MicroPara Lec

• Chemotherapy


  Treatment of disease by using chemical compounds
• Chemotherapy drug


  Originally employed against infectious organisms
• Quinine


  From tree bark was long used to treat malaria
• Paul Ehrlich


  • First to coin the term chemotherapy
  • One of the proponent of Gram staining
  • German physician
  • Proposed the term "selective toxicity" that would kill pathogens and not human cells
• Selective toxicity


  • Specific inhibition of some types of the cell but they will not harm other cells
  • The drug has the ability to injure the target cell or organism without injuring the not target or host cells
• Paul Ehrlich's work


  • Dye trypan- trypanosome
  • Arsenicals- syphilis-infected rabbits
  • Arsphenamine/ Salvarsan® - syphilis spirochetes
• Alexander Fleming


  • Penicillin (1896)
  • Observed that Penicillium fungus produced an antibiotic, penicillin, that killed S. aureus

  
• Gerard Domagk


  • Prontosil Red – for pathogenic streptococci and staphylococci in mice
  • Sulfonamides or sulfa drugs (1939)

  
• Therapeutic dose


  The drug level required for clinical treatment of particular infection
• Toxic dose


  • The drug level which the agent becomes too toxic for the host
  • Dose that will exhibit adverse drug reaction
• Therapeutic index


  • The ratio of the toxic dose (TD50) to the therapeutic dose/effective dose (ED50)
  • The larger the therapeutic index, the better the chemotherapeutic agent
  • The higher the TI the safer the drug
• Side effects


  • Undesirable effects on the host and it may involve almost any organ system
  • Chemotherapeutic agents must be administered with care
  • It may vary on each individual
• Narrow spectrum drugs


  • Effective only against a limited variety of pathogens
  • Use on specific infection especially when the causative agent is known
• Narrow spectrum drugs


  • Will not kill as many normal biota as broad spectrum
  • Lesser ability to cause superinfections
  • Lesse bacterial resistance because it is targeted (deal with special bacteria)

  
• Broad spectrum drugs


  • Attack many different kinds of pathogens
  • Larger group of organism
• Agents on general microbial group

  • Antibacterial
  • Antifungal
  • Antiprotozoal
  • Antiviral

  
• Example of agent used against more than one group

  Sulfonamide against bacteria and some protozoa

  
• Sources of chemical therapeutic agents

  • Molds
  • Fungi- penicillium cresogenum
  • Bacteria- streptomyces, bacillus species (bacitracin)

  
• Natural


  • Totally synthesized by one of a few bacteria or fungi
  • From living organisms
• Synthetic


  • Sulfonamide, Trimethoprim, Chloramphenicol, Ciprofloxacin, Isoniazid, Dapsone
  • Drugs that are synthesize by chemical procedures in the laboratory

  
• Semisynthetic


  • Natural antibiotics that have been chemically modified by the addition of extra chemical groups to make them less susceptible to inactivation by pathogens
  • Parent compound are from natural

  
• Semisynthetic antibiotics


  • Ampicillin
  • Carbenicillin
  • Methicillin

  
• Antibiotics


  • Substance produced by microorganisms that, in small amounts, inhibits another microorganism
  • Not all antimicrobials are antibiotics
  • Sources are living organisms (mold, fungi, and bacteria)

  
• Antibiotics and their producing microorganisms

  • Bacitracin - B. subtilis
  • Polymyxin - B. polymyxa
  • Amphotericin B - S. nodosus
  • Chloramphenicol - S. venezuelae
  • Streptomycin - S. griseus
  • Gentamicin - Micromonospora purpurea
  • Cephalothin - Cephalosporium spp.
  • Penicillin - Penicillium notatum

  
• Bactericidal


  Kills the target pathogen; its activity is concentration dependent and the agent may be only static at low levels
• Bacteriostatic


  • Inhibit growth; if agent is removed, the microorganisms will recover and grow again
  • Not effective if host's resistance is too low
  • Don't kill bacteria
• There are agents that are capable of killing some species, but are only bacteriostatic for others
• Examples of bactericidal vs bacteriostatic agents

  • Chloramphenicol - Inhibits growth of E. coli but kills Haemophilus influenzae
• All protein synthesis inhibitors and antimetabolites are "static" except aminoglycosides

  
• Antimetabolites


  Substances that inhibits chemicals on the body that is part of the normal metabolism of an organism
• Actions of antimicrobial drugs

