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Meeting 6 Disease Manifestations Virulence Factors Antimicrobial resistance 1 Aug 2009.

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1 Meeting 6 Disease Manifestations Virulence Factors Antimicrobial resistance 1 Aug 2009

2 Manifestations of infectious disease  Classic Signs Signs Fever, swelling, rashes, vomiting, diarrheaFever, swelling, rashes, vomiting, diarrhea Skin signs: lesions, erythema, papule (pimple), vesicles, pustule, ulcer or erosion or abscessSkin signs: lesions, erythema, papule (pimple), vesicles, pustule, ulcer or erosion or abscess Symptoms Symptoms Pain, headache, nausea, malaisPain, headache, nausea, malais Inflammation Inflammation  Result of Immune reactions Hematologic ( leukocytosis, anemia ) Hematologic ( leukocytosis, anemia ) Cardiac (tachycardia to heart failure) Cardiac (tachycardia to heart failure) Respiratory (hyperventilation) Respiratory (hyperventilation) Renal Renal Hepatic Hepatic Upper GI bleeding Upper GI bleeding

3 Manifestations of infectious disease  Classic Signs Signs Fever, swelling, rashes, vomiting, diarrheaFever, swelling, rashes, vomiting, diarrhea Skin signs: lesions, erythema, papule (pimple), vesicles, pustule, ulcer or erosion or abscessSkin signs: lesions, erythema, papule (pimple), vesicles, pustule, ulcer or erosion or abscess Symptoms Symptoms Pain, headache, nausea, malaisePain, headache, nausea, malaise Inflammation Inflammation Table 1 Types of skin lesions Flat lesions (in the plane of the skin) Elevated lesions (above the plane of the skin) Depressed lesions (below the plane of the skin) Macule IInfarct Sclerosis Telangiectasis† Vesicle and bulla Pustule Abscess‡ Cyst‡ Papule Wheal plague Nodule‡ Vegetation Keratosis Desquamation (scales) Exudate (crusts) Lichenification Atrophy§ Sclerosis§ Erosion Excoriation Scar† Ulcer Sinus‡ Gangrene§ May also be below the plane of skin † May also be above the plane of skin ‡ May also be in or below the plane of skin § May also be in the plane of skin

4 Flat lesion  MACULE A macule is a change in the color of the skin. It is flat, if you were to close your eyes and run your fingers over the surface of a purely macular lesion, you could not detect it. A macule greater than 1 cm. may be referred to as a patch. A macule is a change in the color of the skin. It is flat, if you were to close your eyes and run your fingers over the surface of a purely macular lesion, you could not detect it. A macule greater than 1 cm. may be referred to as a patch.

5 Elevated lesion  PAPULE is a solid raised lesion that has distinct borders and is less than 1 cm in diameter. Papules may have a variety of shapes in profile (domed, flat-topped, umbilicated) and may be associated with secondary features such as crusts or scales. is a solid raised lesion that has distinct borders and is less than 1 cm in diameter. Papules may have a variety of shapes in profile (domed, flat-topped, umbilicated) and may be associated with secondary features such as crusts or scales.

6 Elevated lesion  TUMOR is a solid mass of the skin or subcutaneous tissue; it is larger than a nodule. is a solid mass of the skin or subcutaneous tissue; it is larger than a nodule.

7 Elevated lesion  PAPULE is a solid raised lesion that has distinct borders and is less than 1 cm in diameter. Papules may have a variety of shapes in profile (domed, flat- topped, umbilicated) and may be associated with secondary features such as crusts or scales. is a solid raised lesion that has distinct borders and is less than 1 cm in diameter. Papules may have a variety of shapes in profile (domed, flat- topped, umbilicated) and may be associated with secondary features such as crusts or scales.

8 Depressed lesion  ATROPHY Atrophy is thinning or absence of the epidermis or subcutaneous fat. Atrophy is thinning or absence of the epidermis or subcutaneous fat.

9 Depressed lesion  EROSION Erosions are slightly depressed areas of skin in which part or all of the epidermis has been lost Erosions are slightly depressed areas of skin in which part or all of the epidermis has been lost

10 Depressed lesion  ULCERATION occur when there is necrosis of the epidermis and dermis and sometimes of the underlying subcutaneous tissue. occur when there is necrosis of the epidermis and dermis and sometimes of the underlying subcutaneous tissue.

