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Lect 01 introduction to antibiotics 19 08-142
This document provides an introduction to antibiotics. It defines antibiotics as substances produced by microorganisms that suppress or kill other microorganisms at low concentrations. The document discusses the history of antibiotic discovery from ancient times through the work of scientists like Ehrlich, Fleming, Waksman, and others. It outlines the ideal properties of antibiotic drugs, including selective toxicity against pathogens, desirable pharmacokinetics, and preventing resistance development.
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Lect 01 introduction to antibiotics 19 08-142
- 1. Antibiotics: An Introduction DrRavi Kant Agrawal, MVSc, PhD, Senior Scientist (Veterinary Microbiology) Food Microbiology Laboratory Division of Livestock Products Technology ICAR-Indian Veterinary Research Institute Izatnagar 243122 (UP) India
- 2. Antibiotics and Antimicrobials •Antibiotics: Greek words anti (against) and biotikos (concerning life) refers to substances produced by microorganisms, which selectively suppress the growth of or kill other microorganisms at very low concentration. • Chemotherapeutic agents: The use of drugs (chemical entity) with selective toxicity against infections/ viruses, bacteria, protozoa, fungi and helminthes. • Antimicrobials: derived from the Greek words anti (against), mikros (little) and bios (life) and refers to all agents of natural, synthetic or semi-synthetic origin which at low concentrations kill or inhibits the growth of microorganisms but causes little or no host damage. Antimicrobials include both chemotherapeutic agent + Antibiotics.
- 3. Antibiotics • OLD: Anantibiotic is a chemical substance produced by various species of microorganisms that is capable in small concentrations of inhibiting the growth of other microorganisms. • NEW: An antibiotic is a product produced by a microorganism or a similar substance produced wholly or partially by chemical synthesis, which in low concentrations, inhibits the growth of other microorganisms. • An antibiotic is a selective poison. • It has been chosen so that it will kill the desired bacteria, but not the cells in your body. Each different type of antibiotic affects different bacteria in different ways.
- 4. History Use ofsubstances with antimicrobial properties is known to have been common practice for at least 2000 years. Ancient Egyptians and ancient Greeks used specific molds and plant extracts to treat infection. Although, for centuries preparations derived from living matter were applied to wounds to destroy infection, the fact that a microorganism is capable of destroying one of another species was not established until the latter half of the 19th cent when Pasteur noted the antagonistic effect of other bacteria on the anthrax organism and pointed out that this action might be put to therapeutic use. Microbiologists such as Louis Pasteur and Jules Francois Joubert observed antagonism between some bacteria and discussed the merits of controlling these interactions in medicine. Before Ehrlich Period: Chaulmoogra oil by hindus in leprosy. Cinchona bark for fever. Mouldy curd by chinese for boils. Chinese used artemisia for malaria treatment (1970-isolated Artemisinin). Mercury by Paracelsus for syphilis. Jordan people- used red soils to treat skin infections- isolated Actinomycetes and many other antibiotic producing bacteria.
- 5. History…… Paul Ehrlich (EhrlichPeriod – 1900-1930) • The German chemist Paul Ehrlich developed the idea of selective toxicity: that certain chemicals that would be toxic to some organisms, e.g., infectious bacteria, would be harmless to other organisms, e.g., humans. • Paul Ehrlich - derived from finding that dyes used in histochemistry became bound to cell-specific receptors. He asked “Why can’t such dyes be toxic for specific organisms?” • Paul Ehrlich, Alfred Bertheim and Sahachiro Hata (1910) looking for something to target Treponema pallidum, developed hundreds of organo-arsenic compounds from highly toxic drug Atoxyl and 606th compound tested was effective against syphilis. • Hoechst - Salvarsan (Arsphenamine). • First documented case of a chemical that could selectively kill pathogens w/o permanently harming the human host. • The concept of chemotherapy to treat microbial diseases was born. • Coined the term ‘CHEMOTHERAPY’ • NOBEL: 1908 • FATHER OF CHEMOTHERAPY • He used the term ‘MAGIC BULLETS’ • MOA- still not known.
