Clinical Pharmacology And Prescribing For Antibiotic Induced Colitis Biology Essay
Antibiotic induced inflammatory bowel disease, a cause of antibiotic associated diarrhoea ( AAD ) is defined as colon redness following antibiotic intervention, peculiarly Principen, Amoxil, clindamycin, 2nd and 3rd coevals Mefoxins. The incidence of AAD varies from 5 % to 39 % depending on the antibiotics used where 10 % of these instances may perplex into psedudomembranous colitis.1 Pseudomembranous inflammatory bowel disease is a more terrible status of antibiotic induced inflammatory bowel disease which is characterised by the presence of grossly pseudomembranes dwelling of nodules or big plaques incorporating mucous secretion, fibrin, leucocytes and epithelial cells slackly attached to the surface of the inflamed mucosa.2Clostridium difficile is the taking causative micro-organism in antibiotic induced inflammatory bowel disease, which is 50 % to 75 % of the instances, or 90 % to 100 % of antibiotic-associated pseudomembranous inflammatory bowel disease.
It is the 2nd most common enteral pathogens, following Camphylobacter jejuni.3 Clostridium difficle inflammatory bowel disease usually involves hospitalized patients where 28 % of hospitalized patients are infected with C. difficle.4 Incidence of C. difficile associated diarrhoea ( CDAD ) is estimated to be 7 to 12 instances per 100,000 grownup populations.
1 Its mortality rate ranges from 6 % to 30 % when pseudomembranous inflammatory bowel disease is present.5C. difficile is a gram positive, spore organizing obligate anaerobiotic B. It is an uncommon GI vegetation found in the stool of merely 3 % of healthy population. However, it may be present in the stool of 16 % to 35 % of hospitalized patients, where the rate is relative to the continuance of hospitalization and usage of antibiotics.5 When antibiotics are given, most of the normal GI vegetations are killed. This provides more foods for proliferation and growing of C. difficile.
Overgrowth of C. difficile release inordinate 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, ensuing in pore formation which aids endocytosis of toxins B to the damaged mucous membrane. These toxins cause glycosylation of Rho and Ras protein, hence depolymerisation and break of epithelial actin cytoskeleton. Consequently, intracellular tight junction is opened and ensuing in an addition of vascular permeableness, voluminous diarrhoea and sometime hemorrhage.3,5,6 Cytotoxic consequence of toxin B is claimed to be 1000 times more powerful than toxin A.
7 Besides that, toxin A besides acts as a chemoattractant for neutrophils and a macrophages and mast cells activator. It stimulates tissue infiltration of neutrophils every bit good as production of tumour mortification factor-alpha and inflammatory go-betweens such as IL-8, IL-16, leukotrienes B4 and interferon-? . This redness response ensuing in pseudomembranous formation.7,8Symptoms of antibiotic induced inflammatory bowel disease usually present on the first twenty-four hours of antibiotics intervention to 2 month after completing antibiotics intervention. Patients infected with C. difficile may demo different badness scope from symptomless colonisation to severe diarrhoea, inflammatory bowel disease, pseudomembranous inflammatory bowel disease and fulminant inflammatory bowel disease which may take to toxic megacolon, colonic perforation and even decease. Clinical presentation of antibiotic induced inflammatory bowel disease include abdominal spasm, profuse diarrhoea with light-green, fetid and watery stools, febrility and sometime bloody stools. Blood trial usually shows leucocytosis ( up to 40,000 white blood cells/µL ) while endoscopy shows marks of hydrops and erythema.
1,6,9 Antibiotic induced inflammatory bowel disease will normally come on to pseudomembranes inflammatory bowel disease where the pseudomembranes may blend to befog colonic mucous membrane. Such patients usually have hypoalbuminaemia and high serum C-reactive protein.9 In instances of drawn-out or terrible antibiotic induced inflammatory bowel disease, patients are at hazard of desiccation, electrolyte depletion every bit good as hypoproteinemia.
