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GI L28 Antimicrobial treatment of enteric & hepatic infections

Cholera

Life-threatening watery
diarrhoea

cholera toxin from Vibrio Cholerae In faecally

Salmonellosis

contaminated food or water

Typhoid fever

Fluid replacement with oral rehydration salts (ORS)

Short-course board-spectrum antibacterials for

rd

Treatment with board-spectrum AB 3 gen.


cephalosporins, fluoroquinolones, chloramphenicol,
co-trimoxazole, amoxicillin

Non-typhoid salmonella GE

AB not required unless severely ill

Campylobacter
gastroenteritis

Diarrhoea or dysentery mild & self-limiting

With abdominal pain & fever

Macrolides (motilin receptor agonist) accelerate

severe cases
e.g. tetracycline, fluoroquinolones, co-trimoxazole

Shigellosis

Self-limiting disease

Oral rehydration treatment/ IV fluid replacement

AB therapy ONLY in cases of dysentery

clearance in severe illness

Rapid rise in resistance in co-trimoxazole &


ampicillin (few isolates still sensitive to)

rd

effective

Fluoroquinolones & 3 gen. cephalosporin

Travellers diarrhoea

Mostly caused by ETEC

Oral rehydration therapy

Broad-spectrum AB for 3-5 days shown to


severity & duration

Viral gastroenteritis

Protozoal infections

Mostly due to overgrowth of Clostridium difficile in gut


C. difficile toxin watery diarrhoea or
pseudomembranous colitis

e.g. fluoroquinolones

Hepatitis C (chronic)

supportive management by fluid and electrolyte


replacement with ORT

Hepatitis B (chronic)

Antibiotic-associated

diarrhoea

Fluoroquinolones & other broad-spectrum AB also

[No anti-viral agent]

st

Metronidazole (1 line);

nd

Oral Vancomycin (2 line)

Combination therapy Pegylated interferon alfa (PegIFN) + oral


ribavirin (synthetic guanosine analogue)

Antiviral therapy to clear virus

&chance of chronic liver disease

a)

Lamivudine (nucleoside analogue)

b) Entecavir (guanosine analogue)

Interferon--2b (IFN)

c)

Adefovir, tenofovir (nucleotide analogue)

d) Newer telbivudine (L-thymidine analogue)

Metronidazole

Nematode infections

Mebendazole

For amoebiasis & giardiasis

(hokeworm, roundworm,

Interfere with assembly of parasites microtubules

HBV polymerase inhibitor

pinworm, whipworm)

Trematode infections

Praziquantel

Cestode infections

Niclosaide

(schistosomiasis)

cell Ca permeability

(tapeworms)

Inhibit parasitess mitochondrial phosphorylation of ADP

contracture & paralysis of parasite

to generate ATP

Drug types

Uses/ properties

Mechanism

Side effects

Tetracyclines

Broad spectrum

Bacteriostatic

Local tissue irritation

e.g. Doxycyclin, Minocycline

Resistance problem

Binding specifically to 30S ribosome

GI irritation & superinfections

a)

Prevent access of amino acid-tRNA to

Hepatotoxicity (jaundice and fatty liver esp. pregnant

not for common bacterial

b) drug efflux

women)

acceptor site on mRNA-ribosome complex

infections

Preventing addition of amino acid to the

[avoid IM injection]

Permanent teeth discoloration in children


[avoid giving to pregnant women & children < 8 yr old]

Indications treatment for

growing peptide chain

uncommon infections

inhibit protein synthesis

e.g. Rickettsia, Chlamydia,

Photosensitization (abnormal sunburn reaction)

Vestibular problem (dizziness)

Mycoplasma, spirochetes, protozoa

Pharmacokinetics

Absorption

Variable degree of absorption in GIT


Acid lability

ii)

Lipid solubility

iii)

Complex formation with metal ions


2+

2+

Ca , Fe , Mg , Al

Wide distribution including pleural, synovial fluids,

Elimination

3+

Subtherapeutic CSF conc (10-20% serum level),

EXCEPT minocycline

After single oral dose, peak plasma conc.

Doxycycline

Uses/ properties

Eliminated by glomerular filtration in


kidneys

Cross placental barrier accumulate in fetal bone &

Doxycycline excreted in bile & faeces


used in patients with renal

dentition delay bone growth

insufficiency

reacted in 2-4 hours

Drug types

Metabolized in liver glucuronides


enterohepatic circulation

aqueous humor & abcess fluid

i)

2+

Distribution

Drug types

Uses/ properties

Glycylcycline

New class broad spectrum AB derived from tetracycline

e.g. tigecycline

Effective VS multi-resistance G+ve, G-ve & anaerobic pathogens

(IV infusion)

NOT effective VS Proteus & Pseudomonas spp.

