Clostridium septicum Bacteremia Its Clinical Significance
JACK R. KORANSKY. M.D. MICHAEL D. STARGEL, M.D.* V. R. DOWELL. Jr., Ph.D. Atlunto, Georgia
The medical records of 59 patients with Clostridium septicum bacteremia were reviewed; 42 (71 per cent) of these patients had malignancies. One half had hematologic malignancies, and one half had solid tumors. Of the 21 patients with solid tumors, 14 (67 per cent) had cancer of the colon. Among these patients, the cecum was the most frequent site of malignancy. The cecum and distal ileum were the most probable portals of entry for C. septicum bacteremia among the 28 patients examined at autopsy. Patients admitted to the hospital with C. septicum bacteremia usually have fulminating clinical courses and, unless the appropriate antibiotics are administered soon after admission, the outcome is fatal. The results of this study demonstrate the high association of C. septicum bacteremia and malignancy, and the need for early recognition and therapy. The association of clostridial infections and malignancy, especially cancer of the colon, has been demonstrated by several case reports in the literature [l-4]. In 1969, Alpern and Dowel1 [5] discussed the high frequency of malignancy in patients with C. septicum infection; they reported that 23 of the 27 patients (85 per cent] whose cultures were referred to the Center for Disease Control (CDC) for identification had malignancies. They also demonstrated the importance of early antibiotic therapy in patients with C. septicum infection. Recently, five patients with C. septicum bacteremia were described in the “Epidemiology notes” of the British Medical Journal [6]. Of the five patients, four had malignancies. Since 1969, the Anerobe Section at the CDC has received blood culture isolates of C. septicum from 62 patients with bacteremia. We examined the available hospital records of these patients to characterize further the epidemiology, pathology and clinical course of C. septicum bacteremia. MATERIALS
From the Center for Disease Control, Public Health Service, U.S. Department of Health, Education, and Welfare, Atlanta, Georgia. Requests for reprints should be addressed to Dr. Jack R. Koransky. Enterobactcriology Branch, Center for Disease Control, 1600 Clifton Road, N.E.. Atlanta. Georgia 30333. Manuscript accepted July 11, 1978. * Present address: Parkland Memorial Hospital, 5201 Harry Hines Boulevard. Dallas, Texas 75235.
AND METHODS
Isolates were referred for identification to the CDC, Anaerobe Section, from state and local health departments throughout the United States. From February 1969 until January 1977. 62 isolates of C. septicum from blood cultures were identified at CDC. Each isolate was tested by standard bacteriologic technics including toxin testing as described in the CDC Manual Labor-dory Methods in Anaerobic Hucteriology (71. For each patient with C. septicum bacteremia, clinical and pathologic information was obtained from the attending physician and pathologist. In addition, transcripts of hospital charts, autopsy protocols [when available], and clinical information questionnaires were submitted to the CDC and reviewed. One patient [Case 57) was interviewed and examined by one of us (J.K.J. Diagnoses were made from autopsy findings, pathologic examination of tissue obtained at surgery or biopsy, bone marrow examination or definitive clinical and laboratory data.
January 1979
The American Journal of Medicine
Volume 66
63
CLOSTRIDIUM
TABLE I
SEPTICUM
BACTEREMIA-KORANSKY
ET AL.
Primary Diagnosis in 42 Patients with Malignancy and C. septicum Bacteremia Patients
Hematologic malignancy Granulocytic leukemia Lymphocytic leukemia Monocytic leukemia Lymphoma or Sarcoma Solid tumor malignancy Outside colon Colon cancer Cancer of cecum Outside cecum* l
Total No.
No.
Diagnosis
21 10 5 1 5 21 7 14 8 7
One patient had two primary colon cancers.
