Antibiotics I Flashcards
minimal inhibitory concentration (MIC)
concentration of antimicrobial that inhibits growth of an organism
minimal bacteriocidal concentration (MBC)
concentration that KILLS bacteria
breakpoint
the MIC that is used to designate between sensitive and resistant; arbitrarily set by a committee
if MIC > breakpoint, the organism is (resistant or sensitive?)
RESISTANT
if MIC < breakpoint, the organism is (resistant or sensitive?)
SENSTITIVE (susceptible)
pharmacodynamics for beta lactams
time above MIC
*needs to be > 50%
*continuous infusion is good for this
pharmacodynamics for aminoglycosides
Cmax/MIC
*needs to be > 5
*high dosage once a day is good for this (gets the highest peak possible)
pharmacodynamics for fluoroquinolones
area under the curve (AUC) / MIC
*needs to be > 35
synergy
2 antibiotics work better together than either one of them could do alone
*ex. one inhibits cell wall and one inhibits ribosome
antagonism
two antibiotics “get in each other’s way”
*usually when the 2 antibiotics are competing for the same target
which antibiotic classes target cell wall synthesis
beta lactams, cephalosporins, carbapenems, vancomycin, bacitran
subclasses of beta lactam antibiotics
penicillins, cephalosporins, carbapenems, monobactam (aztreonam)
beta lactam antibiotics - target
*binds to penicillin binding proteins (PBPs) in cell wall
beta lactam antibiotics - overview
*binds to PBPs in cell wall
*bactericidal
*spectrum dependent on subclasses
*generally good serum, urine, and tissue levels; CSF level variable
*time dependent pharmacodynamics (time above MIC > 50%)
beta lactam ring - structure
amide bond - essential for the function of these antibiotics
beta lactam antibiotics - mechanism of action
*act on penicillin binding proteins (PBPs; aka transpeptidases) to INHIBIT CROSS-LINKING of PEPTIDOGLYCAN via pentaglycine bridge
*causes osmotic dysregulation, which causes lysis
beta lactam antibiotics - mechanisms of resistance
- production of beta-lactamases (cleave the beta lactam ring)
- alteration of PBPs (so the antibiotic cannot bind)
- decreased permeability
how do beta lactamases work in gram positive organisms
beta-lactamase diffuses away, leading to weak concentrations of the enzyme
*happens b/c there is only one cell membrane/wall
how do beta lactamases work in gram negative organisms
beta-lactamase gets concentrated between the membranes
*leads to more potent activity of beta-lactamases
beta-lactamase inhibitors
*bind to beta-lactamase irreversibly at the active site
*often given simultaneously with a beta lactam antibiotic, which “neutralizes” the beta-lactamases
what are the 4 beta lactamase inhibitors
-clavulanic acid
-sulbactam
-tazobactam
-avibactam
penicillin class antibiotics
- penicillin
- aminopenicillins
- antistaphylococcal penicillin
- extended spectrum (antipseudomonal penicillin)
2 important aminopenicillins
*ampicillin (IV)
*amoxicillin (PO)
note - augmentin = amoxicillin/clavulanate
2 important antistaphylococcal penicillins
-methicillin (IV)
-dicloxacillin (PO)
important extended spectrum (antipseudomonal) penicillin
piperacillin
penicillin G
*“prototype” of penicillin
*used for strep, enterococci, and spirochetes
*resistance is NOT a concern in group A and group B strep
*resistance occurs (through altered PBPs) for pneumococcus, enterococci, and viridans strep
benzathine penicillin
*used for direct observed therapy for syphilis
*has a LONG half-life, so one injection lasts for about 3 weeks
resistance mechanism for staph aureus (MRSA)
*resistance through altered PBPs
*resistance transferred via MecA operon
*causes resistance to ALL beta-lactams
benefit of anti-staphylococcal penicillins
bactericidal to staph
(NOTE - developing resistance [MRSA] via altered PBPs)
benefit to aminopenicillins
*extend the spectrum to include more gram negative rods
*good drug for head/neck and respiratory tract infections
benefits to antipseudomonal penicillins (piperacillin)
extends activity to include pseudomonas & gram negative rods
*downside: must be given IV
type 1 beta lactam allergy (immediate hypersensitivity)
*IgE/mast cell mediated
*urticaria (hives) and anaphylaxis
*most serious
type 2 beta lactam allergy (innocent bystander)
*adherence of drug as a hapten to a cell (attaches to RBC membrane and IgG attacks, lysing the cell)
*hemolytic anemia
type 3 beta lactam allergy (“Arthus” immune complex)
*serum sickness: fever, glomerulonephritis, arthritis, adenopathy (not all at the same time)
*the penicillin clumps into a ball and antibodies attach; the complex gets stuck in joints, kidneys, etc
type 4 beta lactam allergy (delayed hypersensitivity)
*most common beta lactam allergy
*T cell mediated
*usually after 7-10 days of antibiotic
*rash, usually with fever
*eosinophilia
cephalosporins
*subclass of beta lactam antibiotics (bind to PBPs)
*more stable to beta lactamases than other subclasses
*examples: “-CEFs”: ceftriaxone, cefepime, etc
benefits of cephalosporins
*SAFE (high therapeutic to toxicity ratio)
*3rd generation cephalosporin (ceftriaxone) has good CNS penetration
1st generation cephalosporins
*active against gram positive organisms (Staph and Strep)
1. cefazolin** (IV)
2. cephalothin (IV and PO)
2nd generation cephalosporins
*active against gram positive and some gram negative organisms (Haemophilus, enterobacteriaceae)
1. cefoxitin (IV)
2. cefuroxime (IV and PO)
3rd generation cephalosporins
*broader spectrum
1. ceftriaxone (broad spectrum but not pseudomonas; CROSSES BLOOD-BRAIN BARRIER)
2. ceftazadime (good against pseudomonas and other GNRS; loses potency against gram positives)
ceftriaxone
*3rd generation cephalosporin
*crosses the blood-brain barrier (for bacterial meningitis)
*not effective against pseudomonas
4th generation cephalosporins
- cefepime (broad, GP, GN, includes pseudomonas)
5th generation cephalosporins
*enhanced antipseudomonal activity
1. ceftolozane (given with tazobactam)
MRSA active cephalosporin
ceftaroline
cefiderocol (new cephalosporin)
*uses the bacterial active iron transport channels to penetrate in the periplasmic space of gram negative bacteria
*overcomes many resistance mechanisms because it can cross the outer membrane, even if there is a loss of porins
aztreonam
*monobactam (beta lactam)
*active ONLY against gram negative AEROBES
*no cross reaction with type 1 hypersensitivity
carbapenems
*subclass of beta lactams (bind to PBPs)
*one of the broadest spectrums of antibiotics
*can NOT kill MRSA, enterococci, listeria
*examples: “-penems:” imipenem, meropenem, ertapenem
carbapenems - mechanism of resistance
*reduced permeability of gram negative rod outer membrane (loss of porins [D2 porin] - antibiotic can’t get in)
*carbapenemases increasing in incidence
3 examples of carbapenems
- imipenem
- meropenem
- ertapenem
