Current Infectious Disease Reports

, Volume 12, Issue 5, pp 383–391

Clostridial Myonecrosis: New Insights in Pathogenesis and Management

Authors

    • Infectious Diseases SectionVeterans Affairs Medical Center
    • University of Washington School of Medicine
  • Dennis L. Stevens
    • Infectious Diseases SectionVeterans Affairs Medical Center
    • University of Washington School of Medicine
Article

DOI: 10.1007/s11908-010-0127-y

Cite this article as:
Bryant, A.E. & Stevens, D.L. Curr Infect Dis Rep (2010) 12: 383. doi:10.1007/s11908-010-0127-y

Abstract

Clostridial myonecrosis remains an important cause of human morbidity and mortality worldwide. Although traumatic gas gangrene can be readily diagnosed from clinical findings and widely available technologies, spontaneous gas gangrene is more insidious, and gynecologic infections due to Clostridium sordellii progress so rapidly that death often precedes diagnosis. In each case, extensive tissue destruction and the subsequent systemic manifestations are mediated directly and indirectly by potent bacterial exotoxins. The management triumvirate of timely diagnosis, thorough surgical removal of necrotic tissue, and treatment with antibiotics that inhibit toxin synthesis remains the gold standard of care. Yet, despite these measures, mortality remains 30% to 100% and survivors often must cope with life-altering amputations. Recent insights regarding the genetic regulation of toxin production, the molecular mechanisms of toxin-induced host cell dysfunction, and the roles of newly described toxins in pathogenesis suggest that novel prevention, diagnostic, and treatment modalities may be on the horizon for these devastating infections.

Keywords

Gas gangreneMyonecrosisTraumaClostridiumClostridium perfringensClostridium septicumClostridium sordelliiManagementPathogenesisToxinsα ToxinPhospholipase Cθ ToxinPerfringolysin OLethal toxinCholesterol-dependent cytolysinPlateletNeutrophilVascular injuryToxin regulationVirRSQuorum-sensingImmunization

Introduction

Clostridial myonecrosis (gas gangrene) is a rapidly progressive infection of muscle and overlying fascia and skin characterized by marked tissue destruction, gas in the tissues, shock, and frequently death. Potent extracellular clostridial toxins mediate these pathologies. This review discusses the clinical aspects, the important virulence factors of the different histotoxic clostridial species, and how recent insights in pathogenesis may translate to novel prevention and therapy measures.

Clinical Presentations and Microbiology

There are two major presentations of clostridial myonecrosis: traumatic and spontaneous. Traumatic gas gangrene is most commonly caused by Clostridium perfringens (~80% of cases); spontaneous gangrene is most commonly caused by Clostridium septicum. Other species associated with traumatic gangrene include Clostridium septicum, Clostridium novyi, Clostridium histolyticum, Clostridium bifermentans, Clostridium tertium, and Clostridium fallax. Gas gangrene of the uterus caused by Clostridium sordellii has received renewed attention following a recent cluster of fatal cases associated with medically induced abortion (reviewed in [1]).

Traumatic Gas Gangrene due to C. perfringens

Crush-type injury, laceration of large or medium-sized arteries, and open fractures of long bones that are contaminated with soil predispose to C. perfringens gas gangrene. Gas gangrene also occurs after penetrating abdominal injuries (eg, knife, gunshot) or bowel/biliary tract surgery where bowel contents leak into the soft tissues. Traumatic gas gangrene can also be associated with abortion, retained placenta, prolonged prepartum rupture of fetal membranes, or intrauterine fetal demise. Cutaneous gas gangrene caused by C. perfringens, C. novyi type A, and C. sordellii has also been described among drug abusers injecting black-tar heroin subcutaneously (“skin-popping”) [26].

Clostridial myonecrosis is characterized by the sudden onset of excruciating pain at the infection site and rapid development of a foul-smelling wound containing a thin serosanguineous discharge and gas bubbles. Brawny edema and induration give way to cutaneous blisters containing maroon-colored fluid. Later, such tissue may become liquified and slough. The margin between healthy and necrotic tissue can advance several inches per hour if treatment is delayed or inadequate, and at this point radical debridement of truncal lesions or amputation of an infected limb remains the single best life-saving treatment. Bacteremia occurs in about 15% of cases and may be associated with brisk intravascular hemolysis. Shock and organ failure are frequent late-stage complications and portend death in more than 50% of cases; mortality is highest for patients in shock at the time of diagnosis. The prognosis is more favorable when the infected site is one that can be readily debrided.