1Fulminant inflammatory bowel disease is a dangerous complication nowadays in 1 % to 3 % of inflammatory bowel disease patients.8 Apart from diarrhoea, badly sick patients may show with small or without diarrhoeas due to toxic megacolon, an ague and rapid signifier of colonic dilation. Toxic megacolon can be suspected in patients with radiographic grounds of colonic dilation ( & A ; gt ; 7cm in its greatest diameter ) , three of the undermentioned symptoms, febrility ( & A ; gt ; 38.6 & A ; deg ; C ) , tachycardia ( & A ; gt ; 120 beats/min ) , leucocytosis ( & A ; gt ; 10,500 white blood cells/µL ) or anaemia and one of the undermentioned symptoms, desiccation, altered mental position, electrolyte abnormalcy or hypotension.10 Mortality reported in toxic megacolon is 24 % to 38 % . Furthermore, colonic perforation is a unsafe medical status which requires aggressive medical intercession. Leaking of toxins into blood stream may do sepsis and peritoneal inflammation which are life threatening.8In term of diagnosing, C.
difficile should be suspected in patients with history of antibiotics within 2 months of the oncoming of diarrhoea or development of diarrhoea at least 72 hours after hospital admittance. When marks and symptoms present in such patients, stool civilization should be performed to place the being in the stools. Stool cultures allowed antibiotic susceptibleness testing and molecular typewriting. However, it is non widely available and has prolonged turnaround clip of 48 hours.
It besides has low prognostic value due to the prevalence of nonpathogenic or symptomless bearers. Furthermore, negative consequence of stool civilization does non except C. difficile infection and extra trial should be performed. Other than that, farther proving like cell cytotoxicity assays or enzyme linked immunosorbent check ( ELISA ) should be performed as stool civilizations is unable to distinguish toxin bring forthing strains from nontoxigenic strains.3 Stool cytotoxicity check is the gilded criterion diagnostic trial due to its high sensitiveness and specificity. However, it is clip devouring ( 48-72hours ) and expensive along with 5 % to 10 % false negative rate.1,3 Even though ELISA has low sensitiveness where a minimal sum of 100 to 1000 pg of toxin is required to be detected and false negative rate of 10 % to 20 % , it is the preferable pick in sing of monetary value, clip, specificity ( about 100 % ) and overall understanding ( more than 98 % ) .
1Furthermore, abdominal radiogram may be performed to demo mucosa hydrops or intestine obstructor in order to govern out megacolon or colonic perforation. In add-on, endoscopy such as sigmoidoscopy and colonoscopy can be carried out to analyze the status of colonic mucous membrane, scope from minimum erthema or hydrops to cankerous mucous membrane every bit good as crumbly, farinaceous or haemorrhagic mucous membrane with pseudomembranes. Endoscopy is an utile tool for immediate diagnosing and induction of therapy before the handiness of stool civilization results.1 However, it is an expensive trial that reserved for earnestly sick patient where C. difficile diarrhoea is strongly suspected but test consequences are delayed or shows negativity.2
2.0 Treatment options
2.1 Nonspecifec supportive therapy
Nonspecific supportive therapy includes replacing therapy with fluid and electrolytes to forestall desiccation and electrolyte instability.
As recommended by World Health Organisation ( WHO ) , unwritten rehydration salt ( ORS ) consists of 2.6g Na chloride, 2.9g dehydrated trisodium citrate, 1.5g K chloride and 13.5g anhydrous glucose, to be dissolved in 1L of clean imbibing H2O. Present of glucose and salt aid in soaking up of H2O from enteric lumen.2 Furthermore, antibiotics taken should be withdrawn if possible to let host immunological system to contend the infection.
5 Studies showed that 15 % to 23 % of patients recovered from C. difficile inflammatory bowel disease within 48 to 72 hours of antibiotics discontinuation.5 It is of import to take note that disposal of antiperistalsis and medicine which induce irregularity such as opiate should be avoided as these may dissemble the patient ‘s symptoms every bit good as accretion of toxic in colon.2
2.
