Antimicrobials Flashcards
Talk a little on the history of antibiotics
Greatest medical breakthrough of the 20th century
First antibiotic salvarson deployed in 1910
Penicillin in 1928 - golde age of natural produce antibiotic discovery
Over 100 years theyve drastically changed medicine
Extended human life span by 23 years
Invasive procedures now possible e.g. open heart surgery and infections now survivable
However no new antibiotics in recent years - were now in the postantibiotic era
Why are no new antibiotics being made?
theres no money in antibiotics
Any new drugs will eventually incur resistance - companies wont make money from them
Talk about the UK O’Neill report, what are some of the findings
A report on resistance comissioned by the UK government
Determined that 700,000 deaths occur due to resistant bacteria at the moment
Predict that 10 million deaths will occur due to resistant bacteria by 2050
How was Penicillin discovered
S. aureus plates were left in an incubater over the weekend
Fungus grew on plates
Observed antimicrobial affect of fungus on the S. aureus
What has been our most recent large discovery in antibiotics
Macrolides
Define antimicrobials, what are the three types?
Agents used to kill or inhibit the growth of microorganisms such as bacteria, fungi, viruses or pasites
Antibiotics are used to control bacterial growth
Annifungals are used to control fungal growth
Anivirals used to control viral growth
What three things must be balanced when selecting an antibiotic to use
Effective treatment
Minimisation of toxicity
Prevention of resistance
What are the different properties of an antibiotic, what properties of a drug should be considered
Spectrum of activity: broad or narrow
Mechanism of action: bacteriostatic vs bactericidal
Pharmacokinetic properties: absorption, distribution, metabolism, excretion
Pharmacodynamic properties: time-dependent killing, concentration-dependent killing
Toxicity and safety profile: organ toxicity, allergic reactions, side effects
Interactions with other drugs
Stability and formulation
Impact on normal flora
Cost and availability
Talk about broad spectrum antibiotics
Effective against both gram positive and negative organisms
Most commonly used is Norfloxacin
They are used in empirical treatment where we dont have time to ID the causative organism
They attack every bacteria and thus disrupt microbiome
Cause side effects such as GI distress and yeast infections in women
Talk about narrow spectrum antibiotics
Act against a limited number of bacteria
e.g. penicillin targetting peptidoglycan and thus only being affective against gram +/ves
We often switch to narrow spectrum to target therapy when we have ID’d the organism
More targetted therapy means more effective treatment - means patient needs to be treated for less time
Often has fewer side effects and little impact on normal flora
Compare baceriostatic vs bactericidal antibiotics
Bacteriostatic only inhibit bacteria from reproducing but doesnt actively kill them
Bactericidal actively kills bacteria - kills at least 99% in the first 4-8 hours
What is the most commonly used antibiotic in empirical treatment?
Norfloxacin
Some antibiotics can have both bacteriocidal and bacteriostatic affects, comment on this and give an example
Different affects on different organisms e.g.