Histologically, polymorphonuclear leukocytes (PMNs) are notably absent from infected tissues but accumulate along the endothelium of capillaries, small arterioles, and postcapillary venules. Such features were reported as early as 1917 [7••] and have stood the test of time. Exotoxins are largely responsible for these unusual histologic findings and the cellular and molecular mechanisms were recently elucidated (see below).

Spontaneous, Nontraumatic Gas Gangrene due to C. septicum

Spontaneous gas gangrene occurs in the absence of an obvious portal of bacterial entry. Classically, it presents as a primary infection of the perineum, scrotum, or extremity following translocation of the more aerotolerant C. septicum from the gut to the bloodstream via a colonic lesion (eg, neoplasm) with subsequent hematogenous metastatic infection.

The first symptoms include confusion followed by the abrupt onset of severe pain and the rapid progression of tissue destruction with demonstrable gas in the tissue (reviewed in [8]). As with traumatic gas gangrene due to C. perfringens, soft-tissue swelling and fluid-filled bullae appear, and the surrounding skin has a purple hue, reflecting toxin-mediated vascular compromise. The mortality of spontaneous gangrene ranges from 67% to 100% with the majority of deaths occurring within 24 h of onset. Predisposing host factors include colonic carcinoma, diverticulitis, gastrointestinal surgery, leukemia, lymphoproliferative disorders, cancer chemotherapy, radiation therapy, and, more recently, AIDS [9, 10]. Cyclic, congenital, or acquired neutropenia is also strongly associated with an increased incidence of spontaneous gas gangrene, and in such cases necrotizing enterocolitis, cecitis (typhlitis), or distal ileitis are common and provide bacterial access to the bloodstream. Thus, patients surviving bacteremia or spontaneous gangrene due to C. septicum should have aggressive diagnostic studies to rule out gastrointestinal pathology.

Lastly, C. tertium has also been associated with spontaneous myonecrosis. It can grow aerobically so may be mistaken for a contaminating diphtheroid or bacillus species. Unlike most clostridial species, it is resistant to penicillin, cephalosporins, and clindamycin.

Infections due to C. sordellii

In a recent review, Aldape et al. [1] summarized the clinical features of 45 reported cases of C. sordellii infection. Of these, 18% (8/45) were associated with normal childbirth, 11% (5/45) with medically induced abortion, and 0.4% (2/45) with spontaneous abortion. These gynecologic infections presented with a unique clinical picture consisting of little or no fever, lack of a purulent discharge, refractory hypotension, extensive peripheral edema and effusions, significant hemoconcentration (hematocrit ≥ 70), and a markedly elevated white blood cell (WBC) count (50–200,000 cells/mm3) with a left shift termed a “leukemoid reaction” [1]. Death ensued rapidly and the infection was almost uniformly fatal [1]. The remainder of C. sordellii soft-tissue infections (70%) occurred in injecting drug users, or following trauma or surgery. Mortality in these patients was ~50%.

Eighty-five percent of all fatal cases of C. sordellii infection died within 2 to 6 days and nearly 80% developed leukemoid reactions [1]. The magnitude of the leukemoid reaction was the sole predictor of fatal outcome; nonsurvivors generally had an average WBC count of greater than 75,000/mm3 compared to only 18,000 cells/mm3 among survivors [1]. More modest leukemoid reactions (30–50,000/mm3) are characteristic of C. novyi and C. difficile infections, and a common mechanism is being sought. Neuraminidase, an exotoxin unique to C. sordellii (see below), is thought to enhance this common mechanism and drive the extreme leukemoid reaction characteristic of this infection.

Microbial Etiology

Clostridium species are widespread in nature because of their ability to form endospores that persist in the environment. They are commonly found in soil and marine sediments, as well as in human and animal intestinal tracts.