Excreted in bile (NOT kidney) used in renal impaired

Elimination via Biliary excretion

patients

Adverse effect similar to tetracyclines

Indication treatment of complicated skin & soft tissue infections,

Semi-synthetic AB with longer duration of action

Oral administration 90-100% absorbed

Absorption by about 20% with milk or food

complicated intra-abdominal infections

Drug types

Uses/ properties

Mechanism

Side effects

Sulphonamides

Broad spectrum

Bacteriostatic

Allergic reactions (e.g. skin rashes)

e.g. Sulphadiazine,

Problem of drug resistance

Inhibit dihydropteroate synthetase

GI disturbances (e.g. nausea, vomiting, diarrhoea)

SUlphamidine,

Cotrimoxazole

synthesis of folic acid

Urinary tract disturbances (e.g. crystalluria, hematuria or

Sulphamethoxazole

combination of

conversion of PABA to dihydrofolic acid

Trimethoprim +

Formation of tetrahydrofolic acid

sulphamethoxazole

a)

synergistic anti-B activity

b) Purine synthesis
c)

Trimethoprim

obstruction)

Hematopoietic disturbances(e.g. anaemia, granulocytopenia,


thrombocytopenia) greater risk in G6PD deficiency

amino acid synthesis

Thymidine synthesis

Danger of kernicterus in newborns displacement of


bilirubin from binding sites on plasma albumin

Similar AB spectrum to

Inhibit bacterial dihydrofolate reductase (DHFR)

sulphonamides

Formation of tetrahydrofolic acid

granulocytopenia)

synthesis of folic acid

a)

Folic acid deficiency (e.g. megaloblastic anaemia, leucopenia,


Esp. in pregnancy or under poor diet condition

b) Reverse by intake of folinic acid

Drug types

Uses/ properties

Chloramphenicol

Mechanism

Broad spectrum

Bacteriostatic

Only used in life-threatening infections

Bind to 50S (reversible) & inhibits


peptidyltransferase

e.g. bacteremias, meningitis


Pharmacokinetics:

Clindamycin

Good PO absorption & distribution

Inhibits oxidative metabolism

Undergo glucuronidation

Similar to erythromycin

Spectrum similar to erythromycin VS G+ve bacteria

Mainly for sever anaerobic infections caused by

Side effects

Irreversible and fatal toxicity in


bone marrow aplastic anaemia

Grey baby syndrome in


premature infants

Preventing amino acids being added to new peptide


chain

[drug interaction!]

Protein synthesis inhibited

Bind to 50S ribosome & inhibit protein synthesis

GI irritation (nausea, vomiting,


Epigastric distress, abdominal pain)

Pharmacokinetics:

Most serious = potentially fatal

Bacteroides fragilis

Undergoes extensive oxidative metabolism

pseudomembranous colitis caused

[Clostridium difficile always resistant!!!]

excreted into bile & urine

by toxin from overgrown


Clostridium difficile

Drug types

Uses/ properties

Mechanism

Side effects

Vancomycin

Tricyclic peptide antibiotic

Bactericidal

analog = teicoplanin

Low incidence of B resistance

Inhibit trans-glycosylase

[slow IV administration for systemic

[VRE superbugs emerging]

Block bacterial cell wall synthesis

therapy!]

Treatment reserved for serious infections

Weakened cell wall susceptible to

Red man syndrome if rapid IV infusion

Nephrotoxicity & ototoxicity (uncommon)

Nausea, vomiting and headache, metallic

Penicillin-allergic patients

osmotic pressure cell lysis

VS resistant organisms e.g. MRSA & MESA infections

Pharmacokinetics:

Oral route for treatment of enterocolitis

Almost completely excreted in urine

e.g. Clostridium difficile colitis

dosage adjusted in renal failure

Treatment:

Nitro group chemically reduced by PFOR

Anaerobic infections e.g. Bacteroides, Clotridium

Product disrupts DNA helical structure

Metronidazole

Drug types
Human
recombinant
interferon-

[Bactericidal vs Bacteroides fragilis]

Interfere with DNA replication

Protozoal infections e.g. Entamoeba, Giardia

Pharmacokinetics

Very well absorbed, excellent penetration

Metabolized in liver & excreted in urine

Uses/ properties

taste (common)

Alcoholic intolerance, seizures, peripheral


neuropathy (uncommon)

Mechanism

Side effects

Given IM/ deep SC; twice weekly; 3-6

Induce host resistance to viral infection

Myelotoxicity

months (in chronic HBV infection)

MHC class I display facilitate immune recognition of infected cells

Influenza-like symptoms

pegylated formulation (SC once

NK cell activity

weekly) delays absorption &its

Induce intracellular enzymes which interfere with viral protein synthesis

clearance

High incidence of pain & thrombophlebitis

chance of subsequent liver disease &


limits disease spread

a)

2,5-oligoadenylate synthetase activate RNAase to cleave viral


mRNA

b) Protein kinases inhibit first step of viral protein synthesis

with malaise and fever