Exam 2

Question 1

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

Answer 1

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

Question 2

How does transpeptidase cross-link peptidoglycan strands?

Answer 2

1. -OH of the transpeptidase (serine residue) binds where the amide is in the peptidoglycan between 2 D-Ala residues
2. a tetradehral intermediate is formed
3. a oxygen double bond is formed, which kicks out the terminal D-Ala residue
4. the terminal lysine of a new peptidoglycan comes and attacks the ester (oxygen double bond)
5. the oxygen double bond is formed again, which kicks out the transpeptidase. Now two peptidoglycans are connected & the transpeptidase is recycled!

Question 3

What is the MOA of penicillins?

Answer 3

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.

1. 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
2. this forms a tetrahedral intermediate
3. an ester forms, which results in an extremely stable compound that is inactive

Question 4

Why do penicillins display selective toxicity for bacteria but not the host?

Answer 4

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).

Question 5

What are the mechanisms of bacterial resistance for penicillins?

Answer 5

1. Decreased cellular uptake of the drug
2. Mutation of the penicillin-binding proteins to decrease their affinity for penicillins
3. efflux pump that pumps the antibiotic out of the cell
4. 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)

Question 6

What is the mechanism of penicillin allergenicity?

Answer 6

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.

Question 7

How do penicillins degrade under acidic and basic conditions?

Answer 7

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

Question 8

What is the main chemical feature of penicillins that confers resistance to degradation under acidic conditions?

Answer 8

If the side chain is more election attracting (more electrophilic), it will be less likely to degrade.

Question 9

How does degradation under acidic and basic conditions affect biological activity?

Answer 9

• Penicillin hydrolysis products have no antibiotic activity
• Hydrolysis of the β-lactam is irreversible

Question 10

What conditions promote penicillin degradation?

Answer 10

Heavy metal ions catalyze penicillin degradation (so these should be kept away from penicillin solutions).

Question 11

How does the lipophilicity of penicillins affect their serum protein binding?

Answer 11

The more lipophilic the side chain is, the more highly protein bound the penicillin will be.

Question 12

How does serum protein binding of penicillins affect penicillin degradation?

Answer 12

Protein binding protects drugs from degradation.

Question 13

How does serum protein binding of penicillins affect their half-life?

Answer 13

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.

Question 14

How does penicillin serum protein binding affect bioavailability?

Answer 14

Protein binding reduces bioavailability by reducing the effective concentration of the free drug.

Question 15

What are the mechanisms of penicillin excretion?

Answer 15

1. Renal (90% tubular secretion, 10% glomerular filtration)
2. Biliary

Most penicillins are excreted through the kidneys (except nafcillin, which is cleared by biliary excretion)

Question 16

How does renal disease affect penicillin half life?

Answer 16

Half lives of penicillins that are excreted by the kidneys are prolonged in cases of renal disease or failure

Question 17

How does probenecid affect penicillin half life and what is the mechanism involved?

Answer 17

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.

Question 18

How are penicillins distributed in the body?

Answer 18

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.

Question 19

How are penicillins synthesized?

Answer 19

Synthetic penicillins are made by acylation of 6-aminopenicillanic acid (6-APA)

Question 20

What is the β-lactam nomenclature? (5 classes)

Answer 20

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

Question 21

What are the main differences between phenoxymethyl penicillin (pen V) and penicillin (pen G) and what chemical feature is responsible for this difference?

Answer 21

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

Question 22

What major penicillins are β-lactamase-resistant parenteral or oral penicillins, β-lactamase-sensitive, broad-spectrum, oral penicillins?

Answer 22

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

Question 23

What is the main chemical feature of methicillin that confers resistance to hydrolysis by β-lactamases?

Answer 23

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.

Question 24

Why is methicillin so unstable to hydrolysis under acidic conditions?

Answer 24

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.

Question 25

What is nafcillin's β-lactamase sensitivity and acid stability?

Answer 25

not sensitive to β-lactamase Slightly more stable in acid than methicillin, but clinically, it's identical to methicillin.

Question 26

What are the structural similarities of oxicillin, cloxicillin, and dicloxicillin? What are their β-lactamase sensitivity, protein binding, and cross-resistance with methicillin?

Answer 26

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

Question 27

Why is ampicillin stable in acid?

Answer 27

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.

Question 28

What is the main difference between amoxicillin and ampicillin with regard to absorption?

Answer 28

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.

Question 29

How do the β-lactamase inhibitors (clavulanic acid & sulbactam) work?

Answer 29

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

Question 30

Why do the acylureidopenicillins have a broadened spectrum of antibacterial activity and enhanced potency?

Answer 30

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*.

Question 31

What are the main starting materials for the synthesis of cephalosporins? Where do they originate from? How are the cephalosporins synthesized?

Answer 31

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.

Question 32

What is the MOA of cephalosporins?

Answer 32

They react with transpeptidases, which results in inhibition of peptidoglycan cross-linking.

Question 33

How are cephalosporins acted on by β-lactamase?

Answer 33

Cephalosporins are hydrolyzed by β-lactamases. The β-lactamase opens their ring structure and renders them inactive.

Question 34

How do cephalosporins compare with penicillins in terms of allergenicity?

Answer 34

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.

Question 35

What is the main classification scheme for cephalosporins?

Answer 35

1st gen through 5th generation. From the 1st through 3rd generation, Gram-negative activity is gained and Gram-positive is lost.

Question 36

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?

Answer 36

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.

Question 37

What is the main structural feature that distinguishes if a cephalosporin is orally active vs. parenteral?

Answer 37

Orally active cephalosporins have substituents at C3 that are not chemically reactive (ex. Cephalexin).

Question 38

What structural feature of the cephalosporin C-3 side chain confers acid stability?

Answer 38

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.

Question 39

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?

Answer 39

The syn methoximino group is more resistant to β-lactamases than the anti isomer.

Question 40

How do cephalosporins with acetate vs. carbamate side chains at C3 differ with respect to enzymatic hydrolysis by esterases?

