week 1 Flashcards
define antibiotics?
chemical products of microbes that inhibit or kill other organisms
what is antimicrobial agents? Give examples
it is a umbrella term of agent that kills a wide rang of different things. Antibacterial, antifungal and antiviral
what are the different types of antimicrobial agents?
antibiotics, synthetic compounds with similar affects or semi synthetic compounds
what are semisyntheti compounds?
are modified versions of antibiotics.
They have different antimicrobial activity/spectrum, pharmacological properties or toxicity
what is Bacteristatic and what does it affect?
it inhibits bacterial growth –> stops the growth of bacteria and therefore allows the human immune system to destroy the bacteria.
It is a protein synthesis inhibitor
what is bacteriacidal? What does it affect?
it kills the bacterial and affect cell wall-active agent
what is minimum inhibitory concentration MIC?
Minimum concentration of antibiotic at which visible growth is inhibited
can someantibiotic act as both bacteristatic and bacteriacidal? Explain
yes at low concentration the antibiotic can be bacteristatic but then at high become bacteriacidal
what is Synergism?
the activity of 2 antimcrobials together is greater than activity given seperately
What is antagonism?
when one agent diminishes the activity of another?
what is Indifference in terms of antibiotics?
the addition of antibiotic have no affect on the other antibiotic activity
what is the treatment of streptococcal endocarditis? What type of interaction is it?
β-lactam/aminoglycoside combination therapy
Synergism interaction
what are antibacterial target types ?
molecules, structures and enzymes?
what are structures?
things bigger than molecules
what are the two types of selective toxicity?
Tackle a Target not present in human host but in the bacteria
Tackle a Target significantly different in the bacteria compared to the human host
what are the main 5 antibacterial targets?
Cell wall Protein synthesis DNA synthesis RNA synthesis Plasma membrane
what is bacterial cell wall made up of?
peptidoglycan
do animals have cell wall?
no
what type of bacteria have cell wall?
both gram positive and gram negative bacteria have cell walls
what is peptidoglycan made up of?
Polymer of glucose-derivatives, N-acetyl muramic acid (NAM) and N-acetyl glucosamine (NAG)
why is antibiotics targeting cell walls so effective?
all bacteria have cell wall while humans do not
why do bacteria need cell wall?
Need cell wall for protection and is constantly remolding –> essential for their life
what are the 2 classes of cell wall inhibitors?
B lactams and Glycopeptides
what is the most common type of B lactams?
penicillin
what was the first true B lactam antibiotics?
Benzylpenicillin ( Penicillin G)
what do all B lactam antibiotics contain in their structure?
B lactam ring
what does B lactam ring contain?
Four-membered ring structure (C-C-C-N)
Structural analogue of D-alanyl-D-alanine
how do B lactam antibiotics work?
They intefere with penicillin binding proteins. These are Transpeptidases enzymes that are invovled in peptideoglycan cross linking ( cell walls)
what is the first oral B lactam?
phenoxymethyl penicillin (penicillin V).
what was the first antibiotic to be active against the family of Enterobacteriaceae?
Ampicillin
what two B lactam can only be given parenterally?
Benzylpenicillin and ampicillin
what does parental dosage mean?
are intended for administration as an injection or infusion
what is the oral equivilant of Ampicillin ?
amoxycillin
what is Meticillin ?
anti-staphylococcal penicillin.
what is key about the structure of meticillin?
it has a side chain that prevents the hydrolysis of the drug by staphylococcal b-lactamase
what two drugs have replaced meticillin?
cloxacillin and flucloxacillin
what are the 4 main key antibiotics underneath B lactam antibiotics?
Penicillins
Cephalosporins
Carbapenems
Monobactams
give me examples of penicillin and what is the most common type? What type of spectrum does it have?
Benzylpenicillin,
amoxicillin –> most common
flucloxacillin
Relatively narrow spectrum
give me examples of Cephalosporins and what is the most common type? Does it cover gram negative bacteria?
Cefuroxime–> common
ceftazidime
Broad spectrum
covers gram negative bacteria
give me examples of Carbapenems?
Meropenem, imipenem
Extremely broad spectrum
what type of antibiotics is used when allergic to penicillin? give example of this type of antibiotic? what Type of bacteria is it active too?
Monobactams
type of monovactams is: Aztreonam
Gram-negative activity only
give me examples of glycopeptides antibiotics?
Vancomycin –> more common
teicoplanin
how does glycopeptides work?
Inhibit binding of transpeptidases and thus peptideoglycan cross-linking
what type of bacteria can glycopeptides be active against?
only active against gram positive bacteria.