RESULTS
Of the 62 patients with C. septicum bacteremia, complete medical information was obtained for 59; 32 were female and 27 male. Their ages ranged from one to 88 years. On admission to the hospital, all patients were acutely ill and extremely toxic. Their oral temperatures ranged from 37’ to 42’C. Thirty-eight of the 52 patients (73 per cent] whose temperature records were available had oral temperatures greater than 39S’C. Other than fever and toxemia, the most frequent complaint was abdominal pain (64 per cent). Only one patient had documented intravascular hemolysis. Ten patients had evidence of gas formation during life, two of whom had pneumotosis cystoides intestinalis. Three patients were admitted with distant “metastatic” infections (eye, shoulder, leg] and cancer of the colon. None of the 59 patients was jaundiced. In those patients without leukemia or leukopenia, the peripheral white blood cell count ranged between 4,700 and 25,699/mm3 with a mean of 13,300/mm3. Of the 59 patients whose medical histories were obtained, 42 (71 per cent) had malignancies; 21(50 per cent]
TABLE II
Probable Portal of Entry of C. septicum and Autopsy Findings in 28 Patients with Bacteremia Patients
ProbablePortal of Entry or Autopsy findings Distal ileum or cecum Distal ileitis or cecitis Cancer of cecum Perforation of cecum lleocecal intussusception Leukemic infiltration of cecum Air filled cysts distal ileum Bowel infarction Perforation, transverse colon cancer Unknown
64
No.
Total No. 17
11 2 1 1 1 1 3 2 6
had solid tumo?s, and 21(50 per cent) had hematologic malignancies (Table I]. Fourteen (67 per cent] of the patients with solid tumors had cancer of the colon, with the most frequent site being the cecum (53 per cent]. Sixteen of the 42 patients with malignancy [six solid tumor, 10 hematologic malignancy] were receiving chemotherapy or radiation therapy. In one patient the diagnosis of cancer of the cecum was made two years after an episode of C. septicum bacteremia. Seventeen of the 59 patients had no detectable malignancy. Of the 17 patients, six had a primary diagnosis of granulocytopenia and six had severe arteriosclerotic cardiovascular disease with a gangrenous extremity or gangrenous bowel. In one patient a gangrenous extremity developed after an insect bite: one had hemorrhagic necrosis of the cecum; and three had C. septicum bacteremia without a definite clinical or pathologic diagnosis. The distal ileum or cecum was identified as the most probable portal of entry of the C. septicum in 17 of the 28 patients examined at autopsy (Table II]. Autopsy findings revealed a cecitis or distal ileitis in 11 of these patients. Infection with C. septicum was the apparent cause of death in 40 patients (68 per cent). All but one of the 19 survivors had malignancies. All surviving patients were given penicillin, cephalothin, chloramphenicol or carbenicillin (antibiotics to which Clostridia have been found to be sensitive [8]) soon after they were admitted to the hospital (Table III]. Twelve patients who received antibiotic therapy, not including one of the aforementioned antibiotics, or no antibiotics, died; all but one died within 48 hours (usually within 12 hours] of admission to the hospital. Twenty-two patients in therapy group 1 [Table III] died. Twelve died during the first day after admission, seven had fecal peritonitis from bowel perforation or gangrene, and two refused surgery for gangrenous extremities. The remaining patient had severe abdominal pain and died three days after the administration of appropriate antibiotics. An autopsy was not performed on this patient. COMMENTS C. septicum bacteremia is not a commonly diagnosed condition. A possible reason for this is that some hospital laboratories do not identify clostridial isolates other than C. perfringens. However, with the greater availability and understanding of good anaerobic technics, many laboratories are now able to accurately identify to the species level most of their Clostridium isolates. Of 360 blood cultures found positive for Clostridium at the Mayo Clinic during a 15 month period, only three were C. septicum [9]. During a similar length of time at Cook County Hospital in Chicago, only two C. septicum isolates were present among 65 isolates of Clostridium cultured from blood [lo]. The CDC is a national reference center for the identification of anaerobic bacteria and receives isolates of C. septicum from throughout the
January 1979 The American Journal of Medicine Volume 66
CLOSTRIDIUM
