Meeting 6 Disease Manifestations Virulence Factors Antimicrobial resistance 1 Aug 2009.
Transcript of Meeting 6 Disease Manifestations Virulence Factors Antimicrobial resistance 1 Aug 2009.
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Meeting 6
Disease ManifestationsVirulence Factors
Antimicrobial resistance
1 Aug 2009
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Manifestations of infectious disease Classic
Signs• Fever, swelling, rashes, vomiting, diarrhea• Skin signs: lesions, erythema, papule (pimple), vesicles,
pustule, ulcer or erosion or abscess Symptoms
• Pain, headache, nausea, malais Inflammation
Result of Immune reactions Hematologic ( leukocytosis, anemia ) Cardiac (tachycardia to heart failure) Respiratory (hyperventilation) Renal Hepatic Upper GI bleeding
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Manifestations of infectious disease
Classic Signs
• Fever, swelling, rashes, vomiting, diarrhea
• Skin signs: lesions, erythema, papule (pimple), vesicles, pustule, ulcer or erosion or abscess
Symptoms• Pain, headache,
nausea, malaise
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
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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.
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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.
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Elevated lesion
TUMOR is a solid mass of the skin
or subcutaneous tissue; it is larger than a nodule.
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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.
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Depressed lesion
ATROPHY Atrophy is thinning or
absence of the epidermis or subcutaneous fat.
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Depressed lesion
EROSION Erosions are slightly
depressed areas of skin in which part or all of the epidermis has been lost
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Depressed lesion
ULCERATION occur when there is
necrosis of the epidermis and dermis and sometimes of the underlying subcutaneous tissue.
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FEVER
1. Fever increases 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, speed up the multiplication of lymphocytes, 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.
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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.
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Stages in the Progression of Disease
1. No signs or symptoms2. Prodormal illness
Mild signs or symptoms Some chilling occur
3. Acute identifiable signs and symptoms Intermittent fever
4. Recovery Action of immune system Action of antibiotics
5. Convalescence
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Stages in the Progression of Disease
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Stage: Acute pyogenic: Chronic
granulomatous:
Encounter Often with symptomatic patient or after trauma.
Often impossible to pin down.
Entry/ Establishment
Obvious if associated with trauma. Adhesins and entry mechanisms well-studied.
Not well understood but uptake into macrophages a common feature.
Spread Often associated with damage.
Usually imperceptible.
Multiplication Rapid. Slow.
Damage Acute inflammation, toxins.
Cell mediated immunity.
Outcome Easy to treat with antibiotics.
Difficult.
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Manifestations of infectious disease
Result of Immune reactions
Hematologic ( leukocytosis, anemia ) Cardiac (tachycardia to heart failure) Respiratory (hyperventilation) Renal Hepatic Upper GI bleeding
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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
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Case study 1
erythematous, inflammed tonsils
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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
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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!”
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Case study 3
maculopapular rash
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Disease state: complex interaction between pathogen and host
1. If a bacterium is present, is it causing disease? a. Normal flora b. Colonization c. Carrier state d. Infection:
• i. Asymptomatic• ii. Symptomatic
2. Is the bacterium capable of causing disease? a. Nonpathogen b. Opportunistic pathogen c. Primary pathogen
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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
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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
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Case study 3: Typhoid MarySalmonella 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!”
