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 is started on clindamycin. A few days after starting treatment, he develops watery diarrhea and abdominal cramps. The patient is hospitalized, and complete blood count reveals leukocytosis. The toxin responsible for his current condition most directly impairs which of the following components of intestinal mucosal cells?

Question

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 is started on clindamycin.  A few days after starting treatment, he develops watery diarrhea and abdominal cramps.  The patient is hospitalized, and complete blood count reveals leukocytosis.  The toxin responsible for his current condition most directly impairs which of the following components of intestinal mucosal cells?

Quizplus · Accepted Answer

11ec160b_37f9_9f7a_9249_af68f08d53a9_MD0001_00 Clostridioides (formerly Clostridium) difficile is part of the gut's normal microbial flora in 2%-3% of healthy adults and in approximately 70% of healthy infants. Administration of antibiotics (eg, clindamycin, fluoroquinolones, and broad-spectrum penicillin) that are lethal to other commensal gut organisms can result in C. difficile colitis due to 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 Rho-regulatory proteins involved in actin cytoskeletal structure maintenance. 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 in pain and 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 can be 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 ingestion of contaminated food or water. Educational objective: Pathogenic Clostridioides difficile can proliferate due to loss of commensal gut flora following use of broad-spectrum antibiotics (eg, clindamycin). C. difficile toxins A and B exert their effects by stimulating an inflammatory reaction and disrupting the actin cytoskeletal structure. The result is pseudomembranous colitis characterized by crampy abdominal pain, watery diarrhea, and leukocytosis. __________ References: The role of toxin A and toxin B in Clostridium difficile infection. (http://www.ncbi.nlm.nih.gov/pubmed/20844489)

A 65-Year-Old Man Comes to the Office Due to Pain