United States. This gives us a unique opportunity to characterize the epidemiology and pathology of a rarely diagnosed infection. C. septicum is a gram-positive, sporulating, spindleshaped rod. In young cultures, it is motile. This fact accounts for the spreading growth that can be seen when C. septicum is grown on anaerobic blood agar. C. septicum is easily differentiated from C. perfringens by the spreading growth on blood agar as well as by reactions on egg yolk agar and differences in the fermentation of various carbohydrates. C. septicum produces four toxins, which have been designated alpha, beta, gamma and delta [ll]. Alpha toxin is necrotic and lethal for certain animals such as mice. The lethal action of the alpha toxin is neutralized by antitoxin. Animal toxin neutralization tests are necessary to differentiate C. septicim from C. chauvoei which has very similar cultural and biochemical characteristics [7,ll]. Although it is frequently stated that C. septicum is normally found in the human intestine [X2],there is little evidence to support this belief. C. septicum was isolated only once in an exhaustive study of stool specimens from 33 subjects partaking of a Japanese or a western diet [l3]. C. septicum was not isolated from any of the stool specimens of 175 patients from various countries around the world [la]. Further investigations are needed to determine whether C. septicum is or is not an inhabitant of the normal gastrointestinal tract. Our finding that 71 per cent of the patients with C. septicum bacteremia had malignancies confirms what had been speculated in previous case reports and studies of this infection [l-6,15,16]. The fact that one half of our patients had hematologic malignancies and that many of them were receiving chemotherapy at the time of the infection suggests that C. septicum may be an opportunistic invader of the immunosuppressed and compromised host. This possibility receives support from the presence of six cases of granulocytopenia among our 17 patients without malignancy. However, none of our cases occurred in association with other diseases which required patients to receive immunosuppression, such as those with a renal transplant or collagen vascular disease. In our study a predilection of solid tumors for the colon was noted (67per cent). Similarly, in Alpern and Dowell’s previous report [5], six of nine solid tumors were in the colon. The frequencies of colon cancer in the various anatomic sites of the colon in our study [Table I) were compared with those from national cancer statistics [17]. These two sets of frequencies were significantly different (P 24 hours from onset of sepsis; (3) an antibiotic different from aforegoing; (4) no antibiotics. l
commonly identified portals of entry for C. septicum in our patients (Table II). The distal ileum and cecum were demonstrated to be the portals of entry in two diabetic patients with C. septicum infection, as reported by Werner et al. [18]. Because of pH, electrolyte and osmotic differences, the cecum and distal ileum may promote the growth of C. septicum better than other areas of the gastrointestinal tract. An early study suggested that C. septicum was commonly found in the appendix [19]. However, a subsequent study failed to confirm this finding [ZO]. More studies are needed to identify and quantify the normal microflora of the various anatomic regions of the human gastrointestinal tract. The presence of diabetes mellitus and severe arteriosclerotic cardiovascular disease in six of the 17 patients without malignancy suggests that these diseases may play a role in the development of ischemia and tissue necrosis, important predisposing factors for clostridial growth. Clostridial gas gangrene has been reported to be more common in diabetic patients [21]. The three cases of “metastatic” C. septicum infections and cancer of the colon illustrate the importance of searching for bowel cancers when C. septicum is cultured from a local infection outside the bowel. Warren and Mason [l5] reported a case of suppurative thyroiditis caused by C. septicum in a man with adenocarcinoma of the ascending colon. The importance of early recognition and prompt therapy in patients with C. septicum bacteremia cannot be overemphasized. When these patients are admitted to the hospital, they are acutely ill and toxic, frequently have high fevers and commonly have an associated malignancy. Diabetic patients may have a gangrenous extremity and severe toxemia. Blood cultures, both aerobic and anaerobic, should be rapidly performed, and therapy should be instituted before the results of cultures are received. Table III illustrates the need to begin antibiotic therapy almost as soon as the patient arrives in the hospital. Almost half of the patients who received the appropriate antibiotics (81 within 12 hours after the onset of the infection survived. Nearly all of the
January 1979
The American Journal of Medicine
Volume 66
65
CLOSTRIDIUM SEPTICLJM BACTEREMIA-KORANSKY
ET AL.
patients who died, but who received appropriate antibiotic therapy promptly, did not receive necessary surgery or died before an adequate blood level of the antibiotics could be achieved. Penicillin remains the drug of choice [8], but some of our patients were treated successfully with chloramphenicol, carbenicillin or cephalothin. The use of hyperbaric oxygen in the therapy of C. septicum infection has not been adequately
studied. In vitro studies suggest that C. septicum is considerably more resistant to hyperbaric oxygen than other Clostridium species [22]. Radical surgery is sometimes necessary to remove a gangrenous extremity or gangrenous bowel. In the future, the combination of early antibiotic therapy and necessary surgical intervention may help to alter the fulminating nature of C. septicum infections.