Answer 40

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.

Question 41

How does the distribution of cefuroxime differ from most of the other cephalosporins? How is this clinically useful?

Answer 41

Cefuroxime penetrates the BBB into the cerebrospinal fluid which makes it useful in the treatment of *Haemophilus influenzae* meningitis.

Question 42

What is the relationship between cefuroxime and cefuroxime axetil? What are their differences of bioavailability and route of administration?

Answer 42

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.

Question 43

What is the effect that the large oxime ether has on ceftazidime's stability vs. β-lactamases?

Answer 43

The large oxime ether increases stability against β-lactamases.

Question 44

What does the charged pyridinium ring of ceftazidime do in regard to β-lactam reactivity and with aqueous solubility?

Answer 44

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.

Question 45

What is the effect that the charged N-methylpyrrolidine moiety of cefepime has on β-lactam reactivity?

Answer 45

The N-methylpyrrolidine moiety is a good leaving group, which increases the reactivity of the β-lactam, making it too reactive for oral use.

Question 46

What effect does the syn methoximino group on the C7 side chain of cefepime have on stability vs. β-lactamases?

Answer 46

The syn methoximino group stabilizes cefepime against β-lactamases.

Question 47

What is the distinguishing structure of the cephamycins? What does this do for β-lactamases? What are 2 names of cephamycins?

Answer 47

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

Question 48

What adverse reaction does cefotetan cause?

Answer 48

Due to releasing N-methylthiotetrazole, the pt could experience hypoprothrombinemia or a disulfiram reaction.

Question 49

Why can't thienamycin be used as a drug? How has this been overcome?

Answer 49

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.

Question 50

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?

Answer 50

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.

Question 51

What is the unique feature that the antibiotic imipenem has vs. β-lactamases?

Answer 51

Imipenem reacts with and inhibits β-lactamases, on top of reacting with penicillin-binding proteins.

Question 52

What effect does renal enzyme dehydropeptidase-1 have on imipenem? How has this limitation been overcome?

Answer 52

renal dehydropeptidase-1 hydrolyzes imipenem. By co-administering cilastatin, a dehydropeptidase-1 inhibitor, we can overcome this.

Question 53

Mechanistically, how do the monobactams react with penicillin-binding proteins (transpeptidases)?

Answer 53

Because the sulfamic acid is so electronegative, it activates the β-lactam ring toward chemical hydrolysis and to react with PBPs

Question 54

Do the monobactams have cross allergenicity with the penicillins and cephalosporins?

Answer 54

No cross allergenicity has been reported, except with ceftazidime, since it has an identical oxime ether sidechain.

Question 55

What do the structures of vancomycin and teicoplanin look like?

Answer 55

These molecules are very large and appear to be lipophilic.

Question 56

What is the difference between the MOA of vancomycin and that of penicillin?

Answer 56

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.

Question 57

What is the mechanism of bacterial resistance of vancomycin?

Answer 57

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.

Question 58

What is the route of administration of vancomycin?

Answer 58

Vanc is usually administered IV (horrible bioavailability if given orally).

Question 59

What are the main toxic effects of vancomycin?

Answer 59

1. Red man's syndrome 2. Nephrotoxicity

Question 60

What are the differences in clinical uses of teicoplanin and vancomycin?

Answer 60

Same as vancomycin, but has a much longer 1/2 life than vanc.

Question 61

What is the PK of vancomycin?

Answer 61

Doesn't achieve good blood levels if given orally. Highly distributed in tissue and 90% eliminated by glomerular filtration.

Question 62

How can you tell if something is a lipoglycopeptide or lipopeptide? What are oritavancin, telavancin, dalbavancin, and daptomycin?

Answer 62

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

Question 63

What are the MOAs of oritavancin, telavancin, dalbavancin, and daptomycin?

Answer 63

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.

Question 64

β-lactam antibiotics - MOA, mechanisms of resistance, pharmacodynamic properties, elimination half life, route of elimination, and potential for cross-allergenicity

Answer 64

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

Question 65

Which gram positive aerobes (1) and gram negative aerobes (8) and gram negative anaerobes (1) produce β-lactamase?

Answer 65

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*

Question 66

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?

Answer 66

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*

Question 67

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)

Answer 67

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.**

Question 68

What spectrum of activity do the carboxypenicillins and ureidopenicillins have? (esp. think about *Staph aureus*, *Enterococcus spp.*, *Pseudomonas aeruginosa*, and *Bacteroides fragilis*)

Answer 68

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*

Question 69

What spectrum of activity do the β-lactamase inhibitor combinations have? (esp. think about *Staph aureus*, *Enterococcus spp.*, *Pseudomonas aeruginosa*, and *Bacteroides fragilis*)

Answer 69

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

Question 70

What are the common agents in these classes: natural penicillins, penicillinase-resistant penicillins, aminopenicillins, carboxypenicillins, ureidopenicillins, and β-lactamase inhibitor combinations

Answer 70

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)

Question 71

What are the distribution characteristics of the penicillins into the CSF, urinary tract, lungs, skin/soft tissue, and bone?

Answer 71

- 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

Question 72

What penicillins are NOT primarily eliminated by the kidneys? Which penicillins need dosage adjustment in renal insufficiency? Which penicillins are removed during hemodialysis?

Answer 72

- 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)

Question 73

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?

Answer 73

Aqueous Sodium Penicillin G - 2.0 mEq Nafcillin - 2.9 mEq **Ticarcillin - 5.2 mEq** Piperacillin - 1.85 mEq

Question 74

What are the main clinical uses of the representative agents within each group of penicillins?

Answer 74

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)

Question 75

What are the major adverse effects associated with the penicillin antibiotics (8)? Which ones are most likely to cause interstitial nephritis?

