Antibiotics Flashcards
What are antibiotics?
Where did they come from?
What do we do to make them useful in medicine?
Natural products of fungi and bacteria - soil dwellers
- they result in natural antagonism and selective advantage
- kill or inhibit the growth of other microorganisms
- mostly derived from natural products by fermentation
- then modified chemically to increase pharmacological properties and increase the anti-microbial effect
When do we use antibiotics?
Acute?
Exposure?
When is it INAPPROPRIATE
Treatment of BACTERIAL INFECTIONS
prophylaxis : close contacts of transmissible infection, prevention of infection, peri-operative cover
inappropriate - VIRAL SORE THROAT
What makes a good antibiotic?
8 things
Selective toxicity
Good killing activity
Slow emergence of resistance
Narrow spectrum of activity
non-toxic to host
long plasma half life (low dosage)
oral/parental dosing forms (compliance)
no interaction with other drugs
What is the reason for selective toxicity?
What is the aim of selective toxicity?
Why is it not appropriate to use Abx with viruses/fungi?
Mechanism of action - exploits the differences in METABOLIC and STRUCTURAL differences between the host and the pathogen
YOU WANT TO HARM MICROORGANISMS - not host!
difficult for viruses - as they are intracellular organisms and go into the hosts cells
Difficult for fungi as they share similar components to host cells
What are the TWO different types of mechanisms of Abx with regards to bacteria?
Good KILLING activity
Bactericidal and Bacteriostatic
What are bactericidals
When are they used?
Host/Infection
- Kill bacteria
- Used when Host defense mechanisms are IMPAIRED
- required in DIFFICULT TO TREAT infections - endocarditis
What are bacteriostatic?
When are they used?
Host/Infection
Inhibit the bacteria
used when host defence mechanisms are intact
Used successfully in many infections
Why do we want slow emergence of resistance?
What normally happens when bacteria mutate?
What happens if Abx are used with bacteria?
What can Abx do to some bacteria?
Most mutations leading to resistance are associated with a fitness cost –> die out BUT they can survive if antibiotics are present
Using Abx - selects out the resistance bacteria which survive and multiply
Different antibiotics have different capacity to induce resistance
Some bacteria have inducible resisistance mechanisms triggered by certain antibiotics
Spectrum of activity….
When do we used broad vs narrow?
Different stage of infection require different antibiotics
Prior to knowing cause : BROAD spectrum
after finding cause: results of cultures/investigations are back - TARGET - NARROW SPECTRUM
What is a conseqeunce of Abx- natural flora?
Condition that occurs after losing natural flora?
Which Abx is this associated with? CLEAN FLOORS BREAK COLON
Loss of natural flora due to Abx use - leads to bacterial or pathogen OVERGROWTH
(due to lack of microbial anatagonism normal flora normally OUTGROW pathogens)
Antibiotic associated colitis
- clindamycin, broad spectrum lactams, fluoroquinolones)
- psuedomembranous colitis - leads to C.DIFFICILE OVERGROWTH
Symptoms
- ulcerations
- severe diarrhoea
- serious hospital cross infection risks
What indicates the non-toxicity to host?
MIC vs Toxic effect
What indicates safety? Large or small
Therapeutic index - ratio comparing the blood concentration at which a drug becomes TOXIC and ratio at which it is EFFECTIVE
Active dose (MIC) vs toxic effect
Larger TI - safer the drug
What are two examples of narrow TI
What does this indicate
Narrow TI indicates TOXICITY
Ototoxic : aminoglycosides
Nephrotoxic : vancomycin
Why do we want a long plasma half life?
Once a day administration
- more stable concentration
- better compliance
- easy administration
Why do we need a range of dosing forms?
When is oral not an option?
What is ideal for sepsis patients?
What is the risk with IV?
IV/IM/PO/Topical
More flexibility
Some patients cannot take PO - cannot absorb/cannot swallow
Septicemia - IM due to poor blood flow
IV - INFECTION in cannula, cellulitis at cannula site (strep pyogenes)
What are example of interactions with Abx and other drugs?