11 FEVER  1. Fever i ncreases the environmental temperature above the optimum growth temperature for many microorganisms. If the microorganisms are growing more slowly, the body's defenses have a better chance of removing them all.  2. Fever leads to the production of heat shock proteins that are recognized by some intraepithelial T-lymphocytes (delta gamma T-cells) resulting in the production of inflammation-promoting cytokines.  3. Fever elevates the temperature of the body increasing the rate of enzyme reactions, and speeding up metabolism within the body. can increase the production and activity of phagocytes, can increase the production and activity of phagocytes, speed up the multiplication of lymphocytes, speed up the multiplication of lymphocytes, increase the rate of antibody and cytokine production, increase the rate of antibody and cytokine production, increase the rate at which leukocytes are released from the bone marrow into the bloodstream, and speed up tissue repair. Too high of a body temperature, however, may cause damage by denaturing the body's enzymes. increase the rate at which leukocytes are released from the bone marrow into the bloodstream, and speed up tissue repair. Too high of a body temperature, however, may cause damage by denaturing the body's enzymes.

12 FEVER  Fever may have certain signs in relation to its course.  Fever in infectious diseases usually is of short duration  Long duration (weeks or months) is always a very serious problem. If it is not possible to determine the cause of fever at the beginning, it is called the fever of unknown origin (FUO). This term is used to describe fever lasting at least 2 weeks, reaching temperatures above 38,2, and the cause of the origin is uncertain.  Fever may last long in some infections with subacute or chronic course.

13 Stages in the Progression of Disease 1. No signs or symptoms 2. Prodormal illness Mild signs or symptoms Mild signs or symptoms Some chilling occur Some chilling occur 3. Acute identifiable signs and symptoms Intermittent fever Intermittent fever 4. Recovery Action of immune system Action of immune system Action of antibiotics Action of antibiotics 5. Convalescence

14 Stages in the Progression of Disease

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17 Manifestations of infectious disease  Result of Immune reactions Hematologic ( leukocytosis, anemia ) Hematologic ( leukocytosis, anemia ) Cardiac (tachycardia to heart failure) Cardiac (tachycardia to heart failure) Respiratory (hyperventilation) Respiratory (hyperventilation) Renal Renal Hepatic Hepatic Upper GI bleeding Upper GI bleeding

18 Case study 1  S. T. was seen by you in the Emergency Room in December  23 y/o medical student in Southern California  c/o sudden onset of fever, chills, malaise, headache, myalgia, sore throat, runny nose, sneezing  Room-mate has same symptoms  Exam: erythematous, inflammed tonsils,  no pharyngeal exudates  Throat culture: Group A streptococci

19 Case study 1 erythematous, inflammed tonsils

20 Case study 2  P. A. is a patient in the Intensive Care Unit  65 y/o man  Intubated, on respirator: good oxygenation  Nurse says that he hasn’t had fever or purulent sputum  Exam: clear breath sounds, no rhonchi nor rales  CXR: clear without infiltrates or effusions  Sputum Gram stain: mixed flora with Gram positive cocci; thin, long Gram negative rods  Sputum culture: normal respiratory flora, 2+ Pseudomonas aeruginosa

21 Case study 3  T. M. was referred to you by the Public Health Department  38 y/o woman  Private cook in Manhattan  In the past 10 years, 7 of the 8 families she has worked for have had outbreaks of illness:  Fever, malaise, headache, myalgia, maculopapular rash, bradycardia, constipation, bloody diarrhea  T. M. denies h/o similar illness and denies current symptoms  “But, Doctor, I’m not sick!”

22 Case study 3 maculopapular rash

23 Disease state: complex interaction between pathogen and host  1. If a bacterium is present, is it causing disease? a. Normal flora a. Normal flora b. Colonization b. Colonization c. Carrier state c. Carrier state d. Infection: d. Infection: i. Asymptomatici. Asymptomatic ii. Symptomaticii. Symptomatic  2. Is the bacterium capable of causing disease? a. Nonpathogen a. Nonpathogen b. Opportunistic pathogen b. Opportunistic pathogen c. Primary pathogen c. Primary pathogen

24 Case study 1: Viral pharyngitis + Group A strep normal respiratory flora  S. T. was seen by you in the Emergency Room in December  23 y/o medical student in Southern California  c/o sudden onset of fever, chills, malaise, headache, myalgia, sore throat, runny nose, sneezing  Room-mate has same symptoms  Exam: erythematous, inflammed tonsils,  no pharyngeal exudates  Throat culture: Group A streptococci

