ra p y

emot he
Ch Jagir R. Patel
Asst Professor
Dept. Pharmacology
Chemotherapy
• Chemo + Therapy
• The use of drugs (chemicals or derived from
microorganisms) to treat any disease or condition.
• which has selective toxicity against organisms like virus,
bacteria, Protozoa, Fungi & Helminthes is called
Chemotherapy.
• Objective
• The objective of chemotherapy is to study and to apply the
drugs that have highly selective toxicity to the pathogenic
microorganisms in host body and have no or less toxicity to the
host, so as to prevent and cure infective diseases caused by
pathogens.
Jagir R. Patel, Asst Prof Dept. Pharmacology, APC
Cont.…
• Bactericidal: A bactericide or bacteriocide, sometimes
abbreviated Bcidal, is a substance that kills
bacteria. Bactericides are disinfectants, antiseptics, or
antibiotics.
• Bacteriostatic: they inhibit the growth and multiplication of
microorganisms. At high concentration bacteriostatic agents can
be bactericidal.
• Minimum Inhibitory Concentration (MIC)
• Minimum concentration of antibiotic required to inhibit the
growth of the test organism.
• Minimum Bactericidal Concentration (MBC)
• Minimum concentration of antibiotic required to kill the test
organism.
Jagir R. Patel, Asst Prof Dept. Pharamcology, APC
Definitions
• An antimicrobial agent is any chemical (drug) used to treat
an infectious disease, either by inhibiting or killing
pathogens in vivo. Some antimicrobial agents are antibiotics.

• An antibiotic is a substance produced by a microorganism

that kills or inhibits growth of other microorganisms.

• Antibiotics that have been chemically modified to kill a wider

variety of pathogens or reduce side effects are called
semisynthetic antibiotics; examples include semisynthetic
penicillins such as ampicillin and carbenicillin.
Jagir R. Patel, Asst Prof Dept.
Pharamcology, APC
Time dependent and concentration dependent
killing
• Concentration-Dependent Killing
• The rate & extent of killing increases as the peak drug concentration increases
• Eg: drugs inhibiting protein or DNA synthesis, largest for AMINOGLYCOSIDES &
FLUOROQUINOLONES
• These drugs also exhibit a “POST-ANTIBIOTIC EFFECT” or persistent suppression of
bacterial growth after limited exposure to an antibiotic 
• Proposed mechanisms include:
• slow recovery of bacteria after non-lethal damage to cell structures
• persistence of the antibiotic at its binding site
• a need for bacteria to synthesize new proteins before growth can continue
• CLINICAL SIGNIFICANCE:
• Antibiotics with a long post-antibiotic effect can be administered at longer dosing
intervals than would be predicted by their pharmacokinetic half-life
• Fewer doses per day tends to increase adherence to therapy
Jagir R. Patel, Asst Prof Dept. Pharamcology, APC
 Cont..
• Time-Dependent Killing
• A property associated with cell
wall synthesis inhibitors e.g. β-
LACTAMS & VANCOMYCIN

• Bactericidal activity continues as

long as the plasma concentration
is greater than the minimum
bactericidal concentration (or
MIC).

• CLINICAL SIGNIFICANCE:
• The concentration of these
drugs should be maintained
above the MIC for the entire
time interval between
repetitive doses.
Jagir R. Patel, Asst Prof Dept. Pharamcology, APC
 • Chemotherapeutic agents need to act at a concentration that can
Chemotherapeutic index

