Pharmacology Third Year

1. Introduction to Antimicrobials

2. Definitions
CHEMOTHERAPY :
• Treatment of infection/cancer with drugs that selectively kill
the micro-organisms or cancer cells
• Anti-microbials: Drugs/substances to kill micro-organisms
(viruses, bacteria, fungi & protozoa, etc)
• Antibiotics – Antimicrobials obtained from
microorganisms, such as fungus, etc.
– Bactericidal – kill the bacteria
– (Beta lactam antibiotics, Cotrimoxazole, Aminoglycosides, etc.)
– Bacteriostatic – prevent the multiplication of bacteria
– (Macrolides, Tetracyclines, Sulfonamides, Trimethoprim, etc.)
CHEMOPROPHYLAXIS:
• Prevention of infection by chemicals/drugs

3. Mechanism of Action of Antibacterial drugs
• Inhibition of bacterial cell wall synthesis:
– Penicillins, Cephalosporins, Vancomycin, etc
• Inhibition of cell membrane:
– Polymixins, Amphotericin B & Nystatin
• Inhibition of protein synthesis :
– Tetracyclines, Aminoglycosides, Macrolides,
• Inhibition of DNA synthesis :
– Flouroquinolones, Rifampicin, Metronidazole
• Anti-metabolites:
– Sulphonamides (inhibit folic acid synthesis),
– Trimethoprim (inhibits conversion of folic acid to folinic acid)

4. Mechanism of action (overview)
50S & 30S
Inhibitors of cell wall
synthesis
Inhibitors of DNA
& cell division
Inhibitors of cell membrane
synthesis
Inhibitors of protein
synthesis
PABA
Pteridine
Folic acidFolinic acid
Purines Pyrimidines
DNA
Ribosome
mRNA

5. Resistance to Antibiotics
Unresponsiveness of microorganisms to an antimicrobial agent
Mechanisms of Resistance:
• Inactivation of the drug by bacterial enzymes
– beta-lactamases inactivate some Penicillins & Cephalosporins
• ↓↓bacterial permeability to drug: Tetracyclines
• ↑↑elimination of the drug from the cell: Fluoroquinolones
• Change in ribosomal binding site: Erythromycin
• Genetic methods - Mutation, Plasmid mediated,
Cross resistance: Resistance to one drug usually leads to
resistance against other drugs in the same group

6. Prophylactic Antibiotics
Certain clinical situations require the use of antibiotics for the
prevention of infections.
• 1. Prevention of streptococcal infections in patients with a
history of rheumatic heart disease.
– Patients may require years of treatment
• 2. Bacterial endocarditis following dental extractions
• 3. Tuberculosis in close contacts of an infective TB patient
• 4. Surgical procedures (bowel surgery, joint replacement &
some gynecological operations) to prevent infections
• 5. Neonatal HIV infection (Vertical transmission) Zidovudine
to HIV infected pregnant mother
• 6. Prevention of epidemics: Meningitis, Influenza, Cholera,
Typhoid

7. Antimicrobial drug combinations
• Broad-spectrum empiric therapy in seriously ill pts
• To treat mixed (polymicrobials) infections
– Intra-abdominal abscesses due to a combination of anaerobic & aerobic
gram-negative organism, and enterococci)
• To enhance (synergism) anti-microbial activity
• To decrease the emergence of resistance

8. Antimicrobial drug combinations
• Synergism: When the inhibitory or killing effects of two or
more antimicrobials used together are greater than expected
from their effects when used individually.
• Penicillin or Ampicillin in combination with Gentamicin or
Streptomycin is superior to monotherapy with penicillin
– Enterococcal endocarditis
– Febrile neutropenic patients
– Infections caused by Pseudomonas aeruginosa
Trimethoprim-sulfamethoxazole –treatment of bacterial infections and
Pneumocystis jiroveci (carinii) infection
Beta lactamase inhibitors – prevent the hydrolysis of Beta lactams by
inhibiting beta lactamases produced by the bacteria

9. Antimicrobial drug combinations
• Mechanisms of synergism
a. Inhibition of enzymatic inactivation
Beta-lactam antibiotics (penicillins & ceophalosporins) combined
with beta-lactamase inhibitors (clavulanic acid)
b. Increased uptake:
Penicillins increase uptake of aminoglycosides
c. Blockade of sequential steps in metabolic pathway
Sulphonamides folic acid synth. & Trimethoprim
conversion of folic acid to folinic acid
Mechanisms of antagonism
a. Inhibition of -cidal activity by -static agents
Tetracyclines decrease action of penicillins & cephalosporins
b. Enzyme induction: Imipenem & ampicillin formation of beta-
lactamase by some bacteria, will action of effective antibiotics

10. SULFONAMIDES
• Bacteriostatic
• Folate antagonists
Mechanism of Action : Inhibition of bacterial folic acid synthesis
• Sulfonamides inhibit the enzyme Dihdropteroate synthetase
which is responsible for the incorporation of PABA into the
precursor of folic acid.
– PABA - essential metabolite of bacterial cells required for the synthesis
of folic acid.

11. Uses:
• Sulfacetamide: Bacterial conjunctivitis
• Sulmethoxazole: Urinary tract infection
• Sulfadiazine + Pyrimethamine: Acute toxoplamosis
• Sulfadoxin + Pyrimethamine (FANSIDAR)
– Chloroquine resistant Malaria.
Sulmethoxazole + Trimethoprim (COTRIMOXAZOLE)
SULFONAMIDES

12. SULFONAMIDES
Adv effects:
• Crystalluria
• Allergy, Skin rash, Stevens-Johnson Syndrome- skin & mm
eruptions
• Kernicterus ( Displace bilirubin from serum albumin, the free
bilirubin can cross the immature blood brain barrier in new
born babies ).
• Hemolytic anaemia in G6PD deficiency
• Megaloblastic anemia
Contraindications:
• Pregnancy at term,
• New born & infants < 2 months of age.
• Hypersensitivity

13. COTRIMOXAZOLE
• Trimethoprim/Sulmethoxazole ratio (1:5)
• Synergistic action
Mech of action :
Sequential blockade in the synthesis of Folic acid.
Sulfamethoxazole inhibits the incorporation of PABA into
dihydrofolic acid precursors, and trimethoprim prevents
reduction of dihydrofolate to tetrahydrofolate.
– Tetrahydrofolate is required for purine, pyrimidine, & amino acid
synthesis.
Adv effects: Skin rash, Megaloblastic anaemia, Hemolytic
anemia in patients with G6PD deficiency
Uses: Lower UTI, Chronic bronchitis, Pneumocystis carinii
pneumonia, Shigellosis, Salmonellosis,