Review articles

By Ms. Win Zee Teong , Ms. Shu Wei Chee , Ms. Nor Faezah Marzuki , Ms. Nurul Nabila Amer @ Amir , Ms. Irwa Nazira Mohd Adenan , Mr. Mohd Idham Ilias , Prof. Mohd Zaini Asmawi
Corresponding Author Prof. Mohd Zaini Asmawi
Discipline of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, - Malaysia
Submitting Author Ms. Win Zee Teong
Other Authors Ms. Win Zee Teong
School of Pharmaceutical Sciences, Universiti Sains Malaysia, - Malaysia

Ms. Shu Wei Chee
School of Pharmaceutical Sciences, Universiti Sains Malaysia, - Malaysia

Ms. Nor Faezah Marzuki
School of Pharmaceutical Sciences, Universiti Sains Malaysia, - Malaysia

Ms. Nurul Nabila Amer @ Amir
School of Pharmaceutical Sciences, Universiti Sains Malaysia, - Malaysia

Ms. Irwa Nazira Mohd Adenan
School of Pharmaceutical Sciences, Universiti Sains Malaysia, - Malaysia

Mr. Mohd Idham Ilias
School of Pharmaceutical Sciences, Universiti Sains Malaysia, - Malaysia


infectious diarrhoea, antibiotic

Teong W, Chee S, Marzuki N, Amer @ Amir N, Mohd Adenan I, Ilias M, et al. Infectious Diarrhoea. WebmedCentral PHARMACEUTICAL SCIENCES 2011;2(12):WMC002686
doi: 10.9754/journal.wmc.2011.002686

This is an open-access article distributed under the terms of the Creative Commons Attribution License(CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submitted on: 18 Dec 2011 03:45:31 AM GMT
Published on: 18 Dec 2011 05:42:16 AM GMT


Diarrhoea is the passage of three or more loose or liquid stools per day, or more frequently than it is normal for the individual. It is usually a symptom of gastrointestinal tract infection caused by bacteria. Some common causing bacteria are Campylobacter, Salmonella, Shigella and Escherichia coli. These microorganisms are spread through contaminated water or food, unsanitary disposal of human waste and poor personal hygiene. Antibiotics used in the treatment of gastrointestinal tract infection are ampicillin, ceftrixone, ciprofloxacin, cotrimoxazole, a combination of trimethoprim and sulfamethoxazole; and macrolides, including erythromycin and azithromycin. The alternative treatments are fluid replacement, advice about eating and anti-diarrhoea medicines include loperamide, codeine and activated charcoal. Gastrointestinal tract infection can be prevented by improving water supplies and sanitation, hand washing with soap and consuming clean food.


Diarrhoea is greater looseness of stool or increase in the bowel frequency movements, usually three or more times a day. Diarrhoea can cause dehydration, which is a condition where the body lack of fluid and electrolytes; salts, including sodium, potassium, and chloride to function properly. Acute diarrhoea is usually caused by bacterial, viral, or parasitic infection while chronic diarrhoea is usually related to a functional disorder such as irritable bowel syndrome or an intestinal disease such as Crohn’s disease (Diarrhoea 2011). Acute diarrhoea is a common cause of death, which appears rapidly and can last up to ten days in developing countries.
Bacteria and parasites contaminate food or water, thus they are transmitted into the body. Some of the more common bacteria that may cause diarrhoea are Campylobacter, Salmonella, Shigella and Escherichia coli (E. coli). Traveler's diarrhoea is usually caused by bacteria or parasites. (Medical News Today, 2011). These microorganisms are usually spread through the contaminated water and food; unsanitary disposal of human wastes and poor personal hygiene. (WaterAid, n.d.)
Diarrhoea can be classified as non-inflammatory, inflammatory or invasive. Non-inflammatory diarrhoea is caused by enterotoxin-producing organisms such as enterotoxigenic Escherichia coli, or by viruses that adhere to the mucosa and disrupt the absorptive and/or secretory processes of the enterocyte without causing acute inflammation or mucosal destruction (Udayakumar N and Raph A.G 2008).
Inflammatory diarrhoea is caused by two groups of organisms, which are cytotoxin-producing, non-invasive bacteria (for example E. coli, Clostridium difficile) or by invasive organisms, such as Salmonella spp., Shigella spp. and Campylobacter spp.. The cytotoxin-producing organisms adhere at the mucosa and activate cytokines. Intestinal mucosa is stimulated to release inflammatory mediators. Cytotoxins produced by invasive organisms invade the intestinal mucosa to induce an acute inflammatory reaction, involving the activation of cytokines and inflammatory mediators (Udayakumar N and Raph A.G 2008).
Antibiotics treat infectious diarrhoea by targeting causative agents (bacteria) of diarrhoea; for example, ceftriaxone, erythromycin, azithromycin, ciprofloxacin, co-trimoxazole, and ampicillin.
Loperamide (Imodium®) slows down peristalsis so that more fluid and nutrients from the foods ingested can be absorbed by the small intestine (Imodium, 2011).
Codeine, which belongs to the opioids group, has a constipating effect.
Activated charcoal is one of the finest absorptive and absorptive agents known. It is able to extract and neutralize gases, heavy metals, toxins, poisons and other chemicals (Enzyme Stuff, 2001).