Answer 75

- 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)

Question 76

What is the spectrum of activity for the 1st and 2nd generation cephalosporins? (what are the representative agents for these)

Answer 76

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*

Question 77

What is the spectrum of activity for the 3rd and 4th generation cephalosporins? (what are the representative agents for these)

Answer 77

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*

Question 78

What is the spectrum of activity for ceftaroline, cefiderocol, and cephalosporins with β-lactamase inhibitors?

Answer 78

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*

Question 79

What are cephalosporins generally NOT active against (3)

Answer 79

MRSA (except ceftaroline) *Enterococcus* spp *Legionella pneumophila*

Question 80

What are the best cephalosporins for *Staphylococcus aureus*, *Pseudomonas aeruginosa*, resistant bacteria (ESBL, AmpC, and KPC-producing), and anaerobes like *Bacteroides fragilis*?

Answer 80

*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

Question 81

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?

Answer 81

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.

Question 82

What are the major adverse effects associated with the cephalosporins? (5)

Answer 82

- Hypersensitivity - Hematologic: leukopenia, neutropenia, or thrombocytopenia from prolonged use - GI: C. diff, biliary sludging (ceftriaxone) - Nonconvulsive status epilepticus (pts improve after d/c)

Question 83

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?

Answer 83

- 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

Question 84

Which cephalosporins contain a MTT (methylthiotetrazole) side chain and what is the significance of it?

Answer 84

Cefamandole, cefotetan, cefmetazole, cefoperazone, and moxalactam all have an NMTT side chain. - These cause unique adverse effects. 1. Hypothrombinemia 2. Disulfiram reaction

Question 85

What is the spectrum of activity of the carbapenems (inc. meropenem/vaborbactam, imipenem/relebactam, and aztreonam) What are doripenem and meropenem the DOC for?

Answer 85

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

Question 86

What don't carbapenems cover? (4)

Answer 86

MRSA *C. diff* *Stenotrophomonas maltophilia* *atypical bacteria*

Question 87

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?

Answer 87

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

Question 88

What are the major adverse effects with carbapenems and aztreonam? What risk factors are associated with the development of CNS toxicity with the carbapenems?

Answer 88

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

Question 89

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?

Answer 89

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

Question 90

Which antibiotics are present in streptogramin?

Answer 90

quinupristin & dalfopristin (Synercid is a 30/70 mixture of the two)

Question 91

Which atoms in quinupristin and dalfopristin allow salt formation and enhance water solubility?

Answer 91

the amino side chains allow for salt formation & enhance water solubility needed to make a useful formulation

Question 92

Are quinupristin and dalfopristin bacteriostatic or bactericidal?

Answer 92

they are bacteriostatic by themselves. Together (synercid) is bacteriostatic against *Enterococcus faecium* and **bactericidal** against strains of MSSA and MSRA.

Question 93

What is the route of administration of streptogramin?

Answer 93

parenterally

Question 94

What is the mechanism of action of dalfopristin?

Answer 94

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.

Question 95

What is the MOA of quinupristin?

Answer 95

Quinupristin binds in the ribosomal tunnel and causes blockage of the tunnel

Question 96

What are the therapeutic uses of synercid? (3)

Answer 96

1. Vancomycin-resistant *Enterococcus faecium* (VRE) (not *E. faecalis*) 2. Skin infections caused by MRSA 3. Vancomycin-resistant *Enteroccus faecium* UTIs

Question 97

What are the mechanisms of resistance to quinupristin?

Answer 97

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)

Question 98

What are the main side effects from synercid?

Answer 98

Generally not problematic. - Some mild side effects include inflammation and pain at the side of injection, nausea, diarrhea, muscle weakness, rash

Question 99

What is the PK of synercid and what is the metabolism of quinupristin and dalfopristin?

Answer 99

- 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

Question 100

What drug interactions (+ mechanisms) does synercid have?

Answer 100

**Streptogramins inhibit CYP3A4**

Question 101

What is the MOA of the oxazolidinones?

Answer 101

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.

Question 102

What are the main therapeutic uses of linezolid? (3)

Answer 102

1. Vancomycin-resistant *Entercoccus faecium* 2. Nosocomial pneumonia caused by methacillin-resistant strains of *Staphylococcus aureus* 3. Skin infections caused by MRSA

Question 103

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?

Answer 103

To reduce the development of drug-resistant bacteria & maintain the effectiveness of linezolid

Question 104

What is the mechanism of resistance for linezolid?

Answer 104

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)

Question 105

What are the main side effects of linezolid?

Answer 105

- N/V/D - Headache - Tongue discoloration - oral *Candidiasis* Serious: (fully reversible myelosuppession) - thrombocytopenia - GI bleeding - anemia - neuropathy (after 6 months of treatment)

Question 106

What are the main metabolic pathways of linezolid?

Answer 106

- Metabolized via morpholine ring oxidation - 30% of dose is excreted in urine - 2 major metabolites

Question 107

What is the PK and ROA of linezolid?

Answer 107

PK: 100% bioavailable after PO administration, t1/2 is 4-6 hours ROA: excellent PO bioavailability, also available for IV administration

Question 108

What drugs interactions (+ mechanism) does linezolid have?

Answer 108

No CYP450 interactions Linezolid is a reversible, nonselective inhibitor of **monoamine oxidase**, which creates a potential for interaction with adrenergic and serotonergic agents. (use with caution in pts who are sensitive to increases in BP & pts should not consume large quantities of foods/bevs that are rich in tyramine to avoid a significant pressor response)

Question 109

What are the differences in potency and MOA between tedizolid phosphate and linezolid?

Answer 109

Tedizolid is more potent than linezolid against MRSA. It has the **same MOA** as linezolid. Can be administered PO or IV.

Question 110

What structural features are common in aminoglycoside antibiotics?

Answer 110

The aminoglycosides have 1,3-diaminocyclitol core structures that are usually linked to one or more aminoglycoside rings. The core structures are named Streptidine and 2-Deoxystreptamine and they are cyclohexane rings with 3 or more -OH groups. Due to polarity, these are incapable of crossing lipid-containing cellular membranes (poor PO absorption, poor penetration through meninges, poor lung penetration)

Question 111

What is the MOA of aminoglycosides?

