Chapter 135. Gas Gangrene and Other Clostridial Infections (Part 5) Diagnosis The diagnosis of clostridial disease, in association with positive cultures, must be based primarily on clinical findings. Because of the presence of clostridia in many wounds, their mere isolation from any site, including the blood, does not necessarily indicate severe disease. Smears of wound exudates, uterine scrapings, or cervical discharge may show abundant large gram-positive rods as well as other organisms. Cultures should be placed in selective media and incubated anaerobically for identification of clostridia. The diagnosis of clostridial myonecrosis can be established by frozen-section biopsy of muscle. The urine of patients with severe clostridial sepsis may contain protein and casts, and some patients may develop severe uremia. Profound alterations of circulating erythrocytes are seen in severely toxemic patients. Patients have hemolytic anemia, which develops extremely rapidly, along with hemoglobinemia, hemoglobinuria, and elevated levels of serum bilirubin. Spherocytosis, increased osmotic and mechanical red blood cell fragility, erythrophagocytosis, and methemoglobinemia have been described. DIC may develop in patients with severe infection. In patients with severe sepsis, Wright's or Gram's staining of a smear of peripheral blood or buffy coat may demonstrate clostridia. X-ray examination sometimes provides an important clue to the diagnosis by revealing gas in muscles, subcutaneous tissue, or the uterus. However, the finding of gas is not pathognomonic for clostridial infection. Other anaerobic bacteria, frequently mixed with aerobic organisms, may produce gas. Clostridial Infections: Treatment (Table 135-1) Traumatic wounds should be thoroughly cleansed and debrided. Traditionally, the antibiotic of choice for severe clostridial infection has been penicillin G (20 million units per day in adults). Penicillin G treatment of gas gangrene has become more controversial because of increasing resistance to this drug and data obtained from animal models of infection. In a mouse model of gas gangrene, antibiotics inhibiting toxin synthesis appeared to be preferable to cell wall–active drugs; clindamycin treatment enhanced survival more than therapy with penicillin; and the combination of clindamycin and penicillin was superior to penicillin alone. For severe clostridial sepsis, clindamycin may be used at a dose of 600 mg every 6 h in combination with high-dose penicillin (3–4 million units every 4 h). Although no clinical trials validate this choice, it is gaining acceptance in the infectious disease community. Table 135-1 Treatment of Clostridial Infections a Condition Antibiotic Treatment Penicillin Allergy Adjunctiv e Treatment/Note Contaminatio n None — — Gas gangrene Penicillin, 3– 4 million units IV q4h, plus Clindamyci n, 600 mg IV q6h Chloramphenico l, metronidazole, imipenem, doxycycline (see text) b Surgical debridement with wide excision is essential. Consider hyperbaric oxygen. Clostridial sepsis Penicillin, 3–4 mill ion units IV q4h, plus Clindamyci n, 600 mg IV q6h Chloramphenico l, metronidazole, imipenem, doxycycline (see text) b Transient bacteremia may be clinically insignificant. Suppurative deep-tissue infections (e.g., abdominal wall, gynecologic) Penicillin, 3– 4 million units IV q4h, plus Gentamicin, 5 mg/kg IV q24h, or A third- generation cephalosporin (e.g., ceftriaxone, 2 g IV q12h) As above, plus gentamicin or a quinolone Empirical therapy should be given. Therapy should be based on Gram's stain and culture results when available. a Treatment recommendations for C. difficile colitis, tetanus, and botulism are found in Chaps. 123, 133, and 134, respectively. b Perform sensitivity testing; consider desensitization. In cases of penicillin sensitivity or allergy, other antibiotics should be considered, but all should be tested for in vitro activity because of the occasional isolation of resistant strains. Clostridia are frequently, but not universally, susceptible in vitro to cefoxitin, carbenicillin, chloramphenicol, clindamycin, metronidazole, doxycycline, imipenem, minocycline, tetracycline, third-generation cephalosporins, and vancomycin. For severe clostridial infections, sensitivity testing should be done before an antimicrobial agent with unpredictable activity is used. Simple contamination of a wound with clostridia should not be treated with antibiotics. Localized skin and