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Basic principles of chemotherapy

        S. Parasuraman, M.Pharm., Ph.D.,
       Senior Lecturer, Faculty of Pharmacy,
                 AIMST University
Chemotherapy

Chemotherapy:         chemo + therapy

The use of drug (chemical entity/ substance derived form
microorganisms) with selective toxicity against infections/
viruses, bacteria, protozoa, fungi and helminthes is called as
chemotherapy.
Antibiotics and Antimicrobials
• Antibiotics: Antibiotics are substances produced by
  microorganisms, which selectively suppress the growth of or
  kill other microorganisms at very low concentration.

• Antimicrobials: (chemotherapeutic agent + Antibiotics)
  Any substance of natural, synthetic or semisynthetic origin
  which at low concentrations kill or inhibits the growth of
  microorganisms but causes little or no host damage.
History of chemotherapy
History of chemotherapy
Before Ehrlich’s period (till 1900)
• Chaulmoogra oil by Hindus in leprosy
• Cinchona bark for fever
• ‘Mouldy curd’ by chines on boils
• Mercury by Paracelsus for syphilis


Ehrlich’s period (1900 to 1930)
• Organometallic dye for treatment for cane


After Ehrlich’s period (1930 to till date)
• discovery of sulfonamide (Prontosil)
Timeline history of
                                                                             chemotherapy development
 1908- Discovery
                                                      1959- Antitumor
 of Arsphenamine
                                                      antibiotics                                           2007- Target specific
                    Alexander Fleming 1928-                                                                 screens
                    Penicillin                        1958- Methotrexate
                                                                                                         2005- Tyrosine kinase
                                                      1957- 5-Fluorouracil                               inhibitors

                                                      1951- Thiopurines                                     1997- Monoclonal
                                                                                                            antibody approved
        Paul                                                                                                for the treatment of
                                                       1948- Anitfolates
       Ehrilich                                                                                             tumor.
    Father of       Gerhard Domagk 1939-
                    Sulfonamidochrysoidine            1944- Waksman et            1963-
  Chemotherapy                                                                                           1996- Imatinib
                          (Prontosil)                 al., discovered             Vinca alkaloids
                                                      streptomycin.

                                                                                     1962- nalidixic acid
  1900- Paul                                          1943- Nitrogen
  Ehrilich                                            mustard in
  Chemotherapy            1932- Prontosil-            lymphomas                      1963 to 1970-
  Animal model            First sulfonamide-                                         Treatment for
  developed               Bayer’s Laboratory                                         Hodgkin’s disease



1900                                                                       1960                       1980                    2015
                   1920                        1940
Principles of antimicrobial therapy
Principles of antimicrobial therapy
• Diagnosis: Site of infection, responsible organism,
   sensitivity of drug

• Decide- chemotherapy is necessary: Acute
   infection require chemotherapy whilst chronic infections
   may not. The chronic abscess respond poorly, although
   chemotherapy cover is essential if surgery is undertaken
   to avoid a flare-up of infection.

• Select the drug: Specificity (spectrum of activity,
   antimicrobial activity of drug), pharmacokinetic factors
   (physiochemical properties of the drug) , patient related
   factors (allergy, renal disease)
Principles of antimicrobial therapy
                                                                     Cont.,
• Frequency and duration of drug administration: Inadequate
  dose may develop resistance, intermediate dose may not cure
  infection, optimize dose should be used for therapy.

• Continue therapy: Acute infection treated for 5-10 days. But some
  of the bacterial infection exceptions to this. E.g.: Typhoid fever,
  tuberculosis and infective endocarditis (after clinical cure, the therapy
  is continued to avoid relapse).

• Test for cure: After therapy, symptoms and signs may disappear
  before pathogen eradicated.

