DRUG RESISTANCE-WPS Office(1).pdf TYPES OF DRUG RESISTANCE

TYPES OF DRUG RESISTANCE

1. ANTIMICROBIAL
RESISTANCE

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DEFINITION

Drug resistance is the ability of microbes, such
as bacteria, viruses, parasites, or fungi, to grow
in the presence of a chemical (drug) that would
normally kill it or limit its growth.

It is the reduction in effectiveness of a drug in
curing a disease or condition

3. TYPES OF DRUG RESISTANCE

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TYPES OF DRUG RESISTANCE

PRIMARY/NATURAL/ INTRINSIC /NON GENETIC ORIGIN OF
RESISTANCE:

It refers to the innate ability of a bacterium to resist
a class of antimicrobial agents due to its inherent
structural and functional characteristics

This imposes only little threat to the world as very
few organism show intrinsic resistance

The bacteria may infect host at sites where drugs
are inaccessible or not active seen in Salmonellae

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The cell wall may be covered with an outer
membrane that establishes a permeability
barrier against the antibiotic as seen in Gram
negative bacteria.

Bacteria may remain in dormant resting state
without multiplying and become phenotypically
resistant to drugs as seen in M. tuberculosis.

Micro-organisms may lose the specific target
structure for a drug for several generations and
become resistant.

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ACQUIRED/GENETIC ORIGIN OF DRUG RESISTANCE

Bacteria acquire/develop resistance to antibiotics
either through the modification of existing genetic
material (mutation) or the acquisition of new
genetic material from another source (plasmid/
gene transfer).

Most of the antimicrobial resistance shown by
bacteria belong to the category

Over use and misuse of antimicrobial agents is
the single most imp cause of development of
acquired resistance

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Thus the resistant bacteria flourish in areas of high
antimicrobial use

The resistant strain then spreads in the
environment and transfer the genes coding for
resistance to other unrelated bacteria
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Evolution of resistant strains is a natural
phenomenon, which can occur among bacteria
especially when an antibiotic is over used

Use of particular antibiotic poses selective
pressure in a population of bacteria which in turn
promotes resistant bacteria to thrive and the
susceptible bacteria to die off

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Other factors favouring the spread of
antimicrobial resistance include-

Poor infection control practices in hospitals
eg: poor hand hygiene practices can facilitate
transmission of resistant strains
Inadequate sanitary conditions
Inappropriate food - handling.
Irrational use of antibiotics by doctors, not
following antimicrobial susceptibility report
Uncontrolled sale of antibiotics over the
counters without prescription

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1. CHROMOSOME MEDIATED RESISTANCE:

Resistance acquired due to spontaneous mutation
of gene that controls the susceptibility to a given
antimicrobial drug.

Structurally alters the target of the drug or the
transport system that controls the uptake of the
drug.
2 types:

Stepwise mutation: Penicillin

One step mutation: Streptomycin

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Single-step resistance studies involve the
formation of resistant mutants in one
exposure to the antimicrobial agent

multi-step resistance studies involve
exposing the bacteria to the antimicrobial
agent over many passages (subcultures),
allowing for formation of resistance
mutations over time.

11. •Resistance is not transferable to other organism
but spread to offspring by vertical spread only


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Vertical gene transfer of resistant genes to
progeny.
Seen in M. tuberculosis and streptomycin.

12. 2. TRANSFERABLE DRUG RESISTANCE

A. PLASMID MEDIATED RESISTANCE: Resistance
acquired through the transfer of extrachromosomal
resistance plasmids


B. TRANSPOSON MEDIATED RESISTANCE:
Transposons are genes/segments of DNA that are
transferred within themselves or between
chromosomes and extrachromosomal plasmids.They
are also known as jumping genes and this mode of
genetic transfer as transposition. Transposons attach
themselves to chromosomal, plasmid or phage DNA
molecule and confer resistance to drugs under suitable
environmental conditions. Transposons are not self
replicating.

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Horizontal gene transfer

Bacteria can share genes with each other in a
process called horizontal gene transfer.

Resistance is transferable to other organisms

This can occur both between bacteria of the
same species and between different species
and by different mechanisms

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Ways for bacteria to share their genes:

Conjugation: Two bacteria can pair up and connect
through structures in the cell membranes and then
transfer DNA from one bacterial cell to another

Transduction: There are viruses called bacteriophages
that can infect bacteria. These viruses sometimes
bring along genes that they picked up during
infection of another bacterium. These genes may
then be incorporated into the DNA of the new
bacterial host.

Transformation: Some bacteria can take up pieces of
DNA directly from the environment around the cell.

