Antibiotics Flashcards
what are four things to consider when trying to select the appropriate drug
- selective toxicity
- risk vs benefit
- type of organism
- empirical treatment: initial therapy based on most likely pathogen
- identification and susceptibility
- anatomical location
- drug penetration and distribution, or cidal vs static
- host status
- age, allergies, renal/heptic function, pregnancy, host defenses
Bacteriostatic vs Bactericidal
- sliding scale, relative terms
- clinically achievable levels in plasma
- effect on most pathogens for which its considered useful
static=stop growth
cidal=kill organism
MIC
Minimum inhibitory (static) concentration
MBC
minimal bactericidal concentration, kills 99.99% of bacteri
infections where cidal drugs should have an advantage
-patients with compromised immune function (the point of a static is that you slow down growth to let the host immune system kill the organism, but if they are immunocompromised then you need to use a cidal bc their immune system isn’t really capable of killing
- OR infections at the following sites in immune competent people
- meningitis
- endocarditis
- deep bone infections
- artificial device implants
Time dependent killin
- amount (%) of time above the MIC
- how much time is the host having antibiotic concentrations that re above the MIC
- maximize duration of effective concentration, these drugs work best when concentration exceed 4x the MIC for over 50% of the total time.
-have to envision multiple doses
**you shoul dhave the drug be 4x MIC for 50% of the treatment time)**
-B-lactams are time dependent killing
what is an example of a type of drug that is time-dependent killing
B-lactams
- keep the drug 4-fold above the MIC for over 50% of the total treatment time
- since B-lactamases have short half-lives, it implies shorter dosing intervals ( to keep the concentration of the drug up even though the half-life is short)
Concentration dependent killing
- maximize peak concentration
- Cmax/MIC ration greater than or equal to 8 is best.
-aminoglycosides
**it doesn’t really matter how long you stay at the peak concentration as long as you get there at some point adn get it to a ratio of Cmax/MIC of 8
Concentration x time dependence (area under the curve, AUC)
- AUC (conc*time)
- MIC (conc)
-AUC/MIC expressed in hours
gernally desire over 125. so want AUC/MIC to be over 125.
example quinolones
how does the charge of the gram positive cell wall relate to resistance
-the cell wall is very negatively charged so some positively charged drugs can’t get through
how does the porin of the gram neg relate to resistance
sometimes whether or not an antibiotic will work is dependent on size.characteristic of the porin adn whether or not it lets the antibiotic in
List the drugs that target the cell wall
- B-lactmas
- penicillins
- cephalosporins
- carbapenems
- monobactams
- beta-lactamase inhibitors
- Vancomycin
- Fosfomycin
- Bacitracin
General properties of the B-lactam drugs as a group
- Bactericidal: static under some conditions
- activity is maximal on actively growing bacteria (it functions by irreversibly binding to PBP which is responsible for cross-linking in cell wall synthesis, if you aren’t growing you aren synthesizing cell walls and therefore can’t be killed by interfering with that process if that process isn’t happening in the first place!
Mechanism of B-lactams
- B-lactams covalently bind to PBPs (irreversible, competitive)
- aka penicillin binding proteins; transpeptidases
- irreversible, competitive
- inhibits the transpeptidase activity that catalyzes cell wall cross-links (gives rapid lysis in a short period of time bc it irreversibly inhibits an enzymes that should work on thousands of substrates, so it is like ti is interfering with 100s of cross linking for every one PBP that is binds to)
- rapid bacterial lysis can cause symptoms: chills fever, aching due to release of bacterial components
resistance to Beta-lactams
- beta-lactamases
- altered PBP
- B-lactam cannot reach PBP
* eg: intrinsic mechanism of some gram negatives
B-lactamases
- (mostly gram neg according to immuno, but also for MSSA)
- most prevalent
- cleaves B-lactam ring
- chromosomal and plasmid encoded
- some inducible
- extracellular activity: implications for mixed infections
Methicillin sensitive staph aureus has Beta lactamases
Altered PBPs
- (mostly gram positives according to immuno)
- no longer bind B-lactam effectively
- methicillin resistant staph aureus has an altered PBP. and also penicillin resistant strep. pneumoniae
Explain how a b-lactamase positive bug can influence the safety of nearby bugs
- if a bacteria is releasing b-lactamase into the environment and killing the b-lactam drug, then the drug is not able to kill any bacteria in that environment, even if there are bugs there that are beta lactamase negative
- therefore beta-lactamases can protect other bacteria in the vicinity and normal flora have many beta lactamses
how common are b-lactamases
- most common for of b-lactam resistance
- over 400 b-lactamases have been described
distribution of penicillins
-generally well distributed, but low penetration into the CSF. however!!!! this penetration into the CSF is increased during meningitis while the meninges are inflamed. ( but as the penicillin starts to work and the meninges become less inflamed the penetrance of the drug will decrease
administration of penicillins
only some oral, other require IV or Im
elimination of penicillins
- renal elimination
- anion transport-implications
****when someone takes an anionic drugs (eg Probenecid) it will slow elimination because the anion transporter is blocked up.
