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Introduction: Clostridium perfringens and other gas gangrene-forming clostridia are commensals of the human gut and vaginal microbiota, but can cause serious or even fatal infections. As there are relatively few published studies on antibiotic susceptibility of these bacteria, we decided to perform a 10-year retrospective study in a South-Eastern Hungarian clinical centre. Methods: A total of 372 gas gangrene-forming Clostridium spp. were isolated from clinically relevant samples and identified with rapid ID 32A (bioMérieux, France) and MALDI-TOF MS (Bruker Daltinics, Germany) methods. Antibiotic susceptibility was determined with E-tests. Results: We identified 313 C. perfringens , 20 C. septicum , 10 C. sordellii , 10 C. sporogenes , 9 C. tertium , 6 C. bifermentans , 4 C. histolyticum isolates. In C. perfringens isolates, the rate of penicillin resistance was 2.6% and the rate of clindamycin resistance 3.8%. Penicillin resistance was found in 6.8% and clindamycin resistance in 8.5% of the non-perfringens Clostridium spp. isolates. Conclusion: The antibiotic susceptibility of C. perfringens isolates was in good agreement with previous publications. The rates of resistance to penicillin and clindamycin were very low. The resistance rates of non-perfringens Clostridium spp. isolates were higher than those of C. perfringens strains, but lower than those published in the literature.

A mycotic aneurysm caused by a Clostridium septicum is a rare infection and has a strong association with colorectal cancer. If left untreated, the mortality rate of the first 24 h is high. This case report discusses the optimal treatment of emergency surgery combined with antibiotic treatment to improve survival. We present a fatal case of a 71-year-old male with abscedation of a caecal carcinoma who shortly after developed a mycotic aneurysm of the infrarenal aorta as a result of a C. septicum infection.

Gas gangrene is a potentially fatal disease that is primarily caused by the ubiquitous, anaerobic bacteria Clostridium perfringens and Clostridium septicum. Treatment is limited to antibiotic therapy, debridement of the infected tissue, and, in severe cases, amputation. The need for new treatment approaches is compelling. Opioid-based analgesics such as buprenorphine and morphine also have immunomodulatory properties, usually leading to faster disease progression. However, here we show that mice pretreated with buprenorphine and morphine do not die from clostridial myonecrosis. Treatment with buprenorphine after the onset of infection also arrested disease development. Protection against myonecrotic disease was specific to C. perfringens-mediated myonecrosis; buprenorphine did not protect against disease caused by C. septicum infection even though infections due to both species are very similar. These data provide the first evidence of a protective role for opioids during infection and suggest that new therapeutic strategies may be possible for the treatment of C. perfringens-mediated myonecrosis., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Our report presents a case of Clostridium septicum gas gangrene in an unusual, orbital localization. The predisposing factors are typical: colon tumour and lymphatic malignancy. Most probably bacteria from the intestinal flora entered the bloodstream through the compromised intestinal wall and settled in the orbit resulting in the development of an abscess containing gas. At the site of the gas gangrene, an indolent B cell lymphoma was present. After surgery and antibiotic treatment, the patient healed from the C. septicum infection; but subsequently died as a consequence of the tumour.

Clostridium perfringens, the most broadly distributed pathogen in nature, produces a prototype phospholipase C, also called α-toxin, which plays a key role in the pathogenesis of gas gangrene. α-Toxin causes plasma membrane disruption at high concentrations, but the role of intracellular mediators in its toxicity at low concentrations is unknown. This work demonstrates that α-toxin causes oxidative stress and activates the MEK/ERK pathway in cultured cells and furthermore provides compelling evidence that O(2)(-.), hydrogen peroxide, and the OH(.) radical are involved in its cytotoxic and myotoxic effects. The data show that antioxidants and MEK1 inhibitors reduce the cytotoxic and myotoxic effects of α-toxin and demonstrate that edaravone, a clinically used hydroxyl radical trap, reduces the myonecrosis and the mortality caused by an experimental infection with C. perfringens in a murine model of gas gangrene. This knowledge provides new insights for the development of novel therapies to reduce tissue damage during clostridial myonecrosis.