25 Case study 2: Colonization with Pseudomonas aeruginosa  P. A. is a patient in the Intensive Care Unit  65 y/o man  Intubated, on respirator: good oxygenation  Nurse says that he hasn’t had fever or purulent sputum  Exam: clear breath sounds, no rhonchi nor rales  CXR: clear without infiltrates or effusions  Sputum Gram stain: mixed flora with Gram positive cocci; thin, long Gram negative rods  Sputum culture: normal respiratory flora, 2+ Pseudomonas aeruginosa

26 Case study 3: Typhoid Mary Salmonella typhi carrier  T. M. was referred to you by the Public Health Department  38 y/o woman  Private cook in Manhattan  In the past 10 years, 7 of the 8 families she has worked for have had outbreaks of illness:  Fever, malaise, headache, myalgia, maculopapular rash, bradycardia, constipation, bloody diarrhea  T. M. denies h/o similar illness and denies current symptoms  “But, Doctor, I’m not sick!”

27 Outbreak 2001

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30  Virulence Factors that Promote Colonization and Invasion  Virulence factors that damage the host Exotoxins Exotoxins Endotoxins Endotoxins  Ability to resist innate immunity  Ability to evade adaptive immunity  Ability to induce autoimmune response

31 Virulence Factors that Promote Colonization and Invasion  Basic requirements: receptor + adhesin Receptor Receptor Specific carbohydrate or peptide residues on the cell surfaceSpecific carbohydrate or peptide residues on the cell surface Adhesin or adherence factor Adhesin or adherence factor A macromolecular component of the bacterial cell surface interacting to the receptorA macromolecular component of the bacterial cell surface interacting to the receptor

32  Surface proteins called adhesins in the bacterial cell wall bind to receptor molecules on the surface of a susceptible host cell enabling the bacterium to make intimate contact with the host cell, adhere, colonize, and resist flushing. Virulence Factors that Promote Colonization and Invasion

33  Specific adherence of bacteria to cell and tissue surfaces Tissue tropism Tissue tropism Strep mutans in dental plaque but not in the tongueStrep mutans in dental plaque but not in the tongue Species specificity Species specificity Neisseria gonorrheae limited to humansNeisseria gonorrheae limited to humans Genetic specificity within a species Genetic specificity within a species  Mechanism of specific adherence Reversible attachment – “docking” Reversible attachment – “docking” Non-reversible attachment – “anchoring” Non-reversible attachment – “anchoring” Virulence Factors that Promote Colonization and Invasion

34 (Tabulate according to the ff: Bacterium:Adherence Factor:Receptor (optional): Attachment Site: Disease)  Streptococcus pyogenes:  Protein F  Aminoterminus of fibronectin  Pharyngeal Epithelium  Sore Throat Virulence Factors that Promote Colonization and Invasion: Example

35 S. pyogenes fibronectin F-protein lipoteichoic acid

36  Fimbriae  Adhesins Protein F Protein F  Capsules  Invasins Cleaves secretory IgA (Glycosyl transferase) Cleaves secretory IgA (Glycosyl transferase) Spreading factors: Spreading factors: Hyaluronidase – attacks the interstitial cement of connective tissue by depolymerizing hyaluronic acidHyaluronidase – attacks the interstitial cement of connective tissue by depolymerizing hyaluronic acid CollagenaseCollagenase NeuraminidaseNeuraminidase Streptokinase and staphylokinaseStreptokinase and staphylokinase  Siderophores Low molecular weight compounds that chelate iron with very high affinity Low molecular weight compounds that chelate iron with very high affinity Competing for iron and other nutrients Competing for iron and other nutrients Virulence Factors that Promote Colonization and Invasion:

37 Virulence Factors that Promote Colonization and Invasion

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39 Glycocalyx  Polysaccharide or peptide slime Capsule Capsule Slime layer Slime layer  Functions: Resists phagocytosis Resists phagocytosis Enhanced attachment Enhanced attachment Virulence Factors that Promote Colonization and Invasion

40 Shigella Passing Through the Mucous Membrane and Invading Mucosal Epithelial Cells Virulence Factors that Promote Colonization and Invasion

41  Properties Secreted during exponential growth Secreted during exponential growth Protein toxins Protein toxins High biological activity High biological activity Exhibits specificity of action Exhibits specificity of action  Components A = active A = active B = binding B = binding Virulence Factors that Promote Damage to the Host: EXOTOXINS

42 A-B toxins Active Binding A Cell surface B

43 Binding and Entry of an A-B Toxin  A-B toxins consist of two parts, an A (active) component and a B (binding) component. The B component of the exotoxin binds to a receptor on the surface of a susceptible host cell. The exotoxin now enters the host cell, in this case by endocytosis, and causes harm by inactivating a host cell target protein through ADP-ribosylation.