Following reports of fatal cases of C. sordellii infection after medically induced abortion, a project to estimate the prevalence of vaginal and rectal colonization with C. perfringens and C. sordellii in women of reproductive age was initiated in the United States [11]. A recent report examined the factors necessary for C. sordellii spore germination in vitro [12••]. The authors showed a requirement for three structurally different L-amino acids including phenylalanine, a slightly acidic pH (5.7–6.5) and a carbonic acid/bicarbonate ratio of 1. The authors point out that in the normal female reproductive tract, phenylalanine is absent, and the vaginal pH is strongly acidic (<4.5), resulting in a carbonic acid/bicarbonate ratio greater than 1. However, using available data to estimate the germinant conditions in the pregnant uterus, the authors speculated that after abortion or delivery, all three growth-promoting circumstances would be present, thus providing a window of opportunity for germination of C. sordellii spores.

Changes in Antimicrobial Susceptibility

The principal agents of clostridial myonecrosis (C. perfringens, C. septicum, C. sordellii) remain susceptible to penicillin, clindamycin, tetracycline, chloramphenicol, metronidazole, and several cephalosporins [13]. C. perfringens and C. sordellii are also susceptible to vancomycin, imipenem, and linezolid [13].

The vast majority of C. perfringens isolates from humans have remained susceptible to the first-line antibiotics described previously. However, a recent report from the United Kingdom described a case of anaerobic cellulitis caused by a clindamycin-resistant strain of C. perfringens [14]. Linezolid and erythromycin coresistance was also recently demonstrated in C. perfringens isolates from pigs [15••]. This latter finding underscores the notion that agents routinely used in veterinary practice can lead to resistance to antibiotics considered reserve agents in humans.

Differential Diagnosis

Several other clinical entities can be confused with clostridial myonecrosis, including necrotizing fasciitis/myonecrosis due to group A streptococcus or Vibrio vulnificus, pyomyositis due to Staphylococcus aureus, and skeletal muscle rhabdomyolysis due to virus infection such as acute influenza type A.

Host Susceptibility

Host factors that predispose to clostridial myonecrosis include underlying malignancies and an immunocompromised status. Interventions to be avoided include prolonged application of tourniquets and surgical closure of contaminated traumatic wounds or compound fractures. In vitro, a reduction in gangliosides renders cells more susceptible to the effects of C. perfringens α toxin [16]. Thus, patients taking glycosphingolipid synthesis inhibitors for storage disorders (eg, Tay-Sachs) or diabetes treatment may be at increased risk.

Pathogenesis

Major Exotoxins of the Histotoxic Clostridia

Traditionally, the major clostridial lethal toxins have been given Greek letter designations with the letter “α” always assigned to the most potent or most significant lethal factor. This nomenclature has caused some confusion because the α toxins of the various histotoxic clostridial species vary widely in their mechanisms of action. These toxins, their genetic regulation, and their roles in pathogenesis are discussed below.

Clostridium perfringens

The α and θ toxins are the major extracellular toxins implicated in C. perfringens gas gangrene. The α toxin has both phospholipase C (PLC) and sphingomyelinase activities and is required for lethality [17]. Active immunization with the C-terminal domain of α toxin completely protected mice from experimental C. perfringens infection [18, 19] in part by improving tissue perfusion and restoring the tissue inflammatory response [18]. The θ toxin from C. perfringens (also known as perfringolysin O; PFO) is a member of the growing cholesterol-dependent cytolysin family that includes streptolysin O from group A streptococcus, pneumolysin from Streptococcus pneumoniae, septicolysin from C. septicum, and several others. After binding cholesterol in the host’s cell membranes, θ toxin monomers oligomerize and insert into the membrane, forming pores and resulting in cell lysis [20]. Although θ toxin is not required for lethality [17], it contributes to pathogenesis of gas gangrene via its ability to modulate the host inflammatory response [21, 22].

Clostridium septicum

The C. septicum α toxin is a pore-forming hemolysin that induces rapid necrosis of cultured cells (without induction of apoptosis mechanisms) by causing efflux of intracellular potassium and adenosine triphosphate depletion [23]. In experimental animal models, active immunization against α toxin significantly protects against lethal C. septicum myonecrosis [24]. The roles of C. septicum’s other principal toxins have not been defined.

Clostridium sordellii

Pathogenic strains of C. sordellii produce up to seven identified exotoxins. Of these, lethal toxin (TcsL) and hemorrhagic toxin (HT) are regarded as the major virulence factors. TcsL and HT are members of the large clostridial cytotoxin (LCC) family that also includes C. difficile toxins A and B and C. novyi α toxin. All LCCs have molecular weights between 250 and 308 kDa and possess glycosyltransferase activity. LCCs modify and inactivate target host cell signaling molecules, causing cellular dysfunction. For example, LCC-induced disruption of the actin cytoskeleton contributes to the massive capillary leakage characteristic of C. sordellii infection.