• Prophylactic chemotherapy: To avoid surgical site infections.
Classification of antimicrobials
Classification of antimicrobials

A.   Chemical structure
B.   Mechanism of action
C.   Type of organisms (against which primarily active)
D.   Spectrum of activity
E.   Type of action (bacteriostatic and bactericidal)
F.   Source of antibiotics
A. Chemical structure
• Sulfonamides and related drugs: Dapsone (DDS), Sulfadiazine,
    Paraaminosalicylic acid (PAS)
•   Diaminopyrimidines: Trimethoprim, Pyrimethamine
•   Quinolones: Nalidixic acid, Norfloxacin, Ciprofloxacin
•   Beta lactam antibiotics: Penicillins, Cephalosporins
•   Tetracyclines: Oxytetracycline, Doxycycline
•   Nitrobenzene derivative: Chloramphenicol
•   Aminoglycosides: Streptomycin, Gentamycin, Amikacin, Neomycin
•   Macrolides antibiotics: Erythromycin, Clanthromycin, Azithromycin
A. Chemical structure
                                                                       Cont.,

•   Lincosamide antibiotics: Clindamycin
•   Glycopeptide antibiotics: Vancomycin
•   Polypeptide antibiotics: Polymyxin-B, Bacitracin, Tyrothricin
•   Nitrofuran derivatives: Nitrofurantoin
•   Nitroimidazoles: Metronidazole, Tinidazole
•   Nicotinic acid derivatives: Isoniazid, Pyrczinamide, Ethionamide
•   Polyene antibiotics: Amphotericin-B, Nystatin, Hamycin
•   Azole derivatives: Miconazole, Clotrimazole, Ketoconazole, Fluconazole
•   Others: Rifampin, Ethambutol, Griseofulvin
B. Mechanism of action

cell membrane


                           THFA
                                  Ribosomes
                          PABA
                                                           DNA gyrase
metabolism



                                                      protein
                                                      synthesis
         Cell wall synthesis             m-RNA code
B. Mechanism of action
                                                                                                          Cont.,
        Leakage form
        cell membrane
 Polypeptides- Polymyxines,
 colistin.                                                                                 Inhibition of Cell
 Polyenes- Amphotericin B,                                                                 Membrane
 Nystatin, Hamycin                                                                              Fluoroquinolones
                                           THFA                                                 Rifampin
                                                               Ribosomes
     Inhibition of
                                           PABA
     metabolism                                                                             Inhibition of DNA
Sulfonamides                                                                                gyrase
Sulfones
Trimethoprim                                                                               Fluoroquinolones
PAS                  Inhibition of
Pyrimethamine        Cell wall synthesis
Ethumbutol              Beta-lactams
                                              Misreading of                Inhibition of
                        Cephalosporins        m-RNA code                   protein
                        Vancomycin                                         synthesis

                                            Aminoglycosides-           Tetracyclines
                                            Streptomycin,              Aminoglycosides
                                            Gentamicin                 Macrolides
                                                                       Clindamycin
                                                                       Chloramphenicol
C. Type of organisms (against which primarily active)

• Antibacterial: Penicillins, Aminoglycosides, Erythromycin,
  etc.
• Antiviral: Acyclovir, Amantadine B, Zidovudine, etc.
• Antifungal: Griseofulvin, Amphotericin B, Ketoconazole, etc.
• Antiprotozoal: Chloroquine, Pyrimethamine, Metronidazole,
  etc.
• Anthelminthic: Mebendazole, Niclosamide, Diethyl
  carbamazine, etc.
D. Spectrum of activity

  Narrow-spectrum                Broad-spectrum
Penicillin G, Streptomycin,        Tetracyclines,
       Erythromycin               Chloramphenicol



  effective against specific   effective against a wide
       type of bacteria           range of bacteria,
   either gram-positive or     both gram-positive and
        gram-negative               gram-negative
D. Type of action
             (bacteriostatic and bactericidal)
         Bacteriostatic:
Inhibit the growth of Bacteria.
 E.g.: Sulfonamides, Tetracyclines,
 Chloramphenicol, Erythromycin,
             Ethambutol



            Bactericidal:
         Kill the microbes.
    E.g.: Penicillins, Aminoglycosides,
    Polypeptides, Rifampin, Isoniazid,      Note: Some b’static drugs may act
Vancomycin, Ciprofloxacin, Metronidazole,     b’cidal at high concentration
              Cotrimoxazole                  (Sulfonamides, nitrofurantion)
E. Source of antibiotics

• Fungi: Penicillin, Griseofulvin, Cephalosporin

• Bacteria: Polymyxin B, Tyrothricin, Colistin, Aztreonam,
  Bacitracin

• Actinomycetes: Aminoglycosides, Macrolides, Tetracyclines,
  Polyenes, Chloramphenicol
Hypersensitivity
                   reaction

                                        Drug
Toxicity                             resistance



       Problems with AMAs

Drug tolerant

                          Superinfection
Toxicity
Local irritancy:
• exerted site of administration. E.g.: Gastric irritation, pain and
  abscess formation at the site of i.m. inection,
  thrombophlebitis of injected vein.