half life of penicillins
short (30 min to 3 hours) and because they work via time dependent killing that means that it is important to increase dose frequency
route for penicillin V
oral
route for penicillin G
IV/IM
spectrum for penicillin v/G
-anaerobes (esp grampositives)
*Clostridium, Peptococcus, Peptostreptococcus, Veillonella,
Actinomyces • not Bacteroides fragilis
- gram positive (not b-lactamase producing)
- many streptococcus infact penicillin is 1st line for strept throat
- not staph due to b-lactamase
- very limited gram negative bacteria (non-beta-lactamse producing)
- Neisseria meningitidis
- spirochetes
- syphillis (treponema pallidum) also alternate for lyme disease for pregnancy and children instead of doxycyclines
How do you get steady levels of penicillin B over time
- slow release IM
- they are poorly soluble forms that DISSOLVE SLOWLY from the injection site; this CONTINUOUS release provides effective levels over time
- one in the blood the elimination half life is the same as IV penicillin G (about 30 minutes)
- SOOOO moral of story is they are extended release due to the slow dissolving, but there is NO CHANGE in the half life.
What do we use IM penicillin G benzathine for
syphilis
Penicillins for B-lactamse positive staphylococci
-methcillin type drugs
- oxacillin
- Staph aureus that are sensitive to these drugs are called MSSA (Methicillin sensitive Staph aureus)
-these drugs are not degraded by the Staph B-lactamase
Ampicillin, Amoxicillin
- maintain reasonable gram positive spectrum (B-lactamase negatvie)
- listeria streptococcus
- incl. enterococcus (eg UTI)
- expanded gram negatvie spectrum
- Neisseris
- Haemophilus
- escherica, Salmonella
- increasing number of isolates are resistant to B-lactamases
What was one of the main uses of amoxicillin
-high does amoxicillin has been the most common drug of initial choice for otitis media in otherwise healthy children
however now there has been an increase in Haemophilus and Moraxelia causing otitis media lately
Besides otitis media what is another use of amoxicillin
-it is an alternate choice for lyme disease in young children and pregnant or breast feeding people who can’t take doxycycline
Amipillin vs. Amoxicillin
- amoxicillin: oral only
- Ampicillin: available IV or oral
- Ampicillin has two uses that amoxicillin doesn’t
- Meningitis (eg Neisseria, Listeria) can use ampicillin IV
- GI infections: bc more ampicillin stays in the GI tract
List the two penicillins with extended gram negative spectrum
- ticarcillin
- piperacillin
ticarcillin
- retain some gram positive activity
- good for some anaerobes including gram negative
- often used with B lactamase inhibitor
- gram negative spectrum extended to include:
- Pseudomonas aeruginosa
- susceptible to B-lactamases
piperacillin
- gram negative, spectrum like ticarcillin, but also:
- some pseudomonas and Klebsiella
- including those that are ticarcillin resistant
- often used with a B-lactamase inhibitor
Penicillin allergy VERY SEVERE reaction
- 70% report having had penicillin prevously
- 33% report having prior allergic reaction
-less common with synthetic penicillins than with natural penicillins but ALL penicillins still pose allergic risk
predicting severe penicillin allergic reactions
- PRE-PEN skin test.
- skin test is 90-95% reliable at identifying those at risk for serious allergic reaction to major penicilloyl core
What is the more common penicillin allergic reaction
-Allergic rash
other side effects of penicillins besides allergic reaction/rash
- fever (4-8%)
- diarrhea (less than 25%)
- enterocolitis (note all antibacterials can cause enterocolitis)
- elevated liver enzymes
- hemolytic anemia
- seizures
B lactamase inhibitors
-clavulanic acid, tazobactam
B-lactamase MOA
- Beta-lactam “analogs” that bind irreversibly to B-lactamase
- inhibits some types of B-lactamase
- restores utility of some B-lactmase (ampicillin, amoxicillin, ticaricillin, piperacillin
Not all B-lactam resistance is due to B-lactamase: what is the mechanism for penicillin resistance strep. pneumoniae caused by
-changes in PBPs
Not all B-lactam resistance is due to B-lactamase: what is the mechanism for Methicillin-resistanct Staph. aureus (MRSA) caused by
-acquisition of new PBP2a encoded by MecA
Cephalosporins
- well distributed
- only some reach CSF
- majority require injection
- short half-lives
- mechanism: same as penicillins (bind to PBP)
- resistance mechanisms are comparable to those of penicillins (but some Cephalosporins have been designed to be poor substrates of common B-lactamases
Cephalospsorin and MSSA
-Staphylococcus (MSSA) 1st generation has best MICs
Streptococcus and Cephalosporin
-all 3 generations have good activity
gram negative and cephalosporins
- 1st generations are poor
- 2nd generations effect some gram negative bacteria (Haemophilus, Neisseria)
- 3rd goof for many gram negatives
1st generation cephalosporins
- mostly gram positive spectrum: good alternative for MSSA and Strep
- commonly used for outpatient skin infections
- surgical prophylaxis
two examples of 1st generation cephalosporins
- Cefazolin:
- IV/IM
