| disease | Pseudomembranous Colitis |
| alias | Clostridium Difficile Colitis, Postoperative Enteritis, PMC, Pseudome Mbranous Colitis, Antibiotic-associated Clostridium Difficile Colitis, Antibiotic-associated Colitis |
Pseudomembranous colitis (PMC), also known as Clostridium difficile colitis, postoperative colitis, antibiotic-associated colitis, or antibiotic-induced Clostridium difficile colitis, often occurs in patients after major surgery or those with severe and chronic debilitating diseases. The use of broad-spectrum antibiotics, especially oral lincomycin, disrupts the intestinal flora, leading to the abnormal proliferation of Clostridium difficile. This produces toxins that cause acute fulminant inflammation of the intestinal mucosa, resulting in the formation of pseudomembranes on the necrotic mucosa.
bubble_chart Etiology
Most scholars believe that this disease occurs after the use of broad-spectrum antibiotics such as tetracycline, terramycin, chloramphenicol, doxycycline, ampicillin, and lincomycin. According to Swarlzherg's report, among 1,000 infected patients treated with clindamycin, the incidence of pseudomembranous enteritis was 2–10%. Diarrhea rarely occurs in children treated with clindamycin. A prospective analysis of 1,484 pediatric patients showed that only 38 cases (2.5%) developed diarrhea, which usually stopped within 3–8 days after discontinuation of the drug, and very few cases progressed to pseudomembranous enteritis.
In the past, because coagulase-positive Staphylococcus aureus was found in the feces and pseudomembranes of patients with this disease, it was initially classified as a type of staphylococcal enteritis caused by intestinal dysbiosis due to broad-spectrum antibiotics. Currently, it is believed that pseudomembranous small intestine colitis and staphylococcal intestinal infection are two distinct diseases. In pseudomembranous enteritis, Staphylococcus aureus is merely a concomitant bacterium and does not play a pathogenic role. In 1977, Larson et al. reported a 12-year-old girl who developed pseudomembranous enteritis after penicillin use. The filtrate of her stool exhibited cytotoxic effects on tissue cultures, even at high dilutions. Similar observations were made in 4 out of 5 other pseudomembranous enteritis patients. Moreover, the stool filtrate from one patient caused similar lesions in experimental animals. This led to the conclusion that the disease was caused by a toxin, which was later confirmed to be neutralized by antitoxin against Clostridium sordellii, while other antitoxins had no such effect. However, Clostridium sordellii has never been known to cause gastrointestinal diseases in humans, making it difficult to attribute the disease to this bacterium. In recent years, some scholars have isolated another Clostridium species—Clostridium difficile—from the feces of patients with this disease and confirmed that it produces an exotoxin that causes necrosis of the intestinal mucosa. This toxin can induce disease in animals and cross-reacts with the toxin of Clostridium sordellii, allowing it to be neutralized by the latter's antitoxin. The use of broad-spectrum antibiotics, especially clindamycin, suppresses the normal intestinal flora. For unknown reasons, antibiotic use may allow Clostridium species to escape inhibition, promoting their proliferation and synthesis of pathogenic factors. Vancomycin and non-absorbable sulfonamides can effectively inhibit Clostridium species. Animal experiments have shown that vancomycin can prevent or treat pseudomembranous enteritis caused by lincomycin and clindamycin, further supporting the idea that the toxin produced by Clostridium difficile may be the true pathogenic factor of this disease.
After major surgeries or in chronic wasting diseases, the body's immune and disease-resistance mechanisms may weaken. Factors such as intestinal stasis, ischemia, or dysbiosis create favorable conditions for the proliferation of Clostridium difficile, leading to disease. When the disease occurs postoperatively, gas in the intestinal lumen can enter the intestinal wall, worsening the lesions.
Chinese medicine believes that the disease cause of this condition is dampness-heat obstructing the middle, leading to dysfunction in ascending and descending, and failure to separate the clear from the turbid, resulting in incessant diarrhea.