REFERENCES
1. Wyman AL: Endogenous gas gangrene complicating cancer 2. 3. 4. 5. 6. 7.
of the colon. Br Med J 1: 266,1949. Valentine JC: Gas gangrene septicemia due to carcinoma of the cecum and muscular trauma. Br J Surg 44: 630, 1957. B&s DR, Frei E, Thomas LB: Clostridial gas yanyrene and septicemia in four patients with IeukeAa. fi Eigl J Med 259: 1255.1958. Gazzaniga AB: Nontraumatic, clostridial. gasgangrene of the right arm and adenocarcinoma of the cecum: report of a case. Dis Colon Rectum 10: 298, 1967. Alpern RJ, Dowell VR Jr: Clostridium septicum infections and malignancy. JAMA 209: 385, 1969. Epidemiology notes: Clostridium septicum bacteremia. Br Med I 1: 969,1976. Dowel1 ‘VRJr, Hawkins TM: Laboratory Methods in Anaerobic Bacteriology. Washington, DC.. U.S. Department of Health, Education, and Welfare No. (CDC) 74-8272,
12. 13. 14. 15. 16. 17. 18.
1974.
8.
Weinstein L: Chemotherapy of microbial diseases. The Pharmacological Basis of Therapeutics, 5th ed [Goodman LS, Gilman A, eds], New York, MacMillan Co. Inc., 1975. 9. Wilson WR. Martin WI. Wilkowske Cl. et al.: Anaerobic bacteremia. Mayo Cl;n Proc 47: 639, i972. 10. Gorbach SL, Thadepalli H: Isolation of Clostridium in human infections: evaluation of 114 cases. J Infect Dis 131 (suppl): S81.1975. 11. Smith LD: The Pathogenic Anaerobic Bacteria, Springfield,
66
January 1979 The American Journal of Medicine
19.
20. 21. 22.
Volume 66
III., Charles C Thomas, 1975. Maclennan JD: The histotoxic clostridial infections of man. Bacterial Rev 26: 177, 1962. Finegold SM, Attebery HR. Sutter VL: Effect of diet on human fecal flora: comoarison of laoanese and American diets. Am J CIin Nutr 2?: 1456,19+4: Drasar BS, Goddard P, Heaton S, et al.: Clostridia isolated from feces. J Med Microbial 9: 63, 1976. Warren CPW, Mason BJ: Clostridium septicum infection of the thyroid gland. Postgrad Med 46: 586, 1970. Mzabi R, Himal HS, MacLean LD: Gas gangrene of the extremity: the presenting clinical picture in perforating carcinoma of the caecum. Br J Surg 62: 373,1975. Third National Cancer Survey: Incidence Data. Washington, DC.. U.S. Department of health, Education, and Welfare Publication r\jo. (NIH] 75-787,1975, p 22. Werner H, Gott U, Rintelen G: Zur kasuistik der enterogenen nichttraumatischen gasodeminfektionen durch Clostridiurn septicum. Z Med Mikrobiol Immunol 156: 265,197l. Lanz 0, Tavel E: Bacteriologic de I’appendicite. Rev Chir 30: 43, 1904. Weinberg M. Prevot AR, Davesne J, et al.: Recherches sur la bacteriologic et la serotherapie des appendicites aigues. Ann Inst Pasteur suppI 42, p 1167,1928. Weinstein L. Barza MA: Gas gangrene-current concepts. N Engl J Med 289: 1129,1973. Hill GB, Osterhout S: Experimental effects of hyperbaric oxygen on selected clostridial species. I. In vitro studies. J Infect Dis 125: 117. 1972.
