A 65-year-old man comes to the office due to pain, redness, and swelling in his right calf. The patient is diagnosed with cellulitis and clindamycin is initiated. A few days after starting treatment, he develops watery diarrhea and abdominal cramps. The patient is hospitalized, and a complete blood count reveals leukocytosis. The toxin responsible for this patient's condition most directly affects which of the following components of intestinal mucosal cells?
Clostridioides difficile colitis | |
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*Genes specific to toxigenic strains are assessed. EIA = enzyme immunoassay; IV = intravenous; PCR = polymerase chain reaction; PPI = proton pump inhibitor. | |
Clostridioides difficile is part of the gut's normal microbial flora in 2%-3% of healthy adults and approximately 70% of healthy infants. The administration of antibiotics (eg, clindamycin, fluoroquinolones, broad-spectrum penicillin) that are lethal to other commensal gut organisms can result in C difficile colitis due to an unchecked replication of pathogenic strains of C difficile.
These strains produce toxin A and toxin B, which act synergistically, although toxin B is significantly more virulent. The toxins bind specific receptors on intestinal mucosal cells and are internalized, allowing them to inactivate the Rho-regulatory proteins involved in the maintenance of actin cytoskeletal structure. The result is loss of cytoskeleton integrity, leading to cell rounding/retraction, disruption of intercellular tight junctions, and increased paracellular intestinal fluid secretion (eg, watery diarrhea). Both toxins also have inflammatory effects (eg, neutrophil recruitment) and can induce apoptosis, resulting pseudomembrane formation.
(Choice A) Apical ion transport is most directly affected by the cholera toxin (main exotoxin of Vibrio cholerae) through activation of adenylate cyclase, which leads to decreased salt reabsorption and increased transport of sodium and chloride out of the gut mucosal cell. Apical ion transporters are indirectly affected by C difficile toxins due to loss of cell polarity (secondary to cytoskeletal dysfunction).
(Choice B) Loss of cell membrane integrity is characteristic of alpha toxin lecithinase, one of many exotoxins released by Clostridium perfringens. C perfringens can cause transient, watery diarrhea. However, it is most frequently associated with clostridial myonecrosis (ie, gas gangrene), a rapidly progressive form of fasciitis associated with penetrating injury by soil-contaminated objects.
(Choice D) Mitochondria are the primary source of ATP in human cells. Cyanide and nucleoside reverse transcriptase inhibitors are examples of drugs associated with mitochondrial toxicity.
(Choice E) Ribosomal protein synthesis is inhibited by Shiga and Shiga-like toxins. Shiga toxin is the main exotoxin released by Shigella species; Shiga-like toxin (ie, verotoxin) is produced by enterohemorrhagic Escherichia coli (eg, O157:H7). These toxins cause inflammatory diarrhea (eg, fever, pain, blood) 3-4 days after the ingestion of contaminated food or water.
Educational objective:
Pathogenic Clostridioides difficile can proliferate due to loss of commensal gut flora following the use of broad-spectrum antibiotics (eg, clindamycin). C difficile toxins A and B stimulate an inflammatory reaction and disrupt the actin cytoskeletal structure, resulting in pseudomembranous colitis characterized by crampy abdominal pain, watery diarrhea, and leukocytosis.