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Significance of clostridial bacteremia
Significance of Clostridial Bacteremia Joseph J. Pietrafitta, MD, Boston, Massachusetts Peter J. Deckers, MD, Boston, Massachusetts
Several distinct, clinically significant clostridial syndromes exist. They consist primarily of histocytotoxic infections manifested by (1) invasive skin and soft tissue infections such as clostridial cellulitis, fasciitis and myonecrosis; (2) fulminant intravascular hemolysis, most commonly associated with postpartum uterine gas gangrene; (3) intestinal disorders characterized by food poisoning, enteritis necroticans and pseudomembranous colitis; and (4) the neurologic effects of exotoxins observed in botulism and tetanus. There is abundant testimony in the medical literature concerning the morbid significance of these conditions. Agreement, however, is not so uniform concerning the significance of clostridial bacteremia when it is not associated with the aforementioned clinical conditions. Clostridium, a species ubiquitous in nature, is composed of over 60 types and is found in human feces in a concentration of log to lOlo organisms per gram [ 1,2]. Clostridium perfringes is the most common type seen in clinical infections. Over 30 types, however, have been isolated in man [3]. With the advent of improved techniques for anaerobic culture, additional types of clostridial organisms are regularly and frequently identified. Their clinical significance, however, remains controversial. Many investigators have noted that bacteremia due to Clostridium species is occasionally seen in patients with solid tumor malignancies, significant gastrointestinal bleeding, myeloproliferative disorders, biliary tract disease and intraabdominal catastrophies [4-111. The significance of such bacteremia, however, is rarely mentioned. Gorbach [12], in his classic review of Clostridium, states that there is a poor correlation between isolation of this organism in the bloodstream and the clinical findings of sepsis, and further states that “the presence of Clostridium in the blood is often of little clinical significance.” The present study was done in an effort (1) to analyze a group of patients who had definite bacteremia due to the spore-forming clostridial organisms, and (2) to determine those clinical and laboratory factors From the Section of Suroical Oncotoav. Division of Suraerv. Boston University School of Medicine, Boston, Massachusetts. Thisinvestigation was supported in part by U.S. Public Health Service Grant 3325 CA18019 awarded by the National Cancer Institute. DHH5. Requests for reprints should be addressed to Peter J. Decker% MD, University Hospital 0512, 75 East Newton Street, Boston, Massachusetts 02118. Presented at the 62nd Annual Meeting of the New England Surgical Society, Dixville Notch, New Hampshire, September 25-27. 1981. I_.
Volume 143, April 1992
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which were significantly come in these patients.
related to an adverse out-
Material and Methods The records in the microbiology laboratory of University Hospital, Boston, from January 1975 to December 1980 were analyzed. All positive blood cultures for Clostridium species were identified and the hospital records of these patients reviewed. It is the practice of this laboratory to identify only the spore-forming clostridial organisms. A total of 53 positive blood cultures for spore-forming clostridial organisms were identified in 29 patients with nonhistocytotoxic clostridial bacteremia. The organisms isolated included Clostridium perfringes in 26 patients and Clostridium septicum, Clostridium limosum and Clostridium subterminale in 1 patient each. The patients’ charts were reviewed for age, sex, disease state, clinical signs of sepsis at the time of the positive blood culture, primary focus of infection, significant laboratory data, presence of additional organisms and ultimate clinical outcome.
