chemotherapy dr. rajendra nath professor. chemotherapy the term chemotherapy is used for the drug...
TRANSCRIPT
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.
CHEMOTHERAPY
(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
CHEMOTHERAPY
Antibiotics –
They are antibacterial substances produced by various species of micro-organisms ( 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
CHEMOTHERAPY
Natural Sources of AntibioticsA. Fungus –1. Penicillin - Penicillium notatum & P. crysogenum 2. Cephalosporins – Cephalosporium acremonium 3. Griseofulvin – P. griseofulvum
CHEMOTHERAPY
B. Bacteria C. Actinomycetes 1. Bacitracin – 1. Streptomycin -
B. Subtilis Streptomyces griseus
2. Polymyxin –
B. polymyxa 2. Chlortetracycline-
3. Colistin – S. aureofaciens
B. colistinus 3. Chloramphenicol -
S. venezuelae
4. Erythromycin-
S. erythreus
CHEMOTHERAPY
AntibacterialAntibacterial term includes the synthetic drugs e.g.- Sulfonamides & Quinolones .
Antimicrobials- include both antb.s as well as synthetic drugsHistory –
The Ancient Hindus treated Leprosy with Chaulmoogra oil.
CHEMOTHERAPY
(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.
CHEMOTHERAPY
& 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.
CHEMOTHERAPY
It causes a revolution in scientific & medical field as many cases of severe bacterial infections were treated successfully .
CHEMOTHERAPY
In 1928 FlemingFleming accidentally rediscover the long known ability of Penicillium fungi to suppress the growth of bacterial culture but could
not purify it .
CHEMOTHERAPY
In 1939 Florey & ChainFlorey & 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 WalksmanWalksman in 1944
( Actinomycetes proved to be the important source
CHEMOTHERAPY
of antibiotics & soon Tetracyclines , chloramphen. & Erythromycin emerged )
For above discoveries all three gps of
scientists were awarded Noble prize
for medicine.
CHEMOTHERAPY
Classification : Based on chemical structure & mech.
of action- i) Agents that inhibit synthesis of
bacterial cell wall e.g. – β lactum class – Penicillin ,Cephalosporin , CarbepenemCarbepenem etc.
- other dissimilar antb.s e.g. -
CHEMOTHERAPY
Cycloserine , VancomycinCycloserine , Vancomycin & bacitracinbacitracin
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 -BAmphotericin -B .
CHEMOTHERAPY
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
CHEMOTHERAPY
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 / Topo-isomerases
CHEMOTHERAPY
vi) Antimetabolites - e.g.-Trimethoprim & Sulfonamides which blocks essential enzyme of folate metabolism.
CHEMOTHERAPY
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.
CHEMOTHERAPY
ii) Bactericidal – those which act primarily by killing of bact. such as – Penicillins, Cephalosporins , Aminoglycosides, INH &
CHEMOTHERAPY
Rifampicin etc. they act more on
rapidly dividing organisms
This classification is arbitrary because
most bacteriostatic drugs can act as
bactericidal on high concentrations.
CHEMOTHERAPY
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
CHEMOTHERAPY
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.
CHEMOTHERAPY
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 .
CHEMOTHERAPY
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
CHEMOTHERAPY
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
CHEMOTHERAPY
( 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 ) .
CHEMOTHERAPY
- Rapid diag. tests-
-Gram –ve or Gram +ve staining of body secretions .
- Ziehl Neelsen’s staining for acid fast bacteria.
CHEMOTHERAPY
-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) .
CHEMOTHERAPY
- 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
CHEMOTHERAPY
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 .
CHEMOTHERAPY
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 .
CHEMOTHERAPY
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.
CHEMOTHERAPY1. 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 G-ve . 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 sub-
inhibitory concentration .
CHEMOTHERAPY
c) Host factors-
i) 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 )
CHEMOTHERAPY
There may be generalized impairment
of host defenses as in Diabetes,
Leukemia , Lymphoma , AIDS , Steroid
& immunosuppressant therapy.
There may be
CHEMOTHERAPY
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
CHEMOTHERAPY
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.
CHEMOTHERAPY
3. Synergy with immune syst. – Macrolides & Quinolones . 4. Increased immune function- some of Cephalosporins. Immune system plays impt. role in final elimination of microbes therefore drugs that ↑ immune func. are preferr.
CHEMOTHERAPY
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 .
CHEMOTHERAPY
-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
CHEMOTHERAPY
( especially having low safety margin)need to be modified e.g. following antbneed dose reduction in renal failure pts. - Aminoglycosides - Amphotericin B - Cephalosporins - Vancomycin
CHEMOTHERAPY
- Metronidazole - Co- trimoxazole & FluroquinolonesDrugs should not be given- -Nitrofurantoin -Nalidixic acid -Tetracyc. ( except Doxycyc.) - Cephalothine & Cephaloridine
CHEMOTHERAPY
Drugs to be avoided / used in low doses in Liver disease –
-Erythromycin estolate
- Tetracyclines
- Nalidixic acid
-Pyrazinamide ,Isoniazid &Rifampicin
- Chloramphenicol etc.
