Download Chemotherapy

CHEMOTHERAPY
Dr. Rajendra Nath
Professor
CHEMOTHERAPY
The term Chemotherapy is used
for the drug treatment of parasitic
infections in which parasites ( e.g.
Virus ,Bacteria , Protozoa ,
Fungi & Worms) / invading cells
are selectively destroyed or
removed without significant injury
to the host.
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(CANCER CELLS – they are host cells
but considered as invading cells or
parasite since they escape from the
regulating devices , which govern
normal cells .As they are very similar to
host cells so difficult to tackle )
Differential toxicity: based on the concept
that the drug is more toxic to the infecting
organism than to the host
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Antibiotics –
They are antibacterial substances
produced by various species of microorganisms ( Bacteria , Fungi &
Actinomycetes ) that suppress the
growth of other microorganism .
• Majority of antibiotics are based on naturally
occurring compounds
• or may be semi-synthetic or synthetic
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Natural Sources of Antibiotics
A. Fungus –1. Penicillin Penicillium notatum &
P. crysogenum
2. Cephalosporins –
Cephalosporium acremonium
3. Griseofulvin –
P. griseofulvum
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B. Bacteria
1. Bacitracin –
B. Subtilis
2. Polymyxin –
B. polymyxa
3. Colistin –
B. colistinus
C. Actinomycetes
1. Streptomycin Streptomyces griseus
2. ChlortetracyclineS. aureofaciens
3. Chloramphenicol S. venezuelae
4. ErythromycinS. erythreus
CHEMOTHERAPY
Antibacterial term includes the
synthetic drugs e.g.- Sulfonamides &
Quinolones .
Antimicrobials- include both antb.s as
well as synthetic drugs
History –
The Ancient Hindus treated Leprosy
with Chaulmoogra oil.
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(The earliest use of antibiotics was probably in the
treatment of skin infections with moldy curd by the ancient
Chinese . Modern antibiotics can be traced to the work of
Louis Pasteur who observed that the in vitro growth of one
microbe was inhibited when another added to culture
,Pasteur called this phenomenon as antibiosis )
CHEMOTHERAPY
in 16th century – Mercury for Syphilis
was used .
in 17th century – Cinchona bark was
used against Malaria .
Modern rational chemotherapy begin
when Ehrlich said that Aniline dyes
selectively stained bacteria in tissue
microscopic prep.
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& could selectively kill them .(He discovered
Arsphenamine –Salvarsan , an arsenical comp. for Tt. Of Syphilis )
- He also invented the term ‘Chemotherapy’
in 1906.
-Antimalarials Primaquine & Mepacrine
were developed from dies .
- In 1935 first Sulfonamide linked with dye
Prontosil was introduced by Domagk.
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It causes a revolution in scientific &
medical field as many cases of
severe bacterial infections were
treated successfully .
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In 1928 Fleming accidentally
rediscover the long known ability of
Penicillium fungi to suppress the
growth of bacterial culture but could
not purify it .
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In 1939 Florey & Chain prepared
Penicillin & confirmed its remarkable
lack of toxicity.
subsequently other antibiotics were
came into being by another group of
microbes called Actinomycetes e.g.
Streptomycin by Walksman in 1944
( Actinomycetes proved to be the important source
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of antibiotics & soon Tetracyclines , chloramphen. &
Erythromycin emerged )
For above discoveries all three gps of
scientists were awarded Noble prize
for medicine.
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Classification :
Based on chemical structure & mech.
of actioni) Agents that inhibit synthesis of
bacterial cell wall e.g. – β lactum
class – Penicillin ,Cephalosporin
, Carbepenem etc.
- other dissimilar antb.s e.g. -
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Cycloserine , Vancomycin &
bacitracin
ii) Agents that act directly on the cell
membrane of the micro-organism
increasing their permeability &
leading to leakage of intracellular
components. e.g. – Polymixin ,
Nystatin & Amphotericin -B .
