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Disease causing factors?
-disease/pestilence was purported(expressed) to be caused by a # of factors...
- the wrath of God
- planetary alignments
- evil stares/ curses
- bad smells / marsh gases etc.
-miasmatic theory(dangerous/poisonous) of diseases held that diseases such as cholera/the Black Death were caused by miasma(Greek Language:"pollution"), a noxious form of "bad air".
Germ theory of disease
-Scientists began to work with microbes
-Establishing a connection btwn a microbe and an infection?
A golden age for microbiology
First vaccination (smallpox) in 1798 by Edward Jenner
Germ Theory in 1840 by Friedrich Henle
Bacterial/yeast characterization (lactic acid fermentation)/vaccines in 1857 by Louis Pasteur
Methods for study of bacteria in pure culture in 1881 by Robert Koche
Establishing a connection btwn a microbe and an infection?
-Robert Koch's Postulates!
-assisted in the connection btwn a microbe and disease thru a series of postulates involving isolation and experimental analysis of an infectious agent.
-a major step forward for identifying pathogenic microorganisms
-still relevant today
-however, there are certain shortcomings.
-Must be able to isolate organism from site of damage
- 1st Postulate
- -association of the microbe w/ the disease
ex: Isolation of Clostridium perfringens from a necrotic, gas-gangrene lesion.
Problems w/ the 1st Postulate.
1. EX of Chlamydia pneumoniae and atherosclerosis.
-conditions in which fatty material collects along the walls of arteries.
-thickens, hardens, and may eventually block the arteries.
-a common cause of mild respiratory tract infections, invades human cells, therefore leakage into the bloodstream is possible.
Where can C. pneumoniae be found?
-can be found at sites w/ atheroscierosis (but NOT all!) but also at sites of healthy blood vessel tissue.
Columbia University Medical Center Report
-subjects with higher levels of a specific bacteria associated with periodontal disease also had an increased carotid artery thickness, even after accounting for other cardiovascular risk factors
-Atheroscelerosis is also associated specifically with the type of bacteria that causes periodontal disease and not with other oral microbes.
One other explanation for C. pneumoniae...
-Bacteria that cause peridontal disease can migrate thruout body via bloodstream (esp. w/ vigorous tooth brushing) and stimulate the immune sys, causing inflammation that results in build up of deposits in arteries.
Problems w/ 1st Postulate
2. Example of Helicobacter pylori and ulcers
-almost all people in developing countries carries H. pylori, but only a few have ulcers (cancer)
-other factors (such as obtaining H. pylori later in life) may contribute to the disease.
-isolating bacterium in pure culture
pure culture: a culture containing a growth of a single kind of organism free 4rm other organisms...descendants of a single organism free form 4rm all other types of organisms..
How to obtain a pure culture...
transferring a small sample into new, sterile growth medium in such a manner as to disperse individual cells across the medium surface/ by thinning the sample many fold before inoculating new medium -- aka serial dilution to extinction-last man standing
Problems with the 2nd Postulate
-some bacteria are difficult or impossible to culture with present day methods. (not-yet-cultivable
- Chlamydia pneumoniae only grows inside human cells, with a special atmosphere. Normal media and conditions, not appropiate.
- Treponema pallidum, the cause of syphilis, has not been grown on lab media, testicles of rabbit used as growth chamber.
Probs with 2nd Postulate
-Molecular techniques may have to satisfy the 2nd postulate(PCR).
-circumvent the need for cultivation
DNA amplied can be accurately identified to species level demonstratng the presence of the organism in question.
-show that isolated bacterium causes disease in humans or animals.
PROBs with 3rd Post.
-difficult to find animal models for some diseases.
- -do not grow on artifical media
- -Mycobacterium leprae, only grows in the "9-banded armadillo"
-some pathogens cause diff. types of diseases in animal models
Salmonella typhi seems to cause disease in humans.