Answer 111

Aminoglycosides inhibit protein biosynthesis by binding to the 30S ribosomal subunit. They also bind to the 16S rRNA, which forms the A site. This blocks further translation and causes premature termination. Additionally, it causes nonsense proteins to be produced (due to 30S binding). All of this together leads to the leakage of ions and disruption of the cytoplasmic membrane, resulting in cell death.

Question 112

What are the aminoglycoside uptake mechanisms?

Answer 112

1. Entry of positively charged aminoglycosides through the outer membrane kicks the Mg2+ and Ca2+ out, which form salt bridges w/ phosphates of the phospholipids in the membrane. This makes the membrane more permeable to aminoglycoside entry. 2. Active transport to pass through cytoplasmic membrane

Question 113

What are the resistance mechanisms to the aminoglycosides?

Answer 113

1. Metabolism by bacteria- acetylation, adenylation, and phosphorylation of the aminoglycosides can inactivate them. 2. Altered ribosomes - 16S binding site an be altered through point mutations. 3. Altered aminoglycoside uptake - More rare

Question 114

What is the toxicity of aminoglycosides? What are the symptoms of aminoglycoside ototoxicity? Which toxicities are reversible vs. irreversible?

Answer 114

Ototoxicity - irreversible; Symptoms can initially start with tinnitus & high-frequency hearing loss, or in vestibular damage (vertigo, loss of balance, ataxia) Nephrotoxicity - reversible;

Question 115

What is the potential toxic effect that aminoglycosides have on respiration? How can it be reversed or treated?

Answer 115

Respiratory paralysis - can be reversed by neostigmine or calcium gluconate, but mechanical respiratory assistance may be needed.

Question 116

What are the risk factors for manifestation of aminoglycoside toxicity?

Answer 116

- Taking loop diuretics or vancomycin (or other nephrotoxic antimicrobial drugs) - Compromised renal function - Genetic vulnerability - Longer treatment durations

Question 117

What are the main clinical uses of aminoglycosides?

Answer 117

Aminoglycosides have broad spectrum activity against both Gram(+) and Gram(-) bacteria, but they are almost always used for treatment of Gram(-) bacteria. They are often used in combination with penicillins for synergistic effects.

Question 118

Why shouldn't aminoglycosides and penicillins be administered together in the same solution/injection site?

Answer 118

They should be administered separately to avoid the chemical reaction between the two classes, which would render both drugs inactive.

Question 119

What is the aminoglycoside-induced frame shift? What are its consequences?

Answer 119

This results in the formation of altered proteins (nonsense proteins) -> cell death

Question 120

Why is amikacin less susceptible to bacterial metabolism than kannamycin?

Answer 120

Amikacin has an L-hydroxyaminobuteryl amide moiety that inhibits bacterial metabolism, which makes it more potent than kanamycin.

Question 121

What features of gentamicin have made it the most important (widely used) aminoglycoside antibiotic?

Answer 121

- low cost - reliable activity against all but the most resistant Gram(-) aerobes

Question 122

What is the polyketide biosynthesis pathway?

Answer 122

The polyketides are produced by sequential addition of propionate groups to a growing chain. This results in methyl groups on alternate carbon atoms in the macrolide ring.

Question 123

What do the structures of the macrolides look like?

Answer 123

The structure has a desosamine sugar (critical for activity) & cladinose sugar (not critical for activity),

Question 124

How is the solubility of erythromycin increased?

Answer 124

If the amine forms salts, it will be more soluble.

Question 125

What is the MOA of the macrolides?

Answer 125

Macrolides inhibit bacterial protein synthesis by binding reversibly to the P site of the bacterial ribosome, which also inhibits translocation of peptidyl-tRNA from the A site to the P site. This involves the bacterial 23S RNA. (mostly bacteriostatic)

Question 126

What are the resistant mechanisms to the macrolide antibiotics?

Answer 126

1. Lactone ester hydrolase - decrease the macrolides by hydrolysis of the macrocycle 2. Production of an RNA methylase - Inhibits binding of macrolides to the 50S subunit 3. Mutation of adenine to guanine at the specific site A2058 - Results in 10,000x reduction in binding of erythromycin and clarithromicin to the 23S ribosomal RNA 4. Efflux pump

Question 127

Why is resistance to macrolides by *Pseudomonas* spp. and *Enterobacter* spp. unable to be avoided?

Answer 127

These inhibit intrinsic resistance by not allowing entry of the macrolides.

Question 128

How can acidic conditions inactivate erythromycin? How has this been overcome with some of the newer macrolide antibiotics?

Answer 128

Under acidic conditions, a process involving 6-OH and 12-OH groups can result in an inactive ketal product (which causes GI cramping) Clarithromycin replaces the 6-OH with an OCH3, which stabilizes the molecule and enhances oral absorption. Azithromycin have an N-methylated methyleneamino moiety that replaces the C-9 ketone, so the ketal formation is no longer possible. This makes the molecule stable for oral absorption.

Question 129

What is the metabolism of erythromycin?

Answer 129

Main route - demethylation in the liver to be eliminated in bile (small portion in the urine). Metabolism by CYP3A4 results in a demethylated metabolite that has narrower spectrum and is less active.

Question 130

What is the basis for drug interactions with the macrolides? Which macrolides are more likely to be involved in drug interactions?

Answer 130

Erythromycin and clarithromycin bind and inhibit CYP3A4 (need to dose reduce with ergotamine, digoxin, methylprednisolone, carbamezepine, etc.) *With rifampicin and rifabutin, activity of erythromycin is reduced* Azithromycin does not display this interaction.

Question 131

What are the main side effects of the macrolides?

Answer 131

Relatively safe - vomiting, gastric cramps, abdominal pain - minor and severe allergic skin reactions (from hives to SJS) - reversible cholestatic hepatitis with long term use - erythromycin shows increased risk of pyloric stenosis in children whose mothers took the drug during the late states of pregnancy or while nursing

Question 132

Why are erythromycin PO dosage forms given as either enteric coated or more stable salts or esters?

