ROLE OF PHARMACISTS IN COMBATING DRUG RESISTANCE.

BY Neel Ratnam

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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

Bacterial sensitivity test and find out the possible causes of development

Treat Infection

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

Patient Counselin

g, Awareness Program

4.PRESCRIBER RELATED

Inappropriate use of available drugs

Increased empiric poly-antimicrobial use

Poor clinical practice

Inadequate dosing

Lack of current knowledge and training

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

SELECTION OF ANTIMICROBIAL AGENTS

Selection of the most appropriate antimicrobial agent requires knowing

1) The organism’s identity : gram +/-2) The organism’s susceptibility to a particular agent3) The site of the infection- blood-brain barrier effects,

protein binding, lipid solubility and MW of the drug4) Patient’s factor- Renal/Hepatic nature,age, gender,

pregnancy, lactation and immune system5) The cost of therapy

MECHANISM OF ANTIMICROBIAL AGENTS

1. Inhibition of cell wall synthesis

2. Inhibition of function of cell membrane

3. Inhibition of protein synthesis

4. Inhibition of nucleic acid synthesis

5. Inhibition of folic acid synthesis

ANTIBIOTIC RESISTANCEDefined 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 naturally1.  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.

• 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

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

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 co-integration

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

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

STRUCTURALLY MODIFIED ANTIBIOTIC TARGET SITE

Interior of organism

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

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

Environment

Cytoplasm

Porin

Efflux System Pump

Efflux System Exit Portal

Linker Lipoprotein

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

SulfonamidesActive export out of the cell & reduced affinity of enzymes

HOW PHARMACISTS CAN HELP COMBAT DRUG RESISTANCE… Developing new antibiotics Judicious use of the existing

antibiotics Community Pharmacists as Gateway

Practitioners-Prevent Antibiotic Misuse.

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

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 pharmacist has the time and skills to

monitor antibiotic prescribing and manage it appropriately

Key roles for 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

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

Ceftobiprole: 5th generation cephalosporins Ceftaroline: Advanced generation cephalosporin

Iclaprim: Inhibits Dihydrofolate reductase

TAKE HOME MESSAGE Target definitive therapy to known pathogen

Treat infection, not contamination

Treat infection, not colonization

Isolate Pathogen, utilise microbiology lab

Break the chain of contagion – Keep our hands clean.

END

Thank You !!!!!!!!!!

!!

Hope is not exhausted….yet