Linezolid is bacteriostatic against staph and enterococcus but bactericidal against strep
What is pharmacokinetics
The study of how the body interacts wih administered substanced for the entire duration of exposure
Defined as the kinetics of drug absorption, distribution, metabolism and excretion (KADME)
Talk about the absorption PK property of antibiotics
How well the antibiotic is absorbed into the bloodstream when taken orally or through other routes
IV or oral etc
Talk about the distribution PK property of antibiotics
How the drug spreads throughout the body’s tissues and fluids
Some antimicorobials will penetrate well into specifric tissues e.g. CNS while others will not
Talk about the metabolism PK property of antibiotics
The process by which the drug is broken down
Some antimicrobials are metabolised in the liver, and understandin this helps avoid drug-drug interactions
Chronic illness e.g. those affecting liver and kidney can affect the metabolism of antimicrobials
The same can happen with other medications- they can interfere with metabolisation of antibiotics
Talk about the excretion PK property of antibiotics
How the drug is removed from the body, primarily through the kidneys or liver
Patients with renal or hepatic impairment may need dosage adjustments to compensate for this - might need lower dosage etc
What are pharmacodynamic properties
The effects of drugs in the body and the mechanism of their action
Time-dependent killing and conentration-dependent killing
Monitoring concentration of antibiotics done in bio lab to balance conc above MIC
Talk about time-dependent killing PD property of antimicrobials
The effectiveness of some antimicorbials such as B-lactams is dependent on how long the drug concentration remains above the minimum inhibitory concentration of the pathogen
Talk about concentration -dependent killing PD property of antimicrobials
Some antimicrobials such as aminoglycosides and fluoroquinolone effectiveness increases with higher concentration
What are the differences between pharmacokinetics and pharmacodynamics
PK is the study of what the body does to the drug
- absorption, metabolism etc etc
PD is the study of what the drug does to the body
- in tems of antimicrobials this is the effect of concentrations and time of drug on body
Talk about the organ toxicity property of antimicrobials, give examples
Some can be toxic to specific organs e.g. aminoglycosides are nephrotoxic and isoniazid is hepatotoxic
Monitoring is necessary for high-risk patients
Talk about allergic reactions in antimicrobials
Some such as penicillins can cause severe allergic reactions
Talk about the side effects of antimicrobials
Can range from mild e.g. GI upset to severe eg. anaphylaxis or C. diff associated diarrhea
What are the properties of a good antibiotics
Selective toxicity ie. the ability to kill or inhibit growth of an organism without harming the cells of the host
Talk about the ability of antimicrobials to inteact with other drugs
Can inteact with others to either affect their own activity of the acivity of the othe drug
Can reduce efficacy or increase toxicity
Talk about stability and formulation of antimicrobials
Stability: what tempeature does it have to be stored at, does it work best at certain pHs etc
Formulation: does it have to be made up, oral, intravenous, topical etc
Talk about the impact of antimicrobials on normal flora
Broad spectrum disrupt normal flora
Can potentially cause secondary infections usch as yeast
Can cause superinfections such as C. diff
Talk about superinfections
Infections which follow treatment
Either opportunistic e.g. C, diff or resistant following antimicobirl resistance
Talk about the cost and availability of antimicrobials
The expense and availability can impact their use especially in low-resource settings
Generic formulations are often preferred to reduce costs
What are the four ideal properties of an antimicrobial
Selective toxicity
Bactericidal activity
Narrow spectrum of activity (if appropriate)
Slow emergency of resistance
What does the duration of treatment depend on?
Give examples of reflections of this
Nature of infection
Site of infection
Growth rate of pathogen
3-5days reatment for UTIs (updated guidelines, used to be 5-7)
2-3 weeks for BSIs
6 wekks for IEs
9 weeks for TB
What are the three main mechanisms of antibiotics
Disrupt cell structures or processes
- by interfering with cell wall synthesis or maintenance
Interfere with the function of enzymes required to synthesise or assemble macromolecules
- by targetting nucleic acid replication or
- by targetig protein synthesis
Destroy structures already formed in the cell
Talk about cell wall inhibitors, give examples
These are bacteriocidal and are selectively toxic for bacterial cell walls
Include B-lactams, bacitracin, vancomycin and isoniazid
Talk about protein synthesis antimicrobials, give examples
Bacteriostatic but selective
Attack 30S and 50S ribosomoal subunits of bacteria that humans dont have
e.g. azithromycin, clindamycin, aminoglycosides such as gentamycin, tetracyclines and linezolid
Talk about antimicrobials against cytoplasmic membrane, give examples
Bacteriocidal but not selective
Targets both human and bacterial cells
hence used with caution
e.g. polymixin or daptomycin
How do cell wall antibiotics work, give examples
Target peptidoglycan - blcoking synthesis - cells lyse and die
Beta-lactams:
- Penicilins, cephalosporens, carbapenems, monobactams
Glycopeptides:
- Vancomycin and teicoplanin
Polypeptides:
- Bacitracin (strep)
What is peptidoglycan, describe its structure
A strong, mesh-like polymer that forms a protective layer around bacterial cells giving structural integrity and shape
It is made up of glycan chains (sugars) that are cross-linked by peptide chains (amino acids)
Its glycan backone consisits of alternating units of NAG and NAM
Short peptide chain attached to NAM unit
- D-alanine-D-alanine
Traspeptidase facilitates cross linkage between peptides by acting on D-ala D-ala
What does NAM and NAG stand for?