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iii) Agents that disrupts funct. of 30S or
50S ribosomal subunits to reversibly
↓ protein synthesis ( Bacteriostatic)
e.g. –
Chloramphenical , Tetracycline ,
Erythromycin etc.
iv) Agents that bind to 30S ribosomal
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subunit & alter protein synthesis
(Bactericidal) e.g.- Aminoglycosides.
v) Agents that affect bact. nucleic acid
metabolism e.g.- Rifampicin which ↓
RNA-Polymerase & Quinolones
which ↓DNA- Gyrase / Topoisomerases
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vi) Antimetabolites - e.g.Trimethoprim & Sulfonamides
which blocks essential enzyme of
folate metabolism.
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CHEMOTHERAPY
Other Classification :
Antimicrobial agents ( AMA ) can also be
classified broadly as under :
i)
Bacteriostatic – those that act primarily
by arresting bacterial multiplication e.g.
Sulfonamides , Tetracyc.s &
Chloramphenicol.
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ii) Bactericidal – those which act
primarily by killing of bact. such as –
Penicillins, Cephalosporins ,
Aminoglycosides, INH &
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Rifampicin etc. they act more on
rapidly dividing organisms
This classification is arbitrary because
most bacteriostatic drugs can act as
bactericidal on high concentrations.
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Principles of Antimicrobial
Chemotherapy
1.Make a diagnosis – As precisely as
possible
- Define the site of infection
- The micro-organism responsible
& their sensitivity to drugs
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It is advisable that all related
biological samples (e.g.-Blood , Pus , Urine,
CSF, Sputum etc. ) should be taken before
starting treatment.
Once antibiotic has been administered
isolation of the underlying organism
may be inhibited & its place may be
taken by resistant , colonizing bact.
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which obscure the true causative
pathogen .
2.Removal of barriers for cure :
- lack of free drainage of abscess .
- obstruction in urinary or respiratory
tract.
- Infected I.V. catheters .
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3.Decision that whether chemoth. is
really necessary :
As a general rule acute inf.s require
chemoth. while other measures are
more important for resolution of
chronic inf.s e.g. chr. abscess or empyma need
drainage along with chemotherapy
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4. Select the best drug :
To select a few pearls from
the big ocean of anti-microbials is indeed the need of the day.
a.) Specificity AM activity should match that of the
infecting organism. Indiscriminate
use of broad spectrum antibiotics
promote AM resistance & encourage
opportunistic inf.s
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( in absence of precise identification of
responsible microbe, best guess chemoth. of
broad spectrum most often be given )
-Simplest , least expensive & useful of all rapid methods
of identification – Gram stain can be used to identify
the presence of bacteria & its morphological feature .
Spectrum of cover should be narrowed
once the causative organism have
been identified .But it should be changed only
after adequate trial ( usually 3 days ) .
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- Rapid diag. tests-Gram –ve or Gram +ve staining of
body secretions .
- Ziehl Neelsen’s staining for acid fast
bacteria.
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-Polymerase chain reaction ( nucleic
acid detection assay ) for reliable
therapy .
Modification of treatment can be made
later if necessary in light of C/S tests
( Tt. should be changed after 2-3
days) .
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- b)Route of administration :
Parenteral
therapy ( I.M. or I.V. ) is preferred
for serious inf.s (to achieve high conc.
then switch on to oral therapy) & in
cases having vomiting/ diarrhea etc.
Topical – in cases of skin inf.s , ant .
nasal , mouth & eye inf.s
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bi) Pharmacokinetic Factors :
Absorption -polar cations are poorly
absorbed e.g. Aminogl.s
- inactivation in GIT , e.g. Penicill.s
- Presence of divalent ions e.g. Ca ,
Mg , Al ↓ Tetracycl.s & Quinol.s
absorption .
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Distribution :
Natural barriers limit the entry to the
sites like brain , bones & prostate .
Chosen drug is not capable of
reaching the site of infection in
adequate amount e.g.1. By crossing BBB as Penicill.s &
Aminog.s .
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2. Prostate – many drugs do not cross the
prostatic epithelium so difficult to treat
prostatitis
bii) Pharmacodynamic factors : AM.s
can exhibit –
CONCENTRATION & TIME DEPENDENT EFFECTS
AM drugs exhibit various conc.& time dependent effects
that influence their clinical efficacy , dosage & frequency
of administration e.g.
