Beta-Lactam Antibiotics Flashcards
classes of beta lactams
penicillins, cephalosporins, carbapenems, monobactams
what characteristic do all members of beta-lactams share?
they all share a similar structure: the beta-lactam ring that is essential for activity
- substitutions on the ring are used to increase resistance to beta-lactamase enzymes, enhance
penicillin drug classifications
- natural penicillins: penicillin G
- amino penicillins: ampicillin, amoxicillin
- anti-staph penicillins: oxacillin
- extended spectrum penicillins: piperacillin
penicillin MOA
- prevention of cell wall formation and lysis of bacteria: bactericidal action!
- inhibition of peptidoglycan synthesis by interfering with enzymes called PBPs: penicillin-binding proteins
penicillins are bactericidal for what type of cells?
growing cells: only bactericidal for those undergoing cell-wall synthesis
what has a faster rate of kill activity: penicillins or fluoroquionolones
fluoroquinolones
how are beta-lactams bactericidal?
the ring of betalactams has a 3D structure that mimics a terminus that acts as a natural substrate for transpeptidase activity during cell wall synthesis
- by blocking the formation of theses covalent bonds, the cell weakens and leads to lysis from high internal osmotic pressure
what determines if beta lactams will be effective on cells?
variation in activity for Gram + vs Gram - depends on:
- differences in receptor sites on PBPs
- relative amount of peptidoglycan present
- ability to penetrate outer cell membrane of Gm-
- resistance to different types of betalactamase enzymes present
bactericidal of beta-lactams is dependent on
time
are beta lactams time or concentration dependent?
time dependent: length of time that abx concentrations at site of infection exceed the MIC (T>MIC) should be at least 50-60% of the dosing interval)
- thus, these drugs are often dosed MORE FREQUENTLY than the concentration dependent drugs like fluoroquinolones
you need to give Muffin, a 9 year old crusty white dog, antibiotics. You decide on a beta lactam, and because you are an astute CSU grad, you know that these drugs are time-dependent. what does this mean for how often you are likely going to dose Muffin?
muffin will likely be dosed more frequently because of the time-dependency: need to be above the MIC to constantly block the transpeptidase in cell wall formation
why is the “eagle” or paradoxical effect important with beta lactams?
- if you give concentrations above an optimal killing concentration, you get reduced bactericidal (killing) effect because PBPs get bound and cause a growth arrest. this failure to grow means failure to be killed by the antibiotic
- important because there can be a tendency to overdose with these drugs due to the large margin of safety. more doesn’t always mean better!!
resistance to beta-lactam abx
- beta lactamase enzymes produced by bacteria
- these enzymes break the beta-lactam ring, destroying the active part of the drug
where do gram + produce beta lactamases?
gram + produce inducible beta-lactamase extra-cellularly
where do gram - bacteria produce beta lactamases?
constitutively produce beta-lactamase in the peri-plasmic space
gram - bacteria beta lactamase enzymes are more active against what drugs?
penicillins
what is better at killing gram - bacteria: penicillins or cephalosporins?
cephalosporins: the beta lactamase enzymes are more active against penicillins than cephalosporins
why has the discovery of beta-lactamase inhibitory drugs been so important
they irreversibly bind the beta-lactamase enzyme and allow the antibiotic to exert the bactericidal effect: we use these with beta-lactams to block the bacteria’s ability to break down the drug
what beta-lactamase enzyme inhibitors are often mixed with beta-lactam antibiotics?
avibactam, clavulanic acid, tazobactam
best way to block resistance via b-lactamase enzymes is to inhibit them!
are penicillins well or poorly absorbed orally?
poorly absorbed orally
why are penicillins often given frequently?
they have very short half lives/rapid elimination = frequent administration + slowly absorbing formulations like procaine penicillin has helped combat this
PK properties of penicillins
- acid labile, poorly absorbed orally
- short half-lives/rapid elimination
- small volume of distribution, don’t cross membranes easily
- eliminated almost entirely through renal excretion = very high urine concentrations
why would you not want to use penicillins for a intracellular bacterial infection/mycoplasma?
penicillins have a very small volume of distribution and do not cross biologic membranes readily. they are very water soluble and are limited to extra-cellular water
how are penicillins eliminated?
almost entirely through renal excretion = very high urine concentrations. don’t really need to worry about giving to renally impaired patients because of the wide margin of safety
natural penicillin
benzyl penicillin and long-acting parenteral forms
penicillin G activity
most active against Gm+ aerobes and anaerobes
less activity against Staph, Gm- and enterobacter are generally resistant
is penicillin G more active against Gm + or Gm- bacteria?
