Anti-biotics and chemotherapeutics PDF

Anti-biotics and chemotherapeutics Teacher: Mennatu-allah Mustafa Animicrobial agent & chemotherapeutics  Animicrobial: Is a chemical that destroy disease, minimizing damage to host.  Can be natural (anti biotic)or synthatic (drugs)  Chemotherapeutics: a chemical that combats...

Anti-biotics and chemotherapeutics Teacher: Mennatu-allah Mustafa Animicrobial agent & chemotherapeutics  Animicrobial: Is a chemical that destroy disease, minimizing damage to host.  Can be natural (anti biotic)or synthatic (drugs)  Chemotherapeutics: a chemical that combats disease.  Paul Ehrlich discovered salvarsan  Alexander Fleming discovered penicillin Characteristics of antimicrobial agent  Selective targeting to germ cells ( selective toxicity). Theraputic index= largest amount of antimicrobial that can’t cause harm/lowest does that can kill microorganism The higher the index the better the antimicrobial  Should not produce sensitivity (in most patients).  Have broad spectrum activity to germs.  Dosen’t cause excessive harm to normal flora.  Stable in storage, soluble in body fluids, and be retained in the body long enough to be effective.  Ideally, should no induce drug resistance. Mechanism of action Either direct killing or inhibition of growth 1. Inhibition of cell wall (bacterial) synthesis (penicillin, cephalosporin) 2. Inhibition of protein synthesis, targeting ribosoms (tetracyclin, erythromycin, linomycin, gentamycin, tobramycin). 3. Antimetabolites: simulate essential substance (para amino benzoic acid), used to synthesize nucleic acid in microbs, so the microbe uses it resulting in blocking nucleic acid synthesis. (trimethobrime, sulphamethoxazole) 4. Inhibition of nuclic acid replication (rifampicin nalidixic acid, ciprofloxacine  Anti-viral limited because of toxicity General rules of using antibiotics  Give medicine in sufficient amount for sufficient time, to keep it under effect.  Don’t prescribe a medicine that isn’t proved to be effective on bacteria.  When giving a combination, be sure that no antagonist effect.  Misuse of anti-biotics, will create resistant organism (mutation)  Ati-biotic should be taken for 48h after recovery.  Synergistic: using small quantities of multible anibiotics to provide bigger effect and less toxicity. General rules of using antibiotics  The best way to deal with antimicrobials should: 1. Be sure that infection is present. 2. Check the sensitivity of microbe to drugs. 3. Stop using drug byond indicated period. Defenses of the host Select this paragraph to edit Defenses of the host  Resistance: is the ability to prevent disease through body defenses.  Susceptibility: is the lack of resistance.  Nonspecific resistance: all body defences that protect from all kinds of pathogens.  Specific resistance: defenses ageinst specific microorganism. Nonspecific defenses 1. Primary defense mechanism:  Mechanical factors: Structure of the skin and keratin that prevent pathogen invasion. Lachrymal apparatus (tears production), protect the eye from substances and microorganisms. Saliva washes microorganisms from the mouth. Mucus traps microorganisms Colliery escalator (cilia) moves mucus up and out of the respiratory tract. Urine and vaginal secretions move microorganisms our of the tracts. Nonspecific defenses  Chemical factors: Sebum (oil produced by sebaceous glands), contains bacteria static fatty acids. Lysozyme ( enzyme that destroys cell wall) found in tears, saliva, and nasal secretions. High acidity of the stomach (1.2-3.0), prevent microbial growth. Nonspecific defenses 1. Secondary defense mechanism:  Phagocytosis: the ingestion of a pathogen or a partical by a cell.  Phagocytes: blood cells like (Macrophages,nutrophils,monocytes). 2. Among granulocytes, nutrophils are the most imprtant phagocytes (and the most abundent). 3. Enlarged (mature) monocytes, become wandering macrophages and fixed macrophages. 4. Granulocystes predominates during early stages of infection, whereas monocytes predominate as infection sunsides. Nonspecific defenses  Mechanism of phagocytosis: 1. Phagocytes are attrachted to microorganisms by chemotaxis. 2. Then adhere to the cell, facilitated by opsonization (coating the pathogen with opsonin by immune system). 3. Pseudopods (arm-like extensions) engulf the microorganism, enclosing it in a phagosome (vesicle) to complete ingestion. 