Systemic toxicity:
• Dose related organ damage.
   – High therapeutic index agents may not damage host cells, E.g.:
     penicillin, erythromycin.
Toxicity
                                                                      Cont.,

Systemic toxicity:
• The agent which have low therapeutic index exhibits more toxicity.
  E.g.:,




aminoglycosides            tetracycline                 chloramphenicol
(renal and CNS toxicity)   (liver and renal toxicity)   (bone marrow depression)
Toxicity
                                                           Cont.,

Systemic toxicity:

• Very low therapeutic index drug is used when no suitable
  alternative AMAs available,
• E.g.: Vancomycin
        (hearing loss, kidney damage,
        “red man’ syndrome)
• polymyxin B
        (neurological and renal toxicity)




                                         Vancomycin toxicity
Hypersensitivity reaction
• All AMAs are capable to causing hypersensitive reaction, and
  this this reactions are unpredictable and unrelated to dose.
  E.g.: Penicillin induced anaphylactic shock (prick skin testing)




                                To avoid




      Inj. Penicillin induced              Perform sensitivity test before
       anaphylactic shock                   administering penicillin Inj.
Resistance
• Unresponsiveness of a microorganism to an AMA, and is
  similar to the phenomenon of drug tolerance.
   – Natural resistance
   – Acquired resistance

• Natural resistance: Some microbes have resistant to
  certain AMAs. E.g.: Gram negative bacilli not affected by
  penicillin G; M. tuberculosis insensitive to tetracyclines.
• Acquired resistance: Development of resistance by an
  organism (which was sensitive before) due to the use of
  AMA over a period of time. E.g.: Staphylococci, tubercle
  bacilli develop resistance to penicillin (widespread use for
  >50 yr). Gonococci quickly developed resistant to
  sulfonamides in 30 yr.
Resistance
                                                               Cont.,

Development of resistance
• Resistance mainly developed by mutation or gene transfer.
• Mutation: Resistance developed by mutation is stable and
  heritable genetic changes that occurs spontaneously and
  randomly among microorganism (usually on plasmids).
• Mutation resistance may be single step or multistep.
   – Single gene mutation may confer high degree of resistance. E.g.:
     enterococci to streptomycin
   – Multistep mutation may modify the more number of gene that will
     decreases the sensitivity of AMAs to pathogens.
Resistance
                                                                      Cont.,
• Development of resistance
• Gene transfer (Infectious resistance): From one organism to
  another organism.
   – Conjugation
   – Transduction
   – Transformation


       a                                   a
                          a                                  a



        b                  b
   Transposon           Plasmid            b                 b
      donor           cointegrate

       Transfer of resistance genetic elements within the bacterium
Resistance
                                                             Cont.,
Development of resistance
Gene transfer - Conjugation:
• cell-to-cell contact; transfer of chromosomal or
  extrachromosomal DNA from one bacterium to
  another through sex pili. The gene carrying the
  resistance or ‘R’ factor is transferred only if another
  “resistance transfer factor” (RTF) is present. This will
  frequently occurs in gram negative bacilli.
• The nonpathogenic organisms may transfer ‘R’ factor
  to pathogenic organisms, which may become wide
  spread by contamination of food and water.
• The multidrug resistance has occurred by
  conjugation.
    – Chloramphenicol resistance to typhoid bacilli
    – Penicillin resistance to Haemophilus, gonococci
    – Streptomycin resistance to E.coli
Resistance
                                         Cont.,