Results Twenty-seven patients were included in the study group since two charts were lost. There were 13 men and 14 women. The age range was 39 to 92 years and the average age 67.4 years (66.5 for women and 68.4 for men). Twenty-three patients were over 50 years of age and 15 patients were over 65. Polymicrobial infections were seen in 55 percent of the patients and Clostridium alone in 45 percent. The mortality rate was 60 percent in patients with polymicrobial infections but 42 percent in patients with Clostridium alone in their blood. Mortality rates increased in both groups when the number of positive cultures increased. Patients with mixed infections and only one positive blood culture had a mortality rate of 50 percent, but if more than one positive blood culture was drawn, the mortality rate was 71 percent. Patients with Clostridium alone in their blood and only one positive blood culture had a mortality rate of 17 percent. If, however, more than one positive blood culture was drawn, the mortality rate was 67 percent. Overall, the mortality rate was 69 percent for patients with more than one positive blood culture and 36 percent for those with a single positive culture. The distribution of patients in terms of their particular clinical setting, that is, primary disease state, is similar to that previously reported in other series. 519
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Most patients either had a solid tumor malignancy (44 percent), significant gastrointestinal bleeding (37 percent), were on systemic chemotherapy (30 percent) or had a myeloproliferative disorder (22 percent). Other associated conditions included urinary tract infections (22 percent), pneumonia (19 percent), biliary tract disease (15 percent), intraabdominal catastrophe (15 percent), postsurgical wound infection (11 percent), fistula (7 percent) and ethanol abuse (7 percent). No patients with histocytotoxic infections were included. Sixteen patients (60 percent) had evidence of sepsis at the time blood cultures were drawn, manifested by high fever, shaking chills, hypotension or change in mental status; 56 percent of them died. Eight of the patients (30 percent) with evidence of sepsis had only Clostridium in their blood, and 38 percent died. The remaining eight patients (30 percent) with evidence of sepsis had polymicrobial infections, and 74 percent of them died. Seven patients had a white blood cell count greater than 20,000/mm3 and in 13 it was greater than 10,000. Six patients had a temperature greater than 103.6’F and in 12 it was greater than 101.6”. Thirteen patients presented with hypotension and 12 had abnormal mental status. In general, antibiotic use did not appear to affect the clinical outcome in these patients. All patients treated with antibiotics received either penicillin or clindamycin. Nineteen patients were treated with antibiotics, 10 of whom died (53 percent); 8 patients did not receive antibiotics, 3 of whom died (38 percent). Further analysis of the data allowed definition of three specific groups of patients. The first consisted of patients with documented biliary tract disease which, in addition, was felt to be the source of their positive blood cultures. There were four patients in this group, three men and one woman. They were elderly; three were 75 years of age or older. All patients in this group had Clostridium alone in their blood. No mixed infections were seen, and no patient died. There was no consistent clinical or laboratory presentation among these patients except for the positive blood cultures for Clostridium alone and an elevated white blood cell count (average 20,700/ mm3). Temperatures ranged from 98’ to 106’F; one patient was in septic shock, one was comatose, and three of four were treated with antibiotics. Two patients were treated with surgery plus antibiotics, one with antibiotics alone, and one patient with supportive therapy alone, yet all survived. The second group consisted of seven patients, all women, who also were elderly. Most had been referred from nursing homes and, in general, presented with hypotension, dehydration and marked deterioration in mental status just before admission to the hospital. The average age of these patients was 84 years. Five of the seven patients in this group had Clostridium alone in their blood. Only two (28 per520
cent) died. All patients had acute infection at the time of admission, either in the urinary tract or in the lungs. None had chronic severe debilitating illnesses. White blood cell counts in this group tended to be lower, with an average of 12,700/mm3; only three patients had a count higher than 10,000. Temperatures tended to vary, ranging from 96 to 104.5’F. Only four patients had temperatures of 1Ol’F or greater. All patients presented with hypotension which was, at least initially, responsive to intravenous fluids. Five patients in this group were treated with antibiotics, which appeared unrelated to survival. Unlike the first two groups, the 17 patients in the third group were much younger, ranging in age from 44 to 81 years (mean 61). There were eight men and nine women. Fifteen of these patients had a malignancy and metastatic disease had been documented in 10. One patient had a long history of alcohol abuse and one had a systemic vasculitis. This group tended to have a much worse prognosis than the patients in the other two groups. The overall mortality was 65 percent and, among the patients treated with antibiotics, was 73 percent. White blood cell counts fell in the intermediate range, with an average of 14,700/mm3. Temperatures were higher, with an average of 101.6’F. Ten patients had a temperature greater than 