bubble_chart Pathological Changes
In the initial stage [first stage] of the disease, before the formation of the pseudomembrane, the superficial epithelium of the crypts first undergoes swelling and degeneration, with a few cells shedding. The stroma shows edema and eosinophilic fluid exudation, with grade I neutrophil infiltration and vascular dilation, and microthrombi may form. If the condition progresses, more epithelial cells degenerate and shed, their basement membrane is destroyed, and the diseased stroma exudes fibrin, eosinophilic fluid, and inflammatory cells into the intestinal lumen, along with shed epithelial cells, mucus, and necrotic cell debris, forming the initial stage [first stage] pseudomembrane. This membrane tightly covers the crypt openings, preventing the discharge of mucus, shed epithelium, and exuded inflammatory cells, leading to crypt dilation. As the disease progresses and the affected area expands, the pseudomembranes also increase in number, varying in size and slightly raised. Some appear as small dots, while others merge into patches. In severe cases, the entire intestinal segment may be covered by the pseudomembrane. The pseudomembrane appears yellow-green or brown, soft and fragile, and when peeled away, it exposes an ulcerated surface. Between the unmerged pseudomembranes, normal edematous mucosa can still be seen, with intestinal lumen dilation and increased fluid in the cavity. Microscopically, the pseudomembrane is composed of fibrin, neutrophils, monocytes, mucin, and necrotic cell debris. The lamina propria of the mucosa is infiltrated by neutrophils, plasma cells, and lymphocytes. The glands dilate and fill with mucus due to obstructed secretion, and some may even rupture. The submucosa thickens due to inflammation and mucus exudation, accompanied by vascular dilation, congestion, and thrombosis. Necrosis is generally limited to the mucosal layer, but in some cases, it may extend into the submucosa, and rarely, it may involve the entire intestinal wall, leading to perforation.
In surviving cases, the intestinal lesions tend to recover, leaving only small scars. Intestinal atrophy leading to stenosis is rare.bubble_chart Clinical Manifestations
The disease has a sudden onset, usually occurring in patients who have undergone major abdominal surgery and are on antibiotics. The earliest symptoms can appear within hours to two days after starting medication, while the latest may occur within three weeks after discontinuing the drugs. Symptoms typically manifest 4–6 days after medication use. At onset, patients suddenly experience fever, malaise, abdominal pain (sometimes severe, resembling acute abdomen), nausea, abdominal distension and fullness, and diarrhea. Diarrhea can be classified into two types: one involves large amounts of green watery stools, resembling cholera, with daily stool output reaching 4000–5000 ml, leading to massive fluid loss, dehydration, and electrolyte imbalances. This is further complicated by metabolic acidosis due to the absorption of bacterial toxins and necrotic tissue toxins. Patients often develop shock, accompanied by oliguria or even signs of renal insufficiency. The other type involves yellow-green mucous stools, occurring 3–4 times a day or up to over 10 times, with small volumes and occasional bloody stools. A few patients may pass patchy pseudomembranes, known as "tubular pseudomembranes" or "colonic tubular pseudomembranes." Diarrhea usually stops 5–8 days after discontinuing the medication, though in some cases, it may persist for 2–3 weeks or even two months.
Toxemia results from the absorption of bacterial toxins, causing fever (even high fever), tachycardia, and generalized weakness. Some patients may experience confusion, disorientation, or drowsiness. In rare cases, toxic shock, toxic megacolon, intestinal paralysis, or intestinal perforation may occur.
Literature reports indicate that without proper treatment, the mortality rate for severe cases can reach 10–40%.
Chinese medicine categorizes this condition into four types:
1. **Exuberant Dampness-Heat Type**: Due to severe dampness-heat, improper treatment leads to the accumulation of dampness-heat toxins, resulting in the binding of dampness and pathogenic heat, stagnation in the middle energizer, and the failure to separate the clear from the turbid. This causes incessant diarrhea, with dampness-heat entering the blood aspect. Symptoms include high fever, extreme thirst, epistaxis, scanty dark urine, sudden explosive diarrhea with clear or egg-drop-like watery stools. In severe cases, heat blockage internally consumes essence and scorches fluids, leading to reversal cold of limbs, mental confusion, a red tongue texture, and a wiry-rapid or thin-rapid pulse.
2. **Exuberant Heat and Yin Consumption Type**: Due to inherent yin deficiency or post-partum/post-operative qi and blood depletion, prolonged retention of dampness-pathogenic heat further damages yin-blood. Profuse diarrhea exacerbates yin exhaustion, worsening yin deficiency and intensifying toxic-heat manifestations, leading to a critical state of deficient upright qi and excessive pathogenic factors. Symptoms include persistent high fever, late afternoon tidal fever, dry mouth with or without thirst, flushed cheeks, vexing heat in the chest, palms, and soles, scanty dark urine, frequent loose stools, a red tongue texture, and a rapid pulse.
3. **Spleen Deficiency with Dampness Exuberance Type**: Due to inherent spleen deficiency, dampness-turbidity encumbers the spleen, impairing its transforming and transporting functions, causing water to rush to the large intestine and failure to separate nutrients from waste, resulting in diarrhea. Prolonged dampness infiltration and improper treatment not only deplete stomach yin but also damage spleen yang, leading to spleen deficiency with dampness exuberance and failure to separate the clear from the turbid. Symptoms include a pale complexion, mental fatigue, reluctance to speak, poor appetite, thirst without desire to drink, or fear of cold, edema, diarrhea with frequent loose stools, a white tongue coating, and a deep-thin pulse.