NAM = N-acetylglucosamine
NAG = N-acetylmuramic acid
How do Beta lactams work?
They mimic D-ala D-ala and thus confuse transpeptidase - thus blocking cross linkage of PG
What are the four major classes of beta lactams, ive examples
Penicillins: narro spectrum
- augmentin
- methicillin
Cephalosporins: extended spectrum
- cefotaxime
Carbapenems: reserve
- meropenem
Monobactams: newest
Comment on the use and side effects of beta lactams
Most commonly used antimicrobials
Rearded as safe but can be associated with diarrhoea and allergy
Usage can range from superficial infections to bloodstream infections
What is the main strucutral component of beta lactam antibiotics how does this differ between classes?
The beta-lactam ring
- a four-membered ring structure essential for action
Classes are defined by the structure of the ring or attachments e.g.
- five-membered ring in penicillins
- six-membered ring in cephalosporins
- side chains attached
Why do we make new classes of B-lactams and new generations
We develop new classes to increase the spectrum of activity and to address specific resistance mechanisms
Within each class there are generational hierarchy e.g. 1st, second, thrid and fourth generation cephalosporins to target specific resistance
List the penicillins
Penicillin
Methicillin
Amoxicillin
Ampicillin
Ticarcillin
Piperacillin
List the cephalosporins
Cefuroxime
Cefotoxime
Ceftazidime
Cefepime
Cefaroline
List the carbapenems
Imipenem
Meropenem
Ertapenem
Give an example of a monobactam
Aztreonam
Talk about the formation of peptidoglycan
Precursor of NAG and NAM are synthesised in cytoplasm
NAM is attached to a short peptide chain (D-ala D-ala) used later in cross-linking
NAG an NAM units are transported across the cell membrane by bactoprenol
Bactoprenol delivers these units to the growing PG layer outside the cell membrane
Once outside the NAG and NAM units link together to form a glycan chain which provid the backbone of PG layer which supports bacteial cell wall
Penicillin-binding proteins such as transpptidases link the peptide side chains of NAM to form cross-links and thus a strong, mesh-like structure
What is bactoprenol and what does it do?
Bactoprenol is a lipid carrier molecule
It helps deliver NaG and NAM units across the cell membrane to outside the cell membrane
What is transpeptidase, what does it do?
An example of a penicillin-binding protein
Which cross links the D-ala D-ala s of NAM molecules to form cross linked PG
How exactly do B-lactams work?
They resemble D-ala-D-ala
Thus they act as a flas substrate in PG synthesis
They bind to transpeptidase enzymes (hence penicllin binding protein) responsible for final stages of cell wall cross-linkage
Thus inhibit transpeptidation in PG synthesis
This results in accumulation of precursors of cell wall units and activation of cells autolytic system and thus cell lysis
How do B-lactams affect gram positives?
Gram positive cell walls are rich in Peptidoglycan and thus the Penicillin binding proteins/transpeptidase are easily accessible
Following exposure to B-lactams GPs release lipoteichoic acid fom the cell wall
This lipoteichoic acid triggers a generalised autolytic dismantling of the PG i.e. suicidal activation of wall autolysins
What are released from GPs following exposure to Beta lactams?
Lipoteichoic acid
What does Leipoteichoic acid trigger
Activation of wall autolysins thus incurring cell suicide
How do B-lactams affect gram negatives?