2 Specific antibiotic therapy
Metronidazole, Vancocin, teicoplanin and fusidic acid can be used to handle inflammatory bowel disease. Surveies conducted by Weinisch et Al. on 119 patients suggest that these antibiotics have similar remedy rate ( 93 % to 96 % ) , and failure rate ( 4 % to 7 % ) . However, fusidic acid is reported to hold higher backsliding rate, 28 % every bit good as side effects. Even though teicoplanin is every bit effectual as Vancocin and Flagyl, its expensive cost makes it the last line in practice.11 Hence, merely Flagyl and Vancocin which are normally prescribed and licenced to handle inflammatory bowel disease in UK will be discussed here.
2.2.
1 Metronidazole
Metronidazole is given orally in a dosage of 800mg ab initio so 400mg three times daily or 500mg three times daily for 10 to 14 yearss for intervention of C. difficile colitis.12 Metronidazole is a prodrug which is activated by nitroreductase, an triping enzyme found in anaerobiotic enzyme merely. The decreased Flagyl inhibits DNA reproduction by interrupting and suppressing fix of DNA.
In a randomised, double-blind, placebo-controlled test conducted by Zar et Al, Flagyl showed really high remedy rates of 98 % in handling mild C. difficile infection but merely 76 % in terrible infection. Its recurrent rate is reported to be 15 % .13 Pharmacy cost for metronidazole intervention is $ 4.00 for a 10-day intervention course.
6Oral bioavailability of Flagyl is about 100 % , 67 % to 82 % via rectal path and significantly less via endovenous injection, 5 % -10 % .14 Its plasma half life is around 8 hours and it is non bound to plasma protein. It distributes uniformly throughout the organic structure and excreted unchanged or as metabolites in the piss. Generally, Flagyl is good tolerated when given for short periods. Its side effects include sickness, purging, abdominal hurt, diarrhoea and seldom it turns the urine dark or red-brown. However, it has unpleasant metallic gustatory sensation which may cut down patient credence and the patient may besides be at hazard of irreversible neuropathy associated with drawn-out administration.9 It causes dilsulfiram-like reaction such as abdominal spasm, puke, blushing and concern during attendant ingestion of intoxicant. Crucial drug interaction to be noticed is the potentiation consequence on action of unwritten decoagulants.
Furthermore, a small sum of Flagyl may be oxidised to acetamide, which is found to be carcinogenic in rats, and it is able to traverse the placental barrier. Therefore, its usage is discouraged in the first trimester of gestation and children.2 In add-on, IV Flagyl can be given if unwritten dosage is non tolerated.
2.
2.2 Vancomycin
Vancomycin is a glycopeptides antibiotic indicated against gm positive bacteriums such as C. diffile and staphylococci aureus. For intervention of inflammatory bowel disease, it is given in a dosage of 125mg up to 500mg four times daily for 10 to 14 yearss depending on patient ‘s severity.
12 Vancomycin is disinfectant, it prevents binding of peptide to peptidoglycan synthetase, therefore suppressing bacterial cell wall synthesis.15 Vancomycin shows consistent remedy rate of 98 % and 97 % in handling both mild and terrible C. difficile infection respectively.
13 Recurrent rate of Vancocin is 14 % . Pharmacy cost for dose of vancomycin scope from $ 175.00 to $ 873.00.6 In add-on, usage of Vancocin is limited in consideration of development of Vancocin immune enterococci.1Oral bioavailability of Vancocin is low ( less that 10 % ) , therefore its unwritten signifier is indicated for intervention of inflammatory bowel disease merely. Intravenous Vancocin is non indicated for inflammatory bowel disease due to its hapless soaking up into GI lumen.