- 6. Post Ehrlich Period:1930- till date • Over the next 20 years, progress was made against a variety of protozoal diseases, but little progress was made in finding antibacterial agents untill introduction of Proflavine in 1934. • Proflavine is a yellow coloured amino-acridine structure which is particularly effective against deep wound bacterial infections. • Used in world war II. • Interesting drug as it targets bacterial DNA rather than protein. • Despite success of this drug, it was not effective against infections in Bloodstream and there was urgent need for agents which could fight systemic infections. History…… Proflavine
- 7. Post Ehrlich Period:1930- till date • Ehrlich approach of systematic screening of compounds became the cornerstone of the pharma industry. • This approach led to the discovery of Sulfonamidochrysoidine (KI-730) – synthesized by Bayer chemists Josef Klarer and Fritz Mietzsch and tested by Gerhard Domagk for antibacterial activity. • Marketed under the brand name Prontosil. • Effective against streptococcal infections invivo. • Prontosil was a prodrug and its active compound sulfanilamide was not patentable as had been in use in dye industry. • Cheap to produce, off-patent and easy to modify – many companies started producing sulfonamide derivatives. • NOBEL: 1939 History……
- 8. History…. Alexander Fleming • In1928, Sir Alexander Fleming, a Scottish biologist, observed that Penicillium notatum, a common mold, had destroyed staphylococcus bacteria in culture. • Fleming unable to purify compound • NOBEL: 1945 • Penicillin was isolated in 1939 by Oxford chemists Howard Florey and Ernst Chain. • 1940: first clinical trials of penicillin were performed. • Mass production of penicillin started from 1945 and used during WWII.
- 9. Selman Waksman • SoilStreptomyces make antibiotics • Comes up with definition of antibiotic • In 1944, Selman Waksman and Albert Schatz, American microbiologists, isolated streptomycin and a number of other antibiotics from Streptomyces griseus. • NOBEL: 1952 History……
- 10. • In 1947,Chloramphenicol was first used clinically to treat Typhus. • G. Brotzu discovered Cephalosporins. • Benjamin M. Duggar isolated Chlortetracycline from a mud sample obtained from a river in Missouri. • 1960 onwards second generation antibiotics like Methicillin were discovered. • Following this, semi synthetic derivatives of older antibiotics with more desirable properties and different spectrum of activity were produced e.g. Fluoroquinolones, Oxazolidinones etc.
- 11. 1900 1920 19401960 1980 2015 1900- Paul Ehrilich Chemotherapy Animal model developed 1908- Discovery of Arsphenamine 1932- Prontosil- First sulfonamide- Bayer’s Laboratory Gerhard Domagk 1939- Sulfonamidochrysoidine (Prontosil) Alexander Fleming 1928- Penicillin 1943- Nitrogen mustard in lymphomas 1948- Anitfolates 1951- Thiopurines 1958- Methotrexate 1957- 5-Fluorouracil 1959- Antitumor antibiotics 1963 to 1970- Treatment for Hodgkin’s disease 1962- nalidixic acid 1997- Monoclonal antibody approved for the treatment of tumor. 2005- Tyrosine kinase inhibitors 2007- Target specific screens 1996- Imatinib Paul Ehrilich Father of Chemotherapy Timeline history of chemotherapy development 1944- Waksman et al., discovered streptomycin. 1963- Vinca alkaloids
- 12. Between 1962 and2000, no major classes of antibiotics were introduced Fischbach MA and Walsh CT, Science 2009 Methicillin
- 13. Timeline of antibioticresistance Penicillin Penicillin resistant S.aureus Methicillin MRSA VRE VRSA Vancomycin Pencillin:1943, Resistance in 1947 within 4 years Methicillin: 1959, resistance in 1961 Vancomycin: 1958 VRE:1987 VRSA:2002
- 14. The Ideal Drug* 1.Should have powerful action against MOs. 2. Selectively kill or inhibit the growth of pathogens - cause no damage to the host - greater harm to microbes than host, done by interfering with essential biological processes common in bacteria but not human cells. 3. Therapeutic index (the lowest dose toxic to the patient divided by the dose typically used for therapy). High TI are less toxic to the patient. 4. Should not be inactivated rapidly by tissue enzymes or GI microflora 5. Should have good oral bio-availability 6. Should penetrate efficiently to various body tissues and fluids - reach target site in body with effective concentration remain in specific tissues in the body long enough to be effective 7. Favorable pharmacokinetics - drug interactions, how drug is distributed, metabolized and excreted in body (unstable in acid, can it cross the Blood-brain barrier, etc) • Drugs differ in how they are distributed, metabolized and excreted • Important factor for consideration when prescribing • Rate of elimination of drug from body expressed in half-life -Time it takes for the body to eliminate one half the original dose in serum • Half-life dictates frequency of dosage • Patients with liver or kidney damage tend to excrete drugs more slowly