Development of resistance Gene
transfer- Transduction:
• Transfer resistance gene through
   bacteriophage (bacterial virus) to
   another bacteria of same
   species.
   – E.g.: Transmission of resistance
     gene between strains of
     staphylococci and between strains
     of streptococci.
Resistance
                                                       Cont.,
Development of resistance
Gene transfer - Transformation:
• It will occur in natural conditions.
• Bacteria taking up naked DNA form its environment and
  incorporating it into its genome through the normal cross-
  over mechanism.
Drug Tolerant
• Loss of affinity of target biomolecule of the microorganism
  with particular AMAs, E.g.: Penicillin resistance to
  Pneumococcal strain (alteration of penicillin binding proteins)




              Drug target site                  Change in protein
                                               configuration- loss of
                                                      affinity
Superinfection (Suprainfection)

• A new infection occurring in a patient having a
  preexisting infection. Superinfections are most
  difficult to treat.
Superinfection
                                                                   Cont.,

• Development of superinfection associated with the use of
  broad/ extended-spectrum of antibiotics, such as
  tetracyclines, chloramphenicol, ampicillin and newer
  cephalosporins.
• Superinfections are more common when host defence is
  compromised.
• Superinfections are generally most difficult to treat.
   – bacterial superinfection in viral respiratory disease
   – infection of a chronic hepatitis B carrier with hepatitis D virus
   – Piperacillin-tazobactam may cause superinfection with candida
Superinfection
                                                                        Cont.,

• Treatment for superinfection
   – Candida albicans: Monilial diarrhoea, Candidal vulvovaginitis or vaginal thrush
     (an infection of the vagina's mucous membranes) treat with nystain or
     clotrimazole
   – Resistant Staphylococci: treat with coxacillin or its congeners
   – Pseudomonas: Urinary tract infection, treat with carbenicillin, piperacillin or
     gentamicin.


• Superinfections minimized by
   – using specific (narrow-spectrum) AMA (whenever possible)
   – avoid using (do not use) antimicrobials to treat self limiting or untreatable
     (viral) infection
   – avoid prolong antimicrobial therapy.
Choice of an antimicrobial agents
      Patient related factors

                       Drug factors


                            Organism-related considerations
Choice of an antimicrobial agents
Patient related factors:
• Patient age (chloramphenicol produce gray baby syndrome in
  newborn; Tetracyclines deposition in teeth and bone-below
  the age of 6 years)
• Renal and hepatic function (aminoglycoside, vancomycin-
  renal failure; erythromycin, tetracycline- liver failure)
• Drug allergy (History of known AMAs allergy should be
  obtained) .
   – Syphilis patient allergic to penicillin – drug of choice is tetracycline
   – Fluoroquinolones cause erythema multiforme
• Impaired host defence
Choice of an antimicrobial agents
                                                                  Cont.,
Drug factor:
• Pregnancy
   – All AMAs should be avoided in the pregnant
   – many cephalosporins and erythromycin are safe, while safety data on
     most others is not available.


• Genetic factors
   – Primaquine, sulfonamide fluoroquinolones likely to produce
     haemolysis in G-6-PD deficient patient)
Choice of an antimicrobial agents
                                                         Cont.,
Organism-related considerations:
• A clinical diagnosis should first be made, and the choice of the
  AMAs selected
• Clinical diagnosis itself directs choice of the AMA
• Choice to be based on bacteriological examination
  (Bacteriological sensitivity testing)
Choice of an antimicrobial agents
                                                  Cont.,
Drug factor:
• Spectrum of activity (Narrow/ broad spectrum)
• Type of activity
• Sensitivity o f the organism (MIC)
• Relative toxicity
• Pharmacokinetic profile
• Route of administration
• Cost
Combined use of antimicrobials
Combined use of antimicrobials

• To achieve synergism, Rifampin+ isoniazid for tuberculosis
•


• To reduce severity or incidence of adverse effects,
  Amphotericin B + rifampin (rifampin enhance the antifungal
  activity of amphotericin B)
• To prevent resistance (Concomitant administration of
  rifampin and ciprofloxacin prevents Staph. aureus
  resistance ciprofloxacin)
• To broaden the spectrum of antimicrobial action
  (cotrimoxazole: Trimethoprim/sulfamethoxazole)
Prophylactic use of antimicrobials
Prophylactic use of antimicrobials