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Outbreak 2001
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Virulence Factors that Promote Colonization and Invasion
Virulence factors that damage the host Exotoxins Endotoxins
Ability to resist innate immunity Ability to evade adaptive immunity Ability to induce autoimmune response
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Virulence Factors that Promote Colonization and Invasion
Basic requirements: receptor + adhesin Receptor
• Specific carbohydrate or peptide residues on the cell surface
Adhesin or adherence factor• A macromolecular component of the bacterial cell
surface interacting to the receptor
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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
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Specific adherence of bacteria to cell and tissue surfaces
Tissue tropism• Strep mutans in dental plaque but not in the tongue
Species specificity• Neisseria gonorrheae limited to humans
Genetic specificity within a species
Mechanism of specific adherence Reversible attachment – “docking” Non-reversible attachment – “anchoring”
Virulence Factors that Promote Colonization and Invasion
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(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
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S. pyogenes
fibronectin
F-proteinlipoteichoic acid
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Fimbriae Adhesins
Protein F Capsules Invasins
Cleaves secretory IgA (Glycosyl transferase) Spreading factors:
• Hyaluronidase – attacks the interstitial cement of connective tissue by depolymerizing hyaluronic acid
• Collagenase• Neuraminidase• Streptokinase and staphylokinase
Siderophores Low molecular weight compounds that chelate iron with very high affinity Competing for iron and other nutrients
Virulence Factors that Promote Colonization and Invasion:
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AdhesionAdhesion
adhesinadhesin
EPITHELIUMEPITHELIUM
receptorreceptor
BACTERIUMBACTERIUM
Virulence Factors that Promote Colonization and Invasion
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Virulence Factors that Promote Colonization and Invasion
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Glycocalyx Polysaccharide
or peptide slime Capsule Slime layer
Functions: Resists
phagocytosis Enhanced
attachment
Virulence Factors that Promote Colonization and Invasion
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Shigella Passing Through the Mucous Membraneand Invading Mucosal Epithelial Cells
Virulence Factors that Promote Colonization and Invasion
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Properties Secreted during exponential growth Protein toxins High biological activity Exhibits specificity of action
Components A = active B = binding
Virulence Factors that Promote Damage to the Host: EXOTOXINS
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A-B toxins
ActiveBinding
A
Cell surface
B
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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.
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Based on structure A-B prototype
• Botulinum toxin, diphtheria toxin, shiga toxin, tetanus toxin
Membrane disrupting toxin• Lacks A & B• Pore forming• Phospholipase
Superantigens
Virulence Factors that Promote Damage to the Host: EXOTOXINS
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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)
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2-subunit A-B exotoxinNeurotoxin: Clostridium
botulinum
Murray, P.R. et al. Medical Microbiology, 3rd edition, 1998, p. 156
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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.
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• Proteases • Phospholipases• Detergent-like action
Membrane damaging exotoxins
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Based on modes of action Breaks down cells
• Alpha toxins, hemolysins, leukocidins Enhance microbial spread
• Spreading factors: hyaluronidase, mucinase etc Interfere in cellular metabolism
• Tetanus toxin, botulinum toxin
Virulence Factors that Promote Damage to the Host: EXOTOXINS
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3 ways this can contribute to the progression of disease:
Ingestion of preformed toxin Colonization of wound or mucosal surface
followed by exotoxin production Colonization of wound followed by local
exotoxin production
Virulence Factors that Promote Damage to the Host: EXOTOXINS
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Neutralization of Exotoxins
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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
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Requirement for iron
1. Most iron in the body is intracellular 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)
3. Some bacteria produce siderophores to capture iron e.g. Escherichia coli
Siderophores bind iron with high affinity
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Virulence Factors that Promote Damage to the Host: ENDOTOXINS
Outer membrane of the gram negative cell wall Lipid A:polysaccharide:O antigen Toxicity is associated with Lipid A Immunogenicity is associated with the polysaccharide
component Less potent, less specific Does not form antitoxin Released when the bacterial cell is damaged
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GRAM NEGATIVE CELL ENVELOPE
Cytoplasm
Inner (cytoplasmic) membrane
Outer Membrane(Major permeability barrier) LipopolysaccharidePorin
Braun lipoprotein
Periplasmic space Degradative enzyme
Periplasmic binding proteinPermease
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• Septic shock • hypotension (tissue pooling of fluids)• disseminated intravascular coagulation• fever• lack of effective oxygenation• overall system failure
• Septicemia
Septic shock
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Exotoxin vs Endotoxin
Exotoxin Endotoxin
Gram negative & positive Gram negative only
Secreted Liberated upon bacterial lysis
Highly toxic Not as toxic
Highly antigenic Less antigenic
Inactivated to form toxoid Heat stable
Anti-toxoid often protective No toxoid
No fever (except pyrogenic toxins)
Fever and septic shock
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Bacterial Pathogenesis 1. Microbial pathogens and their hosts
have often co-evolved
2. Clinical disease a. Non-adapted host/pathogen b. May promote pathogen’s survival and
transmission c. Can result from host response to pathogen
3. Extracellular bacteria produce toxins and enzymes
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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
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Bacterial Pathogenesis: Concepts 1. Virulence genes that encode virulence
factorsA 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
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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
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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
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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
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Antibiotics
BC Yang
Antibiotics and vaccines are among the biggest medical advances since 1000. (Culver Pictures)
For lecture only
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A brief history of antibiotics 1495, mercury to treat syphilis. 1630, quinine (chinchona tree) for malarial fever by South
American Indians. 1889, Buillemin defined antibiosis. 1910, Paul Ehrlich developed arsenical compound (Salvarsan) for
syphilis, term: the chemical knife. 1929, Alexander Fleming found penicillin. 1935, Gerhard Domagk showed the value of sulfonamides. 1940, Ernst Chain and Howard Flory demonstrated the effect of
penicillin. 1940-1970, then searching for new antibiotics ~ recent year: modifying old drugs, finding new discipline in
antibacterial combats Early time in war: thanks penicillin, we can go home now Now a day……….Oh eh?!
