Version May 2024
(Clostridium sordellii)
INTRODUCTION — Paeniclostridium sordellii is a cause of toxic shock syndrome associated with gynecologic procedures, childbirth, and abortion (including spontaneous, surgical, and medical abortion) [1-6]. Hemoconcentration, edema, capillary leak, and leukemoid reaction are hallmarks of this infection, in addition to the classic refractory hypotension and organ dysfunction associated with toxic shock syndrome.
P. sordellii is part of the normal flora of the vagina and may gain entry to the uterus via the cervix during spontaneous or induced abortion, childbirth, or menstruation. P. sordellii toxic shock (CSTS) is an uncommonly reported condition with a limited number of case reports and small case series.
The epidemiology, microbiology, pathogenesis, clinical manifestations, diagnosis, and management of CSTS syndrome will be reviewed here. Other issues related to clostridial myonecrosis are discussed separately. (See "Clostridial myonecrosis".)
EPIDEMIOLOGY — P. sordellii can be found in soil, sewage, and the gastrointestinal tracts of humans and animals [7]. P. sordellii has been identified in the gastrointestinal tracts of 0.5 percent of humans [8].
Healthy women can harbor clostridial species in the vagina. Clostridium perfringens is the most common clostridial species (4 to 18 percent of healthy women); P. sordellii is less common (0.5 to 10 percent of healthy women) [8-11]. Clostridial vaginal colonization following abortion has been observed in up to 29 percent of women [10]. Similarly, fecal vaginal contamination during or after childbirth could be the source of P. sordellii infection [8].
The incidence of P. sordellii toxic shock (CSTS) is unknown; one review of death certificates suggested that CSTS was the cause of 1 in 200 deaths among young women of childbearing age [6].
P. sordellii has also been reported as a cause of endometritis in many different animals [12].
Risk factors — Risk factors for CSTS include abortion, childbirth, other gynecologic procedures, gastrointestinal mucosal breach, and intravenous drug use.
Abortion — Medically induced and spontaneous abortions are risk factors for CSTS [8]. The sentinel description of abortion and CSTS included four deaths within one week of medically induced abortions using intravaginal misoprostol and oral mifepristone [3,4,13]. Additional cases have been subsequently reported [8,14,15]. (See "First-trimester pregnancy termination: Medication abortion".)
Misoprostol is a synthetic prostaglandin that stimulates heavy vaginal secretions when administered by the intravaginal route and can impair innate immune responses of the female reproductive tract. It has also been postulated that the intravaginal insertion of misoprostol may lead to ascending infection. (See "Misoprostol as a single agent for medical termination of pregnancy".)
Mifepristone inhibits the action of progesterone and can block glucocorticoid receptors, which may favor growth of P. sordellii [14,16].
Childbirth — One review described eight fatal cases of CSTS within one week of childbirth in previously healthy women following normal childbirth [8]. The source of P. sordellii is likely the vagina, where this organism may be a part of the normal flora and may gain entry to the uterus through the cervix during childbirth.
Other gynecologic cases — CSTS has been reported following procedures on the cervix including laser therapy and conization [6]. A fatal case of spontaneous P. sordellii endometritis has been reported, as has a fatal case following episiotomy infection [17-20].
Intravenous drug use — There have been outbreaks of necrotizing soft tissue infections associated with subcutaneous or intramuscular infection of black-tar heroin ("skin or muscle popping") [21-25]. In one review including 10 cases of P. sordellii infection occurring in intravenous drug users, 50 percent were fatal related to toxic-shock syndrome [8]. Possible sources of P. sordellii include soil contamination of the drug or paraphernalia; the organism can multiply in the setting of local ischemia with resultant anaerobic conditions.
Necrotizing infections are discussed separately. (See "Necrotizing soft tissue infections".)
MICROBIOLOGY — The genus Paeniclostridium consists of anaerobic gram-positive, spore-forming bacilli most commonly found in soil and in the gastrointestinal tracts of animals and humans. Well-known species include C. perfringens, C. septicum, and C. tetani.