102°F. Forty-seven percent of these patients presented in shock. However, unlike in the second group, it was felt to be due to the bacteremic process, not to dehydration. In 65 percent of these patients blood cultures revealed multiple organisms including Clostridium. This, again, is unlike the first two groups, where generally only Clostridium was identified. An identifiable, surgically correctable focus of infection was found in only four of these patients, and despite surgical intervention three of these patients died. Comments When clinicians are confronted with a positive blood culture for a clostridial organism in a patient who may appear relatively well or, alternatively, critically ill, a quandary exists as to the appropriate method of therapy. It has been recognized since the report of Ramsay [13] in 1949, in which he described the presence of Clostridium in the blood of women in the postpartum or postabortal state as “nothing more than a harmless saprophyte,” that clostridial bacteremia is seen in various diseases [3-111. The patients in Ramsay’s series, however, were otherwise healthy persons without concomitant disease, unlike the patients in this report, many of whom had terminal illnesses. In spite of this, a mortality rate of 12 percent was still observed. The occurrence of such bacteremia was described by Gorbach [12] as being of “little clinical significance,” since patients with clostridial bacteremia often do not manifest signs of systemic sepsis, most survive, and treatment should, therefore, be guided by that patient’s particular clinical setting. Gorbach The American Journal of Surgery
Significance of Clostridial Bacteremia
refers to three studies. The first [3] is his own series of 29 patients with positive blood cultures for Clostridium. In that report, however, he notes that 17 of 29 patients had clinical sepsis of unknown cause and were seriously ill. The second study referred to is by Rathbun [14] and describes 20 patients with clostridial bacteremia who had underlying serious chronic disease or were in the postpartum or postabortal state. These patients generally had fever and leukocytosis and responded well to antibiotics or surgical intervention. However, 20 percent of them died. The third report cited, by Alpern and Dowel1 [9], describes 86 patients with clostridial bacteremia, almost all of whom had fever and leukocytosis and some of whom had hypotension. This series also had a mortality rate of 12 percent, which did not appear to be affected by antibiotic use. Considering these data, one must wonder whether it is true that clostridial bacteremia is of little clinical significance. In the present report, 60 percent of the patients had evidence of sepsis at the time the blood cultures were drawn, consisting of spiking fever, shaking chills, signs of cardiovascular collapse or change in mental status. This finding is similar to Gorbach’s study, in which 17 of 29 patients, or 59 percent, had signs of systemic sepsis. The overall mortality rate of 48 percent in our series is certainly higher than the rates previously reported by others. The reason for this is somewhat unclear. However, most of our patients were seriously ill with malignancy. A majority (50 percent) had metastatic disease and were on chemotherapy. Also of note is that of the 13 patients who died, 8 did so within the first 72 hours, 6 of those within the first 24 hours of the septic episode. Many of these patients, therefore, did not have the benefit of appropriate antibiotic treatment or surgical therapy since the culture results and the specific source of sepsis were not known before death. However, most were treated with antibiotic combinations directed toward the more common forms of sepsis encountered in a hospital setting. The high mortality rate appears to indicate that clostridial bacteremia in the absence of overt tissue necrosis is a significant clinical event. Analysis of our data allowed identification of three distinct clinical groups. There is no controversy in the literature regarding the significance of Clostridium in a diseased gallbladder [7,8], and postoperative gangrene of the abdominal wall secondary to clostridial species is well-recognized [15]. The patients in group 1 responded to appropriate intervention, which consisted of cholecystectomy in two cases and systemic antibiotics in one case. A fourth patient did not receive the benefit of either form of therapy, yet survived. The etiology of many of these types of bacteremia remains unclear. Several investigators have suggested that the cause is increased permeability of the gastrointestinal tract to bacteria because of either direct damage to the inner surface of the gut, as seen with Volume 143, April 1992
chemotherapy [16], or ischemic damage secondary to hypoperfusion, which may occur in shock states. Certainly, many of the patients in group 2 had severe hypotension. It is interesting, however, that among the patients in this report, as well as the patients previously reported by others, no case of documented ischemic colitis is noted; if the aforementioned theory were correct, this condition should be well represented in the collected literature about this disease, but it is not. Conflicting results have also been obtained concerning the results of portal blood cultures. Several workers [17,18] have identified portal bacteremia intraoperatively; however, others [19] have failed to substantiate this event. The occurrence of clostridial bacteremia in patients with malignant disease is certainly well described. Since the report of Govan [zO] in 1946, it has been shown by several investigators [II ,21-251 that the intravenous injection of Clostridium