Antimicrobial drug resistance

ANTIMICROBIAL
DRUG RESISTANCE
PRESENTED BY: DR. MANAS KR. NATH, PGT, DEPTT. OF
PHARMACOLOGY, SMCH.
MODERATED BY: DR. (MRS.) DOLLY ROY, ASSOCIATE
PROFESSOR, DEPTT. OF PHARMACOLOGY, SMCH.

09-06-2017Department of Pharmacology, SMCH. 2

OBJECTIVES
• Introduction.
• Definition.
• Timeline.
• Factors.
• Mechanisms.
• Control strategy.
• Conclusion.
09-06-2017 3Department of Pharmacology, SMCH.

INTRODUCTION
• Discovery of anti-microbial agents created a new era
in the field of Medical Science.
• Microbes, on the other hand, developed various
mechanisms to counter this threat to their existence.
• Antimicrobial drug resistance is the ability of a
microbe to resist the effects of medication which was
previously used to treat them.

Contd..
• This is responsible for millions of death worldwide
and is considered as a major health concern
nowadays.
• Antimicrobial resistance (AMR) threatens the
effective prevention and treatment of an ever-
increasing range of infections caused by the
microbes.
• The cost of health care for patients with resistant
infections is higher.

DEFINITION
• Antimicrobial resistance is the ability of a
microorganism (like bacteria, viruses, and some
parasites) to stop an antimicrobial (such as
antibiotics, antivirals and antifungals) from working
against it.

TIMELINE OF AMR

FACTORS OF AMR
Antimicrobial
Resistance
Drug
Related
Factors
Environmental
Factors
Patient
Related
Factors
Prescriber
Related Factors

Contd..
• Environmental Factors
• Huge populations and overcrowding.
• Rapid spread due to better transport facilities.
• Poor sanitation.
• Increase in community acquired resistance.

Contd..
• Ineffective infection control program.
• Widespread use of antibiotics in animal husbandry
and agriculture and as medicated cleansing products.
• Release of large quantities of antibiotics into the
environment during pharmaceutical manufacturing through
inadequate wastewater treatment.

Contd..
• Drug Related Factors
• Over the counter availability of antimicrobials.
• Counterfeit and substandard drug causing sub-
optimal blood concentration.
• Irrational fixed dose combination of antimicrobials.
• Increasing use of antibiotics.

Contd..
• Patient Related Factors
• Poor adherence of dosage Regimens.
• Poverty.
• Lack of sanitation concept.
• Lack of education.
• Self-medication.

Contd..
• Prescriber Related Factors
• Inappropriate use of antibiotics.
• Increased empiric poly-antimicrobial use.
• Overuse of antimicrobials.
• Prolonged use of antimicrobials.
• Inadequate dosing.
• Lack of current knowledge and training.

MECHANISMS OF AMR

Contd..
• A) Intrinsic or Natural.
• B) Acquired:
• Genetic Methods:
• Chromosomal Methods: Mutations.
• Extra-chromosomal Methods: Plasmids:
• Transfer of r-Genes from one bacterium to another:
• Conjugation.
• Transduction.
• Transformation.
• Transfer of r-Genes between plasmids within the bacterium:
• By Transposons.
• By Integrons.
• Biochemical Mechanisms:
• Production of Antibiotic inactivating enzymes.
• Preventing drug accumulation within bacterium.
• Modifying/protecting target site.
• Use of alternative pathways for Metabolism/Growth.
• Quorum Sensing.

INTRINSIC OR NATURAL RESISTANCE
• Some microbes have always been resistant to certain
AMAs.
• They lack the metabolic process or the target site which is
affected by the particular drug.
• This type of resistance does not pose significant clinical
problem.
• E.g.:
• Mycobacterium tuberculosis is resistant to tetracyclines.
• Aerobic organisms are not affected by metronidazole.
• Gram –ve bacilli are normally unaffected by penicillin G.