soft tissue infection can be managed by debridement rather than with systemic antibiotics. Drugs are required when the process extends into adjacent tissue or when fever and systemic signs of sepsis are present. Surgery is a mainstay of therapy for gas gangrene. Amputation is often required for rapidly spreading infection involving a limb, as the process frequently fails to respond to antibiotics. Hysterectomy is required for uterine myonecrosis. Abdominal wall myonecrosis usually continues despite initial aggressive surgery and antibiotic therapy and requires repeated surgical debridement of all involved muscle. Suppurative infections should be treated with antibiotics. Frequently, broad-spectrum antibiotics must be used because of the mixed flora involved in these infections. Aminoglycosides can be used for the aerobic gram-negative bacteria involved in mixed infections. The use of a polyvalent gas gangrene antitoxin is still recommended by some authorities. At present, no such antitoxin is produced in the United States, and most centers have discontinued its use in the management of patients with suspected gas gangrene or clostridial postabortion sepsis because of questionable efficacy and the substantial risk of hypersensitivity to horse serum, from which the antitoxin is derived. The use of hyperbaric oxygen in the treatment of gas gangrene is also controversial. Studies in humans are not well designed to answer questions on efficacy, but several knowledgeable authors believe that hyperbaric oxygen therapy has contributed to dramatic clinical improvement. Such therapy may, however, be associated with untoward effects due to oxygen toxicity and high atmospheric pressure. Some centers without hyperbaric chambers have reported acceptable mortality rates; thus expert surgical and medical management and control of complications are probably the most important factors in the treatment of gas gangrene. Fasciotomy should not be delayed for hyperbaric oxygen therapy. Acknowledgments The authors acknowledge the contributions of Dori F. Zaleznik, MD, to this chapter in earlier editions Further Readings Borriello SP: Clostridial disease of the gut. Clin Infect Dis 20:S242, 1995 Centers for Disease Control and Prevention: Clostridium sordellii toxic shock syndrome after medical abortion with mifepristone and intravaginal misoprostol—United States and Canada, 2001–2005. MMWR 54:724, 2005 Lorber B: Gas gangrene and other Clostridium- associated diseases, in Principles and Practice of Infectious Diseases , 6th ed, GL Mandell et al (eds). Philadelphia, Elsevier Churchill Livingstone, 2005, pp 2828–2838 Murray-Lillibridge K et al: Epidemiological finding s and medical, legal, and public health challenges of an investigation of severe soft tissue infections and deaths among injecting drug users— Ireland, 2000. Epidemiol Infect 134:894, 2006 [PMID: 16316497] Prinssen HM et al: Clostridium septicum myonecros is and ovarian cancer: A case report and review of literature. Gynecol Oncol 72:116, 1999 [PMID: 9889043] Rood JI: Virulence genes of Clostridium perfringens . Annu Rev Microbiol 52:333, 1998 [PMID: 9891801] Stevens DL, Bryant AE: The role of clostridia l toxins in the pathogenesis of gas gangrene. Clin Infect Dis 35:S93, 2002 Wang C et al: Hyperbaric oxygen for treating wounds: A systematic review of the literature. Arch Surg 138:272, 2003 [PMID: 12611573] Bibliography Ellemor DM et al: Use of genetically manipulated strains of Clostridium perfringens reveals that both alpha-toxin and theta- toxin are required for vascular leukostasis to occur in experimental gas gangrene. Infect Immun 67:4902, 1999 [PMID: 10456947] Schalch B et al: Molecular methods for the analysis of Clostridium perfringens relevant to food hygiene. FEMS Immunol Med Microbiol 24:281, 1999 [PMID: 10397312] Tibbles PM, Edelsberg JS: Medical progress: Hyperbaric- oxygen therapy. N Engl J Med 334:1642, 1996 [PMID: 8628361] . Chapter 135. Gas Gangrene and Other Clostridial Infections (Part 5) Diagnosis The diagnosis of clostridial disease, in association with positive. mifepristone and intravaginal misoprostol—United States and Canada, 2001–2005. MMWR 54:724, 2005 Lorber B: Gas gangrene and other Clostridium- associated diseases, in Principles and Practice. may produce gas. Clostridial Infections: Treatment (Table 135- 1) Traumatic wounds should be thoroughly cleansed and debrided. Traditionally, the antibiotic of choice for severe clostridial