Antimicrobial Therapies Flashcards
Pronto I’ll and penicillin were the first antibiotics, what happened befor the discovery of these?
Minor infections were potentially fatal. Surgery was a major risk
What are the origins of penicillin and prontosil?
Prontosil, took years for its potential to be realised and was never patented
Penicillin, discovered by chance by SAF. Other scientists then figured out ways to mass produce and administer it
What is an antibiotic?
An anti microbial agent produced by a microorganism that kills it inhibits other microorganisms
Where do antibiotics come from?
Produced by soil dwelling fungi (penicillum and cephalosporium) or bacteria (streptomyces or bacillus)
However they encompass a range of natural, semi synthetic and synthetic chemicals with anti microbial activity
What is an anti microbial?
A chemical that selectively kills or inhibits bacteria, fungi or viruses
What do bactericidal and bacteriostatic mean?
Bactericidal- kills them
Bacteriostatic - stops them growing
What is an antiseptic?
Chemical that kills or inhibits microbes. Usually used topically to prevent infection
Production of new antibiotics has slowed, why?
Most antibiotics in use today were developed in the 1940s and 50s
However many microorganisms are developing resistance to our usual drugs
Eg MRSA
Why does antibiotic resistance lead to increased mortality, morbidity and cost?
Increased time to effective therapy
Requirement for additional approaches eg surgery
Use of expensive therapy (newer drugs)
Use of more toxic drugs that have to be administered in hospital (in patient)
Use of less effective second choice antibiotics
What are aminoglycosides?
Eg gentamicin and streptomycin
Bactericidal
They target protein synthesis, RNA proofreading and cause damage to the cell membrane
It’s toxicity (eg hearing loss) has limited use but resistance to other antibiotics has lead to its increased use
What is rifampicin?
Bactericidal
Targets RpoB subunits of RNA polymerase
Spontaneous resistance to it is frequent
It makes secretions go orange/red which can affect compliance to long courses of it
What is vancomycin?
Bactericidal
Targets lipid II component of cell wall biosynthesis, as well as wall cross linking via D-ala residues
Its toxicity means it has limited use, however due it AB resistance to other antibiotics it’s use is increasing (especially in treatment of MRSA)
What is linezolid?
Becteriostatic
Inhibits the initiation of protein synthesis by binding to the 50S rRNA subunit
Only has a Gram positive spectrum of activity
What is daptomycin?
Bactericidal
Targets bacterial cell membrane
Only gram positive spectrum of activity
Higher toxicity
What are beta lactams?
Most commonly prescribed class of antibiotics (eg penicillin and methicillin)
These interfere with the synthesis of the peptidoglycan component of the bacterial cell wall
They have bactericidal activity
They bind to penicillin-binding proteins that help manufacture the cell wall, inhibiting cell wall biosynthesis
They have a characteristic beta lactam ring (square)
Antibiotics exhibit selective toxicity, how?
They target cellular processes that, in bacteria, invoke such different mechanisms and molecules than in humans
They also effect some pathways in bacteria that are unique to them (eg production of peptidoglycans)
What are macrolides?
Eg. Erythromycin and azithromycin
Effect gram positive AND some gram negative infections
Target the 50S ribosomal subunit preventing amino Acyl transfer and truncating polypeptides
What are quinolones?
Bactericidal
Synthetic
Broad spectrum
In gram negative, they target DNA gyrase
In gram positive they target topoisomerase IV
What are broad and narrow spectrum antibiotics?
Broad spectrum - effect a wide range of bacteria
Narrow - only affect a small range
What is meant by resistance?
Antibiotics act at diffferent doses.
The MIC (minimal inhibitory conc) is the lowest concentration of antibiotic required to inhibit growth
There is a scale, from sensitive to intermediate to resistant
At the sensitive end the bacteria is holy succeptible to the AB however past a break point concentration, the AB is no longer effective so the bacteria is resistant
How does resistance come about?
The use of antibiotics selects for resistant strains
Population diversity —> application of a selection pressure —> becomes an advantage so the drug resistant bacteria survive
What are the 4 mechanisms by which antibiotic resistance occurs?
Altered target site
In activation of antibiotic
Altered metabolism
Decreased drug accumulation
How do alterations in antibiotic target site arise?
Via aquisition of an alternative gene or a gene that encodes a target modifying enzyme changing the shape of the protein the AB targets
MRSA encodes an alternative PBP (penicillin binding protein) with low affinity for beta lactams
Bacteria can use chemical processes to modify the target site
How does the inactivation of antibiotic arise?
Enzymatic degradation or alteration, rendering antibiotic ineffective
ESBL and NDM-1 are examples of broad spectrum beta lactamases (these degrade a wide range of beta lactams, includibb the newest ones)
How does the alteration of metabolism arise?
Increased production of enzyme substrate can out compete antibiotic inhibitor (so the AB binds to these instead of the bacteria)
How does decreased drug accumulation occur?
Reduced penetration of AB into bacterial cell (either by reduced permeability, or increased efflux of the AB out of the cell)
So the drug doesn’t reach the concentrations required to be effective
How do bacteria become resistant through the changing of DNA?
Plasmids - extra chromasal DNA is plasmids can contain AB resistant genes transposing swap genes from plasmid to chromosomal DNA and vice versa
Naked DNA - some bacteria can take up DNA from dead bacteria released into the environment
What are the three ways bacteria can share DNA?
Transformation - uptake of extracellular DNA (chromosomal or plasmid)
Transduction - phages (viruses) infect bacteria, take uo DNA, spread this when they infect other bacteria
Conjugation - pilus are used to transfer dna between bacterial cells
What are some examples of hospital acquired infections?
MRSA, VISA, C. Diff, E. coli, p. Aeruginosa
What are some risk factors for hospital acquired infections?
Lots of immunosuppressed and I’ll people
Crowding
Presence of pathogens
Broken skin (wounds and iv)
Intubation
AB therapy (can alter the usual microbiota)
Transmission by staff
What are some ways we can address AB resistance?
Prescribing strategies - controls, temporary withdrawal of certain classes
Reduce use of broad spectrum ABs
Quicker identification of infections caused by resistant strains
Combination therapy (use of Two ABs together to overcome resistance)
Knowledge of local strains and resistance
There are also some reactive approaches that we can take after resistance