Clostridium perfringens causes gas gangrene with inflammatory myopathies and infrequently septicemia associated with massive intravascular hemolysis. The microorganism is known to produce a variety of toxins and enzymes that are responsible for severe myonecrotic lesions. Notably, alpha-toxin, which possesses hemolytic, necrotic and lethal activities, and phospholipase C and sphingomyelinase activities, is an important agent for the diseases. The cytokine storm induced by alpha-toxin, mainly the release of TNF-alpha, plays an important role in the death and massive hemolysis. The toxin-induced release of TNF-alpha from neutrophils and macrophages is dependent on the activation of ERK1/2 signal transduction via TrkA receptor. In addition, 14- and 15-membered macrolides specifically block the toxin-induced events through the activation of neutrophils and macrophages.

Toxoplasmosis is a protozoan infection caused by Toxoplasma gondii. We report a case of Toxoplasma gondii and Clostridium perfringens co-infection complicating uterine gas gangrene following a term pregnancy. The histological examination of the necrotic uterine tissues and uterine swab cultures obtained at laparotomy revealed T. gondii and C. perfringens, respectively. Treatment was administered with bactericidal activity against both pathogens and the patient had an uneventful post-operative recovery. Although there have been some cases that have documented an association between toxoplasmosis and non-uterine C. perfringens infection, such a relationship has not been established. It is of interest to determine if the presence of both organisms can explain the severe myonecrosis that occurs in some cases of uterine gas gangrene., (© 2012 The Authors. Journal of Obstetrics and Gynaecology Research © 2012 Japan Society of Obstetrics and Gynecology.)

Spontaneous clostridial myonecrosis (gas gangrene) is an uncommonly encountered presentation of skin and soft-tissue infections with high morbidity and mortality. The diagnosis has been associated with colorectal carcinoma, hematologic malignancies, and diabetes. We report the case of an 81-year-old man who experienced a sudden onset of left ankle and foot pain in association with nonpalpable purpura and hemorrhagic bulla. The diagnosis was initially suspected on clinical presentation, gas in tissue on plain-film radiography, and Gram staining of aspirated bulla contents. Cultures grew Clostridium septicum, and a large cecum mass was found by computed tomography of the abdomen. A subsequent right hemicolectomy confirmed a well to moderately differentiated mucinous adenocarcinoma. We emphasized that the early recognition of necrotizing skin and soft-tissue infections warrants further evaluation and appropriate management.

Bacterial neuraminidase has been highlighted as a key enzyme for pathogenic infection and sepsis. Six pterocarpans displaying significant levels of neuraminidase inhibitory activity were isolated from the root bark of Lespedeza bicolor. The isolated compounds were identified as three new pterocarpans (1-3) together with known compounds erythrabyssin II (4), lespebuergine G4 (5), and 1-methoxyerythrabyssin II (6). The new compounds were characterized as bicolosin A (1), bicolosin B (2), and bicolosin C (3). All compounds inhibited bacterial neuraminidase in a dose-dependent manner with significant inhibition (IC(50)=0.09-3.25 μM). All neuraminidase inhibitors screened were found to exhibit noncompetitive kinetics. The three most potent neuraminidase inhibitors (1, 3 and 6) feature a methoxy substitution on C-1., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Microscopy of gram-stained impression smears is used for the rapid diagnosis of microorganisms in the wound. The shin tissues of patient P. with suspected gas gangrene of lower extremity soft tissues were microscopically found to have gram-positive spore-forming bacteria that were morphologically similar to C. bifermentans that were identified as C. septicum on cultural diagnosis. The pathogenic C. septicum strain spores were likely to be formed in the macroorganism upon exposure of the pathogen to a patient's defense factors and to a package of therapeutic measures. Microbiological data should be used only in combination with clinical and instrumental findings and the results of other laboratory studies when the optimal technology is chosen to treat gas infection. By keeping in mind that there may be clostridial gangrene in the patients and the experience of clinicians and bacteriologists may be insufficient in diagnosing this pathology, it is necessary to strengthen the training of physicians in the diagnosis of this pathology.

