PROBLEM OF ANTIBIOTIC RESISTANCE & RATIONAL USE OF ANTIBIOTICS to the pharmacist

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2. PROBLEM OF ANTIBIOTIC
RESISTANCE & RATIONAL USE
OF ANTIBIOTICS
SUHAIL K
Lecturer
Crescent college of pharmaceutical sciences
suhailk4@gmail.com
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3. INTRODUCTION
Throughout history there has been a continual battle
between human beings and multitude of micro-organisms
that cause infection and disease.
ANTIBIOTICS:
Produced by micro organism, which selectively
suppress the growth of or kill other micro organisms at
very low concentrations.
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4. PROBLEMS WITH USE OF AMAs
1. Toxicity:
Local irritancy
Systemic toxicity
2. Hypersensitivity reactions
3. Superinfection
4. Nutritional deficiencies
5. Masking of an infection
6. Drug resistance 4

5. Drug resistance occurs in :
Bacteria—Antibiotic Resistance
Endoparasites
Viruses—Resistance to antiviral drugs
Fungi
Cancer cells
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6. 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, and the same
thing has occasionally happened in the body……and by
exposing his microbes to non-lethal quantities of the
drug make them resistant.”
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7. Why resistance is a concern:
•Resistant organisms lead to treatment failure
•Increased mortality
•Resistant bacteria may spread in Community
•Low level resistance can go undetected
•Added burden on healthcare costs
•Threatens to return to pre-antibiotic era
•Selection pressure
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8. Antibiotic Resistance
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.
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. 8

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11. Antibiotic Resistance
Some microorganisms may ‘born’ resistant, some
‘achieve’ resistance by mutation or some have
resistance ‘thrust upon them’ by plasmids
Some are born great, some achieve greatness or
some have greatness thrust upon them.
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12. 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
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13. Acquired resistance
Mutations
• 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
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14. 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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16. 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
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17. Decreased permeability: Porin Loss
Antibiotics normally enter bacterial cells via porin
channels in the cell wall
New porin channels in the bacterial cell wall do not
allow antibiotics to enter the cells
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20. Structurally modified antibiotic target site
Antibiotics normally bind to specific binding proteins
on the bacterial cell surface
Antibiotics are no longer able to bind to modified
binding proteins on the bacterial cell surface
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21. Modification/Protection of the Target site
Target sites Resistant Antibiotics
Ribosomal point mutation
eg.: Tetracyclines,Macrolides, Clindamycin
Altered DNA gyrase. Eg: Fluoroquinolones
Modified penicillin binding proteins
(Strepto.pneumonia) Eg: Penicillins
Mutation in DNA dependant RNA polymerase
(M.tuberculosis) Eg: Rifampicin
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22. Antibiotic inactivation
Inactivating enzymes target antibiotics
Enzymes bind to antibiotic molecules and destroy or
prevent binding to target sites
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23. a)Inactivation of b-lactam antibiotics
•S. aureus, N. gonorrohoea, H.influenza, Produce
blactamase which cleaves -lactam ring
b)Inactivation of Chloramphenicol
• Inactivated by chloramphenicol acetyltransferase .
• Gram-ve (enzyme present constitutively hence higher
resistance) gram +ve bacteria (enzyme is inducible )
c)Inactivation of Aminoglycosides
• Inactivated by acetyl, phospho & adenylyl transferases
Present in gram +ve and gram –ve .
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25. 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 over
production of PABA
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26. 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.
• 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
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27. 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.
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28. Factors of
Antibiotic
Resistance
Drug
Related
Factors
Environ
mental
Factors
Prescriber
Related
Factors
Patient
Related
Factors
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29. Environmental Factors
Huge populations and overcrowding
• Rapid spread by better transport facility
• Poor sanitation
• Increases community acquired resistance
• Ineffective infection control program
• Widespread use of antibiotics in animal husbandry
and agriculture and as medicated cleansing products
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30. Drug Related Factors
• Over the counter availability of antimicrobials
• Counterfeit and substandard drug causing suboptimal
blood concentration
• Irrational fixed dose combination of antimicrobials
• Soaring use of antibiotics
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31. Patient Related Factors
• Poor adherence of dosage Regimens
• Poverty
• Lack of sanitation concept
• Lack of education
• Self-medication
• Misconception
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32. Prescriber Related Factors
• Inappropriate use of available drugs
• Increased empiric poly-antimicrobial use
• Over use of antimicrobials
• Inadequate dosing
• Lack of current knowledge and training
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33. Strategy to Contain Resistance
• Develop new antibiotics
– Bypass the drug resistance
• Judicious use of the existing antibiotics:
– Containment of drug resistance
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34. • Only 15 antibiotics of 167 under development had a
new mechanism of action with the potential to combat
of multidrug resistance.
• Lack of incentive for companies to develop
antibiotics.
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36. 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).
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37. Phage therapy
• Phage Therapy is the therapeutic use of lytic
bacteriophages to treat pathogenic bacteria infections
• Bacteriophages are viruses that invade bacterial cells and
disrupt bacterial metabolism.
• The success rate was 80–95%
• British studies also demonstrated significant efficacy of
phages against Escherichia coli, Acinetobacter sp,
Pseudomonas sp and Staphylococcus aureus.
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38. Prevention and control
Antibiotic resistance is accelerated by the misuse and
overuse of antibiotics, as well as poor infection
prevention and control.
Steps can be taken at all levels of society to reduce the
impact and limit the spread of resistance.
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Individuals
• Only use antibiotics when prescribed
• Never demand antibiotics if your health worker says
you don’t need them.
• Always follow your health worker’s advice when using
antibiotics.
• Never share or use leftover antibiotics.