ACQUIRED RESISTANCE
• It is the development of resistance by an organism (which
was earlier sensitive) due to the use of an AMAs over a
period of time.
• This can happen with any microbes and is a major clinical
problem .
• This type of resistance develops either by gene transfer or
by mutation or by modification in biochemical
mechanisms.

GENETIC METHODS
CHROMOSOMAL METHODS: MUTATIONS
It refers to a stable and heritable change in the DNA
structure of the bacterial gene.
Spontaneous and random mutations occur in bacterial
cells at a frequency of approximately one per million
cells.
In any population of a microbe few mutant cells are
present which require higher concentration of antibiotic
for their elimination.

Contd..
During a course of antibiotic therapy, the resistant
bacteria continue to grow and multiply resulting in
‘selection of mutants’ which confer resistance to the
antibiotic.
Mutants resulting from chromosomal mutations have
reduced pathogenicity, except in cases of
Mycobacteria (both tuberculosis and leprosy) and
Methicillin Resistant Staphylococcus aureus.

Contd..
Single step Mutation
(Point Mutation)
• Mutation occurring in a single
gene.
• Rapid emergence with high
degree of resistance.
• E.g.
• Enterococci to
Streptomycin.
• E. coli and Staphylococci
to Rifampin.

Contd..
Multi step Mutation
A number of genetic mutations are involved.
Sensitivity to AMAs decrease in a step-wise manner.
E.g. Resistance to Erythromycin, Tetracycline &
Chloramphenicol.

Contd..
Extra-chromosomal Methods: Plasmids
Plasmids are extra-chromosomal genetic materials
serving as vectors for carrying DNA molecule.
Plasmids can replicate independently and freely in
cytoplasm.
Plasmids which carry genes resistant to antibiotics (r-
Genes) are called R-plasmids.
These r-Genes can get readily transferred from one R-
plasmid to another plasmid or to a chromosome.

Contd..
Most of the drug resistance encountered in
clinical practice is plasmid mediated.
Transfer of resistant genes can occur between
bacteria of same species or of different species.
There are three mechanisms for gene transfer:
Conjugation.
Transduction.
Transformation.

Contd..
Conjugation
It is the main mechanism for transfer of resistance.
The conjugative plasmids which contain the transfer r-
Genes, make a connecting tube (sex pili) between the two
bacteria through which the plasmid itself can pass [in
presence of a Resistance Transfer Factor (RTF)].
This is commonly observed with bacterial population at
high density (as in gut  resident micro-flora can serve
as reservoir for the resistant genes which can later be
transferred to other invading pathogens).

Contd..
Transduction
This process involves
bacteriophages which
encloses a plasmid DNA and
transfers it to another
bacterium of the same
species.
Usually observed in
transmission of resistant
genes between strains of
staphylococci and
streptococci.

Contd..
Transformation
Certain bacteria have the
ability to pick up free DNA
from the environment (i.e.,
from a cell belonging to
closely related or the same
strain), which then gets
incorporated in the genome
of the bacteria thereby
making it resistant.

Contd..
Transfer of r-Genes between plasmids within
the bacterium
 By Transposons
These are DNA segments that cannot self-replicate but
can self-transfer between plasmids or from plasmid to
chromosome.
The donor plasmid containing a transposon having r-
Genes co-integrates with the acceptor plasmid  during
the process the transposon replicates  the plasmids
separate, each containing the r-Gene.
E.g., some strains of staphylococci and enterococci 
conferring nosocomial infection.

Contd..

Contd..
 By Integrons
It is a larger mobile DNA unit which can be located
on a transposon.
Each integron is packed with multiple gene cassettes,
each containing a r-Gene attached to a small
recognition site.
They cannot promote self transfer, but are commonly
associated with and work with transposons and
conjugative plasmids.
Multidrug resistance can be conferred by integrons.