Salmonella typhimurium causes a typhoid fever-like disease in mice, but doesn't cause food poisoning as found in humans
PROBS with 3rd Post.
Barry Marshall (Australia) in early 1980s, went against established theory of stress and excess stomach acid causing stomach ulcers.
H, pylori could be isolated 4rm infected areas but..lack of animal model.
Marshall was having trouble infecting lab animals so he used himself, Japanese monkey are now used as models.
Responsible for 90% of gastric and duodenal ulcers.
-Re-isolate same bacterium from the intentionally infected animal.
-normally the easiest to satisfy.
-very imp. in establishing the fact that the same organism is responsible for the disease.
-much easier due to molecular methods ex. 16S rRNA gene sequencing.
-info from the 1st 4 Posts should lead to effective therapeutics against the particular organism.
- 5th Postulate
- -effective treatments that eliminate the organism and disease can be used to further implicate a microbe as the cause of disease.
Problems with Koch's Postulates...
-Koch designed postulates for one organism causing one disease.
- Microbiota Shift Disease
- -a change in a population/mixture of bacteria at a particular site can contribute/cause disease.
- ex: Peridontal disease, Bacterial Vaginosis, Irritable Bowel Syndrome.
-3rd postulate esp. is in difficulty here (proving the bacteria or a # of diff. organisms cause the disease.)
-however if a shift from one state to another can be reversed this may lead to the disease being cured.
-use of pre and pro-biotics?
Original postulates have weaknesses but are still fundamental to modern pathogenic microbiology.
-Molecular Koch's Postulates?
1. Gene/product should be found only in strains that cause the disease and not in avirulent strains.
2. gene should be isolated by "cloning."
- 3. Disruption of the gene should reduce or eliminate the virulence of the strain.
- -or the introduction of the gene in an avirulent strain should transform the strain to a virulent form.
4. The gene should be expressed when in animal or human volunteers.
# of deaths that occur at a given time, in a given group, or from a given cause.
-incidence of a disease in populations and includes both fatal and non-fatal cases.
-statistically more accurate as many diseases have a low mortality rate but can affect many individuals.
Diagnostic for Lyme Disease
Erthema migrans or Bullseye rash
bacteria occupy and multiply in a particular area of the human
colonization of the body by an organism capable of causing disease
an infection that produces symptoms
individual who may spread a disease.
Asymptomatic states: no observable symptoms
May be indivduals in the incubation period
may have recovered from disease but still harbor the pathogen; may have been so mild that little/no symptoms may have been observed.
Carrier of Salmonella typhi
in 1906 Typhoid Mary: a cook and hospital worker, refused to admit she was the carrier of typhoid fever, they had to arrest her.
Neisseria meningitidis (Carrier)
meningococcal meningitis 70-80% carrier rate
Pathogeneis of Bacterial Diseases
Reservoir: place to live before and after causing infection
Transported to host
Adhere to, colonize, and invade host
Multiply or complete life cycles on or in host and initially evade host defenses.
Leave host and return to reservoir or enter new host.
Damage to host-2 mechanisms
Mechanisms that causes the disease
Bacterial Mediated Pathogenesis
To cause disease, a pathogen must grow and reproduce in the host..?
-not strictly true with C. botulinum where a pre-formed is the causative agent (intoxication).
-a well adapted pathogen lives in balance w/ its host, taking what it needs and causing only minimum harm.
-such pathogens may cause chronic (long-term) infections in the host.
Pathogen can cause devastating acute diseases...how?
Transfer of antibiotic resistance
Transfer of toxin genes
Species barrier crossed (animal to human aka zonotic/zoonosis)
sites in which infectious agents remain viable and 4rm which infections can occur
a disease that primarily infects animals but is occasionally transmitted to humans
- human-to-human (may be much more virulent)
West Nile Disease (USA 2001)
Mostquitoes..feed on infected birds...humans...
birds=amplifying hosts, developing sufficient viral levels to transmit the infection to other biting mosquitoes which go on to infect other birds.
