MBBS,BDS

1. BACTERIAL DRUG RESISTANCE

2. What is drug resistance?
• Drug resistance(Antibiotic resistance)- it is
defined as the reduction in effectiveness of a drug
in curing the disease.
• Also known as dosage failure or drug intolerance
• It is the ability of bacteria to resist the antibiotic
action by either not being killed or no inhibition
of growth.
• Major problem in antibiotic therapy
• The small number of bacteria which remain
unkilled get a chance to flourish and increase in
number

4. Causes of emerging resistance
• Overuse or misuse of antibiotics
• Natural phenomenon for evolution of resistant strains
• Use of a particular antibiotic puts a selective pressure on a
bacterial population which promotes resistant bacteria
• Resistant bacteria spread in environment and transfer genes
coding for resistance to another bacteria
• Poor infection control practices in hospitals(poor hand
hygiene) which can facilitate spread of resistant strains
• Inadequate sanitary conditions
• Irrational antibiotic use by not following susceptibility
report
• Over the counter sale of drugs without prescription
• Extensive agricultural use
• Availability of few antibiotics

5. TYPES
1. ACQUIRED RESISTANCE- Emergence of
resistance in bacteria that are ordinarily
susceptible to antimicrobials by acquiring
genes for resistance.
2. INTRINSIC RESISTANCE- It refers to
innate ability of a bacterium to resist a class
of antimicrobial agents due to its inherent
structural or functional characteristics. Eg ;
gram negative bacteria are intrinsically
resistant to vancomycin.

8. INTRINSIC ANTIMICROBIAL RESISTANCE
Anaerobic bacteria Aminoglycosides
Aerobic bacteria Metronidazole
Gram negative bacteria Vancomycin
Klebsiella species Ampicillin
Pseudomonas Sulfonamides, trimethoprim, tetracycline,
chloramphenicol
Enterococci All cephalosporins
Serratia, Proteus, Burholderia Polymyxin B and colistin
Stenotrophomonas maltophila Carbapenems

9. 3. MUTATIONALAND TRANSFERABLE
DRUG RESISTANCE- Under selective
antibiotic pressure, bacteria acquire new genes
by following mehods.
a. Mutational resistance- Occurs due to resistance
in resident genes. Eg: Mycobacterium
tuberculosis for Anti tubercular drugs.
b. Transferable drug resistance- This is plasmid
(R plasmid carrying multiple genes encoding
resistance to a class of antibiotic) encoded and
transferred by conjugation and rarely by
transduction and transformation.

10. MUTATIONAL DRUG RESISTANCE TRANSFERABLE DRUG RESISTANCE
Resistance to one drug at a time Resistance to multiple drugs at a time
Low degree of resistance High degree resistance
Resistance can be overcome by drug
combination
R cannot be overcome by drug
combination
Resistant mutants have lowered virulence Resistant mutants do nor show lowered
virulence
Resistance spread by vertical transmission to
offsprings i.e non transferable
Resistance is transferable and spread by
horizontal
spread(conjugation,transduction/transf
ormation)

11. MECHANISMS OF
ANTIMICROBIAL RESISTANCE
1. Decreased permeability across the cell wall
2. Efflux pumps
3. Enzymatic inactivation
4. By modification of target sites

13. 1. Decreased permeability across the cell wall
• Modification (frequency, size, selectivity) of
porin channels by bacteria
• Prevention of antibiotic entry inside bacterial
cell
• Egs: Pseudomonas, Enterobacter, Klebsiella
against drugs like imipenem,
aminoglycosides, quinolones.

15. 2.Efflux pumps
• Mediate drug expulsion soon after entry
• Prevent intracellular drug accumulation
• Eg:
• E. coli against tetracyclines ,chloramphenicol
• Staphylococci against macrolides and
streptogramins
• S. aureus and S.pneumoniae against
flouroquinolones.