44  Based on structure A-B prototype A-B prototype Botulinum toxin, diphtheria toxin, shiga toxin, tetanus toxinBotulinum toxin, diphtheria toxin, shiga toxin, tetanus toxin Membrane disrupting toxin Membrane disrupting toxin Lacks A & BLacks A & B Pore formingPore forming PhospholipasePhospholipase Superantigens Superantigens Virulence Factors that Promote Damage to the Host: EXOTOXINS

45 Superantigens  1. Some exotoxins are superantigens  2. Produced by bacteria and viruses  3. Action: polyclonal stimulation of subset of lymphocytes to divide and produce cytokines  4. Best known example: Staph Toxic Shock Syndrome Toxin-1 (TSST-1)  5. Also Strep exotoxins  6. Pyrogenic toxins cause fever (unlike other exotoxins)

46 2-subunit A-B exotoxin Neurotoxin: Clostridium botulinum Murray, P.R. et al. Medical Microbiology, 3rd edition, 1998, p. 156

47 Botulism Exotoxin Blocking Acetylcholine Release  The botulism exotoxin binds to the presynaptic neuron and blocks its release of acetylcholine. This causes a flaccid paralysis, a weakening of the involved muscles.

48 ProteasesProteases PhospholipasesPhospholipases Detergent-like actionDetergent-like action Membrane damaging exotoxins

49  Based on modes of action Breaks down cells Breaks down cells Alpha toxins, hemolysins, leukocidinsAlpha toxins, hemolysins, leukocidins Enhance microbial spread Enhance microbial spread Spreading factors: hyaluronidase, mucinase etcSpreading factors: hyaluronidase, mucinase etc Interfere in cellular metabolism Interfere in cellular metabolism Tetanus toxin, botulinum toxinTetanus toxin, botulinum toxin Virulence Factors that Promote Damage to the Host: EXOTOXINS

50  3 ways this can contribute to the progression of disease: Ingestion of preformed toxin Ingestion of preformed toxin Colonization of wound or mucosal surface followed by exotoxin production Colonization of wound or mucosal surface followed by exotoxin production Colonization of wound followed by local exotoxin production Colonization of wound followed by local exotoxin production Virulence Factors that Promote Damage to the Host: EXOTOXINS

51 Neutralization of Exotoxins

52 Evasion of host immune response: IgA protease  1. Cleaves IgA, which is important for mucosal immunity  2. An enzyme produced by Neisseria gonorrhoeae, Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae

53 Requirement for iron  1. Most iron in the body is intracellular In hemoglobin and myoglobin In hemoglobin and myoglobin  2. There is very little free iron Extracellular iron is bound to transferrin (in plasma) and lactoferrin (in milk and other secretions) Extracellular iron is bound to transferrin (in plasma) and lactoferrin (in milk and other secretions)  3. Some bacteria produce siderophores to capture iron e.g. Escherichia coli Siderophores bind iron with high affinity Siderophores bind iron with high affinity

54 Virulence Factors that Promote Damage to the Host: ENDOTOXINS  Outer membrane of the gram negative cell wall Lipid A:polysaccharide:O antigen Lipid A:polysaccharide:O antigen Toxicity is associated with Lipid A Toxicity is associated with Lipid A Immunogenicity is associated with the polysaccharide component Immunogenicity is associated with the polysaccharide component  Less potent, less specific  Does not form antitoxin  Released when the bacterial cell is damaged

55 GRAM NEGATIVE CELL ENVELOPE Cytoplasm Inner (cytoplasmic) membrane Outer Membrane (Major permeability barrier) Lipopolysaccharide Porin Braun lipoprotein Periplasmic space Degradative enzyme Periplasmic binding protein Permease

