Antibiotics

A Review on antibiotics and bacterial resistance

1. ANTIBIOTICS Presented by: E. Madhan Mohan Associate Professor Department of Pharmacology, SCHOOL OF PHARMACY , Nalla Narasimha Reddy Education Society’s Group of Institutions. 1 NNRG SCHOOL OF PHARMACY 6 MAY 2016

2. Contents Introduction to Pharmacology Difference between animal cell & Bacterial cell Types of bacteria Antibiotics- Classification. Mechanism of action of various antibiotics. Bacterial resistance Conclusion References 2 NNRG SCHOOL OF PHARMACY 6 May 2016

3. Introduction to Pharmacology Pharmacology: (derived from 2 Greek words: Pharmakon - drugs and logos - science ). Pharmacology is the branch of science deals with the study of various drugs on living system. It includes physicochemical properties, biochemical and physiological effects, mechanism of action, therapeutic uses and adverse effects of drugs. 6 May 2016 NNRG SCHOOL OF PHARMACY 3

4. Difference between Animal cell and Bacterial cell 4 NNRG SCHOOL OF PHARMACY 6 May 2016 Eukaryotic cell: e.g . Animal Prokaryotic cell: e.g. Bacteria

5. Types of Bacteria 6 May 2016 NNRG SCHOOL OF PHARMACY 5

6. Types of Bacteria Peptidoglycan is the material that makes up bacterial cell walls 6 May 2016 NNRG SCHOOL OF PHARMACY 6 Thicker Peptidoglycan layer but not outer membrane means gram + ve Thinner Peptidoglycan layer with an outer membrane means gram - ve

7. Types of Bacteria 6 May 2016 NNRG SCHOOL OF PHARMACY 7 Gram-Positive Bacteria Gram-Negative Bacteria Simple cell wall. More complex cell wall. Thick peptidoglycan cell wall layer. Thin peptidoglycan cell wall layer. No outer lipopolysaccharide wall layer. Contain outer lipopolysaccharide wall layer. Retain crystal violet/iodine. Retain safranin . Appear blue/purple. Appear pink/red. Eg . Streptococcus pneumoniae Streptococcus pyogenes Streptococcus viridans group Bacillus anthracis Corynebacterium diphtheriae Eg . Neisseria gonorrhoeae Neisseria meningitidis Escherichia coli Haemophilus inuenzae Salmonella typhi

8. Mode of Transmission of Bacterial Infections 6 May 2016 NNRG SCHOOL OF PHARMACY 8

9. ANTIBIOTICS 6 May 2016 NNRG SCHOOL OF PHARMACY 9 Definition: These are substances produced by microorganisms or synthetically which selectively suppress the growth of or kill other microorganisms at very low concentrations.

10. 10 Classification of Antibiotics: NNRG SCHOOL OF PHARMACY 6 May 2016 MECHANISM OF ACTIONS Inhibition of cell wall synthesis Inhibition of bacterial protein synthesis Inhibition of Nucleic Acid Synthesis Inhibition of Folic Acid Synthesis Penicillins Cephalosphorins Imipenem Meropenem Aztreonam vancomycin Aminoglycosides Chloramphenicol Macrolides Tetracycline Streptogrmins linezolid Fluoroquinolones Rifampin Sulfonamides Trimethoprim Pyrimethamine

11. 11 NNRG SCHOOL OF PHARMACY 6 May 2016 Inhibition of Cell wall synthesis: Beta- Lactam Antibiotics : These are antibiotics having a β- lactam ring. The two major groups are penicillins and cephalosporins. 1. PENICILLINS: Eg : Penicillin-G, Penicillin V, Amoxicillin, Ampicillin , Cloxacillin . 2. CEPHALOSPORINS: Eg : Cefixime , Cefpodoxime proxetil , Cephalexin , Cefuroxime axetil Bacteria cell wall unique in construction Contains peptidoglycan layer. Antimicrobials that interfere with the synthesis of cell wall do not interfere with eukaryotic cell. Due to the lack of cell wall in animal cells.

