1. Antimicrobial Drugs: Resistance إعداد الطالبة : ولاء إبراهيم الهندي 220060349

2. There are four major mechanisms that mediate bacterial resistance to drugs: There are four major mechanisms that mediate bacterial resistance to drugs: (1) Bacteria produce enzymes that inactivate the drug; eg,B- lactamases (1) Bacteria produce enzymes that inactivate the drug; eg,B- lactamases (2) Bacteria synthesize modified targets against which the drug has no effect

3. (3) Bacteria decrease their permeability such that an effective intracellular con- centration of the drug is not achieved; eg, changes in porins. (4) Bacteria actively export drugs using a "multidrug resistance pump" (MDR pump, or "efflux" pump) eg.(quinolones)

5. Mycobacterium avium intracellulare: present in soil and water, entry is usually via the GI tract but also can be via the lungs.GI tract lungs can occur in the later stages of AIDS. It can also affect women who do not have AIDS and usually first presents as a persistent cough.AIDS

6. It causes fever, diarrhoea, malabsorption and anorexia and it can disseminate to the bone marrow.feverdiarrhoea malabsorptionanorexiabone marrow

7. Most drug resistance is due to a genetic change in the organism, either (1)a chromosomal mutation (2)the acquisition of a plasmid or transposon. Chromosomal resistance is less of clinical problem than is plasmid-mediated resistance.

8. Chromosome-Mediated Resistance: Chromosomal resistance is due to a mutation in the gene that codes (1) the target of the drug. (2)the transport system in the membrane that controls the uptake of the drug.

9. Plasmid-Mediated Resistance: (1)It occurs in many different species, gram-negative rods (2)mediate resistance to multiple drugs. (3) high rate of transfer from one cell to another, usually by conjugation.

10. .

11. Properties of Plasmid: (1) Drug resistance. (2) They can replicate independendy of the bacterial chromosome. (3) they can be transferred not only to cells of the same species.

12. R factors exist in two categories: R factors exist in two categories: (1) large plasmids with molecular weights of about 60 million (contain extra DNA for conjucation process) (1) large plasmids with molecular weights of about 60 million (contain extra DNA for conjucation process) (2)small ones with molecular weights of about 10 million (only resistane genes).

13. Importance of Plasmid: (1)antibiotic resistance (2)resistance to metal ions (code for an enzyme that reduces mercuric ions to elemental mercury) (3) resistance to certain bacterial viruses (restriction endonucleases for the DNA of bacteriophage)

14. Transposon-Mediated Resistance: - Transposon-Mediated Resistance: Transposons :are pieces of DNA that move readily from one site to another, within or between the DNAs of bacteria, plasmids, and bacteriophages. (Jumping genes)

15. (1) inverted repeats, which are involved in the integration of the transposon into the recipient DNA. (2) the gene for the transposase, the enzyme that mediates the excision and integration processes. (2) the gene for the transposase, the enzyme that mediates the excision and integration processes.

16. (3) the gene for the repressor that regulates the synthesis of the transposase and the gene product of the fourth domain. (4) The drug resistance gene

17. NONGENETIC BASIS OF RESISTANCE: ( 1) Bacteria can be walled offwithin an abscess cavity that the drug cannot penetrate effectively.

18. (2) Bacteria can be in a resting state, ie, not growing; they are therefore insensitive to cell wall inhibitors. M. tuberculosis can remain dormant in tissues for many years. (3)Under certain circumstances, organisms that would ordinarily be killed by penicillin can lose their cell walls, survive as protoplasts, and be insensitive to cell-wall-active drugs.

19. (4)The presence of foreign bodies such as splinters and shrapnel. (5) Several artifacts, (1) administration of the wrong drug (2)the wrong dose or failure of the drug to reach the appropriate site in the body (poor penetration into spinal fluid by several early-generation cephalosporins.) (3)Failure of the patient to take the drug (noncompliance, nonadherence) artifact.

20. Mechanism of resistance: Penicillins& cephalosporins: 1- Cleavage by B_lactamases (staphylococuss aureus ). 2- Changes in the penicillin binding protein ( strepto coccus pneumaiae). 2- Changes in the penicillin binding protein ( strepto coccus pneumaiae). 3-Poor permeability to the drug (Neisseria gonerrhoeae). 4- Tolerance: (isolates of Staphylococcus aureus).

21. Quinolones:againts?? 1- chromsomal mutation modify bacterial DNA gyrase. 2- changes in the bacterial outer-membrane proteins. Isoniazid : Mutation in catalse or peroxidase enzyme

22. Vancomycin:(againts???) Vancomycin:(againts???) (D-alanyl – D-alanine to D-alanine-D-lactate) The responsible gene is VanA Tetracycline: (bacteriostatic againts Gram+ve &Gram-ve ) 1-reduce the uptake of the drug. 2-enhance it ’ s transport out of the cell.

23. Rifampin: Chromosomal mutation in the gene for bacterial RNA Polymerase lead to inffective binding of the drug. Note: preferred in the prevention of the infection not the treatment. why?

24. Pyrazinamide (PZA) (TB): Mutation in the gene that encode amidase which converta PZA to the active form.

25. SELECTION OF RESISTANT BACTERIA BY OVERUSE & MISUSE OF ANTIBIOTICS (1) Some physicians use multiple antibiotics when one would be sufficient, use antibiotics in self limited infections, overuse anribiotics for prophylaxis before and after surgery. (2) Antibiotics are sold over the counter to the general puplic.,

26. (3) Antibiotics are used in animal feed to prevent infections and promote growth. ANTIBIOTIC SENSITIVITY TESTING Minimal Inhibitory Concentration : Is the lowest concentration of drug that inhibits the growth of the organism.

28. the disk diffusion method:

29. Minimal Bactericidal Concentration

30. Bactericidal drugs usually have an MBC equal or very similar to the MIC, whereas bacteriostatic drugs usually have an MBC significantly higher than the MIC. Serum Bactericidal Activity (1)a serum sample from the patient, rather than a standard drug solution, that is diluted in 2-fold steps.

31. (2) a standard inoculum of the organism has been added and the mixture has been incubated at 35°C for 18 hours. (3) a small sample is subcultured onto blood agar plates, and the serum dilution that kills 99.9% of the organisms is determined

32. B-lactamase production: A commonly used procedure is the chromogenic B- lactam method, in which a colored B-Lactam drug is added to a suspension of the organisms. If B - lactamase is made, hydrolysis of the B- lactam ring causes the drug to turn a different color in 2-10 minutes. Disks impregnated with a chromogenic B- Lactam can also be used.

33. USE OF ANTIBIOTIC COMBINATIONS (1) To treat serious infections before the identity of the organism is known. (2) To achieve a synergistic inhibitory effect against certain organisms. (3) To prevent the emergence of resistant organisms. (If bacteria become resistant to one drug, the second drug will kill them, thereby preventing the emergence of resistant strains.)

34. a synergistic interaction, in which the effect of the two drugs together is significandy greater than the sum of the effects of the two drugs acting separately. antagonistic, in which the result is significantly lower activity than the sum of the activities of the two drugs alone.

35. the combination of a penicillin and gentamicin has a synergistic action against enterococci (E. Faecalis), because penicillin damages the cell wall suffidendy to enhance the entry of gentamicin the use of penicillin G combined with the bacteriostatic drug tetracycline in the treatment of meningitis caused by S. pneumoniae (antagonism).

36. Antagonism occurs because the tetra cycline inhibits the growth of the organism, thereby pre- venting the bactericidal effect of penicillin G, which kills growing organisms only.