Answer 132

These dosage forms allows for more stability in acid.

Question 133

What is the role that phagocytes have in the delivery of erythromycin to the site of action?

Answer 133

Erythromycin is found in high concentrations in phagocytes. These transport erythromycin to the tissues/site of infection, which is a very efficient drug delivery system.

Question 134

What is the MOA of vancomycin, quinupristin-dalfopristin, the oxazolidinones, daptomycin, and the lipoglycopeptdes?

Answer 134

vancomycin - (1) inhibits bacterial cell wall synthesis through locking glycopeptide polymerization, (2) inhibits synthesis and assembly during the second stage of cell wall synthesis (binds D-ala-Dala) by preventing cross-linking and further elongation of the peptidoglycan - slowly bactericidal quinupristin-dalfopristin - each bind differently to the 50S ribosomal subunit, inhibiting early and late stages of bacterial protein synthesis - bacteriostatic alone, when used together they have a synergistic effect (time-dependent bactericidal, when bactericidal) oxazolidinones - bind to the 50S ribosomal subunit near the interaface with the 30S subunit, preventing the 70S initiation complex, ultimately inhibiting protein synthesis - bacteriostatic daptomycin - binds to bacterial membranes and inserts its lipophilic tail to form a transmembrane channel that causes leakage of cellular contents, ultimately resulting in bacterial cell death - rapid, conc. dependent bactericidal activity lipoglycopeptides - interferes with polymerization by binding to the D-Ala-D-Ala terminus. Oritavancin and telavancin (not dalbavancin) also insert their lipophilic tails into the membrane to leak out cellular contents. - conc. dependent bactericidal

Question 135

How do bacteria become resistant to vanc, quinupristin-dalfopristin, the oxazolidinones, daptomycin, and the lipoglycopeptides?

Answer 135

vancomycin - modification of the D-ala-D-ala vancomycin binding site; In VRE, thickening of the peptidoglycan layer of the cell wall restricts access of vancomycin to its site of activity quinupristrin-dalfopristin - alteration of ribosomal binding site, enzymatic inactivation oxazolidinones - resistance is pretty rare, but occasionally can be alteration of the ribosomal subunit target site - cross resistance is seen between tedizolid and linezolid daptomycin - rarely reported, but has been seen with altered cell membrane binding due to loss of a membrane protein lipoglycopeptides - alteration in the D-Ala-D-Ala terminus (but oritavancin still maintains activity in this case)

Question 136

What is the spectrum of activity for vancomycin?

Answer 136

activity against gram(+) aerobes and anaerobes - group/viridans strep - *Strep pneumoniae*, inc. **PRSP** - *Enterococcus faecalis* and *faecium* - *Staph aureus* and coagulase-negative staph, both **MSSA** and **MRSA** - *Corynebacterium* spp. - *Listeria monocytogenes* - *Actinomyces* - *Clostridium* spp (inc. **C. Diff**) Not active against Gram-negative aerobes or anaerobes

Question 137

What is the spectrum of activity for quinupristin-dalfopristin?

Answer 137

Gram(+): - group/viridans Strep - *Streptococcus pneumoniae*, including **PRSP** - *Enterococcus **faecium***, including **VRE**, but NOT *E. faecalis* - *Staphylococcus aureus* and CNS, inc. **MSSA** and **MRSA** - anaerobes: *Listeria monocytogenes*, *Clostridium* (not C. diff), *Peptostreptocuccus* Gram(-): limited activity against *Neisseria* and *Moraxella*, NOT active against Enterobacteriaceae Atypicals: *Mycoplasma pneumoniae*

Question 138

What is the spectrum of activity for the oxazolidinones, daptomycin, and the lipoglycopeptides?

Answer 138

oxazolidinones - - group/viridans Strep - *Streptococcus pneumoniae* (inc. **PRSP**) - *Enterococcus faecium AND faecalis*, including **VRE**!! - MSSA, MRSA, VISA, VRSA (not 1st line tho) - activity against anaerobes, but not C. diff - gram negative: no G(-) organisms - atypicals: some activity, not used clinically daptomycin - - group/viridans Strep - *Streptococcus pneumoniae* (inc. **PRSP**) - *Enterococcus faecium AND faecalis*, including **VRE**!! - MSSA, MRSA, VISA, VRSA, LR (#2 for MRSA) - *Corynebacterium jeikeium* - gram neg: no G(-) organisms lipoglycopeptides - don't really have a great place in therapy - group/viridans Strep - *Streptococcus pneumoniae* - *Enterococcus faecium* AND *faecalis*, but some VRE strains show resistance to tela and dalbavancin - MS, MR, VI, oritavancin also has activity against VRSA - gram negative: none

Question 139

What are the major PK characteristics of vancomycin and quinupristin-dalfopristin (bioavailability, half-life, CSF penetration, route of elimination, dosage adjustments in renal insufficiency, and removal during HD)?

Answer 139

vancomycin - - doesn't get absorbed orally, but this is good for C. diff, since we want the drug to concentrate in the colon. For systemic infections, we only treat IV (not IM). - distributed in tissues/fluids (esp. adipose tissue), but variable penetration in the CSF. We must wait ~1 hour before getting a level due to the wide distribution. - renally eliminated, need dose adjustment in renal deficiency - somewhat removed during HD (~10% per hour) quinupristin-dalfopristin - - displays significant post-antibiotic effect - only available parenterally - minimal penetration into CSF - mostly eliminated through hepatic clearance (CYP450), dosage adjustments unnecessary in renal insufficiency, but suggested with hepatic insufficiency

Question 140

What are the major PK characteristics of the oxazolidinones, daptomycin, and the lipoglycopeptides (bioavailability, half-life, CSF penetration, route of elimination, dosage adjustments in renal insufficiency, and removal during HD)?