Massive hemolysis secondary to sepsis caused by Clostridium perfringens is a rare entity but appears fairly often in the literature. In nearly all published reports, the clinical course is rapid and fatal. We describe the case of a 75-year-old woman with diabetes who was admitted with symptoms consistent with acute cholecystitis. Deteriorating hemodynamics and laboratory findings were consistent with intravascular hemolysis, coagulation disorder, and renal failure. Gram-positive bacilli of the Clostridium species were detected in blood along with worsening indicators of hemolysis. In spite of antibiotic and surgical treatment, hemodynamic support and infusion of blood products, the patient continued to decline and died in the postoperative recovery unit 14 hours after admission. Mortality ranges from 70% to 100% in sepsis due to Clostridium perfringens, and risk of death is greater if massive hemolysis is present, as in the case we report. Only a high degree of clinical suspicion leading to early diagnosis and treatment can improve the prognosis. This bacterium should therefore be considered whenever severe sepsis and hemolysis coincide.

A 39-year-old Indian man presented with necrotizing soft tissue infection of his right forearm and previously undiagnosed diabetes mellitus. The infection progressively worsened to involve his right lateral chest wall despite multiple debridements and systemic antibiotics. His right arm was eventually disarticulated along with wide debridement of the surrounding tissue. Aggressive wound debridement, mechanical scrubbing, and irrigation were then initiated every 8 hours. A superoxidized solution was later introduced as a wound irrigant and dressing agent. The large defect was suitable for split-thickness skin grafting after 16 days of a strict wound management routine with the superoxidized solution.

Clostridium perfringens is responsible for a number of clinical conditions ranging from relatively mild food poisoning to the potentially life-threatening gas gangrene. Fortunately, C. perfringens has remained relatively susceptible to first line antibiotics in the treatment of soft tissue infection, however, the prevalence of antibiotic resistance is increasing amongst other anaerobic organisms. A case of anaerobic cellulitis caused by a clindamycin-resistant C. perfringens is described here, emphasising the emerging problem of antimicrobial resistance.

Gas gangrene is a rare and devastating infectious process that can occur after liver transplantation, most often following hepatic artery thrombosis. We here report 3 cases of gas gangrene following orthotopic liver transplantation. Blood cultures were positive for Clostridium clostridiiforme in one case. In 2 other cases liver tissue from explanted specimens was positive for Enterobacter cloacae. Ultrasound demonstrated hepatic artery thrombosis and computed tomography imaging revealed diffuse liver necrosis with gas formation in each case. All 3 patients were successfully treated with a combination of antibiotics and emergent re-transplantation. We review previously published cases of gas gangrene after liver transplant and emphasize the importance of hepatic artery thrombosis in the development of this syndrome as well as the frequent involvement of non-clostridial organisms. Early diagnosis and aggressive combined medical and surgical treatment including re-transplantation are essential for successful treatment of these rare and catastrophic infections.

Azathioprine and 6-mercaptopurine have been used for many years in the treatment of inflammatory bowel disease. Approximately 0.3% of the population are homozygous for variant alleles associated with extremely low thiopurine S-methyltransferase enzyme activity. We describe the case of a young patient with ulcerative colitis, homozygous for TPMT*3A alleles, who suffered fatal azathioprine-induced myelotoxicity after standard dosing with azathioprine. Screening for decreased activity of TPMT in patients prior to azathioprine treatment is advised to minimize the risk of drug-induced toxicity.

Objective: Gas gangrene of the abdominal wall is a rare clinical occurrence with high rates of morbidity and mortality. The primary source of the infection is often unknown. To analyze the primary underlying intestinal etiologies and diagnostic approaches of gas gangrene of the abdominal wall, and to highlight specific treatment problems, particularly that of constructing a colostomy exteriorized through a massively infected abdominal wall., Patients and Methods: Seven cases of abdominal wall gas gangrene due to a gastrointestinal etiology were identified. (Cases arising from proctologic sources or related to recent abdominal surgery were excluded.) During the same period, 39 other patients presenting with abdominal wall gangrene from non-intestinal sources were treated., Results: The etiologies were: perforated sigmoid diverticulitis (n=2), perforated appendicitis (n=1), acute pancreatitis with associated cecal perforation (n=1), and perforated colorectal cancer (n=3). Four of the seven patients died despite treatment (mortality of 57%)., Conclusion: The clinical presentations of these seven cases demonstrate that a GI source must be suspected whenever a patient presents with abdominal wall gas gangrene, even when there are no specific GI symptoms. Imaging, particularly with CT scan, is essential both to visualize the extent of tissue necrosis and to reveal underlying primary GI pathology. This optimizes the surgical approach both by allowing for complete debridement and drainage of infected tissue, and by focussing the intervention on correction of the underlying primary GI source of infection.

