Antibiotic resistance in bacteria 1


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Antibiotic resistance in bacteria 1

  1. 1. Antibiotic resistance in Bacteria MBBS/BDS 1st year 27.10.2010
  2. 2. Antibiotic resistance in bacteria Emergence of antibiotic resistance is a major factor limiting long term successful use of an antimicrobial agent. Antibiotic resistance is a type of drug resistance where a microorganism is able to survive exposure to an antibiotic. Resistant organism: One that will not be inhibited or killed by an antibacterial agent at concentrations of the drug achievable in the body after normal dosage. If a bacterium carries several resistance genes, it is called multiresistant or, informally, a superbug or super bacteria.
  3. 3. Factors contributing for resistance Misuse of antibiotics< Use of antibiotics with no clinical indication (e.g, for viral infections)< Use of broad spectrum antibiotics when not indicated< Inappropriate choice of empiric antibiotics Overuse of antibiotics Addition of antibiotic to the feed of livestock Failure to follow infection control practices
  4. 4. Settings that Foster Drug Resistance Community< Day-care centers< Long term care facilities< Homeless shelters< Jails
  5. 5. Settings that Foster Drug Resistance Hospital< Intensive care units< Oncology units< Dialysis units< Rehab units< Transplant units< Burn units
  6. 6. Antibiotic resistance in bacteria Two types: Intrinsic:  Naturally occuring trait  Species or genus specific Acquired:  Acquired resistance implies that a susceptible organism has developed resistance to an agent to which it was previously susceptible, and can occur in two general ways: by mutation (s) in the existing DNA of the organims or by acquisition of new DNA.  Present in only certain strains of a species or of a genus
  7. 7. Genetics of ResistanceMutational resistance:  A single chromosomal mutation may result in the synthesis of an altered protein: for example, streptomycin resistance via alteration in a ribosomal protein, or the single aminoacid change in the enzyme dihydtropteroate synthetase resulting in a lowered affinity for sulfonamides  A series of mutations, for example, changes in penicillin binding proteins (PBPs) in penicillin resistant pneumococci
  8. 8. Genetics of Resistance Resistance by acquisition of new DNA – By Transformation – Conjugation – TransductionNature of elements involved in transferring DNA:  Plasmids: plasmid mediated resistance much more efficient than the resistance ass. with chromosomal mutation  Transposons
  9. 9. Mechanism of action of antibiotics
  10. 10. DNA gyrase DNA-directed RNA polymerase Quinolones Cell wall synthesis Rifampin ß-lactams & Glycopeptides (Vancomycin) DNA THFA mRNATrimethoprim Protein Ribosomes synthesisFolic acid inhibitionsynthesis DHFA 50 50 50 30 30 30 Macrolides & LincomycinsSulfonamides PABA Protein synthesis Protein synthesis inhibition mistranslation Tetracyclines Aminoglycosides Cohen. Science 1992; 257:1064
  11. 11. Mechanisms of antibiotic resistance : how DO the bacteria do it ??
  12. 12. Mechanisms of resistance (Contd.)2. Alteration of Access to the target site (altered uptake or increased exit) Involves decreasing the amt of drug that reaches the target by either:  Altering entry, for example, by decreasing the permeability of the cell wall,  Pumping the drug out of the cell (known as efflux mechanisms)3. Enzymatic inactivation: Enzymes that modify or destroy the antibacterial agent may be produced (drug inactivation)e.g., Beta lactamases Aminoglycoside modifying enzymes Chloramphenicol acetyl transferase4. Bypass of an antibiotic sensitive steps
  13. 13. Mechanisms of resistance: Resistance mechanisms can be broadly classified into 4 types:1. Alteration of the target site – The target site may be altered so that it has a lowered affinity for the antibacterial (antibiotic), but still functions adequately for nomal metabolism to proceed. Alternatively, an additional target (e.g enzyme) may be synthesized.
