There are many ways that drug-resistant infections can be prevented: immunization, safe food preparation, handwashing, and using antibiotics as directed and only when necessary. In addition, preventing infections also prevents the spread of resistant bacteria.The main cause of antibiotic resistance is antibiotic use. When we use antibiotics, some bacteria die but resistant bacteria can survive and even multiply. The overuse of antibiotics makes resistant bacteria more common. The more we use antibiotics, the more chances bacteria have to become resistant to them.

1. COMBATING
DRUG
RESISTANCE
Ashok
Mpharmacy 1st Year
210121210013
Guided By:- Dr. Manoj Medal
Dept. Of Pharmaceutical Sciences,
GJUS&T . Hissar

2. Contents
 1. Drug Resistance and Causes
 2. Genetic Principle of Drug Resistance
 3. Mechanism of Drug Resistance
 4. Strategies to Combat Drug Resistance

3. Drug resistance
 Drug resistance is the reduction in effectiveness of a medication such as an
antimicrobial or an antineoplastic in treating a disease or condition.
 When an organism is resistant to more than one durg, it is said to be multi-
drug resistant
 Antimicrobial resistance and anti-neoplastic resistance challenge clinical
care and drive research

4. Causes And Mechanism of Drug Resistance

5. Mechanisms for Drug Resistance
 The four main mechanisms by which microorganisms exhibit resistance to
antimicrobials are:
 Drug inactivation or modification: e.g., enzymatic deactivation of Penicillin G
in some penicillin-resistant bacteria through the production of β-lactamases.
 Alteration of target site: e.g., alteration of PBP — the binding target site of
penicillins — in MRSA and other penicillin-resistant bacteria.
 Alteration of metabolic pathway: e.g., some sulfonamide-resistant bacteria do
not require para-aminobenzoic acid (PABA), an important precursor for the
synthesis of folic acid and nucleic acids in bacteria inhibited by sulfonamides.
Instead, like mammalian cells, they turn to utilizing preformed folic acid.
 Reduced drug accumulation: by decreasing drug permeability and/or increasing
active efflux (pumping out) of the drugs across the cell surface.

6. Causes for Drug Resistance
1. Microbial behaviour:-
Resistance may be developed by mutation or gene transfer.
Mutation:- It is the stable and heritable genetic change that occurs
spontaneously and randomly among microorganisms.
Any sensitive population of a microbe contains a few mutant cells which
require higher concentration of AMA for inhibition.These are selectively
preserved and get a chance to proliferate when the sensitive cells are
eliminated by AMA. Thus in time, it would appear that a sensitive straun has
been replaced by a resistant one.
Eg. When a single Anti tb drug is used.

7. Causes for drug resistance
Mutation may be single or multi step.
Single step:- A single step mutation may confer high degree of resistance, emerges
rapidly.
Eg. Enterococci to Streptomycin and E. Coli to Rifampin.
Multi step:- A no. Of gene modifications are induced.
Eg. Resistance to erythromycin, tetracyclin and chloramphenicol is developed by many
organism in this manner.
Streptomycin

8. Causes for drug resistance
Gene transfer:- Microbes can pick up genes from other Microbes. Genes with
drug resistant qualities can easily transfers between microorganisms.
2. Overuse:-
As early as 1945, Sir Alexander Fleming raised the alarm regarding antibiotic
overuse when he warned that the “public will demand [the drug and] … then
will begin an era … of abuses.”The overuse of antibiotics clearly drives the
evolution of resistance. Antibiotics remove drug- sensitive competitors, leaving
resistant bacteria behind to reproduce as a result of natural selection. Despite
warnings regarding overuse, antibiotics are overprescribed worldwide.

9. Causes for Drug Resistance
3.Inappropriate Prescribing :-
Incorrectly prescribed antibiotics also contribute to the promotion of resistant bacteria.
Incorrectly prescribed antibiotics have questionable therapeutic benefit and expose patients
to potential complications of antibiotic therapy.
4. Extensive Agricultural Use : In both the developed and developing world, antibiotics are
widely used as growth supplements in livestock.
Treating livestock with antimicrobials is said to improve the overall health of the animals,
producing larger yields and a higher- quality product.The antibiotics used in livestock are
ingested by humans when they consume food.

10. Causes for Drug Resistance
This occurs through the following sequence of events:
 antibiotic use in food-producing animals kills or suppresses susceptible
bacteria, allowing antibiotic-resistant bacteria to thrive;
 resistant bacteria are transmitted to humans through the food supply;
 these bacteria can cause infections in humans that may lead to adverse health
consequences.

11. Some Antibiotics and their resistance toward body

12. Strategies to Combat Drug Resistance in Antibiotic
Therapy
.
 One way to minimize the effect of target enzyme mutation in drug resistance
would be to design a drug that is very close in structure to that of the
substrate for the target enzyme.
 Prefer rapidly acting and selective (narrow spectrum) AMAs whenever
possible. Broad spectrum drugs should be used only when a specific drug
cannot be determined or is suitable.
 Use combination of AMAs whenever prolonged therapy is undertaken. Eg.
TB, AIDS, etc.
 Destruction of resistant bacteria can also be achieved by Phage Therapy, in
which a specific bacteriophage is used.