tetani spores as well as the spores of other species resulted in localization of the vegetative forms of the organisms almost exclusively within tumors with extensive lysis of malignant tissue. The significance of this phenomenon, however, is not known, and pathologic studies of patients dying with clostridial bacteremia have failed to reveal any foci of infected malignant tissue [26]. In general, the third group of patients in this report did the poorest. Fifteen of these patients had malignant disease, which was metastatic in 10, for an overall mortality rate of 65 percent in this group. The most plausible explanation for this phenomenon is an inability to cope with transient bacteremia because of an immunocompromised condition. This may be due to a combination of factors, including nutritional depletion, as well as to the effects of chemo- and radiotherapeutic regimens delivered to these patients. Several important points can be made. First, Clostridium in the blood, when associated with polymicrobial infection, carries a grave prognosis and a mortality rate of 60 percent. Second, Clostridium as a sole isolate found in multiple sequential cultures also carries a grave prognosis, with a mortality rate of 67 percent. Finally, Clostridium as the sole isolate in association with signs of sepsis also carries a high mortality (38 percent). No patient in this study was felt to have an “incidental positive blood culture for Clostridium,” even patients who had only one positive blood culture with Clostridium as the only organism present in that culture. These patients still had a mortality rate of 17 percent which was, however, considerably lower than in all of the other groups. When presented with a patient with a positive blood culture for Clostridium, it is important to rule out biliary tract disease as the source of the positive culture. Concomitant infections which are often present must be looked for and treated aggressively. In patients with malignant disease, appropriate expanded antibiotic coverage should be considered because of the extremely high mortality 521
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rate associated with clostridial bacteremia. Maximum supportive measures must be instituted in an attempt to reverse the hypotension that is often present. Therefore, our data generally fail to support the belief commonly expressed in the medical literature regarding the benign nature of clostridial bacteremia. Such bacteremias are frequently lethal and must be aggressively treated with appropriate antibiotics and, when necessary, appropriate surgical intervention. A high index of suspicion should be maintained in patients with malignant disease, especially those undergoing chemotherapy. Summary In the absence of overt tissue necrosis, clostridial bacteremia has been considered a bacteriologic finding of little clinical significance. This study was done to examine this belief and determine the incidence and significance of clostridial bacteremia. In the past 6 years in a referral hospital, 6,030 positive blood cultures were seen in 2,542 patients. Fifty-three of the positive isolates contained spore-forming Clostridium species. They were found in 29 patients, for an incidence of 0.88 percent in all positive cultures in 1.14 percent in all patients. Mortality rates were 60 percent in patients with mixed (polymicrobial) positive blood cultures and 42 percent in patients with Clostridium alone in their blood. The mortality rate increased with an increasing number of positive blood cultures both in patients with mixed positive cultures and in patients with Clostridium alone in their blood. The mortality rate for patients with one positive blood culture for Clostridium alone was 17 percent; however, when more than one culture was positive, the mortality rate increased to 67 percent. Sixteen patients (60 percent) had evidence of systemic sepsis at the time blood cultures were drawn, and 56 percent of them died. Eight patients (30 percent) with evidence of sepsis had Clostridium alone in their blood, and 38 percent of them died. Most patients with clostridial bacteremia had solid tumor malignancies, significant gastrointestinal bleeding or myeloproliferative disorders. No patient with biliary tract disease as the primary diagnosis had polymicrobial infections. Clostridium alone was isolated from their blood, and none died. Three general groups of patients were defined. The first group with biliary tract disease carried a good prognosis regardless of therapy. The second group, the elderly nursing home patients who presented with a septic picture, responded well to supportive therapy and treatment of their associated infection, usually pneumonia or urinary tract infection. The third group, patients with malignant disease, did the poorest and had the highest mortality rate with antibiotics or surgical intervention not affecting the outcome. These findings vary considerably from those in previously reported studies which consider the presence of Clostridium in the blood an incidental finding with minimal clinical significance. 522