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1.
Minimal inhibitory conc. ( MIC ) – Lowest conc. of a drug that ↓
bacterial growth .
2.
Conc. Dependent killing ( CDK ) – Some Aminoglycosides (
Tobramycin ) & some Fluoroquinolones ( Ciprofloxacin) exhibit
CDK against a large gp . of Gram –ve bacteria e.g. P.
aeuroginosa & members of family Enterobacteriaceae .
3. Post antibiotic effect ( PAE ) - After removal of AB drug from bact.
culture, evidence of a persistent effect on bact. growth may exist ,
this is known as PAE e.g. Penicil.-against G+ve & Aminog. for Gve . It is due to post antb, leukocyte enhancement i.e. increased
sensitivity to the phagocytic & bacteriological action and altered
bacterial morphology and decrease rate of growth due to subinhibitory concentration .
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c) Host factorsi) History of previous ADRs
ii) Critical determinant of the
therapeutic effectiveness of AM
agents is the functional states of
host defense mech.
( in an immunocompetent patient a static drug may be sufficient . If
host defenses are impaired cidal drugs are essential for the cure )
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There may be generalized impairment
of host defenses as in Diabetes,
Leukemia , Lymphoma , AIDS , Steroid
& immunosuppressant therapy.
There may be
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a) Inadequacy of type , quality &
quantity of the immunoglobulins
b) Alteration of the cellular immune
system or a qualitative / quantitative
defect in phagocytic cells which may
result in therapeutic failure despite
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the use of appropriate & effective
drugs .
ABs may affect host defense acting
as biologic response modifiers :
1. With no effect on host defense –
β – lactams .
2. Inhibition of immune syst.-Tetracyc.
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3. Synergy with immune syst. –
Macrolides & Quinolones .
4. Increased immune functionsome of Cephalosporins.
Immune system plays impt. role in
final elimination of microbes therefore
drugs that ↑ immune func. are preferr.
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c-ii) Age –
Mech . of elimination esp. renal exc.
& hepatic metabolism are poorly
developed in the new born and
cause disastrous consequences e.g.
– Grey baby syndrome caused by
Chloramphenicol .
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-Elderly – excrete drug with less
efficacy because of ↓ creatinine
clearance. They also metabolize drug
less rapidly.
c-iii) Renal & Hepatic function :
When renal &/ or hepatic function
are impaired the dose of the AMA
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( especially having low safety margin)
need to be modified e.g. following antb
need dose reduction in renal failure pts.
- Aminoglycosides
- Amphotericin B
- Cephalosporins
- Vancomycin
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- Metronidazole
- Co- trimoxazole & Fluroquinolones
Drugs should not be given-Nitrofurantoin
-Nalidixic acid
-Tetracyc. ( except Doxycyc.)
- Cephalothine & Cephaloridine
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Drugs to be avoided / used in low
doses in Liver disease –
-Erythromycin estolate
- Tetracyclines
- Nalidixic acid
-Pyrazinamide ,Isoniazid &Rifampicin
- Chloramphenicol etc.
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c-iv) Pregnancy –
All AMA should be avoided in pregnancy due to the risk to
the foetus
( Penicillins , , most of the Cephalosporins
& Erythromycin are safe & can be given when especially
needed ) .
c-v) Genetic factor
: Primaquine , Chloramphenicol ,
Sulphonamides & Fluroquinolones can produce
hemolysis in G-6 PD deficient pts .
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d.) Local factors –
presence of pus , low pH & other
confined spaces like – pleural space
, CSF , urine & anaerobic condition
can reduce AM action e.g.
Aminoglycosides
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- Presence of foreign body in the
infected site ↓ AMA e.g. – prosthetic
cardiac valves , joints , pacemaker,
vascular grafts & shunts . They
promote formation of a bact. biofilm
that impairs phagocytosis.
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- Presence of intracellular pathogen
e.g.- Salmonella, Brucella , Listeria &
M. tub. as they are protected from the
actions of AB agents .
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5. Administer the drug- in optimum
doses & frequency and by the most
appropriate routes (inadequate dose
may encourage the dev. of resist.) .