JACK R. KORANSKY. M.D. MICHAEL D. STARGEL, M.D.* V. R. DOWELL. Jr., Ph.D. Atlunto, Georgia
The medical records of 59 patients with Clostridium septicum bacteremia were reviewed; 42 (71 per cent) of these patients had malignancies. One half had hematologic malignancies, and one half had solid tumors. Of the 21 patients with solid tumors, 14 (67 per cent) had cancer of the colon. Among these patients, the cecum was the most frequent site of malignancy. The cecum and distal ileum were the most probable portals of entry for C. septicum bacteremia among the 28 patients examined at autopsy. Patients admitted to the hospital with C. septicum bacteremia usually have fulminating clinical courses and, unless the appropriate antibiotics are administered soon after admission, the outcome is fatal. The results of this study demonstrate the high association of C. septicum bacteremia and malignancy, and the need for early recognition and therapy. The association of clostridial infections and malignancy, especially cancer of the colon, has been demonstrated by several case reports in the literature [l-4]. In 1969, Alpern and Dowel1 [5] discussed the high frequency of malignancy in patients with C. septicum infection; they reported that 23 of the 27 patients (85 per cent] whose cultures were referred to the Center for Disease Control (CDC) for identification had malignancies. They also demonstrated the importance of early antibiotic therapy in patients with C. septicum infection. Recently, five patients with C. septicum bacteremia were described in the “Epidemiology notes” of the British Medical Journal [6]. Of the five patients, four had malignancies. Since 1969, the Anerobe Section at the CDC has received blood culture isolates of C. septicum from 62 patients with bacteremia. We examined the available hospital records of these patients to characterize further the epidemiology, pathology and clinical course of C. septicum bacteremia. MATERIALS
From the Center for Disease Control, Public Health Service, U.S. Department of Health, Education, and Welfare, Atlanta, Georgia. Requests for reprints should be addressed to Dr. Jack R. Koransky. Enterobactcriology Branch, Center for Disease Control, 1600 Clifton Road, N.E.. Atlanta. Georgia 30333. Manuscript accepted July 11, 1978. * Present address: Parkland Memorial Hospital, 5201 Harry Hines Boulevard. Dallas, Texas 75235.
AND METHODS
Isolates were referred for identification to the CDC, Anaerobe Section, from state and local health departments throughout the United States. From February 1969 until January 1977. 62 isolates of C. septicum from blood cultures were identified at CDC. Each isolate was tested by standard bacteriologic technics including toxin testing as described in the CDC Manual Labor-dory Methods in Anaerobic Hucteriology (71. For each patient with C. septicum bacteremia, clinical and pathologic information was obtained from the attending physician and pathologist. In addition, transcripts of hospital charts, autopsy protocols [when available], and clinical information questionnaires were submitted to the CDC and reviewed. One patient [Case 57) was interviewed and examined by one of us (J.K.J. Diagnoses were made from autopsy findings, pathologic examination of tissue obtained at surgery or biopsy, bone marrow examination or definitive clinical and laboratory data.
January 1979
The American Journal of Medicine
Volume 66
63
CLOSTRIDIUM
TABLE I
SEPTICUM
BACTEREMIA-KORANSKY
ET AL.
Primary Diagnosis in 42 Patients with Malignancy and C. septicum Bacteremia Patients
Hematologic malignancy Granulocytic leukemia Lymphocytic leukemia Monocytic leukemia Lymphoma or Sarcoma Solid tumor malignancy Outside colon Colon cancer Cancer of cecum Outside cecum* l
Total No.
No.
Diagnosis
21 10 5 1 5 21 7 14 8 7
One patient had two primary colon cancers.