References 1. Haldeman LV, Moore WEC. Anaerobe laboratory manual. Blacksburg, VA: Anaerobe Laboratory of Virginia Polytechnic Institute and State University, 1975. 2. Finegold SM, Atterbery HR, Sutter VL. Effect of diet on human fecal flora: comparison of Japanese and American diets. Am J Clin Nutr 1974;27: 1456. 3. Gorbach SL, Thadepalli H. Isolation of Clostridium in human infections: evaluation of 114 cases. J Infect Dis 1975; 13l[Suppl]:61. 4. Thadepalli H, Gorbach SL, Broida PW, et al. Abdominal trauma. anaerobes and antibiotics. Surg Gynecol Obstet 1973; 137:270. 5. Cabrera A, Tsukada Y, Pickren JW. Clostridial gas gangrene and septicemia in malignant disease. Cancer 1965;16: 600. 6. Alpern RJ, Dowell VR Jr. Clostridium septicium infections and malignancy. JAMA 1969;209:365. 7. Gordon-Taylor G, Whitby LEH. The incidence of anaerobic infections in the gallbladder. Br J Surg 1932;19:619. 8. Sarmiento RV. Emphysematous dialecystitis: report of four cases and review of the literature. Arch Surg 1966;93: 1009. 9. Alpem RJ, Dowell VR Jr. Nonhistotoxic clostridial bacteremia. Am J Clin Pathol 1971;55:717. 10. Boggs DR, Frei E, Thomas IS. Clostridial gas gangrene and septicemia in 4 patients with leukemia. N Engl J Med 1958;259:1255. 11. Wyaman AL. Endogenous gas gangrene complicating carcinoma of the colon. Br Med J 1949;1:266. 12. Gorbach SL. Other Clostridium species (including gas gangrene). In: Mandell GL, Douglas RG, Bennett JE, eds. Principles and practices of infectious disease. New York: John Wiley and Sons, 1978:1876-85. 13. Ramsay AM. The significance of Clostridium welchii in the cervical swab and blood stream in postpartum and postabortum sepsis. J Obstet Gynaecol Br 1949;56:247. 14. Rathbun HK. Clostridial bacteremia without hemolysis. Arch Intern Med 1968; 122:496-501. 15. McNally JB, Prince WR, Wood M. Gas gangrene of the anterior abdominal wall. Am J Surg 1968;116:779. 16. Moore GE, Watson TG. Triethylene tiophosphoramide therapy complicated by overwhelming infection with Clostridium Welchii. Report of 2 cases. Cancer 1957;10:246. 17. Schatten WE, Despraz JD, Holden WD. A bacteriologic study of portal vein blood in man. Arch Surg 1955;71:404. 18. Eade MN, Brooke BN. Portal bacteremia in cases of ulcerative colitis submitted to colectomy. Lancet 1969;1:1008. 19. Dencker H. Kammi C, Norryd C, et al. Examination for anaerobic bacteria in human portal blood collected by transumbilical catheterization. Stand J Gastroenterol 1974;9:367. 20. Govan ADT. An account of the pathology of some cases of Clostridium welchii infections. J Pathol Bacterial 1976;58: 423-30. 21. Malmgren RA, Flanigan CC. Localization of ths vegetative forms of Clostridium tetani in mouse tumors following intravenous spore administration. Cancer Res 1955;15:473. 22. Engelbart K, Gericke D. Oncolysis by Clostridium. V. Transplanted tumors of the hamster. Cancer Res 1964;24: 239-42. 23. Gericke D, Engelbart K. Oncolysis by Clostridium. II. Experiments on a tumor spectrum with a variety of Clostridium in combination with heavy metal. Cancer Res 1964;24:217. 24. Mose JR, Mose G. Oncolysis by Clostridium. I. Activity of Clostridium butyricum (M-55) and other nonpathogenic Clostridium against the Erlich carcinoma. Cancer Res 1964;24:212. 25. Thiele EH, Arison RN, Boxer GE. Oncolysis by Clostridium. Ill. Effects of Clostridium and chemotherapeutic agents on rodent tumors. Cancer Res 1964;24:222-33. 26. Thiele EH, Arison RN, Boxer GE. Oncolysis by Clostridium. IV. Effect of nonpathogenic clostridial spores in normal and pathologic tissues. Cancer Res 1964;24:234-8. The American Journal of Surgery
Several distinct, clinically significant clostridial syndromes exist. They consist primarily of histocytotoxic infections manifested by (1) invasive skin and soft tissue infections such as clostridial cellulitis, fasciitis and myonecrosis; (2) fulminant intravascular hemolysis, most commonly associated with postpartum uterine gas gangrene; (3) intestinal disorders characterized by food poisoning, enteritis necroticans and pseudomembranous colitis; and (4) the neurologic effects of exotoxins observed in botulism and tetanus. There is abundant testimony in the medical literature concerning the morbid significance of these conditions. Agreement, however, is not so uniform concerning the significance of clostridial bacteremia when it is not associated with the aforementioned clinical conditions. Clostridium, a species ubiquitous in nature, is composed of over 60 types and is found in human feces in a concentration of log to lOlo organisms per gram [ 1,2]. Clostridium perfringes is the most common type seen in clinical infections. Over 30 types, however, have been isolated in man [3]. With the advent of improved techniques for anaerobic culture, additional types of clostridial organisms are regularly and frequently identified. Their clinical significance, however, remains controversial. Many investigators have noted that bacteremia due to Clostridium species is occasionally seen in patients with solid tumor malignancies, significant gastrointestinal bleeding, myeloproliferative disorders, biliary tract disease and intraabdominal catastrophies [4-111. The significance of such bacteremia, however, is rarely mentioned. Gorbach [12], in his classic review of Clostridium, states that there is a poor correlation between isolation of this organism in the bloodstream and the clinical findings of sepsis, and further states that “the presence of Clostridium in the blood is often of little clinical significance.” The present study was done in an effort (1) to analyze a group of patients who had definite bacteremia due to the spore-forming clostridial organisms, and (2) to determine those clinical and laboratory factors From the Section of Suroical Oncotoav. Division of Suraerv. Boston University School of Medicine, Boston, Massachusetts. Thisinvestigation was supported in part by U.S. Public Health Service Grant 3325 CA18019 awarded by the National Cancer Institute. DHH5. Requests for reprints should be addressed to Peter J. Decker% MD, University Hospital 0512, 75 East Newton Street, Boston, Massachusetts 02118. Presented at the 62nd Annual Meeting of the New England Surgical Society, Dixville Notch, New Hampshire, September 25-27. 1981. I_.