13. Overcome towards the Antibiotics Resistance
 Enzymatic inactivation: An existing bacterial enzyme is modified to interact
with an antibiotic in order to make them inactive towards bacteria. The most
significant examples are beta-lactamase enzymes, which hydrolyze beta-
lactams (penicillins, cephalosporins).
 Drug extrusion by efflux pumps: These proteins, which are able to extrude a
wide variety of compounds (including antibiotics) out of the cell, are
overexpressed by the bacteria to extrude the antibiotic.
 Decreased uptake by changes in the outer membrane permeability or by
presence of porins: These variations interfere with the entrance of antibiotics.
 Modification of the drug target: These changes impede the binding of the
antibiotic and limit its potency.

14. Drug Resistance in ANTI-CANCER Therapy
 Anticancer drugs resistance is a complex process that arises from alterations in the
drug targets. Advances in the DNA microarray, proteomics technology and the
development of targeted therapies provide the new strategies to overcome the drug
resistance. The promising option for cancer treatment is chemotherapy.
 Currently, 90% of failures in the chemotherapy are during the invasion and
metastasis of cancers related to drug resistance. In the chemotherapy, by following
the administration of a certain drug, a large number of patient tumor cells become
resistant to the drug. So, the drug resistance appears as a serious problem in the
field of cancer.

15. Causes for Drug Resistance in ANTI-CANCER Therapy
 Alterations in drug targets
 Alterations in Drug detoxification
 Defective Apoptosis
 Increased DNA Repair
 Alterations in intracellular retention of drug
 Drug inactivation
 Dose skip form the patient

16. Intrinsic and acquired drug resistance in
Cancer
Intrinsic resistance
 It is usually defined as the innate resistance that exists before the patient is
administered with (exposed to) drugs, which usually causes reduced efficacy of
the drug treatment. Intrinsic resistance can be caused by:
 (1) pre-existing (inherent) genetic mutations in a majority of tumors that result in
decreased responsiveness of cancer cells, such as triple negative breast cancer
cells, to both chemo and target drugs;
 (2) heterogeneity of tumours in which pre-existed insensitive subpopulations,
including cancer stem cells, will be selected upon drug treatment thus leading to
relapse in later stages of therapeutic treatment;
 (3) activation of intrinsic pathways used as defence against environmental toxins

17. Acquired resistance
 Acquired resistance can be identified by gradual reduction of anticancer efficacy
of a drug after the drug treatment. Acquired resistance can be a result of:
 (1) activation of second proto-oncogene that becomes the newly emerged driver
gene;
 (2) mutations or altered expression levels of the drug targets;
 (3) changes in tumor microenvironment (TME) after treatment

18. Strategies to Combat Drug Resistance in ANTI-
CANCER therapy
Some strategies used clinically are:-
 pharmaco-kinetic strategies,
 pharmaco-genetic based strategies , and
 basic tumour biology directed strategies for dosing.
PHARMACOKINETIC MONITORING
One strategy to overcome tumour cell resistance to chemotherapy is to
employ pharmacokinetic strategies to further intensify doses of drugs by
giving the maximally tolerated dose of drugs as close together as possible.

19. Strategies to Combat Drug Resistance in ANTI-
CANCER therapy
PHARMACOGENETIC MONITORING
Pharmacogenetic based strategies are currently used to identify
monogentic traits in patients that would alter either a predisposition
to toxicity or the efficiency of response and currently, these
strategies are not used prospectively in patients to alter dosing in
prior.
BIOLOGIC INHIBITION OF TUMOR CELL PROPERTIES
(ABC TRANSPORTERS)
Expression of mutated cells causes defects in the apoptotic pathway,
allowing cancerous cells to avoid death. Re-expression of the wild
type gene in cancer cells has been shown to inhibit cell proliferation,
induce cycle arrest and apoptosis.

20. Genetic Principle of Drug Resistance
Generally Drug resistance arises one or more of the following reasons.
 Selection of cells that have increased expression of membrane
glycoproteins, increase in levels of cytoplasmic thiols, increasing in
deactivating enzymes or decrease in activating enzymes by changes in
specific gene sequences and increase in DNA repair
 Membrane glycoproteins (P-glycoproteins) are responsible for the
efflux of drugs from cells and represent a type of Multi Drug
Resistance (MDR). These P-glycoproteins bind and extrude drugs from
tumor cells. By increasing pools of cytoplasmic thiols, such as
glutathione, the cell increases its ability to destroy reactive
electrophilic anticancer drugs.
 .

21. Genetic Principle of Drug Resistance
 More specifically gene encoding the family of glutathione S-transferases,
which catalyze the reaction of glutathione with electrophilic compounds, may
be altered so that enzymes are overproduced (gene amplification).
 Many drugs bind to DNA require enzymatic activation (prodrugs). The genes
encoding these enzymes may be altered so that certain tumor cells no longer
produce sufficient quantities of the activating enzymes to allow drugs to be
effective

22. THANK YOU
For Listening