P. sordellii is an anaerobic gram-positive rod with subterminal spores and peritrichous flagella [26]. The organism grows on blood agar with a small zone of beta-hemolysis [8]. It was initially named Bacillus oedematis sporogenes, reflecting the marked edema observed in clinical presentation [8]. It has similarities with C. bifermentans, but urease production differentiates these species. Many strains of P. sordellii appear nonpathogenic, but virulent toxin-producing strains cause fatal infections. P. sordellii has been identified from clinical specimens by culture, by matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) [27], and by molecular methods (including polymerase chain reaction), especially from autopsy tissue [28].
Antibiotic susceptibility studies indicate that P. sordellii is susceptible to clindamycin, beta-lactams, tetracycline, and chloramphenicol [29]. The antitoxin properties of clindamycin may be of benefit in addition to its antibiotic effect.
P. sordellii antitoxin is used for identification of Clostridioides difficile: the P. sordellii antitoxin neutralizes the cytopathic effect and all pathologic effects caused by C. difficile toxins A and B. (See "Clostridioides difficile infection in adults: Clinical manifestations and diagnosis".)
PATHOGENESIS — The virulence of P. sordellii is related to production of exotoxins, which may lead to P. sordellii toxic shock even with minimal signs of local infection [2]. Diffuse capillary leak, massive edema, and hemoconcentration probably occur due to one or more exotoxins.
The most studied toxins are large molecular weight cytotoxins designated lethal toxin (LT) and hemorrhagic toxin (HT). Administration of these toxins to animals results in rapidly spreading edema, necrosis, and shock [5]. Both have some antigenic and pathophysiological similarities with C. difficile toxins A and B [30]. The LT inhibits glucocorticoid receptor function and can act to prevent glucocorticoid suppression of tumor necrosis factor-alpha [31].
Another toxin, P. sordellii neuraminidase (NanS), modifies vascular cell adhesion molecules and stimulates promyelocytic proliferation [32]. NanS appears to modulate the leukemoid reaction by preventing margination and movement of leukocytes through the vascular endothelium, such that these cells remain in the circulation, causing profound leukocytosis [32].
Sordellilysin is a cholesterol-dependent cytolysin that serves as a cytotoxin in strains without LT [33]. Non-toxigenic P. sordellii have also been reported [34,35].
Bacteremia due to P sordellii without lethal toxin has been reported [36].
PATHOLOGY — Histological examination of surgical or autopsy tissue may demonstrate acute inflammatory changes, localized thrombosis of blood vessels, and massive coagulation necrosis of the uterine wall [16]. Autopsy findings include massive pleural effusions and ascites [2,5,18]. Necrotizing endomyometritis may be found in fatal cases following medical and spontaneous abortions [16].
Immunohistochemical and molecular studies have been performed on hysterectomy and other postmortem tissues. Polymerase chain reaction assays on extracted DNA, 16sRNA methodology, and sequencing of amplified products can be used to confirm the presence of clostridial species, P. sordellii, and specific toxins [16,28].
Necrotizing fasciitis pathologic findings have been described in patients who inject drugs [24].
CLINICAL MANIFESTATIONS — P. sordellii causes a spectrum of clinical disease, including localized skin infection, bacteremia, and infection localized to a single organ system such as pneumonia, empyema, endocarditis, septic arthritis, omphalitis, and surgical site infection [7,26,37-44]. Post-traumatic P. sordellii gas gangrene and malignant edema have also been described [45,46].
P. sordellii toxic shock is characterized by rapid onset of severe illness with shock; the illness frequently occurs in previously healthy individuals [2]. The clinical presentation generally consists of systemic manifestations including edema, effusions, profound leukocytosis, and hemoconcentration, followed by shock and multiorgan failure [47].
Early symptoms are often nonspecific and may include nausea, vomiting, lethargy, influenza-like symptoms, and abdominal tenderness [18,48]. Progression from early symptoms to severe disease occurs within hours, and mortality is high [8]. The systemic nature of the presentation with the paucity of localizing symptoms may make early diagnosis difficult [47]. Distinctive clinical features include:
●Rapid development of generalized and massive tissue edema [8,17].
●Pleural, pericardial, and peritoneal effusions are common [2,8]. These develop due to capillary leak from toxin-mediated changes in the vascular endothelium, together with hypoalbuminemia [2].