  14. 14. Mechanism of resistance to particular antibiotics
  15. 15. Resistance to β -lactams: Resistance due to β -lactamases: most prevalent Alteration in the pre-existing penicillin binding proteins (PBPs) Acquisition of a novel PBP insensitive to beta β – lactams: e.g, methicillin resistance in Staphylococcus aureus (MRSA) Changes in the outer membrane proteins of Gram negative organisms that prevent these compounds from reaching their targets
  16. 16. Aminoglycoside Resistance:Intrinsic and acquired resistance due to decreased uptakeAcquired resistance is frequently due to plasmid encoded modifying enzymes: Three classes of aminoglycoside modifying enzymes:  Acetyltransferases,  Adenyltransferases and  PhosphotransferasesRibosomal target modification
  17. 17. Tetracycline resistanceMost common antibiotic resistance encountered in natureMechanisms:  Altered permeability due to chromosomal mutations  Active efflux or Ribosomal protection (by production of a protein) resulting from acquisition of exogenous DNA
  18. 18. Macrolide, Lincosamide and Streptogramin resistance: Intrinsic resistance is due to low permeability of outermembrane protein Acquired resistance occurs most often by alteration of the ribosomal target Drug inactivation and active efflux may also occur
  19. 19. Chloramphenicol resistance Enzymatic inactivation: – From acquisition of plasmids encoding chloramphenicol acetyl transferase Decreased permeability:
  20. 20. Quinolone resistance Alteration of target i.e, DNA gyrase (by mutation in gyrA gene) Decreased permeability
  21. 21. Glycopeptide resistance Alteration of targete.g, Vancomycin resistance in Enterococci
  22. 22. Cotrimoxazole (Sulfonamides and trimethoprim) resistance Intrinsic resistance: outer membrane impermeability Acquired resistance: – Chromosomal mutations in the target enzymes [low level resistance) – Plasmid mediated resistance: high level resistance
  23. 23. Resistance to antimycobacaterial agents First line essential antituberculous agents: Rifampin, isoniazid and Pyrazinamide First line supplemental: Ethambutol and Streptomycin Second line: Para-aminosalicylic acid, ethionamide, cycloserine, kanamycin, amikacin, capreomycin, thiacetazone
  24. 24.  Resistance to Rifampin: – From spontaneous point mutations that alter the beta subunit of the RNA polymerase (rpoB) gene Resistance to Isoniazid: – Mutations in the catalase peroxidase gene or inhA gene Resistance to Pyrazinamide: – Mutations in the pncA gene, which encodes for pyrazinamidaseMultidrug resistance/ XDR
  25. 25. Some resistant pathogensStaphylococcus aureus:  Penicillin resistance in 1947  Methicillin resistance in 1961: MRSA causing carious fatal diseases  Vancomycin resistance in the recent years: As VRSA and VISAEnterococci:  Penicillin resistance seen in 1983  Vancomycin resistant Enterococcus (VRE) in 1987  Even emergence of linezolid resistance
  26. 26. Some resistant pathogens (contd.) Pseudomonas aeruginosa: – One of the worrisome characteristic: low antibiotic susceptibility – Multidrug resistance common: due to mutation or horizontal transfer of resitant genes Acinetobacter baumanii  Multidrug resistance  Some isolates resistant to all drugs Salmonella, Esherichia coli Mycobacterium tuberculosis
  27. 27. Tests for detecting antibacterial resistance Disk diffusion method Screening method: eg, oxacillin resistance screening for Staphylococcus, Vancomycin resitance screeening for enterococci Agar dilution method: by determining minimum inhibitory concentration Special tests: detection of enzymes mediating resistance- colorometric nitrocefin and acidometric method for beta lactamase detection
  28. 28. Limitation of Drug Resistance Emergence of drug resistance in infections may be minimized in the following ways: By prudent use of antibiotics; by avoiding exposure of microorganisms to a particularly valuable drug by limiting its use, especially in hospitals. By maintaining sufficiently high levels of the drug in the tissues to inhibit both the original population and first-step mutants; By simultaneously administering two drugs that do not give cross- resistance, each of which delays the emergence of mutants resistant to the other drug (eg, rifampin and isoniazid in the treatment of tuberculosis); and By institution of infection control practices
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