This document provides an introduction to principles of anti-microbial therapy. It discusses key topics including: - Sir Alexander Fleming's discovery of penicillin in 1928. - The definition of chemotherapy and agents used to treat infections and cancer. - Factors considered in selecting appropriate anti-microbial agents, including the infecting organism, site of infection, and patient factors. - Mechanisms of anti-microbial resistance that can develop, including genetic alterations in microbes and changes in target sites or drug accumulation. - Complications of anti-microbial therapy like hypersensitivity, direct toxicity, and superinfections.

1. Introduction To
Principles of
Anti-microbial
Therapy

2. Sir Alaxender Fleming
Discovered penicillin in 1928 after 1st World
war from Penicillium chrysogenum.

3. Chemotherapy is defined as the use of
synthetic, semisynthetic and naturally
occurring chemicals to kill or suppress the
growth of specific organism causing
infectious disease
OR
Agent that shows effectiveness in the
treatment of cancer.

4. Infection
Successful invasion,
establishment and growth of
disease producing organisms in
the tissues of the host; is called
infection.

5. Microorganism
Disease producing organisms are:
Bacteria Fungi
Viruses Protozoa
Helminths (Worms)
Transmitted from one person to other by direct
or indirect contact.

6. Overview
Antimicrobial drugs are effective in
the treatment of infections because
of their selective toxicity; that is,
They have the ability to injure or kill
an invading microorganism without
harming the cells of the host.

7.  The concentration of the drug be
carefully controlled to attack the
microorganism while still being
tolerated by the host.

8. Selection of Antimicrobial Agents
 Selection of the most appropriate
antimicrobial agent requires
knowledge of
1) The organism's identity,
2) The organism's susceptibility to a
particular agent,
3) The site of the infection,
4) Patient factors,
5) The safety of the agent, and
6) The cost of therapy.

9.  However, some critically ill patients
require “empiric therapy” that is,
immediate administration of drug(s) prior
to bacterial identification and
susceptibility testing.

10. A. Identification of the
infecting organism
Gram stain
Culture and sensitivity; it is essential to obtain
a sample culture of the organism prior to
initiating treatment.
Definitive identification of the infecting
organism may require other laboratory
techniques, such as detection of microbial
antigens, microbial DNA or RNA, or detection of
an inflammatory or host immune response to
the microorganism

11. B. Empiric therapy prior to identification of
the organism
Ideally, the antimicrobial agent used to
treat an infection is selected after the
organism has been identified and its drug
susceptibility established.
However, in the critically ill patient (as
meningitis), such a delay could prove fatal,
and immediate empiric therapy is indicated.

12. Therapy is initiated after specimens for
laboratory analysis have been obtained
but before the results of the culture are
available.
Broad-spectrum therapy may be
needed initially for serious infections
when the identity of the organism is
unknown or the site makes a
polymicrobial infection likely.

13. Two things are considered
1. Timing of therapy
e.g neutropenic or meningitis patients
2. Selecting a drug
• Site of infection
• Patient history
• Known association of particular organism in
particular clinical setting
e.g gram positive cocci in the spinal fluid of 40
years old patient is Streptococcus pneumonae so
cephalosporins are required to remove the infection

14. C. Determination of antimicrobial
susceptibility of infective organisms
 Somepathogens, such as
Streptococcus pyogenes and
Neisseria meningitidis, usually
have predictable susceptibility
patterns to certain antibiotics.

15. In contrast, most gram-negative bacilli,
enterococci, and staphylococcal species
often show unpredictable susceptibility
patterns to various antibiotics and require
susceptibility testing to determine
appropriate antimicrobial therapy.
The minimum inhibitory and bactericidal
concentrations of a drug can be
experimentally determined

16. 1. Bacteriostatic vs. bactericidal drugs:
Bacteriostatic drugs
do not kill but arrest the growth and
replication of bacteria at serum levels
achievable in the patient, thus limiting the
spread of infection while the body's
immune system attacks, immobilizes, and
eliminates the pathogens.

17. Bactericidal drugs kill bacteria at
drug serum levels achievable in the
patient. Because of their more
aggressive antimicrobial action, these
agents are often the drugs of choice
in seriously ill patients.
It eradicates infection in the absence
of host defence mechanism.

18. it is possible for an antibiotic to be
bacteriostatic for one organism and
bactericidal for another. For example,
chloramphenicol is bacteriostatic against
gram-negative rods and is bactericidal
against other organisms, such as
S. pneumoniae.

19. 2. Minimum inhibitory concentration
the MIC is; the lowest concentration of
antibiotic that inhibits bacterial growth.
To provide effective antimicrobial therapy,
the clinically obtainable antibiotic
concentration in body fluids should be
greater than the MIC.

