GIS28 Antibacterial Treatment Of Enteric Infections Flashcards
Enteric infections
- acute diarrhoea caused by microbial enteropathogens
—> often self-limiting
—> fluid / electrolyte replacement
—> antimicrobial therapy: reduce severity and duration
Time of onset:
- acute: <2 weeks
- persistent: 2-4 weeks
- chronic: >4 weeks
Types of stool:
- watery diarrhoea
- dysentery (invasive diarrhoea)
Severity of diarrhoea
Mild:
- <=3 unformed stool/day
- minimal associated symptoms
Moderate:
- >=4 unformed stool/day
- systemic symptoms
Severe:
- >=6 unformed stool/day
- fever
- systemic symptoms
Mechanisms of diarrhoea
- ***Secretory: H2O secretion > H2O absorption due to toxins
- ***Osmotic: excessive solute in the gut lumen —> H2O can’t be absorbed e.g. lactose intolerance
- ***Infectious / inflammatory: epithelial destruction, loss of absorptive capacity
—> bacterial: do not use anti-motility drugs
Bacteria that cause diarrhoea
- Vibrio cholera
- Shigella
- Escherichia coli
- Salmonella
- Campylobacter jejuni
- Staphylococcus aureus
- Bacillus cereus (food poisoning)
- Clostridium difficile (food poisoning)
Subtypes of E. coli
- Enterotoxigenic (ETEC)
—> 2 toxins —> watery diarrhoea
- traveller’s diarrhoea - Enteropathogenic (EPEC)
—> watery diarrhoea
- infantile diarrhoea (in nurseries) - Enterohaemorrhagic / verocytotoxigenic / Shiga toxin-producing (EHEC / VTEC / STEC)
—> person-to-person transmission in day care setting
- haemorrhagic colitis (bloody diarrhoea)
- haemolytic uraemic syndrome
- thrombotic thrombocytopenic purpura - Enteroinvasive (EIEC)
—> developing world
- dysentery - Enteroaggregative (EAggEC)
- diarrhoea in adults and children - Diffusely adherent (DAEC)
- diarrhoea in children
Medically important diarrhoea
- ***community outbreaks
- ***inflammatory, blood diarrhoea
- severe volume depletion
- ***high fever
- severe abdominal pain
- duration > 4-5 days
- impaired host (e.g. HIV)
Cholera
Life-threatening watery diarrhoea
- due to cholera toxin by vibrio cholerae
- in faecally contaminated food / water
Treatment:
1. Oral Rehydration Salts (ORS fluid replacement)
- Short course ***broad spectrum antibiotics for severe cases
- Fluoroquinolones (ciprofloxacin)
- Co-trimoxazole (trimethoprim + sulfamethoxazole)
- Tetracycline (doxycycline)
- Macrolide (azithromycin) - Vaccination
Salmonella infection / Salmonellosis
Contaminated food / drink
Symptoms:
- within 12-72 hours: N+V, fever, diarrhoea, abdominal cramps
- 4-7 days: mild to severe symptoms, most recover without treatment
- severe case: break through intestinal wall to bloodstream
Typhoid fever:
***Broad-spectrum antibiotics (depend on resistance pattern)
- Fluoroquinolones (Ciprofloxacin)
- Co-trimoxazole
- 3rd gen Cephalosporin (Ceftriaxone)
- Penicillins (amoxicillin, ampicillin)
Non-typhoid salmonella gastroenteritis
- antibiotics NOT required unless severe
Shigellosis
Self-limiting
Treatment:
1. Oral rehydration / IV fluid replacement
2. Antibiotic required ONLY in dysentery
- Fluoroquinolones
- 3rd gen Cephalosporin
- ampicillin / co-trimoxazole (few bacteria still sensitive because of resistance)
Campylobacter gastroenteritis
- diarrhoea / dysentery mild and self-limiting
- abdominal pain and fever
Treatment:
- Macrolide (used in severe)
- Fluoroquinolones (increasing frequencies of resistance) / other broad-spectrum antibiotics
Traveller’s diarrhoea
- change in climate, social conditions, sanitation standards and facilities
- diarrhoea likely within 2-10 days
- usually due to ETEC
Treatment:
1. Oral rehydration
2. Broad spectrum antibiotics for 3-5 days (↓ severity and duration)
—> Co-trimoxazole (1st choice)
—> Fluoroquinolone
—> 3rd gen Cephalosporin
Antibiotic-associated diarrhoea
- Majority due to overgrowth of C. difficile in the gut
- Clostridium difficile toxin produces
—> water diarrhoea
—> pseudomembranous colitis
Treatment:
1. Metronidazole
2. Oral vancomycin
Drugs used in the treatment of enteric infections
- β-lactam (penicillins, cephalosporins)
- Fluoroquinolones (ciprofloxacin)
- Co-trimoxazole
- Macrolides (erythromycin, azithromycin)
- Tetracycline (doxycycline)
- Metronidazole
