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. 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.
5. Settings that Foster Drug Resistance
Community
< Day-care centers
< Long term care facilities
< Homeless shelters
< Jails
6. Settings that Foster Drug Resistance
Hospital
< Intensive care units
< Oncology units
< Dialysis units
< Rehab units
< Transplant units
< Burn units
7. 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
8. 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
9. 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
14. 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
15. 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.
17. 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
18. 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
19. 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
20. 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
21. Chloramphenicol resistance
Enzymatic inactivation:
– From acquisition of plasmids encoding
chloramphenicol acetyl transferase
Decreased permeability:
24. 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
25. 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
26. 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
27. 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
28. 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
29. 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
30.
31. 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