Role of pharmacists in combating drug resistatnce

Mweetwal-Pharmacologist
 ROLE OF PHARMACISTS IN COMBATING DRUG RESISTANCE BY ENHANCING
EVIDENCE BASED PRACTICE
 BY MWEETWA L-PHARMACOLOGIST

 What is antimicrobial resistance
 Why antibacterial resistance is a concern To
Pharmacists
 How antibacterials work
 Mechanisms of resistance to antibacterials
 Strategies to contain resistance

Microbiologist
Physician
Pharmacologist
Advise the
proper and
adequate
antibiotics with
balancing the
economy of
hospital

 Throughout history there has been a
continual battle between human beings and
multitude of micro-organisms that cause
infection and disease.
 The pharmacist's role in combating and
preventing infectious diseases is essential as
antibiotic and vaccine regimens become
more complex due to the continuously
evolving epidemiology of infections.

 The decrease in drug development makes the
preservation of currently available
antibiotics paramount.
 Pharmacists as Custodian and experts in
Medicines Must Play a Pivotal Role In
combating Drug Resistance and Must
understand How drug resistance happens at
molecular level.

In his 1945 Nobel Prize lecture, Fleming
himself warned of the danger of resistance –
“It is not difficult to make microbes
resistant to penicillin in the laboratory by
exposing them to concentrations not
sufficient to kill them”
History
Nobel Lecture, December 11, 1945
Sir Alexander Fleming
The Nobel Prize in Physiology or Medicine
1945

Environmental
Factors
Drug
Related
Factors
Patient
Related
Factors
Prescriber
Related
Factors
Antibiotic
Resistance

 Huge populations and overcrowding
 Poor sanitation
 Ineffective infection control programs
 Widespread use of antibiotics in animal husbandry and
agriculture and as medicated cleansing products

 Over the counter availability of antimicrobials
 Counterfeit and substandard drug causing sub-
optimal blood concentration
 Irrational fixed dose combination of
antimicrobials
 Soaring use of antibiotics
Policy
Decision at
Higher
level

 Poor adherence of dosage Regimens
 Poverty
 Lack of sanitation concept
 Lack of education
 Self-medication
 Misconception

 Inappropriate use of available drugs
 Increased empiric poly-antimicrobial use
 Poor clinical practice
 Over prescribing is an antibiotic warranted for a given patient?
 Empirical antimicrobial selection,Is there clinical evidence,(Evidence-
based medicine
 Inadequate dosing
 Lack of current knowledge and training

 Resistant organisms lead to treatment failure
 Increased mortality
 Resistant bacteria may spread in Community
 Add burden on healthcare costs
 Threat to return to pre-antibiotic era
 Selection pressure

• The concentration of drug at the site of
infection must inhibit the organism and
also remain below the level that is toxic to
human cells.
•Principles Of Chemotherapy Must be
applied when selecting Which antibiotic to
use
Antibiotic Resistance

Defined as micro-organisms that are not
inhibited by usually achievable systemic
concentration of an antimicrobial agent with
normal dosage schedule and / or fall in the
minimum inhibitory concentration (MIC)
range.

Understanding Mechanism of Antibiotic
Resistance at Molecular Level
Intrinsic (Natural) Acquired
Genetic Methods
Chromosomal Methods
Mutations
Extra chromosomal Methods
Plasmids

 It occurs naturally
1. Lack target :
• No cell wall; innately resistant to
penicillin
2. Innate efflux pumps:
• Drug blocked from entering cell or
↑ export of drug (does not achieve
adequate internal concentration).
Eg. E. coli, P. aeruginosa
3. Drug inactivation: Cephalosporinase
in Klebsiella

Acquired Resistance
Mutations
• It refers to the change in DNA structure
of the gene.
• Occurs at a frequency of one per ten
million cells.
• Eg.Mycobacterium.tuberculosis,Mycobact
erium lepra , MRSA.
• Often mutants have reduced
susceptibility

Plasmids
• Extra chromosomal genetic elements can replicate
independently and freely in cytoplasm.
• Plasmids which carry genes resistant ( r-genes) are
called R-plasmids.
• These r-genes can be readily transferred from one
R-plasmid to another plasmid or to chromosome.
• Much of the drug resistance encountered in clinical
practice is plasmid mediated