- 15. 8. Desired Spectrumof activity: broad vs. narrow • broad spectrum – wide • Narrow spectrum - narrow range (pathogen must be ID’d) 9. Bactericidal vs. bacteriostatic • Bacteriostatic drugs rely on host immunity to eliminate pathogen • Bacteriocidal drugs are useful in situations when host defenses cannot be relied upon to control pathogen 10. Should have a long elimination half life and not rapidly excreted by kidney or bile 11. Should not interfere the host immune mechanism 12. Should not show adverse drug interactions with other antimicrobial drugs Combination some times used to treat infections When action of one drug enhances another, effect is synergistic When action of one drug interferes with another, effect is antagonistic When effect of combination is neither synergistic or antagonistic, effect said to be additive 13. Should have no/short withdrawl time in food producing animals. 14. Little resistance development- Should not favour bacterial resistance and show cross resistance with other antimicrobial agents 15. Stable when stored in solid or liquid form 16. Affordable and easily available 17. Lack of “side effects” allergic, toxic side effects, suppress normal flora • Allergic reactions: Allergies to penicillin • Toxic effects: Aplastic anemia- Body cannot make RBC or WBC • Suppression of normal flora • Antibiotic associated colitis * There is no perfect drug
- 16. 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
- 17. 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, Clarithromycin, Azithromycin • Lincosamide antibiotics: Clindamycin • Glycopeptide antibiotics: Vancomycin • Polypeptide antibiotics: Polymyxin-B, Bacitracin, Tyrothricin • Nitrofuran derivatives: Nitrofurantoin • Nitroimidazoles: Metronidazole, Tinidazole • Nicotinic acid derivatives: Isoniazid, Pyrezinamide, Ethionamide • Polyene antibiotics: Amphotericin-B, Nystatin, Hamycin • Azole derivatives: Miconazole, Clotrimazole, Ketoconazole, Fluconazole • Others: Rifampin, Ethambutol, Griseofulvin
- 18. B. Mechanism ofaction THFA PABA Ribosomes cell membrane metabolism Cell wall synthesis m-RNA code protein synthesis DNA gyrase
- 19. B. Mechanism ofaction THFA PABA Ribosomes Inhibition of protein synthesis Inhibition of DNA gyrase Inhibition of metabolism Inhibition of Cell wall synthesis Sulfonamides Sulfones Trimethoprim PAS Pyrimethamine Ethumbutol Beta-lactams Cephalosporins Vancomycin Tetracyclines Aminoglycosides Macrolides Clindamycin Chloramphenicol Fluoroquinolones Inhibition of Cell Membrane Leakage form cell membrane Polypeptides - Polymyxines, colistin. Polyenes- Amphotericin B, Nystatin, Hamycin Fluoroquinolones Rifampin Misreading of m-RNA code Aminoglycosides- Streptomycin, Gentamicin
- 20. C. Type oforganisms (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.
- 21. D. Spectrum ofactivity Narrow-spectrum Penicillin G, Streptomycin, Erythromycin Broad-spectrum Tetracyclines, Chloramphenicol effective against specific type of bacteria either gram-positive or gram-negative effective against a wide range of bacteria, both gram-positive and gram-negative
- 22. D. Type ofaction (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, Vancomycin, Ciprofloxacin, Metronidazole, Cotrimoxazole Note: Some b’static drugs may act as bactericidal at high concentration (Sulfonamides, nitrofurantion)
- 23. E. Source ofantibiotics • Fungi: Penicillin, Griseofulvin, Cephalosporin • Bacteria: Polymyxin B, Tyrothricin, Colistin, Aztreonam, Bacitracin • Actinomycetes: Aminoglycosides, Macrolides, Tetracyclines, Polyenes, Chloramphenicol
- 24. Principles of antimicrobialtherapy • 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)
- 25. Principles of antimicrobialtherapy 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.
