Antimicrobial Drug Resist.


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Antimicrobial Drug Resist.

  3. 3. <ul><li>There are two main issues that we will talk about: </li></ul><ul><li>* mechanisms of drug resistance </li></ul><ul><li>* Origins of drug resistance </li></ul><ul><li>1- mechanisms: </li></ul><ul><li>a) micro organisms produce enzymes that destroy the activity of the drug eg: </li></ul><ul><li>~staphylococcus  B-lactamase </li></ul><ul><li>~Gram –ve rods  adenylating ,phosphorylating ,and acetylating enzymes ,against aminoglycosides . </li></ul>INTRODUCTION:
  4. 4. ~Gram –ve  chloramphinicol acetyl transferase against chloramphinicol . b)Microorganism alters its permeability to the drug eg tetracyclin and polymyxin . Streptococci have natural barrier to aminoglycosides . acer:
  5. 5. c)Microorganism develops an altered structural target eg:chromosomal resistance to aminoglycosides “30s ribosomal subunit’’ Erythromycin resistant organisms altere receptors in 50s ribosomal subunit. Penicillin resistance  change in penicillin binding protein “PBP”.
  6. 6. <ul><li>d)Microorganisms develop an altered metabolic pathways that  bypass the reaction inhibited by the drug eg: </li></ul><ul><li>Sulfonamides  can use the preformed folic acid without need to extracellular PABA. </li></ul><ul><li>e)Microorganisms alter an enzyme eg: </li></ul><ul><li>Trimethprim resistant bacteria  dihydrofolic acid reductease is inhibited . </li></ul>
  7. 7. Origins of the drug resistance ORIGINS Non genetic Genetic chromosomal Extrachromosomal
  8. 8. <ul><li>*Active replication of bacteria is required for most antibacterial drug action eg : </li></ul><ul><li>Mycobacterim tuberclosis stay many years in the body with slow multiplying. </li></ul><ul><li>* Microorganism may lose target structure and so becomes resistant ,eg: penicillin susceptible organisms may have difficiency in L-aminoacids  cell wall diff- and so become resistant to cell wall </li></ul> 1  Non genetic origin:
  9. 9. <ul><li>Inhibitor drugs (penicillin + cephalosporins). </li></ul><ul><li>*microorganisms may infect cells which drug cann ’ t reach them,eg: </li></ul><ul><li>Aminoglycosides  salmonella enteric fever </li></ul><ul><li>Because salmonellae are intracellular microorganisms and aminoglycosides cannt enter the cell. </li></ul>
  10. 10. <ul><li>Either :a)chromosomal “mutation” :this develops as a result of spontaneous mutation in a locus that controles susceptibility to a given drug </li></ul><ul><li>* Chromosomal mutants are most commonly resistant by virtue of changes in a structural receptor of drug ,eg mutation in the gene controlling the structural protein “of streptomycin </li></ul> 2  Genetic origin :
  11. 11. <ul><li>Receptor ) result in streptomycin resistance . </li></ul><ul><li>b)extrachromosomal “plasmid mediated resistance”: bacteria often contain extrachromosomal gentic elements called plasmids . </li></ul><ul><li>*R-factor are a class of plasmids , circular ,double stranded DNA that carry genes for resistance to one –and often several – antimicrobial drug and heavy metals “Co ,Hg”. </li></ul>
  12. 12. <ul><li>*R-factor composed of two parts : </li></ul><ul><li>1 resistant – transfer factor “RTF” segment of plasmid that responsible for intracellular transfer .and </li></ul><ul><li>2 R-determinant : that carries the resistance genes . </li></ul><ul><li>~Dissemintion by bacterial conjugation mainly. </li></ul>
  13. 13. Clinical importance of extrachromosomal resistance : <ul><li>1) It occurs in many different species , specially gram –ve rods . </li></ul><ul><li>2) Plasmids frequentely mediate resistance to multiple drugs . </li></ul><ul><li>3)plasmids have a high rate of transfer from one cell to another by conjugation. </li></ul>
  14. 14. The mechanisms of resistance : <ul><li>The plasmid genes control the formation of enzs capable to destory the drugs eg:plasmids determine resistance to penicillins and cephalosporins by carring genes for the fomation B-lactamase </li></ul><ul><li>~Genetic material and plasmid can be transferred by transformation ,transduction ,conjugation and transposition. </li></ul>
  15. 15. Transformation: <ul><li>Is the up take of the extra cellular DNA by bacteria thus ,altering its genotype . </li></ul><ul><li>This can occur through labrotary manipulation (e.g: in recombinant DNA technology ). </li></ul><ul><li>Steps: </li></ul><ul><li>a) DNA must bind to the cell surface. </li></ul><ul><li>b) The bound DNA taken up through the cell membrane . </li></ul><ul><li>c)the DNA fragment is integrated into the host chromosome or replicates as plasmid. </li></ul>
