered non-pathogenic.
      • •
        C. tertium is a significant cause of bacteremia in neutropenic patients.
      • •
        All patients had neutropenic fever at the time of C. tertium bacteremia diagnosis.
      • •
        Infection in this population is likely due to the unusual susceptibility pattern.
      • •
        The pathogen has low virulence and low mortality when treated appropriately.

      Summary

      Objective

      Clostridium tertium is considered an uncommon pathogen in humans, but is a cause of bacteremia in patients with underlying hematological malignancies and neutropenia. A case series highlighting 10 years of experience with C. tertium as a cause of bacteremia in this population is presented; the cases were seen at a National Cancer Institute designated cancer center.

      Methods

      Institutional review board approval was obtained prior to the start of the study. All cases of C. tertium bacteremia seen at H. Lee Moffitt Cancer Center and Research Institute from 2005 to 2015 were reviewed. The study population was identified by positive blood cultures obtained from the microbiology laboratory over the same time period.

      Results

      Seven patients were found to have had C. tertium bacteremia. These patients had a temperature of >38.3 °C at the time of diagnosis and severe neutropenia. All patients had a history of hematological malignancy, five having acute myeloid leukemia and two having myelodysplastic syndrome. All of the patients’ blood cultures cleared within ≤3 days of antibiotic therapy.

      Conclusions

      The unusual susceptibility pattern of C. tertium, with resistance to beta-lactams and clindamycin, likely explains its presence in immunosuppressed patients. Vancomycin remains the drug of choice. The pathogen continues to have a low virulence and a low mortality when treated appropriately.

      Keywords

      1. Introduction

      Clostridium species are a diverse group of anaerobic, Gram-positive, endospore-forming bacilli known to cause botulism, tetanus, gas gangrene, and necrotic enteritis in humans. Clostridium tertium is a non-exotoxin-producing, aerotolerant species that is considered an uncommon pathogen in humans.
      • Ray P.
      • Das A.
      • Singh K.
      • Bhansali A.
      • Yadav T.
      Clostridium tertium in necrotizing fasciitis and gangrene.
      Emerg Infect Dis. 2003; 9: 1347-1349
      C. tertium was initially isolated by Herbert Henry from war wounds in 1917, and was recognized as a human pathogen when cases of bacteremia were reported in 1963.
      • Henry C.
      An investigation of the cultural reactions of certain anaerobes found in wounds.
      J Pathol. 1918; 21: 344-385
      , 
      • King B.
      • Ranck B.
      • Daugherty F.
      • Rau C.
      Clostridium tertium septicemia.
      N Engl J Med. 1963; 269: 467-469
      This bacterium is found in soil, animal and human gastrointestinal tracts, and the commensal flora of the oral cavity. Infections with C. tertium have been described in the literature with various clinical presentations, including enterocolitis, septicemia, pneumonia and empyema, spontaneous peritonitis, abdominal and cutaneous abscesses, meningitis, gas gangrene, and septic arthritis.
      • Ray P.
      • Das A.
      • Singh K.
      • Bhansali A.
      • Yadav T.
      Clostridium tertium in necrotizing fasciitis and gangrene.
      Emerg Infect Dis. 2003; 9: 1347-1349
      , 
      • Vanderhofstadt M.
      • André M.
      • Lonchay C.
      • Levecque P.
      • Holemans X.
      • Canon J.L.
      • D'Hondt L.
      Clostridium tertium bacteremia: contamination or true pathogen?. A report of two cases and a review of the literature.
      Int J Infect Dis. 2010; 14: e335-e337
      , 
      • Gredlein C.
      • Silverman M.
      • Downey M.
      Polymicrobial septic arthritis due to Clostridium species: case report and review.
      Clin Infect Dis. 2000; 30: 590-594
      A case series of C. tertium bacteremia in patients with underlying hematological malignancies is presented. This series represents a 10-year experience at a National Cancer Institute designated cancer center, and the aim was to share this experience of C. tertium as a true cause of clinical infection in cancer patients.

