1. MEDICAL MICROBIOLOGY ANTIBIOTICS AND CHEMOTHERAPEUTICS: AN OVERVIEW

2. Simple Definitions
Chemotherapeutic: Treating of diseases with chemical compounds. Natural or synthetic.
Antibiotic: Acting against an infectious agent. May be sourced from living microorganism (e.g. from a microbe) or synthesized chemical compound.
Synonyms: Antimicrobial – acting against microbe
Drug – Any substance used to treat diseases or infections.

3. First antibiotic, penicillin, was discovered in 1929 by Alexander Flemming.
Penicillin became available for clinical use in 1940
It is a product of a mould, Penicilium notatum
Selective toxicity is the ability to kill, inhibit the growth of micro organisms without harming the cells of the host.
An essential requirement for a good antibiotic.

4. Antimicrobial therapy
A major role of the laboratory is to provide information regarding the susceptibility of an infecting causative agent to selected antibiotics.
Antimicrobial therapy aims at treating infections with a drug to which a microbe is sensitive and which has selective toxicity for only the infecting agent (i.e. without harming the host cells).

5. Bacteriostatic antimicrobial
They arrest the multiplication of bacteria which will eventually lead to the eradication of the micro-organisms ( e.g. erythromycin, chloramphenicol).
Bactericidal antimicrobials
These cause the death of the microbes (e.g. penicillin).

6. Antimicrobials differ in the range of bacteria they inhibit:
Broad spectrum: Active against both Gram positive and gram negative organisms e.g. Ampicillin, tetracycline.
Narrow spectrum: Active against only Gram positive or gram negative e.g. Fluoxacillin.

7. Combination of drugs is indicated in some situations:
To achieve synergistic effect e.g. a combination of sulphanamide and trimethoprim to form cotrimoxazole (septrin)
To prevent the development of resistance e.g. in the treatment of tuberculosis.
To treat mixed infections.

8. Mode of action of antimicrobial agents
Antimicrobial drugs act on bacteria in 5 main different ways:
1. Inhibition of cell wall synthesis
They inhibit cell wall synthesis of bacteria by preventing the cross-linking of the polysaccharide chains in the peptidoglycan layer of the cell wall.

9. 2. Damage to cell membrane
Some antimicrobial agents act as cationic detergents and bind to the cell membrane.
This results in the loss of the semi – permeability of the cell membrane thus leading to the loss of cell contents and cell death e.g. the polymixins, amphotericin B.

10. 3. Inhibition of protein synthesis
These drugs arrest the protein synthesis by affecting the translation in the cell e.g. Chloramphenicol, aminoglycosides (e.g. gentamicin), erythromycin.
4. Inhibition of nucleic acid synthesis
These prevent multiplication in the bacteria e.g. quinolones and nalixidic acid inhibit DNA synthesis while rifampicin inhibit RNA synthesis.

11. 5. Inhibition of folic acid synthesis
Folic acid, a co-factor in the synthesis of thymidine and other nucleotides.
Sulphanamide structurally resembles para-aminobenzoic acid (PABA) and can enter into the synthesis of folic acid in place of PABA.
And so non functional analogs of folic acid are formed thus preventing the synthesis of thymidine which is an essential ingridient of nucleic acid.
Further growth of the organisms is thus arrested.

12. Some Antimicrobial Drugs of Clinical Importance
Antibiotics are produced from living microbes or from synthesized chemical compound.
Common antibiotics include the penicillins, cephalosporins, aminoglycosides, chloramphenicol, erythromycin and vancomycin. Amphotericin B, Griseofulvin and Nystatin are antifungal antibiotics.

13. The common synthetic antimicrobials are the sulphonamides, cotrimaxazole, trimethoprim, nitrofurantoin, nalidixic acid, metronidazole and isoniazid. Flucytosine is a chemical antifungal drug.
1. Penicillins
Penicillin is a metabolic product of a mould, Penicillium notatum.
Structure: a B-lactam ring with 4 members.
Mode of action: Inhibits cell wall synthesis. Bactricidal.

14. Antibacterial activity: Broad spectrum.
Resistance: The enzyme b-lactamase (penicillinase) produced by some bacteria inactivates the action of penicillin.
Staph. aureus, Neisseria gonorrhoeae, Haemophilus influenzae all produce b lactamase.
Toxicity: Penicillin also elicits severe adverse allergic reaction in some individuals.

