Exam 2 Flashcards
What are the differences between Gram pos and Gram neg bacteria:
- drug penetration of the cell membrane
- distribution of β-lactamases
- peptidoglycan thickness
- number of membranes in the cell wall
- peptidoglycan content
- peptidoglycan bridging
Gram positive -
- drugs can penetrate the outer layers of the cell wall effectively
- β-lactamases are excreted through the cell wall to the external environment (this means G+ needs to produce more β-lactamases compared to G-)
- very thick peptidoglycan
- 1 bacterial membrane (this membrane is the main barrier keeping drugs out of the cell)
- peptidoglycan an L-lysine residue replaces the meso-diaminopimelic acid residue found in G-, meaning an H replaces the COOH of the DAP in G-
- peptidoglycan bridging exists between the L-Lys strand and the terminal D-Ala of the second molecule
Gram negative -
- drugs don’t penetrate much due to the outer membrane
- β-lactamases are confined to the periplasmic between the outer membrane and the inner membrane
- thin peptidoglycan
- 2 (inner & outer): The outer membrane excludes drugs, but some drugs can still get in through porins.
- peptidoglycan contains meso-diaminopimelic acid residue (DAP)
- peptidoglycan is cross-linked by a bridge between the DAP residue of one strand and the D-Ala of another
How does transpeptidase cross-link peptidoglycan strands?
- -OH of the transpeptidase (serine residue) binds where the amide is in the peptidoglycan between 2 D-Ala residues
- a tetradehral intermediate is formed
- a oxygen double bond is formed, which kicks out the terminal D-Ala residue
- the terminal lysine of a new peptidoglycan comes and attacks the ester (oxygen double bond)
- the oxygen double bond is formed again, which kicks out the transpeptidase. Now two peptidoglycans are connected & the transpeptidase is recycled!
What is the MOA of penicillins?
Penicillins inhibit the transpeptidases that cross-link the peptidoglycan. This results in a defective bacterial cell wall -> cell death. The reactivity of the β-lactam system is due to the highly strained 4-membered ring, and because the ketone carbonyl is more reactive than the amide carbonyl due to steric inhibition.
- penicillin fools the transpeptidase into thinking it’s D-Ala-D-Ala, so the serine residue on the transpeptidase attacks oxygen double bond on the penicillin
- this forms a tetrahedral intermediate
- an ester forms, which results in an extremely stable compound that is inactive
Why do penicillins display selective toxicity for bacteria but not the host?
The bacterial transpeptidases do not catalyze reactions with host cell proteins because the bacterial substrate contains unnatural D-Ala amino acid residues that are not found in the host cell proteins (mammalian cell proteins have L-Ala, not D-Ala).
What are the mechanisms of bacterial resistance for penicillins?
- Decreased cellular uptake of the drug
- Mutation of the penicillin-binding proteins to decrease their affinity for penicillins
- efflux pump that pumps the antibiotic out of the cell
- production of β-lactamases that hydrolyze the β-lactam moiety (β-lactamase binds to penicillin, forms an intermediate, then the compound lyses to form an inactive penicillin & regenerated β-lactamase)
What is the mechanism of penicillin allergenicity?
Allergenicity of β-lactam antibiotics results from the drug acting as a hapten. It acetylates host cell proteins, which then raises antibodies that result in an allergic reaction.
The allergic reaction originates from the pharmacophore of the drug, which means we can’t overcome it by structural manipulation & if you’re allergic to one β-lactam, you’re likely allergic to almost all of them.
How do penicillins degrade under acidic and basic conditions?
Acidic: main degradation products are Benzylpenicillenic Acid, Benzylpenillic Acid, and Benzylpenicilloic Acid
- With the help of anchimeric assistance, the side chain attacks the β-lactam ring. After going through a few intermediates, A Penicilloic Acid is formed. If the side chain is rotated, eventually A Penillic Acid will be formed. The A Penicillenic Acid is formed when a sulfhydryl group is eliminated during the conversion of A Penicilloic Acid -> A Penillic Acid.
- If the side chain is more election attracting, it will be less likely to degrade.
Basic:
- hydroxide from basic conditions attacks the carbonyl of the β-lactam, eventually resulting in A Penicilloic Acid
- no anchimeric assistance
What is the main chemical feature of penicillins that confers resistance to degradation under acidic conditions?
If the side chain is more election attracting (more electrophilic), it will be less likely to degrade.
How does degradation under acidic and basic conditions affect biological activity?
- Penicillin hydrolysis products have no antibiotic activity
- Hydrolysis of the β-lactam is irreversible
What conditions promote penicillin degradation?
Heavy metal ions catalyze penicillin degradation (so these should be kept away from penicillin solutions).
How does the lipophilicity of penicillins affect their serum protein binding?
