Immuno - Antimicrobial Therapies Flashcards
What is prontosil?
antibacterial drug used for blood infection
What type of antibiotic is prontosil?
Sulphonamide
What are some sulphonamide antibiotics?
Sulphamethoxazole
What are sulphonamides sometimes used together with
Trimethoprim
What is prontosil used to treat?
UTIs. RTIs, bacteraemia, HIV prophylaxis
What is prontosil only effective against in terms of bacterial structure?
Only effective against gram negative bacteria
What is an antibiotic?
Antimicrobial agent produced by microorganism that kills or inhibits another microorganism
What is an antimicrobial?
Chemical that selectively kills or inhibits microbes
What is a bactericidal?
Kills bacteria
What is a bacteriostatic?
Stops the growth of bacteria
What is an antiseptic?
Kills or inhibits microbes - usually applied topically to prevent infection.
What can we attribute to antimicrobial resistance?
Lack of new antibiotics and countries prescribing high levels of antibiotics to their patients
What does AMR lead to?
Increased mortality, morbidity and cost/burden on society.
How does AMR lead to increased time to effective therapy?
We must spend more time trying to figure out what the patient responds well to
How does AMR lead to requirement for additional approaches?
For example, we may need surgery as the patient will not respond well to antibiotics
How does AMR lead to use of expensive therapy?
We must try out many new methods of treatment rather than simply administering antibiotics
How does AMR lead to use of more toxic drugs?
E.g. vancomycin is needed which is toxic, to generate the same response as the normal antibiotic that a microbe has become resistant to.
How does AMR lead to use of less effective antibiotics?
We must resort to second choice antibiotics, as bacteria have developed resistance to our antibiotic of choice.
What are aminogylcosides?
Potent bactericidal activity - target protein synthesis, membrane integrity and RNA proof reading.
What does a lack of RNA proof reading lead to?
Abhorrent proteins which damage the membrane
What is the downside of aminoglycosides?
They are toxic and can sometimes cause hearing loss - they are only used as other antibiotics are ineffective.
What is Rifampicin?
Bactericidal - targets the RpoB subunit of RNA polymerase and is very effective
What is the downside of Rifampicin?
Spontaneous resistance can occur and can sometimes cause orange/red secretions from the patient
What is vancomycin?
Bactericidal that targets the lipid component of the cell wall biosynthesis and the wall cross linking via D-ala-residues.
What is the downside of vancomycin?
Very toxic and needs to be given intravenously
When do we use vancomycin?
Due to resistance e.g. MRSA
What is linezolid?
Bacteriostatic that inhibits the initiation of protein synthesis by binding to the 50s rRNA subunit.
What is a limitation of linezolid?
Only affects gram positive but not negative
What is daptomycin?
Bactericidal that targets the membrane
What are some of the limitations of daptomycin?
Only positive against gram positive bacteria and is relatively toxic therefore needs to be given intravenously in inpatient settings
What are beta-lactams?
Interfere with the synthesis of the peptidoglycan component of the bacterial cell wall
What are examples of beta-lactams?
Penicillin
Methicillin
How are antibiotics selectively toxic?
Machinery that the antibiotics target are specific to the targeted bacteria.
What are macrolides?
Affect both gram positive and negative bacteria, and target the 50s subunit of ribosomes to prevent amino-acyl transfer, thus truncating polypeptides to stop growth.
What are some examples of macrolides?
Erythromycin
Azithromycin
What are Quinolones?
Synthetic broad spectrum antibiotics
Target the DNA gyrase in gram negative bacteria, and topoisomerase 4 in positive bacteria - causes DNA damage and subsequent death of an organism.
What are the main misconceptions at the dawn of the antibiotic era?
Resistance against more than 1 class of antibiotic would not occur in the same bacterium.
Resistant bacteria would be significantly less potent/fit
Resistance arising from horizontal gene transfer would not occur
When does resistance occur?
When a bacteria can grow at antibiotics at or above the breakpoint
What is the breakpoint?
The clinically achievable concentration at which a microbe is susceptible
What is the minimal inhibitory concentration?
Minimum concentration of an antibiotic required to inhibit growth - related to the breakpoint
What arises from the routine use of antibiotics?
Selection pressure for the acquisition and maintenance of resistant genes.
In the absence of selection pressure, what happens with the antibiotics?