Some strains of C. sordellii also produce the cholesterol-dependent cytolysin sordellilysin. Voth et al. [25] recently demonstrated that in vitro cytotoxicity of exotoxin preparations from strains of C. sordellii lacking TcsL is attributable to sordellilysin. However, the strains studied were derived from cadaver-derived tissue transplant material from nonseptic patients. Thus, it is difficult to infer a role for sordellilysin in pathogenesis from this work.

The C. sordellii neuraminidase was recently shown to contribute to the marked leukemoid reaction characteristic of this infection, in part, by enhancing proliferation of granulocyte progenitor cells [26]. However, not all clostridial species causing infections characterized by leukemoid reactions make this toxin. Thus, other mechanisms driving the leukemoid reaction remain to be elucidated.

Lastly, the mechanisms responsible for the unique lack of fever and local signs of inflammation in C. sordellii infection are not understood. It is clear, however, that these features are not attributable to failure of macrophages to recognize and respond to the pathogen [27].

Genetic Regulation of Exotoxin Production

Genetic regulation of exotoxin production among histotoxic clostridial species has been investigated principally in C. perfringens. Here, regulation of toxin production has largely been attributed to a two-component signal transduction system consisting of a membrane-bound environmental sensor (VirS) that relays signals to a gene response regulator (VirR) (reviewed in [28]). Although θ toxin production is strictly VirSR-dependent, α toxin production is only partly dependent on this system. The VirSR system also involves several regulatory RNA molecules [29, 30•] and controls up to 147 genes in various functional categories [31•], though this number varies widely among C. perfringens strains [32•].

In seeking the extracellular signal that triggers VirS, recent studies have identified homologues of the S. aureus agr quorum-sensing system in C. perfringens [33••, 34•]. Specifically, gene homologues of an autoinducing peptide (agrDCp) and its membrane-associated exporter (agrBCp) have been found in all strains of C. perfringens sequenced [33••]. That this system provides a soluble molecule that triggers the VirSR system is supported by the fact that θ toxin gene transcription could be restored in a C. perfringens agrBDCp mutant by the addition of culture supernatant from a wild-type strain [33••]. Although it appears that the agrBDCp/virSR/VR-RNA system in C. perfringens is quite similar to the S. aureus agrBDSa/agrAC/RNAIII system, important distinctions exist. First, the system components in S. aureus are contained within a single operon; in C. perfringens, only agrBCp and agrDCp are in close proximity and no identifiable RNAIII homologue driving θ toxin production can be located. Second, the S. aureus system is engaged during the post-exponential/stationary phases of growth when the concentration of the quorum-sensing autoinducing peptide reaches a critical threshold level; in C. perfringens, this system is principally operative during early log phase. This calls into question the position of the agrBDCp/virRS/VR-RNA system in the hierarchy of other known toxin regulatory systems (eg, LuxS). Lastly, and perhaps most importantly, the identity of the in vivo VirS signaling molecule needs to be established.

Initiation and Propagation of Infection

In traumatic clostridial myonecrosis, the temporal events from injury to life-threatening infection can conceptually be divided into five stages (reviewed in [35]). Management practices vary depending on the stage of infection (Table 1).
Table 1

Current concepts in stage-dependent management of traumatic clostridial myonecrosis

Stage(s)

Clinical features

Management practices

Comments

1

Open, contaminated traumatic wound

A) Re-establish blood supply/vascular integrity.

Practices A–C: Prevent development of anaerobic niche.

B) Remove foreign material and use copious irrigation to cleanse wound.

Practice D: Provides sustained protection against vegetative and newly sporulated organisms.

C) Do NOT close the wound.

 

D) Institute prolonged prophylactic antibiotic treatment.

 

E) Provide tetanus immunization.

 

2–3

Intense pain, crepitus at injured site

A) Obtain prompt and thorough surgical inspection and debridement with specimens for Gram stain, culture and sensitivity testing.

Practices A, B: Provide physical source control.

B) Ensure daily surgical reinspection.

Practice E: HBO is controversial; do not delay other management practices while pursuing HBO therapy.