• Prophylaxis against specific organisms (Cholera: tetracycline
  prophylaxis; Malaria: for travelers to endemic area may
  take chloroquine/ mefloquine)
• Prevention of infection in high risk situations
•   Prophylaxis of surgical site infection
•   Prophylaxis against specific organisms
•   Prevention of infection in high risk situations
•   Prophylaxis of surgical site infection
Failure of antimicrobial therapy
Failure of antimicrobial therapy

• Improper selection of AMAs, dose, route or duration of
  treatment.
• Treatment begun too late
• Failure to take necessary adjuvant measures
• Poor host defence
• Trying to treat untreatable (viral) infections
• Presence of dormant or altered organisms which later give
  risk to a relapse
Common side effects with
chemotherapeutics agents




                           Think before dispensing


                           Thank U

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Basic principles of chemotherapy

  • 1. Basic principles of chemotherapy S. Parasuraman, M.Pharm., Ph.D., Senior Lecturer, Faculty of Pharmacy, AIMST University
  • 2. Chemotherapy Chemotherapy: chemo + therapy The use of drug (chemical entity/ substance derived form microorganisms) with selective toxicity against infections/ viruses, bacteria, protozoa, fungi and helminthes is called as chemotherapy.
  • 3. Antibiotics and Antimicrobials • Antibiotics: Antibiotics are substances produced by microorganisms, which selectively suppress the growth of or kill other microorganisms at very low concentration. • Antimicrobials: (chemotherapeutic agent + Antibiotics) Any substance of natural, synthetic or semisynthetic origin which at low concentrations kill or inhibits the growth of microorganisms but causes little or no host damage.
  • 5. History of chemotherapy Before Ehrlich’s period (till 1900) • Chaulmoogra oil by Hindus in leprosy • Cinchona bark for fever • ‘Mouldy curd’ by chines on boils • Mercury by Paracelsus for syphilis Ehrlich’s period (1900 to 1930) • Organometallic dye for treatment for cane After Ehrlich’s period (1930 to till date) • discovery of sulfonamide (Prontosil)
  • 6. Timeline history of chemotherapy development 1908- Discovery 1959- Antitumor of Arsphenamine antibiotics 2007- Target specific Alexander Fleming 1928- screens Penicillin 1958- Methotrexate 2005- Tyrosine kinase 1957- 5-Fluorouracil inhibitors 1951- Thiopurines 1997- Monoclonal antibody approved Paul for the treatment of 1948- Anitfolates Ehrilich tumor. Father of Gerhard Domagk 1939- Sulfonamidochrysoidine 1944- Waksman et 1963- Chemotherapy 1996- Imatinib (Prontosil) al., discovered Vinca alkaloids streptomycin. 1962- nalidixic acid 1900- Paul 1943- Nitrogen Ehrilich mustard in Chemotherapy 1932- Prontosil- lymphomas 1963 to 1970- Animal model First sulfonamide- Treatment for developed Bayer’s Laboratory Hodgkin’s disease 1900 1960 1980 2015 1920 1940
  • 8. Principles of antimicrobial therapy • Diagnosis: Site of infection, responsible organism, sensitivity of drug • Decide- chemotherapy is necessary: Acute infection require chemotherapy whilst chronic infections may not. The chronic abscess respond poorly, although chemotherapy cover is essential if surgery is undertaken to avoid a flare-up of infection. • Select the drug: Specificity (spectrum of activity, antimicrobial activity of drug), pharmacokinetic factors (physiochemical properties of the drug) , patient related factors (allergy, renal disease)
  • 9. Principles of antimicrobial therapy Cont., • Frequency and duration of drug administration: Inadequate dose may develop resistance, intermediate dose may not cure infection, optimize dose should be used for therapy. • Continue therapy: Acute infection treated for 5-10 days. But some of the bacterial infection exceptions to this. E.g.: Typhoid fever, tuberculosis and infective endocarditis (after clinical cure, the therapy is continued to avoid relapse). • Test for cure: After therapy, symptoms and signs may disappear before pathogen eradicated. • Prophylactic chemotherapy: To avoid surgical site infections.
