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Antibiotic resistance in Bacteria

MBBS/BDS 1st year 27.10.2010

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


Community

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Day-care centers Long term care facilities Homeless shelters Jails

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Settings that Foster Drug Resistance


Hospital < Intensive care units

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Oncology units Dialysis units

Rehab units
Transplant units

Burn units

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 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

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

DNA gyrase

Cell wall synthesis


-lactams &

Quinolones

DNA-directed RNA polymerase


Rifampin

Glycopeptides (Vancomycin) Trimethoprim

DNA
THFA mRNA Ribosomes
50 30 50 30 50 30

Folic acid synthesis


Sulfonamides

DHFA

Protein synthesis inhibition


Macrolides & Lincomycins

PABA
Protein synthesis mistranslation
Aminoglycosides
Cohen. Science 1992; 257:1064

Protein synthesis inhibition


Tetracyclines

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 lactamases Aminoglycoside modifying enzymes Chloramphenicol acetyl transferase

4. Bypass of an antibiotic sensitive steps

Mechanisms of resistance:
Resistance mechanisms classified into 4 types: can be broadly

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 -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

Ribosomal target modification

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

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 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

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 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

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 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 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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