Role of pharmacists in combating drug resistatnce

Mweetwal-Pharmacologist

PHARMACEUTICAL SOCIETY OF ZAMBIA-PSZ

ROLE OF PHARMACISTS IN COMBATING DRUG RESISTANCE BY ENHANCING EVIDENCE BASED PRACTICE

BY MWEETWA L-PHARMACOLOGIST


OBJECTIVES

What is antimicrobial resistance

Why antibacterial resistance is a concern To Pharmacists

How antibacterials work

Mechanisms of resistance to antibacterials

Strategies to contain resistance


WHO’S WORK?

Microbiologist

Physician

Pharmacologist

Advise the proper and

adequate antibiotics with

balancing the economy of

hospital


INTRODUCTION 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.


INTRODUCTION 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 FlemingThe Nobel Prize in Physiology or

Medicine 1945


FACTORS INFLUENCING ANTIBIOTIC RESISTANCE

Environmental Factors

Drug Related Factors

Patient Related Factors

Prescriber Related Factors

Antibiotic Resistanc

e


1. ENVIRONMENTAL FACTORS

Huge populations and overcrowding

Poor sanitation

Ineffective infection control programs

Widespread use of antibiotics in animal husbandry

and agriculture and as medicated cleansing

products


2. DRUG RELATED

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


3. PATIENT RELATED Poor adherence of dosage Regimens

Poverty

Lack of sanitation concept

Lack of education

Self-medication

Misconception


4.PRESCRIBER RELATED 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

14

1962 AND 2000, NO MAJOR CLASSES OF ANTIBIOTICS WERE INTRODUCED


WHY RESISTANCE IS A CONCERN 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



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


INTRINSIC RESISTANCE 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 ResistanceMutations• It refers to the change in DNA

structure of the gene.• Occurs at a frequency of one per ten

million cells.

• Eg.Mycobacterium.tuberculosis,Mycobacterium 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.


Transfer of r-genes from one Bacterium to Another Transduction : Less common

method The plasmid DNA enclosed in a

bacteriophage is transferred to another bacterium of same species. Seen in Staphylococci , Streptococci


Transfer of r-genes from one Bacterium to Another Transformation : least clinical

problem. Free DNA is picked up from the

environment (i.e.. From a cell belonging to closely related or same strain.


MECHANISMS OF RESISTANCE GENE TRANSFER TRANSPOSONS

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.


TRANSPOSONS


MECHANISM OF RESISTANCE GENE TRANSFER-INTEGRONS 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.


BIOCHEMICAL MECHANISMS OF ANTIBIOTIC RESISTANCE• 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



STRUCTURALLY MODIFIED ANTIBIOTIC TARGET SITE


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


EFFLUX PUMP MECHANISM

• 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

, ClindamycinAltered 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

SulfonamidesActive 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


QUORUM SENSING 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


WHY NAMED QUORUM SENSING

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.


3D ANIMATION OF DRUG RESISTANCE


HOW PHARMACISTS CAN HELP COMBAT DRUG RESISTANCE… Develop new antibiotics

Pharmacist-directed antibiotic stewardship programs (ASPs)

Judicious use of the existing antibiotics


HOW PHARMACISTS CAN HELP COMBAT DRUG RESISTANCE..

Community Pharmacists as Gateway Practitioners-Prevent Antibiotic Misuse.

Vaccination-by preventing primary infection and indirectly by preventing bacterial superinfection


HOW PHARMACISTS CAN HELP COMBAT DRUG RESISTANCE… Education:-

-Patient and clinician education

infection-control practices such as general hygiene, hand hygiene, cough etiquette, immunizations, and staying home when sick


HOW PHARMACISTS CAN HELP COMBAT DRUG RESISTANCE…. 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


HOW PHARMACISTS CAN HELP COMBAT DRUG RESISTANCE…. 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


HOW PHARMACISTS CAN HELP COMBAT DRUG RESISTANCE…. Many physicians, medical

microbiologists and infectious diseases physicians might feel threatened by such proposals but Pharmacists are inseparable to drugs

TB & Leprosy Corners?


HOPE IS NOT EXHAUSTED….YET

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


ALTERNATIVE APROACHES 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


ROLES OF PHARMACIST ANTIBIOGRAM EXPERT

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


SOME NEWER ANTIBIOTICS

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


TAKE HOME MESSAGE 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


DISCLAIMER 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, logos and any other content used belong to their original innovators.


END

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

Role of pharmacists in combating drug resistatnce

Health & Medicine

Transcript of Role of pharmacists in combating drug resistatnce