  • 11. Classification of antimicrobials A. Chemical structure B. Mechanism of action C. Type of organisms (against which primarily active) D. Spectrum of activity E. Type of action (bacteriostatic and bactericidal) F. Source of antibiotics
  • 12. A. Chemical structure • Sulfonamides and related drugs: Dapsone (DDS), Sulfadiazine, Paraaminosalicylic acid (PAS) • Diaminopyrimidines: Trimethoprim, Pyrimethamine • Quinolones: Nalidixic acid, Norfloxacin, Ciprofloxacin • Beta lactam antibiotics: Penicillins, Cephalosporins • Tetracyclines: Oxytetracycline, Doxycycline • Nitrobenzene derivative: Chloramphenicol • Aminoglycosides: Streptomycin, Gentamycin, Amikacin, Neomycin • Macrolides antibiotics: Erythromycin, Clanthromycin, Azithromycin
  • 13. A. Chemical structure Cont., • Lincosamide antibiotics: Clindamycin • Glycopeptide antibiotics: Vancomycin • Polypeptide antibiotics: Polymyxin-B, Bacitracin, Tyrothricin • Nitrofuran derivatives: Nitrofurantoin • Nitroimidazoles: Metronidazole, Tinidazole • Nicotinic acid derivatives: Isoniazid, Pyrczinamide, Ethionamide • Polyene antibiotics: Amphotericin-B, Nystatin, Hamycin • Azole derivatives: Miconazole, Clotrimazole, Ketoconazole, Fluconazole • Others: Rifampin, Ethambutol, Griseofulvin
  • 14. B. Mechanism of action cell membrane THFA Ribosomes PABA DNA gyrase metabolism protein synthesis Cell wall synthesis m-RNA code
  • 15. B. Mechanism of action Cont., Leakage form cell membrane Polypeptides- Polymyxines, colistin. Inhibition of Cell Polyenes- Amphotericin B, Membrane Nystatin, Hamycin Fluoroquinolones THFA Rifampin Ribosomes Inhibition of PABA metabolism Inhibition of DNA Sulfonamides gyrase Sulfones Trimethoprim Fluoroquinolones PAS Inhibition of Pyrimethamine Cell wall synthesis Ethumbutol Beta-lactams Misreading of Inhibition of Cephalosporins m-RNA code protein Vancomycin synthesis Aminoglycosides- Tetracyclines Streptomycin, Aminoglycosides Gentamicin Macrolides Clindamycin Chloramphenicol
  • 16. C. Type of organisms (against which primarily active) • Antibacterial: Penicillins, Aminoglycosides, Erythromycin, etc. • Antiviral: Acyclovir, Amantadine B, Zidovudine, etc. • Antifungal: Griseofulvin, Amphotericin B, Ketoconazole, etc. • Antiprotozoal: Chloroquine, Pyrimethamine, Metronidazole, etc. • Anthelminthic: Mebendazole, Niclosamide, Diethyl carbamazine, etc.
  • 17. D. Spectrum of activity Narrow-spectrum Broad-spectrum Penicillin G, Streptomycin, Tetracyclines, Erythromycin Chloramphenicol effective against specific effective against a wide type of bacteria range of bacteria, either gram-positive or both gram-positive and gram-negative gram-negative
  • 18. D. Type of action (bacteriostatic and bactericidal) Bacteriostatic: Inhibit the growth of Bacteria. E.g.: Sulfonamides, Tetracyclines, Chloramphenicol, Erythromycin, Ethambutol Bactericidal: Kill the microbes. E.g.: Penicillins, Aminoglycosides, Polypeptides, Rifampin, Isoniazid, Note: Some b’static drugs may act Vancomycin, Ciprofloxacin, Metronidazole, b’cidal at high concentration Cotrimoxazole (Sulfonamides, nitrofurantion)
  • 19. E. Source of antibiotics • Fungi: Penicillin, Griseofulvin, Cephalosporin • Bacteria: Polymyxin B, Tyrothricin, Colistin, Aztreonam, Bacitracin • Actinomycetes: Aminoglycosides, Macrolides, Tetracyclines, Polyenes, Chloramphenicol
  • 20. Hypersensitivity reaction Drug Toxicity resistance Problems with AMAs Drug tolerant Superinfection
  • 21. Toxicity Local irritancy: • exerted site of administration. E.g.: Gastric irritation, pain and abscess formation at the site of i.m. inection, thrombophlebitis of injected vein. Systemic toxicity: • Dose related organ damage. – High therapeutic index agents may not damage host cells, E.g.: penicillin, erythromycin.
  • 22. Toxicity Cont., Systemic toxicity: • The agent which have low therapeutic index exhibits more toxicity. E.g.:, aminoglycosides tetracycline chloramphenicol (renal and CNS toxicity) (liver and renal toxicity) (bone marrow depression)