      2. Materials and methods

      Institutional review board approval was obtained prior to the start of the study. In an effort to further study C. tertium bacteremia, all cases of C. tertium bacteremia that occurred at H. Lee Moffitt Cancer Center and Research Institute from April 10, 2005 to April 8, 2015 were reviewed. The study population was identified by positive blood cultures obtained from the microbiology laboratory over the same time period. All culture results were identified by the microbiology laboratory at the Moffitt Cancer Center. Retrospectively, records were reviewed for demographic, clinical, and bacteriological data, including sex, age, underlying disease and history of chemotherapy, symptoms, absolute neutrophil count (ANC), antibiotic therapy, and clinical outcome. Neutropenia was defined as an ANC of <0.5 × 109/l. Neutropenic fever was defined as a patient with neutropenia and a one-time fever of ≥38.3 °C or a fever of ≥38 °C sustained for more than 1 h.
      The identification of microorganisms was performed using standard microbiological methods. The patient's blood was inoculated into a bioMérieux BacT/Alert standard aerobic bottle and standard anaerobic bottle. Once the anaerobic bottle was flagged as being positive by the instrument, it was Gram-stained. The bottle was then subcultured onto a blood, chocolate, and CDC anaerobic agar plate. Once the anaerobic plate showed growth of an anaerobic Gram-positive rod, an IDS Rapid ANA II identification panel was set up for identification as C. tertium. anaerobic susceptibilities are performed at the hospital.

      2.1 Case presentation

      Please refer to the following link to review a detailed presentation of the cases: https://sites.google.com/site/clostridiumtertium/.

      3. Results

      Seven patients were found to have had C. tertium bacteremia between April 2005 and 2015 at the cancer institution, all of whom were neutropenic. Interestingly, six patients (85%) had received CLAG-M chemotherapy (cladribine, cytarabine, filgrastim, and mitoxantrone) within 7–14 days before the onset of C. tertium bacteremia. All seven patients (100%) had a temperature of ≥38.3 °F at the time when C. tertium bacteremia was diagnosed, as well as severe neutropenia with an ANC of <0.2 × 109/l. All patients had a history of hematological malignancy, five having acute myeloid leukemia and two having myelodysplastic syndrome. Four patients had gastrointestinal symptoms including diarrhea, nausea, vomiting, and abdominal pain; two patients had respiratory symptoms including dyspnea and hypoxia; one patient remained asymptomatic. Two patients had computed tomography scans of the abdomen performed; none of them identified the potential source of infection and none of them demonstrated colitis despite the presence of gastrointestinal symptoms. Blood cultures from three patients were polymicrobial with Enterococcus species. All of the patients’ blood cultures cleared within ≤3 days of antibiotic therapy. Five patients died within 4 months after the isolation of C. tertium (Table 1).
      Table 1Clinical summary of seven patients with Clostridium tertium bacteremia
      PatientSex/age (years)Underlying diseaseSource of infectionDays with positive C. tertium blood culturesIsolates in addition to C. tertiumAntibiotics receivedSurvived
      1F/82Acute myeloid leukemiaAbdomen3NoneVancomycin, piperacillin–tazobactam, ciprofloxacinNo
      2F/36Acute myeloid leukemiaAbdomen1NoneVancomycin, piperacillin–tazobactam, metronidazole, clindamycinNo
      3F/42Acute myeloid leukemiaUnknown2NonePiperacillin–tazobactam, clindamycinYes
      4M/55Myelodysplastic syndromeAbdomen3Enterococcus faeciumCefepime, vancomycin, piperacillin–tazobactamNo
      5M/60Acute myeloid leukemiaUnknown2Enterococcus faeciumVancomycin, metronidazoleNo
      6M/69Myelodysplastic syndromeUnknown2Enterococcus gallinarumCefepime, vancomycin, piperacillin–tazobactamNo
      7M/60Acute myeloid leukemiaUnknown2NoneCiprofloxacin, cefepime, vancomycinYes
      F, female; M, male.

