antimicrobial and mechanism

1. TOPIC 5
Antimicrobial Resistance + Cues for action
PBL E

2. General Usage of Antimicrobials Drugs
• Act as bactericidal agent (kills bacteria) or bacteriostatic
agent (inhibit the growth of bacteria)
Combined use of antimicrobials
• To achieve synergism
(E.g. rifampin + isoniazid in tuberculosis)
• To broaden the spectrum of antimicrobial actions
- Treatment of mixed infection
- Initial treatment of severe infections since bacterial diagnosis is still not known
• To reduce adverse effects
(if combination is synergistic, doses of drug can be reduced, therefore lesser adverse effects)
• To prevent emergence of resistance:
(for chronic infections, such as tuberculosis, leprosy and HIV)

3. DEVELOPMENT OF
ANTIMICROBIALS

4. • Golden age of antibiotics
• Discovery
• Development
• Clinical exploitation
• Arguably the most significant medical advance of the century
• Considerable pharmaceutical investment
• 11 distinct antibiotic classes
• >270 antibiotics in clinical use
20th Century

5. The History of Chemotherapy
Paul Ehrlich and Sahachiro
Hata developed Salvarsan
(Arsphenamine) against
syphilis in 1910: The concept
of chemotherapy to treat microbial
diseases was born.
Sulfa drugs (sulfanilamide)
discovered in 1932 
against Gram+ bacteria

6. Fig 20.1
1928: Fleming discovered
penicillin
1940: Howard Florey and Ernst
Chain performed first clinical
trials of penicillin.

7. Alexander Fleming
Discovered penicillin while working with
Staphylococcus
Noticed there were no Staph colonies growing
near a mold contaminant
Identified mold as Penicillium and was
producing a bactericidal substance that was
effective against a wide range of microbes
Fleming unable to purify compound

8. Ernst Chain and Howard Florey successfully purified
penicillin
In 1941 tested on human subject with life threaten
Staphylococcus aureus infection
Treatment effective initially, but the supply of penicillin
ran out before disease under control
Drug tested again with adequate supply and the patients
recovered fully
Mass production of penicillin during WWII

9. • When penicillin was first made at the end of the
second world war using the fungus Penicillium
notatum, the process made 1 mg dm-3.
• Today, using a different species (P. chrysogenum) and
a better extraction procedures the yield is 50 g dm-3.
• There is a constant search to improve the yield.

10. Antibiotic production
• There are over 10 000 different antibiotics known, but only about
200 in commercial use.
• Since most new antibiotics are no better than existing ones.
• There is a constant search for new antibiotics. Antibiotics are the
most-prescribed drugs and are big business.
• Finding a new antibiotic and getting it on to the market is a very
long process and can take 15 years.

11. Antibiotic Production Methods
• Antibiotics are produced on an industrial scale using a
variety of fungi and bacteria.
• Penicillin is produced by the fungus Penicillium
chrysogenum which requires lactose, other sugars, and a
source of nitrogen (in this case a yeast extract) in the
medium to grow well.
• Like all antibiotics, penicillin is a secondary metabolite,
so is only produced in the stationary phase.

12. Fermentation
• Like all antibiotics, penicillin is a
secondary metabolite, so is only
produced in the stationary
phase.
• It requires a batch fermenter,
and a fed batch process is
normally used to prolong the
stationary period and so
increase production of penicillin
(secondary metabolite).

13. Downstream Processing (Purification)
• To purify the products in a
fermenter which are impure and
dilute
• This usually involves filtration to
separate the microbial cells from
the liquid medium, followed by
chemical purification and
concentration of the product
• Downstream processing can
account for 50% of the cost of a
process.

14. Chemical and enzymatic modification
• The resulting penicillin (called
penicillin G) can be chemically
and enzymatically modified to
make a variety of penicillins with
slightly different properties.
• These semi-synthetic penicillins
include penicillin V, penicillin O,
ampicillin and amoxycillin.

16. 1) Bacterial cell wall synthesis inhibitors
eg: penicillin ( bind to traspeptidase & inhibit cross linking of PG)
2) Protein synthesis inhibitors (eg: aminoglycoside)
Effectiveness of antimicrobial agents
• 3)Bacterial Folate Antagonist
Inhibitor of folate synthesis (sulphonamides) &
folate reduction (trimethoprim)

17. • 4) Inhibitor of nucleic acid function (quinolones and
fluoroquinolones)
inhibit topoisomerase II (a bacterial DNA gyrase), the
enzyme that produces a negative supercoil in DNA and
thus permits transcription or replication.