Plasmids
• Extra chromosomal genetic elements can
replicate independently and freely in
cytoplasm.
• Plasmids carry resistant genes ( r-genes) or
R-plasmids.
• These r-genes can be readily transferred
from one R-plasmid to another plasmid or to
chromosome.
• Much of the drug resistance encountered in
clinical practice is plasmid mediated

Mechanism of Resistance by
Gene Transfer
• 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

Transfer of r-genes from one
Bacterium to Another
 Conjugation : Main mechanism for spread of
resistance
The conjugative plasmids make a connecting
tube between the 2 bacteria through which
plasmid itself can pass.

 Transduction : Less common method
The plasmid DNA enclosed in a
bacteriophage is transferred to another
bacterium of same species. Seen in
Staphylococci , Streptococci

 Transformation : least clinical problem.
Free DNA is picked up from the
environment (i.e.. From a cell belonging
to closely related or same strain.

 Transposons are sequences of DNA that can
move around different positions within the
genome of single cell.
 The donor plasmid containing the
Transposons, co-integrate with acceptor
plasmid. They can replicate during
cointegration
 Both plasmids then separate and each
contains the r-gene carrying the transposon.

 Integron is a large mobile DNA that can
spread Multidrug resistance
 Each Integron is packed with multiple
gene casettes, each consisting of a
resistance gene attached to a small
recognition site.
 These genes encode several bacterial
functions including resistance and
virulence.

• Prevention of drug accumulation in the bacterium
• Modification/protection of the target site
• Use of alternative pathways for metabolic / growth
requirements
• By producing an enzyme that inactivates the antibiotic
• Quorum sensing Mechanism-RGEFPD.

Decreased permeability: Porin Loss
Interior of organism
Cell wall
Porin channel
into organism
Antibiotic
Antibiotics normally enter bacterial cells via porin channels
in the cell wall

Decreased permeability: Porin Loss
Cell wall
New porin channel
into organism
Antibiotic
New porin channels in the bacterial cell wall do not allow
antibiotics to enter the cells

Cell wall
Modified target site
Antibiotic
Changed site: blocked binding
Antibiotics are no longer able to bind to modified binding proteins
on the bacterial cell surface

• Bacterias are capable of flushing out
antibiotics before they reach their target
site.

Modification/Protection of the Target site
Resistance resulting from altered target
sites :
Target sites Resistant Antibiotics
Ribosomal point mutation Tetracyclines,Macrolides
, Clindamycin
Altered DNA gyrase Fluoroquinolones
Modified penicillin binding
proteins (Strepto.pneumonia)
Penicillins
Mutation in DNA dependant
RNA polymerase
(M.tuberculosis)
Rifampicin

Drug Mechanism of resistance
Pencillins &
Cephalosporiins
B Lactamase cleavage of the Blactam ring
Aminoglycosides Modification by phosphorylating,
adenylating and acetylating enzymes
Chloramphenicol Modification by acetylytion
Erythromycin Change in receptor by methylation of r
RNA
Tetracycline Reduced uptake / increased export
Sulfonamides
Active export out of the cell & reduced
affinity of enzymes

Use of alternative pathways for
metabolic / growth requirements
• Resistance can also occur by alternate
pathway that bypasses the reaction
inhibited by the antibiotic.
• Sulfonamide resistance can occur from
overproduction of PABA

 Microbes communicate with each other and
exchange signaling chemicals (Autoinducers)
 These autoinducers allow bacterial
 population to coordinate gene expression for
virulence, conjugation, apoptosis, mobility
and resistance

 Single autoinducer from single microbe is incapable
of inducing any such change
 But when its colony reaches a critical density
(quorum), threshold of autoinduction is reached and
gene expression starts
 QS signal molecules AHL, AIP, AI-2 & AI-3 have been
identified in Gm-ve bacteria
 AI-2 QS –system is shared by GM+ve bacteria also