      4. Discussion

      Clostridium species account for 0.5–2% of all clinically significant bacteremia, with Clostridium perfringens being the most common isolate. C. tertium is the second most common Clostridium bacteremia at the study institution after C. perfringens and has been seen as a cause of true clinical infection especially over the last 2 years. C. tertium has been traditionally considered non-pathogenic.
      • Steyaert S.
      • Peleman R.
      • Vaneechoutte M.
      • Baere T.
      • Claeys G.
      • Verschraegen G.
      Septicemia in neutropenic patients infected with Clostridium tertium resistant to cefepime and other expanded-spectrum cephalosporins.
      J Clin Microbiol. 1999; 37: 40-42
      , 
      • Valtonen M.
      • Sivonen A.
      • Elonen E.
      A cluster of seven cases of Clostridium tertium septicemia in neutropenic patients.
      Eur J Clin Microbiol Infect Dis. 1990; 9: 40-42
      , 
      • Speirs G.
      • Warren R.
      • Ramp A.
      Clostridium tertium septicemia in patients with neutropenia.
      J Infect Dis. 1988; 158: 1336-1340
      It is now increasingly reported as a human pathogen, having a strong association with septicemia in patients with neutropenia and hematological malignancies.
      Unlike other Clostridium species, C. tertium does not produce exotoxins; therefore the pathogenesis of infection is not well understood. It has been postulated that compromise of the intestinal mucosa heightens the risk of C. tertium translocation into the systemic circulation.
      • Ray P.
      • Das A.
      • Singh K.
      • Bhansali A.
      • Yadav T.
      Clostridium tertium in necrotizing fasciitis and gangrene.
      Emerg Infect Dis. 2003; 9: 1347-1349
      , 
      • Tappe D.
      • Dirks J.
      • Müller R.
      • Abele-Horn M.
      • Suerbaum S.
      • Kurzai O.
      Fatal Clostridium tertium septicemia in a nonneutropenic patient.
      J Infect. 2005; 50: 76-80
      Additionally, chemotherapy agents can lead to inflammation and abrasion of the intestinal mucosa, which may explain why patients with a hematological malignancy who are undergoing chemotherapy have an increased susceptibility to infection.
      • Vanderhofstadt M.
      • André M.
      • Lonchay C.
      • Levecque P.
      • Holemans X.
      • Canon J.L.
      • D'Hondt L.
      Clostridium tertium bacteremia: contamination or true pathogen?. A report of two cases and a review of the literature.
      Int J Infect Dis. 2010; 14: e335-e337
      Common characteristics of C. tertium infection included fever and generalized gastrointestinal complaints such as abdominal pain, diarrhea, rectal bleeding, and nausea. However, in some cases, patients with C. tertium infection were completely asymptomatic. Additionally, most patients were neutropenic without a defined source of infection.
      It can be difficult for laboratories to correctly identify C. tertium isolates, as it is aerotolerant and can grow weakly under aerobic conditions. Due to this, C. tertium is often confused with Bacillus species, although C. tertium is catalase-negative and only produces spores under anaerobic conditions, while Bacillus species are catalase-positive and produce spores under aerobic conditions.
      • Steyaert S.
      • Peleman R.
      • Vaneechoutte M.
      • Baere T.
      • Claeys G.
      • Verschraegen G.
      Septicemia in neutropenic patients infected with Clostridium tertium resistant to cefepime and other expanded-spectrum cephalosporins.
      J Clin Microbiol. 1999; 37: 40-42
      , 
      • Tappe D.
      • Dirks J.
      • Müller R.
      • Abele-Horn M.
      • Suerbaum S.
      • Kurzai O.
      Fatal Clostridium tertium septicemia in a nonneutropenic patient.
      J Infect. 2005; 50: 76-80
      , 
      • Leegaard T.
      • Sandven P.
      • Gaustad P.
      Clostridium tertium: 3 case reports.
      Scand J Infect Dis. 2005; 37: 230-232
      , 
      • Thaler M.
      • Gill V.
      • Pizzo P.
      Emergence of Clostridium tertium as a pathogen in neutropenic patients.
      Am J Med. 1986; 81: 596-600
      This may cause delays in treatment or patients may receive incorrect antibiotic therapy.
