Clostridium sordellii

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University of Oklahoma Study Abroad Microbiology in Arezzo, Italy[1]

Hematoxylin and Eosin Staining image of Clostridium difficile at 100x magnification. From: cid.oxfordjournals.org [2]

Etiology/Bacteriology

Taxonomy

| Domain = Bacteria | Phylum = Firmicutes | Class = Clostridia | Order = Clostridiales | Family = Clostridiaceae | Genus = Clostridium | species = Clostridium sordellii

NCBI: [5] Genome: [6]

Description

Clostridium sordelli is a gram positive, spore-forming, anaerobic rod [1]. This bacterium was first discovered by Alfredo Sordelli in 1922 who named it Bacillus oedematis because of the distinct edematous characteristics it causes in cases of infection [1]. In 1927 the organism was renamed Bacillus sordellii and two years later it became classified as Clostridium sordellii, as it is almost indistinguishable from Clostridium oedematoides [1]. Previous research on this organism can be found under these former species names. Clostridium sordelli is a virulent strain of Clostridium bifermentans that causes pneumonia, endocarditis, arthritis, peritonitits, myonecrosis, bacteremia and sepsis in humans in more serious strains of the disease [1][2]. The most published manifestations of this infection are those causing severe toxic shock syndrome in association with gynecological complications in women [2]. However, cases of C. sordelli infections are recorded equally among men and women [3]. This microorganism is only found in 0.5% of human intestines, but more commonly isolated from soil [1]. There are various treatments for this disease, some being more effective than others, ranging from antibiotic to supplemental oxygen usage [3]. Two notable virulence factors, Lethal Toxin (LT) and Hemorrhagic Toxin (HT), aid in the pathogenicity of the organism [3]. The method of transmission of Clostridium sordellii is unknown [1]. Microbiologists and health professionals continue to work in conjunction to prevent the spread of these bacteria during gynecological procedures, non-gynecological procedures and in cases involving injury to soft tissues [2]. Illicit drug users are especially susceptible to C. sordellii infections and certain drugs have shown more apt to transmit the bacterium [4].

Pathogenesis

Transmission

The mechanism of transmission for Clostridium sordellii between person to person or person to environment is not known (2). There are no known zoonotic Clostridium species, meaning they cannot transmit directly from animal to human (5). Some microbiologists hypothesize that the bacteria can travel from person to person and from contaminated surfaces to person in a similar manner to other Clostridium species, although there has yet to be a study confirming this to be true for C. sordellii. In general, Clostridium species are transmitted through contaminated wound sites and discontinuities in the gastrointestinal tract (5). An outbreak in California revealed that black tar heroin (BTH) was able to carry C. sordellii and transmit itself into injection drug users (IDU) (4). Along with IDU, C. sordelli infections have been associated with medically induced abortions, minor traumas and surgeries, spontaneous abortions and normal childbirth—the tools used in these operations are not found to carry C. sordellii on their surfaces (1). A major theme in these cases is transmission via the mucosal surfaces of the urogenital tracts in males and females, yet there are still uncommon cases of transmission through other surfaces of the body.

Lethal dose, Incubation, Colonization

A study published by The American Journal of Pathology investigated the effects of Clostridium sordellii in mice. The lethal dose (MLD)/kg for mice were determined to be 150ng (6). This information does not conclude the lethal dose in humans; however, it reveals that toxins produced by C. sordellii are more lethal than in any other Clostridium spp., besides C. botulinum and C. tetani (6). The exact infectious dose is unknown. In Clostridium species the average incubation is 6 hours to 3 days (5). Numerous case studies suggest that the incubation of C. sordellii after infection is 1 to 5 days (1,3). Around the 5th or 6th day of infection the microorganism is fatal to the host. Colonization of C. sordellii occurs in the urogenital tract of females and lacerated soft-tissue of both male and females (1,2,4). Toxins released by the bacteria can affect many organs of the body including the heart, lungs, and kidneys (1,6).