●Profound leukocytosis (leukemoid reaction) consisting of white blood cell (WBC) count >50,000 cells/microL, which can increase to 200,000 cells/microL within 48 hours [2-4,8,49]. In general, an increased percentage of mature and immature neutrophils and increased absolute numbers of lymphocytes and monocytes are observed. The presence of leukemoid reaction is highly predictive of mortality [8]. In one study, patients who died had average WBC count of >75,000 cells/mm3; survivors had average WBC count of 18,000 cells/mm3 [8].
●Hemoconcentration is common; hematocrit levels up to 80 percent have been reported [2,4,5,16,48,49].
●Absence of fever [2,4,8].
●Refractory hypotension and tachycardia [2,8].
In postpartum women, the uterus can be large, but usually there is no evidence of retained fetal or placental tissue. Gas in tissues suggests the presence of other organisms such as C. perfringens or Bacteroides species.
P. sordellii is rarely reported in children. There is a case report of P. sordellii infection with toxic shock syndrome in a two-year-old boy in the setting of the hemolytic uremic syndrome, in which the organism was isolated from blood cultures [50]. Cases of neonatal omphalitis have also been reported [51].
DIAGNOSIS — P. sordellii infection should be suspected in young women with rapid clinical deterioration in the postpartum period or in the setting of recent abortion or other gynecological procedure [17]. P. sordellii sepsis should also be suspected in patients who took mifepristone within 24 hours of presenting with nausea, vomiting, or diarrhea without fever. The diagnosis should also be considered in the setting of intravenous drug use, especially with the use of black-tar heroin.
Features of hemoconcentration, effusions, and leukemoid reaction should further increase suspicion.
Empiric antibiotic therapy should be instituted promptly while diagnostic studies are pending. (See 'Treatment' below.)
Blood cultures (both aerobic and anaerobic bottles) should be obtained; in one series, blood cultures were positive in 20 percent of cases [8]. Gram stain and cultures (aerobic and anaerobic) of specimens from suspected sites of infection (including vaginal specimens and/or wound aspirates) should be performed. Gram staining may demonstrate mixed gram-negative and gram-positive bacilli; P. sordellii is frequently identified together with other pathogens, such as Peptostreptococcus, Streptococcus milleri, C. perfringens, Escherichia coli, and a variety of other coliforms and anaerobes [2,5,8,18,52].
A complete blood count should be obtained to evaluate for presence of hemoconcentration, leukocytosis, or a leukemoid reaction.
Computed tomography and ultrasound examinations, in cases related to abortion or childbirth, have demonstrated ascites [4,8], pleural effusions [5], and a thickened or enlarged uterus [5,8].
If surgery is performed, tissue samples should be obtained for microbiologic and histopathologic evaluation to assist in diagnosis. In one report, endometrial biopsy was the diagnostic procedure [5]. Histopathology of resected necrotic tissue and/or intraoperative frozen section biopsies may confirm the presence of necrotizing subcutaneous infection; Gram stain and culture should also be performed [17].
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of toxic shock due to P. sordellii includes:
●In peripartum and postpartum patients:
•Retained products of conception – Both retained products and P. sordellii infection may be associated with pelvic pain and/or uterine tenderness. Fever may be observed in the setting of retained products but is not typically seen in the setting of P. sordellii infection. The diagnosis of retained products of conception is established by ultrasonography. (See "Retained products of conception in the first half of pregnancy".)
•Postpartum hemorrhage – Postpartum hemorrhage refers to excessive bleeding following delivery, which can lead to hypotension and tachycardia. P. sordellii infection is also associated with these findings but differs in that hemoconcentration is common. (See "Overview of postpartum hemorrhage".)
•Uterine perforation – Uterine perforation is associated with abdominal pain, abdominal distension, and hypotension, which can also occur in the setting of P. sordellii infection. The diagnosis is established by direct visualization via hysteroscopy or laparoscopy. (See "Uterine perforation during gynecologic procedures".)
●In patients who inject drugs and present with toxic shock syndrome or necrotizing skin and soft tissue infection:
•Other microbiologic causes of toxic shock include Streptococcus pyogenes, Staphylococcus aureus, and C. perfringens. P. sordellii toxic shock may be distinguished from these other causes by clinical history, absence of rash and fever, and profound leukocytosis [2]. (See "Invasive group A streptococcal infection and toxic shock syndrome: Epidemiology, clinical manifestations, and diagnosis" and "Staphylococcal toxic shock syndrome" and "Necrotizing soft tissue infections".)