Resistant strains do not gain an advantage therefore do not proliferate, as they do not have anything to gain an advantage over.
What happens when you add a selection pressure to bacteria?
There is now an advantage for resistant bacteria, therefore they proliferate over other antibiotics and we gain a high population of resistant bacteria as long as there is pressure
What are the mechanisms of resistance?
Altered target site
Inactivation of antibiotics
Altered metabolism by bacteria to bypass antibiotic
Decreased drug accumulation
What is an altered target site?
Change to peptide sequence of bacteria so that the antibiotic can no longer bind to the bacteria
What is an example of an altered target site?
MRSA encodes alternative PBP to PBP2a with a lower affinity to beta lactase therefore giving it resistance
What is inactivation of the antibiotic?
Occurs via enzymes that degrade or alter antibiotics to render them ineffective
What is an example of antibiotic inactivation?
Beta lactamase hydrolyses the beta-lactam ring and chloramphenicol acetyl transferase (CAT)
What is altered metabolism?
Bacteria overproduce metabolic intermediates which can outcompete antibiotic for target site. or they can switch to other metabolic pathways from pathways which antibiotics would have otherwise targeted.
What is decreased drug accumulation?
Efflux pumps in the bacteria eject antibiotics to stop then from reaching their MIC.
When can multiple resistance mechanisms co-exist?
E.g. N.gonorrhoea - some strains encoded penicillinases, some encoded efflux pumps and also underwent target site modification to quinolones
What are the exogenous sources of resistance
Bacteria can acquire plasmids
Bacteria can acquire transposons
Bacteria can acquire naked DNA from environment
What are the main mechanism bacteria can share DNA?
Transformation
Transduction
Conjugation
What is transformation?
Allows bacteria to take up DNA from their environment
What is transduction?
Phage mediated transfer between a virus that infects bacteria and goes on to take up some of their DNA and spread it between different bacteria
What is conjugation?
Plus mediated DNA transfer in which plasmids are shared.
What are some of the non genetic mechanisms of resistance?
- Biofilm - matrix encased communities of bacteria
- Intracellular location in human cells
- Slow growth of bacteria therefore too hard to target.
- Spores can be resistant to heat, antiseptics and ABs
- Persister bacteria - bacteria are dormant
What are some miscellaneous reasons for treatment failure?
Wrong choice of treatment
Poor AB penetration
Inappropriate dose level/ technique
AB resistance within commensal flora which may secrete beta lactamases for example.
Where do we typically find the highest rates of resistance?
Critical care units
Renal in patient units
Where do we typically find the lowest rates of resistance?
Community settings
What are some of the risk factors for acquiring resistant bacteria?
Immunosuppression Crowded wards Broken skin Indwelling devices e.g. catheter AB therapy may suppress microbiota Transmission by staff.
what are some of the ways in which we can address resistance?
New strategies for prescribing
Reserving/withdrawing certain classes of antibiotic
Reducing broad spectrum ABs which damage microbiota
Development of more rapid diagnosis
Combination therapy research/ more research in general
What are broad spectrum antibiotics?
Effective against a wider number of bacteria types.
How can we overcome resistance?
Modification of antibiotics e.g. amoxicillin
Infection control measures
Antibiotic combination
What is an example of overcoming resistance?
Methicillin is modified so that its B-lactam ring is resistant to lactamases
Along with bacteria, what organisms are also becoming affected by antimicrobial resistance?
Fungi
How do fungi digest food?
Outside the cell by secreting hydrolytic enzymes which can break down biopolymers to be absorbed for nutrition
What are the 3 broad classes of fungal conditions in humans?
Allergy
Mycotoxicoses
Mycoses
what is allergic fungal condition?
Allergic reactions to fungal products e.g. Allergic Broncho-pulmonary aspergillosis (ABPA)
What is mycotoxicoses?
Ingestion of fungi and their toxic products e.g. aflatoxin
What are mycoses?
Superficial, subcutaneous or systemic colonisation, invasion and destruction of human tissue
What are the 3 classes of mycoses?
Superficial
Subcutaneous
Systemic
(Mucosal too)
What are the targets for anti fungal therapies?
Cell membrane - uses ergosterol instead of cholesterol
DNA synthesis
Cell wall - fungi have one unlike mammalian cells.