OCP - Rid
Warfarin - FMS
Pharmacokinetic - ADME
WARFARIN - effect is POTENTIATED via antibiotcs
- fluoroquinolones, macrolides, sulfonamids INHIBIT metabolism
Rifamcin - rids the pill !! affects OCP
Mechanisms of action of antibiotics?
Can people not make cells?
5 x routes
- Cell wall synthesis
- Protein synthesis
- Nucleic acid synthesis
- Metabolic Pathways
- Membrane Functions
What is the TARGET of cell wall synthesis with antibiotics?
Where does penicillin target?
What type of Abx is penicillin?
Where does vancomycin target?
What type of Abx is vancomycin?
Cell walls of gram positive and gram negative bacteria have PEPTIDOGLYCAN WALL
- made up of Penicillin binding proteins and D-ala D-ala peptide side chains
- Penicllin - target PBP - prevent crosslinking
- Beta Lactam
- Vancomycin - binds to D-ala D-ala
- glycopeptides
DISRUPTS cell wall peptidoglycan - leads to bacterial lysis
What do antibiotics target in protein synthesis?
RIBOSOMES
Abx - INHIBIT 30s RIBOSOMES and 50s RIBOSOMES
Examples of Antibiotics for 30S ribosomes?
AT 30 Proteins
30S examples:
A=A
Aminoglycosides (gentamicin, amikacin) - bind near A side - premature termination of translation of mRNA
T=T
Tetracyclines (doxycycline) - prevent binding of t-RNA to A site
What are examples of 50s inhibitors for protein synthesis
“CML STOPs Protein”
Chloramphenicol - interact with peptidyl transferase cavity of 50s subunit
cause premature detachment of incomplete peptide chains =
Macrolides - erythromycin,
Linosamides - clindamycin
streptogramins
Oxazolidinones (linezolid)
- prevent formation 70s initiation complex
What Abx targets nucleic acid synthesis?
Fluoroquinolones (ciprofloxacin, levofloxacin) - inhibit the bacterial enzyme involved in protein synthesis (DNA gyrase)
What is required by all bacterial cells for growth?
How do antibiotics affect this metabolic pathway?
SOME THINGS STOP FA
Folic acid is required by all bacterial cells
SULFOMAMIDES
TRIMETHOPRIM
inhibit folic acid synthesis
Cell Membrane Function - how to Abx stop this?
Polly - Negative - Leak
Polymyxins - Abx are positively charged so they are attracted to the negatively charged bacterial membrane (gram negative)
Polymyxins insert into the cell membrane of bacteria
Leakage of bacterial cell contents
Lysis of bacterial cell
What is termed a resistant bacteria in terms of Abx resistance?
Resistant organism is one that will NOT BE inhibited or killed by an antibacterial agent @ concentrations of the drug at normal dosage
Mechanisms of resistance?
Modification of target site
Use of alternative pathway (folic acid)
Lack of access to target site via reduction in permeability or efflux pumps or biofilms
Inactivation/destruction of antibiotic
What can staph aureus do to modify the target site of Abx (beta lactams)
What does it prevent?
Staph aureus - when treated with beta-lactams (bind to PBP)
Staph aureus: acquires the MecA gene - makes PBP2 instead which has LOW AFFINITY for beta-lactam (cannot bind therefore not antibiotic cell wall synthesis destruction)
Prevents Cell wall synthesis destruction
What can bacteria do to avoid metabolic pathway disruption
Sulfonamides - target the folic acid synthesis pathway
Resistant bacteria - produce extra PABA or develop alternative pathway
How can bacteria reduce access to target site?
Reduce permeability - loss of outer membrane porins (pseudomonas aeruginosa)
Efflux pumps - located in plasma membrane (expel toxic/waste substances from cytoplasm) e.g. MexAB-OprM pump
Biofilms - polymicrobial - form a the site of foreign bodies (prostehtic joints)
bacteria secrete a protective matrix
What can beta-lactams do to inactivate Abx
What can aminoglycosides do to inactivate Abx
Beta lactams - USE beta-lactamases to inactivate
Aminoglycosides - use aminoglycoside modifying enzymes to inactivate