The more lipophilic the side chain is, the more highly protein bound the penicillin will be.
How does serum protein binding of penicillins affect penicillin degradation?
Protein binding protects drugs from degradation.
How does serum protein binding of penicillins affect their half-life?
Half-life is usually not affected by protein binding, since the penicillins’ dissociation rates from the protein are fast and the renal excretion rates are rate-limiting.
How does penicillin serum protein binding affect bioavailability?
Protein binding reduces bioavailability by reducing the effective concentration of the free drug.
What are the mechanisms of penicillin excretion?
- Renal (90% tubular secretion, 10% glomerular filtration)
- Biliary
Most penicillins are excreted through the kidneys (except nafcillin, which is cleared by biliary excretion)
How does renal disease affect penicillin half life?
Half lives of penicillins that are excreted by the kidneys are prolonged in cases of renal disease or failure
How does probenecid affect penicillin half life and what is the mechanism involved?
Probenecid and penicillins are both anionic. So when the penicillin is administered with probenecid, it competes for the secretion mechanism, which in turn extends the half life of the penicillin.
How are penicillins distributed in the body?
Penicillins are distributed to most tissues except the CSF. But, if the meninges are inflames, some parenteral penicillins can enter the CSF. This is good because some can then be used for the treatment of meningitis.
How are penicillins synthesized?
Synthetic penicillins are made by acylation of 6-aminopenicillanic acid (6-APA)
What is the β-lactam nomenclature? (5 classes)
penam - house with a sulfur on the roof & a garage
penem - house with a sulfur on the roof, double bond on the wall, & a garage
carbapenem - house with a double bond on the wall & a garage
cephem - house with a sulfur on the room, a basement, a double bond in the basement, & a garage
monobactam - just a garage
What are the main differences between phenoxymethyl penicillin (pen V) and penicillin (pen G) and what chemical feature is responsible for this difference?
Main difference is that penicillin V is more stable in acid due to the electronegative ether oxygen in the side chain. This means Pen V is less nucleophilic, so it decreases participation in the β-lactam hydrolysis degradation reaction.
- Pen V more stable in the stomach
- β-lactamase sensitivity and toxicity are about the same as penicillin G though
What major penicillins are β-lactamase-resistant parenteral or oral penicillins, β-lactamase-sensitive, broad-spectrum, oral penicillins?
β-lactamase resistant parenteral penicillins:
- Methicillin
- Nafcillin
- Oxacillin
β-lactamase resistant oral penicillins:
- Oxacillin
- Cloxacillin
- Dicloxacillin
β-lactamase sensitive, broad-spectrum, oral peniciillins:
- Piperacllin
- Azlocillin
- Mezlocillin
What is the main chemical feature of methicillin that confers resistance to hydrolysis by β-lactamases?
Steric hindrance of the nucleophilic attack by the enzyme on the β-lactam carbonyl. The phenyl ring is directly attached tot he amide carbonyl & there are two methoxy substituents in the ortho position. If you take off a methoxy or if you change the position to para, it would be sensitive to β-lactamases again.
Why is methicillin so unstable to hydrolysis under acidic conditions?
It is unstable due to electron donation toward the amide carbonyl oxygen by the ortho methoxy groups, which mades the amid carboxyl oxygen more nucleophilic.
What is nafcillin’s β-lactamase sensitivity and acid stability?
not sensitive to β-lactamase
Slightly more stable in acid than methicillin, but clinically, it’s identical to methicillin.
What are the structural similarities of oxicillin, cloxicillin, and dicloxicillin? What are their β-lactamase sensitivity, protein binding, and cross-resistance with methicillin?
Structure: they are all isoxazoles
Non sensitive to β-lactamases
Protein binding: highly protein bound, so they are not good for treatment of septicemia
Cross-resistance: generally cross-resistant with methicillin
Why is ampicillin stable in acid?
The amino group is protonated in the stomach, which makes it more electron-attracting. This decreases nucleophilicity of the amide carbonyl oxygen so that it does not participate in the ring-opening of the lactam.
What is the main difference between amoxicillin and ampicillin with regard to absorption?
Amoxicillin is an analog of ampicillin. It has a phenolic hydroxyl group that is now in the aromatic ring. This results in better oral absorption.
How do the β-lactamase inhibitors (clavulanic acid & sulbactam) work?
These acylate the serine hydroxyl group in the active site of the β-lactamase.
Using these with the β-lactamase sensitive β-lactams will increase the activity of the β-lactam antibiotic activity
Why do the acylureidopenicillins have a broadened spectrum of antibacterial activity and enhanced potency?
These have added side chain fragments that resemble a longer section of the peptidoglycan than ampicillin does.
These have activity against G(+), but also some G(-), like Pseudomonas aeruginosa, Klebsiella pneumoniae, and Bacteroides fragilis.
