Deficient Skeletal Muscle Regeneration after Injury Induced by a Clostridium perfringens Strain Associated with Gas Gangrene.

Gas gangrene, or clostridial myonecrosis, is usually caused by Clostridium perfringens and may occur spontaneously in association with diabetes mellitus, peripheral vascular disease, or some malignancies but more often after contamination of a deep surgical or traumatic lesion. If not controlled, clostridial myonecrosis results in multiorgan failure, shock, and death, but very little is known about the muscle regeneration process that follows myonecrosis when the infection is controlled. In this study, we characterized the muscle regeneration process after myonecrosis caused in a murine experimental infection with a sublethal inoculum of C. perfringens vegetative cells. The results show that myonecrosis occurs concomitantly with significant vascular injury, which limits the migration of inflammatory cells. A significant increase in cytokines that promote inflammation explains the presence of an inflammatory infiltrate; however, impaired interferon gamma (IFN-γ) expression, a reduced number of M1 macrophages, deficient phagocytic activity, and a prolongation of the permanence of inflammatory cells lead to deficient muscle regeneration. The expression of transforming growth factor ß1 (TGF-ß1) agrees with the consequent accumulation of collagen in the muscle, i.e., fibrosis observed 30 days after infection. These results provide new information on the pathogenesis of gas gangrene caused by C. perfringens, shed light on the basis of the deficient muscle regenerative activity, and may open new perspectives for the development of novel therapies for patients suffering from this disease.

Molecular and cellular basis of microvascular perfusion deficits induced by Clostridium perfringens and Clostridium septicum.

Reduced tissue perfusion leading to tissue ischemia is a central component of the pathogenesis of myonecrosis caused by Clostridium perfringens. The C. perfringens alpha-toxin has been shown capable of inducing these changes, but its potential synergy with perfringolysin O (theta-toxin) is less well understood. Similarly, Clostridium septicum is a highly virulent causative agent of spontaneous gas gangrene, but its effect on the microcirculation has not been examined. Therefore, the aim of this study was to use intravital microscopy to examine the effects of C. perfringens and C. septicum on the functional microcirculation, coupled with the use of isogenic toxin mutants to elucidate the role of particular toxins in the resultant microvascular perfusion deficits. This study represents the first time this integrated approach has been used in the analysis of the pathological response to clostridial toxins. Culture supernatants from wild-type C. perfringens induced extensive cell death within 30 min, as assessed by in vivo uptake of propidium iodide. Furthermore, significant reductions in capillary perfusion were observed within 60 min. Depletion of either platelets or neutrophils reduced the alteration in perfusion, consistent with a role for these blood-borne cells in obstructing perfusion. In addition, mutation of either the alpha-toxin or perfringolysin O structural genes attenuated the reduction in perfusion, a process that was reversed by genetic complementation. C. septicum also induced a marked reduction in perfusion, with the degree of microvascular compromise correlating with the level of the C. septicum alpha-toxin. Together, these data indicate that as a result of its ability to produce alpha-toxin and perfringolysin O, C. perfringens rapidly induces irreversible cellular injury and a marked reduction in microvascular perfusion. Since C. septicum induces a similar reduction in microvascular perfusion, it is postulated that this function is central to the pathogenesis of clostridial myonecrosis, irrespective of the causative bacterium.

Histotoxic Clostridial Infections.

The pathogenesis of clostridial myonecrosis or gas gangrene involves an interruption to the blood supply to the infected tissues, often via a traumatic wound, anaerobic growth of the infecting clostridial cells, the production of extracellular toxins, and toxin-mediated cell and tissue damage. This review focuses on host-pathogen interactions in Clostridium perfringens-mediated and Clostridium septicum-mediated myonecrosis. The major toxins involved are C. perfringens α-toxin, which has phospholipase C and sphingomyelinase activity, and C. septicum α-toxin, a ß-pore-forming toxin that belongs to the aerolysin family. Although these toxins are cytotoxic, their effects on host cells are quite complex, with a range of intracellular cell signaling pathways induced by their action on host cell membranes.

Use of Viable Cryopreserved Umbilical Tissue for Soft Tissue Defects in Patients With Gas Gangrene: A Case Series.

INTRODUCTION: Gas gangrene is a rapidly progressive bacterial infection leading to necrosis that usually develops as a result of trauma or postoperative complications. This condition requires early diagnosis with immediate surgical intervention. With a poor prognosis, a high incidence of amputation, and comorbidities such as diabetes and peripheral vascular disease, patients with gas gangrene are put at further risk for surgical complications. OBJECTIVE: This case series reports the clinical outcomes of using a commercially available viable cryopreserved umbilical tissue (vCUT) in the surgical management of 10 patients (9 males, 1 female) with acute lower extremity gas gangrene. MATERIALS AND METHODS: All 10 patients had aggressive debridement and irrigation, followed by an intraoperative application of vCUT to cover the large, complex wounds with exposed bone, tendon, and soft tissue, which was fenestrated and sutured to the surrounding skin edges. RESULTS: The average wound size following debridement was 45.9 cm2 (range, 8 cm2-105 cm2). Average percent area reduction of the wounds at 4 weeks post-vCUT application was 68.4% (range, 49%-99.5%). The average length of hospital stay was 9 days (range, 2-16 days), and postdischarge patients were treated with negative pressure wound therapy and standard of care (nonadherent dressing, dry gauze, and mild compression) until wound closure was achieved (average, 3.3 months [range, 1.25-4.5 months]). With a 1-time application of vCUT, all patients reached complete wound closure with decreased time to closure, fewer complications, and a shorter duration of hospitalization as compared with traditional inpatient management of gas gangrene (incision and drainage with staged procedures). CONCLUSIONS: The positive clinical outcomes indicate that vCUT may be an effective aid as an intraoperative application to cover wounds following aggressive debridement in the presence of gas gangrene.

