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BACTERIAANTIBIOTIC RESISTANCE
Endoparasites
VirusesResistance to antiviral drugs
Fungi
Cancer cells
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.
GOODMAN & GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS - 11th Ed. (2006)
Antibiotic Resistance
Genetic Methods
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
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
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
Mechanisms of Resistance Gene Transfer
Quorum sensing
Decreased permeability: Porin Loss
Antibiotic
Porin channel
into organism
Cell wall
Interior of organism
Decreased permeability: Porin Loss
New porin channels in the bacterial cell wall do not allow
antibiotics to enter the cells
Cell wall
Interior of organism
Efflux pumps
Cytoplasmic membrane transport proteins.
Antibiotic
Cell wall
Interior of organism
Structurally modified antibiotic target site
Antibiotic
Modified target site
Cell wall
Antibiotic
Enzyme
Binding Target site
Cell wall
Interior of organism
Antibiotic inactivation
Enzymes bind to antibiotic molecules
Antibiotic Enzyme
binding
Cell wall
Interior of organism
Antibiotic inactivation
Enzymes destroy antibiotics or prevent binding to target sites
Antibiotic
Cell wall
Interior of organism
By producing enzymes that inactivates antibiotic
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 .
Use of alternative pathways for metabolic / growth
requirements
Antibiotic
Resistance
Prescriber
Patient Related
Related Factors
Factors
1. 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
2. Drug Related
Over the counter availability of antimicrobials
Overuse of antimicrobials
Inadequate dosing
Or is it prudent to wait
until such clinical
findings become
apparent?
Empirical Microbial Selection
Can some simple bed side test done to
confirm your suspicion?
Microscopy
Gram staining
Empirical Microbial Selection
Have appropriate clinical
specimens been obtained to
establish a microbial diagnosis?
Empirical Microbial Selection
What are the likely etiologic agents
for the patients illness?
Empirical Microbial Selection
What measures should be taken to protect
individuals exposed to the index case to
prevent secondary cases (1), and what
measures should be implemented to prevent
further exposure (2)?
2 1
Empirical Microbial Selection
Is there clinical evidence (e.g. from clinical
trials) that antimicrobial therapy will confer
clinical benefit for the patient?
(Evidence-based medicine)
Definitive Treatment
1. Can a narrower spectrum agent be
substituted for initial empiric drug?
Definitive Treatment (2)
1. Is one agent or combination of agents
necessary?
Examples
-lactam + Aminoglycosides
Extended spectum Penicillins + -lactamase
Inhibitors
Anti-tubercular regimen
Anti-leprotic regimen
Co-trimoxazole
Sulphadoxin + pyrimethamine
Artemisinin based Combination Therapy (ACT) in
Malaria
Definitive Treatment
What are the
optimum dose,
route of administration and
duration of therapy?
Definitive treatment
Microbiologist
Bacterial
sensitivity test
and find out
the possible
causes of Physician
development
Treat Infection
Whos Work?
Microbiologist