What are the main starting materials for the synthesis of cephalosporins? Where do they originate from? How are the cephalosporins synthesized?
7-aminocephalosporanic acid is the starting material for cephalosporins (it has an amine to react with things to add side chains). It is the product of some conversions of Cephalosporin C, which was isolated from Cephalosporium acremonium.
Also, 7-amino-3-deacetoxycaphalosporanic acid is a useful starting material for the synthesis of cephalosporins. It’s synthesized from phenoxymethylpenicillin.
What is the MOA of cephalosporins?
They react with transpeptidases, which results in inhibition of peptidoglycan cross-linking.
How are cephalosporins acted on by β-lactamase?
Cephalosporins are hydrolyzed by β-lactamases. The β-lactamase opens their ring structure and renders them inactive.
How do cephalosporins compare with penicillins in terms of allergenicity?
Cephalosporin allergic reactions are generally less common and less severe than penicillins. But cross-allergenicity is common, so cephalosporins should be used with caution in pts who are allergic to penicillin.
What is the main classification scheme for cephalosporins?
1st gen through 5th generation.
From the 1st through 3rd generation, Gram-negative activity is gained and Gram-positive is lost.
How do you classify the main cephalosporins as 1st gen, 2nd gen, 3rd gen, or 4th gen? What is the structural feature that aids in their classification?
1st gen - Methyl at C3. primarily active against Gram (+) cocci
2nd gen - Carbamate at C3. these have Gram(+) activity like the 1st gens, but they are also active against Haemophilus influenzae. These also have better Gram(-) activity.
3rd gen - Pyridinium ring at C3. Aminothiazole/oxime ether at C7. Less active against staph than the 1st gens, but more active vs. Gram (-) bacteria than the 1st/2nd gens (due to side chain carboxyl). More frequently used against nosocomial multidrug-resistant strands.
4th gen - N-methylpyrrolidine at C3. Syn methoximino at C7. Add Pseudomonas aeruginosa and some enterobacteria that are resistant to 3rd gens. These are also more active against Gram (+).
5th gen - Ceftaroline Fosamil is broad-spectrum prodrug that can be used against MRSA.
What is the main structural feature that distinguishes if a cephalosporin is orally active vs. parenteral?
Orally active cephalosporins have substituents at C3 that are not chemically reactive (ex. Cephalexin).
What structural feature of the cephalosporin C-3 side chain confers acid stability?
The less reactive it is, the more stable it will be in acid. In 1st gen orally active cephalosporins, there is only a methyl at C3.
In 2nd gens, there is a carbamate that is not a good leaving group, which enhances PO bioavailability.
How do cephalosporins with syn and anti oxime ethers on the C7 side chain differ in terms of hydrolysis by β-lactamases? What is the reason for this difference?
The syn methoximino group is more resistant to β-lactamases than the anti isomer.
How do cephalosporins with acetate vs. carbamate side chains at C3 differ with respect to enzymatic hydrolysis by esterases?
The carbamate will be more stable, so it will undergo less hydrolysis by esterases. This is due to the electron-donating NH2 on the carbamate.
How does the distribution of cefuroxime differ from most of the other cephalosporins? How is this clinically useful?
Cefuroxime penetrates the BBB into the cerebrospinal fluid which makes it useful in the treatment of Haemophilus influenzae meningitis.
What is the relationship between cefuroxime and cefuroxime axetil? What are their differences of bioavailability and route of administration?
Cefuroxime axetil is the orally active prodrug of cefuroxime. It is more lipophilic due to the 1(acetyloxy)ethyl ester, so it’s more readily absorbed from the GI tract. After absorption, it’s hydrolyzed back to cefuroxime.
What is the effect that the large oxime ether has on ceftazidime’s stability vs. β-lactamases?
The large oxime ether increases stability against β-lactamases.
What does the charged pyridinium ring of ceftazidime do in regard to β-lactam reactivity and with aqueous solubility?
The pyridinium ring at C3 is a really good leaving group and it strongly activates the β-lactam ring. It also results in enhanced aqueous solubility and makes it parenterally active, since it’s too reactive to be given orally.
What is the effect that the charged N-methylpyrrolidine moiety of cefepime has on β-lactam reactivity?
The N-methylpyrrolidine moiety is a good leaving group, which increases the reactivity of the β-lactam, making it too reactive for oral use.
What effect does the syn methoximino group on the C7 side chain of cefepime have on stability vs. β-lactamases?
The syn methoximino group stabilizes cefepime against β-lactamases.
What is the distinguishing structure of the cephamycins? What does this do for β-lactamases? What are 2 names of cephamycins?
The cephamycins have a 7α-methoxyl group & are often classified as 2nd gen cephalosporins. The 7α-methoxyl group increases stability against β-lactamases.