- Vancomycin
Vancomycin
- ***Glycopeptide
- almost completely excreted in urine
- renal failure: dosage adjustment
Mechanism of action:
- bacteriCIDAL
- ***block bacterial cell wall synthesis —> susceptible to osmotic pressure (cell lysis)
- effective vs many drug-resistant bacteria
- lower incidence of bacterial resistance (VRE, VISA superbugs are emerging)
Administration:
- **Slow IV for systemic therapy —> high incidence of pain and thrombophlebitis
- Rapid IV infusion —> **“red man syndrome”
- Reserved for
—> serious infection in penicillin-allergic patients
—> resistant organisms (MRSA, MRSE infection)
- Oral route: useful for treatment of Enterocolitis (Clostridium difficile colitis)
Adverse effects:
- **Nephrotoxicity
- **Ototoxicity
Co-trimoxazole
- Trimethoprim + Sulfamethoxazole (1:5)
- Synergistic antibacterial effect against Gram +ve and Gram -ve bacteria
—> except P. aeruginosa, Enterococcus, Gram -ve anaerobes
Adverse effects:
- GI discomfort
- Hypersensitivity
- Low incidence of serious adverse effects
MOA of Co-trimoxazole
BacteriCIDAL
Sulfamethoxazole (sulfonamides):
- inhibit **Dihydropteroate synthetase
- Para-aminobenzoic acid —X—> Dihydrofolic acid
- interferes with bacterial **folic acid synthesis and growth
Trimethoprim:
- inhibit **Dihydrofolate reductase
- blocks production of **Tetrahydrofolic acid
- Caution in patients with severe ***G6PD
Mechanisms of resistance to co-trimoxazole
- Alteration of different substrate enzymes / their overproduction
- Loss of bacterial drug-binding capacity
- Decreased cell permeability
Metronidazole
- Synthetic Nitroimidazole derivative
- important agent in anaerobic infections (intra-abdominal infections)
- BacteriCIDAL vs Bacteroides fragilis
Spectrum:
- **Anaerobic bacteria (Bacteroides, Clotridium)
- **Protozoa (Entamoeba, Giardia)
Resistance:
- Rare
- Decreased activation (↓ redox reaction) of drug
SE:
- N/V
- headache
- ***Metallic taste
- alcohol intolerance, seizures, peripheral neuropathy (rare)
MOA of metronidazole
- Enter bacteria via diffusion
-
Nitro group of metronidazole is chemically reduced by redox enzyme pyruvate-ferredoxin oxidoreductase (PFOR)
—> forms highly reactive ***Nitro radical anion
—> disrupts the DNA helical structure
—> inhibit DNA synthesis
—> cell death
Pharmacokinetics of metronidazole
- very well absorbed
- excellent penetration
- metabolised in Liver
- Urine excreted
Viral gastroenteritis
Acute infection, self-limiting
- Rotavirus
- Norovirus
- Adenovirus
Treatment:
- Fluid and electrolyte replacement with ORS
- NO antiviral drugs available
Summary
Mild:
- fluids only (ORS)
- lactose free diet
- avoid caffeine
Moderate:
- anti-motility agent (loperamide)
Severe:
- Fluoroquinolones
- Co-trimoxazole
- Macrolides
β-lactam (penicillins, cephalosporins) (transpeptidase / PBP)
Macrolides (50s —> block A site to P site) (bacteriostatic)
Tetracycline (30S —> block A site) (bacteriostatic)
Fluoroquinolones (Topoisomerase IV, II —> DNA cleavage)
More information see CPRS L71
β-lactam:
Mimics structure of D-Ala-D-Ala link
—> covalently bind to and inhibit ***transpeptidase/penicillin binding protein (PBP)
—> inhibit pentapeptide cross linking between NAM subunits
—> bacterial cell wall weakens
—> autolysin activated to destroy existing cell wall / osmotic lysis
Macrolide:
Irreversible binding to 50S subunit
—> Inhibit ***translocation of polypeptide chain from A to P site by peptidyltransferase
—> block movement of peptidyl tRNA from A to P site
—> incoming tRNA cannot bind to A site
—> stop protein synthesis
Tetracycline:
Bind to 30S
—> prevent **access of amino acid tRNA to A site on mRNA-ribosome complex
—> block addition of amino acid to existing peptide chain
—> stop protein synthesis
- **Teeth discolouration
- **Reduced bone growth (children <8)
- **Photosensitivity
Fluoroquinolones:
1. Inhibit DNA gyrase (topoisomerase II)
—> quinolone-DNA-gyrase complex
—> induced cleavage of DNA
2. Inhibit DNA topoisomerase IV
- GI symptoms
- CNS symptoms (dizziness, confusion, insomnia)
- **Photosensitivity
- **Ruptured tendons / Arthropathy (CI in children, pregnant and nursing women)
