Antibiotics Flashcards
Differential toxicity
Based on the concept that the drug is more toxic to the infecting organism than to the host
Minimum inhibitory concentration (MIC)
Minimum concentration of antibiotic required to INHIBIT the growth of the test organism
Minimum bactericidal concentration
Minimum concentration of antibiotic required to KILL the test organism
(allows less than 0.1% of the original inoculum to survive)
Prophylaxis
Antimicrobial agents are administered to prevent infection
Treatment
Antimicrobial agents are administered to cure existing or suspected infection
Therapeutic index
Toxic dose/ Effective dose
Drugs with a low TI may require therapeutic drug monitoring to ensure drug levels are both adequate for maximal efficacy, but not toxic to the patient
2 classes of drugs that have a small TI
Aminoglycosides
Vancomycin
What is the ideal antibiotic
No/low toxicity to the host (well tolerated)
Low propensity for development of resistance
Does not induce hyper-sensitivities in the host
Rapid and extensive tissue distribution
Relatively long half-life (10-12 hours)
Free of interactions with other drugs
Convenient for administration
Relatively cheap
4 advantages to combination therapy
- Treating polymicrobial infections
- Initial empiric therapy (broad coverage)
- Synergy
- May prevent the emergence of resistance (TB, S aureus, H pylori)
4 disadvantages of combination therapy
- Antagonism
- Cost
- Increased risk of side effects/drug drug interactions
- Usually not necessary for maximal efficacy
- Transformation
- Conjugation
- Transduction
- Transfer of free DNA
- Plasmid transfer
- Transfer by viral delivery
How long should you avoid repeating macrolide prescriptions to minimize resistance?
3 months
6 general mechanisms of resistance
- Altered permeability
- Inactivation/destruction of antibiotic
- Altered binding site
- Novel binding sites
- Efflux mechanisms
- Bypass of metabolic pathways
3 main classes of cell wall synthesis inhibitors
Beta lactams (penicillins, cephalosporins, carbapenems)
Glycopeptides (vancomycin)
Fosfomycin
2 examples of penicillins
Cloxacillin (anti-staphylococcal)
Piperacillin (anti-pseudomonal)
What changes as you move from first to fifth generation cephalosporins?
First is really good against gram positives
As you move up you lose gram positive and gain gram negative activity
Beta lactam drugs are substrate analogs of what?
D ala D ala
Competitive inhibitors of PBPs
Penicillin binding proteins
Essential enzymes involved in bacterial cell wall production
Transpeptidases
Target of beta lactam antibiotics
4 mechanisms of beta lactam resistance
- Production of a beta lactamase (most common)
- Altered PBP
- Novel PBP
- Altered permeability
What is the most common beta lactam/beta lactamase inhibitor combo?
Amoxicillin-clavulanic acid
2 examples of beta lactamase inhibitors
Clavulanic acid
Tazobactam
Glycopeptides
Vancomycin
Gram positives only!
Bind to the terminal D ala of nascent cell wall peptides and prevent cross linking of these peptides to form mature peptidoglycan
Sterically hinders its addition onto cell wall
Vancomyin resistance
how, effects, which 2 organisms
Bacteria substitudes D-lac for D-ala
Vancomycin cannot bind and you get normal cell wall synthesis
Enterococcus/ S aureus is main problem
Fosfomycin
Inactives the enzyme enol-pyruvyl transferase
Blocks condensation of UDP-N-acetylglucosamine with p-enolpyruvate
Works in the cytoplasm to inactivate the enzyme
Fluoroquinolones
Really good to use against atypical pathogens
Concentration dependent and highly bactericidal
Moxifloxacin is the best
Good against gram positives and gram negatives
DNA synthesis inhibitors
Two enzymes fluoroquinolones target
DNA gyrase
Topoisomerase 4
Inhibit DNA synthesis
Qnr
Binds to protein and protects DNA gyrase from binding of the antibiotic
Main adverse effect of fluoroquinolones
Cartilage toxicity/ tendon rupture
Restrict pediatric usage
Metronidazole
Go to anaerobic drug
Works by damaging DNA - inhibits nucleic acid synthesis
3 benefits of metronidazole
Bioavailable - can take orally
Very little resistance
Cheap
4 main classes of drugs that inhibit protein synthesis
- MLS (macrolides, lincosamides, streptogramins)
- Tetracyclines
- Aminoglycosides
- Linezolid
3 drugs in the macrolide class
Erythromycin
Clarithromycin
Azithromycin
Macrolides
Bind to 50S subunit of bacterial ribosomes to inhibit protein synthesis
Works by:
1. Blocking growth of nascent peptide chain by stimulating dissociation of the peptidyl-tRNA from the ribosome
2. Inhibiting assembly of new large ribosomal subunits
Good against atypical pathogens
2 mechanisms of macrolide resistance
Efflux pump (M phenotype) Target site modification erm (MLS phenotype)
Clindamycin
Anaerobic
Gram positives
Doesn’t work well against gram negatives
Associated with C difficile colitis
Tetracyclines
Tetracycline, Doxycycline, Minocycline
Bind reversibly to the 30S ribosomal subunit
Really good against atypical
Discolouration of teeth
Aminoglycosides
Gentamicin, tobramicin, amikacin
Highly bactericidal
Bind to irreversibly to 30S subunit of ribosomes and inhibit protein synthesis
Cannot use these to treat anaerobic infections or abscesses
Why cant you use aminoglycosides to treat anaerobic infections or abscesses?