Volume 143, April 1992
.
which were significantly come in these patients.
related to an adverse out-
Material and Methods The records in the microbiology laboratory of University Hospital, Boston, from January 1975 to December 1980 were analyzed. All positive blood cultures for Clostridium species were identified and the hospital records of these patients reviewed. It is the practice of this laboratory to identify only the spore-forming clostridial organisms. A total of 53 positive blood cultures for spore-forming clostridial organisms were identified in 29 patients with nonhistocytotoxic clostridial bacteremia. The organisms isolated included Clostridium perfringes in 26 patients and Clostridium septicum, Clostridium limosum and Clostridium subterminale in 1 patient each. The patients’ charts were reviewed for age, sex, disease state, clinical signs of sepsis at the time of the positive blood culture, primary focus of infection, significant laboratory data, presence of additional organisms and ultimate clinical outcome.
Results Twenty-seven patients were included in the study group since two charts were lost. There were 13 men and 14 women. The age range was 39 to 92 years and the average age 67.4 years (66.5 for women and 68.4 for men). Twenty-three patients were over 50 years of age and 15 patients were over 65. Polymicrobial infections were seen in 55 percent of the patients and Clostridium alone in 45 percent. The mortality rate was 60 percent in patients with polymicrobial infections but 42 percent in patients with Clostridium alone in their blood. Mortality rates increased in both groups when the number of positive cultures increased. Patients with mixed infections and only one positive blood culture had a mortality rate of 50 percent, but if more than one positive blood culture was drawn, the mortality rate was 71 percent. Patients with Clostridium alone in their blood and only one positive blood culture had a mortality rate of 17 percent. If, however, more than one positive blood culture was drawn, the mortality rate was 67 percent. Overall, the mortality rate was 69 percent for patients with more than one positive blood culture and 36 percent for those with a single positive culture. The distribution of patients in terms of their particular clinical setting, that is, primary disease state, is similar to that previously reported in other series. 519
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Most patients either had a solid tumor malignancy (44 percent), significant gastrointestinal bleeding (37 percent), were on systemic chemotherapy (30 percent) or had a myeloproliferative disorder (22 percent). Other associated conditions included urinary tract infections (22 percent), pneumonia (19 percent), biliary tract disease (15 percent), intraabdominal catastrophe (15 percent), postsurgical wound infection (11 percent), fistula (7 percent) and ethanol abuse (7 percent). No patients with histocytotoxic infections were included. Sixteen patients (60 percent) had evidence of sepsis at the time blood cultures were drawn, manifested by high fever, shaking chills, hypotension or change in mental status; 56 percent of them died. Eight of the patients (30 percent) with evidence of sepsis had only Clostridium in their blood, and 38 percent died. The remaining eight patients (30 percent) with evidence of sepsis had polymicrobial infections, and 74 percent of them died. Seven patients had a white blood cell count greater than 20,000/mm3 and in 13 it was greater than 10,000. Six patients had a temperature greater than 103.6’F and in 12 it was greater than 101.6”. Thirteen patients presented with hypotension and 12 had abnormal mental status. In general, antibiotic use did not appear to affect the clinical outcome in these patients. All patients treated with antibiotics received either penicillin or clindamycin. Nineteen patients were treated with antibiotics, 10 of whom died (53 percent); 8 patients did not receive antibiotics, 3 of whom died (38 percent). Further analysis of the data allowed definition of three specific groups of patients. The first consisted of patients with documented biliary tract disease which, in addition, was felt to be the source of their positive blood cultures. There were four patients in this group, three men and one woman. They were elderly; three were 75 years of age or older. All patients in this group had Clostridium alone in their blood. No mixed infections were seen, and no patient died. There was no consistent clinical or laboratory presentation among these patients except for the positive blood cultures for Clostridium alone and an elevated white blood cell count (average 20,700/ mm3). Temperatures ranged from 98’ to 106’F; one patient was in septic shock, one was comatose, and three of four were treated with antibiotics. Two patients were treated with surgery plus antibiotics, one with antibiotics alone, and one patient with supportive therapy alone, yet all survived. The second group consisted of seven patients, all women, who also were elderly. Most had been referred from nursing homes and, in general, presented with hypotension, dehydration and marked deterioration in mental status just before admission to the hospital. The average age of these patients was 84 years. Five of the seven patients in this group had Clostridium alone in their blood. Only two (28 per520