- 26. Choice of anantimicrobial agents Patient related factors Drug factors Organism-related considerations
- 27. Choice of anantimicrobial 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 defense
- 28. Choice of anantimicrobial 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) • Spectrum of activity (Narrow/ broad spectrum) • Type of activity (bactericidal/ bacteriostatic) • Sensitivity of the organism (MIC) • Relative toxicity • Pharmacokinetic profile • Route of administration • Cost
- 29. Choice of anantimicrobial 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)
- 30.
- 31. ToxicityLocal irritancy: • exertedsite of administration e.g. Gastric irritation, pain and abscess formation at the site of i.m. inection, thrombo-phlebitis of injected vein. Systemic toxicity: • Dose related organ damage. – High therapeutic index agents may not damage host cells, E.g.: penicillin, erythromycin. – The agent which have low therapeutic index exhibits more 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 aminoglycosides (renal and CNS toxicity) tetracycline (liver and renal toxicity) chloramphenicol (bone marrow depression)
- 32. Hypersensitivity reaction • AllAMAs 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) Inj. Penicillin induced anaphylactic shock To avoid Perform sensitivity test before administering penicillin Inj.
- 33. Drug Tolerance • Lossof 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
- 34. Superinfection (Suprainfection) • Anew infection occurring in a patient having a preexisting infection. • 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 defense 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
- 35. Superinfection Cont., • Treatment forsuperinfection – 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.
- 36. Resistance • Unresponsiveness ofa 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.
- 37. COMMON MODES OFANTIMICROBIAL RESISTANCE e.g. Penicillins e.g. aminoglycosides , chloramphenicol & penicillins e.g.tetracyclines e.g. aminoglycosides & tetracyclines
- 38. Acquired Resistance Cont., Development ofresistance •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.
- 39. • Development ofresistance • Gene transfer (Infectious resistance): From one organism to another organism. – Conjugation – Transduction – Transformation Transposon donor a b a a a b b b Plasmid cointegrate Transfer of resistance genetic elements within the bacterium Resistance Cont.,
- 40. 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.,
- 41. Development of resistanceGene 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.,
- 42. Development of resistance Genetransfer - 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. Resistance Cont.,
- 43. Combined use ofantimicrobials • 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)
- 44. Prophylactic use ofantimicrobials • 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
- 45. Failure of antimicrobialtherapy • Improper selection of AMAs, dose, route or duration of treatment. • Treatment begun too late • Failure to take necessary adjuvant measures • Poor host defense • Trying to treat untreatable (viral) infections • Presence of dormant or altered organisms which later give risk to a relapse
- 46. Why do weneed newer antimicrobials • Bacterial resistance to antimicrobials-health and economic problem • Chronic resistant infections contribute to increasing health care cost • Increase morbidity & mortality with resistant microorganisms
- 47. A Changing Landscapefor Numbers of Approved Antibacterial Agents Bars represent number of new antimicrobial agents approved by the FDA during the period listed. 0 0 2 4 6 8 10 12 14 16 18 Numberofagentsapproved 1983-87 1988-92 1993-97 1998-02 2003-05 2008 Infectious Diseases Society of America. Bad Bugs, No Drugs. July 2004; Spellberg B et al. Clin Infect Dis. 2004;38:1279-1286; New antimicrobial agents. Antimicrob Agents Chemother. 2006;50:1912 Resistance
- 48. Common side effectswith chemotherapeutics agents Think before dispensing Thank U
- 50.
- 51. Disinfection Disinfection is theprocess that reduces the number of potential pathogens on a material until they no longer represent a hazard. • Disinfection is complex of measures that are directed to prevention spread of microorganisms which can be agent of disease. • Disinfection, refers to the use of a physical process or a chemical agent (a disinfectant) to destroy vegetative pathogens but not bacterial endospores. It is important to note that disinfectants are normally used only on inanimate objects because, in the concentration required to be effective, they can be toxic to human and other animal tissue.