They have to be actively transported into the bacterial cell – requires oxygen for transport
What is the most common form of resistance for aminoglycosides?
Enzymatic modification
2 adverse effects of aminoglycosides
Ototoxic
Nephrotoxic
Colistin
Gram negative agent with some gram positive activity
Also called polymyxin
Relatively toxic
Disrupts outer membrane
Daptomycin
Gram positive agent
You cannot use this drug to treat respiratory tract infections because surfactant inactivates it
Works just as well as vancomycin and has a larger TW, but is still under patent so really expensive
Inserts into membrane and causes depolarization and potassium flux
The beta-haemolytic strep are NEVER resistant to…
Penicillin or any beta lactam
Enterococcus are all intrinsically resistant to what class of drugs?
Cephalosporins
ALWAYS
E. cloacae and Citrobacter can have inducible resistance to what type of drugs?
Beta lactams
Nitrocephin disks
Quick screen for beta-lactamase production
Nitrocephin is a cephalosporin
When you break open the beta lactam ring it changes color
The Kirby-Bauer Test
Disc diffusion method
Antibiotic impregnated filter disc
Susceptibility test against more than one antibiotic measuring size of inhibition zone
The qualitative results of filter disk diffusion assay correlated well with quantitative results from MIC tests
Factors Affecting Size of Zone of Inhibition:
- Inoculum density
- Timing of disc application
- Temperature of incubation
- Incubation time
- Larger zones with light inoculum and vice versa
- If after application of disc the plate is kept for longer time at room temperature, small zones may form
- Larger zones are seen with temps less than 35degC
- Ideal 16-20 hours - less time does not give reliable results
Factors Affecting Size of Zone of Inhibition:
- Depth of the agar medium
- Proper spacing of the discs
- Potency of antibiotic discs
- Thin media yields excessively large inhibition zones and vice versa
- Avoids overlapping of zones
- Deterioration in contents leads to reduced size
Factors Affecting Size of Zone of Inhibition:
- Composition of medium
- Acidic pH of media
- Alkaline pH of media
- Reading of zones
- Affects rate of growth, diffusion of antibiotics and activity of antibiotics
- Tetracycline, novobiocin, methicillin zones are larger
- Aminoglycosides, erythromycin zones are larger
- Subjective errors in determining the clear edge
E-Test
MIC is the point where the zone of inhibition intersects the strip
The strip has a gradient of antibiotics on it, place on bacterial lawn, measure
Broth dilution method
Permit quantitative results
Indicates concentration of drug necessary to inhibit or kill the microorganisms tested
Doubling dilutions of antibiotic in broth
Turbidity visualization = MIC
Grow non turbid tubes, growth overnight = MBC
What broth is usually used?
Muller-Hinton
Agar dilution method
Permit quantitative results
Indicates concentration of drug necessary to inhibit or kill the microorganisms tested
Doubling dilutions of antimicrobial agent in incorporated agar media
One concentration of antibiotic/plate, several different strains/plate
What is the replicating inoculator device called that is used for the agar dilution method?
A Steers-Foltz replicator
It delivers 0.001 mL of bacterial inoculum
Vitek
Automated system
Doesn’t work well for organisms that are harder to grow (need special conditions, etc)
Which drug classes are good for treating atypical pathogens?
Fluoroquinolones
Macrolides
Tetracyclines
Beta lactams should not be used on patients with..
Immediate hypersensitivity reaction history
What 3 bacteria NEED combination therapy
Mycobacterium tuberculosis
S aureus
H pylori