Epidemiology

Most susceptible population. From: www.oblp.co.uk [3]

The populations most susceptible to Clostridium sordellii infections are women nearing the end of pregnancy, whether that concludes in live birth, medical abortion, or miscarriage (2). 5-10% of non-pregnant women have Clostridium species isolated from their vaginal secretions, whereas possibly 29% of women possess bacterial colonization of this genera after abortion (2). Microbiologists and health care providers continue to investigate the exact percentage of C. sordellii colonization in the vaginal and rectal areas of the body. An infection with this bacteria is rare and underreported because many health care providers are unaware that their patients have this disease. Over a 79 year period, Index Medicus, Pubmed, and Medline databases reported 43 patients with C. sordellii infections (1). 63% of cases occurred in women, with 35% associated with normal childbirth, 22% with medically induced abortions, and 9% with miscarriage (1). 37% of cases occurred in males and were associated with surgical procedures or trauma to soft tissue (1). 100% of these cases ended in mortality, however, only two of the patients were exclusively infected with C. sordellii bacteria (1). In general, diseases from Clostridium spp. occur globally and are found in many environments, such as soil, feces, sewage, and marine sediments (5). People with previous medical conditions, elderly, children, and injection drug users have a heightened risk of developing infection. C. sordellii becterial infections are most common in animals and has caused outbreaks of enterotoxemia, intermittent cases of necrotic and hemorrhagic enteritis, and toxic infections (6).

Virulence Factors

Clostridium sordellii produces numerous virulence factors: lethal toxin (TcsL), hemorrhagic toxin (HT), phospholipases, extracellular proteases, hemlysins, DNase, and cytotoxin (6). Of these 7, TcsL and HT are the major virulence factors that are the most lethal to hosts (1). TcsL, part of the family of large clostridial cytotoxins, contains three functional domains: C-terminal, involved in cell surface recognition, a hydrophobic segment, facilitating translocation into the cytosol of the N-terminal part across the endosomal membrane, and N-terminal, possessing the enzymatic site and promoting intracellular activity (6). TcsL inhibits signaling proteins Rac, Cdc42, Ras, and Rap in host cells and catalyzes the glucosylation of small GTPases from UDP-glucose (1,6). HT, like TcsL, inhibits signaling proteins Rac and Cdc42, and also inhibits signaling protein Rho (1). The functions of the additional toxins produced by C. sordellii are as follows: hemolysin, chlosterol-dependent hemolysin, neuraminidase, cleaves sialic acids from sialoglycoconjugates, phospholipase C, hydrolyses lecithin, DNase, potential degeneration of host cell nuclei, hyaluronidase, splits hyaluronic acid which increases permeability, and collagenase, hydrolyzes collagen and gelatin (1).

Clinical features

Early Symptoms

Early symptoms of Clostridium sordellii include symptoms of vomiting, nausea, diarrhea and occasional abdominal pain without fever (2). All of these indicators can occur in women after childbirth, spontaneous abortion, or medical abortion, so further testing is needed to conclude the source of the symptoms. Additional clinical features of C. sordellii infections, listed most to least prevalent include: septic shock, mild infection site pain, leukemoid reaction, afebrile, tachycardia, hemoconcentration, tissue or visceral edema, reduced serum protein, metabolic acidosis, decreased platelet count and RBCs and WBCs in urine (3). These symptoms are characteristic signs leading to more serious symptoms that manifest in C. sordellii infections.

Late Symptoms

Severe cases of Clostridium sordellii infections are extremely rare, but deadly. The progression from early to late symptoms is usually rapid, occurring within hours after the first signs of any illness (1). In women, the C. sordellii infection can develop into Clostridium sordellii Toxic Shock Sydrome (CSTS), which is associated with gynecological procedures, childbirth and abortion (5). CSTS is an acute illness that often manifests in previously healthy persons (5). The symptoms of this syndrome are edema, effusion, intense leukocytosis and hemoconcentration and eventually multi-organ failure (5). In males, C. sordellii infections occur after trauma or surgery on the soft-tissue of the body (1). Soft-tissue edema and collections of fluid in the peritoneal cavities and pleural spaces ensues (1). Severe necroses, along with interstitial hemorrhage and neutrophilic infiltrates, have appeared in histopathologic examinations of deceased patients with this disease(1). From 1927-2006, 43 patients were reported in medical databases to have contracted C. sordellii infections with a mortality rate of 100% (1). Tachycardia and hypotension were strong indicators of subsequent mortality (1).

