antibiotic resistance in bacteria 1
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Antibiotic resistance in Bacteria
MBBS/BDS 1st year27.10.2010
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.
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
Settings that Foster Drug Resistance
< Day-care centers
< Long term care facilities
< Homeless shelters
< Jails
Community
Hospital < Intensive care units
< Oncology units
< Dialysis units
< Rehab units
< Transplant units
< Burn units
Settings that Foster Drug Resistance
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
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
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
Mechanism of action of antibiotics
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
Mechanisms of antibiotic resistance : how DO the bacteria do it ??
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
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.
Mechanism of resistance to particular antibiotics
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
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
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
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
Chloramphenicol resistance
Enzymatic inactivation:– From acquisition of plasmids encoding
chloramphenicol acetyl transferase
Decreased permeability:
Quinolone resistance
Alteration of target i.e, DNA gyrase (by mutation in gyrA gene)
Decreased permeability
Glycopeptide resistance
Alteration of targete.g, Vancomycin resistance in Enterococci
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
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
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
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
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
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
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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