Increase susceptibility to West Nile disease..
a genetic factor: a MUTATION of the gene CCRS (delta 32) increases susceptibility to West Nile disease.
stands for severe acute respiratory virus syndrome
pandemic started in China 2002 infecting 37 countries in early 2003.
1000 deaths and 9000 cases
- sources: bats⇢
- civet cat⇢human
-frequently make the jump from animal to human hosts aka ebola, hendra, nipah viruses.
not everyone exposed to a disease-causing organism will get the disease
in 1 stain (bacterial/viral/fungal) to another (virulence)
.....lead to alternative disease outcomes.
- 4rm 1 host to another (immune system)
Interaction btwn host and pathogen may result in....
no disease = clearance of the organism
carrier state = no disease, but possible transmission
disease = huge range of affects; mild effect to death
- -organism (pathogen) enters and begins to grow in host
- Incubation period
- time btwn infection and apearance of disease symptoms ex headache, fever, feeling ill, diarrhea, etc.
(multiplicity), virulence and life cycle of pathogen, relationship of site of entry and focus of infection.
flu, food/water borne diseases -hours, TB, AIDS -years, decades.
disease is at its height, overty symptoms- fever and chills, vomiting, diarrhea.
symptoms are declining, temp falls, feeling of well-being returns; hours-days.
patients regains strength and returns to normal; hours,days,wks, or maybe yrs!
Why do we have infectious diseases?
1. Disease causing organisms are attempting to reach equilibrium w/ humans and not cause diseases
2. Humans are accidental hosts and interrupt the normal ecology for the microorganism. [Lyme Disease, Plague]
Disease is separated into parts of the body that are affected
Skin and eyes
Upper and Lower Respiratory Tracts
Cardiovascular and Lymphatic Systems
-can be classified by their mechanism of transmission
-but all have several common stages
-entry into a host⇢ escape 4rm host ⇢ travel to new host ↺
Routes of Transmission for Respiratory Pathogens
airborne -aerosols (liquid) or dust (particles)
Routes of Transmission for Intestinal Pathogens
contaminated food/water (feces)
Routes of Transmission for seasonal infections
insect vectors, animal and bird migrations
Direct host-to-host Transmission
-respiratory route and direct bodily contact
respiratory infections ⇢ infectious droplets
Human respiratory pathogens
humans are often the only reservoir (well adapted to host)
often initiate secondary probs that can be life threatening (viral infections lead to secondary bacterial infections)
accurate and rapid diagnosis required to limit host damage
immunization programs and antibiotic treatments are widely available.
S. pyrogenes, streptococcal pharyngitis, Group A strep.
(Strep throat) -toxin damages RBC
-more serious infections, toxic shock syndrome, scarlet fever, rheumatic fever.
Necrotizing fasciitis (NF), commonly known as flesh-eating disease/bacteria.
-Corynebacterium diphtheriae (largely eradicated (destroyed) in industrialized nations)
- -fungi (ringworm)
- -Staphylcocci (boils/pimples)
- -Streptococcus pyogenes (red irritated skin)
STDs (venereal diseases)
Sexually Transmitted Diseases
-Treponema pallidum (syphilis)
-Neisseria gonorrhoeae (gonorrhea)
trasmitted via bodily fluids in genitourinary tracts during sexual activity.
1/3 of cases - teenagers w/multiple sex partners
- symptoms can be minor so medical treatment is not sought
- social stigma- also inhibts people seeking aid, esp males!
can lead to infertility, cancer, heart disease birth defects, stillbirth, immune problems, death.
gram (-), spirochete (long twisted rod-shaped)
normally viewed using dark field microscopy
Some organism that cause STD's have no known animal reservoirs?
- -bc overtime it evolved to be a tight & close relationship with humans and and don't need add'l vectors for transmission.
- -we're the only animal to use sex othen than for reproduction
When are the significant peaks of STD throughout the year?