4. **Spleen-Kidney Deficiency and Yang Collapse Type**: Due to incessant diarrhea, yin exhaustion is inevitable, leading to yin collapse and yang detachment. Symptoms include emaciation, reversal cold of limbs, fear of cold and lethargy, abdominal distension and fullness with pain, continuous diarrhea, rectal prolapse, and in severe cases, a curled tongue and retracted scrotum, with a faint pulse on the verge of expiration.
bubble_chart Auxiliary Examination
(1) Stool Examination: Microscopic examination of stool reveals increased pus cells and white blood cells, with a positive occult blood test. Gram staining of stool smears shows a significant increase in gram-positive cocci and a decrease in gram-negative bacilli. Repeat smear examinations may be necessary to observe changes in the ratio of cocci to bacilli. If conditions permit, the harmonizing method using Clostridioides difficile antitoxin can be employed to detect the presence of Clostridioides difficile toxin in the stool. The cytotoxic effect of cell-free stool filtrates in tissue culture can be neutralized by antitoxin, aiding in diagnosis.
(2) Blood Generation and Transformation Examination: Electrolyte imbalances are often observed, including hypokalemia, hyponatremia, and hypoproteinemia. Serum albumin levels may fall below 3%, and the white blood cell count can exceed 20×109/L, predominantly consisting of neutrophils.
(3) Histological Examination: The mucous membrane is covered with a pseudomembrane composed of mucus, fibrin, necrotic cells, and polymorphonuclear leukocytes. Inflammatory areas of the intestinal mucosa show necrosis, with the deep layers of the mucosa remaining intact. However, the lamina propria is infiltrated with polymorphonuclear leukocytes, plasma cells, and lymphocytes. Thrombosis is observed in the vascular lumen.
(4) Anoscopy and Sigmoidoscopy: The mucous membrane appears congested, edematous, eroded, and ulcerated. Multiple raised patches or large, confluent gray-green or brown pseudomembranes cover the rectal and sigmoid mucosa, which is a hallmark of the disease. In severe cases, these features may overlap. Adjacent mucosa may show edema and congestion and bleeds easily upon contact. Scattered ulcers may also be seen. Pseudomembrane formation primarily affects the left colon or entire colon, with a minority of cases involving the ileocecal region.
(5) X-ray Examination: Abdominal X-ray plain films may show no specific findings but can reveal intestinal paralysis or distended loops of bowel with fluid levels. Due to colonic edema, thumb-like indentations may appear. Spontaneous megacolon may occasionally occur. Barium X-rays in early or mild cases show no specific changes, but in advanced or severe cases, increased colonic motility, thickened mucosa, spasmodic and twisted bowel loops, and mucosal ulcers may be observed. Barium enema often exacerbates the condition and is generally not recommended.
bubble_chart Treatment Measures
(1) Early diagnosis and timely treatment are extremely important for improving cure rates and reducing mortality. Once diagnosed, the original antibiotics should be discontinued immediately.
(2) Supportive therapy: Ensure adequate rest. Intravenous fluids should be administered to correct typical edema and electrolyte imbalances. Address hypoalbuminemia. In recent years, it has been found that for watery diarrhea caused by external toxins, oral glucose-saline solution can be used to replenish sodium chloride loss while correcting acidosis.
(3) Promote normal intestinal flora to inhibit Clostridioides difficile growth: Typically, 5–10 g of normal human feces is mixed with 200 mL of saline, filtered, and administered as a retention enema once or twice daily for 3–5 days. Alternatively, enemas with lactobacillus-containing milk or oral administration of vitamin C, B vitamins, folic acid, lactasin, and glutamic acid may be used.
(4) Drug therapy: Vancomycin and non-absorbable sulfonamides are effective in treating and preventing experimental hamster pseudomembranous enteritis and artificially induced pseudomembranous enteritis, rapidly eliminating Clostridioides difficile and its toxins from feces. Thus, vancomycin is the first-choice antibacterial drug, administered orally at 250–500 mg four times daily. Sulfonamides such as SG and PST are given orally at 1 g four times daily. Metronidazole is also effective in treating pseudomembranous enteritis, with an adult dose of 1.5 g daily for 10–15 days per course. Although metronidazole is rapidly absorbed in the upper digestive tract, oral administration remains clinically valuable for combating Clostridioides difficile.
Recently, some researchers have used polyvalent antitoxin against Clostridium perfringens to treat Clostridioides difficile infections with favorable results. The method involves intravenous infusion of 50,000 U in 500 mL of 5% glucose-saline twice daily. Additionally, hyperbaric oxygen therapy has been employed for this condition.
