Exam 2 lecture 1 Flashcards
What are the different B lactams? describe their structures
Penicillin- house with garage (has SUlfur)
Cephalosporin- House with basement and garage- six ring with sulfur
Carbapenems- Like penicillin but has a carbon instead of sukfure
Monobactam- only garage
What are 6 general characteristic of B lactams for exam
- They have same MOA: Inhibit cell wall synthesis
- Same MOR: B lactamase degradation, PBP alteration, decreased penetration
- Bactericidal in time dependent manner, except against enterococcus spp
- Short elimination half life of <2 hrs
- Primarliy eliminated unchanged in kidneys
6 Cross allergenicity
What are exceptions to B lactams being excreted unchanged in kidneys?
Naficillin, oxacillin, ceftriaxone, cefoperazone
What do we not see cross alergenicity in B lactams (lack of cross reactivity)
Aztreonam
MOA of penicillins?
Interfere with cell wall synthesis by binding to and inhibiting penicillin binding proteins (PBPs) located in bacetrial cell wall (PBPs are transpeptidases).
When are PBPs expressed? Do PPs varry?
only during cell division
Number, type and location of PBPs vary between bacteria.
Is penicillin bacteriostatic? bacteriocidal?
ARe bactericidal (not against enterococcus)
How does the general structure of B lactam affect its activity on PBPs
It dictates which B lactam it inhibits
Where do PBPs exist for gram positive bacteria? For gram Negative bacteria?
For gram positive they exist on cell surface
For gram negative PBPs are cell membane
Compare the rate at which B lactams and penicillin kill bacteria
They are medium rate killers
What are the 3 mechanisms of resistance to Penicillin? Which is the most important?
- production of B lactamase (most important)
- Alteration in structure of PBPs leading to decreased binding affinity
- Alteration of outer membrane porin proteins leading to decreased penetration
Which gram positive bacteria produce B lactamase? Gram negative? Gram negative anaerobes
Gram positive- Penicillin resistant staph aureus
Gram negative- Haemophilus influenzae, Moraxella, Neisseria gonorrhea, E coli, Enterobacter spp, klebsiella pneumoniae
Gram neagtive anaerobes- bacteroides fragilis
Why do gram positive bacteria not make any B lactams? Compare to gram negative
Except PRSA, It is not very efficient as it releases B lactamase in the environment
For gram negative, It concentrates the B lactams between the outer membrane so its easier to produce B lactamases to digest them
Which gram positive bacteria are primarily resistant to penicillin via alteration in structure of PBPs leading to decreased affinity
MRSA (methicillin resistant staph Aureus)
PRSP (penicillin resistant staph pneumoniae
WHen staph aureus becomes methicillin resistant what is the only B lactam that retains activity
Anti MRSA cephalosporin
What kind of mutation causes PRSP? How is it caused? What antibitotics does it wipe out
Chromosomally mediated mutation
It is caused by secondary to overexposure to B lactams
PRSP wipes out all penicillins, most cephalosporins, Carbopenems and monobactams
Would b lactamase inhibitors help with MRSA or PRSP?
No
What bacteria usually alter porin protein content? How does this affect B lactam in cell
Gram negative.
Decreases penetration into cell
Why were semi synthetic penicillins developed?
To provide enhanced antibacterial activity
Which are the natural pencillins
Aqueous Pen G (IV)
Benzathine pen G (IM)
Procaine penicillin G (Oral)
Phenoxymethyl penicillin VK
1st group to be discovered and used
Describe history of Penicillin and staph aureus? Strep pneumoniae? How did resistance occur? WHat percent are susceptible?
100% of staph aureus was susceptible to penicillin, but penicillinase enzymes caused resistance to where today <5% are sesceptible to Penicilin. Led to penicillinase resistant penicillins were developed.’
Strep pneumoniae was also 100% susceptible, PBP alterations caused 15-20% of pneumo have high level penicillin resistance. (not used for empiric therapy, but may be used for directed therapy)
What are gram positive organisms susceptible to Natural Penicillin
Group streptococci
Viridians Streptococci
Enterococcus spp
Pen susceptible S pneumoniae
Pen susceptible S aureus
Bacillus Spp
What are gram negative organisms susceptible to natural penicillin
Only agaonst gram negative cocci
Neiseria spp
Pasteurella Multocida
What anaerobic drugs are natural penicillin drugs effective against
Pepto spp
clostridium spp
What other organism are natural penicillins used against (exam)
Treponema Pallidum (syphillis)
Why were penicillinase resistant penicillins created (AKA Antistaphylococcal penicillins) ? How do they work (SAR)? Examples?
