Antibiotic resistance

Relative or complete lack of effect of antimicrobial agent against a previously susceptible microbe/pathogen.
It is an evolutionary principal that organism adopt genetically to change in their environment.

since the doubling time of bacteria can be as short as 20 mnt, there may be many generations in even a few hours, providing ample opportunity for evolutionary adaptation.

The phenomenon of resistance imposes serious constraints on the options available for the treatment of many bacterial infections.

The resistance to chemotherapeutic agents can also develop in protozoa, in multicellular parasites and in population of malignant cells.
Today there are different strains of S. aureus resistant to almost every form of antibiotic in use.

1. Antibiotic
Resistance
VINAY GUPTAVINAY GUPTA
DEPT OF PHARMACOLOGYDEPT OF PHARMACOLOGY
UP UNIVERSITY OF MEDICAL UP UNIVERSITY OF MEDICAL
SCIENCES,SCIENCES,
SAIFAI, ETAWAH (UP) INDIASAIFAI, ETAWAH (UP) INDIA

2. Drug Resistance
Relative or complete
lack of effect of
antimicrobial agent
against a previously
susceptible
microbe/pathogen.

3. Fast breeders
Bacteria reproduce
very quickly.
Eschericia coli can
complete a life cycle
in 30 minutes.
E. Coli
© 2008 Paul Billiet ODWS

4.  It is an evolutionary principal that organism adopt
genetically to change in their environment.
 since the doubling time of bacteria can be as short as
20 mnt, there may be many generations in even a few
hours, providing ample opportunity for evolutionary
adaptation.
 The phenomenon of resistance imposes serious
constraints on the options available for the treatment of
many bacterial infections.
 The resistance to chemotherapeutic agents can also
develop in protozoa, in multicellular parasites and in
population of malignant cells.
Drug Resistance

5. Resistance
It took less than 10 years for, bacteria to
show signs of resistance.
Staphylococcus aureus, which causes
blood poisoning and pneumonia, started
to show resistance in the 1950.
Today there are different strains of S.
aureus resistant to almost every form of
antibiotic in use.
© 2008 Paul Billiet ODWS

6. Multiple resistance
It seems that some resistance was already
naturally present in bacterial populations
The presence of antibiotics in their
environment in higher concentrations
increased the pressure by natural selection
Resistant bacteria that survived, rapidly
multiplied
They passed their resistant genes on to other
bacteria (both disease causing pathogens
and non-pathogens)
© 2008 Paul Billiet ODWS

7. Sex in bacteria
Bacteria do exchange genes forming new
combinations
Bacteria exchange genes is by conjugation
This involves the transfer of genetic material via
a cytoplasmic bridge between the two organisms
Recent studies on bacteria in the wild show that
it definitely occurs in the soil, in freshwater and
oceans and inside living organisms
© 2008 Paul Billiet ODWS

8. Drug Resistance
Types
Natural resistance
Acquired resistance

9. Natural resistance:
already resistant for certain AMA
Lack the target site OR metabolic process which
was earlier affected by particular drug.
It is may be for a group OR may be some species
of microorganism.
Eg: Gm –ve bacilli are unaffected by Penicillin G
: M. tuberculosis is insensitive to tetracycline's.
This type of resistance usually
does not show any significant
clinical problem.

10. Acquired resistance:
It is development of resistance by an microorganism for a
particular drug for which it was earlier sensitive.
It happens mainly due to the use of an AMA over a longer
duration of time / sub therapeutic / suboptimal doses.
Development of resistance depends on both the
microorganism as well as the drug.
The drug resistance can happen with any microbes & it is a
major clinical problem.
some bacteria are notorious for rapid acquisition of resistance
eg: staphylococci, tubercle bacilli etc.
However few microorganism are still listed which do not show
any significant resistance even used for more than 50 yrs eg:
S. pyogenes & spirochetes for penicillins.