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• Prevent infections by regularly washing hands, preparing food
hygienically, avoiding close contact with sick people, practicing
safer sex, and keeping vaccinations up to date.
• Prepare food hygienically, following the WHO Five Keys to Safer
Food (keep clean, separate raw and cooked, cook thoroughly, keep
food at safe temperatures, use safe water and raw materials) and
choose foods that have been produced without the use of antibiotics
for growth promotion or disease prevention in healthy animals.

41. Poor Clinical Practice
Poor clinical practice that fail to incorporate the
pharmacological properties of antimicrobials amplify
the speed of development of drug resistance
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42. Faulty Antibiotic Use
• Antimicrobials are over prescribed
• Available without prescription
• Clinician should first determine whether
antimicrobial therapy is warranted for a given
patient
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43. Empirical Microbial Selection
• Is antimicrobial agents indicated on the basis of clinical
findings?
• Or is it prudent to wait until such clinical findings
become apparent?
•Can some simple bed side test done to confirm your
suspicion?
– Microscopy
– Gram staining
Have appropriate clinical specimens been obtained to
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44. • What are the likely etiologic agents for the patient’s
illness?
• Is there clinical evidence (e.g. from clinical trials) that
antimicrobial therapy will confer clinical benefit for the
patient? (Evidence-based medicine)
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45. Definitive Treatment
• Can a narrower spectrum agent be substituted for initial
empiric drug?
• Is one agent or combination of agents necessary?
• What are the
– optimum dose,
– route of administration and
– duration of therapy?
• What specific test to identify patients who will not respond
to treatment? 45

46. • What adjunctive measures can be undertaken to
eradicate infection?
– Vaccination
– Steroid
– Drainage of pus
– Amputation
– Removal of catheter
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47. Microbiologist
Bacterial sensitivity test and find out the possible
causes of development
Physician
treatment
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48. PHARMACOLOGIST
Advise the proper and adequate antibiotics with
balancing the economy of hospital
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49. Role of Pharmacist in Combating Resistance:
• Promote awareness among the population, for ethical or
proper safe use of antibiotics.
• Must obtain accreditation and training for disbursement
of knowledge about antibiotic.
• Helping physicians with drug selection and deciding on
duration of therapy, designing and promotion of clinical
practice guidelines, implementation of antibiotic switch
programmes, and documentation of the effectiveness of
interventions.
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50. • All hospitals should have an antibiotic pharmacist who
has the rights to interfere in the treatment which are
associated with antibiotics in the prescription.
• In-order to improve effectiveness and reduce antibiotic
prescribing which will also help in reducing drug-drug
interactions, errors and allergic reactions and adverse
drug reactions associated with the unethical use of
antibiotics.
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51. GUIDELINES FOR RATIONAL USE OF
ANTIBIOTICS
➢ Use antibiotics only when indicated.
➢ Where appropriate, specimen for gram stain, culture and
sensitivity testing should be obtained before commencing
antibiotic therapy
➢ Choice of agent based on causative organism, safety,
previous clinical response, cost, ease of use and potential.
➢ Adequate dose and duration of treatment is essential.
➢ History of allergy or other ADR should be considered.
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THANK YOU .....