18. 3.Enzymatic inactivation
Bacteria produce enzymes to inactivate antibiotic
a. Beta lactamases-
• both gram positive and gram negative organisms.
• Breaks down beta lactam ring.
b. Aminoglycoside modifying enzymes-
(acetyltransferases, adenyltransferases,
phosphotransferases)
• both gram positive and gram negative organisms
produce it.
• It destroys structure of aminoglycoside antibiotic.
c. Chloramphenicol acetyl transferase
• Enterobacteriacae
• destroys structure of chloramphenicol.

19. Beta lactamase enzymes- these enzymes are capable of hydrolyzing
the beta lactam ring of beta lactam antibiotic.
• Extended spectrum beta lactamases, Metallobetalactamases, AmpC
beta lactamases, Oxacillinase
• Produced both by gram positive and gram negative organisms
• Plasmid encoded
• Transferred by conjugation (by transduction in S. aureus)
• Classification –
• 1. Ambler’s clssification
• 2. Bush Jacoby classification

22. 4. By modification of target sites
• Target site is within bacteria
• Eg : MRSA- Methicillin resistant Staphylococcus
aureus
• The target site of penicillin binding is “ Penicillin
binding protein(PBP) ”
• In resistant strains it gets altered to PBP-2a
• mecA gene(chromosomal) codes for this altered
PBP-2a
• As a result Penicillin does not bind to B latam
antibiotic and is prevented from inhibiting cell wall
syntheis

24. • In Mycobacterium TB it acquires antibiotic R
to Streptomycin by modification of ribosomal
protein or 16s rRNA.
• Rifampicin R in Mycobacterium TB is due to
mutation in RNA polymerase.
• Quinolone R in S.aureus and Pneumococcus is
due to mutation in DNA gyrase enzyme.

25. DRUG CLASS EXAMPLES MECHANISM OF RESISTANCE
Beta lactam antibiotics
PENICILLINS Penicillin G, Methicillin,
Oxacillin, Ampicillin,
Amoxicillin, carbenicillin,
aminopenicillins etc
1. Drug inactivation- by beta
lactamase production.
2. Alteration of PBPs- target site
modification
3. Decreased permeability- due to
altered outer membrane porins.
CEPHALOSPORI
NS
1- Cefazolin, Cephalaxin
2. Cefoxitin, cefuroxime
3. Ceftriaxone, Cefotaxime
4. Cefepime, Cefpirome
5. Ceftobiprole, Ceftaroline
ESBL(Extended spectrum beta
lactamases)
CARBAPENEMA
SES
Imipenem,Meropenem,Dorip
enem, Ertapenem
1. Carbapenemases
2. Efflux pump
AZTREONAM Aztreonam ESBL(Extended spectrum beta
lactamases)

26. DRUG CLASS EXAMPLES MECHANISM OF RESISTANCE
OTHER CELL WALL INHIBITORS
GLYCOPEPTIDES
(disrupt
peptidoglycan cross
linkage)
Vancomycin
Teicoplanin
Alteration of target(substitution of D-
ala-D-ala side chain of peptidoglycan)
FOSFOMYCIN Fosfomycin 1. Alteration of target
2. Produce enzymes which inactivate
fosfomycin
BACITRACIN Bacitracin Not defined

27. DRUG CLASS EXAMPLES MECHANISM OF RESISTANCE
PROTEIN SYNTHESIS INHIBITION
Anti -30s ribosmal subunit
AMINOGLYCOSIDES
(Irreversible binding to
30s subunit of ribosome)
Gentamycin
Amikacin
Neomycin
Tobramycin
Streptomycin
1. Drug inactivation by
aminoglycoside modifying enzymes
2. Decreased permeability through
gram negative outer membrane
3. Decreased influx of drug
TETRACYCLINES
(Bind to 30s subunit of
ribosome and block t
RNA attachment)
Tetracycline
Doxycycline
Minocycline
Demeclocycline
1. Decreased intracellular drug
accumulation(active efflux)
2. Ribosomal target site alteration

28. DRUG CLASS EXAMPLES MECHANISM OF RESISTANCE
PROTEIN SYNTHESIS INHIBITION
Anti -50s ribosmal subunit
CHLORAMPHENICOL
(Bind to 50s subunit of
ribosome and interfere
with peptide bond
formation)
Chloramphenicol 1. Drug inactivation by production of
chloramphenicol acetyl transferase
enzyme.
2. Active efflux of drug
MACROLIDES
(Bind to 50s subunit of
ribosome and prevent
translocation of elongated
peptide
Erythromycin
Clarithromycin
Azithromycin
1. Decreased intracellular drug
accumulation(active efflux)
2. Ribosomal target site alteration