12. 12 NNRG SCHOOL OF PHARMACY 6 May 2016 Mechanisms of Action: Penicillins and cephalosporins are considered bactericidal. The weakness in the cell wall causes the cell to lyze . Competitively inhibits function of Penicillin-binding proteins Inhibits peptide bridge formation between glycan molecules This causes the cell wall to develop weak points at the growth sites and become fragile. Penicillins are more effective against Gram+ve bacteria . This is because Gram + bacteria have penicillin binding proteins ( PBPs ) on their walls. The cephalosporins have low affinity to penicillin-binding proteins of Gram + bacteria, therefore, are enter into the bacteria through porin channels most effective against Gram – ve bacteria.

13. 13 NNRG SCHOOL OF PHARMACY 6 May 2016 Mechanism of resistance: By enzyme Penicillinases: break the beta lactam ring structure. Structural changes in PBP’s. Change in porin structure: concerns the gram negative organism Uses: Pharyngitis, rheumatic fever, pneumonia, Gonorrhoea, Syphilis, Diphtheria etc. ADR’S: Local irritancy, Toxicity to the brain, convulsions and coma, Hypersensitivity, fatal anaphylaxis, nephrotoxicity, heamotological disorders, Diarrhea etc.

14. 14 NNRG SCHOOL OF PHARMACY 6 May 2016 Inhibition of protein synthesis: Structure of prokaryotic ribosome acts as target for many antimicrobials of this class Differences in prokaryotic and eukaryotic ribosomes responsible for selective toxicity Drugs of this class include Aminoglycosides 3. Chloramphenicol Tetracyclins 4. Macrolids (Erythromycin)

15. 15 NNRG SCHOOL OF PHARMACY 6 May 2016 Aminoglycosides E.g : Gentamicin , streptomycin and tobramycin MOA: Irreversibly binds to 30S ribosomal subunit Causes distortion and malfunction of ribosome Blocks initiation translation Causes misreading of mRNA Uses: Tuberculosis, Plague, Meningitis ADR’S: with extended use include Otto toxicity, Nephrotoxicity, Neuromuscular blockade.

16. 2. Tetracyclins: Reversibly bind 30S ribosomal subunit Blocks attachment of tRNA to ribosome Prevents continuation of protein synthesis Effective against certain Gram + and Gram - Newer tetracyclines such as doxycycline have longer half-life Allows for less frequent dosing Uses: Cholera, Plague, Rickettsial infections etc. ADR’S: Can cause discoloration of teeth if taken as young child, Liver damage, Kidney damage, Phototoxicity 6 May 2016 NNRG SCHOOL OF PHARMACY 16

17. 6 May 2016 NNRG SCHOOL OF PHARMACY 17 3. Chloramphenicol: Binds to 50S ribosomal subunit Prevents peptide bonds from forming and blocking proteins synthesis Effective against a wide variety of organisms Uses: Generally used as drug of last resort for life-threatening infections, typhoid fever, meningitis, conjunctivitis ADR’S: Rare but lethal side effect is Bone marrow depression, Hypersensitivity reactions, Gray baby syndrome

18. 4. Macrolides antibiotics: Eg : Erythromycin, clarithromycin and azithromycin Reversibly binds to 50S ribosome Prevents continuation of protein synthesis Effective against variety of Gram + organisms and those responsible for atypical pneumonia Often drug of choice for patients allergic to penicillin Uses: respiratory infections, rheumatic fever, Diphtheria, Syphilis and gonorrhea etc. ADR’S: Mild-to-severe epigastric pain, reversible hearing impairment, Hypersensitivity, Jaundice. 6 May 2016 NNRG SCHOOL OF PHARMACY 18

19. 6 May 2016 NNRG SCHOOL OF PHARMACY 19 Mechanisms of resistance: A mutation of ribosomal binding site Enzymatic modification of antibiotic An active efflux of antibiotic out of cell