4. Many microorganisms are killed by lysozomal enzyme. Nonspecific defenses  Inflammation: is a body response to cell damage, characterized by redness, pain, heat, and swelling.  Mechanism of inflammation: 1. Vasodilation, due to histamine, kinins, and prostagrandin. 2. Phagocyte migration, by sticking to blood vessels then squeeze themselves through it 3. Repaire of tissue, from the production of new cells by the stroma or parenchyma (functional cells) of tissue. Nonspecific defenses  Fever: is an abnormally high temperature produced in response to a bacterial or viral infection  Antimicrobial substances: 1. Interferon: is an antiviral substance produced in response to viral infection. 2. Its mode of action is to induce uninfected cells to produce an antiviral protein that prevents viral replication. 3. Complement and properdin: (part of the immune system)they make up to 10% of the serum proteins. These destroy invading microorganism. 4. Hydrochloric acid: present in high concentrations in gastric Juice and kills the majority of ingested microbs. 5. Lysozyme: This is a small molecule protein with antibacterial properties present in granulocytes, tears, saliva and nasal secretions. Nonspecific defenses Nonspecific defenses 1. Saliva: This is secreted into the mouth and washes away food debris that may serve as culture medium for microbes: its slightly acid reaction inhibits the growth of some microbes. 2. Antibodies: These are present In nasal secretions and saliva and are able to inactivate some microbes. Specific Defenses (Immunology)  Immunity is the ability of the body to specifically counteract foreign antigens.  It's a physiological state conducted by lymphocytes enabling the body to recognize self and non-self and resistance against non-self (antigen).  Kinds of immunity: 1. Native immunity (natural):  Species immunity: human may resist some microbes that can infect animals and vice versa.  Racial immunity: black people are more susceptible to tuberculosis than white people.  individual immunity: genetic, nutritional, sex, born with. Specific Defenses (Immunology) 1. Acquired immunity:  It is specific resistance to infection obtained during the life of the individual.  It results from the production of humoral antibodies and cellular immune response. It may be long lasting.  Types: 2. Naturally acquired active immunity:- it is the immunity resulting from infection. 3. Naturally acquired passive immunity:- Humoral antibodies transferred from a mother to a fetus. It may last up to a few months. 4. Artificially acquired active immunity: achieved by vaccination. May be long lasting. 5. Artificially acquired passive immunity:- as humoral antibodies (human or other mammal) acquired by injection. It may last for a few weeks. Specific Defenses (Immunology) Active immunity Passive immunity 1 acquired after exposure to infectious agent acquired after injecting ready (live, weak killed or genetically prepared) antibodies 2 need time to start its effect exert its effect directly 3 last longer (may be life long) last short (weeks) 4 used mainly for prevention used to treat patients or prevent disease in contacts 5 rare to cause allergy may cause allergy if nonhuman origin Specific Defenses (Immunology)  Antigens: 1. An antigen is a foreign chemical substance that causes the body to produce specific antibodies that the antigen can then combine with. Usually its not part of the body's chemistry. 2. Complete antigens possess immunogenicity ability to stimulate antibody formation and reactivity (ability to react with specific antibodies). 3. Most antigens are proteins nucleoproteins, lipoproteins, or large polysaccharides. 4. Specific sites on the surface of an antigen that combine with antibodies -are called antigenic determinant groups; the number of these groups is the valence. 5. Most antigens are multivalent. 6. Hapten (incomplete antigen)is a molecule that has reactivity (combine with antibody) but not immunogenicity. Specific Defenses (Immunology)  Antibodies: 1. An antibody is a protein produced by the body in response to the presence of an antigen and is capable of combining specifically with the antigen. 2. Antibodies are globulin’s (proteins alph,beta,gama) ; thus, they are called immunoglobulin (Ig). 