Clinical Serum Therapy: Benefits, Cautions, and Potential Applications.

Blood serum from immunized humans or animals (e.g., horses) contains relevant antibodies and has been used as serum therapy to treat many diseases or envenomation events. The effectiveness of blood serum was initially discovered in 1890 when Kitasato and von Behring observed the effectiveness of this type of therapy against diphtheria and tetanus. Serum therapies played an important role in the advancement of modern medicine prior to the development of penicillin and steroids. At present, several types of serum therapy remain in clinical use. However, some physicians have a limited understanding of the nature and the benefits of serum therapy and the factors that require particular attention. In this review, we set out to clarify the benefits, cautions, and potential applications of serum therapy in the context of conditions such as gas gangrene, diphtheria, botulism, and tetanus and bites from three snake species (mamushi, habu, and yamakagashi) and the redback spider. It is hoped that this review will help clinicians to learn about clinical serum therapies and become familiar with their applications.

Spontaneous clostridial myonecrosis.

Spontaneous clostridial myonecrosis (SCM) is an uncommon but frequently fatal tissue infection. The case report and review of the literature here provide some insight into the pathophysiology of this entity and clinical settings with which it is associated. It is hoped that this discussion will increase the reader's familiarity with SCM and provide clues that will lead to earlier diagnosis and more effective treatment.

Gas gangrene and necrotizing fasciitis in the upper extremity.

Necrotizing soft tissue infections encompass a wide variety of clinical syndromes resulting from introduction of various pathogens into injured or devitalized tissue. The extent of microbial involvement in such tissue may range from simple contamination to overt and progressive local tissue necrosis, which, if untreated, may lead to septicemia and death. Early differentiation among these infections is not always possible, as there are overlapping classification criteria. These infections exist along a continuum of clinical severity with different etiological agents and associated medical conditions. The often subtle clues heralding the presence of a necrotizing soft tissue infection must be sought so that expeditious surgical debridement and broad-spectrum antibiotic management are initiated. Although experience enables the clinician to make a specific diagnosis based on early findings, aggressive and proper treatment of suspected infections remains the priority. The purpose of the article is to provide an overview of necrotizing soft tissue infections in the upper extremity, focusing on gas gangrene, or clostridial myonecrosis, and necrotizing fasciitis, to facilitate early diagnosis and optimal management of these lethal diseases.

Gas gangrene: certain diagnosis or certain death.

Clostridia are organisms which, in the right environment, can cause a rapidly spreading, fulminant myonecrosis. Early diagnosis and a combined management program are clearly paramount to a successful outcome. Knowledge of this disease and ongoing meticulous assessment are the tools that a nurse must use when dealing with patients who have gas gangrene or are at high risk of developing it. In the face of radical disfigurements that may follow therapeutic measures, the potential transfer to a distant center for treatment, and a deteriorating prognosis, the nurse must remain alert to patient and family psychologic needs.

[Evaluation of vital prognosis in gas gangrene by a method of multivariate analysis of the results of the initial clinical examination]. / Evaluation du pronostic vital des gangrènes gazeuses par une méthode d'analyse multidimensionnelle des résultats de l'examen d'entrée.

Prognosis value of initial clinical symptoms and findings in gas gangrene was evaluated in 72 patients. Fifty eight parameters were recorded. The relationship between the simultaneous effects of several variables upon survival was accomplished using the multivariate technique, discriminant analysis. On the basis of observed patients deaths or survivals, the individual condition weights were statistically derived in a manner that best distinguishes likely survivors from nonsurvivors. Six variables out of the 58 studied gave right classification of outcomes in 97 p. 100 of the patients.

[Fatal appendectomy caused by postoperative gas gangrene of the abdominal wall. 2 cases]. / Appendicectomie mortelle par gangrène gazeuse pariétale post-opératoire. 2 cas.

The authors report two cases of post-appendicectomy gas gangrene with a fatal outcome. Based on the study of these two cases they analyse the incidence, mechanism and prognosis of this serious post-operative complication. They stress the prophylactic measures necessary for prevention.

Gas gangrene. A review.

Gas gangrene continues to cause significant morbidity and mortality. This monograph reviews the entire spectrum of clostridial infection, including its etiology, pathophysiology, diagnosis, current recommended treatment, and prophylaxis. The early diagnosis of gas gangrene is paramount, as delay in aggressive combined treatment may result in death.

Clostridial gas gangrene. I. Cellular and molecular mechanisms of microvascular dysfunction induced by exotoxins of Clostridium perfringens.

Mechanisms responsible for the rapid tissue destruction in gas gangrene are not well understood. To examine the early effects of Clostridium perfringens exotoxins on tissue perfusion, a rat model of muscle blood flow was developed. Intramuscular injection of a clostridial toxin preparation containing both phospholipase C (PLC) and theta-toxin caused a rapid (1-2 min) and irreversible decrease in blood flow that paralleled formation of activated platelet aggregates in venules and arterioles. Later (20-40 min), aggregates contained fibrin and leukocytes, and neutrophils accumulated along vascular walls. Flow cytometry confirmed that these clostridial toxins or recombinant PLC induced formation of P-selectin-positive platelet aggregates. Neutralization of PLC activity in the clostridial toxin preparation completely abrogated human platelet responses and reduced perfusion deficits. It is concluded that tissue destruction in gas gangrene is related to profound attenuation of blood flow initiated by activation of platelet responses by PLC.