C) Administer toxin-suppressing antibiotics.

 

D) Provide ICU support.

 

E) Consider hyperbaric oxygen (HBO) treatment.

 

4–5

Regional progression of infection, shock, organ failure

A) Seek emergent surgical debridement/amputation.

Practice C: Passive antitoxin immunotherapy (although not currently available) would likely have a role at this stage.

B) Administer toxin-suppressing antibiotics.

Practice D: HBO therapy does NOT inhibit toxin production by organisms within muscle; typically, patients in the late stages of infection are not sufficiently stable to consider HBO.

C) Seek novel toxin attenuation strategies (see comment).

 

D) Do not pursue HBO treatment (see comment).

 

F) Provide ICU support, including:

 

•Transfusion to counteract toxin-induced hemolysis

 

•Albumin to combat profound capillary leak

 

•Cardiac monitoring

 

HBO hyperbaric oxygen; ICU intensive care unit

In stage 1, injury introduces organisms (vegetative or spore forms) directly into deep tissue. Not all contaminated wounds will progress to clostridial gas gangrene. However, if trauma compromises the blood supply or if foreign material is introduced and not removed, an anaerobic environment forms, which supports proliferation of clostridial organisms (stage 2). Spontaneous myonecrosis due to the more aerotolerant C. septicum is less dependent on these conditions.

In stage 3, elaboration of toxins by rapidly proliferating organisms inhibits diapedesis of PMNs out of the vasculature into infected tissues and contributes to vascular injury. Indeed, the absence of a tissue inflammatory response is a hallmark feature of these infections. This is in striking contrast to soft-tissue infections caused by organisms such as S. aureus, in which significant influx of PMNs localizes the infection without adjacent tissue or vascular destruction. Toxin-induced leukostasis and vascular injury cause irreversible local perfusion deficits that fuel the rapid progression of tissue destruction and expansion of the anaerobic niche (stage 4).

In C. perfringens myonecrosis, molecular and animal studies have shown that α and θ toxins both contribute to these pathologies (reviewed in [35]). Studies have shown that α toxin potently stimulates platelet/platelet and platelet/PMN aggregation in vitro (Fig. 1) and in vivo [36, 37], and up-regulates adherence molecules on PMN and endothelial cells. In experimental animals, intramuscular α toxin injection caused a rapid, irreversible decline in muscle blood flow and concomitant ischemic necrosis of tissue [36] because of the formation of occlusive intravascular aggregates of platelets, leukocytes, and fibrin [36, 37]. That θ toxin also contributes to these events is supported by the observation that the related toxins streptolysin O [38] and septicolysin (author’s unpublished observations) also promote platelet/neutrophil aggregation in vitro via activation of platelet P-selectin (CD62P). In addition, PMNs burdened with large, toxin-induced platelet aggregates reduce the ability of PMNs to cross the vascular endothelium into infected tissues [39]—a mechanism that explains, in part, the characteristic lack of a tissue inflammatory response.
https://static-content.springer.com/image/art%3A10.1007%2Fs11908-010-0127-y/MediaObjects/11908_2010_127_Fig1_HTML.gif
Fig. 1

Activation of platelet gpIIbIIIa mediates Clostridium perfringens α toxin-induced platelet/platelet (white arrowheads) and platelet/PMN (gray arrows) aggregation. Human whole blood was treated ex vivo with C. perfringens α toxin in the absence (a) or presence (b) of eptifibatide—a high-affinity peptide inhibitor of the platelet fibrinogen receptor, gpIIbIIIa

Our in vitro studies have shown that α toxin stimulates aggregation of platelets and PMNs by directly activating the platelet fibrinogen receptor, glycoprotein IIb/IIIa (Fig. 1) [36, 37, 39]. These findings suggest that platelet glycoprotein inhibitors (eg, eptifibatide, abciximab) may help maintain tissue oxygenation and restore the tissue inflammatory response in traumatic gas gangrene.

In stage 5, cardiovascular collapse and end-organ failure ensue. Shock is attributable to both direct and indirect effects of α and θ toxins. It has been shown that α toxin directly suppresses myocardial contractility and may contribute to profound hypotension via a sudden reduction in cardiac output. In experimental models, θ toxin causes markedly reduced systemic vascular resistance combined with a markedly increased cardiac output (ie, “warm shock”), likely via induction of endogenous mediators such as prostacyclin, platelet-activating factor, and other lipid autocoids that cause vasodilation.