March-May:could be associated with sexual activity during spring break
August: summer sexual activity when adult supervision is poor
November: this time traces back to ancient days when giving birth is during Spring time
Indirect, Host-to-Host Transmission is?
facilitated by living (vectors) or inanimate agents.
examples: arthropods, vertebrates, inanimate agents, food & water aka disease vehicles.
What are examples of indirect, host-to-host transmission?
- 1. Arthropods (mites, ticks or fleas)
- 2. Vertebrates (dogs, cate or rodents -->cat scratch fever)
- 3. Inanimate agents (bedding,toys,books and surgical instruments)
- 4. food and water(aka disease vehicles)
mites,ticks or fleas
may not be hosts but simply carry the agent 4rm 1 host to another.
biting,sucking, transport in blood
Sometimes the pathogen replicated in the vector considered alternative host increases probability that a bite will lead to infection. -> amplifying host.
ex: West Nile Disease
Symptoms of Rickettsia prowazekii ?
Symptom of Borrelia recurrentis..
Symptom of Bartonella quintana
Once colonization takes place some common factors may be seen such as?
Invasion : attachment and colonization by the bacterial pathogen
-adherence: mediated by special molecules or structures (nonspecific and specific adherence)
-colonization: establishment of a site of microbial reproduction on/within host.
What is nonspecific adherence?
-involves nonspecific attractive forces which allow approach of bacterium to euk surface
- 1. hydrophoic interactions
- 2. electrostatic attractions
- 3. recruitment and trapping by biofilm polymer
Examples of specific adherence?
- 1. flagella/pilli
- 2. cell receptors and specialized proteins/structures called adhesins.
What are the mechanisms of specific adherence to cell/tissue surfaces?
permanent formation of many specific lock-and-key bonds btwn complementary molecules on each cell surface
How do clinical laboratories identify organisms?
-aim to grow, isolate and identify most routinely encountered pathogenic bacteria in 48 hrs of sampling. *this method is used frequently.
-these labs are present in all hospitals.
What organism is multiple-resistant?
Steps of Bacterial detection and identification after receiving the clinical sample...
2. Culture / Biochemical rxns
3. Detection of bacterial antigens and antibody response. (serology)
4. Detection of specific nucleic acids and proteins.
*Majority of clinical isolates identified in this manner.
Before taking samples from patient general practitioner / MD / Physician must...?
-ask patient history; on-set of symptoms, time-line, travel,etc.
What are the material's collected to identify the organism in the patient?
to obtain specimen correctly, site, aseptic technique to avoid contamination
- cerebrospinal fluid
transport media, anaerobic conditions maintained. rapid analysis
What are the different types of media?
- 1. Enriched nonselective media
- 2. Selective media
- 3. Differential media
- 4. Specialized media
The selection of appropriate sampling and culture conditions requires knowledge of...?
-bacterial ecology, physiology, nutrition, aerobe/anaerobe, complex nutritional requirements,etc.
growth is usually undertaken on general purpose media that supports most aerobic and facultative anaerobic bacteria
ex: blood agar, Chocolate agar, Mueller-Hinton
Chocolate Agar (CHOC) / Chocolate Blood Agar (CBA)
-non-selective, enriched growth medium.
-contains RBCs that have been lysed by slowly heating to 80°C
Haemophilus influenzae and Neisseria are growing fastidious respiratory bacteria that grow on what kind of agar?
Why do Haemophilus influenzae and Neisseria grow on Chocolate agar?
- -they need growth factors, AKA NAD (factor V) and hemlin (factor X).
- ---> NAD and hemlin are inside RBCs, thus prereq to growth is lysis of RBCS
-heat also inactivates enzymes which could otherwise degrade NAD.
How did Chocolate agar get its name?
the COLOR of it !!!!!!!
What is a Selective Media?
-it contains cmpds that inhibit growth of certain microoganisms while allowing growth of others interest.
