Role of pharmacists in combating drug resistatnce by neel ratnam.
Antibiotic ResistanceROLE 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 resistanceWhos Work?MicrobiologistPhysicianBacterial sensitivity test and find out the possible causes of developmentTreat InfectionWhos Work?MicrobiologistPhysicianPharmacologistAdvise the proper and adequate antibiotics with balancing the economy of hospitalIntroduction 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 increasing6IntroductionThe 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.7 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 themHistory 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 8Factors INFLUENCING Antibiotic ResistanceEnvironmental FactorsDrug Related FactorsPatient Related FactorsPrescriber Related FactorsAntibiotic Resistance1. Environmental FactorsHuge populations and overcrowdingPoor sanitationIneffective infection control programsWidespread use of antibiotics in animal husbandry and agriculture and as medicated cleansing products2. 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 level3. Patient RelatedPoor adherence of dosage RegimensPovertyLack of sanitation conceptLack of educationSelf-medicationMisconceptionPatient Counseling, Awareness Program 4.Prescriber RelatedInappropriate use of available drugsIncreased empiric poly-antimicrobial usePoor clinical practiceInadequate dosingLack 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 failureIncreased mortality Resistant bacteria may spread in CommunityAdd 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 useAntibiotic Resistance 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 dosagesResistant MIC is higher than normally attainable levels in body fluidsIntermediate (moderately sensitive, moderately resistant) MIC is between sensitive and resistant levels, may be able to treat with increased dosage17SELECTION 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 therapyMECHANISM OF ANTIMICROBIAL AGENTSInhibition of cell wall synthesisInhibition of function of cell membraneInhibition of protein synthesisInhibition of nucleic acid synthesisInhibition of folic acid synthesisAntibiotic 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.21Understanding Mechanism of Antibiotic Resistance at Molecular LevelIntrinsic (Natural)AcquiredGenetic Methods Chromosomal Methods MutationsExtra chromosomal Methods PlasmidsINTRINSIC 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 KlebsiellaAcquired 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 mediatedMechanism 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 , StreptococciTransformation : 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-integrationBoth plasmids then separate and each contains the r-gene carrying the transposon.TransposonsMechanism of resistance gene Transfer-integronsIntegron is a large mobile DNA that can spread Multidrug resistanceEach 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 antibioticDecreased permeability: Porin LossInterior of organismCell wallPorin channel into organismAntibioticAntibiotics normally enter bacterial cells via porin channels in the cell wall Structurally modified antibiotic target siteInterior of organismCell wallModified target siteAntibioticChanged site: blocked bindingAntibiotics 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.EnvironmentCytoplasmPorinEfflux System Pump Efflux System Exit Portal Linker LipoproteinIVZ 2005-W-226381-SSSlide 37Shown 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 togetherOptional:It is significant to know, doctor, that hyper-expression of the efflux system leads not only to dramatic increases in MIC for meropenem but it also induces cross-resistance to other antimicrobials such as fluoroquinolones, penicillins, cephalosporins, macrolides, and sulphonamides.Modification/Protection of the Target siteResistance resulting from altered target sites:Target sitesResistant Antibiotics Ribosomal point mutationTetracyclines,Macrolides, ClindamycinAltered DNA gyraseFluoroquinolonesModified penicillin binding proteins (Strepto.pneumonia)PenicillinsMutation in DNA dependant RNA polymerase (M.tuberculosis)Rifampicin Drug Mechanism of resistancePencillins & CephalosporiinsB Lactamase cleavage of the Blactam ringAminoglycosidesModification by phosphorylating, adenylating and acetylating enzymesChloramphenicolModification by acetylytionErythromycinChange in receptor by methylation of r RNATetracyclineReduced uptake / increased exportSulfonamidesActive export out of the cell & reduced affinity of enzymesHow Pharmacists can help combat drug resistanceDeveloping new antibiotics Judicious use of the existing antibioticsCommunity 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 resistanceEducation:--Patient and clinician educationinfection-control practices such as general hygiene, hand hygiene, cough etiquette, immunizations, and staying home when sickHow Pharmacists can help combat drug resistance.Prudent antimicrobial prescribingUK hospitals have appointed microbiologists or infectious diseases physicians with antibiotic management , Pharmacists as Drug Experts Must undertake such roles as Lead Antibiotics PharmacistsEstablishment of Hospital Antibiotic PolicyHow Pharmacists can help combat drug resistance.A dedicated pharmacist has the time and skills to monitor antibiotic prescribing and manage it appropriatelyKey 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 antimicrobialsHow 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 ribosomeDaptomycin: depolarization of bacterial cell membrane Dalbavacin: inhibits cell wall synthesis Telavacin: inhibition of cell wall synthesis and disruption of membrane barrier functionCeftobiprole: 5th generation cephalosporins Ceftaroline: Advanced generation cephalosporinIclaprim: Inhibits Dihydrofolate reductase Take Home MessageTarget definitive therapy to known pathogenTreat infection, not contaminationTreat infection, not colonizationIsolate Pathogen, utilise microbiology labBreak the chain of contagion Keep our hands clean.COLONIZATION means that the organism is present in or on the body but is not causing illness.Adopt WHO Strategies and PoliciesVaccination is the most logical and effective means to contain resistance by preventing infection in the first place. For ARIs, diarrhoeal diseases and malaria in children, WHO has developed the Integrated Management of Childhood Illness (IMCI). For the treatment of TB, WHO recommends use of the DOTS strategy. Antimicrobial resistance surveillance another critical tool in the fight against antimicrobial resistance identifies and tracks resistance trends in specific infections and geographical locations. INFECTION means that the organism is present and is causing illness.47ENDThank You !!!!!!!!!!!!Hope is not exhausted.yet!!!!!!!!!!!!48