Gram + aerobes and anaerobes
toxicities of penicillin G
rare, but most often is hypersensitivity reaction, can cause anaphylaxis
can have toxic effects from the potassium combined, esp if large amts of potassium PenG are injected rapidly: cardiac arrest
orally absorbed penicillins
penicillin V resists acid hydrolysis and is administered orally. same spectrum as benzyl penicillins
Penicillin G Salt Forms
IV or IM use
Penicillin V tablets
oral use (acid stable)
Penicillin G- Benzathine Salt Suspension
- IM
- slow release due to solubility
- lower peak, longer duration in plasma
penicillin G- Procaine Salt Suspension
- IM
- slow release due to solubility
- lower peak, longer duration in plasma
- local anesthetic activity of procaine may alleviate deep muscle pain associated w drug
why would administering procaine salt suspension of Pen G help with pain?
it has local anesthetic activity: may alleviate deep muscle pain associated with drug
what type of penicillin should you NOT use in exotic species?
procaine penicillin!! susceptible to procaine toxicity!!
what species should you NOT use procain penicillin in?
birds, snakes, turtles, guinea pigs, chinchillas
susceptible to procaine toxicity!!!
aminopenicillins
ampicillin + amoxicillin
why are aminopenicillins considered extended-spectrum?
spectrum of activity is increased to include many Gram- aerobes (E.coli, Proteus, Pasteurella)
spectrum of activity of ampicillin and amoxicillins
- spectrum increased to include many Gm- aerobes (E. coli, Proteus, Pasteurella)
- slightly less activity than PenG against Gm+ and anaerobes, but still useful clinically
what has more bioavailability, amoxicillin or ampicillin?
amoxicillin (70% > 40%)
why are aminopenicillins often combined with beta-lactamase inhibitors?
they are susceptible to beta-lactamase hydrolysis
- combos with inhibitors like clavulanic acid, sulbactam or tazobactam increase their effectiveness considerably
antistaphylococcal penicillins
cloxacillin, dicloxacillin, oxacillin, methicillin
why are the antistaphylococcal penicillins useful?
resistant to the beta-lactamases produced by Staph aureus! mainly used in treatment of bovine staphylococcal mastitis
you get called out to a dairy farm for a couple cases of mastitis. you are suspecting they are staphylococcal in origin. if you were to reach for antibiotics, what might be some options?
antistaphylococcal: cloxacillin, dicloxacillin, oxacillin, methicillin
what antistaph abx can be given orally to monogastrics?
cloxacillin and oxacillin
what is oxacillin used to test for?
methicillin sensitivity in vitro
methicillin resistant staphylococcus (MRSA and MRSP) can be considered resistant to
ALL beta lactam antibiotics. have super strong beta lactamases
what causes methicillin resistance?
the MecA gene in bacteria producing an alternative PBP (PBP2A)
antipseudomonal/extended spectrum penicillins
carbenicillin, ticarcillin, piperacillin
what is unique about drugs like carbenicillin, ticarcillin, piperacillin?
they are defined by their superior activity against Pseudomonas, which none of the other penicillins have
- cost and requirement for IV delivery may limit utility
what may limit utility of antipseudomonal/extended spectrum abx?
cost and requirement for IV delivery
what antipseudomonal drug has been used for treatment of otitis externa in dogs?
ticarcillin IV has been used in combo w topical ticarcillin in treatment of otitis externa in dogs caused by Pseudomonas aeruginosa
do you use beta-lactamase inhibitors with antipseudomonals?
yes! they are susceptible to inactivation by beta-lactamase enzymes and thus can be combined with beta-lactamase inhibitors
ticarcillin + clavulonic acid
Timentin
Piperacillin + Tazobactam
Tazocin
carbenicillin, ticarcillin, and piperacillin are all what type of abx?
beta-lactams, penicillins, antipseudomonal/extended spectrum
what are potential issues with extended spectrum penicillins?