11. Antibiotic Resistance

12. Antibiotic Selection for Resistant
Bacteria

13. Origins of resistance:
Selection of primary OR naturally
resistant strains.
Spontaneous mutation with selective
multiplication of resistant strain so that it
eventually dominates as above.
By transmission of genes from other
microorganism. (the commonest & most
important mechanism)

14.  successful antimicrobial therapy of an infection
ultimately depends on the c/n of the antibiotic at
the site of infection, which must be sufficient to
inhibit growth of the offending microorganism.
 the drug c/n at the site of infection must inhibit
the microorganism but also must retain below
the level that is toxic to human cells.
 if this can be achieved the microorganism is
considered sensitive; if not, the microorganism
is considered resistant to the drug.

15. Resistance to Antibiotics
Resistance in bacterial populations can be spread from
person to person by bacteria, from bacterium to
bacterium by plasmid, from plasmid to plasmid (or
chromosome) by transposons.
Plasmid are extra chromosomal genetic elements that
can replicate independently and can carry genes coding
for resistance to antibiotics ( r genes).
Many pathogenic bacteria have developed resistance to
the commonly used antibiotics; eg- some strains of
Mycobacterium tuberculosis have become resistant to
most ant tuberculosis agents. (Multi drug resistant)

16. Phenomena of resistance
Resistant organism can be of the
following three types-
1.Drug tolerant
2.Drug destroying
3.Drug impermeable

17. 1.Drug tolerant-
a particular drug lost the affinity with the targeted
biomolecule of the microorganism.

- eg: resistant Staph. aureus & E. coli
develops a RNA polymerase that does not
binds with rifampin.
another mechanism is acquisition of an alternative
metabolic pathway.

-eg: certain sulfonamide resistant bacteria
switch over to utilize pre formed folic acid in
place of synthesizing it from PABA.
Phenomena of
resistance…..

18. 2. Drug destroying:
 the resistant microbes elaborates an enzyme which
inactivates the drug-
 - eg: β- lactamases are produced by
staphylococci, Haemophilus etc which
inactivates Penicillin-G
 - Some of the amino glycoside resistant coli
forms have been found to produce enzymes
which adenylate/ acetylate/ phosphorylate
specific aminoglycoside antibiotics.
Phenomena of
resistance…..

19. 3. Drug impermeable-
The resistant strains does not have specific transport
channels formed by proteins called as “PORIN” hence
many hydrophilic antibiotics become impermeable & failed
to response.
 eg: concentration of some amino glycosides
& tetracycline's in the resistant gm –ve
bacterial strains has been found to be much
lower than that in the sensitive strains,
when both are exposed to equal oncentrations
of the drug.
Most important in case of Pseudomonas
aerugenosa.
Phenomena of
resistance…..

20. β-lactamase reside at the outer surface of
cytoplasmic membrane of Gm +ve bacteria
& on periplasmic space of Gm –ve
bacteria & destroys β-lactam ab.

21. PORIN

22. What Factors Promote
Antimicrobial Resistance?
Exposure to sub-optimal levels of
antimicrobial.
Exposure to microbes carrying
resistance genes.

23. Antibiotics promote
resistance
If a patient taking a course of antibiotic treatment
does not complete it
Or forgets to take the doses regularly,
Then resistant strains get a chance to build up
The use of antibiotics also promotes antibiotic
resistance in non-pathogens too
These non-pathogens may later pass their
resistance genes on to pathogens
© 2008 Paul Billiet ODWS

24. Inappropriate
Antimicrobial Use
Prescription not taken correctly.
Antibiotics prescribed for viral
infections.
Antibiotics sold without medical
supervision.
Spread of resistant microbes in
hospitals due to lack of hygiene.