  • 23. Toxicity Cont., Systemic toxicity: • Very low therapeutic index drug is used when no suitable alternative AMAs available, • E.g.: Vancomycin (hearing loss, kidney damage, “red man’ syndrome) • polymyxin B (neurological and renal toxicity) Vancomycin toxicity
  • 24. Hypersensitivity reaction • All AMAs are capable to causing hypersensitive reaction, and this this reactions are unpredictable and unrelated to dose. E.g.: Penicillin induced anaphylactic shock (prick skin testing) To avoid Inj. Penicillin induced Perform sensitivity test before anaphylactic shock administering penicillin Inj.
  • 25. Resistance • Unresponsiveness of a microorganism to an AMA, and is similar to the phenomenon of drug tolerance. – Natural resistance – Acquired resistance • Natural resistance: Some microbes have resistant to certain AMAs. E.g.: Gram negative bacilli not affected by penicillin G; M. tuberculosis insensitive to tetracyclines. • Acquired resistance: Development of resistance by an organism (which was sensitive before) due to the use of AMA over a period of time. E.g.: Staphylococci, tubercle bacilli develop resistance to penicillin (widespread use for >50 yr). Gonococci quickly developed resistant to sulfonamides in 30 yr.
  • 26. Resistance Cont., Development of resistance • Resistance mainly developed by mutation or gene transfer. • Mutation: Resistance developed by mutation is stable and heritable genetic changes that occurs spontaneously and randomly among microorganism (usually on plasmids). • Mutation resistance may be single step or multistep. – Single gene mutation may confer high degree of resistance. E.g.: enterococci to streptomycin – Multistep mutation may modify the more number of gene that will decreases the sensitivity of AMAs to pathogens.
  • 27. Resistance Cont., • Development of resistance • Gene transfer (Infectious resistance): From one organism to another organism. – Conjugation – Transduction – Transformation a a a a b b Transposon Plasmid b b donor cointegrate Transfer of resistance genetic elements within the bacterium
  • 28. Resistance Cont., Development of resistance Gene transfer - Conjugation: • cell-to-cell contact; transfer of chromosomal or extrachromosomal DNA from one bacterium to another through sex pili. The gene carrying the resistance or ‘R’ factor is transferred only if another “resistance transfer factor” (RTF) is present. This will frequently occurs in gram negative bacilli. • The nonpathogenic organisms may transfer ‘R’ factor to pathogenic organisms, which may become wide spread by contamination of food and water. • The multidrug resistance has occurred by conjugation. – Chloramphenicol resistance to typhoid bacilli – Penicillin resistance to Haemophilus, gonococci – Streptomycin resistance to E.coli
  • 29. Resistance Cont., Development of resistance Gene transfer- Transduction: • Transfer resistance gene through bacteriophage (bacterial virus) to another bacteria of same species. – E.g.: Transmission of resistance gene between strains of staphylococci and between strains of streptococci.
  • 30. Resistance Cont., Development of resistance Gene transfer - Transformation: • It will occur in natural conditions. • Bacteria taking up naked DNA form its environment and incorporating it into its genome through the normal cross- over mechanism.
  • 31. Drug Tolerant • Loss of affinity of target biomolecule of the microorganism with particular AMAs, E.g.: Penicillin resistance to Pneumococcal strain (alteration of penicillin binding proteins) Drug target site Change in protein configuration- loss of affinity
  • 32. Superinfection (Suprainfection) • A new infection occurring in a patient having a preexisting infection. Superinfections are most difficult to treat.