Diagnosis

Diagnosis of traumatic gas gangrene is not difficult because the infection typically begins at the site of significant trauma, and crepitus in the soft tissue is invariably present on clinical examination. In contrast, early diagnosis of spontaneous gas gangrene is more problematic given the absence of an obvious portal of bacterial entry. These patients usually present with abrupt onset of severe muscle pain, though occasionally only heaviness or numbness is reported. In some patients, the first manifestation may be confusion or malaise. Blood cultures should be obtained for suspected spontaneous gas gangrene because bacteremia usually precedes cutaneous manifestations by several hours.

Gas in the infected soft tissue can be detected by radiography, CT scan, or MRI. CT and MRI are also useful for determining whether infection is localized or spreading along fascial planes. Needle aspiration or punch biopsy provides an etiologic diagnosis in at least 20% of cases. However, these techniques should not replace urgent, thorough surgical exploration of the infected site with retrieval of specimens for Gram stain and culture.

At surgery, involved muscles appear necrotic and do not bleed when cut or contract when stimulated. Histologic examination reveals marked destruction of muscle, fat, and subcutaneous tissues plus an absence of inflammatory cells in involved tissues. Definitive diagnosis of gas gangrene requires demonstration of large, Gram variable rods at the site of infection.

The absence of local evidence of infection and the lack of fever make early diagnosis of C. sordellii infection particularly problematic in patients who develop deep infection following childbirth, therapeutic abortion, gastrointestinal surgery, or trauma (reviewed in [1]). Such patients are frequently evaluated for pulmonary embolization, gastrointestinal bleeding, pyelonephritis, or cholecystitis. Unfortunately, such delays in diagnosis increase mortality. The onset of hypotension and tachycardia prompts aggressive initiation of a variety of diagnostic procedures. CT and MRI scans may show swelling of the affected area; however, in postpartum women, an enlarged uterus is not unusual. Gas in the tissues will not be evident unless other organisms (eg, C. perfringens and Bacteroides spp) are also present. By the time hypotension develops, the complete blood cell count usually shows a marked leukemoid reaction with a left shift and an elevated hematocrit. Hypotension is persistent and refractory to even massive intravenous fluid administration. Liver function tests are usually normal, though the serum albumin drops precipitously to levels of 1.0 g/dL or less because of the diffuse capillary leak syndrome. At this stage of illness, massive peripheral edema is present and radiographs demonstrate pleural and peritoneal effusions and diffuse pulmonary infiltrates. Patients with such findings develop severe respiratory failure. Persistent hypotension results in elevation of serum creatinine, increased lactic acid, a dropping serum bicarbonate level, and hypoxia, necessitating intubation. Although vasopressors are frequently used in such patients, there is little to suggest they are effective.

Physicians should suspect C. sordellii infection in patients who present within 2 to 7 days following injury, surgical procedure, drug injection, childbirth, or medically induced abortion and who complain of pain, nausea, vomiting, and diarrhea, but are afebrile. An increasing WBC count with left shift and evidence of hemoconcentration would strongly suggest C. sordellii infection, and a definitive diagnosis should be intensively sought. Imaging studies may reveal the site of infection and thereby facilitate timely surgical intervention for debridement and obtaining diagnostic material. At present, no rapid tests exist to diagnose C. sordellii infection.

Treatment

Treatment of traumatic gas gangrene consists of surgical debridement, antibiotic therapy, and supportive measures. Novel adjuncts to therapy, based on recent insights in pathogenesis, may soon be forthcoming.

Surgical Exploration and Debridement

Prompt, aggressive, and thorough surgical inspection and debridement of devitalized tissue are mandatory to improve survival, preserve limbs, and prevent complications. In general, multiple surgical debridements over the course of several days may be required.

Antibiotic Therapy

Several different clinical entities can mimic clostridial myonecrosis. Thus, pending definitive etiologic diagnosis of the necrotizing process, empiric antibiotic treatment should cover group A streptococci, Clostridium spp, mixed aerobes and anaerobes as outlined below, and adjusted for renal insufficiency when necessary.