-used with mixed bacterial populations
What is the purpose of using selective media?
selective media/incubation conditions
(O2,CO2, or anaerobic) increase/grow a particular organism or group of desired organisms. Counter-selective for undesired organism
- EX: Mannitol Salt agar--staphylococci
- EX: Lowentein-Jensen (LJ) medium -- mycobacterium
Differential Media is....
specialized media that allow identification of organisms based on their growth
on the media.
- (example : dyes that react to pH changes and produce a color change)
- EX: CHOMagar -- yeast Candida, coliforms
Example of Selective and Differential Media...
Eosin-methylene blue (EMB)
-isolation of Gram (-) bacteria while Gram (+) organisms are inhibited.
-Eosin: a dye that responds to pH changes, colorless-->black under acidic conditions (aka fermenters; contains lactose, but not glucose, as energy source)
Eosin Methylene Blue is selective and differential for?
for Gram (-)
btwn several genera.
- EX: Lactose fermenters: E.coli, Klebsiella and Enterobacter
- acidify media --> appear as black w/ green sheen
- EX: Lactose non-fermenters: Salmonella, Shigella, Pseudomonas
- appear translucent/pink
Specialized Media ?
-developed for organism some of which have metabolically fastidious requirements and contain specific growth factors
Other types of growth requirements:
- animal models
What are miniaturized biochemical kits used for?
- Detect the presence of enzymes and the utilization of particular carbohydrates that serve as energy sources
What are produced when organisms are grown?
Kings A – blue-green fluorescent phenazine pyocyanin
Kings B -yellow-green fluorescent pyoverdin, a pigment that can be oxidized to yellow
Fluoresces under UV light
Advanced methods of clinical microbiology...
1.Fatyy Acid Profiles
- Reference Profiles (can be linked to DNA sequences)
- MIDI developing a method for direct analysis of sputum negating problems of slow growth.
- Mycolic acid -3 forms in M. tuberculosis
2.Matrix-assisted laser desorption ionisation-time of flight (MALDI-TOF)
- mass spectroscopy uses 16s ribosomal proteins
- organisms identification w/in 20 min of starting the process
- European lab have changed method saving money and time--US eventually will.
What changing conditions do diagnostic labs need to respond to?
- larger populations
- more diseases
- emerging diseases
- difficult to grow/not-yet-cultivable organisms
What are the traditional labs?
- stacks of petri dishes
- many diff specialized media/conditions
- specialist knowledge
tend to be more rapid
- use same reagents
- -more economical
- -more simple lab organization/less cluttered lab
- less specialized knowledge required
- -less training required more staff can read results
- safety issues
- -no need to culture large amounts potentially infectious & dangerous organisms
What are the many methods based on 16S rRNA gene ?
- • Present in all living organisms
- • Performs same function
- - ancient molecule
- - changes at a proportional rate, molecular clock
- • Conserved and variable regions ?
- - Allows sequences to be aligned to show regions of similarity and differences
Different approaches of 16S rRNA gene in the labs?
- 1. Direct sequencing
- 2. PCR amplification (amplify 16S rRNA genes, cloned and sequenced.
- 3. Fingerprinting methods (Restriction Fragment Length Polymorphism -RFLP & Random Amplified Polymorphic DNA profile -RAPD fingerprinting)
Difference between the Restriction Fragment Length Polymorphism and the Amplified Polymorphic DNA profile is?
RFLP uses specific primers in PCR rxn while RAPD uses random primers in PCR rxn
What is the purpose of Pulsed-Field Gel Electrophoresis?
1. Separate large DNA molecules using infrequent cutting restriction enzymes.
2. Often used to track hospital-associated organisms
Staphylcoccus, Candida, E. coli, Enterococcus, Enterobacter
CDC surveillance of C. Difficile or di-fecally !
Automatic alerts for novel profiles of more virulent strains causing new outbreaks.
