role of pharmacists in combating drug resistatnce by neel ratnam
TRANSCRIPT
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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
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WHO’S WORK?
Microbiologist
Physician
Bacterial sensitivity test and find out the possible causes of development
Treat Infection
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WHO’S WORK?
Microbiologist
Physician
Pharmacologist
Advise the proper and
adequate antibiotics with
balancing the economy of
hospital
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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.
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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.
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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
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FACTORS INFLUENCING ANTIBIOTIC RESISTANCE
Environmental Factors
Drug Related Factors
Patient Related Factors
Prescriber Related Factors
Antibiotic Resistanc
e
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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
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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
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3. PATIENT RELATED Poor adherence of dosage Regimens
Poverty
Lack of sanitation concept
Lack of education
Self-medication
Misconception
Patient Counselin
g, Awareness Program
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4.PRESCRIBER RELATED
Inappropriate use of available drugs
Increased empiric poly-antimicrobial use
Poor clinical practice
Inadequate dosing
Lack of current knowledge and training
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1962 AND 2000, NO MAJOR CLASSES OF ANTIBIOTICS WERE INTRODUCED
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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
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• 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
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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
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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
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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.
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Understanding Mechanism of Antibiotic Resistance at Molecular Level
Intrinsic (Natural) Acquired
Genetic Methods
Chromosomal Methods Mutations
Extra chromosomal Methods Plasmids
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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
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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
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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
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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
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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.
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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.
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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.
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TRANSPOSONS
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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.
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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
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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
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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
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EFFLUX PUMP MECHANISM
• Bacteria are capable of flushing out antibiotics before they reach their target site.
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Environment
Cytoplasm
Porin
Efflux System Pump
Efflux System Exit Portal
Linker Lipoprotein
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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END
Thank You !!!!!!!!!!
!!
Hope is not exhausted….yet