2. I t is crucial to recognize that effective drug therapy is not a simple
matter .
Drug can be administered (applied) in several different ways & they
do not always spread rapidly throughout the body or immediately kill
all invading pathogens .
A complex array of factors influence the effectiveness of antimicrobial
drugs , Like :
1. Drug must be able to reach the site of infection
2. Pathogen must be susceptible to drug
3. Chemotherapeutic agent reach level in the body
that exceed pathogen MIC value if it is going to
effective
Drug EFFECTIVENESS
3. 1. DRUG MUST BE ABLE TO REACH THE SITE OF INFECTION
• In drug formulation it essential to understood the control
of drug activity , stability & metabolism in vivo state .
• For ex : The mode of administration (appliction) play an
important role .
1. A drug such as PENICILLIC – G is not suitable for
oral administration because it is relatively unstable in
stomach acid .
2. Some antibiotics for ex : GENTAMICIN & OTHER
AMINOGLYCOSIDE are not well absorbed from the
intestinal tract & must be injected intramuscular or
given intravenously ( by injection) .
3. Other antibiotics like NEOMYCIN , BACITRACIN are
so toxic that they can only applied topical to skin
lesions .
4. Use to fight
against bacteria &
several types of
infection Like :
anthrax ,
pneumonia ,
gonorrhea ,
syphilis .
Use in several infections of
the abdomen & urinary
tract as well as bacteremia ,
endocarditis
Use to reduce the risk of infections
following minor skin injuries and to treat
superficial bacterial eye infection .
5. Even when an agent (antimicrobial
drug) applied properly it may be
excluded from the site of infection .
For ex : blood clots , necrotic tissue or
biofilms can protect from a drug .
Either because body fluids containing
the agent may not easily reach
pathogen or because the agent is
absorbed by material surrounding them
.
6. 2 . THE PATHOGEN MUST BE SUSCEPTIBLE TO DRUG
Bacteria in biofilms or abscesses may be replicating very
slowly & are there for resistant to chemotherapy because
many drugs affect pathogen only if they are actively
growing or dividing .
A pathogen even through growing may simply not be
susceptible to a particular drug .
To control resistance drug cocktails can be used to treat
some infection .
A notable example of this is the use of CALVULANIC
ACID combined with AMPICILLIN to treat penicillin
resistance bacteria .
8. 3 . The chemotherapeutic agent reach level in the body that
exceed pathogen MIC value if it is going to effective
The concentration reached will depend on the amount of
drug administered , the route of administration & speed of
uptake & the rate at which the drug is cleared or eliminated
from the body .
It make sense that a drug will remain at high concentration
longer if it is absorbed over an extended period & excreted
slowly .
Finally chemotherapy has been rendered less effective &
much more complex by the spread of drug resistance genes
& prevention of drug access by biofilm component .
9. OVERCOMING DRUG RESISTANCE
Bacteria are very adept at spreading resistance genes
around, both within a population and to other members of
a microbial community.
However, what keeps the resistance genes in a population
and contributes to the generation of drug-resistant
bacterial strains is exposure to the drug.
Clearly, it is important that physicians be able to treat
infectious disease in their patients.
The problem is that drugs are being overused, misused,
and in many cases abused.
Put simply, the more drugs are used, the more likely it is
that bacteria will become resistant to them.
That raises the question: Is there a way to overcome drug
resistance?
10. Several strategies can be employed to discourage the
emergence of drug resistance.
The drug can be given in a high enough concentration to
destroy susceptible microbes and most spontaneous mutants
that might arise during treatment.
1. Sometimes two or even three different drugs can be
administered simultaneously with the hope that each drug
will prevent the emergence of resistance to the other.
• This approach is used in treating tuberculosis, HIV, and
malaria, for example :
11. When treating tuberculosis (TB), several drugs are
administered simultaneously (e.g., isoniazid [INH] plus
rifampin, ethambutol, and pyrazinamide) .
These drugs are administered for 6 to 9 months as a way of
decreasing the possibility that the bacterium develops drug
resistance .
If a patient fails to take prescribed antibiotics as directed
(e.g., does not complete the course of treatment), resistant
mutants survive and flourish because of their competitive
advantage over nonresistant strains .
TB EXAMPLE :
12. Preventing the growth of such mutants is the rationale
behind "directly observed therapy" (DOT).
During DOT, a health care worker observes each TB
patient take each antibiotic dose, thereby ensuring full
antibiotic regimen compliance.
The use of DOT increased from 21% in 1993 to 57% in
2005, the latest year with available data, effectively
contributing to the substantial 50% decline in reported TB
cases in the United States between 1993 and 2006.
Unfortunately, the number of worldwide TB cases doubled
over that same time period.
13.
14. 2. Other strategies used to prevent drug resistance
include the strict control on use of chemotherapeutic
drugs, particularly broad-spectrum drugs, which
should be used only when absolutely necessary.
If possible, the pathogen should be identified, drug
sensitivity tests performed, and the proper narrow-
spectrum drug employed.
Patient compliance is just as important because
completing a full course of antimicrobial therapy often
prevents full mutation to resistant phenotypes.
15. Despite efforts to control the emergence and spread of
drug resistance, the situation continues to worsen.
Thus an urgent need exists for new antibiotics that
microorganisms have never encountered.
3. Pharmaceutical and biotechnology companies
collect and analyze samples from around the world in a
search for completely new antimicrobial agents.
Both culture-based and metagenomics approaches are
used Structure-based or rational drug design is
another option.
16. 4. If the three-dimensional structure of a susceptible
target molecule such as an enzyme essential to
microbial function is known, computer programs can
be used to design drugs that precisely fit the target
molecule.
These drugs might be able to bind to the target and
disrupt its function sufficiently to destroy the
pathogen.
Pharmaceutical companies are using these approaches to
develop drugs for the treatment of AIDS, cancer,
septicemia caused by lipopolysaccharide, and the common
cold.
Information derived from the sequencing and analysis of
pathogen genomes is also useful in identifying new targets
for antimicrobial drugs.
17. For example, genomics studies are providing data for
research on inhibitors of both aminoacyl-tRNA synthetases
and the enzyme that removes the formyl group from the N-
terminal methionine during bacterial protein synthesis.
The drug susceptibility of enzymes required for fatty acid
synthesis is also being analyzed.
5. A most interesting response to the current crisis is
the renewed interest in an idea first proposed early in
the twentieth century by Felix d’ Herelle , one of the
discoverers of bacterial viruses (bacteriophages).
18. d’ Herelle proposed that bacteriophages could be
used to treat bacterial diseases.
Although most microbiologists did not pursue his
proposal actively due to technical difficulties and the
advent of antibiotics, Russian scientists developed
the medical use of bacteriophages.
Currently Russian physicians use bacteriophages to
treat many bacterial infections.
19. Bandages are saturated with phage
solutions, phage mixtures are administered
orally, and phage preparations are given
intravenously to treat Staphylococcus
infections.
Several American companies are actively
conducting research on phage therapy and
preparing to carry out clinical trials.