Antibiotic induced colitis, a cause of antibiotic associated diarrhea (AAD) is defined as colon inflammation following antibiotic treatment, particularly ampicillin, amoxicillin, clindamycin, second and third generation cephalosporins. The incidence of AAD varies from 5% to 39% depending on the antibiotics used where 10% of these cases may complicates into psedudomembranous colitis.1 Pseudomembranous colitis is a more severe condition of antibiotic induced colitis which is characterised by the presence of grossly pseudomembranes consisting of nodules or large plaques containing mucus, fibrin, leukocytes and epithelial cells loosely attached to the surface of the inflamed mucosa.2
Clostridium difficile is the leading causative microorganism in antibiotic induced colitis, which is 50% to 75% of the cases, or 90% to 100% of antibiotic-associated pseudomembranous colitis. It is the second most common enteric pathogens, following Camphylobacter jejuni.3 Clostridium difficle colitis normally involves hospitalized patients where 28% of hospitalized patients are infected with C. difficle.4 Incidence of C. difficile associated diarrhea (CDAD) is estimated to be 7 to 12 cases per 100,000 adult populations.1 Its mortality rate ranges from 6% to 30% when pseudomembranous colitis is present.5
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C. difficile is a gram positive, spore forming obligate anaerobic bacillus. It is an uncommon gastrointestinal flora found in the stool of only 3% of healthy population. However, it may be present in the stool of 16% to 35% of hospitalized patients, where the rate is proportional to the duration of hospitalization and use of antibiotics.5 When antibiotics are given, most of the normal gastrointestinal floras are killed. This provides more nutrients for proliferation and growth of C. difficile. Overgrowth of C. difficile release excessive exotoxins, toxin A (enterotoxin and cytotoxin), toxin B (cytotoxin) and binary toxin.1,2 Binding of toxins A to the receptors on enterocyte disrupts colonic mucosal cell, resulting in pore formation which aids endocytosis of toxins B to the damaged mucosa. These toxins cause glycosylation of Rho and Ras protein, hence depolymerisation and disruption of epithelial actin cytoskeleton. Consequently, intracellular tight junction is opened and resulting in an increase of vascular permeability, voluminous diarrhea and sometime hemorrhage.3,5,6 Cytotoxic effect of toxin B is claimed to be 1000 times more potent than toxin A.7 Besides that, toxin A also acts as a chemoattractant for neutrophils and a macrophages and mast cells activator. It stimulates tissue infiltration of neutrophils as well as production of tumour necrosis factor-alpha and inflammatory mediators such as IL-8, IL-16, leukotrienes B4 and interferon-ϒ. This inflammation response resulting in pseudomembranous formation.7,8
Symptoms of antibiotic induced colitis normally present on the first day of antibiotics treatment to 2 month after finishing antibiotics treatment. Patients infected with C. difficile may show different severity range from asymptomatic colonization to severe diarrhea, colitis, pseudomembranous colitis and fulminant colitis which may lead to toxic megacolon, colonic perforation and even death. Clinical presentation of antibiotic induced colitis include abdominal cramp, profuse diarrhea with greenish, foul-smelling and watery stools, fever and sometime bloody stools. Blood test normally shows leukocytosis (up to 40,000 white blood cells/µL) while endoscopy shows signs of oedema and erythema.1,6,9 Antibiotic induced colitis will commonly progress to pseudomembranes colitis where the pseudomembranes may coalesce to obscure colonic mucosa. Such patients normally have hypoalbuminaemia and high serum C-reactive protein.9 In cases of prolonged or severe antibiotic induced colitis, patients are at risk of dehydration, electrolyte depletion as well as hypoproteinemia.1
Fulminant colitis is a life-threatening complication present in 1% to 3% of colitis patients.8 Apart from diarrhea, severely ill patients may present with little or without diarrhea due to toxic megacolon, an acute and rapid form of colonic dilation. Toxic megacolon can be suspected in patients with radiographic evidence of colonic dilation (>7cm in its greatest diameter), three of the following symptoms, fever (>38.6°C), tachycardia (>120 beats/min), leukocytosis (>10,500 white blood cells/µL) or anemia and one of the following symptoms, dehydration, altered mental status, electrolyte abnormality or hypotension.10 Mortality reported in toxic megacolon is 24% to 38%. Moreover, colonic perforation is a dangerous medical condition which requires aggressive medical intervention. Leaking of toxins into bloodstream may cause sepsis and peritonitis which are life threatening.8