potential for disturbing normal intestinal flora
- after oral administration in dogs and cats this effect is less marked with amoxicillin than ampicillin because of better absorption (less drug remaining in GI tract)
- ampicillin should NOT be administered to small rodents (guinea pigs, gerbils, hamsters) or rabbits since it may produce Clostridial colitis
what is better to use in dogs and cats, amoxicillin or ampicillin?
amoxicillin! less drug remaining in GI tract, better absorption and less disturbance of normal intestinal flora
what drug should NOT be administered to small rodents or rabbits since it may produce Clostridial colitis?
ampicillin!
why should ampicillin not be administered to small rodents and rabbits?
it may produce Clostridial colitis :(
what is the best penicillin for treatment of urinary tract infections?
amoxicillin
what is the drug of choice for treating leptospirosis
amoxicillin
what are the drugs of choice for mixed aerobic-anaerobic infections like cat-bite infections?
ampicillin or amoxicillin
cephalosporins
beta lactam ring is attached to a 6 membered ring which makes this class inherently more resistant to beta-lactamase enzymes
- originally made for txt of penicillinase-producing staph infections
what came first, cephalexin or cefazolin?
cephalexin: ones discovered before 1975 are spelled with ph and ones after 1975 are spelled with f
PK of cephalosporins
- generally similar typical of beta lactams
- usually require parenteral injection
- short half-lives for most, needing frequent administrations (w a few exceptions)
- usually excreted thru kidneys into urine
- widely distributed to extracellular fluids and tissues EXCEPT CNS and eye
- poor intracellular penetration = low volume of distribution
TIME DEPENDENT AND BACTERICIDAL
are cephalsoporins bacteriostatic or bactericidal?
bactericidal
are cephalosporins time dependent or concentration dependent?
time dependent
what is a good alternative for penicillin-sensitive individuals?
cephalosporins
- time dependent, bactericidal activity, relatively non-toxic
antimicrobial activity of cephalosporins
varies with successive “generations”
- in general, as generation # increases (1-4), the Gram- coverage increases but at the cost of Gram+ coverage
what would have more gram - coverage: a 1st generation cephalosporin or a 4th generation cephalosporin?
4th generation
1st generation cephalosporins have similar spectrum of activity to what abx?
aminopenicillins: amoxicillin and ampicillin
how does cephalosporin resistance happen?
same mechanisms as for penicillins
- PBP modification
- reduced permeability and increased efflux
- beta-lactamase production: most important mechanism!!
first generation cephalosporins
- good activity: Gram + aerobes, including beta-lactamase producing staph and strep
- moderate: Gram - Enterobacteriacea
- NO activity against Pseudomonas or Enterobacter
what do first generation cephalosporins have good activity against?
gram + aerobes, including beta lactamase producing staph and strep
what are the injectable formulations of first generation cephalosporins?
cefazolin, cephapirin, cephalothin
what are oral formulations of first generation cephalosporins?
cephalexin and cefadroxil
what do all 2nd generation cephalosporins have in common?
they are all given parentally! NO ORAL FORMULATIONS
clinical applications of first generation cephalosporins
skin and urinary tract infections and other nonspecific infections caused by staph, strep, enterobacteria and some anaerobes
cefazolin and cephalexin are what type of abx?
first generation cephalosporin
antimicrobial activity of 2nd generation cephalosporins
- slightly more gram - and anaerobe coverage than 1st gen
- slightly less gram + coverage than 1st gen
where are 2nd generation cephalosporins derived from?
2 rugs are derived from streptomyces rather than cephalosporium
what is unique about the cephamycins: cefotetan and cefoxitin?
they are very stable to beta-lactamases! including those of bacteroides
clinical applications of 2nd generation cephalosporins
- cefoxitin can be used for aspiration pneumonia, bite infx, peritonitis, colonic surgery (mixed infections)
- cefuroxime for dry-cow therapy and for treatment of clinical mastitis in lactating cattle
how are 2nd generation cephalosporins given?
PARENTALLY! no oral formulations!!
3rd generation cephalosporins activity
- extended activity against Gm- pathogens
- some have good activity against Pseudomonas: Ceftazidime has best
- more resistant to beta lactamase enzymes
examples of 3rd generation cephalosporins
cefovecin, cefoxatime, ceftiofur
ceftiofur is what type of abx?