Developed in response to emergence of penicillinase producing staphylococcus aureus
Semi synthetic derivatives of natural penicillin that contain an acyl side chain that acts as steric hinderance
Examples- Parenteral agents- Naficillin (most used), Oxacillin, Methicillin (no longer used)
Oral- Dicloxacillin
What is the most commonly used penicillinase resistant penicillin? WHat do we call bacteria that are susceptible to this class of medication? Resistant to them
Nafcillin, but it is called methicillin ( even though methicillin was discontinued the name just stuck)
If resistant- we call them MRSA ( methicillin resistant staph aureus)
If susceptible- MSSA (methicillin suscpetible staph aureus)
Why was methicillin dx
Interstitial nephritis
Nafcillin/oxacillin used insetad
What are the penicillinase resistant penicillins? What are they used for?
Developed to overcome the penicillinase enzyme of staph aureus, which is inactivates natural penicillin
Used against MSSA (methicillin susceptible s. aureus) (primary use)
What B lactam is the only one that retains activity agaonst methicillin resistant SA
Cefteroline
What is the primary Anti staph drug? WHat is its activity against gram negatives? Gram negative anaerobes?
Nafcillin
No activity against gram negatives and gram negative anaerobes
Why were aminopemicillins created?
developed in reponse to the need for agents with gram negative activity
Semi synthetic derivative that added amino group
examples of aminopenicillin
Parenteral- Ampicillin
Oral- Ampicillin and Amoxicillin
What is the primary drug used for enterococcus spp
Ampicillin
Spectrum of activity of aminopenicillins (ampicillin/amoxicillin) ? When are they used?
Gram positive- Enterococcus Spp, Listeria
Gram negative- Shigella, Salmonella, E coli Proteus Mirabillis Beta lactamase negative H influenza
Resistances are seen in Salmonella, Shigella and E coli
Are only used against Proteus Mirabillis and Beta lactamase negative influenza
Why were carboxypenicillins created? How do they look structurally? What are the drugs?
Developed to further increase activity against gram negative aerobes
Derived from natural penicillin with addition of carboxyl group
Example- Ticarcillin
What are the organisms carboxypenicillins (ticarcillin) are used against
Gram positive- Marginal
Gram negative- Proteus mirabillis, salmonella, shogella, E coli (same as aminopenicillins) But also add Beta lactamase POSITIVE H influenzae, Enterobacterales Spp,* Pseudomonas aeruginosa* (SHEPMEP)
What is special about ticarcillin
Kills Pseudomonas aeruginosa (not as well as piperacillin)
Why were Ureidopenicillins developed for? What does structure look like? What are Ureidopenicillin drugs?
Developed for further need of activity against gram negative bacteria such as Klebsialla and Seratia
Instead of penicillin as base molecule, they used ampicillin, with acyl side chain
Example- parenteral- Piperacillin
What is the spectrum of activity of Piperacillin
Gram negative-
Proteus Mirabillis, Salmonella, Shigella, E coli, BL + H influenzae, enterobacter spp, pseudomonas aeruginosa
Serratia and some klebsiella spp
(SHEPMEPP + KS)
Anaerobes- Have good activity for below the diaphragm anaerobes
What is the penicillin of choice for pseudomonas aeruginosa
Piperacillin (usually used with B lactamase inhibitor
What are the broadest spectrum penicillins without B lactamase activity
Ureidopenicillins
Why were B lactamase inhibitor combinations used? MOA? Examples?
Developed to enhance activity against B lactamase producing bacteria
B lactamase inhibitors irreversibly bind to catalytic site of B lactamase enzyme
Examples- oral- Amoxicillin Clauvanate
Parenteral- Ampicillin sulbactam (Unasyn), Piperacillin-tazobactam (zosyn)
Spectrum of activity for B lactamase inhibitor combos
Gram positive- MSSA (NOT MRSA)
Anaerobes- Bacteroides spp
Gram Negative- H influenzae, E coli, Proteus Spp, Klebsiella, Neisseria Gonorrhoeae, Moraxella Catarrhalis
What is the primary anti staph penicillin (MSSA)
Nafcillin
Do B lactamase inhibotor combos work for Pseudomonas?
No
What is a traget organism for B lactamase inhibitor combos
Bacteroides spp
What type of bacterial killing do penicillin have, time or concentration dependent? WHat is the goal of dosing penicillins? Half life? How do the PK of the drug affect administration?What type of killing do they have?