In term of diagnosis, C. difficile should be suspected in patients with history of antibiotics within 2 months of the onset of diarrhea or development of diarrhea at least 72 hours after hospital admission. When signs and symptoms present in such patients, stool culture should be performed to identify the organism in the stools. Stool cultures allowed antibiotic susceptibility testing and molecular typing. However, it is not widely available and has prolonged turnaround time of 48 hours. It also has low predictive value due to the prevalence of nonpathogenic or asymptomatic carriers. Moreover, negative result of stool culture does not exclude C. difficile infection and additional test should be performed. Other than that, further testing like cell cytotoxicity assays or enzyme linked immunosorbent assay (ELISA) should be performed as stool cultures is unable to differentiate toxin producing strains from nontoxigenic strains.3 Stool cytotoxicity assay is the gold standard diagnostic test due to its high sensitivity and specificity. However, it is time consuming (48-72hours) and expensive along with 5% to 10% false negative rate.1,3 Even though ELISA has low sensitivity where a minimum amount of 100 to 1000 pg of toxin is required to be detected and false negative rate of 10% to 20%, it is the preferred choice in considering of price, time, specificity (about 100%) and overall agreement (more than 98%).1
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Furthermore, abdominal radiographs may be performed to show mucosa oedema or bowel obstruction in order to rule out megacolon or colonic perforation. In addition, endoscopy such as sigmoidoscopy and colonoscopy can be carried out to examine the condition of colonic mucosa, range from minimal erthema or oedema to ulcerated mucosa as well as friable, granular or hemorrhagic mucosa with pseudomembranes. Endoscopy is an useful tool for immediate diagnosis and initiation of therapy before the availability of stool culture results.1 However, it is an expensive test that reserved for seriously ill patient where C. difficile diarrhea is strongly suspected but test results are delayed or shows negativity.2
2.0 Treatment options
2.1 Nonspecifec supportive therapy
Nonspecific supportive therapy includes replacement therapy with fluid and electrolytes to prevent dehydration and electrolyte imbalance. As recommended by World Health Organisation (WHO), oral rehydration salt (ORS) consists of 2.6g sodium chloride, 2.9g dehydrated trisodium citrate, 1.5g potassium chloride and 13.5g anhydrous glucose, to be dissolved in 1L of clean drinking water. Present of glucose and salt help in absorption of water from intestinal lumen.2 Moreover, antibiotics taken should be withdrawn if possible to allow host immunological system to fight the infection.5 Studies showed that 15% to 23% of patients recovered from C. difficile colitis within 48 to 72 hours of antibiotics discontinuation.5 It is important to take note that administration of antiperistalsis and medication which induce constipation such as opiate should be avoided as these may mask the patient's symptoms as well as accumulation of toxic in colon.2
2.2 Specific antibiotic therapy
Metronidazole, vancomycin, teicoplanin and fusidic acid can be used to treat colitis. Studies conducted by Weinisch et al. on 119 patients suggest that these antibiotics have similar cure rate (93% to 96%), and failure rate (4% to 7%). However, fusidic acid is reported to have higher relapse rate, 28% as well as side effects. Even though teicoplanin is as effective as vancomycin and metronidazole, its expensive cost makes it the last line in practice.11 Hence, only metronidazole and vancomycin which are commonly prescribed and licenced to treat colitis in UK will be discussed here.
Metronidazole is given orally in a dose of 800mg initially then 400mg three times daily or 500mg three times daily for 10 to 14 days for treatment of C. difficile colitis.12 Metronidazole is a prodrug which is activated by nitroreductase, an activating enzyme found in anaerobic enzyme only. The reduced metronidazole inhibits DNA replication by breaking and inhibiting repair of DNA. In a randomized, double-blind, placebo-controlled trial conducted by Zar et al, metronidazole showed very high cure rates of 98% in treating mild C. difficile infection but only 76% in severe infection. Its recurrent rate is reported to be 15%.13 Pharmacy cost for metronidazole treatment is $4.00 for a 10-day treatment course.6
Oral bioavailability of metronidazole is nearly 100%, 67% to 82% via rectal route and significantly less via intravenous injection, 5%-10%.14 Its plasma half life is around 8 hours and it is not bound to plasma protein. It distributes uniformly throughout the body and excreted unchanged or as metabolites in the urine. Generally, metronidazole is well tolerated when given for short periods. Its side effects include nausea, vomiting, abdominal distress, diarrhea and rarely it turns the urine dark or red-brown. However, it has unpleasant metallic taste which may reduce patient acceptance and the patient may also be at risk of irreversible neuropathy associated with prolonged administration.9 It causes dilsulfiram-like reaction such as abdominal cramp, vomit, flushing and headache during concomitant consumption of alcohol. Crucial drug interaction to be noticed is the potentiation effect on action of oral anticoagulants. Furthermore, a little amount of metronidazole may be oxidised to acetamide, which is found to be carcinogenic in rats, and it is able to cross the placental barrier. Therefore, its use is discouraged in the first trimester of pregnancy and children.2 In addition, IV metronidazole can be given if oral dose is not tolerated.