be tolerated by the tissues of the host and therefore they must

have a selective toxicity for micro organism compared with the
host.
• This selective toxicity expressed in terms of the “Chemotherapeutic
Index” that compress the maximum dose that can be tolerated by
the host without causing death
• chemotherapeutic index defined as the maximum tolerated  dose
per kilogram of body weight, divided by minimum dose per
kilogram body weight that will cure the disease.
• Chemotherapeutic Index (CI): the ratio of median lethal dose
(LD50) to median effective dose (ED50). LD50/ED50 or LD5/ ED95
• Generally the bigger the CI of a drug is, the lower its toxicity, the
better its curative effect and the greater its value of clinical
application.
Jagir R. Patel, Asst Prof Dept.
Pharamcology, APC
Anti microbial classification
• Typical bacteria
• Cell wall:
peptidoglycan
• Plasma membrane:
phospholipids no
sterols
• No nucleus
membrane the
genetic material is
single chromosome
• Plasmid : extra
chromosomal DNA
• Flagella: for
movement
• Pilli: sexual organ
during mating and
joints the other
bacteria for DNA
Jagir R. Patel, Asst Prof Dept. transfer
Pharamcology, APC
Metabolic pathway in bacterial
cell

• Class I: the utilization of glucose or some alternative carbon source for the generation
of energy (ATP) and synthesis of simple carbon compounds used as precursors in the
next class of reactions.
• Class II: the utilization of these precursors in an energy-dependent synthesis of all the
amino acids, nucleotides, phospholipids, amino sugars, carbohydrates and growth
factors required by the cell for survival and growth.
• Class III: assembly of small molecules into macromolecules-proteins, RNA, DNA,
polysaccharides and peptidoglycan.

Jagir R. Patel, Asst Prof Dept. Pharamcology, APC

Target to Antimicrobials

Jagir R. Patel, Asst Prof Dept.

Pharamcology, APC
Jagir R. Patel, Asst Prof Dept.
Pharamcology, APC
Jagir R. Patel, Asst Prof Dept.
Pharamcology, APC
 Classification
Class Drugs
Anti bacterial Penicillins,
Aminoglycosides,
Erythromycin
Anti fungal Griseofulvin, Amphotericin
B, ketoconazole
Anti viral Acyclovir, Zedovudine
Anti protozoal Choroquine, Metronidazole
Anthelmintic Mebendazole, Pyrantel

Narrow spectrum Broad spectrum

penicillins tetracycline's
streptomycin chloramphenicol
erythromycin
Jagir R. Patel, Asst Prof Dept.
Pharamcology, APC
Cont.…

Bacteriostatic Bactericidal
Penicillins
Sulphonamides,
Aminoglycoside
Tetracycline's
s
Chloramphenicol
Rifampicin
erythromycin
isoniazid

Fungi Bacteria Actinomycetes

• Penicillin • polymyxin • Tetracycline's
• Griseofulvin • bacitracin • Aminoglycosides
• Cephalosporin's • Macrolides
• polyenes
Jagir R. Patel, Asst Prof Dept.
Pharamcology, APC
What is the ideal antimicrobial drug ?
• Have highly selective toxicity to the
pathogenic microorganisms in host Criteria for
body antimicrobials
• Have no or less toxicity to the host.
• Low propensity for development of Highly selective
resistance. toxicity to
PATHOGENIC
• Not induce hypersensitivies in the ORGANISMS
host.
• Have rapid and extensive tissue
distribution No or less toxicity
to the HOST
• Be free of interactions with other
drugs.
• Be relatively inexpensive
Jagir R. Patel, Asst Prof Dept.
Pharamcology, APC
Problems with Antimicrobials
• Toxicity:
• This arise at the site of application gastric irritation, pain,
abscess formation (i.m.), thrombophlebitis (i.v.) e.g.
tetracycline's, cephalosporin's etc.
• Systemic toxicity:
• Majority of AMAs posses systemic toxicity
• High therapeutic index: penicillins
• Low therapeutic index: aminoglycosides, tetracycline's,
chloramphenicol
• Very low therapeutic index: its only used when no suitable
alternative is available e.g.: vancomycin, amphotericin
Jagir R. Patel, Asst Prof Dept.
Pharamcology, APC
Hypersensitive reactions/ drug
resistance
• Majority of AMAs posses hypersensitive reactions like
rashes and anaphylactic shock which are dose dependent
• E.g. penicillins, cephalosporin's
• Drug resistance:
• It refers to unresponsiveness of microorganism to an
AMAs and causes drug tolerance
• 2 types of resistance
• Natural resistance: some microbes always been resistant
to AMAs
• Cause: they lack metabolic process or the target site
which is affected by AMAs. E.g. gram-ve microbes for
penicillins M.tuberculosis insensitive to tetracycline's
Jagir R. Patel, Asst Prof Dept.
Pharamcology, APC
 Cont..
• Acquired resistance: it is development of resistance by an
organism due to use of an AMA over period of time
• Development of resistance is dependent on the
microorganism e.g. acquisition of resistance, e.g.
staphylococci, coliforms, tubercle bacilli for penicillins
• Resistance may be developed by Mutation or gene transfer
• Mutation
• Mutation It is a stable and heritable genetic change that
occurs spontaneously and random among microorganisms.
• It is not induced by the AMA.
• Any sensitive population of a microbes contains a few
mutant cells which require high concentration of the AMA
for inhibition.