Plasma conc. monitoring can be
performed to optimize therapy &
reduce ADRs.
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6. Continue therapy – until apparent
cure has been achieved . Most
acute inf.s are treated for 5-10 days
except – Typhoid fever , Tuberculosis
and infective endocarditis in which
relapse is possible so the drug is
continued for a longer time
otherwise prolonged therapy is to be
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avoided because it ↑ cost & the risk of
ADRs.
Test for cure : microbiological proof of
cure e.g. culture/ sensitivity of the
blood, urine , sputum & CSF etc.
whichever is needed must be done ,
of course , after withdrawal of
chemotherapy.
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Prophylactic Chemotherapy :
For surg. & dental procedures &
should be of very limited duration ,
often only single large dose at the
beginning of surgical procedure .
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Combinations :
Tt with single AM is sufficient for most
inf.s . The indication for use of two or
more AM are –
1. To avoid the development of drug
resist. esp. in chronic inf.s e.g. –
Tuberculosis.
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2.To broaden the spectrum of antibact.
activity . e.g.-in a known mixed infection as in
peritonitis following gut perforation .
-in septicemia accompanying
neutropenia or pneumonia
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3.To obtain potentiation i.e. an effect
unobtainable with either drug alone
e.g.Penicil. + Gentamycin (endocarditis)
4.To enable the reduction of the dose
of one component hence ↓ the rate of
ADRs e.g.- Flucytosine + Amphot. B
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5.Use two bacteriostatic or two
bactericidal drugs because
bacteriost. drug prevent the organism
from a bactericidal agent .
Chemoprophylaxis :
The basis of effective true
chemoprophy. is the use of a drug in
a healthy person to prevent or
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Suppressing contacted infection before it
becomes clinically manifest .
The difference between treating & prevent.
infections is that Tt is directed against sp.
organism , while prophylaxis is often against
all org.s capable of causing infection
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it may be i) True prevention of primary inf. e.g.Rheumatic fever & rec. UTI .
ii) Prev. of opportunistic inf. due to
commensals getting into wrong place
e.g. – bact. endocarditis after dental
surgery.
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iii) Supp. of existing inf. before it
causes overt disease. e.g.-T.B. ,
Malaria ,animal bites , trauma etc.
iv) Prev. of acute exacerbations of a ch.
inf. e.g. Bronchitis in cyst. fibro. & COPD
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v) Prev. of spread amongst contacts (
as in epidemics ) e.g.- spread of
influenza A can be partially prev. by
Amantadine.
- Contact cases of T.B. by Rifampicin.
vi) In immunocompromized pts (receiving
corticosteroids or antineoplastic chemotherapy & neutropenic pts )
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In Surgery :
1. when risk of inf. is high because of
the presence of large no. of bact.s
in the viscus as in large intestine.
2. Risk of inf. is low but consequences
are disastrous .e.g.- inf. of prosthetic
joints or heart valves.
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AM should be given I.V./I.M. or
occasionally rectally at the beginning
of anesthesia & for no more than 48
hrs. A single preop. dose, given at the
time of induction of anesth. has
shown to give optimal cover for many
different operations e.g. -
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Colorectal surg.
Gastro-duodenal surg.
Gynecological surg.
Insertion of prosthetic Joints .
Antimicrobial prophylaxis in
dentistry
This is warranted for two distinct purposes viz.
• (a) prevention of local wound infection, and
• (b) prevention of distant infection (e.g. bacterial
endocarditis) in predisposed patients following
dental procedures.
Prophylaxis of dental wound infection
Wound infection occurs due to microbial
contamination of the surgical site. It is
important for the dental surgeon to see
that the wound left after tooth extraction,
etc. does not get infected.
Use of :
sterile instruments, cross-infection control
measures (antiseptic/disinfectant, etc.) and good
surgical technique to minimise tissue damage,
haematoma and devascularization are the
primary, and often the only measures needed.
In addition, systemic antimicrobial prophylaxis is
advocated in selected situations.
Prophylaxis should be employed only when
there is a clear risk of wound infection that
outweighs the possible drawbacks of
antibiotic use. In general, antibiotic
prophylaxis is not required for routine dental
surgery, except patients at special risk.