Vancomycin is a glycopeptides antibiotic indicated against gram positive bacteria such as C. diffile and staphylococcus aureus. For treatment of colitis, it is given in a dose of 125mg up to 500mg four times daily for 10 to 14 days depending on patient's severity.12 Vancomycin is bactericidal, it prevents binding of peptide to peptidoglycan synthetase, hence inhibiting bacterial cell wall synthesis.15 Vancomycin shows consistent cure rate of 98% and 97% in treating both mild and severe C. difficile infection respectively.13 Recurrent rate of vancomycin is 14%. Pharmacy cost for dosage of vancomycin range from $175.00 to $873.00.6 In addition, use of vancomycin is limited in consideration of development of vancomycin resistant enterococci.1
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Oral bioavailability of vancomycin is low (less that 10%), hence its oral form is indicated for treatment of colitis only. Intravenous vancomycin is not indicated for colitis due to its poor absorption into gastrointestinal lumen.16 Its elimination half life of is long, ranging from 3 to 13 hours in persons with normal renal function.15 Vancomycin is 30% to 55% protein bound. It is excreted unchanged in the urine in 24 hours suggesting that its pharmacokinetics is not alter much by liver and safe to be used in liver impairment.16 On the other hand, up to 85% of vancomycin clearance is mediated through glomerular filtration, hence dosage adjustment is required in case of impaired renal function, especially elderly.16 Due to the low oral bioavailability, vancomycin has little systemic side effects. Yet red man syndrome, characterised by flushing and erthematous rash around face and neck may present when it is given intravenously. Risk of nephrotoxicity and renal failure suggest monitoring of plasma vancomycin level regularly following vancomycin injection.12 Furthermore, concomitant use of aminoglycoside with vancomycin increases risk of ototoxicity and nephrotoxicity.17 Vancomycin can be used in pregnancy but only when the potential benefit outweighs the risk.12 If patient is unable to accept oral treatment, vancomycin given via nasogastic tube or enema can be considered.
Probiotics contain living microorganisms which bring benefit to the host when given in adequate amount. Probiotics widely used in prevention of C. difficile infection include Saccharomyces boulardii and Lactobacillus GG. S. boulardii produces protease which destructs receptor binding site for toxins A and B of C. difficile. Lactobacillus GG work by increasing immunoglubilin G and interferon release. It also releases an antimicrobial substance that suppress the growth of C. difficile.18 Gao XW et al. conducted a randomized, double-blind placebo controlled study on 255 patients. Patients were randomly divided into three groups which receiving either two probiotic capsule daily, one probiotic and one placebo capsule daily or two placebo capsules daily during antibiotic therapy and 5 days after completion of antibiotic treatment. Each probiotic capsule contained 50 billion c.f.u of live Lactobacillus GG. The incidence rate of C. difficile infection was reported to be 23.8%, 9.4% and 1.2% in placebo group, one probiotic capsule and one placebo capsule group and two probiotic capsules group respectively. Therefore, this study concluded that Lactobacillus GG reduce risk of C. difficile associated diarrhea in a dose dependent manner.19
Furthermore, in a double-blind controlled study conducted by Can M et al. on prophylactic effect of S. boulardii, 151 patients were randomly given placebo treatment or S. boulardii treatment twice daily during antibiotic therapy. Results showed that incidence of antibiotic induced diarrhea was significantly reduced (p<0.05) in treatment group (1.4%) compared to placebo group (9%).20 Surawicz CM et al suggest that administration of combination of 1g of S. boulardii and 2g of vancomycin daily for 28 days is 67% more effective than vancomycin treatment alone.21 Administration of probiotics are encouraged as they are inexpensive and very tolerable with little adverse effects, except in immunocompromised patients.7
2.4 Anion binding resins
Cholestyramine and colestipol are anion exchange resins which act by binding toxin B in the colon. Recommended dose of cholestyramine is 4g three to four times daily whereas colestipol is 5g twice daily for 1 to 2 weeks. Side effect of cholestyramine is obstipation and it binds to vancomycin as well as toxin, therefore it should be taken at least 2 to 3 hours apart from vancomycin.6 Advantage of anion exchange resins over antimicrobial therapy is it does not interfere gastrointestinal flora, hence allow quicker reconstitution of normal gastrointestinal flora. However, reported anion exchange resin showed poor efficacy toward treatment of C. difficile infection, thus limiting its use in practice.6,22