20. 3. Minimum bactericidal concentration
The tubes that show no growth in the MIC
assay are subcultured into antibiotic-free
media.
The minimum bactericidal concentration is
the lowest concentration of antimicrobial
agent that results in a 99.9% decline in
colony count after overnight incubations.

22. Clinical significance of MIC & MBC
 Lower the MIC,MBC more potent the
agent.
 Determines dose of drug.
 Determines type of antibiotic to be
used.
 Lower the MIC,MBC less chances of
resistance to develop.

23. D. Effect of the site of infection on therapy:
The blood-brain barrier
Adequate levels of an antibiotic must
reach the site of infection for the invading
microorganisms to be effectively
eradicated.
Natural barriers to drug delivery are
created by the structures of the capillaries
of some tissues, such as the prostate, the
vitreous body of the eye, and CNS.

24.  Capillaries in the brain, help to
create and maintain the blood-brain
barrier. This barrier impede entry
from the blood to the brain of
virtually all molecules, except those
that are small and lipophilic.

25. The penetration and concentration
of an antibacterial agent in the CSF
is particularly influenced by the
following:
Lipid solubility of the drug; Lipid soluble drugs
such as quinolones and metronidazole have
significant penetration into the CNS
meningitis
Molecular weight of the drug: Low molecular
weight drugs has an enhanced ability to cross the
BBB.

26. Protein binding of the drug; High degree
of protien binding of a drug in the serum
restricts its entry into the CSF. Therefore,
the amount of unbound(free)drug in
serum, rather than the total amount of
drug present, is important for CSF
penetration.

27. E. Patient factors
 We must consider the status of the patient in
selecting an Antibiotic:
1. Immune system, intact immune system is
necessary for the elimination of infecting
organisms.
2. Kidneys, serum creatinine level are used as index
for renal function, direct monitoring of antibiotic
levels(vancomycin), no. of functional neurons
decrease with age

28. Hepatic dysfunction
Liver; erythromycin and tetracycline are
contraindicated in treating patients with
liver disease. Or used with cautions

29. 4. Circulation
5. Age; neonates particularly vulnerable to the
toxic effects of chloramphenicol and
sulfonamides. Young children should not be
treated with tetracyclines, which affect
bone growth.
6. In women, pregnancy or breastfeeding also
affects selection of the antimicrobial agent.

30. United States Food
and Drug
Administration
categories of
antimicrobials and
fetal risk

31. Risk factors for multidrug resistant
organisms
These require broad spectrum antibiotics
Common risk factors are
1. Antimicrobial therapy > 90 days
2. Hospitalization exceeding 5 days
3. Immunosuppressive disease or therapies

32. F. Safety of patient
Penicillin are less toxic as unique site
of action on the microorganism
Other antimicrobial such as
chloramphenicol has less specificity
and cause damage to host cells

33. G. Cost of therapy
Several drugs show similar efficacy but
vary widely in cost
For treating MRSA Includes vancomycin,
clindamycin, daptomycin, linezolid
Although choice of therapy usually centers
on site of infection, severity of illeness,
ability to take oral medicine but cost of
medication is also necessary

34. Route of Administration
The oral route of administration is chosen for
infections that are mild and can be treated on
an outpatient basis.
In patients requiring a course of intravenous
therapy initially, switch over to oral agents
as soon as possible.

35. Parenteral administration is used for
drugs that are poorly absorbed from
the gastrointestinal tract (vancomycin
and amphotericin B) and for treatment
of patients with serious infections

36. Rationale of Antimicrobial
dosing
Rational dosing of antimicrobial depend
on PD and PK properties
Three important factors that influence
frequency of dosing
1. Concentration dependent killing
e.g aminoglycosides and
flouroquinolones exhibited this type of
killing.

37. 2.Time dependent killing
e.g Penicillins and other beta lactam ,
macrolides, clindamycin antibiotics show
this type of killing.
 increasing the conc. Of drug does not
significantly increase the rate of killing
 clinical efficacy is best predicted by
percentage of time that blood conc.
Remains above MIC

38. 3. Post antibiotic effect
Persistent suppression of microbial growth
after level of antibiotic has fallen below
the MIC
 to measure PAE a test culture is first
incubated in antibiotic containing medium
and then transfer to antibiotic free
medium
e.g aminoglycosides, fluoroquinolones
require only once daily dosing

39. Chemotherapeutic Spectra
A. Narrow-spectrum antibiotics
Agents acting only on a single or a limited
group of microorganisms.
For example, isoniazid is active only against
mycobacteria.
B. Extended-spectrum antibiotics
The term applied to antibiotics that are
effective against gram-positive organisms
and also against a significant number of
gram-negative bacteria.
For example, ampicillin