3rd generation cephalosporin
what is ceftiofur used for?
respiratory disease of cattle, sheep, swine, horses, and urinary tract infection of dogs
cefovecin
CONVENIAAAA
what type of drug is convenia?
3rd generation cephalosporin: Cefovecin is a SQ formulation for dogs and cats that can be used as a single treatment: drug levels remain above MIC for Staph pseud for 14 days
half-life in dogs and cats is about 5 1/2-7 days
oral 3rd generation cephalosporins
cefpodoxime (Simplicef)
cefpodoxime
- 3rd generation cephalosporin
- pro-drug that is deesterified in GI tract to release active cefpodoxime
- longer halflife than other oral cephalosporins, allows for once a day dosing!
T/F: cefpodoxime and cefovecin are active against pseudomonas
FALSE. even though they are 3rd gen cephalosporins they are not active against Pseudomonas
what are cefpodoxime and cefovecin not active against?
Pseudomonas
even tho they are 3rd generation
what should you NOT use for uncomplicated infections?
3rd and 4th generation cephalosporins! abx should be chosen that have the narrowest spectrum of activity needed for the infecting agent
most cat bite infections can be successfully treated with
amoxicillin
most staph skin infections can be treated with
cephalexin
why do you not want to use 3rd and 4th generation cephalosporins all the time?
they have the ability to induce “super beta-lactamases” in bacteria that render them super resistant! and thus no beta-lactam may be effective. THIS IS SUPER BAD
- extended spectrum beta-lactamases are a big concern for human health and txt of serious gram-neg infections
there is a ban on what abx in food animals?
extralabel cephalosporins: 3rd and 4th gen have ability to induce super beta lactamases
carbapenems
- beta lactam
- derivative of Streptomyces spp and differ slightly from penam penicillins in structure
- WIDEST ACTIVITY of any abx (exception is a fluoroquinolone)
carbapenems activity
active against almost all clinically important aerobic or anaerobic Gm+ or Gm- cocci or rods
indv species such as MRSA/MRSP may have some resistance
- resistant to almost all bacterial beta-lactamase enzymes
how are carbapenems administered?
all are administered parentally; IV, SQ, IM
what are carbapenems role in human medicine?
“last resort” = super broad spectrum and wide activity
imipenem
- carbapenem
- rapidly hydrolyzed in renal tubules to a NEPHROTOXIC COMPOUND
- therefore ALWAYS administered with cilastatin to inhibit the enzyme that converts it and thus prevents nephrotoxicity
how is imipenem administered?
IV only
what is imipenem always administered with? why?
always administered with cilastatin because imipenem by itself gets hydrolyzed by a dehydropeptidase in the renal tubules to a nephrotoxic compound. cilastatin inhibits the dihydropeptidase
cilastatin is always administered with what drug?
imipenem! a carbapenem
what is impenem used for?
primarily for treatment of ESBL: extended spectrum beta lactamase expressing bacteria when a single drug is required (3-4 doses per day required)
morepenem
carbapenem, sometimes used off-label: ex IV product can be used SQ with similar activity to imipenem
how does cilastatin work
blocks formation of a toxic metabolite and thus prevents nephrotoxicity of imipenem
what is dangerous about using carbapenems?
They have such broad-spectrum bactericidal action that bacterial superinfections with resistant bacteria are a likely sequela which will lead to contamination of the environment with such naturally resistant bacteria.
if using carbapenems for Pseudomonas, what should you combine them with? why?
combine with an aminoglycoside to reduce potential for resistance
monobactams
- aztreonam
- stable to most betalactamase enzymes
- use is mainly as substitute for more toxic aminoglycoside in combo therapy of severe mixed infx (ex w clindamycin or metronidazole for mixed infc)
spectrum of activity of monobactams
almost all gram - aerobic bacteria
- resistance seen in Gm+ and anaerobes
aztreonam
only monobactam drug evaluated in vetmed
classification of beta lactams
- Class of microorganism to which they show activity * Bacteria
- Antibacterial spectrum of activity
* Gram+
* Gram- (varied across the class) - Bacteriostatic or bacteriacidal
* Bacteriacidal
* Bacteriostatic at too high a concentration (paradoxical effect) - Time or concentration-dependent activity
* Time-Dependent (T>MIC)
are beta lactams bacteriostatic or bactericidal?
bactericidal