Atraumatic infections due to Clostridium septicum are known to be associated with immunosuppression or even malignancy. In this case report, we present a patient with severe Clostridium septicum infection related to advanced colon cancer that had not previously been diagnosed. The case demonstrates the strong association between Clostridium septicum infections and malignancy, particularly in the presence of other predisposing diseases such as diabetes mellitus. It strongly suggests excluding malignant neoplasms, especially of the gastrointestinal tract, when severe Clostridium septicum infections occur. Moreover, if patients with known colorectal or other malignancy develop septicaemia or spontaneous gas gangrene, clinicians should be aware of Clostridium septicum as one of the main causative agents, as early diagnosis and aggressive treatment are important to improve prognosis.

Objective: To report 2 cases of severe gas gangrene secondary to Clostridium perfringens in pediatric oncology patients., Methods: We describe 2 children with acute presentations of gas gangrene secondary to C. perfringens. Both children were initially seen and treated in a community hospital emergency department and subsequently were cared for in a pediatric intensive care unit in a tertiary care, university-based children's hospital., Results: Both children demonstrated severe and unrelenting decompensation and required operative intervention within the first hospital day, which included amputation of the infected limb. One child survived and one child expired despite heroic measures., Conclusions: Gas gangrene secondary to C. perfringens is an uncommon but life-threatening and limb-threatening condition in pediatric cancer patients. A high index of suspicion in a immunocompromised child with cancer who presents with extremity pain in combination with neutropenia is the key to early diagnosis and may lead to improved survival. This disease requires prompt recognition and aggressive treatment to allow any hope of recovery. Emergency medicine physicians who treat these children should be aware of this severe and potentially fatal infectious process and should not delay treatment or prompt orthopedic surgery consultation.

Pancreatic gas gangrene is an uncommon and often fatal complication of acute pancreatitis, due to the sporulating anaerobe Clostridium perfringens. C. perfringens is a normal constituent of colonic flora, but infects the pancreas by either transmural spread from the colon or via the biliary tree. Only three reported cases in the world literature describe acute pancreatitis with pneumoretroperitoneum and clostridial infection. Two separate cases, at the same institution, of acute pancreatitis complicated by C. perfringens were analyzed. The records of patients were reviewed for admission history, laboratory and radiology results, intensive care support, surgical intervention, and outcome. Retroperitoneal air was visualized early in the clinical course of both patients by computed tomography. Early surgical debridement, drainage, parental antibiotics, and reexploration resulted in an uncomplicated recovery. Early computed tomography in patients with suspected necrotizing pancreatitis contributes to early intervention and may advantageously enhance survival.

Patients with necrotizing soft tissue infections often present initially to family physicians. These infections must be detected and treated rapidly to prevent loss of limb or a fatal outcome. Unfortunately, necrotizing soft tissue infections have no pathognomonic signs. Patients may present with some evidence of cellulitis, vesicles, bullae, edema, crepitus, erythema, and fever. They also may complain of pain that seems out of proportion to the physical findings; as the infection progresses, their pain may decrease. Magnetic resonance imaging and laboratory findings such as acidosis, anemia, electrolyte abnormalities, coagulopathy, and an elevated white blood cell count may provide clues to the diagnosis. No single organism or combination of organisms is consistently responsible for necrotizing soft tissue infections. Most infections are polymicrobial, with both anaerobic and aerobic bacteria frequently present. Fungal infections also have been reported. Generally, bacterial and toxin-related effects converge to cause skin necrosis, shock, and multisystem organ failure. Aggressive debridement of infected tissues is critical to management. Antimicrobial therapy is important but remains secondary to the removal of diseased and necrotic tissues.

The progression of Clostridium perfringens endomyometritis to gas gangrene is a rare, but greatly feared complication in the obstetrical patient. While endometritis following cesarean delivery is a common complication, recognition of C. perfringens as the pathogen as well as its progression to gas formation in the myometrium is essential to the survival of the patient. We present a patient that we recently cared for, and review the bacteriology, clinical diagnosis, and management.