BIOCHEMICAL MECHANISMS
By producing Antibiotic inactivating enzymes
Staphylococcus aureus, Neisseria gonorrhoea,
Haemophilus influenzae and some enteric Gram negative
rods produce β lactamase enzyme which cleaves the β
lactam ring thereby inactivating β lactam antibiotics.
Some Gram –ve and Gram +ve bacteria inactivates
Chloramphenicol by the enzyme chloramphenicol
acetyltransferase (plasmid mediated).
Inactivation of Aminoglycosides by some Gram –ve and
Gram +ve bacteria are mediated by the enzymes
acetyltransferases, phospotransferases and
adenylyltransferases (plasmid and transposon mediated).

Contd..
By preventing drug accumulation within bacterium
It is mediated either by promoting efflux or by preventing
the influx of the drug.
Efflux pumps (chromosomal or plasmid-mediated) are
cytoplasmic membrane transport proteins which commonly
operates in E. coli, P. aeruginosa, S. typhi, Staph. aureus,
Stretpto. pyogenes, Strepto. Pneumoniae, N. gonorrhoeae,
mycobacteria and enterococci.

Contd..
These efflux pumps are the major mechanism of
resistance for tetracyclines, fluoroquinolones and
erythromycin.
Some Gram –ve bacteria inhibit plasmid mediated
synthesis of porin channels, which obstructs the
influx of antibiotic agents (ampicillin).

Contd..
By modifying or protecting the target site
Ribosomal point mutations for tetracyclines, macrolides
and clindamycin.
Altered DNA gyrase and topoisomerase for
fluoroquinolones.
Modified penicillin binding protein (PBPs) in Strepto.
pneumoniae leading to penicillin resistance.
Point mutation in β subunit of DNA-directed RNA-
polymerase confers resistance to Rifampicin by
Mycobacterium tuberculosis.

Contd..
By use of alternative pathways for Metabolism/Growth
Resistance to antibiotics can be conferred by developing
an alternative pathway that bypasses the reaction
inhibited by the antibiotic.
E.g.,
Sulfonamide resistance occurs from overproduction of
PABA.
Some enteric organisms evade β lactam antibiotics by
overproducing β lactamases.

Contd..
Quorum Sensing (QS)
It is the process by which the microbes communicate
with each other and exchange signaling chemicals
(autoinducers) which allows the bacterial population
to coordinate gene expression for virulence,
conjugation, mobility, apoptosis and antibiotic
resistance, etc.
Any change can only be induced when the microbial
colony reaches a critical density (quorum) and a
threshold of autoinduction is reached and gene
expression starts.

Contd..
Gram –ve bacteria have been found to contain
several chemically distinct classes of QS-signal
molecules like AHLs, AIP, AI-2 & AI-3.
AI-2 QS-system is also shared by Gram +ve bacteria.
Drugs targeting the QS-system may minimize
microbial growth and development of antibiotic
resistance.

STRATEGY TO CONTAIN AMR
• Judicious use of Existing Anti-
microbial Agents.
• Development of new Anti–microbial
Agents.

SCENARIO OF ANTIBIOTIC DEVELOPMENT

NEWER APPROACHES
Phage Therapy
• Phage Therapy is the therapeutic use of lytic
bacteriophages to treat pathogenic bacterial infections.
• Bacteriophage therapy can be an important alternative
to antibiotics.
• The success rate was 80–95% with few
gastrointestinal or allergic side effects.
• British studies also demonstrated significant efficacy
of phages against Escherichia coli, Acinetobacter
spp., Pseudomonas spp. and Staphylococcus aureus.

Contd..
Quorum Sensing Analogues
These agents inhibit the QS system in different
bacteria.
These include AHL, AIP & AI-2 analogues.

CONCLUSION
• Anti microbial resistance is an emerging global threat.
• Strategies to prevent development of antimicrobial
resistance should be devised.
• Judicious use of antimicrobial agents by health care
professionals & general population.
• Preventing un-judicious use of antibiotics in animal
husbandry and farming practices.
• Avoiding incorporation of antibiotics in commercial
cleansing products.
• Proper pharmaceutical waste management.

Antimicrobial drug resistance

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