56 Septic shockSeptic shock hypotension (tissue pooling of fluids)hypotension (tissue pooling of fluids) disseminated intravascular coagulationdisseminated intravascular coagulation feverfever lack of effective oxygenationlack of effective oxygenation overall system failureoverall system failure SepticemiaSepticemia Septic shock

57 Exotoxin vs Endotoxin

58 Bacterial Pathogenesis  1. Microbial pathogens and their hosts have often co-evolved  2. Clinical disease a. Non-adapted host/pathogen a. Non-adapted host/pathogen b. May promote pathogen’s survival and transmission b. May promote pathogen’s survival and transmission c. Can result from host response to pathogen c. Can result from host response to pathogen  3. Extracellular bacteria produce toxins and enzymes

59 Bacterial Pathogenesis  4. Bacteria secrete proteins into host cells to modify host cell function  5. Intracellular bacteria must bind, enter and survive inside host cells  6. Pathogenic bacteria can evade the host immune response and have mechanisms for antibiotic resistance  7. Expression of virulence factors is often regulated in response to the environment and other signals

60 Bacterial Pathogenesis: Concepts  1. Virulence genes that encode virulence factors A virulence gene confers on a bacterium the ability to cause disease Pathogenic strains have acquired virulence genes that allow them to exploit the host as an environmental niche Examples of virulence factors are toxins, enzymes, type III secreted proteins, adhesins, siderophores Virulence factors are obvious targets for prevention or treatment strategies

61 Bacterial Pathogenesis: Concepts  2. Bacteria have found many way to modulate host cell function Exotoxins and type III secreted proteins are virulence factors with specific functions such as to kill host cells or induce the uptake of bacteria by the host cell Knowledge of these mechanisms can help explain the clinical disease caused by a particular bacterium, and the basis for prevention and treatment strategies

62 Bacterial Pathogenesis: Concepts  3. Toxins vs. toxoids vs. antitoxin (antitoxoid) Toxins are made by bacteria and have harmful effects on host cells A toxoid is the inactivated form of an exotoxin that can be used as a vaccine to elicit an immune response Toxoids were traditionally inactivated by heat or formaldehyde, but now can be genetically engineered Antitoxin is the antisera produced in response to the toxoid (can be from animals or humans) and can be given as treatment

63 Bacterial Pathogenesis: Concepts  4. Mechanisms of pathogenesis are conserved among bacteria Virulence genes that provide a selective advantage are spread among different bacterial genera and species by horizontal transfer These virulence genes are often located on mobile DNA elements such as plasmids or bacteriophages

64 … refresh...

65 Antibiotics BC Yang Antibiotics and vaccines are among the biggest medical advances since (Culver Pictures) For lecture only

66 A brief history of antibiotics 1495, mercury to treat syphilis. 1495, mercury to treat syphilis. 1630, quinine (chinchona tree) for malarial fever by South American Indians. 1630, quinine (chinchona tree) for malarial fever by South American Indians. 1889, Buillemin defined antibiosis. 1889, Buillemin defined antibiosis. 1910, Paul Ehrlich developed arsenical compound (Salvarsan) for syphilis, term: the chemical knife. 1910, Paul Ehrlich developed arsenical compound (Salvarsan) for syphilis, term: the chemical knife. 1929, Alexander Fleming found penicillin. 1929, Alexander Fleming found penicillin. 1935, Gerhard Domagk showed the value of sulfonamides. 1935, Gerhard Domagk showed the value of sulfonamides. 1940, Ernst Chain and Howard Flory demonstrated the effect of penicillin. 1940, Ernst Chain and Howard Flory demonstrated the effect of penicillin , then searching for new antibiotics , then searching for new antibiotics ~ recent year: modifying old drugs, finding new discipline in antibacterial combats ~ recent year: modifying old drugs, finding new discipline in antibacterial combats Early time in war: thanks penicillin, we can go home now Early time in war: thanks penicillin, we can go home now Now a day……….Oh eh?! Now a day……….Oh eh?!

67 Thanks to work by Alexander Fleming ( ), Howard Florey ( ) and Ernst Chain ( ), penicillin was first produced on a large scale for human use in At this time, the development of a pill that could reliably kill bacteria was a remarkable development and many lives were saved during World War II because this medication was available. E. ChainH. FloreyA. Fleming

68 A tale by A. Fleming  He took a sample of the mold from the contaminated plate. He found that it was from the penicillium family, later specified as Penicillium notatum. Fleming presented his findings in 1929, but they raised little interest. He published a report on penicillin and its potential uses in the British Journal of Experimental Pathology.