Because it cannot penetrate the outer membrane porins of gram negative bacteria
what is Ribonucleoprotein complexes main up of?
2/3rds RNA and 1/3rd protein
what is mRNa made up of?
50s (large) subunit and 30s (small) subuinte that combine to form the 70s initation complex
give example of Aminoglycosides
Aminoglycosides
Examples are: Gentamicin, amikacin
how does Aminoglycosides work?
Bind to 30S ribosomal subunit
what is the severe side affect of gentamicin?
it is a nephrotoxic
what is nephrotoxicity?
it is toxic to the kidneys
give examples of Macrolides, Lincosamides, Streptogramins (MLS)
Erythromycin, –> most common type
clarithromycin (macrolides)
what is alternative option to erthromycin?
clindamycin–> less side affects
how does MLS antibiotics work?
Bind to 50S ribosomal subunit1
Blockage of exit tunnel
Inhibit protein elongation –> prevent the addition of more peptides
give examples of tetracyclines?
tetracylcine and deoxytetracycline
how does tetracyclines work?
bind to 30s and prevent the translation of tRNA with rRNA
give examples of Oxazolidinones?
Linezolid
how does Linezolid work?
Inhibits initiation of protein synthesis
Binds to 50S ribosomal subunit
Inhibits assembly of initiation complex
May also bind to 70S subunit
what antibiotic prevents folic acid production?
Trimethoprim and sulfonamides
together what are Trimethoprim and sulfonamides called?
co-trimoxazole
why is folic acid inhibited by antibiotics?
it is a precusor for purin synthesis
what is Trimethoprim?
Dihydrofolate reductase
what does Sulfonamides directly inhibit and why?
Dihydropteroate synthetase because it is the enzyme catalyses the first step in folic acid synthesis.
how do bacteria synthesise folic acid?
from para-aminobenzoic acid
what is trimethoprim mainly used for?
used mainly for UTI’s
are together Trimethoprim and sulfonamides together effective against bacterial infection?
in vitro they are but not in real life –> no longer really used
why is sulphonamides rarely used?
It is highly toxic and become highly resistant
when is co-trimoxazole used?
treatment of some protozoal infections and, increasingly, to treat resistant bacterial infections
how does Quinolones and fluoroquinolones work?
Inhibit one or more of two related enzymes:
DNA gyrase and topoisomerase IV
Involved in remodelling of DNA during DNA replication
give me examples of Quinolones and fluoroquinolones
Nalidixic acid, ciprofloxacin, levofloxacin
give me a example of RNA synthesis inhibitors?
Rifampicin
how does Rifampicin work?
RNA polymerase inhibitor
which prevents the synthesis of RNA
what type of antibiotic is Colistin ?
it is a plasma membrane agent that affect gram negative bacteria
what line is colistin used in?
last option as it is very toxic
what type of antibiotic affects plasma membrane of gram positive bacteria?
Daptomycin
how does Daptomycin?
destruction of cell membrane
what is the most common problem with B lactam antibiotics?
people are allergic to them
common adverse affects of antibiotics?
Nausea, vomiting, headache, skin rashes etc.
Allergic reactions
how do bacteria become resistant?
through evolution are bacteria that are resistant to antibiotics and in right enviroment grow and spread
what type of infections can be caused by antibiotic infection? secondary?
Fungal infection –> oral or vaginal thrush
give example of funcal infection that can be caused by antibiotics?
Superficial and invasive candidiasis
what is the adverse effects of Aminoglycosides?
Can cause renal impairment if accumulated so need to be stopped –> reversible
however can cause irrevesible otoxicity
what is otoxiticy?
toxic to the ear –> specifically the cochlea or auditory nerve
what percentage off people have a general rash due to B lactam?
1-10%
what percentage of people have anaphylatic shock due to B lactam?
0.01%
what type of antibiotic is Linezolid? what is its adverse afect?
it is a protein synthesis inhibitor and can cause bone marow depression if used for long time
what can happen if intollerant to B lactam?
Nausea, diarrhoea, headache etc.
what occurs in minor allergic reaction to B lactam?
skin rash
what occurs in severe allergic reaction to B lactam?
Anaphylaxis, urticaria, angio-oedema, bronchospasm, severe skin reaction (Stevens-Johnson syndrome)
what type of antibiotics are safe to use when someone ahs non-severe penicillin allergy
carbapenems
cephalosporins
what type of antibiotic is safe to use with any pencillin allergy?
aztreonam
explain the structure of aztreonam?
it is a Monobactam with a single ring rather than a double ring
what is the most common cause of antibiotic associated diarrhoea?