Antimicrobial Therapy

Ampicillin is a broad-spectrum penicillin with activity against many gram-positive and gram-negative aerobic and anaerobic bacteria.
Mechanism of action: It inhibits cell wall mucopeptide biosynthesis. Ampicillin is, however, degraded by beta-lactamases; hence the spectrum of activity does not include organisms which produce these enzymes.
Contraindications: It is contraindicated in patients with a history of hypersensitivity to any penicillin or cephalosporin and patients with infectious mononucleosis or lymphatic leukemia.
Drug interactions: Ampicillin interacts with several drugs to create unintended side effects. See Table 1 for drug interactions of ampicillin.
Side effects: Some of the common side effects that the patient might experience after taking ampicillin are: inflammation and redness of the tongue; irritation of mouth or throat; nausea; second infection and vomiting. (Wolters Kluwer Health, Inc. 2011.)
Serious and occasional fatal hypersensitivity (anaphylaxis) reactions have been reported in patients on penicillin therapy especially following parenteral administration. These reactions are more apt to occur in individuals with a history of sensitivity to multiple allergens.
Dosage: For adults and children 40 kg or over who are diagnosed with gastrointestinal infections, 500 mg of ampicillin is administered every 6 hours. Children under 40 kg should be given 50 mg/kg/day in equally divided doses at 6- to 8-hour intervals. (Children's dosage is intended for individuals whose weights will not cause a dosage to be calculated greater than that recommended for adults.)
Treatment of all infections should be continued for a minimum of 48 to 72 hours beyond the time that the patient becomes asymptomatic or evidence of bacterial eradication has been obtained. (RxMed, n.d.)
Ceftriaxone is one of the third generation members of cephalosporin which has a wide spectrum of bactericidal activity. Ceftriaxone acts as an important antibiotic in treating dysentery, most commonly caused by typhoid and non-typhoid Salmonella spp. and Shigella spp. Usage of this drug for the treatment is recommended by World Health Organization (WHO). (Silva et al, 2006)
Mechanism of Action: Ceftriaxone is mainly bactericidal and inhibits the cell wall synthesis of bacteria during the third and final stages by preventing the cross linking of peptides on the mucosaccharides chain. The cross linking of the peptides is catalyzed by enzyme transpeptidase, so ceftriaxone will bind to the active site of the enzyme by mimicking the D-alanyl-d-alanine residues that the peptides normally bind to. Ceftriaxone reacts with the serine residue in transpeptidase, thus inhibiting its activity, which result in inhibition of bacterial growth.
Ceftriaxone also interferes with transpeptidase-mediated cell wall synthesis, causing the lysis of the cell. (Gold Standard Inc, 2010)
Common side effects: Commonly, there will be a little pain and minor swelling at the injection part besides some signs of skin rashes. Some less serious side effects include nausea and vomiting, headache and stomach pain. (Finkel et al, 2009)
Dosage: The daily dosage of ceftriaxone depends on the severity of the infection as well as the age of the patient. See Table 3.
The dosage regimen can go up to 4g/day depending on the drug response. The duration of ceftriaxone therapy should be continued in the range of 48-72 hours after being detected.
Patients with mild to moderate renal impairment do not require dosage adjustment, but half-life is increased to 10-12 hours. Dosage adjustment is very important to be monitored in severe renal failure patients, whereby the dosage should not exceed 2 g/day. Ceftriaxone cannot be removed by haemodialysis, therefore it needs close monitoring and dosage adjustment.
Dosage adjustment is not required for pregnant mothers. Studies show that children born to mothers who take ceftriaxone during pregnancy shows normal growth development. (Gold Standard Inc, 2010; Bourget et al, 1993)