- Ex. cefoxitin, cefotetan
What adverse reaction does cefotetan cause?
Due to releasing N-methylthiotetrazole, the pt could experience hypoprothrombinemia or a disulfiram reaction.
Why can’t thienamycin be used as a drug? How has this been overcome?
Thienamycin is too reactive to be used as a drug, since the primary amino group attacks the β-lactam intermolecularly. Instead, the N-formiminoyl group was added, which is seen in Imipenem.
What effect does the replacement of the sulfur atom of the penicillins with a methylene group in the carbapenems have on the reactivity of the β-lactam ring?
Due to replacing the sulfur with a methylene group, reactivity is increased. This is because a methylene is smaller than a sulfur, so the ring strain is greater in the carbapenems.
What is the unique feature that the antibiotic imipenem has vs. β-lactamases?
Imipenem reacts with and inhibits β-lactamases, on top of reacting with penicillin-binding proteins.
What effect does renal enzyme dehydropeptidase-1 have on imipenem? How has this limitation been overcome?
renal dehydropeptidase-1 hydrolyzes imipenem. By co-administering cilastatin, a dehydropeptidase-1 inhibitor, we can overcome this.
Mechanistically, how do the monobactams react with penicillin-binding proteins (transpeptidases)?
Because the sulfamic acid is so electronegative, it activates the β-lactam ring toward chemical hydrolysis and to react with PBPs
Do the monobactams have cross allergenicity with the penicillins and cephalosporins?
No cross allergenicity has been reported, except with ceftazidime, since it has an identical oxime ether sidechain.
What do the structures of vancomycin and teicoplanin look like?
These molecules are very large and appear to be lipophilic.
What is the difference between the MOA of vancomycin and that of penicillin?
Vancomycin is an inhibitor of Gram (+) cell wall biosynthesis. Vanc binds to the peptidyl side chain D-ala-D-ala terminus in the peptidoglycan precursor, before cross-linking. So, cross-linking is inhibited, since the peptidoglycan is already bound up.
Additionally, vanc sterically hinders the attack of the other peptidoglycan by engulfing the peptidoglycan.
What is the mechanism of bacterial resistance of vancomycin?
Mutation of the peptidoglycan cell wall precursor from D-Ala-D-Ala to D-Ala-D-Lactate. Vancomycin doesn’t have the same affinity for the D-Lactate, so it doesn’t bind to it, and therefore, doesn’t inhibit crosslinking.
What is the route of administration of vancomycin?
Vanc is usually administered IV (horrible bioavailability if given orally).
What are the main toxic effects of vancomycin?
- Red man’s syndrome
- Nephrotoxicity
What are the differences in clinical uses of teicoplanin and vancomycin?
Same as vancomycin, but has a much longer 1/2 life than vanc.
What is the PK of vancomycin?
Doesn’t achieve good blood levels if given orally. Highly distributed in tissue and 90% eliminated by glomerular filtration.
How can you tell if something is a lipoglycopeptide or lipopeptide? What are oritavancin, telavancin, dalbavancin, and daptomycin?
Lipoglycopeptides have a peptide, glyco, and lipo portion (obviously).
- Ex. oritavancin, telavancin, dalbavancin
Lipopeptides have a peptide and lipid portion, but no glyco portion.
- Ex. daptomycin
What are the MOAs of oritavancin, telavancin, dalbavancin, and daptomycin?
Oritavancin - Disrupts the membrane of gram(+) bacteria by inhibiting transpeptidation and transglycosylation.
Telavancin - similar to vanc. Binds to D-ala-D-ala terminus. It inhibits transpeptidation and transglycosylation.
Dalbavancin - identical to vanc
Daptomycin - aggregation of dapto in the bacterial membrane creates holes that leak ions.
β-lactam antibiotics - MOA, mechanisms of resistance, pharmacodynamic properties, elimination half life, route of elimination, and potential for cross-allergenicity
MOA - inhibitors of cell wall synthesis by inhibiting peptidoglycan binding proteins
Mechanisms of resistance - 1. destruction by β-lactamase enzymes, 2. alteration in PBPs (so that they can’t bind to them). 3. decreased permeabiltiy of outer cell wall membrane in Gram (-) bacteria
Pharmacodynamics - time dependent (T>MIC) bactericidal activity (except against Enterococcus spp., which is bacteriostatic)
Elimination half-lie - short 1/2 life (<2 hours), except ceftriaxone, cefotetan, cefixime, ertapenem
Route of elimination - Renal elimination. Primarily eliminated unchanged by glomerular filtration and tubular secretion, except nafcillin, oxacillin, ceftriaxone, and cefoperazone
Cross-allergenicity - All have cross-allergenicity, except for aztreonam
Which gram positive aerobes (1) and gram negative aerobes (8) and gram negative anaerobes (1) produce β-lactamase?