18. EFFECTIVENESS :
• B-Lactam antibiotics-
• A)penicillin
• B) cephalosporin
1st 2ND 3RD 4th
G+ and modest activity
against G-
Moderate atvt against
G+
Potency against G-
More active against G-
Some activity against
Pseudomonas Aeruginosa
Against G-
- G+ & G-
G+ bacilli
spirochetes
C) Carbapenem
Active to aerobic&anaerobic G+ &
G-
D)Monobactam
Only to G- aerobic rods

19. • Protein synthesis inhibitor
• 30S inhibitor ( Aminoglycosides)
spectrum :
50S inhibitor ;
1. Gram (-) Aerobic Bacilli
2. Beta-lactamase producers:
Staph. aureus
N. gonorrhea
3. Mycobacteria
30S Inhibitor ( Tetracycline)
Rickettsia, V. cholera, M. pneumonia, Chlamydia,
Shigella, H. pylori, P.tularensis, P. pseudomallei,
Brucella, Psittacosis, Borrelia
Chloramphenicol Macrolides
(eryhtromycin)
Clindamycin
Bactericidal – H. influenzae, N.
meningitides, B. fragilis
Bacteriostatic – S.
epidermidis, S. aureus, , M.
pneumonia, L.
monocytogenes, diphtheria,
Erythromycin has a
narrow Gram (+)
spectrum similar to
Pen. G.
Also active against
Chlamydia and
Legionella
Narrow Gram (+)
spectrum, excellent
activity against
anaerobic bacteria; strep,
pneumococci,
staphylococci

20. • Bacterial Folate Antagonist ( Sulphonamide and Trimethoprim)
• Antimicrob spectrum:
• Inhibitor of nucleic acid function (fluoquinolone)
bactericidal.
effective against gram-negative organisms such as the enterobacteria,
pseudomonas organisms, Haemophilus influenzae, Moraxella catarrhalis,
Legionella, Chlamydia and mycobacteria except for M. avium
intracellulare complex.
They are effective in the treatment of gonorrhea but not syphilis.

21. Penicillin
Cephalosporin
Monobactam
Carbapenem
Maculopapular rash
Diarrhea
Nephritis
Neurotoxicity
Neurotoxicity
Platelet Dysfunction
Allergy
Disulfiram-like reaction
Anti-Vit K
Phlebitis
Rash
Hepatoxicity
GI upset
Eosinophilia
Neutropenia
Lowering of seizure
threshold
Cell wall inhibitor
(β-Lactam Antibiotics)
Vancomycin
(other)
Phlebitis
Red-Man syndrome
Ototoxicity
Nephrotoxicity

22. Protein Synthesis
inhibitior
Tetracyclin
Gi upset
Hepatoxicity
Photosensitivity
Bony deposition
Teeth discolouration
Aminoglycoside
Macrolides
Chloramphenicol
Clindamycin
Nephrotoxicity
Ototoxicity
Neurotoxicity
GI upset
Ototoxicity
Hepatpxicity
Reversible Anaemia
Haemolytic anaemia
Aplastic Anaemia
Grey baby syndrome
Rash
Neutropenia
Trombocytopenia
Pseudomembranous
colitis

23. Inhibitor of
Metabolism
(Folate antagonist)
Sulfonamides Trimethoprim
Rash
Angioedema
Steven-Johnson Syndrome
Kernicterus
Folate deficiency
anaemia
Leukopenia
Granulocytopenia
Inhibitor of Nucleic Acid
Fluoroquinolone
Nausea
Dizziness
Photosensitivity
Nephrotoxicity

24. How antimicrobial
resistance being
developed?

25. What is antimicrobial
resistance?
• Resistance of a microorganism to an antimicrobial drug
that was originally effective for treatment of infections
caused by it.
• occurs when an antibiotic has lost its ability to effectively
control or kill bacterial growth
• The use and misuse of antimicrobial drugs accelerates the
emergence of drug-resistant strains. Poor infection
prevention and control practices, inadequate sanitary
conditions and inappropriate food-handling encourage
the further spread of antimicrobial resistance

27. How it is being developed?
Naturally occurring
Genetic mutation
Acquire resistance from another bacterium

28. 1. Naturally occurring

29. 2. Genetic mutation

30. 3. Bacteria gain resistance by getting copies
of resistance genes from other bacteria.
Bacteria acquire resistance genes through:
1. Conjugation
2. Transduction
3. Transformation

33. Effects of the drug resistant bacteria on
the transmission
• The rate of transmission of
the resistant organism is
increased since the
treatment is unable to
eradicate it.
• Resistance may delay and
hinder treatment, resulting in
complications or even death

34. Ways to Deal With Antimicrobial
Resistance on Transmission of
Disease
• Collect Data
• Strong testimony supporting the acknowledged
association between antibiotic abuse & resistance
• Identify areas of great need for corrective intervention
• Stop Antibiotic Use on the Farm
• The "farm to fork” phenomenon
• Resistant bacteria & resistance genes can be traced from the chickens to the chicken meat in
grocery stores and, finally, to blood cultures in patients
• Practice Antibiotic Stewardship
• Avoid unnecessary antibiotic use
• Switch from intravenous to oral formulations to hasten discharge & reduce risks
associated with IV catheters
• Avoid antibiotic redundancy,

35. • Reduce Inappropriate Antibiotic Use in Outpatients
• The abuse of antibiotics is well known as a large
part reflects consumer demand
• Public campaigns to convince patients & providers
to do better
• Be careful with an anti-antibiotic campaign that goes too far!
• Adopt Rapid Diagnostic Tests
• Facilitate antibiotic decision-making within 1-2 hours of collecting the
culture
• Develop New Drugs

37. • Antibiotic Awareness Week will
take place from 14–20
November 2016
• It is endorsed by the World
Health Organization,
acknowledging the global
importance of this growing
public health issue.