RESULTS
Of the 62 patients with C. septicum bacteremia, complete medical information was obtained for 59; 32 were female and 27 male. Their ages ranged from one to 88 years. On admission to the hospital, all patients were acutely ill and extremely toxic. Their oral temperatures ranged from 37’ to 42’C. Thirty-eight of the 52 patients (73 per cent] whose temperature records were available had oral temperatures greater than 39S’C. Other than fever and toxemia, the most frequent complaint was abdominal pain (64 per cent). Only one patient had documented intravascular hemolysis. Ten patients had evidence of gas formation during life, two of whom had pneumotosis cystoides intestinalis. Three patients were admitted with distant “metastatic” infections (eye, shoulder, leg] and cancer of the colon. None of the 59 patients was jaundiced. In those patients without leukemia or leukopenia, the peripheral white blood cell count ranged between 4,700 and 25,699/mm3 with a mean of 13,300/mm3. Of the 59 patients whose medical histories were obtained, 42 (71 per cent) had malignancies; 21(50 per cent]
TABLE II
Probable Portal of Entry of C. septicum and Autopsy Findings in 28 Patients with Bacteremia Patients
ProbablePortal of Entry or Autopsy findings Distal ileum or cecum Distal ileitis or cecitis Cancer of cecum Perforation of cecum lleocecal intussusception Leukemic infiltration of cecum Air filled cysts distal ileum Bowel infarction Perforation, transverse colon cancer Unknown
64
No.
Total No. 17
11 2 1 1 1 1 3 2 6
had solid tumo?s, and 21(50 per cent) had hematologic malignancies (Table I]. Fourteen (67 per cent] of the patients with solid tumors had cancer of the colon, with the most frequent site being the cecum (53 per cent]. Sixteen of the 42 patients with malignancy [six solid tumor, 10 hematologic malignancy] were receiving chemotherapy or radiation therapy. In one patient the diagnosis of cancer of the cecum was made two years after an episode of C. septicum bacteremia. Seventeen of the 59 patients had no detectable malignancy. Of the 17 patients, six had a primary diagnosis of granulocytopenia and six had severe arteriosclerotic cardiovascular disease with a gangrenous extremity or gangrenous bowel. In one patient a gangrenous extremity developed after an insect bite: one had hemorrhagic necrosis of the cecum; and three had C. septicum bacteremia without a definite clinical or pathologic diagnosis. The distal ileum or cecum was identified as the most probable portal of entry of the C. septicum in 17 of the 28 patients examined at autopsy (Table II]. Autopsy findings revealed a cecitis or distal ileitis in 11 of these patients. Infection with C. septicum was the apparent cause of death in 40 patients (68 per cent). All but one of the 19 survivors had malignancies. All surviving patients were given penicillin, cephalothin, chloramphenicol or carbenicillin (antibiotics to which Clostridia have been found to be sensitive [8]) soon after they were admitted to the hospital (Table III]. Twelve patients who received antibiotic therapy, not including one of the aforementioned antibiotics, or no antibiotics, died; all but one died within 48 hours (usually within 12 hours] of admission to the hospital. Twenty-two patients in therapy group 1 [Table III] died. Twelve died during the first day after admission, seven had fecal peritonitis from bowel perforation or gangrene, and two refused surgery for gangrenous extremities. The remaining patient had severe abdominal pain and died three days after the administration of appropriate antibiotics. An autopsy was not performed on this patient. COMMENTS C. septicum bacteremia is not a commonly diagnosed condition. A possible reason for this is that some hospital laboratories do not identify clostridial isolates other than C. perfringens. However, with the greater availability and understanding of good anaerobic technics, many laboratories are now able to accurately identify to the species level most of their Clostridium isolates. Of 360 blood cultures found positive for Clostridium at the Mayo Clinic during a 15 month period, only three were C. septicum [9]. During a similar length of time at Cook County Hospital in Chicago, only two C. septicum isolates were present among 65 isolates of Clostridium cultured from blood [lo]. The CDC is a national reference center for the identification of anaerobic bacteria and receives isolates of C. septicum from throughout the
January 1979 The American Journal of Medicine Volume 66
CLOSTRIDIUM