16 Its riddance half life of is long, runing from 3 to 13 hours in individuals with normal nephritic function.15 Vancomycin is 30 % to 55 % protein edge. It is excreted unchanged in the piss in 24 hours proposing that its pharmacokinetics is non alter much by liver and safe to be used in liver impairment.16 On the other manus, up to 85 % of vancomycin clearance is mediated through glomerular filtration, therefore dose accommodation is required in instance of impaired nephritic map, particularly elderly.16 Due to the low unwritten bioavailability, Vancocin has small systemic side effects. Yet ruddy adult male syndrome, characterised by blushing and erthematous roseola around face and cervix may show when it is given intravenously.
Hazard of nephrotoxicity and nephritic failure suggest monitoring of plasma vancomycin degree on a regular basis following Vancocin injection.12 Furthermore, accompaniment usage of aminoglycoside with Vancocin additions hazard of ototoxicity and nephrotoxicity.17 Vancomycin can be used in gestation but merely when the possible benefit outweighs the risk.
12 If patient is unable to accept unwritten intervention, vancomycin given via nasogastic tubing or clyster can be considered.
2.3 Probiotics
Probiotics contain populating micro-organisms which bring benefit to the host when given in equal sum. Probiotics widely used in bar of C. difficile infection include Saccharomyces boulardii and Lactobacillus GG. S. boulardii green goodss peptidase which destructs receptor adhering site for toxins A and B of C.
difficile. Lactobacillus GG work by increasing immunoglubilin G and interferon release. It besides releases an antimicrobic substance that suppress the growing of C. difficile.18 Gao XW et Al. conducted a randomized, double-blind placebo controlled survey on 255 patients. Patients were indiscriminately divided into three groups which having either two probiotic capsule daily, one probiotic and one placebo capsule daily or two placebo capsules daily during antibiotic therapy and 5 yearss after completion of antibiotic intervention. Each probiotic capsule contained 50 billion c.
f.u of unrecorded 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 severally. Therefore, this survey concluded that Lactobacillus GG cut down hazard of C. difficile associated diarrhoea in a dose dependant manner.
19Furthermore, in a double-blind controlled survey conducted by Can M et Al. on contraceptive consequence of S. boulardii, 151 patients were indiscriminately given placebo intervention or S.
boulardii intervention twice daily during antibiotic therapy. Consequences showed that incidence of antibiotic induced diarrhoea was significantly reduced ( P & A ; lt ; 0.05 ) in intervention group ( 1.4 % ) compared to placebo group ( 9 % ) .20 Surawicz CM et Al suggest that disposal of combination of 1g of S. boulardii and 2g of vancomycin day-to-day for 28 yearss is 67 % more effectual than vancomycin intervention alone.21 Administration of probiotics are encouraged as they are cheap and really tolerable with small inauspicious effects, except in immunocompromised patients.
7
2.4 Anion binding rosins
Cholestyramine and colestipol are anion exchange rosins which act by adhering toxin B in the colon. Recommended dosage of cholestyramine is 4g three to four times day-to-day whereas colestipol is 5g twice daily for 1 to 2 hebdomads. Side consequence of cholestyramine is obstipation and it binds to vancomycin every bit good as toxin, therefore it should be taken at least 2 to 3 hours apart from vancomycin.6 Advantage of anion exchange resins over antimicrobic therapy is it does non interfere GI vegetations, therefore allow quicker reconstitution of normal GI vegetation. However, reported anion exchange rosin showed hapless efficaciousness toward intervention of C. difficile infection, therefore restricting its usage in practice.
6,22
2.5 Immunoglobulin therapy
MCpherson et al conducted a survey by shooting a individual dosage of 150-400mg/kg immune globulin intravenously into 14 patients. As a consequence, 6 patients reported to be response good within 10days with no backsliding within timeframe reported. However, IV immune globulin has really fringy efficaciousness and deficiency of information on the optimum dosage.