Answer 140

oxazolidinones - - post-antibiotic effect for the Gram positives - linezolid has 100% oral bioavailability - distributed into well-perfused tissues, CAN penetrate into CSF - eliminated by renal and non-renal routes. No dosage adjustments needed in renal insufficiency - linezolid is removed by HD, but not tedizolid daptomycin - - distributes well into tissues - doesn't get into CSF(?) - primarily eliminated by kidneys, dose adjustment required in renal insufficiency lipoglycopeptides - - no PO absorption - no CSF - not removed by HD - telavancin: renal elimination, dose adjustment suggested w/ renal insufficiency - dalbavancin: LONG half life (346h), fecal and renal elim, dose adjustment in pts. w/ severe renal insufficiency who aren't receiving HD - oritavancin: unsure how it's eliminated, no dosage adjustments necessary

Question 141

What are the major clinical uses for vancomycin, quinupristin-dalfopristin, the oxazolidinones, daptomycin, and the lipoglycopeptides?

Answer 141

vancomycin - **drug of choice for MRSA**, serious G(+) infections in penicillin-allergic patients, PRSP, PO vanc is **drug of choice for *C. Diff*** quinupristin-dalfopristin - very expensive, only used when vanc, linezolid, AND dapto cannot be used; **VRE** oxazolidinones - used when vancomycin and β-lactams can't be used; VRE infections, nosocomial pneumonia due to MRSA daptomycin - used when vanc and/or linezolid can't be used; *Staphylococcus aureus* bacteremia or endocarditis (not left sided), VRE, NOT to be used in pneumonia since it's inactivated by a pulmonary surfactant lipoglycopeptides - used when vanc, linezolid/tedizolid, AND daptomycin can't be used... limited clinical use

Question 142

What are the major adverse reactions associated with vancomycin, quinupristin-dalfopristin, the oxazolidinones, daptomycin, and the lipoglycopeptides?

Answer 142

vancomycin - **red-man syndrome** (reaction related to rate of infusion, can slow down infusion to minimize/prevent), nephrotoxicity (inc. risk with higher doses), ototoxicity (irreversible), hypersensitivity skin reacitons, myelosuppression with prolonged therapy quinupristin-dalfopristin - venous irritation, extremely painful myalgias/arthralgias (but pretty rare), rash oxazolidinones - thrombocytopenia & anemia with long-term treatment, GI, CNS (headache, neuropathy with long term linezolid treatment) daptomycin - Myopathy/CPK elevation (stop statin if necessary), acute eosinophilic pneumonia (rare but serious. need to d/c if this happens), N/D, headache, injection site reactions, rash lipoglycopeptides - red-man syndrome, nephrotoxicity (telavancin), QTc prolongation, taste disturbances - black box warning against use in pregnancy!!

Question 143

What are the major drug interactions associated with quinupristin-dalfopristin, the oxazolidinones, daptomycin, and the lipoglycopeptides?

Answer 143

quinupristin-dalfopristin - - **CYP450 3A4 inhibitor**, need to reduce doses for lipid-lowering agent (HMG-CoA reductase inhibitors), immunosuppressive agents (cyclosporine, tacrolimus), carbamazepine, etc. oxazolidinones - - weak inhibitors of **monoamine oxidase**, so there's a potential for drug interactions. Risk of serotonin syndrome in pts receiving serotonergic agents (ex. SSRIs). Use with caution daptomycin - - HMG-CoA reductase inhibitors may lead to increased incidence of myopathy if used during daptomycin therapy lipoglycopeptides - - no significant drug interactions - telavancin and oritavancin interfere with PT and INR tests due to binding to the phospholipid reagents

Question 144

What is the similarity in MOA between clindamycin and erythromycin?

Answer 144

Clindamycin inhibits protein synthesis by binding to the bacterial 50S ribosome. It binds to the same exact site as erythromycin. Because of this, antagonism and cross-resistance has been seen.

Question 145

What are the main clinical uses of clindamycin?

Answer 145

1. aerobic gram (+) cocci (inc. some *Staphylococcus* and *Streptococcus*) 2. anaerobic gram (-) bacilli (inc. some *Bacteroides* and *Fusobacterium*)

Question 146

What is the main side effect of clindamycin that limits its clinical use?

Answer 146

pseudomembranous colitis and diarrhea limit the use of clindamycin, even if it's clearly the superior agent

Question 147

What are the main metabolic pathways of clindamycin? How do those influence its biological activity?

Answer 147

Metabolized by CYP450 enzymes in the liver to the inactive sulfoxide and N-demethylated derivative.

Question 148

What is the absorption, distribution, and elimination of clindamycin?

Answer 148

absorption - ~90% absorbed from GI tract distribution - widely distributed, penetrates CNS enough to be useful in treatment of cerebral toxoplasmosis in AIDS elimination - urine and bile. Dosage adjustment may be needed in hepatic failure

Question 149

What are the main adverse effects of clindamycin?

Answer 149

Common: diarrhea, pseudomembranous colitis, N/V, abdominal cramps, rash

Question 150

What is the significance of pseudomembranous colitis?

Answer 150

pseudomembranous colitis is a potentially lethal condition that affects 2-10% of pts treated with clindamycin. It is due to overgrowth of *Clostridium difficile* and results in the production of a toxin that causes a range of adverse effects, like diarrhea/colitis/toxic megacolon. This should be treated promptly with metronidazole or vancomycin.

Question 151

How do tetracyclines bind to heavy metals?

Answer 151

Tetracyclines form stable chelates with polyvalent metal ions, such as Ca2+, Al3+, Cu2+, and Mg2+. Two of the oxygens with bind to the metal ion.

Question 152

Why shouldn't the tetracyclines be administered with foods that are rich in calcium or with other drugs that are rich in calcium or other heavy metals?

Answer 152

If administered with calcium/heavy metals, it will form chelates that are not absorbed in the GI tract. So, they shouldn't be taken with milk, TUMS, iron pills, etc. If the metals cannot be avoided, they should be consumed at least 1 hour before or 2 hours after tetracyline administration.