cent) died. All patients had acute infection at the time of admission, either in the urinary tract or in the lungs. None had chronic severe debilitating illnesses. White blood cell counts in this group tended to be lower, with an average of 12,700/mm3; only three patients had a count higher than 10,000. Temperatures tended to vary, ranging from 96 to 104.5’F. Only four patients had temperatures of 1Ol’F or greater. All patients presented with hypotension which was, at least initially, responsive to intravenous fluids. Five patients in this group were treated with antibiotics, which appeared unrelated to survival. Unlike the first two groups, the 17 patients in the third group were much younger, ranging in age from 44 to 81 years (mean 61). There were eight men and nine women. Fifteen of these patients had a malignancy and metastatic disease had been documented in 10. One patient had a long history of alcohol abuse and one had a systemic vasculitis. This group tended to have a much worse prognosis than the patients in the other two groups. The overall mortality was 65 percent and, among the patients treated with antibiotics, was 73 percent. White blood cell counts fell in the intermediate range, with an average of 14,700/mm3. Temperatures were higher, with an average of 101.6’F. Ten patients had a temperature greater than 102°F. Forty-seven percent of these patients presented in shock. However, unlike in the second group, it was felt to be due to the bacteremic process, not to dehydration. In 65 percent of these patients blood cultures revealed multiple organisms including Clostridium. This, again, is unlike the first two groups, where generally only Clostridium was identified. An identifiable, surgically correctable focus of infection was found in only four of these patients, and despite surgical intervention three of these patients died. Comments When clinicians are confronted with a positive blood culture for a clostridial organism in a patient who may appear relatively well or, alternatively, critically ill, a quandary exists as to the appropriate method of therapy. It has been recognized since the report of Ramsay [13] in 1949, in which he described the presence of Clostridium in the blood of women in the postpartum or postabortal state as “nothing more than a harmless saprophyte,” that clostridial bacteremia is seen in various diseases [3-111. The patients in Ramsay’s series, however, were otherwise healthy persons without concomitant disease, unlike the patients in this report, many of whom had terminal illnesses. In spite of this, a mortality rate of 12 percent was still observed. The occurrence of such bacteremia was described by Gorbach [12] as being of “little clinical significance,” since patients with clostridial bacteremia often do not manifest signs of systemic sepsis, most survive, and treatment should, therefore, be guided by that patient’s particular clinical setting. Gorbach The American Journal of Surgery
Significance of Clostridial Bacteremia
refers to three studies. The first [3] is his own series of 29 patients with positive blood cultures for Clostridium. In that report, however, he notes that 17 of 29 patients had clinical sepsis of unknown cause and were seriously ill. The second study referred to is by Rathbun [14] and describes 20 patients with clostridial bacteremia who had underlying serious chronic disease or were in the postpartum or postabortal state. These patients generally had fever and leukocytosis and responded well to antibiotics or surgical intervention. However, 20 percent of them died. The third report cited, by Alpern and Dowel1 [9], describes 86 patients with clostridial bacteremia, almost all of whom had fever and leukocytosis and some of whom had hypotension. This series also had a mortality rate of 12 percent, which did not appear to be affected by antibiotic use. Considering these data, one must wonder whether it is true that clostridial bacteremia is of little clinical significance. In the present report, 60 percent of the patients had evidence of sepsis at the time the blood cultures were drawn, consisting of spiking fever, shaking chills, signs of cardiovascular collapse or change in mental status. This finding is similar to Gorbach’s study, in which 17 of 29 patients, or 59 percent, had signs of systemic sepsis. The overall mortality rate of 48 percent in our series is certainly higher than the rates previously reported by others. The reason for this is somewhat unclear. However, most of our patients were seriously ill with malignancy. A majority (50 percent) had metastatic disease and were on chemotherapy. Also of note is that of the 13 patients who died, 8 did so within the first 72 hours, 6 of those within the first 24 hours of the septic episode. Many of these patients, therefore, did not have the benefit of appropriate antibiotic treatment or surgical therapy since the culture results and the specific source of sepsis were not known before death. However, most were treated with antibiotic combinations directed toward the more common forms of sepsis encountered in a hospital setting. The high mortality rate appears to indicate that clostridial bacteremia in the absence of overt tissue necrosis is a significant clinical event. Analysis of our data allowed identification of three distinct clinical groups. There is no controversy in the literature regarding the significance of Clostridium in a diseased gallbladder [7,8], and postoperative gangrene of the abdominal wall secondary to clostridial species is well-recognized [15]. The patients in group 1 responded to appropriate intervention, which consisted of cholecystectomy in two cases and systemic antibiotics in one case. A fourth patient did not receive the benefit of either form of therapy, yet survived. The etiology of many of these types of bacteremia remains unclear. Several investigators have suggested that the cause is increased permeability of the gastrointestinal tract to bacteria because of either direct damage to the inner surface of the gut, as seen with Volume 143, April 1992