Mechanism of resistance: There are a few reported cases about ceftriaxone-resistant Salmonella in the United States and the number is increasing each year. Resistance to ceftriaxone occurs due to expression of β-lactamase mediated by a transferable AmpC plasmid.(Dunne et al, 2000) Other choice of drug for treatment of Salmonellosis and Shigellosis is fluoroquinolones such as ciprofloxacin. (Arpimed Pharmaceutical Company, 2010; Bourget et al, 1993)
Ciprofloxacin is a fluoroquinolone structurally related to nalidixic acid.
Mechanism of action: The primary mechanism of action of ciprofloxacin is inhibition of the activity of the A subunit of DNA gyrase. Inhibition of bacterial gyrase causes relaxation of the supercoiled DNA. These changes lead to termination of chromosomal replication and to interference with cell division and gene expression.
A secondary mechanism, inhibition of the activity of topoisomerase IV, leads to separation of 2 united DNA molecules and subsequent interference with cellular replication.
Ciprofloxacin has been shown to kill bacteria in both growth and stationary phases. This may provide an advantage over other classes of antibiotics such as β-lactams, which are not bactericidal when bacteria are in the stationary phase of growth or growing slowly.
Mechanisms of resistance: Ciprofloxacin does not cross-react with other antimicrobial agents such as β-lactams or aminoglycosides; therefore, organisms resistant to these drugs may be susceptible to ciprofloxacin.
Drug interaction: Interaction of ciprofloxacin with theophylline may lead to elevated serum concentrations of theophylline and prolongation of its elimination half-life, which may increase the risk of theophylline adverse reactions.
Concomitant administration with multivalent cation-containing products will decrease absorption of ciprofloxacin, resulting in serum and urine levels considerably lower than desired.
Ampicillin will reduce clearance of caffeine, thus prolonging its serum half-life. (Diniz-Santos et al, 2006)
Mechanism of resistance: Ciprofloxacin resistance occurs both by mutation in the A subunit of DNA gyrase and by alteration of drug permeation through the outer membrane of the bacterial cell, that is a decreased amount of porin channel on the outer membrane of the bacteria. (, 2011)
Azithromycin is a treatment alternative for those who should not receive fluoroquinolones (e.g., children, pregnant women) and may be a drug of choice for travellers in areas with a high prevalence of fluoroquinolone-resistant Campylobacter (e.g., Thailand, India) or those who have not responded after 48 hours of fluoroquinolone treatment.
Rifaximin is another alternative for treatment of travellers’ diarrhea caused by non-invasive E. coli. (Netdoctor, 2011)
Dosage: The duration of treatment depends upon the severity of infection. For adults, ciprofloxacin should be administered at least 2 hours before or 6 hours after magnesium/aluminum antacids, sucralfate, didanosine chewable/buffered tablets or pediatric powder for oral solution, other highly buffered drugs, or other products containing calcium, iron or zinc. For infectious diarrhoea, the dose is 500mg every 12 hours, taken usually for 5 to 7 days.
For adults with renal insufficiency, modification of dosage is recommended. This is because ciprofloxacin is eliminated primarily by renal excretion. Refer to Table 4 for the respective dosing.
In patients with severe infections and severe renal impairment, a unit dose of 750 mg may be administered at the intervals noted above. Patients should be carefully monitored.
Ciprofloxacin is not recommended for use in pregnancy because it can cause joint disease in immature animals and may therefore have this effect in humans.
Ciprofloxacin passes into breast milk. It is not recommended for use during breastfeeding, as there are usually safer alternative antibiotics available. (NetDoctor, 2011)