Gram positive: Staphylococcus aureus
Gram negative aerobes:
- H. influenzae
- E. coli
- K. pneumoniae
- M. catarrhalis
- N. gonorrhoeae
- Proteus spp.
- P. aeruginosa
- S. marcescens
Gram negative anaerobes: Bacteroides fragilis
What is the spectrum of activity of the natural penicillins? (esp. think about Staph aureus, Enterococcus spp., Pseudomonas aeruginosa, and Bacteroides fragilis)
What is pen G the drug of choice for?
natural penicillins: excellent against non-β-lactamase producing cocci and bacilli
- (+): Group streptococci, Viridans streptococci, Some Streptococcus pneumoniae, most Entercoccus spp., very little Staphylococcus (due to penicillinase production), Bacillus anthracis, Corynebacterium spp.
- (-): some gram(-) cocci: Neisseria meningitidis, non-β-lactamase-producing Neisseria gonorrhea, Pasteurella multocida
- anaerobes: good activity: (above the diaphragm) mouth anaerobes, (below the diaphragm) Clostridium spp, but not C. diff
- other: Treponema pallidum (syphillus) drug of choice for this
Penicillin G is considered a potential drug of choice for infections due to viridans and group strep, N. meningitidis, Corynebacterium diphtheriae, Baccilus anthracis, Clostridium perfringens, and tetani, and Treponema pallidum
What spectrum of activity do the penicillinase-resistant penicillins and aminopenicllins have? (esp. think about Staph aureus, Enterococcus spp., Pseudomonas aeruginosa, and Bacteroides fragilis)
What can the aminopenicillins be the DOC for? (2)
penicillinase-resistant penicillins: antistaphylococcal penicillins
- (+): group and viridans strep (less than Pen G), MSSA (not MRSA), not active against Enterococcus spp. or Streptococcus pneumoniae
- (-): none
- anaerobes: none
aminopenicillins: extended gram negative activity
- (+): similar to natural penicillins, also ineffective against Staph aureus, better than natural penicillins for Enterococcus spp., and excellent against Listeria monocytogenes
- (-): (SHEP) Salmonella/Shigella, Haemophilus influenzae, Escherichia coli, Proteus mirabilis
- anaerobes: similar to Pen G
drug of choice for Listeria monocytogenes and Enterococcus spp.
What spectrum of activity do the carboxypenicillins and ureidopenicillins have? (esp. think about Staph aureus, Enterococcus spp., Pseudomonas aeruginosa, and Bacteroides fragilis)
carboxypenicillins: developed against more resistant Gram (-) and Pseudomonas aeruginosa
- (+): generally pretty weak activity
- (-): (SHEPMEPP) Salmonella/Shigella, Haemophilus influenzae, Escherichia coli, Proteus mirabilis, Morganella spp., Enterobacter spp., Providencia spp., Pseudomonas aeruginosa; not active against Klebsiella spp. or Serratia spp.
ureidopenicillins: more gram (-) activity
- (+): good against group and viridans strep, some activity against enterococcus spp., no activity against Staph
- (-): most enterobacterales (SHEPMEPP+KS) see above for SHEPMEPP, add Klebsiella spp. and Serratia marcescens
- aerobes: similar to Pen G, some activity against Bacteroides fragilis
What spectrum of activity do the β-lactamase inhibitor combinations have? (esp. think about Staph aureus, Enterococcus spp., Pseudomonas aeruginosa, and Bacteroides fragilis)
β-lactamase inhibitor combinations: developed to overcome β-lactamase production
- (+): not many clinical studies, but have activity against MSSA
- (-): enhanced activity against some β-lactamase producing strains of E. coli, Proteus spp., Klebsiella spp., H. influenzae, M. catarrhalis, and N. gonorrhoeae; not very good against inducible β-lactamase enzymes Serratia marcescens, P. aeruginosa, indole-positive Proteus spp., Citrobacter spp., and Enterobacter spp.
- anaerobes: enhanced activity against β-lactamase producing strands of Bacteroides fragilis and B. fragilis group (DOT) organisms
What are the common agents in these classes: natural penicillins, penicillinase-resistant penicillins, aminopenicillins, carboxypenicillins, ureidopenicillins, and β-lactamase inhibitor combinations
natural penicillins - aqueous penicillin G (IV), benzathine penicillin G (IM), procaine penicillin G (IM), penicillin VK (PO)
penicillinase-resistant penicillins - nafcillin (IV), methicillin, oxacillin (IV), dicloxacillin (PO)
aminopenicillins - ampicillin (IV, PO), amoxicillin (PO)
carboxypenicllins - ticarcillin (IV)
ureidopenicillins - piperacillin
β-lactamase inhibitor combinations - amoxicillin/clavulanic acid (PO), ampicillin/sulbactam (IV), piperacillin/tazobactam (IV)
What are the distribution characteristics of the penicillins into the CSF, urinary tract, lungs, skin/soft tissue, and bone?