  16. 16. Transduction: <ul><li>The genetic transfer occur when a fragment of DNA is carried to the recipient cell by virus “bacteriophage “ e.g :the plasmid carring of the gene for B-lactamase production ,can be transferred from apenicillin –resistant to a susceptible staph aureus . </li></ul>
  17. 17. Conjugation (plasmid- mediated transfer): <ul><li>It is a unilateral transfer of genetic material between bacteria of the same or different genera occurs during amating (conjugation ) process. </li></ul><ul><li>This is mediated by afertility factor that result in extension or extrusion of sex pili from the doner (F+) cell to the recipient (F-). </li></ul>
  18. 18. Transposition: <ul><li>A transfer of short DNA sequences (transposons,transposable element ) occurs between one plasmid and another or between a plasmid and a portion of the bacterial chromosome . </li></ul>
  19. 19. cross resistance : <ul><li>Microorganisms resistant to a certain drugs may also be resistant to other drugs that share a mechanism of action eg: </li></ul><ul><li>~different aminoglycosides are closely related chemically </li></ul><ul><li>~macrolides and lincomycins :have a similar mode of action or binding . </li></ul>
  20. 20. Limitation of drug resistance : <ul><li>1 by maintainig sufficiently high level of the drug in the tissues to inhibit both the original population and the first step mutants </li></ul><ul><li>2y simultaneously administering two drugs that don’t give cross resistance (each of which delays the emergence of mutants resistant to the other drug eg :Rifampin and isoniazide in treatment of T.B) </li></ul>
  21. 21. <ul><li>3 by avoiding exposture of microorganism to a particularely valuable drug by limittig its use specially in hospital . </li></ul><ul><li>4health awareness about missuse of antibiotics </li></ul>
  22. 22. Specific mechanisms of resistance <ul><li>*penicillins and cephalosporins : </li></ul><ul><li>1cleavage by B-lactamases </li></ul><ul><li>2due to change in the PBP </li></ul><ul><li>3 esistance of N.gonorrhoea to penicillin is due to poor permeability to the drug. </li></ul><ul><li>4 olerance (decrease of growth but not killing of bacteria) </li></ul>
  23. 23. <ul><li>*Vancomycin :the resistance is caused by a change in the peptide component of peptidoglycan from D-alanine:D-alanine (normally),to D-alanine :D-lactate (abnormal; no drug bindig ) </li></ul><ul><li>* Aminoglycosides :three mechanisms : </li></ul><ul><li>1 modification of the drug by plasmid – encoded phosphorylating , adenylating and acetylating enzymes . </li></ul><ul><li>2chromosomal mutaion </li></ul><ul><li>3Decrease permeability of the bacteria to the drug </li></ul>
  24. 24. MRSA: <ul><li>( hospitals should be the Mecca of all types of Staphylococcus) </li></ul><ul><li>DRErick </li></ul><ul><li>staphylococcus is one of the most resistant organisms to antimicrobial drugs . </li></ul><ul><li>S. Aureus is resistant to methycillin  MRSA </li></ul>
  25. 25. <ul><li>The MRSA pt experience the following: </li></ul><ul><li>* Depending on the site of body infected </li></ul><ul><li>Surgical wounds infection results in : </li></ul><ul><li>-pain </li></ul><ul><li>-redness </li></ul><ul><li>-swelling of the site and wound drains pus . </li></ul><ul><li>*pneumonic pts  cough , breathlessness ,chest pain,chills , sweats may presents </li></ul>SYMPTOMS:
  26. 26. Diagnosis and treatment: <ul><li>*Culture from the infected site is diagnostic. </li></ul><ul><li>*unfortunately limitted ABs are effective </li></ul><ul><li>I.V vancomycin is the most common used for treatment. </li></ul><ul><li>Untreated MRSA can result in severe results ,relapse of infection and even death. </li></ul>
  27. 27. MRSA prevention: <ul><li>1 covering wounds with bandages </li></ul><ul><li>2consulting health provider when use antibiotics. </li></ul>
  28. 28. FOR MORE DETAILS: <ul><li>*Refrences: </li></ul><ul><li>1GOODMAN & GILLMANS pharmacological basis of theraputics </li></ul><ul><li>2 jawetz </li></ul><ul><li>MEDICAL MICROBIOLOGY </li></ul><ul><li>3ESSENTIALS OF MICROBIOLOGY </li></ul><ul><li>WELSY .A.VOLK </li></ul>
  29. 29. Web sites: <ul><li>* ewindex.php * </li></ul><ul><li>* </li></ul><ul><li>* </li></ul><ul><li>* </li></ul>
  30. 30. Preppared and presented by: <ul><li>DrAla Eldin Salah </li></ul><ul><li>Dr Hassan M. Hassan </li></ul>