chemotherapy dr. rajendra nath professor. chemotherapy the term chemotherapy is used for the drug...

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 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

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Natural Sources of AntibioticsA. Fungus –1. Penicillin - Penicillium notatum & P. crysogenum 2. Cephalosporins – Cephalosporium acremonium 3. Griseofulvin – P. griseofulvum

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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

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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.

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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 )

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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 FlemingFleming 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 & 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

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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 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. -

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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 .

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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 / Topo-isomerases

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vi) Antimetabolites - e.g.-Trimethoprim & Sulfonamides which blocks essential enzyme of folate metabolism.

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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.

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 .

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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 )

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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 function- some 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 antbneed dose reduction in renal failure pts. - Aminoglycosides - Amphotericin B - Cephalosporins - Vancomycin

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- Metronidazole - Co- trimoxazole & FluroquinolonesDrugs 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 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.

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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 :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 :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 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.

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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 micro-organism.

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 butmicro-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 )

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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) ,

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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)

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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 .

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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

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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.

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Other mobile elements /transposable elements e.g. Insertion sequences ,Transposons , Integron & gene cassettes also participate in the process .

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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 .

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If the DNA includes the gene for drug resist. the newly infected bact. cell may acquire resistance .

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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 &

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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

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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 .

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(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 .)

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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 .)

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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 ,

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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

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& 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.

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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

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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

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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

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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.

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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 .

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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.

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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 ).

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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

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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)

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