CHEMOTHERAPY
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 .
CHEMOTHERAPY
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
CHEMOTHERAPY
- 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.
CHEMOTHERAPY
- Presence of intracellular pathogen e.g.- Salmonella, Brucella , Listeria & M. tub. as they are protected from the actions of AB agents .
CHEMOTHERAPY
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.
CHEMOTHERAPY
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
CHEMOTHERAPY
avoided because it ↑ cost & the risk ofADRs.
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.
CHEMOTHERAPY
Prophylactic Chemotherapy :
For surg. & dental procedures & should be of very limited duration , often only single large dose at the beginning of surgical procedure .
CHEMOTHERAPY
Combinations :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.
CHEMOTHERAPY
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
CHEMOTHERAPY
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
CHEMOTHERAPY
5.Use two bacteriostatic or two bactericidal drugs because bacteriost. drug prevent the organism from a bactericidal agent .
Chemoprophylaxis :Chemoprophylaxis : The basis of effective true
chemoprophy. is the use of a drug in a healthy person to prevent or
CHEMOTHERAPY
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
CHEMOTHERAPY
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.
CHEMOTHERAPY
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
CHEMOTHERAPY
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 )
CHEMOTHERAPY
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.
CHEMOTHERAPY
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. -
CHEMOTHERAPY
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 periodontalprocedures in otherwise healthy subjects areassociated with very low risk of woundinfection. Incidence of postoperativeinfection is quite low even after difficultsurgery such as removal of impacted thirdmolar, and antimicrobial prophylaxis is notrequired.
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 inwhich a Prosthesis is inserted into the bone or softtissue, such as dental implants. Extensivereconstructive surgery of upper or lower jaw alsowarrants antibiotic prophylaxis.All orodental procedures which disturb/ damagemucosa including extractions, scaling, etc. need tobe covered by prophylaxis in diabetics,corticosteroid recipients and otherImmunocompromised 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 andduration of prophylactic medication is crucial. Itis important that the antibiotic is not startedprematurely and is not continued beyond the timewhen bacteria have access to the surgical wound.
Administration of the AMA has to be so timedthat peak blood levels occur when the clot isforming 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 thepresence of local infection, continuation of theprophylactic AMA beyond 4 hours after thedental procedure may be justified. In case ofprolonged dental surgery, the antibiotic may berepeated i.v. during the procedure.To be maximally effective, a relatively highdose of the AMA is selected which yields peak
blood levels several times higher than MIC for thecommon oral pathogens. Because the residentoral flora is generally the source of the infectingorganism for dental surgery wounds, theprophylactic AMA should be active against grampositive cocci and oral anaerobes.Being bactericidal and safe, amoxicillin is generallythe first choice drug. The commonly employed antibiotics for preventionof 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 For patients allergic to penicillin(20 mg/kg)5. Azithromycin 500 mg(15 mg/kg)
Parenteral (single injection just before procedure)1. Ampicillin 2 g (50 mg/kg) i.m/i.v2. 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 isvancomycin 1 g (20 mg/kg) i.v. over 2 hours + gentamicin120 mg (2 mg/kg) i.m./i.v. just before the procedure.
Antiseptic rinse with chlorhexidine (0.2%) held in the mouthfor 1 minute just before dental treatment has beenadvocated as an adjuvant measure because it has beenshown to reduce the severity of bacteraemia followingDental extraction.
CHEMOTHERAPY
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
CHEMOTHERAPY
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) .
CHEMOTHERAPY
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.
CHEMOTHERAPY
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 micro-organism.
Host Defense -if host defense is intact the bacteriostatic agent having min.
CHEMOTHERAPY
inhibitory effect is sufficient, but if host
defense is impaired then bacteriocidal
agent is required.
CHEMOTHERAPY
-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.) .
CHEMOTHERAPY
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.
CHEMOTHERAPY
Conversely conc. of drug in urine may be much higher than that in plasma butmicro-org. reported as resistant may thus respond to therapy .
Bacterial Resistance – Recent emergence of ABT. resist. in
CHEMOTHERAPY
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.-
CHEMOTHERAPY
- 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 .
CHEMOTHERAPY
-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.
CHEMOTHERAPY
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.
CHEMOTHERAPY
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 .
CHEMOTHERAPY
vi) Appropriate use of prophylactic antb. in surgical procedures.
vii) Infective control procedure to isolate pathogen &
viii) Strict compliance to hand hygiene .
CHEMOTHERAPY
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 .
CHEMOTHERAPY
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
CHEMOTHERAPY
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
CHEMOTHERAPY
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
CHEMOTHERAPY
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.)
CHEMOTHERAPY
3. Target alteration –
a) Mutation of natural target e.g.-
Fluoroquinolones resist.
b) Target modification e.g. –
ribosomal resist. to Macrolides &
Tetracyclines .
CHEMOTHERAPY
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
CHEMOTHERAPY
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 TopoisomeraseIV gene mutation) ,Rifampicin (RNA-polymerase 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 carriersof 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 plasmid-encoded 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 sub- therapeutic 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
THANK YOUTHANK YOU