- Slides: 135
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 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
CHEMOTHERAPY Natural Sources of Antibiotics A. Fungus – 1. Penicillin Penicillium notatum & P. crysogenum 2. Cephalosporins – Cephalosporium acremonium 3. Griseofulvin – P. griseofulvum
CHEMOTHERAPY B. Bacteria 1. Bacitracin – B. Subtilis 2. Polymyxin – B. polymyxa 3. Colistin – B. colistinus C. Actinomycetes 1. Streptomycin Streptomyces griseus 2. Chlortetracycline. S. aureofaciens 3. Chloramphenicol S. venezuelae 4. Erythromycin. S. 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.
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 16 th century – Mercury for Syphilis was used. in 17 th 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 Fleming 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 & 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
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 actioni) Agents that inhibit synthesis of bacterial cell wall e. g. – β lactum class – Penicillin , Cephalosporin , Carbepenem etc. - other dissimilar antb. s e. g. -
CHEMOTHERAPY 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.
CHEMOTHERAPY iii) Agents that disrupts funct. of 30 S or 50 S ribosomal subunits to reversibly ↓ protein synthesis ( Bacteriostatic) e. g. – Chloramphenical , Tetracycline , Erythromycin etc. iv) Agents that bind to 30 S 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 / Topoisomerases
CHEMOTHERAPY vi) Antimetabolites - e. g. Trimethoprim & Sulfonamides which blocks essential enzyme of folate metabolism.
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.
CHEMOTHERAPY 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.
CHEMOTHERAPY c) Host factorsi) History of previous ADRs ii) Critical determinant of 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 functionsome 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 antb need dose reduction in renal failure pts. - Aminoglycosides - Amphotericin B - Cephalosporins - Vancomycin
CHEMOTHERAPY - Metronidazole - Co- trimoxazole & Fluroquinolones Drugs 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 p. H & 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 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.
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 : 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 : 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 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.
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 microorganism. 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 but micro-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 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 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 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 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 (12 th Edition). 2. Clinical Pharmacology by Lawrence (Latest edition) 3. Essentials of Medical Pharmacology by K. D. Tripathi’s ( 7 th Edition)
CHEMOTHERAPY THANK YOU