20. 6 May 2016 NNRG SCHOOL OF PHARMACY 20 Inhibition of Nucleic Acid Synthesis: Eg : Fluoroquinolones ( levofloxacin, norfloxacin, Ciprofloxacin) , Rifampin Bacteriocidal Can inhibit DNA gyrase or RNA polymerase Uses: urinary antiseptic , Gonorrhoea Gastroenteritis, Typhoid: ADR’S : g.i . upset and rashes. neurological—headache, drowsiness, vertigo, visual disturbances, occasionally seizures Mechanism of resistance: an alteration of alpha subunit of DNA gyrase (chromosomal) beta subunit of RNA polymerase (chromosomal) is altered

21. Inhibition of Folic Acid Synthesis: Eg : Sulfonamides, Trimethoprim , Pyrimethamine , Cotrimaxazole . Bacteriostatic Binds and blocks enzymes mainly folate synthase , dihydrofolate reductase responsible for folic acid synthesis. What are Folic Acid? Folic acid is necessary for the synthesis of amino acids, hence necessary for bacterial protein synthesis. 6 May 2016 NNRG SCHOOL OF PHARMACY 21

22. Uses : Trachoma, conjunctivitis, for preventing infection on burn surfaces, malaria etc . ADR’S: Nausea, vomiting. Crystalluria, Hypersensitivity reactions, Hepatitis, Haemolysis Mechanism of resistance: Mutations in the gene for dihydrofolate reductase decreasing binding affinity . 6 May 2016 NNRG SCHOOL OF PHARMACY 22

23. Interference with cell membrane integrity: Few damage cell membrane Polymixn B most common Common ingredient in first-aid skin ointments Binds membrane of Gram - ve cells Alters permeability Leads to leakage of cell and cell death Also bind eukaryotic cells but to lesser extent Limits use to topical application 6 May 2016 NNRG SCHOOL OF PHARMACY 23

24. RESISTANCE- A MOJAR PROBLEM WITH THE USAGE OF ANTIBIOTICS Mechanisms of resistance Drug inactivating enzymes Some organisms produce enzymes that chemically modify drug Penicillinase breaks β - lactam ring of penicillin antibiotics Alteration of target molecule Minor structural changes in antibiotic target can prevent binding Changes in ribosomal RNA prevent macrolides from binding to ribosomal subunits 6 May 2016 NNRG SCHOOL OF PHARMACY 24

25. RESISTANCE- A MOJAR PROBLEM WITH THE USAGE OF ANTIBIOTICS Mechanisms of resistance Decreased uptake of the drug Alterations in porin proteins decrease permeability of cells Prevents certain drugs from entering Increased elimination of the drug Some organisms produce efflux pumps Increases overall capacity of organism to eliminate drug Enables organism to resist higher concentrations of drug Tetracycline resistance 6 May 2016 NNRG SCHOOL OF PHARMACY 25

26. Antibiotics Vs Severe Adverse drug reactions Otto toxicity, Nephrotoxicity, Teratogenic effects, Bone marrow depression, Loss of blood cells, Hypersensitivity reactions, Hepatitis etc. Are Challenging the usage of antibiotics. 6 May 2016 NNRG SCHOOL OF PHARMACY 26

27. Conclusion: Though antibiotics are able to control the growth of microorganisms, the WHO advised to restrict the usage of antibiotics unless usage is needful. Use antibiotics with proper DIAGNOSIS. Use antibiotics when the causative organism is known It is advisable to use low dose of multiple antibiotics instead of high dose of single antibiotic. 6 May 2016 NNRG SCHOOL OF PHARMACY 27

28. References Rang and Dale, Pharmacology, 6 th edition, 2007, pg.685– 690. Bertram G. Katzung , Basic & Clinical pharmacology, 11 th edition, 2009, pg.1070 – 1076. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 10 th edition, pg. 1565-1578. Lippincott's Illustrated Reviews Pharmacology, 4th Edition, pg.529 – 535. K.D.Tripati , Essentials of Medical pharmacology, 6 th edition,2008, pg.727 – 738. 6 May 2016 NNRG SCHOOL OF PHARMACY 28

29. T H A N K u T H A N K u 6 May 2016 29 NNRG SCHOOL OF PHARMACY