Diagnosis

Early diagnosis of Clostridium sordellii infection is problematic because the symptoms are broad and present in many other diseases—sometimes they do not even appear in infected hosts (1). Diagnostic tests for C. sordellii are not aggressively pursued, even after childbirth or gynecological procedures, because the local infection does not appear until hours after the disease has progressed (1). Earlier diagnosis among injection drug users is more common than in other cases of infection, however, because of the apparent swelling, pain and redness at the site of injection (1). These patients have surgical intervention at the dermis of the skin in order to obtain specimens for culture and Gram stain (1). CT and MRI scans may also be conducted to investigate swelling of infected areas. The early diagnosis of injection drug users strongly correlates with a lower mortality rate of those infected with C. sordellii. Health care providers should suspect a C. sordellii infection in patients who present with early disease symptoms, but are afebrile (1).Generally, vigorous diagnostic tests are pursued when patients have hypotension and tachycardia (1). When hypotension develops, physicians may order complete blood cell counts which disclose leukemoid reaction and hematocrit levels (1). C. sordellii infections are systematic; therefore, liver function value tests are necessary to know the levels of bilirubin, alanine aminotransferase, and alkaline phosphatase (1). Diagnostic tests for the heart, kidney, lung, and other organ functions may also be performed to check the extent of the spread of C. sordellii throughout the body.

Treatment

Antibiotics used for treatment of C. sordellii From: family-medicine.info [4]

There is limited information regarding successful treatment of Clostridium sordellii infections because many cases are fatal. Health care providers have yet to find a successful treatment that clears the bacterial infection while avoiding patient mortality. The acute onset of symptoms and death occurs before many diagnostic tests have been performed. C. sordellii can be treated with antibiotics, but many hospital laboratories do not perform antimicrobial susceptibility tests on anaerobes (1). Previous studies suggest that, similar to most Clostridia species, C. sordellii is susceptible to beta-lactam, clindamycin, tetracycline, and chloramphenicol drugs, while resistant to aminoglycosides and sulfonamides (1). Intravenous fluids are used to treat patients with symptoms of tachycardia and hypotension. Removal of necrotic tissue is important to reduce buildup of toxins and diagnosis of disease (1). Other treatments for C. sordellii include plasma injections, vasopressors, steroids, morphine, atropine and supplemental oxygen (3).

Prevention

Prevention of a Clostridium sordellii infection is difficult with so little known about the transmission of the disease. Studies conducted by the Food and Drug Administration (FDA) have not determined that medications taken for medical abortions or the instruments utilized during these procedures are causative agents for the infection (2). The Centers for Disease Control and Prevention (CDC) are working with the FDA to identify more cases of C. sordellii infections and evaluate existing data to determine the common source of the disease. Once the source is identified health care providers and the public can become educated on how to prevent C. sordellii infections. The CDCs main focus for research on this bacterium is women who are having gynecological procedures or natural childbirth (2). Understanding the source of disease in these cases can lead to a better understanding of C. sordellii infections in other cases of surgery and trauma to the soft tissue.

Host Immune Response

The innate immune recognition and response to Clostridium sordellii has not been extensively researched except for the cytokine production in the presence of this pathogen. One study of C. sordellii utilized Human Embryonic Kidney 293 (HEK-293) cells that were transfected with genes for TLR1, TLR2, TLR4, and TLR6 alone and in combination (3). The HEK-293 cells were also transfected with ELAM-1-dependent luciferase reporter system, MD2, and CD14 (3). Then, LPS-free organisms were added as positive TLR4 agonists into the experiment, along with C. sordellii bacteria (3). An enzyme linked immunosorbent assay (ELISA) measured cytokines produced from peripheral blood mononuclear cells (PBMC) that were stimulated in parallel. ELISA showed a significant production of TNF-alpha, mimicking the innate immune system’s inflammation response in the presence of C. sordellii bacteria (3). Cytokine production in an overlying medium was measured by protein microarray which revealed TNF-alpha and IL-6 were the cytokines most produced, followed by IL-1Beta, IL-10, and GM-CSF, respectively (3). The adaptive immune response for C. sordellii has not been extensively researched.

References

1 http://cid.oxfordjournals.org/content/43/11/1436.long
2 http://www.cdc.gov/hai/organisms/csordellii.html#a1
3 http://www.google.it/url?sa=t&rct=j&q=&esrc=s&source=web&cd=2&ved=0CC4QFjAB&url=http%3A%2F%2Fwww.fda.gov%2Fdownloads%2FAboutFDA%2FCentersOffices%2FCDER%2FUCM183782.pdf&ei=Vs7OU-7aAqaj4gTx7oDACw&usg=AFQjCNFABYpXfKu1d9Uvo41AK0uWkNQ-_Q&bvm=bv.71198958,d.bGE
4 http://cid.oxfordjournals.org/content/38/9/e87.short
5 http://www.phac-aspc.gc.ca/lab-bio/res/psds-ftss/clostridium-spp-eng.php
6 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1864880/

Created by Caitlyn Baukal, student of Tyrrell Conway at the University of Oklahoma.