Simple extractions and minor periodontal
procedures in otherwise healthy subjects are
associated with very low risk of wound
infection. Incidence of postoperative
infection is quite low even after difficult
surgery such as removal of impacted third
molar, and antimicrobial prophylaxis is not
required.
However, it may be given when surgery
Involves extensive instrumentation, bone
cutting or is prolonged. It has been found
that the incidence of postoperative infection
is higher when oral surgery had lasted 2
hours or more
Prophylaxis should also be given for procedures in
which a Prosthesis is inserted into the bone or soft
tissue, such as dental implants. Extensive
reconstructive surgery of upper or lower jaw also
warrants antibiotic prophylaxis.
All orodental procedures which disturb/ damage
mucosa including extractions, scaling, etc. need to
be covered by prophylaxis in diabetics,
corticosteroid recipients and other
Immunocompromised subjects
All orodental procedures which disturb/
damage mucosa including extractions,
scaling, etc. need to be covered by
prophylaxis in diabetics, corticosteroid
recipients and other immunocompromised
subjects
The selection of drug, dose, timing and
duration of prophylactic medication is crucial. It
is important that the antibiotic is not started
prematurely and is not continued beyond the time
when bacteria have access to the surgical wound.
Administration of the AMA has to be so timed
that peak blood levels occur when the clot is
forming in the surgical wound.
• Thus, most of the oral drugs are given 1 hour
before tooth extraction or other short
procedures, while i.v. or i.m. drugs are given just
prior to it. Most of the AMAs do not penetrate the
clot once it is formed and is older than 3 hours.
Thus, late and prolonged presence of the
antibiotic in circulation serves no purpose,
but can foster resistant organisms.
• All orodental procedures which disturb/
damage mucosa including extractions,
scaling, etc. need to be covered by
prophylaxis in diabetics, corticosteroid
recipients and other immunocompromised
subjects
However,
when the surgery has been performed in the
presence of local infection, continuation of the
prophylactic AMA beyond 4 hours after the
dental procedure may be justified. In case of
prolonged dental surgery, the antibiotic may be
repeated i.v. during the procedure.
To be maximally effective, a relatively high
dose of the AMA is selected which yields peak
blood levels several times higher than MIC for the
common oral pathogens. Because the resident
oral flora is generally the source of the infecting
organism for dental surgery wounds, the
prophylactic AMA should be active against gram
positive cocci and oral anaerobes.
Being bactericidal and safe, amoxicillin is generally
the first choice drug.
The commonly employed antibiotics for prevention
of wound infection in dentistry are as follows :
Oral (single dose given 1 hour before procedure)
1. Amoxicillin 2 g (50 mg/kg)
2. Cephalexin 2 g (50 mg/kg)
3. Cefadroxil 2 g (50 mg/kg)
4. Clindamycin 600 mg
(20 mg/kg)
5. Azithromycin 500 mg
(15 mg/kg)
For patients allergic to penicillin
Parenteral (single injection just before procedure)
1. Ampicillin 2 g (50 mg/kg) i.m/i.v
2. Cefazolin 1 g (25 mg/kg) i.v.
3. Clindamycin 600 mg (20 mg/kg) i.v. for penicillin allergic patients
The same antibiotics and regimens described
above for prevention of dental wound infection
can be employed for prophylaxis of distant
infections. However, since patients with
prosthetic heart valves, those with history of
bacterial endocarditis in the past and those to be
operated under general anaesthesia are
considered to be at greater risk and have a poorer
prognosis if they develop bacterial endocarditis,
it has been advocated that gentamicin 120 mg
(2 mg/kg) i.m / i.v. may be given just before the
dental procedure in addition to amoxicillin (or
its substitute) and another dose of amoxicillin
500 mg (12.5 mg/kg) be repeated 6 hours after the
procedure.
Another regimen used in patients allergic to penicillin is
vancomycin 1 g (20 mg/kg) i.v. over 2 hours + gentamicin
120 mg (2 mg/kg) i.m./i.v. just before the procedure.