- widely distributed into body tissues & fluids (inc. pleural fluid and bone), but do not peptrate the eye or prostate.
- When inflamed meninges are present & high, maximal parenteral doses of penicillins are used, the penicillins can enter the CSF
What penicillins are NOT primarily eliminated by the kidneys? Which penicillins need dosage adjustment in renal insufficiency? Which penicillins are removed during hemodialysis?
- All penicllins are eliminated primarily by the kidneys and require dosage adjustments, except nafcillin and oxacillin which are eliminated by the liver (piperacillin undergoes dual elim)
NOT primarily eliminated by kidneys: nafcillin, oxacillin, ceftriaxone, and cefoperazone
removed during HD: all except nafcillin and oxacillin (the ones that get removed may need supplemental dosing after HD)
Which penicillins should be used with caution in patients with CHF or renal failure due to the sodium load associated with administration of their parenteral formulations? Which ones contain the most mEq of sodium per gram?
Aqueous Sodium Penicillin G - 2.0 mEq
Nafcillin - 2.9 mEq
Ticarcillin - 5.2 mEq
Piperacillin - 1.85 mEq
What are the main clinical uses of the representative agents within each group of penicillins?
natural penicillins - treponema pallidum (syphilis)
penicillinase-resistant penicillins - infections due to methicillin-susceptible Staphylococcus aureus (MSSA)
aminopenicillins - Enterococcal infections and Listeria monocytogenes meningitis
carboxypenicillins and ureidopenicillins - hospital-aquired infections from gram negative bacteria. piperacillin is the most active penicillin against Pseudomonas aeruginosa
β-lactamase inhibitor combo products - Augmentin = dogmentin (good against human/animal bites) & otitis media, sinusitis, bronchitis, and lower respiratory tract infections; parenterals are good for polymicrobial infections, intraabdominal infections, gynecological infections, and diabetic food infections; pip-tazo is good Pseudomonas aeruginosa (esp. hospital acquired)
What are the major adverse effects associated with the penicillin antibiotics (8)? Which ones are most likely to cause interstitial nephritis?
- hypersensitivity (type 1 is immediate/severe, type 2 is delayed/less severe). cross allergenicity is seen among all penicillins
- neurologic effects like seizures and confusion from toxic doses (not seen with nafcillin)
- hematologic effects like leukopenia, neutropenia, or thrombocytopenia when used for long-term therapy (reversible)
- N/V/D
- Interstitial nephritis - most commonly seen with methicillin (d/c’d now) and nafcillin). This is immune-mediated damage to renal tubules and can progress to renal failure. Manifested through eosinophiluria and an abrupt increase in serum creatinine
- phlebitis (nafcillin)
- hypokalemia
- sodium overload and fluid retention (ticarcillin, piperacillin)
What is the spectrum of activity for the 1st and 2nd generation cephalosporins? (what are the representative agents for these)
1st gen (cefazolin, cephalexin):
- (+): Group and viridans strep, PSSP, MSSA
- (-): (PEK) Proteus mirabilis, Escherichia coli, Klebsiella pneumoniae
2nd gen (cefuroxime, cefoxitin, cefotetan, cefprozil):
- (+): group and viridans strep, PSSP, MSSA (but 1st gens are still better against these)
- (-): (HENPEK) Haemophilus influenzae, Enterobacter, Neisseria, Proteus mirabilis, Escherichia coli, Klebsiella pneumoniae
- anaerobes: (cefoxitin) Bacteroides fragilis
What is the spectrum of activity for the 3rd and 4th generation cephalosporins? (what are the representative agents for these)
3rd gen (ceftriaxone, ceftazidime, cefpodoxime):
- (+): similar to 1st/2nd gen, (ceftriaxone only) activity against penicillin-resistant Streptococcus pneumoniae (PRSP),
- (-): (HENPECKSSS) HENPEK + Citrobacter spp., Serratia marcescens, Salmonella spp., Shigella spp. ONLY ceftazidime and cefoperazone (not ceftriaxone) have activity against Pseudomonas aeruginosa
- anaerobes: limited activity
4th gen (cefepime):
- (+): similar to ceftriaxone (PRSP)
- (-): HENPECKSS + Pseudomonas aeruginosa and β-lactamase producing Enterobacter and E. Coli
What is the spectrum of activity for ceftaroline, cefiderocol, and cephalosporins with β-lactamase inhibitors?