United States. This gives us a unique opportunity to characterize the epidemiology and pathology of a rarely diagnosed infection. C. septicum is a gram-positive, sporulating, spindleshaped rod. In young cultures, it is motile. This fact accounts for the spreading growth that can be seen when C. septicum is grown on anaerobic blood agar. C. septicum is easily differentiated from C. perfringens by the spreading growth on blood agar as well as by reactions on egg yolk agar and differences in the fermentation of various carbohydrates. C. septicum produces four toxins, which have been designated alpha, beta, gamma and delta [ll]. Alpha toxin is necrotic and lethal for certain animals such as mice. The lethal action of the alpha toxin is neutralized by antitoxin. Animal toxin neutralization tests are necessary to differentiate C. septicim from C. chauvoei which has very similar cultural and biochemical characteristics [7,ll]. Although it is frequently stated that C. septicum is normally found in the human intestine [X2],there is little evidence to support this belief. C. septicum was isolated only once in an exhaustive study of stool specimens from 33 subjects partaking of a Japanese or a western diet [l3]. C. septicum was not isolated from any of the stool specimens of 175 patients from various countries around the world [la]. Further investigations are needed to determine whether C. septicum is or is not an inhabitant of the normal gastrointestinal tract. Our finding that 71 per cent of the patients with C. septicum bacteremia had malignancies confirms what had been speculated in previous case reports and studies of this infection [l-6,15,16]. The fact that one half of our patients had hematologic malignancies and that many of them were receiving chemotherapy at the time of the infection suggests that C. septicum may be an opportunistic invader of the immunosuppressed and compromised host. This possibility receives support from the presence of six cases of granulocytopenia among our 17 patients without malignancy. However, none of our cases occurred in association with other diseases which required patients to receive immunosuppression, such as those with a renal transplant or collagen vascular disease. In our study a predilection of solid tumors for the colon was noted (67per cent). Similarly, in Alpern and Dowell’s previous report [5], six of nine solid tumors were in the colon. The frequencies of colon cancer in the various anatomic sites of the colon in our study [Table I) were compared with those from national cancer statistics [17]. These two sets of frequencies were significantly different (P 24 hours from onset of sepsis; (3) an antibiotic different from aforegoing; (4) no antibiotics. l
commonly identified portals of entry for C. septicum in our patients (Table II). The distal ileum and cecum were demonstrated to be the portals of entry in two diabetic patients with C. septicum infection, as reported by Werner et al. [18]. Because of pH, electrolyte and osmotic differences, the cecum and distal ileum may promote the growth of C. septicum better than other areas of the gastrointestinal tract. An early study suggested that C. septicum was commonly found in the appendix [19]. However, a subsequent study failed to confirm this finding [ZO]. More studies are needed to identify and quantify the normal microflora of the various anatomic regions of the human gastrointestinal tract. The presence of diabetes mellitus and severe arteriosclerotic cardiovascular disease in six of the 17 patients without malignancy suggests that these diseases may play a role in the development of ischemia and tissue necrosis, important predisposing factors for clostridial growth. Clostridial gas gangrene has been reported to be more common in diabetic patients [21]. The three cases of “metastatic” C. septicum infections and cancer of the colon illustrate the importance of searching for bowel cancers when C. septicum is cultured from a local infection outside the bowel. Warren and Mason [l5] reported a case of suppurative thyroiditis caused by C. septicum in a man with adenocarcinoma of the ascending colon. The importance of early recognition and prompt therapy in patients with C. septicum bacteremia cannot be overemphasized. When these patients are admitted to the hospital, they are acutely ill and toxic, frequently have high fevers and commonly have an associated malignancy. Diabetic patients may have a gangrenous extremity and severe toxemia. Blood cultures, both aerobic and anaerobic, should be rapidly performed, and therapy should be instituted before the results of cultures are received. Table III illustrates the need to begin antibiotic therapy almost as soon as the patient arrives in the hospital. Almost half of the patients who received the appropriate antibiotics (81 within 12 hours after the onset of the infection survived. Nearly all of the
January 1979
The American Journal of Medicine
Volume 66
65
CLOSTRIDIUM SEPTICLJM BACTEREMIA-KORANSKY
ET AL.
patients who died, but who received appropriate antibiotic therapy promptly, did not receive necessary surgery or died before an adequate blood level of the antibiotics could be achieved. Penicillin remains the drug of choice [8], but some of our patients were treated successfully with chloramphenicol, carbenicillin or cephalothin. The use of hyperbaric oxygen in the therapy of C. septicum infection has not been adequately
studied. In vitro studies suggest that C. septicum is considerably more resistant to hyperbaric oxygen than other Clostridium species [22]. Radical surgery is sometimes necessary to remove a gangrenous extremity or gangrenous bowel. In the future, the combination of early antibiotic therapy and necessary surgical intervention may help to alter the fulminating nature of C. septicum infections.