Soft tissue infections are uncommon but prognosis is severe (20 to 50%). Management consists in surgical debridement, antibiotic therapy against anaerobic and aerobic bacteria, and appropriate intensive care. When available, hyperbaric oxygen therapy is an integral part of the treatment. We report the case of 56-year-old female patient with diabetes (150 kg) was hospitalized in our unit a few days after surgical treatment of a buttocks abscess for clinical signs of peripheral gas gangrene. Surgical exploration showed necrotizing soft tissue infection with fasciitis. Adequate therapy using antibiotics, surgery daily and hyperbaric oxygen was given. Therapy had to be adapted to the patient's obesity. Outcome was good with recovery and few sequelae, allowing transfer to a medical ward.

Gas gangrene is a well recognised complication of contaminated military wounds. A case of Clostridial myonecrosis following elective inguinal hernia repair is described. The pathology, clinical features and management of this life-threatening condition are reviewed.

A 24-year-old healthy man developed Clostridium perfringens myonecrosis with severe sepsis after plating of a closed femoral fracture. The leg could be preserved by complete resection of the fascia from all muscle compartments of the leg, including the pelvitrochanteric and the iliopsoas muscles, radical removal of necrotic muscle tissue, dissection of the para-aortal infrarenal lymphatics, daily débridements over 2 weeks, and systemic antibiotic therapy. The plate was removed because of a second septic episode followed by temporary stabilization with external fixation. After soft-tissue healing, plate fixation was carried out. The patient developed significant deficit of knee flexion (0 degree/0/20 degrees) due to heterotopic ossification of the quadriceps femoris muscle that could be improved by partial resection of heterotopic bone formation. In the same operation the bony defect of the femur was filled with autologous bone graft. The fracture healed 10 months after the accident. The patient can work full time in his previous profession as a mechanic, but again needs operative mobilization of the knee joint, including open arthrolysis and quadriceps plasty.

Endogenous, nontraumatic clostridial myonecrosis has a frequent association with colon carcinoma, leukemia, diabetes mellitus, and drug-induced immunosuppression. We present two cases of Clostridium septicum myonecrosis. An 18-year-old girl developed severe abdominal pain on day 7 after hospitalization for cytostatic treatment of acute lymphoblastic leukemia. Blood cultures yielded Clostridium septicum and histopathological exam of muscle tissue showed extended myonecrosis. Eventually the patient recovered with antibiotics and surgical therapy. A 72-year-old diabetic woman was treated as an outpatient with an intramuscular injection of steroidal antiphlogistics for "acute lumbar disc disease". The next morning persistence of hip pain and discoloration of the right thigh caused hospitalization under the suspected diagnosis "fracture of the neck of the femur". Clostridium septicum was cultured from intraoperatively taken swabs. At autopsy, in addition to the gangrene, there was an adenocarcinoma of the cecum, which had not been diagnosed during life.

Cervical phlegmona is a rare occurrence associated with infections of the ENT region. Spreading of the infection can cause thrombophlebitis, mediastinitis and cardiac tamponade. Three recently treated patients are reported who showed serious complications due to harmless primary infections of the oral cavity, oropharynx or throat. The clinical course of the diseases with the sometimes difficult examinations undertaken and the performed treatment are outlined. Computed tomography and radiography of the lung were useful in confirming the diagnosis, establishing that the infection had spread into deep neck spaces and into the mediastinum. Surgical therapy including extensive surgical drainage of the deep neck spaces and of the mediastinum, multiple antibiotic therapy, and intensive care, resulted in survival of the patients.

The effects of inoculum size and treatment delays on the efficacy of hyperbaric oxygen (HBO) were evaluated in a murine model of Clostridium perfringens myositis in which the infection was treated with an HBO regimen identical to that used for humans. The efficacies of treatment with penicillin, metronidazole, or clindamycin--alone or in combination with HBO--were also assessed. Survival was inversely related to the size of the bacterial inoculum used for challenge, and delays in treatment markedly reduced the efficacies of all single and combination regimens. When animals were challenged with > 10(8) colony-forming units, survival was significantly higher among those treated with clindamycin or metronidazole than among those treated with penicillin. HBO alone did not improve survival at any inoculum tested. However, when administered early, HBO plus metronidazole or penicillin demonstrated significant additive efficacies in animals challenged with > or = 10(9) organisms. Clindamycin was more effective at the higher inocula than penicillin, metronidazole, or HBO, and its superior efficacy was not further enhanced by adjunctive therapy with HBO.