15. Penicillin derivatives
By chemically altering the side chain to B-lactam ring, derivatives of penicillin are formed.
Some Penicillin derivatives:
i. Ampicillin: broad spectrum; inactivated by b- lactamase
ii. Amoxycillin: Similar to ampicillin
iii. Augmentin – a combination of amoxycillin and clavulanic acid; broad spectrum and resistant to b- lactamase.

16. Group of antibiotics that are chemically similar to penicillins.
iv. Cloxacillin/Methicillin: Resistant to b – lactamase, bactericidal in action.
Methicillin resistant Staph.aureus (MRSA) is a superbug and a great medical hazard.
2. Cephalosporins
Group of antibiotics that are chemically similar to penicillins.
Have been developed into first, second and now third generation grades.
Mode of action: same as penicillin but resist b-lactamase more.
Antibacterial activity: broad spectrum.

17. Examples of Cephalosporins
1st generation Targeted pathogens
i. Cephalexin: Ent. faecalis, Ps aeruginosa, H. influenzae, Staph.aureus
ii. Cephaloridine: As above.
2nd generation
i. Cefuroxime Targeted pathogens
As above plus Bacteriodes
ii. Cefoxtin As above

18. Bactericidal, some are ineffective against anerobes.
3rd generation Targeted pathogens
i. Ceftriazone Similar to 2nd generation plus Ps aeruginosa
ii. Ceftazidime As above.
Toxicity: Renal damage in high doses
3. Aminoglycosides
A group of antibiotics that inhibit protein synthesis of bacteria. Derived from various fungal species.
Bactericidal, some are ineffective against anerobes.

19. Some important members of the group
Gentamicin: Broad spectrum, bactericidal
Amikacin: Broad spectrum, bactericidal
Streptomycin: Broad spectrum but resistance develops easily so given in combination with other drugs for TB
Kanamycin: Broad spectrum, bactericidal.
Toxicity: All aminoglycosides have high toxicity potential e.g. Nephrotoxicity, ototoxicity.

20. Some common Tetracyclines i. Oxytetracycline ii. Doxycycline
This is group of closely related antibiotics derived from Streptomyces species.
Broad spectrum
Bacteriostatic.
Some common Tetracyclines
i. Oxytetracycline
ii. Doxycycline
Toxicity: May cause liver damage, mild diarrhoea and depression of normal flora.

21. 5. Chloramphenicol
Derived from Streptomyces species.
Acts by inhibiting protein synthesis by attaching itself to the bacterial ribosomes.
Bacteriostatic
Broad spectrum
Active against Salmonella sp, Mycoplasma sp.
Inactive against Ps. Aeruginosa
Toxicity: Has toxic effect on bone marrow. Restricted usage.

22. 6. Erythromycin
Belongs to the Macrolide group of antibiotics.
Derived from Streptomycin species.
Inhibits protein synthesis by attaching to bacterial ribosomes.
Bacteriostatic
Narrow antibacterial spectrum though most active against Gram negative bacteria and a few Gram positive organisms.
Toxicity: Little or none.

23. 7. Cotrimoxazole
Made up of sulphamethoxazone and trimethoprim in 5:1 ratio (synergistic reaction)
Folic acid synthesis
Broad spectrum
Bacteriostatic
Toxicity: Mild nausea and vomiting.

24. 8. Amphotericin B
Anti fungal agent.
Derived from Streptomyces nodosus
Fungal static
Narrow spectrum
Toxicity: Transient anorexia, headache, nausea and vomiting
9. Nystatin
Anti fungal agent
Derived from Streptomyces noursei

25. Nystatin cont’d
Antibacterial spectrum: Anti fungal
Fungal static
Toxicity: Little or none
10. Griseofulvin
Anti fungal agent
Derived from penicillium species
Antibacterial spectrum: Antifungal
Toxicity: Photosensitivity on high dosage

26. For further reading:
1. Antibiotics and their Laboratory Control by M. C. Bryant.
2. Medical Laboratory Science: Theory and Practice by J. Ochei and A. Kolhatkar.