Question 153

What is the preferred ROA of the tetracyclines?

Answer 153

The preferred route is oral, since oral absorption is adequate in absence of the multivalent metal ions in the GI tract.

Question 154

Why shouldn't children take tetracycline?

Answer 154

When the teeth are still forming, the tetracycline can form a calcium chelate, which results in permanently brown/gray teeth. This discoloration becomes worse as time goes on due to photooxidation.

Question 155

What is tetracycline epimerization? What effect does it have on biological activity?

Answer 155

Since the hydrogen on the amine-bearing carbon is acidic, enolization and epimerization can occur. Basically this makes the H go from the up conformation to the down conformation. The epitetracycline product is inactive, so it's possible to lose even 50% of activity through this epimerization pathway.

Question 156

At what pH is tetracycline epimerization most rapid? What is the relative rate of epimerization in the solid state vs. in solution?

Answer 156

Most rapid at a pH of 5. Epimerization is slower in solid state compared to solution.

Question 157

What is the process of tetracycline dehydration?

Answer 157

Due to the benzylic hydroxyl group at C6 being antiperiplanar to the proton at C5, the OH can easily be eliminated. This results in an inactive and toxic product, 4-epianhydrotetracycline.

Question 158

What is the toxicity of epianhydrotetracycline?

Answer 158

It is toxic to the kidneys and can produce a Fanconi-like syndrome (failure of reabsorption in the proximal convoluted tubule), which can be fatal.

Question 159

Why do minocycline and doxycycline lack renal toxicity of tetracycline?

Answer 159

Minocycline and doxycycline don't have a C6 hydroxyl group, so it's not possible to dehyrate or form the toxic product.

Question 160

How do tetracyclines cleave in under basic conditions?

Answer 160

In a base with a pH of 8.5 or above, tetracylines undergo cleavage. The end product is an inactive lactone.

Question 161

What is the MOA of the tetracyclines?

Answer 161

Tetracyclines bind to the 30S ribosomal subunit and inhibit bacterial protein synthesis by blocking the attachment of the aminoacyl-tRNA to the A site of the ribosome, which results in the termination of peptide chain growth. So these **inhibit the codon-anticodon interaction**.

Question 162

Why are tetracyclines selective to bacteria, and not the host cells?

Answer 162

Eukaryotic cells (host cells) do not have the tetracycline uptake mechanism that bacterial cells have. If the tetracycline were to get into the cell, they would have the same inhibitory effect.

Question 163

What are the main therapeutic uses of the tetracyclines?

Answer 163

Most commonly used for treatment of acne. They are the treatment of choice for infections caused by chlamydia.

Question 164

Why is demeclocycline more stable to dehydration than tetracycline?

Answer 164

It has a secondary hydroxyl group at C6, instead of tertiary (like tetracycline). This means demeclocycline dehydrates more slowly.

Question 165

What are the unique toxicities of minocycline in comparison with other tetracyclines?

Answer 165

Minocycline has vestibular toxicities, like vertigo, ataxia, and nausea. Other tetracyclines don't have this.

Question 166

Why is doxycycline widely considered to be the tetracycline of choice?

Answer 166

Because it can't be dehydrated so it doesn't have the 4-epianhydrotetracycline-mediated toxicity. It also produces fewer GI symptoms. It has great oral bioavailability and can be dosed once daily.

Question 167

Why doesn't tigecycline have potential for 4-epihydrotetracycline-mediated toxicity?

Answer 167

It does not have the C6 hydroxyl group.

Question 168

What are the potential toxic effects of tigecycline? What is unique about resistance development to tigecycline?

Answer 168

Heptotoxicity (rare), pancreatitis, anaphylactoid reactions It is protected from resistance development due to efflux pump and ribosomal protection proteins.

Question 169

What are the main therapeutic uses of sarecycline and omadacycline?

Answer 169

Sarecycline - moderate/severe acne Omadacycline - skin infections and community acquired bacterial pneumonia

Question 170

Why shouldn't sarecycline and omadacycline be administered to pregnant women and are not recommended during breast feeding? What other interactions are there?

Answer 170

They can cause fetal harm/is teratogenic

Question 171

What is the MOA of chloramphenicol?

Answer 171

Binds reversibly to the 50S ribosomal subunit at the site near erythromycin and clindamycin. It inhibits peptidyl transferase activity of the ribosome, thus preventing the peptide bond between the P and A site, and inhibiting protein synthesis

Question 172

What is the mechanism of the reaction that is catalyzed with peptidyl transferase in protein synthesis?

Answer 172

Peptidyl transferase catalyzes the reaction with the amine from the A-site with the peptide in the P site.

Question 173

What is the therapeutic use of chloramphenicol?

Answer 173

Limited due to toxic side effects (Cush didn't mention any specific uses of chloramphenicol)

Question 174

What is the relationship between chloramphenicol sodium succinate and chloramphenicol?

Answer 174

chloramphenicol sodium succinate is a prodrug that is hydrolyzed by the liver to chloramphenicol.

Question 175

what are the main therapeutic uses of chloramphenicol sodium succinate?

Answer 175

bacterial meningitis, typhoid fever, rickettsial infections, intraocular infections, etc.

Question 176

What are the solubility characteristics and distribution of chloramphenicol?

Answer 176

chloramphenicol is lipid soluble. It remains relatively unbound to plasma proteins. It penetrates into all tissues of the body, including the brain.

Question 177

What are the main bacterial resistance mechanisms to chloramphenicol?

Answer 177

1. reduced membrane permeability 2. mutation of the 50S ribosomal subunit 3. elaboration of chloramphenicol acetyltransferase (acetylates hydroxy groups on chloramphenicol, making them unable to bind to the 50S ribosomal subunit)

Question 178

How is chloramphenicol metabolized in humans?