C.difficile
what does C.difficile produce?
toxin A and B
What happens that allows C.difficile to cause sickness?
be the destruction of normal colonisation resistance ( normal bacteria)
what accounts for C.diff clinical features and transmissibility?
spore production
enterotoxin
what strain of C.diff is of cause severe cases?
Hypervirulent strain 027
what 4 antibiotics are most common cause of C.diff?
Co-amoxiclav (amoxicilin-clavulanate) –> B lactam
Cephalosporins –> B lactam
Ciprofloxacin –> inhibit DNA synthesis
Clindamycin –> MLs antibiotics
what are less common causes of C.diff?
Benzylpenicillin, aminoglycosides, glycopeptides
Piperacillin-tazobactam (despite broad-spectrum)
what are the stages of antibiotic use?
emperic therapy
target therapy
susceptibility guided therapy
what is emperic therapy based on?
predicted susceptibility of likely pathogens
likely antimicrobial properties
what information is available at the time of emperic therapy?
organ system involved
exogenous or endogenous infection is likely pathogen
what information is available at the time of target therapy?
infection organism
likely antimicrobial susceptibility
what is target therapy based on?
predicted susceptibility of infected organisms
local antimicrobial policies
what is susceptibility guided therapy based on?
susceptibility testing results
what should be done when first treating a person with antibiotics? start smart
Only start antibiotics if there is clinical evidence of bacterial infection
Use local guidelines
Document indication, duration or review date
Obtain cultures first
Use single dose antibiotics for surgical prophylaxis
what should be done when treating a person after 48 hours? focus
Stop antibiotics if there is no evidence of infection
Switch antibiotics from intravenous to oral
Change antibiotics – ideally to a narrower spectrum – or broader if required
Continue and review again at 72 hours
Outpatient Parenteral Antibiotic Therapy (OPAT)
what is Flucloxacillin used for?
Staphylococcus aureus (not MRSA
what is Benzylpenicillin used for?
Streptococcus pyogenes
what is Cephalosporins used for ? Avoid which age group?
Gram-negative bacilli
avoid elderly
Metronidazole used for?
anaerobes
Vancomycin used for?
Gram-positives (MRSA)
Colistin used for?
last option for multi-resistant Gram-negatives
To treat infections in CSf what antibiotics have good avialability?
β-lactams
Good availability in presence of inflammation
To treat infections in CSf what antibiotics have poor avialability?
Aminoglycosides and vancomycin
to treat infections that are in the urine what antibiotics have good avialability?
Trimethoprim and β-lactams
to treat infections that are in the urine what antibiotics have poor avialability?
MLS antibiotics
what is needed to be considered in terms of Pharmacodynamic ?
time and concentration dependent
reasons for combination therapy?
To reduce resistance
To increase efficacy
Synergistic combination may improve outcome
β-lactam/aminoglycoside in streptococcal endocarditis
To provide adequately broad spectrum
what does Antibiotic era mean?
Term used to describe the time since the widespread availability of antibiotics to treat infection
what does post antibiotic era mean?
term used when there is widespread antibiotic resistance that has reduced the availability for antibiotics to treat infections
What does MRSA stand for?
Meticillin-resistant Staphylococcus aureus
what antibiotics is enterococci resistant to?
Vancomycin/glycopeptide
what is Enterobacteriaceae resistant to?
amoxicillin, ciprofloxacin, gentamicin, carbapenems
what is Pseudomonas resistant to?
ceftazidime, carbapenems
how does antibiotic resistance affect emperic therapy?
risk of under treatment as the antibiotic has no affect or the need to use overal broad spectrum antibiotics that can cause resistance
how does antibiotic resistance affect target therapy?
may have to use alternative treatment that is: toxic, last line or expensive
why is sensitive testing important?
1) transmision from emperic to target therapy
2) Shows whether or not antibiotic is working and therefore if a alternative antibiotic should work.
3) explain why antibiotic is failing
4) Also shows alternative oral antibiotics when IV no longe required
what does MDR-TB) stand for?
Multi-drug resistant tuburculosis
what does XDR-TB stand for?
Extremely-drug resistant tuberculosis
what does ESBL stand for?
Extended-spectrum β-lactamase-producing Enterobacteriaceae
In terms of abx sensitivity testing what is meant by a ‘breakpoint level’?
The breakpoint level is a known value. Its the concentration of that abx which can feasibly be available in the body
what are the basic principle of sensitive testing?