Time dependent bacterial killing (time above MIC Time>MIC)
Goal of dosing- Administer agents to maintain serum concentration > MIC of infecting bacteria for 50% of dosing interval
Because of short half life, require repeated frequent dosing or continous IV to achieve PD goal
Bacteriocidal, except in enterococci (low affinity of PBP so it is bacteriostatic in enterococci)
What are clinically useful synergy of penicilins? When are they used?
Viridians Strep- Penicillin or ampicillin plus gentamicin
Enterococcus Spp- Ampicillin plus gentamicin or streptomycin
Staphylococcus spp- Nafcillin plus gentamicin
Gram negative bacteria- Ticarcillin or piperacillin plus gentamicin, tobramicin or amikacin
Are penicillins degraded by gastric acid? Describe concentrations achieved with PO vs IV for penicillin? When should they be given PO
Many penicillins are degraded by gastric acid
Lower concentartions achieved with PO versus IV dosing so that oral pens should be used for mild to moderate infections only.
Compare oral absorption of Pen Vk and Pen G? What are the two IM penicillin specially formulated for delayed absorption
What is orally absorbed better Ampicillin or amoxicillin
What is the best orally absorbed antistaphylococcal penicillin
Pen Vk absorbed better orally than pen G
Benzathine and procaine pen are the IM drugs
Amoxicillin absorbed better than ampicillin (ampicillin 4x a day, amoxicillin 3x a day)
Dicloxacin absorbed best antistaphylococcal
CSF availability of penicillins? B lactamase inhibitors? (Exam)
All parenteral penicillins penetrate CSF when used at max dose in presence of inflamed meninges
B lactamase inhibitors do not penetrate
How are most penicillins eliminated? (exam) WHat happens incase of disease of the organ? What happens if dose is not adjusted in case of insufficiency?)
Most eliminated unchanged by kidney (adjust dose in renal insufficiency
If not adjusted it will cause neurotoxicity
What are the 2 penicillins that do not need adjustment for renal insufficiency? why? (exam)
Nafcillin and oxacillin are eliminated primarily by liver, so do not require adjustment renally
Half lives of penicillins
Short (<2 hrs)
(EXAM) What is the sodium content of penicillins with a sodium load? What is a caution to do with them?
Sodium Pen G- 2.0 mEQ per 1 million units
Nafcillin- 2.9 mEq per gram
Ticarcillin- 5.2 m Eq per gram
Piperacillin- 1.85 mEq per gram
Must be used with caution in pts with CHF or renal insufficiency
When are natural penicillins THE drug of chouce
Syphillis
When are penicillinase resistant penicillins the drug of choice
Infections due to MSSA (methicillin susceptible staph aureus)
What are the most active penicillins against enterococcus? Listeria monocytogenes
aminopenicillins
Clinical uses of carboxypennicillins and ureidopenicillins
Serious infections due to gram negative aerobic bacteria
Empiric therapy for hospital acquired infections
Infection due to pseudomonas aeruginosa (especially piperacillin)
B lactamase inhibitor combination use of augmentin? Unasyn? Zosyn? Timentin?
Augmentin- Sinusitis, otitis media
Unasyn, zosyn, timentin (IV)- polymicrobial infections
Empiric therapy for hospital acquired infections (zosyn)
What is use for empiric therapy for hospital acquired infections
Zosyn
Adverse effects of penicillins? Cross reactivity?
Hypersensitivity rxn (mild to severe)
Cross reactivity exists among all penicillins and even some B lactams
What type of rxn is type 1 allergic rxn? What is it mediated by? Type 2?
Immediate allergic rxn. Mediated by IgE
Type 2 is delayed, mediated by IGg or IGm. No hives, have rash
Do we use penicillin after type1 rxn? After type 2?
No for either
If someone has rash to penicillin, do we use another penicillin product?
No, if allergic to one, can not change to another penicillin
Penicillin adverse effects
Neurologic- especially in pts on high dose with renal insufficiency. Causes seziures (do not exist in nafcillin)
Hematologic- Neutropenia, thrombocytopenia
Interstitial nephritis
How does penicillin cause interstitial nephritis (exam)? What drugs are most likely to cause it
Immune mediated damage to renal tubules characterized by an abrupt increase in serum createnine
Can lead to renal failure
Methicillin causes it most thats why it was dx
Nafcillin, penicillin or pipercillin can cause it too
Can a patient who has developed a rsh to penicillin safely receive amoxicillin?
No, 100% cross reactivity seen in penicillin group. All penicillins should be avoided