      • Leegaard T.
      • Sandven P.
      • Gaustad P.
      Clostridium tertium: 3 case reports.
      Scand J Infect Dis. 2005; 37: 230-232
      C. tertium has been shown to be sensitive to fluoroquinolones, imipenem, vancomycin, and trimethoprim–sulfamethoxazole, and resistant to other beta-lactams and clindamycin. C. tertium isolates can either be sensitive or resistant to metronidazole.
      • Vanderhofstadt M.
      • André M.
      • Lonchay C.
      • Levecque P.
      • Holemans X.
      • Canon J.L.
      • D'Hondt L.
      Clostridium tertium bacteremia: contamination or true pathogen?. A report of two cases and a review of the literature.
      Int J Infect Dis. 2010; 14: e335-e337
      , 
      • Leegaard T.
      • Sandven P.
      • Gaustad P.
      Clostridium tertium: 3 case reports.
      Scand J Infect Dis. 2005; 37: 230-232
      C. tertium is mostly resistant to broad-spectrum cephalosporins, and given the difficulty in identifying C. tertium isolates, empiric therapeutic strategies may fail in hospitalized patients with sepsis.
      • Steyaert S.
      • Peleman R.
      • Vaneechoutte M.
      • Baere T.
      • Claeys G.
      • Verschraegen G.
      Septicemia in neutropenic patients infected with Clostridium tertium resistant to cefepime and other expanded-spectrum cephalosporins.
      J Clin Microbiol. 1999; 37: 40-42
      , 
      • Leegaard T.
      • Sandven P.
      • Gaustad P.
      Clostridium tertium: 3 case reports.
      Scand J Infect Dis. 2005; 37: 230-232
      , 
      • Gosbell I.
      • Johnson C.
      • Newton P.
      • Jelfs J.
      Clostridium tertium bacteremia.
      Pathology. 1996; 28: 70-73
      Therefore, standard therapeutic regimens for the treatment of septicemia may be inadequate for C. tertium. There is limited literature regarding the duration of antibiotic therapy, although it is believed that approximately 15 to 27 days of treatment is sufficient.
      • Tappe D.
      • Dirks J.
      • Müller R.
      • Abele-Horn M.
      • Suerbaum S.
      • Kurzai O.
      Fatal Clostridium tertium septicemia in a nonneutropenic patient.
      J Infect. 2005; 50: 76-80
      C. tertium is known to have low virulence due to being a non-exotoxin-producing bacterium, unlike Clostridium septicum and C. perfringens, which are subgroups of the Clostridium species known to cause spontaneous and traumatic myonecrosis, respectively.
      • King B.
      • Ranck B.
      • Daugherty F.
      • Rau C.
      Clostridium tertium septicemia.
      N Engl J Med. 1963; 269: 467-469
      , 
      • Nanjappa S.
      • Shah S.
      • Pabbathi S.
      Clostridium septicum gas gangrene in colon cancer: importance of early diagnosis.
      Case Rep Infect Dis. 2015; 2015: 1-3
      , 
      • Rampling A.
      Clostridium tertium and the gut.
      Lancet. 1988; 331: 534
      Bacteremia with C. septicum and C. perfringens can lead to systemic toxicity and septic shock, with a mortality rate greater than 60%, secondary to the toxins produced by these species.
      • Speirs G.
      • Warren R.
      • Ramp A.
      Clostridium tertium septicemia in patients with neutropenia.
      J Infect Dis. 1988; 158: 1336-1340
      , 
      • Shah S.
      • Nanjappa S.
      • Pabbathi S.
      • Greene J.
      Clostridium septicum case series: a 5-year experience at a cancer center.
      Infect Dis Clin Pract. 2016; 24: 72-75
      , 
      • Kennedy C.
      • Krejany E.
      • Young L.
      • O'Connor J.R.
      • Awad M.M.
      • Boyd R.L.
      • et al.
      The α-toxin of Clostridium septicum is essential for virulence.
      Mol Microbiol. 2005; 57: 1357-1366
      Therefore, it is not entirely clear from the literature whether C. tertium is a true pathogen or merely a contaminant. Additionally, C. tertium has been isolated from polymicrobial blood cultures, making the significance of C. tertium bacteremia further indistinct.
      • Steyaert S.
      • Peleman R.
      • Vaneechoutte M.
      • Baere T.
      • Claeys G.
      • Verschraegen G.