Jagir R. Patel, Asst Prof Dept.

Pharamcology, APC
Mutation
• Single step: A single gene mutation may confer high
degree of resistance; emerges rapidly, e.g.
streptomycin, E coli and Staphylococci to rifampin

• Multistep: A number of gene modifications are

involved
• Sensitivity decreases gradually in a stepwise manner
• Resistance to erythromycin, tetracycline's and
chloramphenicol
developed by many organisms in this manner

Jagir R. Patel, Asst Prof Dept.

Pharamcology, APC
 Gene transfer
• Conjugation is the process
by which one bacterium
transfers genetic material to
another through direct
contact.
• During conjugation,
one bacterium serves as the
donor of the genetic
material, and the other
serves as the recipient.
• The donor bacterium carries
a DNA sequence called the
fertility factor, or F-factor.
• Chloramphenicol resistance
of typhoid bacilli,
• streptomycin resistance to
• E coli,
Jagir R. Patel, Asst Prof Dept.
Pharamcology, APC
 Transformation
• A resistant bacterium may
release the resistance carrying
DNA into the medium.
• this may be imbibed by
another sensitive organism-
becoming unresponsive to the
drug
• This mechanism is probably
not
• clinically significant except
isolated instances of
• pneumococcal resistance to
penicillin G due to altered
penicillin binding protein
Jagir R. Patel, Asst Prof Dept.
Pharamcology, APC
 Transduction
• Transduction is the process by which foreign DNA is introduced into a cell by a 
virus or viral vector. An example is the viral transfer of DNA from one 
bacterium to another. E.g. staphylococcus strains for penicillins erythromycin
and chloramphenicol

Jagir R. Patel, Asst Prof Dept.

Pharamcology, APC
 Drug tolerant & Drug
destroying
• Drug tolerant: Loss of affinity of the target biomolecule of the microorganism
for a particular AMA
• e.g. penicillin-resistant pneumococcal strains have altered penicillin binding
proteins
• Trimethoprim-resistance results from plasmid-mediated synthesis of a
dihydrofolate reductase that has low affinity for trimethoprim.

• Drug destroying: The resistant microbe elaborates an enzyme which

inactivates the drug
• E.g. B-lactamases are produced by staphylococci, Haemophilus, gonococci,
etc. which inactivate penicillin G.
• The B-lactamases may be present in low quantity but strategically located
periplasmically (as in gram-negative bacteria) so that the drug is inactivated
soon after entry, or may be elaborated in large quantities (by gram-positive
bacteria) to diffuse into the medium and destroy the drug before entry.
Jagir R. Patel, Asst Prof Dept.
Pharamcology, APC
 Enzymatic inactivation
&
Modification of target sites
• Enzymatic inactivation : The ability to destroy or inactivate the
antimicrobial agents can confer resistance on microorganisms.
• E.g. β-lactamases destroy many penicillins and
cephalosporin's

Modification of target sites

• The β-lactams can resist to organism by alteration of the target
site that is penicillin binding protein(PBP) and mutation of
dihydrofolate reductase which is less sensitivity to inhibition in
organism resistant to trimethoprim.

