Antibiotic Resistance in Bacteria 1
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Antibiotic resistance in Bacteria
MBBS/BDS 1st year27.10.2010
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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.
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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
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Settings that Foster Drug Resistance
< Day-care centers
< Long term care facilities
< Homeless shelters
< Jails
Community
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Hospital < Intensive care units
< Oncology units
< Dialysis units
< Rehab units
< Transplant units
< Burn units
Settings that Foster Drug Resistance
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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
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Genetics of ResistanceMutational 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
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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
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Mechanism of action of antibiotics
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Folic acid synthesis
ß-lactams & Glycopeptides (Vancomycin)
50 50 5030 30 30
DNA
mRNA
Ribosomes
PABA
DHFA
THFA
Cell wall synthesis
DNA gyrase
Quinolones
Protein synthesis inhibition
Protein synthesis inhibitionTetracyclines
Protein synthesis mistranslation
Macrolides & Lincomycins
Cohen. Science 1992; 257:1064
DNA-directed RNA polymerase
Rifampin
Aminoglycosides
Sulfonamides
Trimethoprim
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Mechanisms of antibiotic resistance : how DO the bacteria do it ??
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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 lactamasesAminoglycoside modifying enzymesChloramphenicol acetyl transferase
4. Bypass of an antibiotic sensitive steps
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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.
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Mechanism of resistance to particular antibiotics
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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
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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
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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
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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
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Chloramphenicol resistance
Enzymatic inactivation:– From acquisition of plasmids encoding
chloramphenicol acetyl transferase
Decreased permeability:
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Quinolone resistance
Alteration of target i.e, DNA gyrase (by mutation in gyrA gene)
Decreased permeability
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Glycopeptide resistance
Alteration of targete.g, Vancomycin resistance in Enterococci
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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
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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
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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
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Some resistant pathogensStaphylococcus 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
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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
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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
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Limitation of Drug ResistanceEmergence 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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