  • Inhibition of cell wall synthesis
  • Inhibition of protein synthesis
  • Injury to plasma membrane
  • Inhibition of nucleic acid synthesis
  • Antimetabolites

  
• Inhibiting cell wall synthesis

  • Penicillin [targets g (+)]
  • Bacterium cell wall consists of a macromolecular network called peptidoglycan
  • Penicillin and certain other antibiotics prevent the synthesis of intact peptidoglycan; consequently, the cell wall is greatly weakened, and the cell undergoes lysis

  
• Inhibiting protein synthesis


  • Eukaryotic cells have 80S ribosomes; prokaryotic cells have 70S ribosomes
  • The difference in ribosomal structure accounts for the selective toxicity of antibiotics that affect protein synthesis
  • Mitochondria also contain 70S ribosomes similar to those of bacteria, so antibiotics targeting the 70S ribosomes can have adverse effects on the cells of the host

  
• Inhibiting plasma membrane


  • Antifungal drugs, such as amphotericin B, miconazole, and ketoconazole, combine with sterols in the fungal plasma membrane to disrupt the membrane
  • Certain antibiotics, especially polypeptide antibiotics, bring about changes in the permeability of the plasma membrane, resulting in the loss of important metabolites from the microbial cell
  • Bacterial plasma membranes generally lack sterols, so these antibiotics do not act on bacteria

  
• Inhibiting nucleic acid synthesis

  • A number of antibiotics interfere with the processes of DNA replication and transcription in microorganisms
  • Some drugs with this mode of action have an extremely limited usefulness because they interfere with mammalian DNA and RNA as well

  
• Inhibiting the synthesis of essential metabolites


  • Example: Antimetabolite sulfanilamide (a sulfa drug) and Para Aminobenzoic Acid (PABA)
  • PABA is the substrate for an enzymatic reaction leading to the synthesis of folic acid, a vitamin that functions as a coenzyme for the synthesis of the purine and pyrimidine bases of nucleic acids and many amino acids

  
• Purine and pyrimidine


  Nitrogenous bases in our nucleic acid (RNA and DNA)
• Chemical structures of antibacterial agents

  • Beta Lactams
  • Fusidic Acid
  • Glycopeptides
  • Sulfonamides
  • Aminoglycosides
  • Trimethoprim
  • Tetracyclines
  • Quinolones
  • Chloramphenicol
  • Rifampicin
  • Macrolides
  • Lincosamides

  
• Beta-lactam ring


  3 carbon and a nitrogen
• Properties of some common antibacterial drugs

  • Ampicillin - Cidal, Broad gm(+), and some gm(-), Allergic responses (Diarrhea, anemia)
  • Bacitracin - Cidal, Narrow gm(+), Renal Injury if injected
  • Carbenicillin - Cidal, Broad gm(+), many gm(-), Allergic Responses (Nausea, anemia)
  • Cephalosporins - Cidal, Broad gm(+), and some gm (-), Allergic responses, thrombophlebitis, renal injury
  • Chloramphenicol - Static, Broad gm (+) and gm (-), rickettsia and chlamydia, Bone marrow dysfunction, allergic rxns
  • Ciprofloxacin - Cidal, Broad gm (+), gm (-), GIT upset, allergic rxns
  • Clindamycin - Static, Narrow gm (+), anaerobes, Diarrhea
  • Dapsone - Static, Narrow (mycobacteria), Anemia, allergic responses
  • Erythromycin - Static, Broad gm (+) and some gm (-), GIT upset, hepatic injury
  • Gentamicin - Cidal, Narrow gm (-), Allergic responses, nausea, loss of hearing, renal damage
  • Isoniazid - Static and Cidal, Narrow (mycobacteria), Allergic rxns, GIT upset, hepatic injury
  • Methicillin - Cidal, Narrow gm (+), Allergic rxns, renal toxicity, anemia
  • Penicillin - Cidal, Narrow gm (+), Allergic rxns, nausea, vomiting
  • Polymyxin B - Cidal, Narrow gm (-), Renal damage, neurotoxic rxns
  • Rifampin - Static, Broad gm (+), mycobacteria, Hepatic injury nausea, allergic responses
  • Streptomycin - Cidal, Narrow gm (+), Allergic rxns, renal toxicity, anemia