chemotherapy [16], or ischemic damage secondary to hypoperfusion, which may occur in shock states. Certainly, many of the patients in group 2 had severe hypotension. It is interesting, however, that among the patients in this report, as well as the patients previously reported by others, no case of documented ischemic colitis is noted; if the aforementioned theory were correct, this condition should be well represented in the collected literature about this disease, but it is not. Conflicting results have also been obtained concerning the results of portal blood cultures. Several workers [17,18] have identified portal bacteremia intraoperatively; however, others [19] have failed to substantiate this event. The occurrence of clostridial bacteremia in patients with malignant disease is certainly well described. Since the report of Govan [zO] in 1946, it has been shown by several investigators [II ,21-251 that the intravenous injection of Clostridium tetani spores as well as the spores of other species resulted in localization of the vegetative forms of the organisms almost exclusively within tumors with extensive lysis of malignant tissue. The significance of this phenomenon, however, is not known, and pathologic studies of patients dying with clostridial bacteremia have failed to reveal any foci of infected malignant tissue [26]. In general, the third group of patients in this report did the poorest. Fifteen of these patients had malignant disease, which was metastatic in 10, for an overall mortality rate of 65 percent in this group. The most plausible explanation for this phenomenon is an inability to cope with transient bacteremia because of an immunocompromised condition. This may be due to a combination of factors, including nutritional depletion, as well as to the effects of chemo- and radiotherapeutic regimens delivered to these patients. Several important points can be made. First, Clostridium in the blood, when associated with polymicrobial infection, carries a grave prognosis and a mortality rate of 60 percent. Second, Clostridium as a sole isolate found in multiple sequential cultures also carries a grave prognosis, with a mortality rate of 67 percent. Finally, Clostridium as the sole isolate in association with signs of sepsis also carries a high mortality (38 percent). No patient in this study was felt to have an “incidental positive blood culture for Clostridium,” even patients who had only one positive blood culture with Clostridium as the only organism present in that culture. These patients still had a mortality rate of 17 percent which was, however, considerably lower than in all of the other groups. When presented with a patient with a positive blood culture for Clostridium, it is important to rule out biliary tract disease as the source of the positive culture. Concomitant infections which are often present must be looked for and treated aggressively. In patients with malignant disease, appropriate expanded antibiotic coverage should be considered because of the extremely high mortality 521
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rate associated with clostridial bacteremia. Maximum supportive measures must be instituted in an attempt to reverse the hypotension that is often present. Therefore, our data generally fail to support the belief commonly expressed in the medical literature regarding the benign nature of clostridial bacteremia. Such bacteremias are frequently lethal and must be aggressively treated with appropriate antibiotics and, when necessary, appropriate surgical intervention. A high index of suspicion should be maintained in patients with malignant disease, especially those undergoing chemotherapy. Summary In the absence of overt tissue necrosis, clostridial bacteremia has been considered a bacteriologic finding of little clinical significance. This study was done to examine this belief and determine the incidence and significance of clostridial bacteremia. In the past 6 years in a referral hospital, 6,030 positive blood cultures were seen in 2,542 patients. Fifty-three of the positive isolates contained spore-forming Clostridium species. They were found in 29 patients, for an incidence of 0.88 percent in all positive cultures in 1.14 percent in all patients. Mortality rates were 60 percent in patients with mixed (polymicrobial) positive blood cultures and 42 percent in patients with Clostridium alone in their blood. The mortality rate increased with an increasing number of positive blood cultures both in patients with mixed positive cultures and in patients with Clostridium alone in their blood. The mortality rate for patients with one positive blood culture for Clostridium alone was 17 percent; however, when more than one culture was positive, the mortality rate increased to 67 percent. Sixteen patients (60 percent) had evidence of systemic sepsis at the time blood cultures were drawn, and 56 percent of them died. Eight patients (30 percent) with evidence of sepsis had Clostridium alone in their blood, and 38 percent of them died. Most patients with clostridial bacteremia had solid tumor malignancies, significant gastrointestinal bleeding or myeloproliferative disorders. No patient with biliary tract disease as the primary diagnosis had polymicrobial infections. Clostridium alone was isolated from their blood, and none died. Three general groups of patients were defined. The first group with biliary tract disease carried a good prognosis regardless of therapy. The second group, the elderly nursing home patients who presented with a septic picture, responded well to supportive therapy and treatment of their associated infection, usually pneumonia or urinary tract infection. The third group, patients with malignant disease, did the poorest and had the highest mortality rate with antibiotics or surgical intervention not affecting the outcome. These findings vary considerably from those in previously reported studies which consider the presence of Clostridium in the blood an incidental finding with minimal clinical significance. 522
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