TREATMENT — Treatment of P. sordellii toxic shock (CSTS) syndrome consists of antibiotic therapy, surgical debridement, and aggressive resuscitation [17].
Antimicrobial therapy — Initial empiric therapy should consist of broad-spectrum parenteral antimicrobial therapy that covers beta-lactamase–producing anaerobes. The preferred regimen is piperacillin-tazobactam (4.5 g intravenously [IV] every eight hours) plus clindamycin (900 mg IV every eight hours); for patients with penicillin allergy, a carbapenem (eg, meropenem) combined with clindamycin is appropriate. Vancomycin may be added when methicillin-resistant S. aureus is a possible pathogen (table 1).
Definitive antibiotic therapy for CSTS should consist of penicillin (3 to 4 million units IV every four hours) plus clindamycin (900 mg IV every eight hours) [8]. For patients with penicillin allergy, clindamycin can be used alone. No human trials have compared the efficacy of antibiotics for treatment of P. sordellii toxic shock syndrome; this approach is extrapolated from the treatment of traumatic gas gangrene due to C. perfringens and is based on animal models. (See "Clostridial myonecrosis".)
Surgery — Surgery for removal of necrotic tissue and to obtain tissue for diagnostic testing is important. Repeated surgical procedures may be required [53]. Case series suggest that aggressive debridement including hysterectomy may be warranted in some circumstances [8].
Supportive care — Progressive hypoxia and hemodynamic instability require aggressive resuscitation with intensive care, ventilation, and vasopressive support [8]. (See "Evaluation and management of suspected sepsis and septic shock in adults".)
Antitoxin — It is possible that specific antitoxin may be a beneficial future therapy for P. sordellii infections; in a mouse model, P. sordellii antitoxin prevented mortality [8]. There is a case report of P. sordellii infection in a child whose recovery was linked to the development of antibodies that neutralized the preformed toxin [54].
OUTCOME — P. sordellii toxic shock is frequently fatal [8]. In a review of 45 cases of P. sordellii infections, mortality was 69 percent [8]. Mortality was 100 percent in cases associated with medical-induced abortion, spontaneous abortions, and childbirth; mortality was 50 percent in cases associated with intravenous drug use. The time from onset of symptoms to death was two to six days.
PREVENTION — One group has suggested antepartum screening for P. sordellii should be considered [27]. However, further studies are required before such a practice could be recommended.
Patients who inject drugs should be cautioned to avoid black tar heroin and to practice safe injection techniques.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Skin and soft tissue infections".)
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Paeniclostridium sordellii is a cause of toxic shock syndrome (CSTS) associated with gynecologic procedures, childbirth, and abortion (including spontaneous, surgical, and medical abortion), as well as intravenous drug use. Gastrointestinal and vaginal colonization of P. sordellii can occur in healthy individuals. (See 'Epidemiology' above.)
●Clinical manifestations – Clinical manifestations of CSTS include edema, effusions, profound leukocytosis, and hemoconcentration, followed by shock and multiorgan failure. Fever is typically absent. (See 'Clinical manifestations' above.)
●Pathogenesis – The virulence of P. sordellii is due to production of exotoxins that may lead to CSTS even with minimal signs of local infection. Diffuse capillary leak, massive edema, and hemoconcentration are probably due to one or more exotoxins. (See 'Pathogenesis' above.)
●Diagnosis – Blood cultures (both aerobic and anaerobic bottles) should be obtained; Gram stain and cultures of specimens from suspected sites of infection should be performed. P. sordellii is frequently identified together with other pathogens. (See 'Diagnosis' above.)
●Management – Treatment of CSTS consists of antibiotic therapy, surgical debridement, and aggressive resuscitation [17]. (See 'Treatment' above.)
Initial empiric therapy should consist of broad-spectrum parenteral antimicrobial therapy that covers beta-lactamase–producing anaerobes. For treatment of CSTS, we suggest penicillin (3 to 4 million units intravenously every four hours) plus clindamycin (900 mg intravenously every eight hours) (Grade 2B). (See 'Antimicrobial therapy' above.)
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