29. DRUG CLASS EXAMPLES MECHANISM OF RESISTANCE
PROTEIN SYNTHESIS INHIBITION
LINEZOLID
(Bind to 50s and inhibit
protein synthesis)
Linezolid Alteration of target site
STREPTOGRAMINS
(Bind to 50s and inhibit
protein synthesis)
Quinpristin
Dalfopristin
1. Alteration of target site(dalfopristin)
2. Active efflux (quinpristin)
3. Drug inactivation (Quinpristin and
Dalfopristin
MUPIROCIN
(Inhibits isoleucyl t RNA
synthase)
Mupirocin Mutation of gene for target site protein

30. DRUG CLASS EXAMPLES MECHANISM OF RESISTANCE
NUCLEIC ACID SYNTHESIS INHIBITORS
DNA SYNTHESIS INHIBITORS
FLUOROQUINOLONE
S(FQ) (Inhibition of DNA
GYRASE and
TOPOISOMERASE IV)
1st generation FQ
(Norfloxacin,Ciprofloxaci
n, Ofloxacin)
2nd generation FQ
(Levofloxacin,
lomefloxacin,
moxifloxacin,sparfloxacin)
1.Alteration of target
site(mutation of DNA gyrase
genes)
2. Poor transport across cell
membranes
RNA SYNTHESIS INHIBITORS
RIFAMPIN
(inhibits RNA
polymerase)
Alteration of target ( rpoB gene
mutation)
MYCOLIC ACID SYNTHESIS INHIBITORS
ISONIAZID(Inhibit
mycolic acid synthesis)
Mutation in KatG enzyme which
processes drug to active
metabolite)

31. DRUG CLASS EXAMPLES MECHANISM OF RESISTANCE
FOLIC ACID SYNTHESIS INHIBITORS
PABA—Folate synthase(-sulfonamide)--->DHF Acid----DHFR(Trimethoprim -)---->THF
acid
SULFONAMIDES AND
TRIMETHPRIM
Sulfadiazine
Sulfacetamide
Cotrimoxazole
(Trimethoprim and
sulfamethoxazole)
Production of insensitive targets
like dihydropteroate synthase by
sulfonamides and dihydrofolate
reductase by trimethoprim that
bypass metabolic block
ANTIBIOTICS ACTING ON CELL WALL
GRAMICIDIN ( Forms
pores)
Not known
POLYMYXINS
Polymyxin B
Colistin or Polymyxin E
1. Alteration of LPS
2. Efflux pump mediated

32. DETECTION OF DRUG
RESISTANCE
1. Phenotypic method- estimation of phenotypic expression
ofresistance to one ormore antimicrobial drug
• Disc diffusion
• MIC determination
• Automated methods
2. Genotypic methods- detection of genes or nucleotide
sequences responsible for coding resistance
• DNA hybridisation
• Nucleic acid amplification
• Microarray techniques

33. WHAT CAN BE DONE?
• Find new targets for antibiotics
• Develop new antibiotics
• Improve pharmakinetics and pharmacodynamics of
neglected antibiotics
• Develop treatment protocols based on combination
therapy using existing and new antibiotics
• Develop alternatives for antibiotics (vaccines)
• Develop and study effect of policy measures and
economic stimuli to minimise barriers for the
development and introduction of new antibiotics

34. • Improve existing and develop new diagnostic
tools:
– that more effectively distinguish between viral and
bacterial infections
– that can promote the use of narrow spectrum
antibiotics
– for the identification of antibiotic resistance
bacteria; including their resistance profile

35. • Need for a surveillance system about the AMR
pattern of a country
• To quantify the burden of resistance
• To serve as a warning system
• To guide policy makers
• To track transmission routes
• To detect and control localised outbreaks
• To document impact of interventions and
efforts to reduce AMR