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Thanks to work by Alexander Fleming (1881-1955), Howard Florey ( 1898-1968) and Ernst Chain (1906-1979), penicillin was first produced on a large scale for human use in 1943. 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. Chain H. FloreyA. Fleming
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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.
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An ideal antibiotic
Broad-spectrum Does not induce resistance Selective toxicity, low side effects Preserve normal microbial flora
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Definitions Antimicrobial
Inhibits growth of micro-organisms Antibacterial
Inhibits growth of bacteria Antibiotic
Inhibits growth of micro-organisms Made by other micro-organisms Usually extended to include synthetic
drugs
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Susceptibility test
Tube dilution method Minimal inhibitory
concentration (MIC): the smallest amount of chemotherapeutic agent required to inhibit the growth of organism in vitro
Disk diffusion method 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
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Bacteriostatic vs Bactericidal
Bacteriostatic Reversible inhibition of growth When the antibiotic is removed, almost all of
the bacteria can replicate Bactericidal
Irreversible inhibition of growth When the antibiotic is removed, almost none
of the bacteria (10-7 to 10-3) can replicate
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Guidance of antimicrobial therapy
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
Serum bactericidal title: dilution of serum that kills 99.9% of the inoculum
Synergy test: synergistic activity of multiple antibiotics
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Use of antibiotics; is it properly applied?
Acute infections in outpatients
Acute infections in hospitalized patients
Chronic infection (tuberculosis, AIDS)
Agriculture/veterinary medicine
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In vitro: Factors for optimal antibiotic action
pH of environment: Nitrofurantoin is more active in acid pH; sulfonamides and
aminoglycoside are more active in alkaline pH. Components of medium:
Anionic detergents inhibit aminoglycosides, serum proteins bind to penicillin in varying degrees.
Stability of drug: Aminoglycosides and chloramphenical are stable for long
period in vivo. Size of inoculums:
The larger the bacterial inoculum, the greater the chance for resistnat mutant to emerge.
Metablic activity of microorganisms: Actively and rapidly growing organisms are more
susceptible to drug action
BC Yang
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Affecting factors in vivo
Abscess: circulation is blocked off.
Foreign bodies: obstruction of the
urinary, biliary or respiratory tracts
etc.
Immunity.
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Sites of actionBC Yang
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Modes of action (1)
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 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
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Modes of action (2)
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.
rifamycin
For lecture only BC Yang
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Resistance
Natural (inherent) resistanceStructural barrelLack of targetTransport system
Acquired resistanceMutationGene exchange (conjugation in most)
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Transferable antibiotic resistance in bacteria
Reduced uptake into cell (chloramphenicol) Active efflux from cell (tetracycline) Modification of antibiotic targets (b-lactam,
erythromycin) inactivation of antibiotic by anzymic
modification: hydrolysis (b-lactam, erythromycin); derivatization (aminoglycosides)
Sequestration of antibiotic by protein binding (b-lactam)
Metabolic bypass (sulfonamides) Overproduction of antibiotic target (titration:
sulfonamides)
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Spread of resistanceIn most:
Day-care, nursing homes,
correctional facilities Sanitation, animal feeds (fecal-oral) Sexual/ Respiratory transmission International travel Immunosuppression
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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
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Policy to deal drug resistance (1)
Ideally, bacteriological management of clinical infection should involve:
1. Identification of causative organism2. Sensitivity test3. Follow-up the drug effect4. 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.
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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
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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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