Chemotherapy its introduction , history , classification of antibiotics, resistance , antimicrobial spectrum

1. CHEMOTHERAPY
KRVS Chaitanya

2. CONTENT
1. Introduction And Definition
2. History
3. Classification
4. Mechanism Of Action
5. Type Of Organism Against Which Primarily Active
6. Spectrum Of Activity
7. Type Of Action
8. Antibiotics- Source
9. Problems Arising With Use Of AMAs

3. • Antimicrobial drugs are the greatest contribution of the 20th century to
therapeutics
• Importance is magnified in developing countries where infective
diseases predominate
• As a class, they are one of the most frequently used as well as misused
drugs

4. Antibiotics -
• These are substances produced by microrganisms, which selectively
suppress the growth of or kill other microrganisms at very low
concentrations
• Chemotherapeutic agent
• Antimicrobial agent (AMA)

5. HISTORY – divided into 3 phases
A. Period of empirical use - * ‘ mouldy curd ’ on boils
, chaulmoogra oil by the hindus in leprosy ,
chenopodium by aztecs for intestinal worms ,
mercury by Paracelsus (16th century) for syphillis ,
cinchona bark (17th century) for fever.
B. Ehrlich’s phase of dyes and organometallic
compounds ( 1890 – 1935 ): discovery of
microbes in later half of 19th century – arsenicals –
atoxyl for sleeping sickness and arsphenamine &
neoarsphenamine for syphillis – coined the term
‘chemotherapy’

6. C. Modern era of chemotherapy –domagk-demonstrated
therapeutic effect of prontosil  PYOGENIC
INFECTION
- Penicillium mould  destroy staphylococcus – fleming
(1929)- penicillin
- Chain & Florey (1939) – purified the penicillin – 1st
clinical use of penicillin (1941)
- Waksman ( 1944) – systematic search of actinomycetes as
source – streptomycin

7. A. Mechanism of action -
1. Inhibit cell wall synthesis :
Penicillins, Cephalosporins, Cycloserines, Vancomycin, Bacitracin
2. Cause leakage from cell membranes :
Polypeptides- Polymyxins, Colistin, Bacitracin. Polyenes- Amphotericin
B, Nystatin , Hamycin
3. Inhibit protein synthesis :
Tetracyclines, Chloramphenicol, Erythromycin, Clindamycin, Linezolid
4.Misreading of m-RNA and affect permeability : Aminoglycosides –
Streptomycin, Gentamicin Etc.

8. 5. Inhibit DNA gyrase – Fluoroquinolones-ciprofloxacin and others
6. Interfere with DNA function – Rifampin, Metronidazole
7. Interfere with DNA synthesis – Acyclovir, Zidovudine
8. Interfere with intermediary metabolism – Sulfonamides, Sulfones,
PAS, Trimethoprim, Pyrimethamine, Metronidazole

10. B. Type of organisms against which primarily
active -
1. Antibacterial : penicillins, aminoglycosides, erthryomycin,
fluoroquinolones etc.
2. Antifungal : griseofulvin, amphotericin B, ketoconazole, etc
3. Antiviral : acyclovir, amantadine, zidovudine etc.
4. Antiprotozoal : chloroquine, pyrimethamine, metronidazole,
diloxanide etc.
5. Antihelminthic : mebendazole, pyrantel, niclosamide, diethyl
carbamazine etc.

11. C. Spectrum of activity -
Narrow
spectrum
Penicillin G
Streptomycin
Erythromycin
Broad
spectrum
Tetracyclines
Chloramphenicol

12. Type of action
• Primarily bacteriostatic –
Sulfonamides Erythromycin
Tetracyclines Clindamycin
Chloramphenicol Linezolid
Ethambutol
• Primarily bactericidal –
Penicillins Cephalosporins
Aminoglycosides Vancomycin
Polypeptides Ciprofloxacin
Rifampin Metronidazole
Isoniazid Cotrimoxazole
Pyrazinamide

13. Antibiotics are obtained from :
• Fungi –
Penicillin Griseofulvin
Cephalosporin
• Bacteria –
Polymyxin B Tyrothricin
Colistin Aztreonam
Bacitracin
• Actinomycetes –
Aminoglycosides Macroglycosides
Tetracyclines Polyenes
Chloramphenicol

14. Problems that arise with use of AMAs
1. TOXICITY
a) Local irritancy
a) Systemic toxicity –
high therapeutic index – penicillins , some cephalosporins and erythromycin
lower therapeutic index – aminoglycosides , tetracyclines , chloramphenicol
very low therapeutic index - polymyxin B , vancomycin , amphotericin B

15. 2. HYPERSENSITIVITY REACTIONS
3.DRUG RESISTANCE - a) Natural resistance
b) Acquired resistance
c) cross resistance
4. NUTRITIONAL DEFICIENCIES
5. MASKING OF INFECTION

16. 6.SUPERINFECTION (Suprainfection) –
Appearance of new infection as a result of antimicrobial therapy
common when host defence is compromised
Conditions predisposing to superinfections –
Corticosteroid therapy
Leukemias and other malignancies
AIDS
Agranulocytosis
Diabetes

17. 1. Genetic methods of Antibiotic resistance -
A. Chromosomal Methods : Mutations
B. Extrachromosomal Methods : Plasmids r-genes  R-plasmids
Plasmids which carry genes resistant to antibiotics
METHODS –
i. Transfer of r-genes from one bacterium to another – 3 mechanisms –
CONJUGATION , TRANSDUCTION & TRANSFORMATION
ii. Transfer of r-genes between plasmids within the bacterium –
* by Transposons
* by Integrons

18. TRANSPOSONS –
Transposons are DNA segments that cannot self-replicate but can self-
transfer between plasmids or from plasmid to chromosomes
Donor plasmid containing a Transposon , cointegrates with the target
(acceptor) plasmid
During the process of cointegration the transposon can now replicate
Both plasmids then separate and each contains the r-gene carrying the
transposon

19. • By INTEGRONS –
Mainly the MDR , can also be spread by a larger mobile DNA unit called
“integrons”
Each integron is packed with multiple gene cassettes, each consisting of
a resistant gene attached to a small recognition site
These gene cassettes are encoded with several bacterial functions
including resistance and virulence
Currently , the gene cassettes have been identified for all antibiotics
except fluoroqinolones

22. 2. Biochemical mechanisms of resistance to
Antibiotics -
A. By producing an enzyme that inactivates the antibiotic
* inactivation of β - lactam antibiotics
* inactivation of Chloramphenicol
* inactivation of Aminoglycosides
B. Prevention of Drug accumulation in the Bacterium
C. By Modification/Protection of the target site
D. Use of alternative pathways for metabolic/growth requirement
E. By Quorum Sensing

24. • Patient factors –
1. Age
2. Renal and hepatic function
3. Local factors
4. Drug allergy
5. Impaired host defence
6. Pregnancy
7. Genetic factors
Choice of an Antimicrobial Agent -

25. •Drug factors –
1. Spectrum of activity
2. Type of activity
3. Sensitivity of the organism
4. Relative toxicity
5. Pharmacokinetic profile
6. Route of administration
7. Evidence of clinical efficacy
8. Cost