Side effects: Most of the adverse events reported were described as only mild or moderate in severity, abated soon after the drug was discontinued, and required no treatment. Ciprofloxacin is discontinued because of severe adverse events in 1% of orally treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all dosages, all drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%),liver function tests abnormal (1.3%), vomiting (1%), and rash (1%).
Some of the medically important events that occurred in less than 1% of ciprofloxacin patients are for example palpitation, hallucinations, renal failure, phototoxicity and hearing loss.
Co-trimoxazole is a fixed combination sulfonamide antibiotic product of trimethoprim and sulfamethoxazole, in the ration of 1 to 5. It can be used in treatment of salmonellosis and shigellosis.
Mechanism of action: Co-trimoxazole exhibits the synergistic actions of its components, trimethoprim and sufamethoxazole by ten-fold. Sulfamethoxazole inhibit the formation of dihydrofolic acid from p-aminobenzoic acid (PABA) in the folic acid synthesis pathway. Sulfamethoxazole compete with the natural substrate PABA causing depletion of dihydrofolate (DHF) and subsequent inhibition. Sulfamethoxazole condenses with the 2-amino-4-hydroxy-6-hydroxymethyl-7,8-dihydropteridine pyrophosphate (DHPPP) forming sulfa-dihydropteroate (sulfa-GHP) instead of 7,8 -dihydropteroate. (Patel et al, 2003) Trimethoprim inhibits the reaction of dihydrolic acid to tetrahydrofolic acid, by preventing the action of enzyme dihydrofolate reductase. They inhibit successive steps in the folate synthesis pathway; therefore the effect is greater when given together. (MIMS USA, 2011)
Folic acid is an essential precursor in the de novo synthesis of the DNA nucleosides thymidine and uridinie. Bacteria depend on de novo synthesis of folic acid because bacteria are unable to take up folic acid from the environment. Inhibition of the enzyme needed in folic acid synthesis nterferes DNA replication and transcription of bacteria. (See Figure 1)
Mechaism of resistance: Some salmonella and shigella strains are resistant towards co-trimoxazole. The resistance is due to mutation of the chromosomal DHPS gene in bacteria plasmid. (Ha Vinh et al, 2009) The mutation is involved in the binding of hydrogen to the 4-amino group of trimethoprim. It disrupts the bond with trimetroprim without affecting the binding of DHPS. Production of tetrafolates continues normally in the presence of trimethoprim. (Schmitz et al, 2001) Ciprofloxacin or other fluoroquinolones are the drug of choice for therapy of Shigella and Salmonella infections in both adults and children if resistance occurs. A study shows that 100% of Salmonella spp were sensitive to ciprofloxacin and ceftizoxime. Meanwhile, 54% showed resistance to co-trimoxazole. (Najafi, 2001)
Contraindications: Co-trimoxazole is contraindicated to patients sensitive to co-trimoxazole or sulfonamides. Other medical conditions contraindicated with co-trimoxazole are: pregnant women; nursing mothers; women prior to delivery (danger of producing kernicterus in the infant); folic acid deficiency; patients who receive anticonvulsant medicines (Vancouver General Hospital, 2004); and porphyria.
Dosage: Co-trimoxazole tablet normally contains 80mg of trimethoprim and 400mg of sulfamethoxazole. Adult and children above twelve are given two tablets twice a day after meals or three tablets twice a day in severe cases, which is the maximum dose. The dosage for children from six to twelve years old is one tablet twice a day, after meals. (South African Electronic Packaging Insert, 2004) Dosage for children over two months old is combination of 8mg/kg of trimethoprim and 40mg/kg of sulfamethoxazole a day in two divided doses for 5 days in shigellosis and salmonellosis treatment. (McAuley, 2011)
Patients with impaired hepatic function/ creatinine clearance rate lower than 15mL/min require lower doses. During prolonged therapy, monitoring of blood test or haematological investigation is required. (, 2011)