3. Immunoglobulin is found in blood serum, and when separated by electrophoresis (lab test that separates proteins in the blood), are found in the globulin fraction of serum (portion of blood serum that contains globulin proteins) , so they are sometimes called gamma globulin's 4. Antibodies are composed of four polypeptide chains. Two identical heavy chains and two identical light chains. Specific Defenses (Immunology) Specific Defenses (Immunology) 1. There are five types of heavy chains (gamma, alpha, mu, delta, epsilon), according to it is the name of antibody. 2. There are two types of light chains (kapa & lamda). 3. Within each chain is a variable portion (where antigen bonding occurs) and a constant portion (which serves as a basis for distinguishing the classes of antibodies). 4. Serum antibody level (the concentration of specific antibodies in the blood serum): upon birth the baby has IgG antibody level as his mother (transferred from his mother to him). He has no other types of antibodies. The baby start to form his own antibodies gradually, where he reaches adult serum levels of all antibodies after two years old. Specific Defenses (Immunology) 1. Transferred IgG antibodies decrease gradually to be lost around (6) months old; at the same time his self-made antibodies replace transferred antibodies. -⁠That's why immunization programs start early, in order to protect baby before losing all transferred antibodies. - If newly born baby have IgM antibodies in his serum, a resent infection is suspected, as IgM antibody is the first antibody to appear after infection then the IgG antibody. Specific Defenses (Immunology)  Classes of antibodies: 1. IgG antibodies are the most prevalent in serum; they provide naturally acquired passive immunity (can transfer from mother to fetus transplacental), neutralize bacterial toxins, and enhance phagocytosis. 2. IgM antibodies are involved in agglutination and complement fixation (first line defense). 3. IgA antibodies protect mucosal surfaces from invasion by pathogens. 4. IgD antibodies appear to trigger B cells to produce specific antibodies (At first, these B cells have IgD as their receptors, but later they switch to using IgM.). 5. IgE antibodies are involved in allergic reaction. 6. Only IgG antibody can transfer transplacental, other antibodies can not, as IgG has the smallest molecular weight. Specific Defenses (Immunology)  Types of specific immune response: 1. (1)Humoral immunity: characterized by the production of antibodies to combat invaders. 2. B-lymphocytes are the cells that synthesize and excrete these antibodies. 3. Antibody titer: the amount of antibodies in serum. 4. Primary response: the response of the body to the first contact with antigen. 5. anamnestic response: Subsequent contact with the same antigen results in very high antibody titers, (secondary immune response, the basis for immunization against certain diseases). Specific Defenses (Immunology)  Antibodies perform its defense function by: a) Opsonization: enhancement of phagocytosis by coating microorganism with antibodies. b) Neutralization: inactivation of bacterial exotoxin or virus with antibodies. c) Complement activation: complement combine (it attaches to the antigen- antibody complex) with antigen antibody complex and destroy antigen.  The complement system: is a group of proteins found in the blood and tissues. These proteins work together like a team to help the immune system by marking harmful microbes, causing inflammation, or directly killing them by breaking their outer layer. Specific Defenses (Immunology)  Types of specific immune response: 1. Cellular immunity: T-lymphocytes are the cells that become activated against a specific intracellular antigen and attack those infected cells or attack modified cells (as cancer cells). 2. The combat with antigen in specific immune response take place in lymphoid tissue (lymph nodes, spleen, gastrointestinal tract, and bone marrow).  Humoral immunity uses antibodies to fight pathogens in body fluids (extracellular)  Cellular immunity uses T cells to fight infected cells or pathogens hiding inside cells.(interacellular) Specific Defenses (Immunology) Humoral immunity Cellular immunity Definition immune responses mediated immune responses mediated by T by antibodies produced by B cells cells. Target against extracellular against intracellular pathogens and pathogens abnormal cells Mechanism B cells recognize antigens Cytotoxic T cells: directly kill and produce antibodies that Helper T cells: support other mark pathogens for immune cells by releasing signaling destruction molecules Specific Defenses (Immunology)  B- lymphocytes: 1. Originate from bone marrow lymphocytic stem cells. 