Multilocus Sequence Typing (MLST)
1. 7 house-keeping genes are sequenced
2. Variation within the internal segments is used to assign different alleles
3. Strains are defined as sequence types (STs)
Average of 42 alleles present in each locus, ability to define 200 billion STs
- Used with S. aureus
- Web-site -database from 25 countries, over 1000 strains
- --Is now being used to construct phylogenetic trees
Multilocus Restriction Fragment Typing
1. Similar to MLST, MRFT also uses housekeeping genes
2. Amplicons are directly cut with restriction enzymes and run out on gel
3. Less expensive, more time efficient and requires less specialized equipment and therefore more suitable for the routine clinical lab.
4. But cannot distinguish fine strain differences
DNA bound to nylon membrane and then probes are hybridized to target sequences
Which methods have the highest discriminatory power for strain delineation for hospital-associated pathogens ?
PFGE, MLST and PCR-based methods
Types of samples taken:
Blood: Standard procedure
20 mls taken into 2 blood culture bottles containing anticoagulant
and general purpose media.
One incubated aerobicially
and the 2nd anaerobically
- 1-5days; automatic examination several times/hr, turbidity and CO2 production,
- subculture is +ve. (some can contain chemicals to lyse cells and release
- intracellular pathogens).
presence of bacteria in the blood --extremely uncommon
a blood infection resulting 4rm growth of a pathogenic organism entering the blood 4rm a focus of infection, multiplying, and traveling to various body tissues to initiate new infections...
affecting ENTIRE body, severe systemic symptoms, fever, chills..
What are Gram (-) Blood Pathogens?
- Pseudomonas aeruginosa
- Klebsiella pneumoniae
What are Gram (+) Blood Pathogens?
- Staphylococcus aureus
- Streptococcus pyogenes
What disease is often caused by normal flora that's common in females and Why?
- UTI (normally result 4rm organisms ascending urethra into bladder)
- complex microflora in the vagina
- shorter distance to the outside environment
Methods for UTI indicators have been developed...
dipsticks w/substrates that change color can be used
-Nitrate reduction occurs w/ significant #'s of bacteria present -105 organism
Glucose, bilirubin, ketones, specific gravity, blood, pH, protein, urobilinogen, nitrate, esterase
often combined with test for esterase produced by leukocytes --> indication of an immune system response to an infection
Gram (-) UT pathogens
Gram (+) UT pathogens
- Staphylcoccus saprophyticus
- Enterococcus faecalis
What if no bacteria are found, but urinary tract infection
symptoms persistent……. ?
- Test for organisms that are harder to culture.
- specialized culture methods for Neisseria, Chlamydia etc.
or use serological tests
and molecular probes that circumvent need for cultivation.
What are the Gram (+) pathogens?
What are the Gram (-) pathogens?
- E. coli
- Campylobacter jejuni
Wounds and Abscesses
Traumatic injuries -- animal/human bits, burns, cuts or penetration of foreign objects - care needed to recover relevant pathogen and results interpreted carefully. Frequent contamination with normal flora.
correct sampling procedures-aspirate pus w/needle. aerobes and anaerobes found.
What are the Aerobe Wound / Abscess Pathogens?
Staphylococcus aureus (Gram(+))
Pseudomonas aeruginosa (Gram(-))
What are the anaerobe wound / abscess pathogens?
What are common causes of infection and require special isolation and culture methods?
Obligate anaerobes require richer media and special environments (gas mix of N2,H2, and CO2, anaerobic conditions maintained in jars and chambers)
contain reducing agents (cysteine and thioglycollate)
contain redox indicator (resazurin-colorless when reduced and pink when oxidized - presence of O2)
What does a Paliadium catalyst do?
-removes residual O2; combines H2 to produce H2O.