Jagir R. Patel, Asst Prof Dept.

Pharamcology, APC
Drug impermeable & cross resistance
• Drug impermeable :
• Many hydrophilic antibiotics gain access into the bacterial
cell through specific channels formed by proteins called
'porins', or need specific transport mechanisms. These may
be lost by the resistant strains
• e.g. penicillin-resistant gonococci are less permeable to
penicillin G
• Cross resistance:
• Acquisition of resistance to one AMA conferring resistance
to another AMA, to which the organism has not been
exposed, is called cross resistance.
• resistance to one sulfonamide means resistance to all
others, and resistance to one tetracycline means
insensitivity to all others.
Jagir R. Patel, Asst Prof Dept.
Pharamcology, APC
Prevention of Drug resistance

No indiscriminate and inadequate

or unduly prolonged use of AMAs
should be made.
Prefer rapidly acting and selective
(narrow spectrum)then broad
spectrum
Prevention of AMAs whenever possible
resistance
Use combination of AMAs whenever
prolonged therapy is undertaken e.g.
tuberculosis

Treat intensively when organism are

notorious for developing resistance
Jagir R. Patel, Asst Prof Dept.
Pharamcology, APC
 Superinfection or supra infection
• This refers to the appearance of a new infection as a result
of antimicrobial therapy for another infection

• The causative organism may be different from that of

primary diseases

• E.g. broad spectrum antibiotics like tetracycline's, and

chloramphenicol, alter normal bacterial flora as a result of
which the host defense mechanism is impaired
• Hence pathogenic organisms invade the host multiply and
produce Superinfection e.g. bacteria or fungi
Jagir R. Patel, Asst Prof Dept.
Pharamcology, APC
 Pathogenesis of Superinfection
• It is associated with suppression or change in flora in
the body following treatment of certain AMAs

Inhibit
Normal flora bacteriocins pathogenic
microorganism

Pathogenic
Essential
Normal flora microorganis
nutrients
m

pathogenic organism
Lack of
Change in invade. Multiply and
competitio
flora produce
n
Superinfection
Jagir R. Patel, Asst Prof Dept.
Pharamcology, APC
Factors predisposing to Superinfection
• Superinfection is due to immunocompromised
conditions such as diabetes, AIDS, malignancy etc.
• Can be minimized by
• 1. using special antimicrobials
• 2. avoid unnecessary use of AMAs
• 3. use of probiotics e.g.. Lactobacillus

Jagir R. Patel, Asst Prof Dept.

Pharamcology, APC
 Nosocomial/ hospital acquired
infections
• A hospital-acquired infection (HAI), also known as a nosocomial
infection, is an infection that is acquired in a hospital or
other health care facility.
• To emphasize both hospital and nonhospital settings, it is
sometimes instead called a health care–associated
infection (HAI or HCAI).
• Such an infection can be acquired in hospital, nursing
home, rehabilitation facility, outpatient clinic or other clinical
settings. 
• Spreading of infection
• By health care staff, infected patient etc.
• Infection due to contamination of reused patients bed, surgicals,
plastic equipment's ( like syringe, needle etc.)
Jagir R. Patel, Asst Prof Dept.
Pharamcology, APC
•  In some cases the microorganism originates from the
patient's own skin microbiota, becoming opportunistic
after surgery or other procedures that compromise the
protective skin barrier.
• Contact transmission, airborne transmission, common
vehicle transmission, vector born transmission
• Source of contamination can not be ensured
• Prevention:
• QA/QC measures
• Isolation, sterilization, hand washing, surface sanitation
• Treatment
• Among the categories of bacteria most known to infect
patients are the category MRSA (resistant strain of S.
aureus), member of gram-positive bacteria
and Acinetobacter (A. baumannii), which is gram-negative.
Jagir R. Patel, Asst Prof Dept.
Pharamcology, APC
Jagir R. Patel, Asst Prof Dept.
Pharamcology, APC