69 An ideal antibiotic Broad-spectrum Broad-spectrum Does not induce resistance Does not induce resistance Selective toxicity, low side effects Selective toxicity, low side effects Preserve normal microbial flora Preserve normal microbial flora

70 Definitions  Antimicrobial Inhibits growth of micro-organisms Inhibits growth of micro-organisms  Antibacterial Inhibits growth of bacteria Inhibits growth of bacteria  Antibiotic Inhibits growth of micro-organisms Inhibits growth of micro-organisms Made by other micro-organisms Made by other micro-organisms Usually extended to include synthetic drugs Usually extended to include synthetic drugs

71 Susceptibility test Tube dilution method Tube dilution method Minimal inhibitory concentration (MIC): the smallest amount of chemotherapeutic agent required to inhibit the growth of organism in vitro Minimal inhibitory concentration (MIC): the smallest amount of chemotherapeutic agent required to inhibit the growth of organism in vitro Disk diffusion method Disk diffusion method Zone of inhibition (ZOI): the correlation of ZOI and MIC has been established by FAD Zone of inhibition (ZOI): the correlation of ZOI and MIC has been established by FAD ETest. This commercially-prepared strip creates a gradient of antibiotic concentration when placed on an agar plate

72 Bacteriostatic vs Bactericidal  Bacteriostatic Reversible inhibition of growth Reversible inhibition of growth When the antibiotic is removed, almost all of the bacteria can replicate When the antibiotic is removed, almost all of the bacteria can replicate  Bactericidal Irreversible inhibition of growth Irreversible inhibition of growth When the antibiotic is removed, almost none of the bacteria (10 -7 to ) can replicate When the antibiotic is removed, almost none of the bacteria (10 -7 to ) can replicate

73 Guidance of antimicrobial therapy Minimum inhibitory concentration: lowest concentration of antibiotic that inhibits visible growth Minimum inhibitory concentration: lowest concentration of antibiotic that inhibits visible growth Minimum bactericidal concentration: lowest concentration of antibiotic that kills 99.9% of the inoculum Minimum bactericidal concentration: lowest concentration of antibiotic that kills 99.9% of the inoculum Serum bactericidal title: dilution of serum that kills 99.9% of the inoculum Serum bactericidal title: dilution of serum that kills 99.9% of the inoculum Synergy test: synergistic activity of multiple antibiotics Synergy test: synergistic activity of multiple antibiotics

74 Use of antibiotics; is it properly applied? Acute infections in outpatients Acute infections in hospitalized patients Chronic infection (tuberculosis, AIDS) Agriculture/veterinary medicine

75 In vitro: Factors for optimal antibiotic action pH of environment: pH of environment: Nitrofurantoin is more active in acid pH; sulfonamides and aminoglycoside are more active in alkaline pH. Nitrofurantoin is more active in acid pH; sulfonamides and aminoglycoside are more active in alkaline pH. Components of medium: Components of medium: Anionic detergents inhibit aminoglycosides, serum proteins bind to penicillin in varying degrees. Anionic detergents inhibit aminoglycosides, serum proteins bind to penicillin in varying degrees. Stability of drug: Stability of drug: Aminoglycosides and chloramphenical are stable for long period in vivo. Aminoglycosides and chloramphenical are stable for long period in vivo. Size of inoculums: Size of inoculums: The larger the bacterial inoculum, the greater the chance for resistnat mutant to emerge. The larger the bacterial inoculum, the greater the chance for resistnat mutant to emerge. Metablic activity of microorganisms: Metablic activity of microorganisms: Actively and rapidly growing organisms are more susceptible to drug action Actively and rapidly growing organisms are more susceptible to drug action BC Yang

76 Affecting factors in vivo Abscess: circulation is blocked off. Abscess: circulation is blocked off. Foreign bodies: obstruction of the urinary, biliary or respiratory tracts etc. Foreign bodies: obstruction of the urinary, biliary or respiratory tracts etc. Immunity. Immunity.