-culture time is normally increased 7-14 days
What are normally opportunistic in nature?
exceptions: Clostridium tetani (tetanus) and Clostridium perfringens (gas gangrene and food poisoning)
inflammation of peritoneum (thin tissue that lines inner wall of abdomen and covers most of the ab. organs)
may result 4rm infection (often due to rupture of hollow organ as may occur in abdominal trauma, appendicitis/ surgical error) or 4rm non-infectious process.
How are opportunistic infections caused ?
- by organisms that usually do not cause disease in a person w/ a healthy immune sys, but can effect people with poorly functioning/suppressed immune sys.
- -Need an "opportunity" to infect a person.
Water quality and Coliforms
-screenig w/indicator strain
-facultatively aerobic, gram (-), non-spore forming, rod-shaped bacteria that ferment lactose w/ gas formation w/in 48 hrs at 36°C
Coliform taxonomically difference
- Enterobacter - usually harmless
- Escherichia coli - common intestinal organism / pathogen
- Klebsiella pneumoniae - less common pathogenic intestinal organism
2 Methods for testing coliforms?
- MPN (most-prob-#)
- Membrane filtration
Most Probable Number
-a method to test for coliform
-liquid culture: serial dilution of sample to determine the highest dilution growth-calc # of organisms present
- -100 ml water sample passed thru filter
- -placed on Eosin-methylene blue (EMB)
- -dark colonies w/ shiny appearance are coliforms
Safe Drinking Water Act led to what?
- US Environmental Protection Agency (EPA)
- -improved water quality
-began in 1906 and drops typhoid cases down from 10,000 to 1,000
- -began in 1913
- -drops typhoid cases
Antimicrobial Drug Susceptibility Testing
(tools of trade continued)
-pathogens should be tested for susceptibility to individual antibiotics to ensure appropiate therapy.
-standard procedure that assesses antimicrobial activity are called disk diffusion method (Kirby-Bauer method and MIC(Minimum Inhibitory Concentration))
What is a antibiogram?
result of a laboratory testing for the sensitivity of an isolated of an isolated bacterial strain to different antibiotics.
-physicians use as guide to see which antibiotic will be most affective in their particular hospital against particular strains present.
-each hospital has a chart of most common organisms (which needs to be updated on a regular basis)
-epidemiologists can also track spread of resistant strains
-produced by microorganisms and don't appear in the drug store!
-are ANTI-bacterial that have no affect against viruses.
-few exceptions are inaffective against fungi and protozoa BUT there are antiviral, anti fungal and anti protozoal drugs
Why do physicians dispense antibiotics with colds and flu?
Virus can damage ciliated cells and compromise our immune sys allowing bacterial secondary infections.
Isoniazid only affects organism in the genus Mycobacterium because....
The target is mycolic acid (isoniazid is an agent that is very specific and affect only a single genus.
it kills bacteria
it stops bacterial growth
Antibiotics have low ____________ weight. Whether if it is ingested or injected.
Selective toxicity is...
the ability to inhibit or kill without adversely affecting the host, but notable exceptions.
Specific acting on pivotal enzymes or process....
DNA, Protein, Cell-Wall synthesis
What are the 1st generation of antibiotics?
1. Natural products isolated from Bacteria (soil isolates) and Fungi
Isolates spotted on range of indicator organism (representing groups of pathogens)
What is combinatorial chemistry ?
its known as the "2nd generation antibiotics".
-The known "core" structures are used to add chemical side groups randomly to create derivatives.
-Tested against bacterial protein targets in vitro / silico (lab/computer simulations)
- Fluorine derivative of Nalidixic Acid.
- "F" makes the compound more soluble (in blood)
Rational drug design is....
looking at the target rather than the drug.
What structure of the target molecule is determined and what side chains of antibiotics are designed against this?
Crystal structure of the target molecule is determined and chemical side-chains of antibiotics designed against this.
What are the drawbacks of Rational drug design and combinatorial chemistry?
cmpds synthesized may be perfect match in lab but not guaranteed to reach this target in an intact bacterial cell!
