Antibiotics Flashcards
(81 cards)
1
Q
what are four things to consider when trying to select the appropriate drug
A
- 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
2
Q
Bacteriostatic vs Bactericidal
A
- sliding scale, relative terms
- clinically achievable levels in plasma
- effect on most pathogens for which its considered useful
static=stop growth
cidal=kill organism
3
Q
MIC
A
Minimum inhibitory (static) concentration
4
Q
MBC
A
minimal bactericidal concentration, kills 99.99% of bacteri
5
Q
infections where cidal drugs should have an advantage
A
-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
6
Q
Time dependent killin
A
- 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
7
Q
what is an example of a type of drug that is time-dependent killing
A
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)
8
Q
Concentration dependent killing
A
- 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
9
Q
Concentration x time dependence (area under the curve, AUC)
A
- AUC (conc*time)
- MIC (conc)
-AUC/MIC expressed in hours
gernally desire over 125. so want AUC/MIC to be over 125.
example quinolones
10
Q
how does the charge of the gram positive cell wall relate to resistance
A
-the cell wall is very negatively charged so some positively charged drugs can’t get through
11
Q
how does the porin of the gram neg relate to resistance
A
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
12
Q
List the drugs that target the cell wall
A
- B-lactmas
- penicillins
- cephalosporins
- carbapenems
- monobactams
- beta-lactamase inhibitors
- Vancomycin
- Fosfomycin
- Bacitracin
13
Q
General properties of the B-lactam drugs as a group
A
- 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!
14
Q
Mechanism of B-lactams
A
- 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
15
Q
resistance to Beta-lactams
A
- beta-lactamases
- altered PBP
- B-lactam cannot reach PBP
* eg: intrinsic mechanism of some gram negatives
16
Q
B-lactamases
A
- (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
17
Q
Altered PBPs
A
- (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
18
Q
Explain how a b-lactamase positive bug can influence the safety of nearby bugs
A
- 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
19
Q
how common are b-lactamases
A
- most common for of b-lactam resistance
- over 400 b-lactamases have been described
20
Q
distribution of penicillins
A
-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
21
Q
administration of penicillins
A
only some oral, other require IV or Im
22
Q
elimination of penicillins
A
- renal elimination
- anion transport-implications
****when someone takes an anionic drugs (eg Probenecid) it will slow elimination because the anion transporter is blocked up.
23
Q
half life of penicillins
A
short (30 min to 3 hours) and because they work via time dependent killing that means that it is important to increase dose frequency
24
Q
route for penicillin V
A
oral
25
route for penicillin G
IV/IM
26
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
27
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.
28
What do we use IM penicillin G benzathine for
syphilis
29
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
30
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
31
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
32
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
33
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
34
List the two penicillins with extended gram negative spectrum
- ticarcillin
| - piperacillin
35
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
36
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
37
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
38
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
39
What is the more common penicillin allergic reaction
-Allergic rash
40
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
41
B lactamase inhibitors
-clavulanic acid, tazobactam
42
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
43
Not all B-lactam resistance is due to B-lactamase: what is the mechanism for penicillin resistance strep. pneumoniae caused by
-changes in PBPs
44
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
45
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
46
Cephalospsorin and MSSA
-Staphylococcus (MSSA) 1st generation has best MICs
47
Streptococcus and Cephalosporin
-all 3 generations have good activity
48
gram negative and cephalosporins
- 1st generations are poor
- 2nd generations effect some gram negative bacteria (Haemophilus, Neisseria)
- 3rd goof for many gram negatives
49
1st generation cephalosporins
- mostly gram positive spectrum: good alternative for MSSA and Strep
- commonly used for outpatient skin infections
- surgical prophylaxis
50
two examples of 1st generation cephalosporins
- Cefazolin:
* IV/IM
* Best grm positive activity of 1st generation
- Cephalexin
* oral
51
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
52
-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
53
-cefoxitin
* good for anaerobes including some strains of B. fragilis
| * good tolerance to many gram negative B-lactamases
54
3rd generation
- ceftriaxone
| - ceftazidime
55
ceftriaxone
- very good choice for common type of meningitis (Neisseria meningitidis, strep pneumoniae
- drug of choice for gonorrhe
- long half life (6-9 hours)
56
ceftazidime
- most active of 3rd generation against Psedamonas aeruginosa
- among the poorest 3rd generation for gram positive
- shortest half life (90min)
57
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
58
4th generation cephalosporin
cefepime
59
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
60
cephalosporins
- renal excretion/metabolism
- side effects:
* allergic reactions
* nausea, vomiting, diarrhea, enterocolitis
* heptocellular damage
61
Cross allergies between penicillins and cephalosporins
-shared side chains are associated with increased likelihood of allergic cross reaction
62
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
63
Imipenem spectrum
- broad spectrum
| * resistant to many B-lactamases including ESBL
64
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
65
SIde effect for Imipenem
- allergic reactions: come cross allergies with penicillins and cephalosporins
- seizures, dizziness, confusion
- nausea, vomiting, diarrhea, pseudomembranous colitis, superinfection
66
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
67
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
68
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
69
what is vancomycin a 1st line drug of choice for
clostridium difficile
70
administration of vancomycin
- IV for systemic infections (primarily for serious infections)
- oral for clostridium difficile enterocolitis
71
Vancomycin and meningitis
- empirical treatment for meningitis
| - 3rd generation cephalosporin and vancomycin
72
vancomycin side effects
- red man or red neck syndrome
- nephrotoxicity
- ototoxicity
- phlebitis
73
Fosfomycin
-blocks enolpyruvyl transferase so you can't produce UDP-N-acetylmuramic acid which is a precursor for peptidoglycan synthesis
74
uses of fosfomycin
-uncomplicated UTIs especially caused by E. coli Enterococcus
75
side effects for Fosfomycin
-headache, diarrhea, nausea, vaginitis
76
```
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
77
Drugs that target cell membrane
- Polymyxin B
| - Daptomycin
78
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
79
Daptomycin
| MOA
- binds to bacterial cytoplasmic membrane causing rapid membrane depolarization
- rapidly bactericidal
80
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
81
side effects of daptomycin
- nausea, diarrhea, GI flora alterations (including C diff)
| - muscle pain and weakness