2. B-cells are processed in bone marrow and peyer’s paches (are small areas of specialized lymphoid tissue found in the walls of the small intestine), before migrating to lymphoid tissue. (Spleen, lymph nodes). 3. B-cells are activated when an antigen reacts with receptor site (IgD and IgM) on its surface. 4. The activated B-lymphocyte produces a clone of plasma killer cells and memory cells. 5. Plasma cells produce antibodies of a specific reactivity (Monoclonal antibodies). 6. Memory cells recognize pathogens from previous encounters (secondary immune response). Specific Defenses (Immunology) Specific Defenses (Immunology)  T-lymphocytes: 1. Originate from bone marrow lymphocytes stem cells. 2. T-cells are responsible for conduction of cellular immunity. 3. T-cells are processed in thymus gland, where immunologic competence is conferred upon them. They then migrate to lymphoid tissue. (To spleen and lymph nodes). 4. There are many types of T-cells, each perform an assigned function.  Function: 5. T-helper = cooperate with B-cells to produce antibodies. 6. T-suppressor = inhibit immune response. 7. Killer cells (cytotoxic cells) Kill targeted cells. Specific Defenses (Immunology)  T-lymphocytes: 1. When a particular antigen reacts with a particular T-cell, the T-cell becomes activated. 2. Sensitized T-cells form clones, some of which become killer cells others remain as memory cells. 3. Killer T-cells destroy antigens directly, secrete transfer factor to make other lymphocytes competent, and release macrophage chemotactic factor, which attracts macrophages. (his helps bring more immune cells to the area to fight the infection.) Specific Defenses (Immunology) Specific Defenses (Immunology)  Macrophages: Known as monocytes in blood and histiocytes in dermis, Kupffer cells in liver, glial cells in brain.  It first react with the invading antigen, engulf, destroy.  Then present immunogenic parts to B & T cells, which in turn respond to antigen.  In addition, it secrets chemicals as interlukin-1 that stimulate immune response. Specific Defenses (Immunology)  Interleukin-1: 1. Acts on hypothalamus causes rise in body temperature (by signaling the brain) associated with microbial infection. (high temperature interacts with the growth of an antigen) 2. Stimulate the product of some globulin (acute-phase proteins) by liver. 3. Enhances the production of activated T-lymphocytes. Specific Defenses (Immunology)  Vaccines: a preparation of killed or attenuated (weakened) microorganisms or toxoids (harmless toxic materials from the antigen) to induce artificially acquired active immunity.  Genetic engineering by preparation of immunogenic epitopes (site in the antigen for recognition and attachment) become available for certain diseases (e.g., HBSAG)(Hepatitis B surface Antigen).  Edward Jenner: performed the first successful vaccination against smallpox using cowpox virus.  Immunization for childhood diseases:  Immunization using vaccines have dramatically reduced the incidence of many childhood diseases in Jordan (such as poliomyelitis, whooping cough, diphtheria and measles). Specific Defenses (Immunology)  Types of vaccines: 1. Bacterial vaccine: contain killed bacteria (e.g.: Bordetella pertussis) or live attenuated bacteria (e.g.: Tubercle bacilli) or part of bacteria as polysaccharide (Diplococcus pneumonia). 2. Toxoids: heat or chemically inactivated bacterial toxins (e.g.: diphtheria toxoid) 3. Viral vaccine: consists of suspensions of inactivated viruses (e.g.: Rabis vaccine) or attenuated virus (e.g.: polio vaccine), or genetically engineered (e.g.: HBsAG) 4. Parasitic vaccines are difficult and not yet successful. 5. Combined vaccine: one vaccine against different diseases (DPT: Diphtheria, Pertussis, Tetanus) MMR: Measles, Mumps, Rubella. Specific Defenses (Immunology)  In Jordan, the childhood vaccination program includes: 1. DPT vaccine:  Protect from diphtheria, whooping cough (pertussis), & tetanus.  whooping cough (killed Bordetella pertussis), diphtheria and tetanus (TOXOIDS).  First dose at end of 2nd month, second dose at end of third month, 3rd dose at end of 4th month. a boosting dose at 1.5-2-year age. The next boosting dose is DT only at first year in school. the next. Class boosting dose is DT/Adult type at 10th class.  