      Septicemia in neutropenic patients infected with Clostridium tertium resistant to cefepime and other expanded-spectrum cephalosporins.
      J Clin Microbiol. 1999; 37: 40-42
      , 
      • Tappe D.
      • Dirks J.
      • Müller R.
      • Abele-Horn M.
      • Suerbaum S.
      • Kurzai O.
      Fatal Clostridium tertium septicemia in a nonneutropenic patient.
      J Infect. 2005; 50: 76-80
      Most patients with C. tertium bacteremia have been neutropenic due to chemotherapy, without a defined source of infection.
      • Miller D.
      • Brazer S.
      • Murdoch D.
      • Reller L.
      • Corey G.
      Significance of Clostridium tertium bacteremia in neutropenic and nonneutropenic patients: review of 32 cases.
      Clin Infect Dis. 2001; 32: 975-978
      A literature review demonstrated a summary of 42 cases with C. tertium bacteremia, of which 38 patients were neutropenic from chemotherapy. In these cases, patients developed C. tertium bacteremia within several days after becoming neutropenic.
      • Gosbell I.
      • Johnson C.
      • Newton P.
      • Jelfs J.
      Clostridium tertium bacteremia.
      Pathology. 1996; 28: 70-73
      However, there have been rare cases of C. tertium bacteremia in non-neutropenic patients, such as patients with end-stage liver disease from chronic alcohol use, systemic lupus erythematosus on high-dose steroids, and inflammatory bowel disease. Despite the low pathogenic potential of C. tertium species, effective treatment should not be delayed.
      • Tappe D.
      • Dirks J.
      • Müller R.
      • Abele-Horn M.
      • Suerbaum S.
      • Kurzai O.
      Fatal Clostridium tertium septicemia in a nonneutropenic patient.
      J Infect. 2005; 50: 76-80
      Although C. tertium is rare with low virulence, it appears to be a cause of true clinical infection in neutropenic patients.
      • Steyaert S.
      • Peleman R.
      • Vaneechoutte M.
      • Baere T.
      • Claeys G.
      • Verschraegen G.
      Septicemia in neutropenic patients infected with Clostridium tertium resistant to cefepime and other expanded-spectrum cephalosporins.
      J Clin Microbiol. 1999; 37: 40-42
      Of the cases presented, all patients with monomicrobial bacteremia had a high-grade fever and symptoms that resolved after the initiation of appropriate antibiotic therapy,
      • Miller D.
      • Brazer S.
      • Murdoch D.
      • Reller L.
      • Corey G.
      Significance of Clostridium tertium bacteremia in neutropenic and nonneutropenic patients: review of 32 cases.
      Clin Infect Dis. 2001; 32: 975-978
      demonstrating that C. tertium bacteremia does cause clinical disease. Nevertheless, the mortality related to C. tertium bacteremia that is treated appropriately seems to be low. In patients with neutropenia, especially when there is evidence of gastrointestinal involvement,
      • Thaler M.
      • Gill V.
      • Pizzo P.
      Emergence of Clostridium tertium as a pathogen in neutropenic patients.
      Am J Med. 1986; 81: 596-600
      clinicians should be encouraged to consider C. tertium when Gram-positive rods are found in blood culture, and to initiate appropriate antimicrobial therapy such as vancomycin.
      In conclusion, C. tertium bacteremia is a rare pathogen in neutropenic patients. It is often mistaken for Bacillus species, which may cause delays in treatment. Although uncommon, the presence of C. tertium bacteremia should prompt a high suspicion for disruption to the gastrointestinal tract mucosa. In all of the cases reported at this cancer institution, blood cultures cleared with antibiotic therapy; no patient died as a result of C. tertium bacteremia. Therefore, the pathogen continues to have a low virulence and a low mortality when treated appropriately. C. tertium is known to be a true pathogen in patients with underlying hematological malignancies and neutropenia. It is hoped that this case series will assist clinicians when encountering this pathogen as a true cause of clinical infection.
      Conflict of interest: None of the authors or their immediate family members has an involvement in or affiliation with an organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this article.