Antiseptic rinse with chlorhexidine (0.2%) held in the mouth
for 1 minute just before dental treatment has been
advocated as an adjuvant measure because it has been
shown to reduce the severity of bacteraemia following
Dental extraction.
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Drug Resistance:
Refers to unresponsiveness of a micro
organism to an AMA , it is similar to the
phenomenon of tolerance seen in higher
forms of organisms .
Natural resistance –
Some of the microorg. are always show
resistance to certain AMAs . This may
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be due to lack of the metabolic process or
the target site which is affected by particular
AMA .
e.g.- Gram-ve bacilli are normally unaffected
by penicillin.
(It does not create a significant clinical
problem) .
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Acquired Resistance:
Development of resistance by an organism
which was previously sensitive & over a
period of time develop resistance due to
continuous use of AMA .
Can occur with any microbe & create major
clinical problem.
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Factors that determine the suscept.
& Resist. of Micro-org. to AMAs.
Concentration of antibiotic at the site
of inf.— It must be sufficient to inhibit
growth of the offending microorganism.
Host Defense -if host defense is intact
the bacteriostatic agent having min.
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inhibitory effect is sufficient, but if host
defense is impaired then bacteriocidal
agent is required.
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-If the conc. of drug required to inhibit
or kill the micro-organism is greater
than the conc. that can be safely
achieved , micro-org. is considered to
be resistant to the antibiotic . (The conc.
of drug must also remain below the level that is
toxic to human cells.) .
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Specific infection –
Conc. of drugs at certain specific
places of infection ( e.g.-vitreous fluid
& C.S.F.) may be much lower than
that in plasma. Thus the drug may be
marginally effective or ineffective
even though tests would report the
micro-org. as sensitive.
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Conversely conc. of drug in urine may
be much higher than that in plasma but
micro-org. reported as resistant may
thus respond to therapy .
Bacterial Resistance –
Recent emergence of ABT. resist. in
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bact. pathogen mostly in nosocomial
& community acquired inf.s is a very
serious develop. that threatens the
end of the ABT. era .
- More than 70% bact.s associated with
hospital acquired inf.s are resist. to
one or more drugs e.g.-
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- world wide emergence of
Haemophilus & Gonococcus bact.
that produces β- lactamase ,is a
major therapeutic problem .
- Methicillin resist. strains of S. aurius
are endemic in hospitals .
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-There are now strains of Enterococci,
Pseudomonas & enterobacter that are
resist. to all available antibiotics.
- Epidemic of MDR-TB have been
reported at various places.
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The Centre for Disease Control &
Prev. has outlined a series of steps
to prevent AM resist., important
components are –
i) Appropriate use of Vaccination.
ii) Judicious use & proper attention to
indwelling catheters.
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iii) Early involvm. of infectious disease
experts.
iv) Choosing antibiotic therapy based
on local susceptibilities of
organisms .
v) Proper antiseptic techniques to
ensure inf. rather than
contamination .
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vi) Appropriate use of prophylactic antb. in
surgical procedures.
vii) Infective control procedure to isolate
pathogen &
viii) Strict compliance to hand hygiene .
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Mechanism of Resistance
Bact. resist. to an AMA is attributable to
three general mech.s ( biochemical
mechanism )
1. The drug does not reaching to its target.
2. The drug is not active .
3. The target is altered .
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1. The outer memb. of Gram- ve bact. is a
permeable barrier that excludes large
polar molecule from entry into the cell .
Small polar mol. e.g. antb. enters the cell
through protein channel called porins .
Absence of, mutation or loss of Porin
channel can slow the rate of drug entry
into the cell thus
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-
effectively ↓ drug conc. at the target
site .
If target is intracellular & drug
requires active transport across the
cell memb. , a mutation or
phenotype change that shuts down
this transport mech. can confer
resist. e.g. Gentamycin
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which target ribosomes.
- Bact. have efflux pumps that can
transport drugs out of the cell e.g.
Tetracycl. , Chloramphenicol ,
Fluoroquinol., Macrolide.& β- lactum
antb.s
2. Drug Inactivation –
Bact. resist. to Aminoglycoside & to
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β- lactam antibiotics usually is due to
prod. of Aminoglyc. modifying enz. &
β- lactamases respectively .