- Best grm positive activity of 1st generation
- Cephalexin
- oral
2 generation cephalosporin examples
- cefuroxime
- only 2nd generation drug to penetrate CSF
- best of second generation for Haemophilus
- not the best against enterics
- good tolerance to many gram negative B-lactamases
- cefoxitin
- good for anaerobes including some strains of B. fragilis
- good tolerance to many gram negative B-lactamases
-cefuroxime
- only 2nd generation drug to penetrate CSF
- best of second generation for Haemophilus
- not the best against enterics
- good tolerance to many gram negative B-lactamases
-cefoxitin
- good for anaerobes including some strains of B. fragilis
* good tolerance to many gram negative B-lactamases
3rd generation
- ceftriaxone
- ceftazidime
ceftriaxone
- very good choice for common type of meningitis (Neisseria meningitidis, strep pneumoniae
- drug of choice for gonorrhe
- long half life (6-9 hours)
ceftazidime
- most active of 3rd generation against Psedamonas aeruginosa
- among the poorest 3rd generation for gram positive
- shortest half life (90min)
what are third generation cephalosporins used for
effective against many gram negatives including E coli, Klebsiella, Enterobacter, Proteus
stable against many gram negative B lactamases
4th generation cephalosporin
cefepime
cefepime
- IV, half life=2 hours
- spectrum similar to ceftazidime, except more resistant to inducible chromosomally-encoded type I B lactamases
- empirical treatment of serious inpatient infections
cephalosporins
- renal excretion/metabolism
- side effects:
- allergic reactions
- nausea, vomiting, diarrhea, enterocolitis
- heptocellular damage
Cross allergies between penicillins and cephalosporins
-shared side chains are associated with increased likelihood of allergic cross reaction
Extended Spectrum B-lactamases
- inactive penicillins, but also other drugs considered B-lactamases resistant
- 3rd gen cephalosporins
- monobactams
- carbapenems have become treatment of choice for ESBL organisms
Imipenem spectrum
- broad spectrum
* resistant to many B-lactamases including ESBL
Imipenem therapeutic use
- mixed infections
- ill-defined infections
- those non-responsive or resistant
- including those expressing extended spectrum B-lactamases (ESBLs)
- imipenem given with cilastatin
SIde effect for Imipenem
- allergic reactions: come cross allergies with penicillins and cephalosporins
- seizures, dizziness, confusion
- nausea, vomiting, diarrhea, pseudomembranous colitis, superinfection
Aztreonam
- used against gram negative aerobic rods
- aztreonam is not degraded by several B-lactamases
- no allergic cross-reactions with B-lactams
- side effects:
- seizures, anaphylaxis, transient EKG changes
- vomiting, nausea, cramps, enterocolitis
Vancomycin-MOA
- not a B-lactam it is a glycopeptide
- Bactericidal (but slower than B-lactams)
- inhibits cell wall synthesis
- binds free carboxyl end (D-ala D-ala) of the pentapeptidel this interferes with crosslinking and elongation of the peptidoglycan chains
- Grampositive only
explain the use of vancomycin and gram positive bacteria
- staph including MRSA
- streppneumoniae (including penicillin resistant) hemolytic streptococcus
- enterococcus (20-30% now vanco resistant: VRE)
- Clostridium difficile enterococcus as of March 2018 this is 1st line choice
what is vancomycin a 1st line drug of choice for
clostridium difficile
administration of vancomycin
- IV for systemic infections (primarily for serious infections)
- oral for clostridium difficile enterocolitis
Vancomycin and meningitis
- empirical treatment for meningitis
- 3rd generation cephalosporin and vancomycin
vancomycin side effects
- red man or red neck syndrome
- nephrotoxicity
- ototoxicity
- phlebitis
Fosfomycin
-blocks enolpyruvyl transferase so you can’t produce UDP-N-acetylmuramic acid which is a precursor for peptidoglycan synthesis
uses of fosfomycin
-uncomplicated UTIs especially caused by E. coli Enterococcus
side effects for Fosfomycin
-headache, diarrhea, nausea, vaginitis
Bacitracin -MOA _administration -spectrum -side effects
- polypeptide, not a B-lactam
- interferes with cell wall synthesis by interfering with carrier that moves early wall components through cell membrane
- topical use only
- gram positive spectrum
- including strep and penicillin resistant staph
- side effects: allergic dermatitis
Drugs that target cell membrane
- Polymyxin B
- Daptomycin
Polymyxin B
-act as cationic detergents that bind LPS in the outer membrane of gram negatives
-topical use
-gram negative spectrum
side effects: topical use: few problems, allergies, but systemic use: potential for serious nephrotoxicity and neurotoxicity
Daptomycin
MOA
- binds to bacterial cytoplasmic membrane causing rapid membrane depolarization
- rapidly bactericidal
Daptomycin uses
- gram positive spectrum
- complicated skin and skin structure infections
- staph aureus (MSSA, and MRSA)
- various streptococcus (pyogenes, agalactiae)
- enterococcus (vancomycin-susceptible only)
- bacteremia
- not for pneumonia
side effects of daptomycin
- nausea, diarrhea, GI flora alterations (including C diff)
- muscle pain and weakness