2.5 Immunoglobulin therapy
MCpherson et al conducted a study by injecting a single dose of 150-400mg/kg immune globulin intravenously into 14 patients. As a result, 6 patients reported to be response well within 10days with no relapse within timeframe reported. However, IV immune globulin has very marginal efficacy and lack of information on the optimal dose. It is also very expensive which cost arounf $1,500/ dose for a 70kg patient. This make IV immune globulin the last option for severe or relapse patients when no other therapeutic options are available.22,23
Surgery is required in 0.4 to 5% of C. difficile infection when it progresses into fulminant colitis. Patients present with sepsis, hemorrhage, toxic megacolon and perforation may be indicated for surgery treatment, colectomy. Colectomy also found to be beneficial in elderly patients (>65 year old) with leukocytosis more than 20x109/L or serum lactate between 2.2 to 4.9 mmol/L. Surgery was found to reduce in-hospital mortality rate (OR: 0.11;95% CI: 0.02-0.52). Study showed that in 36 patients underwent colectomy, 64% of the patients were discharged in good condition.6
In this scenario, patient is a 78 years old female suffers from antibiotic induced colitis. Her laboratory result reported C. difficile positive. Due to limited information about the patient, treatment is recommended from the view of different conditions. First of all, the withdrawal of her current antibiotic is strongly recommended or an alternative is suggested if discontinuation of antibiotic is not possible. ORS has to be given to prevent dehydration, especially patient is an elderly. Any antiperistalsis or medication which may induce constipation such as opiate must be stopped when the patient is having antibiotic induced colitis.
Next, patient's laboratory result suggests a C. difficile infection. Assuming patient's condition is mild, metronidazole 800mg initially then 400mg three times daily for 10 to 14 days is recommended. Rational behind choosing metronidazole over vancomycin include the efficacy, side effects and cost. Zar et al. suggest that clinical cure rate of metronidazole is similar (p=0.36) to vancomycin, 90% and 98% respectively. There is no significant different (p=0.27) in relapse rate between patients treated with metronidazole (14%) and vancomycin (7%). Frequency of side effects is similar as well, one case of gastrointestinal side effect resulting in discontinuation of treatment is reported in each group.13 Moreover, metronidazole is much more cost effective that vancomycin, $4.00 and $175.00 to $873 respectively.23 Patient on metronidazole should be advised on interaction between alcohol and anticoagulant with metronidazole. It is worth notice that prolonged administration of metronidazole is not recommended due to the risk of irreversible neuropathy.
Next, assuming patient has severe disease, administration of vancomycin 500mg four times daily for 10 to 14 days will have better efficacy than metronidazole. Patient's age is 78 year old (elder than 60 year old), she can be categorized as severe disease if her endoscopy result shows pseudomembrane or she is present with more than one of the following criteria, temperature more than 38.3°C, peripheral white cell count of more than 15,000 cells/mm3 or albumin level less than 2.5mg/dL. Studies conducted by Zar et al. showed that vancomycin (97%) has significantly higher cure rate than metronidazole (76%), p=0.02 in severe C. difficile infection. In order to limit the development of vancomycin resistantance, it is only reserved for patients who are severely ill, intolerant or fail to respond to metronidazole.
There are few more conditions to be taken into consideration before deciding the treatment regimen. 78 year old patient is at very high risk of renal impairment which may alter vancomycin's clearance. Therefore, vancomycin is best to be avoided or dosage adjustment is required if patient has renal impairment. Moreover, vancomycin would be the choice of drug if patient is present with liver impairment as it is normally excreted unchanged.
In addition, if patient's abdominal radiography shows megacolon or colonic perforation and patient is not responding to medication, colectomy should be considered. In case of frequent recurrent, combination of probiotics, 1g of S. boulardii with 2g of vancomycin daily for 28 days can be prescribed to reduced relapse of infection.