Between 1978 and 1990 98 patients with gas gangrene were treated in the departments of general surgery and traumatology of the University of Kiel. The microbiological results of tissue samples and results of animal infectious experiments were correlated to the clinical outcome. It could be shown, that gas gangrene due to C.perfringens alone had a higher mortality than gas gangrene due to polymicrobial infection. In trauma patients, however, the rate of amputations was lower in cases of clostridial monoinfections (25%), than in patients with mixed infections (48%). The results of animal experiments with guinea pigs which were infected by patients' infectious material showed a correlation to the clinical outcome. This correlation could not bee shown using isolated and cultured clostridia. Therefore and because of the quantity of mixed infections it is necessary to use broad spectrum antibiotics for treatment in cases of gas gangrene and for perioperative antibiotic prophylaxis. Penicillin-G alone can not more be recommended for this purpose.

The prognosis of gas gangrene is changing as the means of treatment become more accurate and are implemented earlier. The authors, in their work referring to 10 cases of gas gangrene, point out to the extreme fastness of debridement and immediate exeresis, of wide-spectrum antibiotic protection and of caloric balance, associated to a treatment using trace elements. The importance of hyperbaric oxygen therapy seems to be increasingly proven with time. Lastly, in their general experience of treatment, the authors suggest the use of a specific frequency soft laser therapy, which might speed up the process of tissue repair.

Possible prolongation of the biological effect of some available immunostimulators such as prodigiozan, salmozan, polyribonate and thymalin by their sorption on aluminium hydrate was studied. It was shown that in comparison to the native immunostimulators the sorbed ones had a more pronounced biological action and provided a more prolonged increase in the host resistance to the causative agents of gas gangrene and typhoid fever. Using prodigiozan as an example it was demonstrated that the observed increase in the anti-infective activity of the sorbed drugs was associated with more intensive stimulation of some immunological factors involved in regulation of host nonspecific resistance. The results of the study are likely to indicate that it was experiment to further investigate the drugs to reveal their efficacy in other infection models and to optimize the schemes of their use.

Untreated gas gangrene is a fulminating infection that can lead to extensive tissue necrosis and death. Hyperbaric oxygen, when used with antibiotics and surgical debridement, can lead to decreased mortality. Nine patients with gas gangrene proven by positive clostridial cultures have been treated at St Luke's Hospital of Kansas City with a mortality of 11.1%. A case of gas gangrene developing from a perirectal abscess is presented.

Among 100 patients with proven gas gangrene surgical treatment was undertaken in 34 who also received 30--60 mega-units of penicillin, in addition to appropriate shock treatment. Since 1967, additional treatment in a hyperbaric chamber was undertaken in 66 patients. There was no clear-cut advantage of hyperbaric oxygenation as far as the death-rate was concerned. There was merely a moderate decrease in the amputation rate after limb injuries. Wide incision of the wound and radical surgical excision of all tissue affected by gas gangrene continues to be an essential form of treatment.

The treatment of experimental gas gangrene caused by Clostridium perfringens was investigated by using combinations of antimicrobial agents. This study demonstrated that rifampin, penicillin, metronidazole, and clindamycin were all bactericidal against standard inocula (10(5) to 10(6) CFU). These antimicrobial agents were then administered to mice beginning 30 min after intramuscular injection of 10(9) CFU of C. perfringens type A. The highest doses used produced levels of drug in blood which exceeded the MIC by at least a factor of 40. In addition, other groups of mice received monotherapy at full dose or one-fourth full dose or combination antimicrobial therapy at full or one-fourth full dose. Among the single and combination antimicrobial treatments, metronidazole alone, clindamycin alone, and clindamycin plus penicillin were the most efficacious (P less than 0.05). Although the survival of mice treated with clindamycin plus penicillin was greater than that of mice treated with clindamycin alone, the difference did not reach statistical significance (P greater than 0.05). In contrast, mice treated with a combination of metronidazole and penicillin demonstrated greater mortality than those treated with metronidazole alone (P less than 0.05). In summary, combination antimicrobial therapy of experimental C. perfringens infection did not improve survival compared to that achieved with metronidazole or clindamycin alone, and some combinations significantly reduced survival (P less than 0.05).