REFERENCES
1. Wyman AL: Endogenous gas gangrene complicating cancer 2. 3. 4. 5. 6. 7.
of the colon. Br Med J 1: 266,1949. Valentine JC: Gas gangrene septicemia due to carcinoma of the cecum and muscular trauma. Br J Surg 44: 630, 1957. B&s DR, Frei E, Thomas LB: Clostridial gas yanyrene and septicemia in four patients with IeukeAa. fi Eigl J Med 259: 1255.1958. Gazzaniga AB: Nontraumatic, clostridial. gasgangrene of the right arm and adenocarcinoma of the cecum: report of a case. Dis Colon Rectum 10: 298, 1967. Alpern RJ, Dowell VR Jr: Clostridium septicum infections and malignancy. JAMA 209: 385, 1969. Epidemiology notes: Clostridium septicum bacteremia. Br Med I 1: 969,1976. Dowel1 ‘VRJr, Hawkins TM: Laboratory Methods in Anaerobic Bacteriology. Washington, DC.. U.S. Department of Health, Education, and Welfare No. (CDC) 74-8272,
12. 13. 14. 15. 16. 17. 18.
1974.
8.
Weinstein L: Chemotherapy of microbial diseases. The Pharmacological Basis of Therapeutics, 5th ed [Goodman LS, Gilman A, eds], New York, MacMillan Co. Inc., 1975. 9. Wilson WR. Martin WI. Wilkowske Cl. et al.: Anaerobic bacteremia. Mayo Cl;n Proc 47: 639, i972. 10. Gorbach SL, Thadepalli H: Isolation of Clostridium in human infections: evaluation of 114 cases. J Infect Dis 131 (suppl): S81.1975. 11. Smith LD: The Pathogenic Anaerobic Bacteria, Springfield,
66
January 1979 The American Journal of Medicine
19.
20. 21. 22.
Volume 66
III., Charles C Thomas, 1975. Maclennan JD: The histotoxic clostridial infections of man. Bacterial Rev 26: 177, 1962. Finegold SM, Attebery HR. Sutter VL: Effect of diet on human fecal flora: comoarison of laoanese and American diets. Am J CIin Nutr 2?: 1456,19+4: Drasar BS, Goddard P, Heaton S, et al.: Clostridia isolated from feces. J Med Microbial 9: 63, 1976. Warren CPW, Mason BJ: Clostridium septicum infection of the thyroid gland. Postgrad Med 46: 586, 1970. Mzabi R, Himal HS, MacLean LD: Gas gangrene of the extremity: the presenting clinical picture in perforating carcinoma of the caecum. Br J Surg 62: 373,1975. Third National Cancer Survey: Incidence Data. Washington, DC.. U.S. Department of health, Education, and Welfare Publication r\jo. (NIH] 75-787,1975, p 22. Werner H, Gott U, Rintelen G: Zur kasuistik der enterogenen nichttraumatischen gasodeminfektionen durch Clostridiurn septicum. Z Med Mikrobiol Immunol 156: 265,197l. Lanz 0, Tavel E: Bacteriologic de I’appendicite. Rev Chir 30: 43, 1904. Weinberg M. Prevot AR, Davesne J, et al.: Recherches sur la bacteriologic et la serotherapie des appendicites aigues. Ann Inst Pasteur suppI 42, p 1167,1928. Weinstein L. Barza MA: Gas gangrene-current concepts. N Engl J Med 289: 1129,1973. Hill GB, Osterhout S: Experimental effects of hyperbaric oxygen on selected clostridial species. I. In vitro studies. J Infect Dis 125: 117. 1972.