25. Inappropriate
Antimicrobial Use
Lack of quality control in manufacturing or
outdated antimicrobials.
Inadequate surveillance or defective
susceptibility assays.
Poverty or war in the country.
Use of antibiotics in foods

26. Antibiotics in Foods
Antibiotics are used in animal feeds
and sprayed on plants to prevent
infection and promote growth
Multi drug-resistant Salmonella typhi
has been found in 4 states in the
people who ate beef fed antibiotics

27. Antibiotic use and abuse
Viral infections are not stopped by
antibiotics.
Yet doctors still prescribe (or are coerced
into prescribing) antibiotics to treat them
© 2008 Paul Billiet ODWS

29. Proposals to Combat
Antimicrobial Resistance
Speed development of new antibiotics
Track resistance data nationwide
Restrict antimicrobial use
Direct observed dosing
Use more narrow spectrum antibiotics
Use antimicrobial cocktails (TB)

30. The key for availability of
effective antimicrobials in the
future requires that the drug
development should keep pace
with drug resistance .

31. •Antimicrobial peptides
•Broad spectrum antibiotics from
plants and animals
–Squalamine (sharks)
–Protegrin (pigs)
–Magainin (frogs)
The Future of Chemotherapeutic
Agents

32. •Antisense agents
–Complementary DNA or peptide nucleic acids
that binds to a pathogen's virulence gene(s) and
prevents transcription
The Future of Chemotherapeutic
Agents

33. Measuring Antimicrobial
Sensitivity
•E Test
•MIC: Minimal
inhibitory
concentration

34. Measuring Antimicrobial Sensitivity:
Disk Diffusion

35. Staphylococcus aureus
Main article: MRSA
Staphylococcus aureus (colloquially known as "Staph aureus" or a Staph
infection) is one of the major resistant pathogens. Found on the
mucous membranes and the skin of around a third of the population, it is
extremely adaptable to antibiotic pressure. It was the first bacterium in which
penicillin resistance was found—in 1947, just four years after the drug
started being mass-produced. Methicillin was then the antibiotic of choice,
but has since been replaced by oxacillin due to significant kidney toxicity.
MRSA (methicillin-resistant Staphylococcus aureus) was first detected in
Britain in 1961 and is now "quite common" in hospitals. MRSA was
responsible for 37% of fatal cases of blood poisoning in the UK in 1999, up
from 4% in 1991. Half of all S. aureus infections in the US are resistant to
penicillin, methicillin, tetracycline and erythromycin.

36. •Prevention
•Rational use of antibiotics may reduce the chances of development of
opportunistic infection by antibiotic-resistant bacteria due to dysbacteriosis.
In one study the use of fluoroquinolones are clearly associated with
Clostridium difficile infection, which is a leading cause of nosocomial
diarrhea in the United States,[46] and a major cause of death, worldwide.
[47]
•There is clinical evidence that topical dermatological preparations containing
tea tree oil and thyme oil may be effective in preventing transmittal of CA-
MRSA. [48]
•Vaccines do not suffer the problem of resistance because a vaccine
enhances the body's natural defenses, while an antibiotic operates
separately from the body's normal defenses. Nevertheless, new strains may
evolve that escape immunity induced by vaccines.
•While theoretically promising, anti-staphylococcal vaccines have shown
limited efficacy, because of immunological variation between
Staphylococcus species, and the limited duration of effectiveness of the
antibodies produced. Development and testing of more effective vaccines is
under way.

38. Appropriateness by Site of Infection
0
10
20
30
40
50
Urinary
Respiratory
G
astrointestinal
Skin/Soft Tissue
Ear/N
ose/Throat
G
enital Tract
O
ther
Appropriate
Inappropriate
p=0.76
Lautenbach, Arch Intern Med 2003;163:601

39. 0
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*p = 0.007 by linear regression
New antibacterial agent º new molecular entity (NME)
with antimicrobial properties, administered for systemic
infection; topical agents, immunomodulators excluded
Trends in Development of New Antibacterials
Edwards J, ICAAC, 2003

40. •6 most frequent resistant bacteria:
Gram-positive-bacteria
-Methicillin-resistant Staphylococcus aureus (MRSA)
-Vancomycin-resistant Enterococcus faecium (VRE)
-Penicillin-resistant Streptococcus pneumoniae
Gram-negative bacteria
-Third-generation cephalosporin-resistant Escherichia coli
-Third-generation cephalosporin-resistant Klebsiella
pneumoniae
-Carbapenem-resistant Pseudomonas aeruginosa