(5) Other treatments: Antispasmodics may be tried. Some reports suggest corticosteroids for severe cases, with adrenal corticosteroids used if necessary. Cholestyramine has been proposed as an option—it binds to Clostridioides difficile in the intestine and is excreted while promoting bile salt absorption in the ileum to alleviate diarrhea. The dosage is 4 g orally every 6 hours for 5 days. For refractory diarrhea with hypoalbuminemia, electrolyte imbalances, or toxic megacolon, surgical decompression with transverse colostomy may be necessary. Antidiarrheals should be avoided to prevent toxic megacolon. For postoperative severe malnutrition, intravenous hyperalimentation may be administered.
(6) Chinese medicine for this condition:
1. **Excessive Damp-Heat Type**: Treatment focuses on clearing heat and removing toxins, separating the clear and turbid. Commonly used herbs include Lonicera, Forsythia, Dandelion, Patrinia, Skullcap Root, Coptis Rhizome, Gardenia, Tokyo Violet Herb, Dyers Woad, Purple Snow Bolus, and Peaceful Palace Bovine Bezoar Pill. To invigorate blood and resolve stasis, Red Peony Root, Moutan Bark, and India Madder Root are used. For clearing heat and draining dampness, separating the clear and turbid, Coix Seed, Plantain Seed, Talc, and raw Liquorice Root are employed. To nourish yin and clear heat, promote fluid production, and protect fluids, Scrophularia Root, Snakegourd Root, and Ophiopogon Tuber are used.
2. **Excessive Heat with Yin Depletion Type**: Treatment emphasizes replenishing qi and nourishing yin, clearing heat and removing toxins, supplemented by separating the clear and turbid. Yin-nourishing herbs include Scrophularia Root, Ophiopogon Tuber, fresh Unprocessed Rehmannia Root, Dendrobium, Snakegourd Root, turtle carapace, Peony Root, Prepared Rehmannia Root, Lalang Grass Rhizome, and American Ginseng. Heat-clearing and toxin-removing herbs include Lonicera, Forsythia, Dandelion, Patrinia, Ophiopogon Tuber, and Schisandra Fruit.
3. **Spleen Deficiency with Dampness Excess Type**: Treatment focuses on strengthening the spleen and resolving dampness, ascending the lucid and descending the turbid. Commonly used spleen-invigorating and dampness-draining herbs include Tangshen, White Atractylodes Rhizome, Poria, Polyporus, Hyacinth Bean, Chinese Yam, and Alisma. Interior-warming and yang-raising herbs include Pueraria Root, Evodia Fruit, blast-fried ginger, cinnamon bark, and Nutmeg. Yin-enriching and qi-astringing herbs include Prepared Rehmannia Root, Ophiopogon Tuber, wine-processed Skullcap Root, and Gardenia. {|109|}
4. Spleen and kidney deficiency decline, yin deficiency and impending collapse type: Treatment should focus on restoring yang to save from collapse, warming and tonifying the spleen and kidney. Commonly used warming interior and restoring yang herbs include Aconite Lateral Root, Dried Ginger, and Cassia Bark. Warming the middle and strengthening the spleen herbs such as Ginseng, White Atractylodes Rhizome, Poria, Nutmeg, Evodia Fruit, Pueraria Root, etc.
Most patients can be cured after treatment. Mild cases may resolve on their own. A very small number of patients may improve with treatment but experience a recurrence of diarrhea. Severe cases, especially elderly patients after intestinal surgery, can have a mortality rate of 50-70%. In recent years, due to timely diagnosis and treatment, the mortality rate has dropped below 30%.
(1) Strictly adhere to the indications for antibiotic use to prevent misuse. The prophylactic use of antibiotics should be particularly stringent.
(2) Clindamycin is effective against Staphylococcus aureus and anaerobic Bacteroides fragilis. However, for infections caused by these bacteria, clindamycin and lincomycin should generally not be used unless other drugs are ineffective or unavailable. Ampicillin is also prone to inducing pseudomembranous colitis, which should be noted in clinical use.
(3) Clinicians must closely monitor complications arising from antibiotic use, identifying and diagnosing them early to avoid delays in treatment. If a patient develops diarrhea, the medication should be promptly discontinued, and stool examinations should be conducted. Sigmoidoscopy should be repeated if necessary, especially for patients clinically suspected of having pseudomembranous colitis or those with unexplained fever following major intestinal surgery.
(4) Bartlet suggests that patients scheduled for clindamycin or lincomycin treatment may take oral vancomycin to prevent the occurrence of pseudomembranous colitis.