Given by injection I.M. Specific Defenses (Immunology) 1. Polio vaccine:  Protect from poliomyelitis.  Live attenuated virus.  Doses: as described for DPT  Given as two oral drops. 2. Measles:  Protect from measles infection.  Live attenuated virus.  Doses: first at 9-12monthes. Second as 1.5-2 year (18-24 month).  Given by injection I.M. Specific Defenses (Immunology) 1. Tuberculosis:  Protect from tuberculosis infection.  Live attenuated tubercle bacilli.  Doses: one dose at the end of first month.  Given intradermal injection. 2. Hepatitis vaccine:  Protect from serum hepatitis.  Genetically engineered vaccine.  Doses: first dose beginning of third month, second dose beginning of fourth month (91days) third dose beginning of fifth month (121days).  Given by injection I.M. Specific Defenses (Immunology) 1. Haemophiles influenzae:  protect from homophiles influenza meningitis  Doses: first dose beginning of third month, second dose beginning of fourth month (91days) third dose beginning of fifth month (121days). Specific Defenses (Immunology)  Antitoxins:  A specific antibody produced by the body in response to bacterial exotoxin or its toxoid.  The purified antitoxin can be used to treat some patients by giving them immediate passive acquired immunity (as in treating diphtheria or tetanus) and can be given as protection for contacts. Hypersensitivity  Hypersensitivity and autoimmunity: 1. Hypersensitivity reactions represent immunologic response to an antigen (allergen), which lead to tissue damage rather than immunity. 2. Hypersensitivity reactions occur only when a person has been sensitized to an antigen. 3. Hypersensitivity reactions are divided into two groups: Immediate and delayed.  Overactive immune response. This occurs when the immune system mistakenly identifies harmless substances as threats, leading to an exaggerated reaction. Hypersensitivity  Immediate hypersensitivity: 1. Immediate hypersensitivity is antibody mediated, develops rapidly in a sensitized host, and can be passively transferred in serum. 2. Types of immediate hypersensitivity reactions are anaphylactic, cytotoxic, and immune-complex reactions. 3. Anaphylaxis: type reactions involve the: d) Production of IgE antibodies that bind to target cells (basophilic & mast cells) to sensitize the host. e) Subsequent exposure to the antigen causes these target cells to release chemical mediators, such as histamine, which causes the observed allergic reactions. f) Systemic anaphylaxis may develop in minutes after injection (e.g: penicillin) or ingestion of the antigen, this may result in respiratory failure and circulatory hypotensive shock. g) Localized anaphylaxis is exemplified by hives, hay fever, and asthma. Hypersensitivity  Skin testing is useful in determining sensitivity to an antegin.  ⁠Desensitization to an antigen can be achieved by repeated injections of small dose of antibiotic. Types of immediate hypersensitivity Type Antibody Complement Examples Mediator cells involved involved Anaphylactic IgE No Anaphylactic Mast cells & reaction shock, hives, Basophilic asthma, hay fever, drug allergies Cytotoxic Primarily IgG Yes Transfusion non reaction reaction RH incompatibility, hemolytic anemia Immune- Primarily IgG or Yes Serum sickness, Primarily complex IgM autumn diseases neutrophils reaction (SLE, Rh.) Hypersensitivity & autoimmunity  Delayed Hypersensitivity: (Cell - Mediated Hypersensitivity): 1. The best example is tuberculin skin test (PPD), where a positive reaction is a reflection of cell mediated hypersensitivity.  PPD: purified protein derivative, a test used to determine if a person is infected with TB bacteria. 2. The reaction develops slowly (1-3days) and can be passively transferred with sensitized lymphocytes. 3. Sensitized T-cells secrete lymphokines in response to the appropriate antigen. 4. Lymphokines attract and activate lymphocytes and macrophages and initiate tissue damage. Hypersensitivity & autoimmunity 1. Contact dermatitis is an allergic skin reaction to certain chemicals in the environment. 2. The environmental chemicals are probably happens that combine with skin proteins, skin oils may act as adjuvant. 3. Identity of the allergens involved in contact dermatitis can be determined by Vollmer patch test. Hypersensitivity & autoimmunity  Transplantation: is the replacement of diseased tissue with natural ones from living or cadaver donors.  