clostridial infections

Clostridium species are Gram-positive bacilli that grow under anaerobic conditions and produce spores that are frequently present in the soil.

Four types of disease are caused by Clostridium:

 Clostridium perfringens, Clostridium septicum, and other species cause cellulitis and myonecrosis of traumatic and surgical wounds (gas gangrene), uterine myonecrosis often associated with illegal abortions, mild food poisoning, and infection of the small bowel of ischemic or neutropenic patients often leading to severe sepsis.

 Clostridium tetani proliferates in puncture wounds and in the umbilical stump of newborn infants in developing countries and releases a potent neurotoxin, called tetanospasmin, that causes convulsive contractions of skeletal muscles (lockjaw). Tetanus toxoid (formalin-fixed neurotoxin) is part of the DPT (diphtheria, pertussis, and tetanus) immunizations given to children, and this has greatly decreased the incidence of tetanus in the United States and in developing countries.

 Clostridium botulinum grows in inadequately sterilized canned foods and releases a potent neurotoxin that blocks synaptic release of acetylcholine and causes a severe paralysis of respiratory and skeletal muscles (botulism).

 Clostridium difficile overgrows other intestinal flora in antibiotic-treated patients, releases toxins, and causes pseudomembranous colitis.

Pathogenesis

C. perfringens will not grow in the presence of oxygen, so tissue death allows the bacteria to proliferate within the host. These bacteria release collagenase and hyaluronidase that degrade extracellular matrix proteins and contribute to bacterial invasiveness, but their most powerful virulence factors are the many toxins they produce. C. perfringens secretes 14 toxins, the most important of which is α-toxin.

This toxin has multiple actions. It is a phospholipase C that degrades lecithin, a major component of cell membranes, and so destroys red blood cells, platelets, and muscle cells, causing myonecrosis; it also has a sphingomyelinase activity that contributes to nerve sheath damage; α-toxin releases phospholipid derivatives such as inositol triphosphate, prostaglandins, and thromboxanes, and these may dysregulate cellular metabolism, increasing cell death.

Ingestion of food contaminated with C. perfringens causes a brief diarrhea. Spores, usually in contaminated meat, survive cooking, and the organism proliferates in cooling food. C. perfringens enterotoxin forms pores in the epithelial cell membranes, lysing the cells and disrupting tight junctions between epithelial cells.

The neurotoxins produced by C. botulinum and C. tetani both inhibit release of neurotransmitters, resulting in paralysis.30 Botulism toxin, eaten in contaminated foods or absorbed from wounds infected with C. botulinum, binds gangliosides on motor neurons and is transported into the cell. In the cytoplasm, the A fragment of botulism toxin cleaves a protein, called synaptobrevin, which mediates fusion of neurotransmitter-containing vesicles with the neuron membrane.

By blocking vesicle fusion, botulism toxin blocks release of acetylcholine at the neuromuscular junction, resulting in flaccid paralysis. If the respiratory muscles are affected, botulism can lead to death. Indeed, the widespread use of botulism toxin (Botox) in cosmetic surgery is based on its ability to cause paralysis of strategically placed muscles on the face. The mechanism of tetanus toxin is similar to that of botulism toxin, but tetanus toxin causes a violent spastic paralysis by blocking release of the neurotransmitter γ-aminobutyric acid from motor neurons.

C. difficile produces toxin A, an enterotoxin that stimulates chemokine production and thus attracts leukocytes, and toxin B, a cytotoxin, which causes distinctive cytopathic effects in cultured cells and is used in the diagnosis of C. difficile infections. Both toxins are glucosyl transferases and are part of a pathogenicity island, which is absent from the chromosomes of nonpathogenic strains of C. difficile.119