Traumatic Gas Gangrene due to C. perfringens

Definitive antibiotic therapy of C. perfringens myonecrosis should consist of the combination of penicillin (3–4 million units every 4 h intravenously [IV]) plus clindamycin (600–900 mg every 8 h IV) or tetracycline (500 mg every 6 h IV) [40]. For patients with penicillin allergy, clindamycin can be used alone. Other antibiotics with excellent in vitro activity against C. perfringens include tetracycline, chloramphenicol, metronidazole, and several cephalosporins.

Antibiotic treatment recommendations are based on efficacy studies in animal models of C. perfringens myonecrosis; clinical trials comparing the efficacy of these agents in humans have not been performed. Despite in vitro susceptibility, penicillin failed in experimental gas gangrene [41, 42], whereas clindamycin treatment significantly increased survival [41, 42]. Other agents with greater efficacy than penicillin in experimental myonecrosis models included tetracycline, erythromycin, rifampin, chloramphenicol, and metronidazole [41, 42]. The superior in vivo efficacy of clindamycin and tetracycline in these studies is attributed to the ability of these agents to inhibit bacterial exotoxin synthesis [43]. Some experimental studies also suggest that clindamycin [4446] and erythromycin [47••] can modulate the human cytokine response to bacterial toxins, including the production of tumor necrosis factor-α in response to C. perfringens α toxin [47••].

Spontaneous Myonecrosis

Antibiotic therapy for spontaneous gas gangrene due to C. septicum should consist of the combination of penicillin (3–4 million units every 4 h IV) plus clindamycin (600–900 mg every 8 h IV) or tetracycline (500 mg every 6 h IV) [40]. This approach is extrapolated from the treatment of experimental gas gangrene due to C. perfringens. If C. tertium is implicated, therapy should consist of vancomycin (1 g every 12 h IV) or metronidazole (500 mg every 8 h IV) because of its resistance to penicillin, cephalosporins, and clindamycin [40].

C. sordellii Myonecrosis and Toxic Shock Syndrome

Treatment of C. sordellii toxic shock syndrome consists of surgical wound debridement, including removal of infected organs (eg, hysterectomy) and antibiotic therapy consisting of the combination of penicillin (3–4 million units every 4 h IV) plus clindamycin (600–900 mg every 8 h IV).

Adjunctive Hyperbaric Oxygen Therapy

The use of hyperbaric oxygen (HBO) therapy for clostridial myonecrosis is controversial, largely because of the lack of data from randomized controlled trials in humans and divergent results from studies in animals. Some nonrandomized studies have reported good results with HBO therapy when combined with antibiotics and surgical debridement. However, patients in the late stages of infection generally are not sufficiently stable for HBO therapy, and thus such studies may contain a patient selection bias. Experimental studies in animals have failed to demonstrate therapeutic efficacy of HBO alone or the ability of HBO to enhance antibiotic efficacy. In addition, HBO failed to inhibit toxin production in vitro when organisms were present within muscle. In short, the absolute necessity of surgical debridement should not be delayed while pursuing HBO treatment.

Novel Therapies and Prevention Measures

Inhibition of toxin production is an important clinical goal for clostridial myonecrosis. Neutralization of circulating toxins would also be a valuable adjunct to traditional antimicrobial regimens; however, antitoxin for passive immunotherapy is not currently available. Active immunization against the cell-binding domain of C. perfringens α toxin has proven protective in animal studies and could be developed for use in persons at risk for gas gangrene (eg, active military personnel, elderly persons undergoing abdominal surgery). Future treatment strategies may include attenuation of toxin-induced vascular leukostasis and resultant tissue injury by targeting endogenous proadhesive molecules (eg, platelet gpIIb/IIIa). Anti-cytokine therapy may also reduce the duration and severity of shock. Inhibition of toxin production by manipulating genetic control mechanisms could also add to the treatment armamentarium. Thus, novel prevention and treatment measures may soon be on the horizon.

Conclusions

Clostridial myonecrosis is a rapidly progressive and often fatal infection that demands equally aggressive measures to make an early, definitive diagnosis and to initiate treatments that curtail bacterial toxin production. Given the speed with which these infections become life-threatening, preventive strategies such as active immunization against principal lethal toxins should be developed for at-risk individuals. Novel adjuncts to treatment are being pursued in hopes of limiting disease severity and improving outcome.

Disclosure

No potential conflict of interest relevant to this article was reported.

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