ceftaroline - Anti-MRSA cephalosporin
- (+): similar to ceftriaxone (including PRSP) & MRSA
- (-): HENPECKSSS (but no Pseudomonas aeruginosa)
cefiderocol - developed to have activity against MDR organisms
- (+): none
- (-): HENPECKSSS + some strains that produce ESBLs, AmpCs, and carbapenemases
ceftolozane-tazobactam -
- (+): Streptococci
- (-): HENPECKSSS, some ESBL producers, but is the most active against Pseudomonas aeruginosa
ceftazidime-avibactam -
- (+): Streptococci
- (-): HENPECKSSS, many ESBL producers, some KPC and OXA producing enterobacterales, AmpC producing Enterobacterales AND Psudomonas aeruginosa
What are cephalosporins generally NOT active against (3)
MRSA (except ceftaroline)
Enterococcus spp
Legionella pneumophila
What are the best cephalosporins for Staphylococcus aureus, Pseudomonas aeruginosa, resistant bacteria (ESBL, AmpC, and KPC-producing), and anaerobes like Bacteroides fragilis?
Staphylococcus aureus - ceftaroline
Pseudomonas aeruginosa - ceftolozane-tazobactam (also ceftazidime-avibactam, some 3rd gens, and cefepime)
resistant bacteria (ESBL, AmpC, and KPC-producing): cefiderocol, ceftolozane-tazobactam, and ceftazidime-avibactam (but carbapenems are best for this)
Bacteroides fragilis - cefoxitin
Which cephalosporins penetrate the CNS and achieve therapeutic concentrations in the cerebrospinal fluid? Which cephalosporin has the longest elimination half-life (BID dosing)? Which cephalosporins do not require dosing adjustments in renal insufficiency?
CSF concentrations are only achieved with parenteral cefuroxime, 3rd gen, and 4th gen agents.
ceftriaxone has a 1/2 life of 8 hours (BID dosing)
ceftriaxone and cefoperazone are eliminated by the biliary system, so they do not need doses adjusted in renal insufficiency.
What are the major adverse effects associated with the cephalosporins? (5)
- Hypersensitivity
- Hematologic: leukopenia, neutropenia, or thrombocytopenia from prolonged use
- GI: C. diff, biliary sludging (ceftriaxone)
- Nonconvulsive status epilepticus (pts improve after d/c)
What is the risk of cross-allergenicity between penicillins and cephalosporins? In which situations should or shouldn’t a penicillin-allergic patient receive a cephalosporin?
- Rate of cross-reactivity is 1-5% (1st gen cephalosporins (not cefazolin) show the greatest risk)
- If ICU admission due to anaphylaxis/interstitial nephritis/delayed severe skin allergic reactions -> Avoid ALL β-lactams
- If immediate or delayed hypersensitivity reactions not requiring ICU admission -> avoid cephalosporins w/ identical side chains, use other cephalosporins with caution/close monitoring
Which cephalosporins contain a MTT (methylthiotetrazole) side chain and what is the significance of it?
Cefamandole, cefotetan, cefmetazole, cefoperazone, and moxalactam all have an NMTT side chain.
- These cause unique adverse effects.
1. Hypothrombinemia
2. Disulfiram reaction
What is the spectrum of activity of the carbapenems (inc. meropenem/vaborbactam, imipenem/relebactam, and aztreonam)
What are doripenem and meropenem the DOC for?
imipenem, meropenem, ertapenem, doripenem -
- (+): imipenem and doripenem have the best activity; group and viridans streptococci, PSSP, Enterococcus faecalis (only imipenem), MSSA
- (-): doripenem and meropenem are the best; drugs of choice for ESBL- and Amp-C producing bacteria, HENPECKSSS, + Pseudomonas aeruginosa (not ertapenem)
- anaerobes: great activity against gram (+)/(-) anaerobes
meropenem/vaborbactam -
- (+): see above
- (-): see above; also have activity against KPC-producing Enterobacterales
- anaerobes: great activity against gram (+)/(-) anaerobes
imipenem/relebactam -
- (+): see above
- (-): see above; also have activity against KPC-producing Enterobacterales
- anaerobes: great activity against gram (+)/(-) anaerobes
aztreonam -
- (+): none
- (-): HENPECKSSS + Psuedomonas aeruginosa
- anaerobes: none
What don’t carbapenems cover? (4)
MRSA
C. diff
Stenotrophomonas maltophilia
atypical bacteria
Which carbapenem has the longest elimination half-life (QD doing)? Which carbapenems and monobactams achieve therapeutic concentrations in the CSF? What is the purpose of co-formulating imipenem with cilastatin? Which carbapenems/monobactams require dosage adjustments in renal insufficiency?
ertapenem can be dosed q24h
CSF: only meropenem (of the carbapenems) should be used for CNS infection, aztreonam also penetrates into CSF
imipenem undergoes hydrolysis in the kidney by DHP, which results in potentially nephrotoxic metabolites. Cilastatin is a DHP inhibitor, which prevents renal metabolism and protects against potential nephrotoxicity.
all carbapenems require dosage adjustment in renal dysfunction, also aztreonam does as well
What are the major adverse effects with carbapenems and aztreonam? What risk factors are associated with the development of CNS toxicity with the carbapenems?