  • 33. Superinfection Cont., • Development of superinfection associated with the use of broad/ extended-spectrum of antibiotics, such as tetracyclines, chloramphenicol, ampicillin and newer cephalosporins. • Superinfections are more common when host defence is compromised. • Superinfections are generally most difficult to treat. – bacterial superinfection in viral respiratory disease – infection of a chronic hepatitis B carrier with hepatitis D virus – Piperacillin-tazobactam may cause superinfection with candida
  • 34. Superinfection Cont., • Treatment for superinfection – Candida albicans: Monilial diarrhoea, Candidal vulvovaginitis or vaginal thrush (an infection of the vagina's mucous membranes) treat with nystain or clotrimazole – Resistant Staphylococci: treat with coxacillin or its congeners – Pseudomonas: Urinary tract infection, treat with carbenicillin, piperacillin or gentamicin. • Superinfections minimized by – using specific (narrow-spectrum) AMA (whenever possible) – avoid using (do not use) antimicrobials to treat self limiting or untreatable (viral) infection – avoid prolong antimicrobial therapy.
  • 35. Choice of an antimicrobial agents Patient related factors Drug factors Organism-related considerations
  • 36. Choice of an antimicrobial agents Patient related factors: • Patient age (chloramphenicol produce gray baby syndrome in newborn; Tetracyclines deposition in teeth and bone-below the age of 6 years) • Renal and hepatic function (aminoglycoside, vancomycin- renal failure; erythromycin, tetracycline- liver failure) • Drug allergy (History of known AMAs allergy should be obtained) . – Syphilis patient allergic to penicillin – drug of choice is tetracycline – Fluoroquinolones cause erythema multiforme • Impaired host defence
  • 37. Choice of an antimicrobial agents Cont., Drug factor: • Pregnancy – All AMAs should be avoided in the pregnant – many cephalosporins and erythromycin are safe, while safety data on most others is not available. • Genetic factors – Primaquine, sulfonamide fluoroquinolones likely to produce haemolysis in G-6-PD deficient patient)
  • 38. Choice of an antimicrobial agents Cont., Organism-related considerations: • A clinical diagnosis should first be made, and the choice of the AMAs selected • Clinical diagnosis itself directs choice of the AMA • Choice to be based on bacteriological examination (Bacteriological sensitivity testing)
  • 39. Choice of an antimicrobial agents Cont., Drug factor: • Spectrum of activity (Narrow/ broad spectrum) • Type of activity • Sensitivity o f the organism (MIC) • Relative toxicity • Pharmacokinetic profile • Route of administration • Cost
  • 40. Combined use of antimicrobials
  • 41. Combined use of antimicrobials • To achieve synergism, Rifampin+ isoniazid for tuberculosis • • To reduce severity or incidence of adverse effects, Amphotericin B + rifampin (rifampin enhance the antifungal activity of amphotericin B) • To prevent resistance (Concomitant administration of rifampin and ciprofloxacin prevents Staph. aureus resistance ciprofloxacin) • To broaden the spectrum of antimicrobial action (cotrimoxazole: Trimethoprim/sulfamethoxazole)
  • 42. Prophylactic use of antimicrobials
  • 43. Prophylactic use of antimicrobials • Prophylaxis against specific organisms (Cholera: tetracycline prophylaxis; Malaria: for travelers to endemic area may take chloroquine/ mefloquine) • Prevention of infection in high risk situations • Prophylaxis of surgical site infection • Prophylaxis against specific organisms • Prevention of infection in high risk situations • Prophylaxis of surgical site infection
  • 45. Failure of antimicrobial therapy • Improper selection of AMAs, dose, route or duration of treatment. • Treatment begun too late • Failure to take necessary adjuvant measures • Poor host defence • Trying to treat untreatable (viral) infections • Presence of dormant or altered organisms which later give risk to a relapse
  • 46. Common side effects with chemotherapeutics agents Think before dispensing Thank U

Notas del editor

  1. Paul Ehrilich dies: father of chemotherapyImatinib is a Bcr-Abl tyrosine kinase inhibitor for the treatment of chronic myelocytic leukemia