(variation in this mech. is failure of the bact. cell to
activate a pro-drug e.g.- Isoniazide in M. tuberculosis.)
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3. Target alteration –
a) Mutation of natural target e.g.Fluoroquinolones resist.
b) Target modification e.g. –
ribosomal resist. to Macrolides &
Tetracyclines .
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c) Acquisition of a resist. form of the
native , susceptible target e.g.Staphylococ. Methicillin resist.
caused by prod. of a low affinity
Penicil. Binding Protein ( PBP ) .
4. Quorum sensing : recently it has been
seen that the microbes communicate with each
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other & exchange signaling chemicals (autoinducers)
which allows bact. population to co-ordinate gene
expression for virulence , conjugation ,mobility ,
apoptosis & antb. resistance . This process is known as
QS.
A single autoinducer from a single microbe is incapable
of inducing any change but its colony reaches a critical
density ( quorum) ,. a threshold of autoinduction is
reached & gene expression starts ,e.g. in G- ve bacteria
( AHLs , AIP, AI-2 & AI-3 )
CHEMOTHERAPY
Genetic determinants of drug
Resistance :
Drug resistance may be acquired by
mutation & selection with passage of
the trait vertically to daughter cells . It
is the molecular basis for resist. to
Streptomycin ( ribosomal mutation) ,
CHEMOTHERAPY
Quinolones ( Gyrase or Topoisomerase
IV gene mutation) ,Rifampicin (RNApolymerase gene mut.), Linezolid
(Ribosomal-RNA mut.) .
(It can be single step involving more powerful genes & confer a considerable
degree of resist. e.g. Streptomycin . Can be multiple stepwise & occurs in a
no. of genes which are responsible for a slight & gradual increase in resist.)
Mutation may occur in the gene encoding –
( mutation refers to a change in DNA structure of a gene)
CHEMOTHERAPY
CHEMOTHERAPY
i) The target protein ,altering its
structure so that it no longer binds
to the drug.
ii) Protein involved in drug transport.
iii) A protein impt. for drug activation or
inactivation , in the case of extended
spectrum β- lactamases .
CHEMOTHERAPY
iv) In a regulator gene or promoter
affecting expressions of the target ,
a transport protein or an inactivating
enz.s .
Horizontal Gene Transfer :
Drug resist. is more commonly acquired
by horizontal trans. of resist. determin.s
CHEMOTHERAPY
from a donor cell, often of another bact
spp. by transduction ,transformation or
conjugation ( through Plasmid ).
It is facilitated by and is largely
dependent on mobile genetic element.
The plasmids & Phages act as carriers
of resist. genes & transferable element.
CHEMOTHERAPY
Other mobile elements /transposable
elements e.g. Insertion sequences
,Transposons , Integron & gene
cassettes also participate in the
process .
CHEMOTHERAPY
Occurs by three main processes:
Transduction :
Refers to the transfer of an R –factor
(genetic material coding for resist. ) carrying
plasmid by a bacterial virus (bacteriophage)
vector along with its own genes e.g.
strains of Staphyl. aureus .
CHEMOTHERAPY
If the DNA includes the gene for drug
resist. the newly infected bact. cell
may acquire resistance .
CHEMOTHERAPY
CHEMOTHERAPY
Transformation :
It is the uptake & incorporation into
the host genome by homologous
recombinat. of free DNA released
into the environment by other bact.
cells. It is the mol. basis of Penicill.
resistance in Pneumococci &
CHEMOTHERAPY
Neisseria .
(Penicil. resist. pneumococ. produces
altered
penicil. binding proteins( PBPs) that have low
affinity binding to penicil.)
Conjugation :
It is the gene transfer (R-factor ) by
direct cell-to-cell contact through a
CHEMOTHERAPY
sex pilus or bridge . This is important
because multiple resist. genes can be
transferred in a single event . The
transferable genetic material consists
of two different sets of plasmidencoded genes that may be on the
same or different plasmids .