- 52. Asepsis asepsis refers toany practice that prevents the entry of infectious agents onto sterile tissues and thus prevent infection • Aseptic techniques commonly practiced in health care range from sterile methods that exclude all microbes to antisepsis.
- 53. Antisepsis is the complexof procedures of growth inhibition and reproduction potential pathogenic microorganisms on skin of mucous membrane • In antisepsis, chemical agents called antiseptics are applied directly to exposed body surfaces (skin and mucous membrane), wounds, and surgical incisions to destroy or inhibit vegetative pathogens. Examples of antisepsis include preparing the skin before surgical incision with iodine compounds
- 54.
- 55.
- 56. MECHANISMS OF ACTION •Inhibitors of cell wall synthesis • Inhibitors of protein synthesis • Inhibitors of nucleic acid (replication/transcription/other mechanism) • Drugs altering cell membranes • Anti-metabolites
- 57. Antibiotics: Mechanisms ofAction Transcription Translation Translation Alteration of Cell Membrane Polymyxins Bacitracin Neomycin
- 58. Categories antimicrobial agentsbased on their application Term Description Examples Disinfec- tant Agent that kills microorganisms on inanimate objects Hypochlorite, formaldehyde Antiseptic Agent that kills of prevents the growth of microorganisms on lining tissues Soap, hydrogen peroxide, iodine, ethanol Sanitizer A disinfectant that is used to reduce numbers of bacteria to levels judged safe by public health officials Ethanol Preserva- tive Agents that prevents microbial growth: often added to products such as foods and cosmetics to prevent microbial growth Lactic acid, benzoic acid, sodium chloride Antibiotic Agent produced by microorganisms that inhibits or kills other microorganisms Penicillin, tetracycline
- 59. The action ofantimicrobial agents Term Action Examples Bactericide Agent that kills bacteria Chlorhexidine, ethanol Biocide Agent that kills living organisms Hypochlorite Fungicide Agent that kills fungi Ethanol Germicide (microbicide) Chemical agent that specifically kills pathogenic microorganisms Formaldehyde, silver, mercury Sporicide Agent that kills bacterial endospores Glutaraldehyde Virucide Inactivates viruses so that they lose the ability to replicate Cationic detergents
- 60. Antimicrobial agents Disinfectants and antiseptics Cankill or inhibit growth and development majority of microorganisms in space around patient, and microorganisms that are on human body surface Chemotherapeuti c medicines Can kill or inhibit reproduction of agents of disease in the patient organism. Have selective influence upon microorganisms.
- 61. Classification of disinfectantsbased on their mode of action Mode of action Type of disinfectant Coagulate proteins Formaldehyde, glutaraldehyde, alcohols, dyes, mercurials, acids Oxidize proteins Halogens: iodine, iodophors, chlorine, chlorine compoynds Destroys cell membrane Phenolics, quaternary ammonium compounds (surface-active agents)
- 62. Chemotherapy is a methodof therapy of infectious disease and cancer with chemical agents – chemotherapeutic medicines
- 63. Chemotherapeutic index Maximal tolerateddose is the most quantity of drug that not cause harmful effect in a patient. Minimal curative dose is the least dose of drug that kill of inhibit reproduction of microorganisms Maximal tolerated dose Minimal curative dose > 3
- 64. Paul Ehrlich’s principlesof chemotherapy Paul Ehrlich have provided principled of chemotherapy. Receptor interaction of drug and microorganism Changing of chemical structure of drug causes change of its activity Changing of drug structure can occur in microorganism’s cell, therapeutic effect can slacken or intensify during it Microbes can develop drug resistance to medicine The drug can be used only if its chemotherapeutic index is not less three.
- 65.