Four types of grafts (transplants) have been defined based on genetic relationships between the donor and the recipient:  Autograft: taken from one part of a person's body and transplanted to another part of the same person.  Isograft: transplant of tissue or organs between two genetically identical individuals.  Allograft: transplant of tissue or organs between two genetically different individuals of the same species.  Xenograft: transplant of tissue or organs between individuals of different species, such as using pig heart valves in humans. Hypersensitivity & autoimmunity  Rejection of transplanted tissue represents an immune response by the recipient to foreign tissue antigens on the transplanted tissue.  Histocompatibility antigens located on cell surfaces, express genetic differences between individuals these antigens are coded for the major histocompatibility complex (MHC), also called the human leukocyte antigen (HLA) gene complex.  To prevent tissue rejection in an allograft, MHC antigens and blood group antigens are matched as closely as possible. Hypersensitivity & autoimmunity  Immunology Tolerance: state of unresponsiveness to a specific antigen. Tolerance to self antigens occurs during fetal life. Tolerance to foreign antigens can be induced.  Autoimmunity: Is a humoral or cell mediated immune response against self antigens. It frequently results in disease.  Serology: Is the study antigen - antibody reactions in vitro mainly for diagnostic purpose  Serologic tests can be performed quickly and are quite specific and sensitive. Hypersensitivity & autoimmunity  Precipitation reactions: 1. The interaction of soluble, multivalent antigens with multivalent antibodies (precipitins) leads to precipitation reactions. 2. Precipitation reactions depend on the formation of lattice (lattice like structure) and occur best when antigen and antibody are present in optimal proportions. Excesses of either component decreases lattice formation and subsequent precipitation. 3. The precipitin ring test is used in typing (identifying) of streptococci. 4. Immunodiffusion procedures involve precipitation reactions carried out in an agar gel medium. Example Elek test for diagnosis of toxigenic strains of Corynebacterium diphtheria.(antigens and antibodies diffuse through a gel and form a visible precipitate) 5. Immunoelectrophoresis combines electrophoresis (separating proteins by charge) with immunodiffusion for the analysis of serum proteins. Hypersensitivity & autoimmunity  Complement Fixation Reactions: 1. Complement system composed of nine proteins that participate in defense against microbes. 2. Complement acts specifically against a microbe in conjunction with a specific antibody binding to that microbe (Classical pathway stimulation of complement). 3. Complement act nonspecifically against a microbe if stimulated by the microbe directly, especially gram-negative bacteria (Alternative Complement pathway stimulation). 4. Complement kills bacteria by lyses (enzyme), opsonization (coating). And chemotaxis (signals to attract immune cells). 5. Complement fixation reactions are serological tests based on the depletion of a fixed amount of complement in the presence of an antigen - antibody reaction. 6. Hemolysins or absence of hemolysins used as an indicator in evaluating complement reactions. (no hemolysins no complement reaction) Hypersensitivity & autoimmunity  Agglutination reactions: 1. Result from interaction of cell-bound (particulate) antigen with multivalent antibodies (agglutinins). 2. Agglutination reactions depend on lattice formation. 3. Diagnosis of some diseases can be made by agglutination reaction as Widal test for diagnosis of typhoid, and Rose Bengal test for diagnosis of Brucellosis. 4. Agglutination reactions can be used to determine antibody titer (tube agglutination test). Rising titer is diagnostic for specific disease. 5. Hemagglutination reactions involve agglutination reactions using red blood cells. They are used in blood typing, diagnosis of certain diseases, and identification of viruses. Hypersensitivity & autoimmunity  Neutralization reaction: 1. The harmful effect of a bacteria exotoxin or virus is eliminated by a specific antibody. 2. Neutralization reactions to determine the presence of antibodies are Dick test (scarlet fever) and Chick test (diphtheria).