15. Mutational v/s transferable drug resistance
Resistance to one drug
at a time
Multiple drug resistance
at the time
Low degree resistanceHigh degree resistance
Resistance can be
overcome by combination
of drugs
Cannot be overcome by
drug combinations
Virulence of resistance
mutants may be lowered
Virulence not decreased
Resistance is not transferable
to other organisms but spread
to offspring by vertical spread
only
Resistance is transferable
to other organisms
Spread : by horizontal
spread

16. MECHANISM OF ANTIMICROBIAL RESISTANCE
Bacteria develop antimicrobial resistance by
several mechanism.
These mechanism include : Decreased permeability
across the cell wall, Efflux pumps , By enzymatic
inactivation & By modifying target sites.


1. Decreased permeability across the cell wall
Certain bacteria modify their cell membrane
porin channels,either in their frequency, size ,or
selectivity,thereby preventing the antimicrobials
from entering into the cell. This strategy has been
observed in many gram negative bacteria ,such as
Pseudomonas,Enterobacter & Klebsiella species
against drugs , such as imipenem , aminoglycosides
and quinolones

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2.Efflux pumps
Certain bacteria possess efflux pumps which
mediate expulsion of drugs from the cell, soon
after their entry, thereby preventing the
intracellular accumulation of drugs. This strategy
has been observed in :
E.coli And other Enterobacteriaceae against
tetracyclines,chloramphenicol
Staphylococci against macrolides and
streptogramins
Staphylococcus aureus & Streptococcus
pneumoniae Against fluoroquinalones

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3.By enzymatic inactivation
Certain bacteria can inactivate the antimicrobial
agents by producing various enzymes , such as

Beta - lactamases enzyme production
Beta lactamase enzymes are capable of
hydrolysing the beta lactam rings ( the active site )
of beta lactam antibiotics; thereby deactivating
their antibacterial properties.They can be produced
by GNB and GPB.They are plasmid coded , and are
transfered from one bacterium to other by
conjugation ( except S.aureus - transduction)

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Beta lactamase are classified into two ways
> Ambler's classification (structural or molecular
classification ) according to this , beta lactamase are
classified into four classes

Class A: Extended spectrum beta lactamases ( ESBL)
Organisms producing ESBL enzymes are resistant
to all penicillins and 1st,2nd and 3rd generation of
cephalosporins and monobactam, however remain
sensitive to carbapenems and cephamycins
Resistance can be overcome by use of beta lactam
along with beta lactamase inhibitor ( eg:
sulbactum or clavulanic acid )
Detected by combination disc test

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Class B-Metallobetalactamase ( MBL )
These organism are resistant to all those antibiotics to
which AmpC beta lactamase producers are resistant.
Inaddition they are also resistant to carbapenems
Resistance cannot be overcome by beta lactam + beta
lactamase inhibitor combination
Detected by EDTA disc synergy test, modified hodge
test
Class C- AmpC beta lactamase
These organism resistant to all those antibiotics to
which ESBL producers are resistant + resistant to
cephamycins ( cefoxitin and cefotetan ) .sensitive to
carbapenems
Resistance cannot be overcome by beta lactam + beta
lactamase inhibitor combination

22. Class C - oxacillinase
•Resistance can be overcome by use of beta lactam
along with beta lactamase inhibitor ( eg: sulbactum
or clavulanic acid )
> Bush Jacoby medeiros classification or functional
( phenotypic) classification. This is the most
advanced and complex classification

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Aminoglycoside modifying enzymes like
( acetyl transferases , adenyl transferases ,
and phosphotranferases produced by both
GPB & GNB): they destroy the structure of
aminoglycosides.

Chloramphenicol acetyl transferase : It is
produced by members of Enterobacteriaceae ,
it destroys the structure of chloramphenicol

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4.By modifying the target sites

Modification of the target sites of antimicrobial
agent ( which are within the bacteria ) is a very
important mechanism. It is observed in:

MRSA: methicillin resistant in S.aureus is
mediated by a chromosomaly coded gene called
mec A gene I.e. penicillin binding protein ( PBP)
gets altered to PBP- 2a. The altered PBP do not
sufficiently bind to beta - lactam antibiotics and
therefore prevent them from inhibiting the cell
wall synthesis.

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Rifampicin resistance in Mycobacterium
tuberculosis - due to mutations in RNA
polymerase

Quinolone resistance seen in many GPB,
particularly S.aureus & S.pneumoniae due to
mutations in DNA gyrase enzyme
•Streptomycin resistance in Mycobacterium
tuberculosis: It is due to modification of
ribosomal proteins or 16 s rRNA.

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Vancomycin resistance in enterococci - VRE is
mediated by Van gene , which alters the target site
for vancomycin present in the cell wall ( D-alanyl- D-
alanine side chain of peptidoglycan layer is altered
to D-alanyl -D- serine or D-alanyl - D- lactate

5 genotypes Van A to van E

Van A gene show high resistance to both
glycopeptides vancomycin and teicoplanin.
Van B gene show low resistance to vancomycin ,
but sensitive to teicoplanin
Van C gene show intrinsic resistance to both
glycopeptides