- 66. Antagonism (ammensalism) Antagonism isa form interaction between organisms when one microorganisms inhibits development of others Mechanisms of antagonism: Competition for nutrient substrate (different spread of growth) Excretion of acids, alcohols, ammonia by microorganisms- antagonist Excretion antibiotics, bacteriocines by microorganisms- antagonist Predation
- 67. Antibiotic Chemotherapeutic preparation producedby living organisms or their synthetic analogs that can selectively inhibit disease agents or inhibit growth tumor cells in patient organism
- 68. Characteristics of successful antimicrobialdrugs Great activity against microbes Selectively toxic to the microbe but nontoxic to host cells Microbicidal rather than mocrobistatic Relatively soluble and functions even when highly diluted in body fluids Remains potent long enough to act and is not broken down or excreted prematurely Not subject to the debelopment of antimicrobial resistance Complements or assists the activities of the host’s defenses Remains active despite the presence of large volumes of organic materials It is readily delivered to the site of infection Does not disrupt the host’s health by causing allergies or predisposing the host to other infections
- 69. Classification based ontype of antibiotic action Microbistatic (bacteriostatic, fungistatic) agents prevent the growth of microorganisms (bacteria, fungi) Microbicidal agent (bactericide, virucide, fungicide) kills microorganisms (bacteria, viruses, fungi)
- 70. Categories based ongroup of organisms that produce of antibiotics Producers Antibiotics Bacteria Polmyxyn Fungi Penicillin, cephalosporin Actinomycetes Streptomycin, tetracycline Plants Imanin, salvin, Animals Lysocim
- 71. Classification of antibioticsbased on spectrum of action Narrow-spectrum agents are effective against a limited array of different microbial types (examples: bacitracin inhibit certain gram-positive bacteria) Broad-spectrum agents are active against a wider range of different microbes (example – tetracycline that affect upon gram-positive and gram-negative bacteria, rickettsias, mycoplasmas)
- 72. Principles of antimicrobialtherapy
- 73.
- 74. 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
- 75. 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
- 76. 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
- 77. B. Mechanism ofaction THFA PABA Ribosomes cell membrane metabolism Cell wall synthesis m-RNA code protein synthesis DNA gyrase
- 78. B. Mechanism ofaction Cont., THFA PABA Ribosomes Inhibition of protein synthesis Inhibition of DNA gyrase Inhibition of metabolism Inhibition of Cell wall synthesis Sulfonamides Sulfones Trimethoprim PAS Pyrimethamine Ethumbutol Beta-lactams Cephalosporins Vancomycin Tetracyclines Aminoglycosides Macrolides Clindamycin Chloramphenicol Fluoroquinolones Inhibition of Cell Membrane Leakage form cell membrane Polypeptides- Polymyxines, colistin. Polyenes- Amphotericin B, Nystatin, Hamycin Fluoroquinolones Rifampin Misreading of m-RNA code Aminoglycosides- Streptomycin, Gentamicin
- 79. C. Type oforganisms (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.
- 80. D. Spectrum ofactivity Narrow-spectrum Penicillin G, Streptomycin, Erythromycin Broad-spectrum Tetracyclines, Chloramphenicol effective against specific type of bacteria either gram-positive or gram-negative effective against a wide range of bacteria, both gram-positive and gram-negative
- 81. D. Type ofaction (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, Vancomycin, Ciprofloxacin, Metronidazole, Cotrimoxazole Note: Some b’static drugs may act b’cidal at high concentration (Sulfonamides, nitrofurantion)
- 82. E. Source ofantibiotics • Fungi: Penicillin, Griseofulvin, Cephalosporin • Bacteria: Polymyxin B, Tyrothricin, Colistin, Aztreonam, Bacitracin • Actinomycetes: Aminoglycosides, Macrolides, Tetracyclines, Polyenes, Chloramphenicol
- 83. Choice of anantimicrobial agents Patient related factors Drug factors Organism-related considerations
- 84. Choice of anantimicrobial 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
- 85. Choice of anantimicrobial 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)
- 86. Choice of anantimicrobial 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)
- 87. Choice of anantimicrobial 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
Editor's Notes
- #6 Paul Ehrlich- derived from finding that dyes used in histochemistry became bound to cell-specific receptors. He asked” Why can’t such dyes be toxic for specific organisms?” 1910 looking for something to target Treponema pallidum. Looked at arsenic compounds and on the 606th one tested. Salvarsan- combo of salvation and arsenic. First documented case of a chemicla that could selectively kill pathogens w/o permanently harming the human host.