What are the alternative sources besides rational drug designing and combinatorial chemistry?
Soil organisms--actinomycetes, Streptomyces species.
also look at other environments, diff groups of organisms normally sceened for antmicrobial substances.
What do genome sequencing and computerized design do?
- -search for -antibiotic biosynthetic genes.
- ex. Mycobacterium tuberculosis and Flavobacterium
- Structural imaging technology--design cmpds to specifically interact with targets and tested in "silico."
What are some ideal targets for antibiotic action ?
-structures or processes that are fundamental to cells of pathogenic microorganisms
-should not be present in euk cells / be sufficiently diff so little or no cross-reactivty occurs.
Other factors to consider about antibiotics...
stability in the body
rate of clearance from blood
ease of application - taken orally / intravenously
localized / systemic distribution
ability to penetrate blood-brain barrier
ability to enter host cells (obligate intracellular pathogens)
the capacity to produce a desired effect from a known amt.
-indicates therapeutic effect of a given treatment / intervention.
The measure of the fraction of the drug that enters the systemic circulation and reaches the site of action / at the rate it does so is known as.....
Why is alcohol consumption while taking antibiotics not recommended ?
-Alcohol interferes with activity/metabolization of antibiotics.
-May affect activity of liver enzymes; which break down antibiotics.
-Some certain antibiotics react chemically with alcohol, leading to serious side effects, including severe vomiting, nausea, and shortness of breath.
2 ways that antibiotics could interfere the efficiency of birth control pills..
thru induction of hepatic enzymes by antifungal medication griseofulvin
broad-spectrum antibiotic rifampicin has been shown to occur.
What are narrow-spectrum antibiotics?
-active against SELECT group of bacterial types
What are broad-spectrum antibiotics?
-active against WIDER # of bacterial types (may be used to treat a variety of infectious diseases--most useful when infecting agent is UNKNOWN/ infection is life threatening, time is of the essence).
What are aminoglycosides ?
-examples of broad spectrum antibiotics
Problem about broad-spectrum antibiotics...
may select for resistance in resident flora, majority of hospital-acquired infections.
Examples of antibiotics that may disturb normal flora..
majority of hospital-acquired infections...
ex: Vancomycin, bacteriocidal for (+), used for penicillin resistant Staphylococcus, Bacillus, and Clostridium.
OVER-use of Vancomycin against Staph. aureus, Vancomycin-Resistant Enterococci species (40% mortality)
Problem about Broad-spectrum Antibiotics
-disrupt normal commensal microbiota
Examples that disrupt normal commensal micriobiota
- - C. difficile -major killer in hospitals
- - spore former and grows rapidly and out competes the commensal flora
- Clostridium difficule Associated Diarrhea - CDAD
Narrow spectrum works on....
a particular group of bacteria and a specific target.
Examples of narrow spectrum...
Fluoroquinolones : can enter phagocytes and kill intracellular pathogens
Rifampin - mycobacteria
Treponema i appear to be naturally resistant!
β-lactam antibiotics share a structural component which is the .... ?
what group is cleaved off of the original penicillin structure to create derivatives?
N-actyl group : endow differences in properties, route of administration, broader spectrum (entry into Gram (-) bacteria), resistant to acids etc.
-allergic rxns to penicillin and cephalosporins, overcome by monobactams that are structurally diff.
What are the "cradle-to-grave" drugs ?
Penicillin - small child with earache
Ampicillin - women with UTI
Penicillin derivative - elderly man w/bacterial pneumonia
What is a target in synthesis of peptidoglycan?
Fosfomycin: blocks conversion of UDP-NAG to UDP-NAM
N-acetylglucosamine --> N-acetylmuramine
What is a target in synthesis of peptidoglycan?
Bacitracin: inhibits deposphorylation and recycling of pyrophosphobactoprenol (membrane lipid anchor).
What is a target in synthesis of peptidoglycan?
β-lactams, vancomycin -blocks transpeptidation