40. Chemotherapeutic Spectra
C. Broad-spectrum antibiotics
Such as tetracycline and
chloramphenicol affect a wide variety of
microbial species
Administration of these disturb the
microbial flora and precipitates as
superinfection due to Clostridium
difficale, Candida albicans

41. Combination of Antimicrobial Drugs
 It is therapeutically advisable to treat patients
with a single agent that is most specific for the
infecting organism.
 This strategy;
1. reduces the possibility of superinfection,
2. decreases the emergence of resistant
organisms and
3. minimizes toxicity.
However, situations for combinations of drugs
do exist. For example, the treatment of
tuberculosis benefits from drug combinations.

42. Advantages of drug combinations
Sulfamethoxazole and Trimethoprim are
bacteriostatic when given alone but the
combination „Cotrimoxazole’ is batericidal,
so, the combination is more effective than
either of the drugs used separately.
Combining a drug which is mainly effective
against gram+ve bacteria with a drug that is
mainly effective against gram-ve bacteria is
also synergestic.(beta lactams and
aminoglycosides

43. Advantages of drug combinations
Drug combination may inhibit bacterial drug
inactivating enzymes like inhibition of
penicillinases by clavulanic acid and
sulbactam.
Decrease in MIC of both drugs,a decrease in
dose of the drugs can be made.
Less intensity or incidence of adverse effects
due to reduced dose of drug.
Broaden the spectrum of antibiotic action.

44. Disadvantages of drug combinations
A number of bactericidals act only when
organisms are multiplying. Thus,
coadministration of an agent that causes
bacteriostasis + a second agent that is
bactericidal may result in, the first drug
interfering with the action of the second.
For example, bacteriostatic (tetracycline) drugs
may interfere with the bactericidal effect of
penicillins and cephalosporins.

45. Disadvantages of drug combinations
There may be more variety of adverse
effects, each antibiotic may cause its own
adverse effects.
There may be an increased chances of
super infections.
Increased chances of emergences of drug
resistance.
Increased cost of therapy.
Less patient compliance.

46. Prophylactic Antibiotics
Certain clinical situations require the use of
antibiotics for the prevention
rather than the treatment of infections.
Because the indis-criminate use of
antimicrobial agents can result in bacterial
resistance and superinfection
prophylactic use is restricted to clinical
situations in which the benefits outweigh the
potential risks

47. Antimicrobial Resistance
Bacteria are said to be resistant to an antibiotic if the
maximal level of that antibiotic that can be tolerated
by the host does not halt their growth.
Some organisms are inherently resistant to an
antibiotic. For example, gram-negative organisms are
inherently resistant to vancomycin.
However, microbial species that are normally
responsive to a particular drug may develop more
virulent, resistant strains through spontaneous
mutation or acquired resistance and selection.

48. A. Genetic alterations leading
to drug resistance
Resistance develop due to ability of DNA
to undergo spontaneous mutation or to
move from one organism to other
B. Altered expression of protein in
drug-resistant organism
 modification of target site
 through mutation e.g S.pneumoniae
resistance to beta lactams

49.  decreased accumulation
 decreased uptake and increased efflux so
unable to attain access to site of action in
sufficient conc.
 e.g gram negative bacteria can limits the
penetration of certain drugs like beta
lactams as a result of alteration in
structure and function of porins
 also presence of efflux pump can limit
levels of a drug in an organism as seen
with tetracyclines

50.  enzymatic inactivation
 beta lactamases inactivates beta lactam
ring of penicillins , cephalosporins
 acetyltransferases that transfer acetyl
group to antibiotics inactivating
chloramphenicol and aminoglycosides
 esterases that hydrolyse lactone ring of
macrolides

52. Factors Promote Antimicrobial
Resistance
Exposure to sub-optimal levels of
antimicrobial
Exposure to microbes carrying
resistance genes

53. Factors Promote Antimicrobial Resistance
 Indiscriminate use of antibiotics
Prescription not taken correctly
Antibiotics for viral infections
Antibiotics sold without medical
supervision
Spread of resistant microbes in
hospitals due to bad hygienic
conditions

54. Complications of Antibiotic
Therapy
Hypersensitivity
Direct toxicity; aminoglycosides can
cause ototoxicity by interfering with
membrane function in the hair cells of the
organ of Corti.
Superinfections; permitting the
overgrowth of opportunistic organisms,
especially fungi or resistant bacteria.

55. Sites of Antimicrobial Actions

56. Aminoglycosides cause
which type of toxicity.
Diarrhea
Hypertension
Ototoxicity
Neurotoxicity

57. Thank YOU