      References

        • Ray P.
        • Das A.
        • Singh K.
        • Bhansali A.
        • Yadav T.
        Clostridium tertium in necrotizing fasciitis and gangrene.
        Emerg Infect Dis. 2003; 9: 1347-1349
        View in Article
        • Henry C.
        An investigation of the cultural reactions of certain anaerobes found in wounds.
        J Pathol. 1918; 21: 344-385
        View in Article
        • King B.
        • Ranck B.
        • Daugherty F.
        • Rau C.
        Clostridium tertium septicemia.
        N Engl J Med. 1963; 269: 467-469
        View in Article
        • Vanderhofstadt M.
        • André M.
        • Lonchay C.
        • Levecque P.
        • Holemans X.
        • Canon J.L.
        • D'Hondt L.
        Clostridium tertium bacteremia: contamination or true pathogen?. A report of two cases and a review of the literature.
        Int J Infect Dis. 2010; 14: e335-e337
        View in Article
        • Gredlein C.
        • Silverman M.
        • Downey M.
        Polymicrobial septic arthritis due to Clostridium species: case report and review.
        Clin Infect Dis. 2000; 30: 590-594
        View in Article
        • Steyaert S.
        • Peleman R.
        • Vaneechoutte M.
        • Baere T.
        • Claeys G.
        • Verschraegen G.
        Septicemia in neutropenic patients infected with Clostridium tertium resistant to cefepime and other expanded-spectrum cephalosporins.
        J Clin Microbiol. 1999; 37: 40-42
        View in Article
        • Valtonen M.
        • Sivonen A.
        • Elonen E.
        A cluster of seven cases of Clostridium tertium septicemia in neutropenic patients.
        Eur J Clin Microbiol Infect Dis. 1990; 9: 40-42
        View in Article
        • Speirs G.
        • Warren R.
        • Ramp A.
        Clostridium tertium septicemia in patients with neutropenia.
        J Infect Dis. 1988; 158: 1336-1340
        View in Article
        • Tappe D.
        • Dirks J.
        • Müller R.
        • Abele-Horn M.
        • Suerbaum S.
        • Kurzai O.
        Fatal Clostridium tertium septicemia in a nonneutropenic patient.
        J Infect. 2005; 50: 76-80
        View in Article
        • Leegaard T.
        • Sandven P.
        • Gaustad P.
        Clostridium tertium: 3 case reports.
        Scand J Infect Dis. 2005; 37: 230-232
        View in Article
        • Thaler M.
        • Gill V.
        • Pizzo P.
        Emergence of Clostridium tertium as a pathogen in neutropenic patients.
        Am J Med. 1986; 81: 596-600
        View in Article
        • Gosbell I.
        • Johnson C.
        • Newton P.
        • Jelfs J.
        Clostridium tertium bacteremia.
        Pathology. 1996; 28: 70-73
        View in Article
        • Nanjappa S.
        • Shah S.
        • Pabbathi S.
        Clostridium septicum gas gangrene in colon cancer: importance of early diagnosis.
        Case Rep Infect Dis. 2015; 2015: 1-3
        View in Article
        • Rampling A.
        Clostridium tertium and the gut.
        Lancet. 1988; 331: 534
        View in Article
        • Shah S.
        • Nanjappa S.
        • Pabbathi S.
        • Greene J.
        Clostridium septicum case series: a 5-year experience at a cancer center.
        Infect Dis Clin Pract. 2016; 24: 72-75
        View in Article
        • Kennedy C.
        • Krejany E.
        • Young L.
        • O'Connor J.R.
        • Awad M.M.
        • Boyd R.L.
        • et al.
        The α-toxin of Clostridium septicum is essential for virulence.
        Mol Microbiol. 2005; 57: 1357-1366
        View in Article
        • Miller D.
        • Brazer S.
        • Murdoch D.
        • Reller L.
        • Corey G.
        Significance of Clostridium tertium bacteremia in neutropenic and nonneutropenic patients: review of 32 cases.
        Clin Infect Dis. 2001; 32: 975-978
        View in Article

      Article info

      Publication history

      Published online: August 27, 2016
      Accepted: August 22, 2016
      Received in revised form: August 19, 2016
      Received: March 10, 2016
      Corresponding Editor: Eskild Petersen, Aarhus, Denmark.

      Identification

      DOI: https://doi.org/10.1016/j.ijid.2016.08.013

      Copyright

      © 2016 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.

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