ROLE OF PHARMACISTS IN COMBATING DRUG RESISTANCE.BY Neel Ratnam
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
MicrobiologistPhysicianBacterial sensitivity test and find out the possible causes of developmentTreat Infection
MicrobiologistPhysicianPharmacologistAdvise 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.
Bubonic plague, TB , Malaria, HIV have affected significant number of human beings and caused mortality and morbidity Adult humans contains 1014 cells, only 10% are human the rest are bacteriaAntibiotic use promotes Darwinian selection of resistant bacterial speciesBacteria have efficient mechanisms of genetic transfer this spreads resistanceBacteria double every 20 minutes, humans every 30 yearsDevelopment of new antibiotics has slowed resistant microorganisms are increasing
IntroductionThe 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, 1945Sir Alexander FlemingThe Nobel Prize in Physiology or Medicine 1945
Antimicrobial agents were viewed as miracle cure when introduced into clinical practice. However it became evident rather soon after the discovery of penicillin that resistance develops quickly terminating the miracle. This serious development is ever present with each new antimicrobial agents and threatens end of antimicrobial area. Today even major class of antibiotics are resistant 8
Factors INFLUENCING Antibiotic ResistanceEnvironmental FactorsDrug Related FactorsPatient Related FactorsPrescriber Related FactorsAntibiotic Resistance
1. Environmental FactorsHuge populations and overcrowdingPoor sanitationIneffective infection control programsWidespread use of antibiotics in animal husbandry and agriculture and as medicated cleansing products
2. Drug RelatedOver the counter availability of antimicrobialsCounterfeit and substandard drug causing sub-optimal blood concentrationIrrational fixed dose combination of antimicrobialsSoaring use of antibioticsPolicy Decision at Higher level
3. Patient RelatedPoor adherence of dosage RegimensPovertyLack of sanitation conceptLack of educationSelf-medicationMisconceptionPatient Counseling, Awareness Program
4.Prescriber RelatedInappropriate use of available drugs
Increased empiric poly-antimicrobial use
Poor clinical practice
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
Resistant bacteria may spread in Community
Add burden on healthcare costs
Threat to return to pre-antibiotic era
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
If this can be achieved, the microorganism is considered susceptible to the antibiotic. If an inhibitory or bactericidal concentration exceeds that which can be achieved safely in vivo, then the microorganism is considered resistant to that drug.
Antibiotic resistance refers to unresponsiveness of microorganism to antimicrobial agents.
Susceptible MIC is at a concentration attainable in blood or other appropriate body fluid using usually recommended dosages
Resistant MIC is higher than normally attainable levels in body fluids
Intermediate (moderately sensitive, moderately resistant) MIC is between sensitive and resistant levels, may be able to treat with increased dosage
SELECTION OF ANTIMICROBIAL AGENTSSelection of the most appropriate antimicrobial agent requires knowingThe organisms identity : gram +/-The organisms susceptibility to a particular agentThe site of the infection- blood-brain barrier effects, protein binding, lipid solubility and MW of the drugPatients factor- Renal/Hepatic nature,age, gender, pregnancy, lactation and immune systemThe cost of therapy
MECHANISM OF ANTIMICROBIAL AGENTSInhibition of cell wall synthesisInhibition of function of cell membraneInhibition of protein synthesisInhibition of nucleic acid synthesisInhibition 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 LevelIntrinsic (Natural)AcquiredGenetic Methods Chromosomal Methods MutationsExtra chromosomal Methods Plasmids
INTRINSIC RESISTANCEIt occurs naturallyLack target : No cell wall; innately resistant to penicillin Innate efflux pumps:Drug blocked from entering cell or export of drug (does not achieve adequate internal concentration). Eg. E. coli, P. aeruginosa 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 anotherConjugationTransductionTransformationTransfer of r-genes between plasmids within the bacteriumBy transposonsBy Integrons
Transfer of r-genes from one Bacterium to AnotherConjugation : 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 AnotherTransduction : 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 TransposonsTransposons 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.
Mechanism of resistance gene Transfer-integronsIntegron 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 resistancePrevention 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 organismCell wallPorin channel into organismAntibiotic
Antibiotics normally enter bacterial cells via porin channels in the cell wall
Structurally modified antibiotic target site
Interior of organismCell wallModified target siteAntibiotic
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.
Efflux System Pump
Efflux System Exit Portal
IVZ 2005-W-226381-SSSlide 37
Shown here, doctor, are the three major components of the efflux system:Mex B which pumps the efflux substrate meropenem to theOprM exit portal which carries it back to the environmentAnd the Linker Lipoprotein (Mex A) which joins the two units together
Optional:It is significant to know, doctor, that hyper-expression of the efflux system leads not