1)Culture of micro-organism in the presence of antimicrobial agent –>Solid or liquid media
2)Determine whether MIC is above a predetermined “breakpoint” level –> High enough to kill the organism
Sustained in the body for long enough using practicable dosing regimens
what are the steps in disck susceptible testing?
1) “Clinical interpretation
2) Read and interpret results
3) Incubate
4) Add antibiotics
5) Add organism
what are the steps in Liquid media - microtitre plate susceptibility testing?
1) Add antibiotic
2) . Add organism
3) Incubate
4) Read MIC
5) Compare with breakpoint
6) Interpret result
what are the limitations of sensitive testing?
1) Certain organisms are “clinically resistant” to antimicrobial agents even where in vitro testing indicates susceptibility
2) The infection may not be caused by the organism that has been tested
3) The correlation between antimicrobial sensitivity and clinical response is not absolute
what are the 6 ways that a bacteria can become antibiotic resistance?
No target – no effect Reduced permeability – drug can’t get in Altered target – no effect Over-expression of target – effect diluted Enzymatic degradation – drug destroyed Efflux pump – drug expelled
give examples of bacteria that have become antibiotic resistnace by reducing permeability?
Vancomycin:Gram-negative bacilli –>Gram-negatives have an outer membrane that is impermeable to vancomycin
Gentamicin:anaerobic organisms –>Uptake of aminoglycosides requires an O2 dependent active transport mechanism
how does MRSA become resistant to B lactams?
target alteration –> Altered penicillin-binding protein (PBP2’, encoded by MecA gene) does not bind β-lactams
how does Vancomycin-resistant Enterococcus become resistant to vancomycin?
Altered peptide sequence in Gram-positive peptideoglycan (D-ala D-ala –> D-ala D-lac)
Reduces binding of vancomycin 1000-fold
how does Gram-negative bacilli become resistant to Trimethoprim?
Mutations in dhr (dihydrofolate reductase gene)
give examples of enzyme degredation?
Penicillins and cephalosporins: β-lactamases (including ESBLs and NDM-1)
Gentamicin: aminoglycoside modifying enzymes
Chloramphenicol: chloramphenicol acetyltransferase (CAT)
give examples of drug efflux?
Multiple antibiotics, specially in Gram-negative organisms
Antifungal triazoles and Candida spp.
by how many genes is resistant mechenism coded by?
usually just by a single gene
give example of antibiotic modified enzymes that are encoded by a single gene? What antibiotics are they resistant to?
Β-lactamases (including ESBL –>Resistant to Penicillins, cephalosporins
Aminoglycoside-modiying enzymes –> resistant to Gentamicin
is it one feature or number of features that make a organism resistant to antibiotic?
usually a number of features
where is resistant gene encoded?
in plasmids–> circular strand of transferred within species and less commonly between species, mainly by conjugation
Which 2 structures enable horizontal transmission of resistance genes?
transposons and integrons
What is meant by a cassette and transponsons and integrons?
transponsons and integrons are dna sequences designed to be transferred from plasmid to plasmid and/or from plasmid to chromosomes - they often contain a cassette with multiple resistance genes
what is Vertical transfer of resistance?
Chromosomal or plasmid-borne resistance genes transferred to daughter cells on bacterial cell-division
describe the steps for horizontal transfer?
1) gene on plasmid 2) gene may stay on plasmid and/or integrate into the chromosome 3) plasmid transferred between organisms by conjugation
describe the steps for verticle transfer?
1) gene on plasmid 2) gene may stay on plasmid and/or integrate into chromosome 3) ‘new’ organism has abx resistance 4) abx resistance transferred on cell division
what is the consequence of antibiotic exposure?
1) sensitive strains exposed to abx at sub lethal conditions eg. clinical and agricultural 2) Chance of survival will be enhanced by development of resistance (spontaneous mutation, aquisition of resistance genes) 3) Resistant strain will out compete sensitive strains 4) Resistance perpetuated by vertical transfer 5) Mixtures of sensitive and resistant strains (eg. normal gut flora) exposed to abx - resistant strains have a survival advantage and will become the dominant colonising strains, subsequent endogenous infection more likely to be caused by resistant strains
what happens when sensitive and resistant strains are exposed to antibiotics?
Resistant strains will have survival advantage and will become the dominant colonising strains
Subsequent endogenous infection more likely to be caused by resistant strains
give example of sensitive and resistant strains in hospital?
normal flora when exposed to antibiotics
how do you avoid antibiotic resistance?
Never use an antibiotic unless absolutely necessary
Always use the most “narrow-spectrum” agent available
Use combination therapy if indicated
Be willing to consult expert information sources