Carbapenems:
- hypersensitivity
- GI: N/V/D
- CNS: Seizures (renal dose adjustments are important)
Aztreonam:
- hypersensitivity
- GI: N/V/D
CNS toxicity risk factors:
- Preexisting CNS disorders (hx of seizures, brain lesions, recent head trauma)
- high doses (>2g imipenem per day)
- presence of renal dysfunction
What is the risk of cross-allergenicity between penicillins and carbapenems or aztreonam? Which β-lactam antibiotic can be used safely in a patient who experiences anaphylaxis to penicillin?
Carbapenems:
- cross reactivity (<1%) can occur in pts with a history of penicillin allergy
- If ICU admission due to allergy -> AVOID ALL β-lactams
- If no ICU admission -> give carbapenems with caution/close monitoring
Aztreonam:
- no cross-reactivity
Which antibiotics are present in streptogramin?
quinupristin & dalfopristin (Synercid is a 30/70 mixture of the two)
Which atoms in quinupristin and dalfopristin allow salt formation and enhance water solubility?
the amino side chains allow for salt formation & enhance water solubility needed to make a useful formulation
Are quinupristin and dalfopristin bacteriostatic or bactericidal?
they are bacteriostatic by themselves.
Together (synercid) is bacteriostatic against Enterococcus faecium and bactericidal against strains of MSSA and MSRA.
What is the route of administration of streptogramin?
parenterally
What is the mechanism of action of dalfopristin?
Dalfopristin interferes with peptidyl transferase, which is supposed to catalyze the formation of a peptide bond between two amino acids during peptide synthesis. This inhibits the formation of peptides.
What is the MOA of quinupristin?
Quinupristin binds in the ribosomal tunnel and causes blockage of the tunnel
What are the therapeutic uses of synercid? (3)
- Vancomycin-resistant Enterococcus faecium (VRE) (not E. faecalis)
- Skin infections caused by MRSA
- Vancomycin-resistant Enteroccus faecium UTIs
What are the mechanisms of resistance to quinupristin?
Adenine methylation of A208 in the 23S rRNA. This sterically hinders the binding of quinupristin. (This results in synercid being only bacteriostatic since dalfopristin is the only active one now)
What are the main side effects from synercid?
Generally not problematic.
- Some mild side effects include inflammation and pain at the side of injection, nausea, diarrhea, muscle weakness, rash
What is the PK of synercid and what is the metabolism of quinupristin and dalfopristin?
- Average t1/2 is 1.5 hours (linear relationship between dose/AUC)
- Does not penetrate BBB
- Synercid cleared 75% through biliary excretion, rest in urine.
Quinupristin: metabolized to quinupristin glutathione conjugate & quinupristin cysteine conjugate
Dalfopristin: metabolised to Pristinamycin IIA -> Pristinamycin IIA Reduction Product & a hydrolysis product
What drug interactions (+ mechanisms) does synercid have?
Streptogramins inhibit CYP3A4
What is the MOA of the oxazolidinones?
Linezolid interacts with the 50S ribosomal subunit, which prevents the formation of the 70S initiation complex, which inhibits the initiation step of bacterial translation, and therefore inhibits bacterial protein synthesis.
What are the main therapeutic uses of linezolid? (3)
- Vancomycin-resistant Entercoccus faecium
- Nosocomial pneumonia caused by methacillin-resistant strains of Staphylococcus aureus
- Skin infections caused by MRSA
Why should linezolid only be used to treat or prevent infections that are proven or strongly suspected to be caused by multi drug-resistant Gram(+) bacteria?
To reduce the development of drug-resistant bacteria & maintain the effectiveness of linezolid
What is the mechanism of resistance for linezolid?
Seen especially by the Enterococcus species.
Resistance is due to target site modification. (modifications in the peptidyl transferase center of 23S rRNA, resulting in reduced affinity of linezolid to the 50S subunit)
What are the main side effects of linezolid?
- N/V/D
- Headache
- Tongue discoloration
- oral Candidiasis
Serious: (fully reversible myelosuppession)
- thrombocytopenia
- GI bleeding
- anemia
- neuropathy (after 6 months of treatment)
What are the main metabolic pathways of linezolid?
- Metabolized via morpholine ring oxidation
- 30% of dose is excreted in urine
- 2 major metabolites
What is the PK and ROA of linezolid?
PK: 100% bioavailable after PO administration, t1/2 is 4-6 hours
ROA: excellent PO bioavailability, also available for IV administration
