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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
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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
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
Genetics of Resistance
Resistance by acquisition of new DNA
By Transformation Conjugation Transduction
DNA gyrase
Quinolones
DNA
THFA mRNA Ribosomes
50 30 50 30 50 30
DHFA
PABA
Protein synthesis mistranslation
Aminoglycosides
Cohen. Science 1992; 257:1064
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 transferase
Mechanisms of resistance:
Resistance mechanisms classified into 4 types: can be broadly
Resistance to -lactams:
Resistance due to -lactamases: most prevalent Alteration in the pre-existing penicillin binding proteins (PBPs)
Acquisition of a novel PBP insensitive to beta 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
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
Tetracycline resistance
Most common antibiotic 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
resistance
Chloramphenicol resistance
Enzymatic inactivation:
From acquisition of plasmids chloramphenicol acetyl transferase encoding
Decreased permeability:
Quinolone resistance
Alteration of target i.e, DNA gyrase (by mutation in gyrA gene) Decreased permeability
Glycopeptide resistance
Alteration of target e.g, Vancomycin resistance in Enterococci
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
Enterococci:
Penicillin resistance seen in 1983 Vancomycin resistant Enterococcus (VRE) in 1987 Even emergence of linezolid resistance
Acinetobacter baumanii
Multidrug resistance Some isolates resistant to all drugs
By simultaneously administering two drugs that do not give crossresistance, 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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