It is besides really expensive which cost arounf $ 1,500/ dosage for a 70kg patient. This brand IV immune globulin the last option for terrible or relapse patients when no other curative options are available.22,23
2.6 Surgery
Surgery is required in 0.4 to 5 % of C. difficile infection when it progresses into fulminant inflammatory bowel disease.
Patients present with sepsis, bleeding, toxic megacolon and perforation may be indicated for surgery intervention, colectomy. Colectomy besides found to be good in aged patients ( & A ; gt ; 65 twelvemonth old ) with leucocytosis more than 20×109/L or serum lactate between 2.2 to 4.
9 mmol/L. Surgery was found to cut down in-hospital mortality rate ( OR: 0.11 ; 95 % CI: 0.02-0.52 ) . Survey showed that in 36 patients underwent colectomy, 64 % of the patients were discharged in good condition.
6
Treatment recommendation
In this scenario, patient is a 78 old ages old female suffers from antibiotic induced inflammatory bowel disease. Her research lab consequence reported C. difficile positive. Due to limited information about the patient, intervention is recommended from the position of different conditions. First of wholly, the backdown of her current antibiotic is strongly recommended or an option is suggested if discontinuance of antibiotic is non possible. ORS has to be given to forestall desiccation, particularly patient is an aged. Any antiperistalsis or medicine which may bring on irregularity such as opiate must be stopped when the patient is holding antibiotic induced inflammatory bowel disease.Following, patient ‘s research lab consequence suggests a C.
difficile infection. Assuming patient ‘s status is mild, metronidazole 800mg ab initio so 400mg three times daily for 10 to 14 yearss is recommended. Rational behind taking Flagyl over vancomycin include the efficaciousness, side effects and cost. Zar et Al. suggest that clinical remedy rate of Flagyl is similar ( p=0.36 ) to vancomycin, 90 % and 98 % severally. There is no important different ( p=0.27 ) in backsliding rate between patients treated with Flagyl ( 14 % ) and Vancocin ( 7 % ) .
Frequency of side effects is similar every bit good, one instance of GI side consequence ensuing in discontinuance of intervention is reported in each group.13 Furthermore, Flagyl is much more cost effectual that Vancocin, $ 4.00 and $ 175.00 to $ 873 respectively.23 Patient on Flagyl should be advised on interaction between intoxicant and decoagulant with Flagyl. It is deserving notice that drawn-out disposal of Flagyl is non recommended due to the hazard of irreversible neuropathy.
Following, presuming patient has terrible disease, disposal of vancomycin 500mg four times daily for 10 to 14 yearss will hold better efficaciousness than Flagyl. Patient ‘s age is 78 twelvemonth old ( elder than 60 twelvemonth old ) , she can be categorized as terrible disease if her endoscopy consequence shows pseudomembrane or she is present with more than one of the undermentioned standards, temperature more than 38.3 & A ; deg ; C, peripheral white cell count of more than 15,000 cells/mm3 or albumin degree less than 2.5mg/dL.
Surveies conducted by Zar et Al. showed that Vancocin ( 97 % ) has significantly higher remedy rate than Flagyl ( 76 % ) , p=0.02 in terrible C. difficile infection. In order to restrict the development of Vancocin resistantance, it is merely reserved for patients who are badly sick, intolerant or fail to react to metronidazole.
There are few more conditions to be taken into consideration before make up one’s minding the intervention regimen. 78 twelvemonth old patient is at really high hazard of nephritic damage which may change Vancocin ‘s clearance. Therefore, Vancocin is best to be avoided or dosage accommodation is required if patient has nephritic damage. Furthermore, Vancocin would be the pick of drug if patient is present with liver damage as it is usually excreted unchanged.In add-on, if patient ‘s abdominal skiagraphy shows megacolon or colonic perforation and patient is non reacting to medicine, colectomy should be considered.
In instance of frequent recurrent, combination of probiotics, 1g of S. boulardii with 2g of vancomycin day-to-day for 28 yearss can be prescribed to cut down backsliding of infection.
