Date post: | 07-May-2015 |
Category: |
Health & Medicine |
Upload: | larry-mweetwa |
View: | 394 times |
Download: | 5 times |
Mweetwal-Pharmacologist
PHARMACEUTICAL SOCIETY OF ZAMBIA-PSZ
ROLE OF PHARMACISTS IN COMBATING DRUG RESISTANCE BY ENHANCING EVIDENCE BASED PRACTICE
BY MWEETWA L-PHARMACOLOGIST
Mweetwal-Pharmacologist
Mweetwal-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
Mweetwal-Pharmacologist
WHO’S WORK?
Microbiologist
Physician
Pharmacologist
Advise the proper and
adequate antibiotics with
balancing the economy of
hospital
Mweetwal-Pharmacologist
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.
Mweetwal-Pharmacologist
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.
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
FACTORS INFLUENCING ANTIBIOTIC RESISTANCE
Environmental Factors
Drug Related Factors
Patient Related Factors
Prescriber Related Factors
Antibiotic Resistanc
e
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
3. PATIENT RELATED Poor adherence of dosage Regimens
Poverty
Lack of sanitation concept
Lack of education
Self-medication
Misconception
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
Mweetwal-Pharmacologist
Mweetwal-Pharmacologist
Mweetwal-Pharmacologist
Mweetwal-Pharmacologist
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.
Mweetwal-Pharmacologist
Mweetwal-Pharmacologist
Understanding Mechanism of Antibiotic Resistance at Molecular Level
Intrinsic (Natural) Acquired
Genetic Methods
Chromosomal Methods Mutations
Extra chromosomal Methods Plasmids
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
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.
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
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.
Mweetwal-Pharmacologist
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.
Mweetwal-Pharmacologist
TRANSPOSONS
Mweetwal-Pharmacologist
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.
Mweetwal-Pharmacologist
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.
Mweetwal-Pharmacologist
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
Interior of organism
Cell wall
New porin channel into organism
Antibiotic
New porin channels in the bacterial cell wall do not allow antibiotics to enter the cells
Mweetwal-Pharmacologist
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
EFFLUX PUMP MECHANISM
• Bacterias are capable of flushing out antibiotics before they reach their target site.
Mweetwal-Pharmacologist
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
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
3D ANIMATION OF DRUG RESISTANCE
Mweetwal-Pharmacologist
HOW PHARMACISTS CAN HELP COMBAT DRUG RESISTANCE… Develop new antibiotics
Pharmacist-directed antibiotic stewardship programs (ASPs)
Judicious use of the existing antibiotics
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
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?
Mweetwal-Pharmacologist
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).
Mweetwal-Pharmacologist
Phage therapy• Bacteriophages are viruses that invade
bacterial cells and disrupt bacterial metabolism and cause the bacterium to lyse.
• Efflux Pump Inhibitors:?
Alternate Approaches
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
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
Mweetwal-Pharmacologist
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.
Mweetwal-Pharmacologist
END
Thank You, Twalumba, Zikomo !!!!!!!!!!!!