CHEMOTHERAPY
(The first set codes for the actual resist. & is
termed the R-determinant plasmid. The second
plasmid termed as the resist. transfer factor
(RTF ) , contains the Genes necessary for bact.
conjugation. Each of these two plasmids can
exist independently or they can combine to form
a complete R-factor which can be disseminated
by bact. Conjugation ). e.g. in GI tracts of
human beings (Vancomycin resist. in
Enterococci by conj. Plasmid .)
CHEMOTHERAPY
Other org.s which dev. resist. by this
method are Shigella , Salmonella
,V. cholerae , Pseud. aerugenosa
(R-factor transfer is usually multiple & resistance can
occur to as many as seven drugs , occurs mainly in
intestinal tract e.g. Penicillin , Tetracyclines,
Chloramph., Erythromycin , Aminoglycos.,
Sulphonamides & Fusidic acid
.)
CHEMOTHERAPY
CHEMOTHERAPY
SUPERINFECTIONS :
All individuals who receive
therapeutic doses of antib. undergo
alterations in the normal microbial
population of the intest. , upper
resp. & genitourinary tracts, as a
result some develop superinfection ,
CHEMOTHERAPY
which defined as the appearance of
bacteriological & clinical evidence
of new infection during the
chemotherapy of a primary one. It
is common & dangerous because the
micro- org. responsible for the new
infection can be resistant strains of
Enterobacteriace , Pseudomonas
CHEMOTHERAPY
& Candida or other fungi . It is due to
the removal of the inhibitory influence
of the normal flora which produces
antibacterial subst.s (Bacitracins) &
compete for essential nutrients.
CHEMOTHERAPY
The broader the spectrum & longer
the duration of Tt. greater is the
alteration in the normal flora. e.g.Tetracyclines & Chloramphenicol
(therefore the most specific &
narrowest spect. AM. ags. should
be chosen for Tt.).
more common in immunocompromised host
CHEMOTHERAPY
Misuses of Antibiotics:
i) Treatment of non-responsive
inf.s:
proved by experimental & clinical
observations e.g.- diseases caused
by viral inf.s are self limit.& do not
respond to any of the anti-infect.
agents (measles ,mumps , 90% of
CHEMOTHERAPY
URTIs & many GI inf.s ) therefore
useless to treat with antibiotics .
ii) Therapy of fever of unknown
origin :
fever of undetermined cause may
persist for only a few days to a wk. ,
in the absence of localizing signs
,mostly assos. with viral inf. & AM
CHEMOTHERAPY
therapy is unnecessary .
Fever for two or more wks commonly
referred as a fever of unknown origin
& has a variety of causes ( only one
fourth are infectious) .Some may req.
Tt. with uncomm. anti bact. agents
e.g.- T.B. or fungal inf.
CHEMOTHERAPY
Occult absc. may req. drainage or
prolong pathogen sp. therap. e.g. inf.
endocarditis .
Non infective causes are reg. enteritis
,lymphoma ,hepatitis ,collagen vas.
disorder & drug fever , which does not
respond to AM therapy at all .
CHEMOTHERAPY
iii) Improper dosage :
Use of either an excessive or a subtherapeutic dose is common. Excess
amounts can cause toxicities e.g.seizures (penicil.) ,vestibular
damage & renal failure ( Amgl. ).Sub therp. dose causes Tt. failure & resist.
CHEMOTHERAPY
iv) Inappropriate reliance on chemth.
Inf. complicated by absc. formation ,
presence of necrotic tissue or foreign
body often can not be cured by AM
therapy alone ( surgical intervention
is necessary ).
CHEMOTHERAPY
v) Lack of adequate bacteriological
information :
In hospitalized pts AM therapy is
oftenly started without microbiolog.
data .
Frequent use of drugs or drug comb.s
CHEMOTHERAPY
with the broadest spectra is a cover for
diagnostic error . So bacteriological
information is a correct practice for
use of AM agents until otherwise
required (e.g.- in emergency
conditions & in cond.s where specific
therapy is needed ) .
1.Goodman & Gilman’s ,The
Pharmacological
Basis of
Therapeutics (12th Edition).
2.Clinical Pharmacology by Lawrence
(Latest edition)
3. Essentials of Medical Pharmacology
by K. D. Tripathi’s ( 7th Edition)
CHEMOTHERAPY
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