77 Sites of action BC Yang

78 Modes of action (1) Inhibitors of cell wall synthesis. Penicillins, cephalosporin, bacitracin, carbapenems and vancomycin. Inhibitors of cell wall synthesis. Penicillins, cephalosporin, bacitracin, carbapenems and vancomycin. Inhibitors of Cell Membrane. Polyenes - Amphotericin B, nystatin, and condicidin. Imidazole - Miconazole, ketoconazole and clotrimazole. Polymixin E and B. Inhibitors of Cell Membrane. Polyenes - Amphotericin B, nystatin, and condicidin. Imidazole - Miconazole, ketoconazole and clotrimazole. Polymixin E and B. Inhibitors of Protein Synthesis. Aminoglycosides - Streptomycin, gentamicin, neomycin and kanamycin. Tetracyclines - Chlortetracycline, oxytetracycline, doxycycline and minocycline. Erythromycin, lincomycin, chloramphenicol and clindamycin. Inhibitors of Protein Synthesis. Aminoglycosides - Streptomycin, gentamicin, neomycin and kanamycin. Tetracyclines - Chlortetracycline, oxytetracycline, doxycycline and minocycline. Erythromycin, lincomycin, chloramphenicol and clindamycin. Amphotericin Tetracyclines Aminoglycosides vancomycin For lecture only BC Yang

79 Modes of action (2) Inhibitors of metabolites (Antimetabolites). Sulfonamides - Sulfanilamide, sulfadiazine silver and sulfamethoxazole. Trimethoprim, ethambutol, isoniazid. Inhibitors of metabolites (Antimetabolites). Sulfonamides - Sulfanilamide, sulfadiazine silver and sulfamethoxazole. Trimethoprim, ethambutol, isoniazid. Inhibitors of nucleic acids (DNA/RNA polymerase). Quinolones - Nalidixic acid, norfloxacin and ciprofloxacin. Rifamycin and flucytosine. Inhibitors of nucleic acids (DNA/RNA polymerase). Quinolones - Nalidixic acid, norfloxacin and ciprofloxacin. Rifamycin and flucytosine. rifamycin For lecture only BC Yang

80 Resistance Natural (inherent) resistance  Structural barrel  Lack of target  Transport system Acquired resistance  Mutation  Gene exchange (conjugation in most)

81 Transferable antibiotic resistance in bacteria Reduced uptake into cell (chloramphenicol) Reduced uptake into cell (chloramphenicol) Active efflux from cell (tetracycline) Active efflux from cell (tetracycline) Modification of antibiotic targets (  -lactam, erythromycin) Modification of antibiotic targets (  -lactam, erythromycin) inactivation of antibiotic by anzymic modification: hydrolysis (  -lactam, erythromycin ); derivatization (aminoglycosides) inactivation of antibiotic by anzymic modification: hydrolysis (  -lactam, erythromycin ); derivatization (aminoglycosides) Sequestration of antibiotic by protein binding (  - lactam) Sequestration of antibiotic by protein binding (  - lactam) Metabolic bypass (sulfonamides) Metabolic bypass (sulfonamides) Overproduction of antibiotic target (titration: sulfonamides) Overproduction of antibiotic target (titration: sulfonamides)

82 Spread of resistance In most: Day-care, nursing homes, correctional facilities Sanitation, animal feeds (fecal-oral) Sexual/ Respiratory transmission International travel Immunosuppression

83 Some probable overuse/misuse of antibiotics Prophylatic use before surgery Empiric use (blinded use) Increased use of broad spectrum agents Pediatric use for viral infections Patients who do not complete course (chronic disease, eg. TB, AIDS) Antibiotics in animal feeds For lecture only BC Yang

84 Policy to deal drug resistance (1) Ideally, bacteriological management of clinical infection should involve: 1. Identification of causative organism 2. Sensitivity test 3. Follow-up the drug effect 4. Monitor antibiotic level to avoid toxicity. In reality, most patients requiring antimicrobial therapy are treated empirically. In serious infections immediate chemotherapy may be life-saving.

85 Policy to deal drug resistance (2) Periodic changes of antibiotics used might change selective pressure and thus avoid the emergence of resistance and retain the therapeutic value of antibiotics over a longer period. The unnecessary prophylactic or animal feeds use should be discouraged. Distribution of information on current/updated infectious microbes (consult microbiologists): use more targeted antibiotics Patient education

86 New antibiotics development Pharmaceutical industry putting resources back into discovery Liaisons with university researches Discoveries in microbial physiology and genetics offering new targets, new disciplines Combinational chemistry (mass screening) For lecture only BC Yang

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