- #9 Alexander Fleming penicillin developed in US in 1941 - spores from mold on coats of scientists
- #12 Paul Ehrilich dies: father of chemotherapy Imatinib is a Bcr-Abl tyrosine kinase inhibitor for the treatment of chronic myelocytic leukemia
- #14 Pencillin:1943.resistance in 1947 within 4 years Methicillin :1959,resistance in 1961 Vancomycin :1958 VRE:1987 VRSA:2002
- #15 Selective toxicity - greater harm to microbes than host, done by interfering with essential biological processes common in bacteria but not human cells. LD50 vs. MIC - Therapeutic index (the lowest dose toxic to the patient divided by the dose typically used for therapy). High TI are less toxic to the patient. Bactericidal vs. bacteriostatic Static rely on normal host defences to kill or eliminate the patogen after its growth has been inhibited. (UTIs) CIDAL given when host defenses cannot be relied on to remove or destroy pathogen. Favorable pharmacokinetics - drug interxns, how drug is distributed, metabolized and excreted in body (unstabel in acid, can it cross the Blood-brain barrier, etc) Spectrum of activity broad spectrum - wide Narrow spectrum - narrow range (pathogen must be ID’d) Lack of “side effects” allergic, toxic side effects, suppress normal flora Little resistance development
- #52 Disinfection is complex of measures that are directed to prevention spread of microorganisms which can be agent of disease. Disinfection, refers to the use of a physical process or a chemical agent (a disinfectant) to destroy vegetative pathogens but not bacterial endospores. It is important to note that disinfectants are normally used only on inanimate objects because, in the concentration required to be effective, they can be toxic to human and other animal tissue.
- #53 Aseptic techniques commonly practiced in health care range from sterile methods that exclude all microbes to antisepsis.
- #54 In antisepsis, chemical agents called antiseptics are applied directly to exposed body surfaces (skin and mucous membrane), wounds, and surgical incisions to destroy or inhibit vegetative pathogens. Examples of antisepsis include preparing the skin before surgical incision with iodine compounds
- #59 Antimicrobial agents used to control microbial growth and prevent infections. A disinfectant is a chemical used for disinfection of inanimate objects, whereas an antiseptics is a disinfectant that is nontoxic enough to be used on human tissue. Washing hands with soap for prevention of microorganisms penetration into organism. Applying antiseptic to wound for prevention of sepsis. To clean skin surfaces with ethanol before giving injections to prevent infection through breaks in the skin Sanitization. Может ли в норме содержать (contain) питьевая вода мо?
- #60 A germicide can be used on inanimate (nonliving) materials or on living tissue, but it ordinarily cannot kill resistant microbial cells.
- #62 Surface-active agents (detergents) like soap reduce the surface tension of liquids. They act against many vegetative bacteria by attacking the cytoplasmic membrane.
- #64 As a characteristic of the quality of medicinal preparation, Paul Ehrlich introduced the chemotherapeutic index which is the ratio of the maximal tolerated dose to the minimal therapeutic (curative) dose. The chemotherapeutic index should not be less than 3.
- #65 Paul Ehrlich have provided principled of chemotherapy.
- #66 Whenever complex mixtures of organisms associate, they develop various dynamic interrelationships based on nutrition and shared habitant. Community interactions that have beneficial, harmful, or neutral effects. When mutualism two members required each other for survival. In contrast, commensalism is one-side and independent. It second microorganism take benefit, first microorganism receives no profit. Parasitism is an intimate relationship whereby a parasite derives its nutrients and habitant or kill susceptible species sharing its habitat. In synergism, two organisms that are usually independent cooperate to break down a nutrient neither one could have metabolized alone. A predator is a form of consumer that actively seeks out and ingests live prey (protozoa that prey on algae and bacteria).
- #67 Antagonism occurs when one population produces a substance inhibitory to another population. The production of antibiotics, for example, can give the antibiotic-producing population an advantage over a sensitive strain when competing for the same nutrient resources.
- #71 Antibiotics are substances produced by the natural metabolic processes of some microorganisms that can inhibit or destroy other microorganisms. Other antimicrobial substances, termed synthetic drugs, are derived in the laboratory from dyes or other organic compounds. Although separation into these 2 categories has bee traditional, they tend to overlap, because many antibiotics are now chemically altered in the laboratory. There are semisynthetic antibiotics.