WHY INHIBIT QUORUM SENSING
 Proved to be very potent method for bacterial
virulence inhibition.
 Several QS inhibitors molecules has been synthesized
which include AHL, AIP, and AI-2 analogues
 QS inhibitors have been synthesized and have been
isolated from several natural extracts such as garlic
extract.
 QS inhibitors have shown to be potent virulence
inhibitor both in in-vitro and in-vivo,using infection
animal models.Mweetwal-Pharmacologist

 Develop new antibiotics
 Pharmacist-directed antibiotic
stewardship programs (ASPs)
 Judicious use of the existing antibiotics

 Community Pharmacists as Gateway
Practitioners-Prevent Antibiotic Misuse.
 Vaccination-by preventing primary infection and
indirectly by preventing bacterial superinfection

 Education:-
-Patient and clinician education
 infection-control practices such as
general hygiene, hand hygiene, cough
etiquette, immunizations, and staying
home when sick

 Prudent antimicrobial prescribing
 UK hospitals have appointed microbiologists or
infectious diseases physicians with antibiotic
management , Pharmacists as Drug Experts Must
undertake such roles as Lead Antibiotics
Pharmacists
 Establishment of Hospital Antibiotic Policy

 A dedicated antibiotic pharmacist has the time
and skills to monitor antibiotic prescribing and
manage it appropriately
 Key roles for antibiotic pharmacists include:-
 education of medical, pharmaceutical and
nursing staff,
 audit of local practices, monitoring of antibiotic
consumption, participation in infection control,
formulary development and appraisal of new
antimicrobials

 Many physicians, medical microbiologists and
infectious diseases physicians might feel
threatened by such proposals but
Pharmacists are inseparable to drugs
 TB & Leprosy Corners?

 Phage therapy
 Use of the lytic enzymes found in mucus and saliva
 Agents that target type IIA topoisomerases
 Antimicrobial peptides (AMPs), lipopeptides (AMLPs)
 target bacterial membranes, making it nearly
impossible to develop resistance (bacteria would
have to totally change their membrane
composition).

Phage therapy
• Bacteriophages are viruses that invade bacterial
cells and disrupt bacterial metabolism and cause the
bacterium to lyse.
• Efflux Pump Inhibitors:?
Alternate Approaches

 Dedicated Hospital Pharmacist Antibiogram
Experts
 Whose task is to perform a periodic summary of
antimicrobial susceptibilities of local bacterial
isolates submitted to the hospital's clinical
microbiology laboratory.
 And assess local susceptibility rates, as an aid in
selecting empiric antibiotic therapy, and in
monitoring resistance trends over time within an
institution


 Provides current appropriate data on use of
antimicrobial therapy with improved patient
outcomes
 Slow the development of antimicrobial resistance
 Acts as Liaison Officer with other clinical staffs to
Develop evidence- based Treatment guidelines
 Educate providers and staff regarding antibiotic
guidelines
 Track resistance patterns and report back to medical
and hospital staff

 Linezolid: targets 50S ribosome
 Tigecycline: targets 30S ribosome
 Daptomycin: depolarization of bacterial cell membrane
 Dalbavacin: inhibits cell wall synthesis
 Telavacin: inhibition of cell wall synthesis and
disruption of membrane barrier function
 Ceftibiprole/ ceftaroline: cephalosporins
 Iclaprim: inhibits Dihydrofolate reductase

 Target definitive therapy to known pathogen
 Treat infection, not contamination
 Treat infection, not colonization
 Isolate Pathogen, utilise your microbiology lab
 Break the chain of contagion – Keep your hands clean.
 Start simple bed side test: Gram stain, microscopy

 The information contained in this presentation is
for information purposes only, and may not apply
to your situation.The author provides no
warranty about the content or accuracy of
content enclosed. Information provided is
subjective. Keep this in mind when reviewing this
guide.
 Neither the Publisher nor Author shall be liable
for any loss of profit or any other commercial
damages resulting from use of this guide. All links
are for information purposes only and are not
warranted for content, accuracy, or any other
implied or explicit purpose, all rights, images,Mweetwal-Pharmacologist

 Thank You, Twalumba, Zikomo !!!!!!!!!!!!

Role of pharmacists in combating drug resistatnce

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