Side effects: The side effects of cotrimoxazole include nausea, vomiting, headache, dizziness, drug fever and skin rashes. Bone marrow depression and blood disorders including agranulocytosis, aplastic anaemia and thrombocytopenia can occur.
Macrolides (Erythromycin, azithromycin)
Mechanism of action: Erythromycin and azithromycin are members of macrolides; hence they share the same mechanism of action.
Erythromycin binds to 23S of rRNA molecule of bacterial ribosome, inhibiting the process of protein synthesis and thus preventing the exit of growing peptide chain. 23S subunit is located in the 50S subunit, both of which are absent in mammalian ribosomal subunit. The incorporation of erythromycin and ribosome is reversible and only occurs when the 50S subunit is free from tRNA molecules. (Ophardt, 2003) Transpeptidation, translocation, chain elongation and bacterial protein synthesis are thus inhibited.
The only difference of azithromycin (figure 2) from erythromycin (figure 3) is that it has 15 membered ring and methyl-substituted nitrogen while erythromycin contains 14 member macrocyclic lactone ring to which are attached two sugar moieties, dosamine and cladinose. This characteristic makes azithromycin more acid-stable, thus improving its oral absorption, tolerance and pharmacokinetic properties. (Graziani, 2011)
Mechanism of resistance: Acquired resistance towards erythromycin occur when components of ribosomal RNA undergo mutation, thus causing failure of the drug to bind to the subunits.
Treatment: Campylobacter jejuni causes acute inflammatory diarrhoea. The microorganism is susceptible to both erythromycin and azithromycin. Usage of erythromycin as a treatment to infection caused by C. jejuni is shown to hasten the removal of microorganism from the stools; however both drugs do not affect the duration of illness.
From the susceptibility data, erythromycin and other macrolides, including azithromycin, remain as the first choice of drug in C. jejuni treatment. So far there are no macrolide-resistance cases reported for Campylobacter strain. (, 2010)
Dosage: In order to treat C. jejuni, erythromycin is given to patients during fasting condition, which is at least half an hour or, more preferably, two hours before meals. For adults, 250 mg of erythromycin tablet is given four times daily in equal interval time. It also can be administered by giving 1 tablet of 500 mg erythromycin every 12 hours. The severity of the infection will determine the appropriate dosage required by the patient. The maximum dose is 4g per day. For children, the age, weight and severity of infection need to be considered in order to determine the appropriate dose. The usual dose is 30 to 50 mg/kg/day in equally divided dose. However in more severe infection the dose can be doubled but not exceeding 4 g per day.
Administration of azithromycin is the same with erythromycin. For adults, azithromycin is administered with 500mg-2g given in multiple or single doses. Normally azithromycin is taken once daily for short course treatment (3 days).
Dosage adjustment for patients with renal and hepatic insufficiencies differs among macrolides. For erythromycin, liver is the main site where it will be metabolised. No dosage adjustments are required for those who have normal renal function. However, incidence of erythromycin-induced hearing loss is seen to appear in patients with renal and hepatic insufficiency. This condition goes to usage of azithromycin as well. However there is no recommended dose adjustment.
Side effects: Some patients will experience nausea, vomiting, stomach pain, fatigue, dark urine, yellowing eyes or skin, hearing problems and muscle weakness. Severe allergic reactions are very rare. Some of the symptoms include rash, severe dizziness, difficulty in breathing and itching or swelling especially of the face/tongue/throat.


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WebmedCentral Article: Infectious Diarrhoea

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