In gram negatives the PBP/transpeptidase are not as easily accessed - they are inside the periplasmic space
B-lactams need to cross the oute membrane through passive diffusion or pass through porin chanels to access the target PBPs
Talk about the Penicillin class, how do they work
Contain a B-lactam ring
- this is the target for resistance (penicillinase)
Work by inhibiting PG cross-linking
They naturally target Gram positives and thus have a narow spectrum of activity
Synthetic penicllins can have broader spectrum
Talk about synthetic penicillins, how do they work
New generations to extend the spectrum of activity and reduce vulnerability to evolving resistance mechanisms
We now have beta lactamase producers so to combat this we made B-lactamase inhibitors such as clavulanate and tazobactam which have weak antibacterial activity but act false/suicide substrate for analogue for penicillin i.e. distract the Beta lactamase enzymes so that penicillins can work
Give three examples of synthetic penicillins
Augmentin: amoxicillin + clavulanate
Timentin:: Ticarcillin + clavulanate
Tazocin: Piperacillin + tazobactam
Talk about cephalosporins
They have an extended spectrum of activity compared to penicillins
They have activity against gram -/ves
3rd and 4th generation have an extended spectrum of activity and are less susceptible to inactivation by beta-lactamases
Theres a need for further generations to reduce vulnerability to ESBL and CPOs
Give some examples of cephalosporins and their usage
Ceftazidime/avibactam -> beta-lactamase gram -ves
Ceftolozane/tazobactam -> beta-lactamase gram-ves
Cefidirocol -> new drug throught to be useful against resistance without moving up a class to carbapenems
How do cephalosporins affect gram negative bacteria
They can penetrate the outer membrane through the porin channels
Talk about Carbapenems
Of all B-lactams, carbapenems posses the broadest spectrum of activity and greatest potency against gram-positive and gram negative bacteria
They were meant to be our reserve but usage is now widespread
Less susceptible than pen and ceph to B-lactamase activity but we now have CPEs
Talk about some of the different carbapenems and their uses
Imipenem was the first clinically used
Meropenem provides the highest bacterial response
Ertapenem can be given as a once a day therapy but lacks activity against P. aeruginosa and Acientobacter
Talk about the redesign of ertapenem
Redesigned in 2017 so that it could be used as a once a day treatment
Talk about monobactams
Mode of action similar to penicillins
Newest form of B-lactam drugs
Some capability in inhibiting B-lactamase but not ESBLs or carbapenemases
Limited for gram-negative bacteria
Give some examples of monobactams
Aztreonam - primary monobactam used in gram-negative infections particularly in patients with penicillin allergies
Aztreonam and avibactam combination is under development for resistant strains
- avibactam is a beta lactamase inhibitor -> this combo is currently in phase 3 trials
What are the three main glycopeptides
Vancomycin
Teicoplanin
Dalbavancin and Oritavancin
Talk about Vancomycin Glycopeptide and its use
The most well known glycopeptide
We tend to limit its use due to high nephrotoxic effect
We tend to limit it to MRSA, endocarditis (and other severe GP infections) and C. diff infections
Talk about Teicoplanin Glycopeptide and its use
Tend to prescribe teicoplanin over vancomycin in Europe
It has a longer half life then vancomycin -> hence have to dose less frequently than vancomycin
Used for gram positive infections
Talk about Dalbavancin and Oritavancin
Newer glycopeptide with a longer half life
Used for skin and soft tissue infections caused by resistant gram positive organisms
These drugs allow for one-weekly dosing
List the modes of action of glycopeptides
Binding to Peptidoglycan Precursors:
- bind directly to D-ala-D-ala portion of the peptidoglycan precursor
Prevents Cross-linking:
- binding to the D-ala-D-ala part of the precursor, glycopeptides block the cross-linking of peptidoglycan strands - cross-linking is essential for cell wall strength and integrity
Prevents Incorporation of Subunits:
-prevents transport of the subunit through the cytoplasmic membrane, stopping the insertion of new peptidoglycan units into the cell wall - inhibiting the transglycosylation and transpeptidation reactions, critical for peptidoglycan chain assembly and maturation
NB: prevents cross linking and prevenys transport of precurosors across cytoplasm to PG chain
*different glycopeptides have slight differences in binding profiles but we dont need to know these