Answer 178

Metabolized by the liver to glucuronide, which is inactive (nucleophilic attack of 1º alcohol on UDPGA, which is catalyzed by glucuronyl transferase). Then, it is excreted by the kidneys. *need dose adjustment in hepatic insufficiency Also metabolized by reduction of the amino group to an amino, resulting in a less active metabolite.

Question 179

What is the most serious potential toxicity of chloramphenicol? How does it limit the use of chloramphenicol?

Answer 179

Aplastic anemia (but it's unpredictable). It is generally fatal and the effect usually becomes apparent weeks/months after chloramphenicol treatment has been stopped.

Question 180

How does the risk of serious toxicity compare in chloramphenicol eye drops vs. oral chloramphenicol?

Answer 180

Highest risk = oral chloramphenicol Lowest risk = eye drops

Question 181

How can chloramphenicol toxicity be minimized?

Answer 181

Monitor blood levels, keep concentrations less than 25mcg/mL.

Question 182

Is chloramphenicol bone marrow suppression a predictor of aplastic anemia?

Answer 182

Bone marrow suppression is common. It's due to impairment of mitochondrial function resulting from inhibition of protein synthesis. This is completely reversible and does NOT predict future development of aplastic anemia.

Question 183

What is the relationship between chloramphenicol-induced childhood leukemia and length of treatment with chloramphenicol?

Answer 183

Increased length of treatment causes increased risk of childhood leukemia

Question 184

What are the drug interactions with chloramphenicol?

Answer 184

Chloramphenicol inhibits CYP450, so be cautious of drugs metabolized by CYP450.

Question 185

What does the effect of inflammation of the meninges have on the brain concentrations of chloramphenicol?

Answer 185

Even is the meninges are not inflamed, chloramphenicol has 30-50% penetration in CSF. It can get to 89% when the meninges *are* inflamed.

Question 186

What are the core structures of the quinolone antibiotics?

Answer 186

quinolone, cinnolone, 1,8-naphthyridone, pyridopyrimidone they are 2-ringed structures with nitrogens in at least 1 of the 2 rings

Question 187

What are the characteristics of the 1st, 2nd, and 3rd generation quinolones?

Answer 187

1st - developed for G(-) activity, so they have limited activity against G(+). These don't achieve good systemic concentrations and are only useful for lower UTI infections. Both agents are discontinued (oxolinic acid, nalidixic acid). 2nd - fluorine at C-6 and heterocyclic ring at C-7. These have a broader spectrum and are more potent. Ciprofloxacin is the most potent fluoroquinolone against G(-), and these also have more G(+). 3rd/4th - improved activity against G(+), particularly *Streptococcus pneumoniae*. None are as potent as Cipro against Gram(-). - ex. Levofloxacin and Moxifloxacin ( moxi is last resort due to severe side effects)

Question 188

What are the functions of topoisomerases and gyrases?

Answer 188

They untangle DNA by cutting one or two strands of DNA, then allowing strand passage through the break, allowing DNA to untwist.

Question 189

How do topoisomerases work?

Answer 189

They cleave DNA by carrying out a nucleophilic attack on a phosphodiester linkage of DNA, so one strand becomes free and the other becomes enzyme-linked. The DNA is then reformed.

Question 190

How does DNA transport by bacterial type IV topoisomerases and gyrases occur?

Answer 190

1. G-segment DNA binds to the binding site across the tops of the two CAP regions. 2. Once DNA is bound, the CAP regions remain in a closed formation. 3. 2 ATP molecules bidn to the ATPase domains, leading to N-gate closure with a T-segment DNA trapped in the DNA capture domain. 4. A gap opens in the G segment DNA, the T-segment passes through, then the G segment is religated 5. Gate opens for release

Question 191

What is the difference between topoisomerase I and topoisomerase II enzymes?

Answer 191

Topoisomerase I - cleaves 1 strand Topoisomerase II - cleaves 2 strands

Question 192

What are the common mechanistic features of bacterial gyrase, bacterial DNA topoisomerase IV, and mammalian topoisomerase II? (6)

Answer 192

1. Dimeric enzyme binds duplex DNA and cleaves both opposing strands with a 4-base stagger 2. Cleavage involves covalent attachment of each subunit of the dimer through a phosphotyrosine linkage to the 5' end of the DNA 3. Two DNA ends are the cleavage site are pulled apart by a conformational change of the enzyme to create an opening in the gated G-segment DNA. The transported DNA (T-segment) is then passed through the opening 4. Transported DNA can be from the same molecule or from a different molecule 5. All type II enzymes can be distinguished by their relative abilities to relax DNA vs. decatenate or catente DNA 6. Catalysis requires Mg2+ and ATP hydrolysis is involved

Question 193

What is the MOA of the quinolones?

Answer 193

Quinolones bind to the cleavage complex that exists after step 2 of DNA unwinding (right after the DNA has been cleaved by the topoisomerase). This stabilized the cleavage and inhibits the religation. The double-strand eventually breaks, leading to apoptosis.

Question 194

What are the therapeutic uses of the quinolones? (6)

Answer 194

1. UTIs - ciprofloxacin 2. prostatitis - ciprofloxacin & ofloxacin 3. STDs 4. GI infections 5. Respiratory tract infections 6. Bone, joint, soft tissue infections

Question 195

What is the main bacterial resistance mechanism to the quinolones?

Answer 195

Decreased cellular permeability (entry is dependent upon diffusion through porin channels) Increased efflux pumps Mutation of target enzymes (in A and B subunits)

Question 196

What are the main features of quinolone absorption, distribution, and elimination?

Answer 196

absorption - readily absorbed orally, high degree of bioavailability; should not be administered with heavy metals due to chelate formation distribution - widely distributed. penetrates CSF elimination - renal and hepatic clearance

Question 197

How is ciprofloxacin metabolized?

Answer 197

Metabolized by UGT (at 3-carboxyl position) to an inactive metabolite. Then it is excreted in the urine.

Question 198

What are the main adverse effects of the quinolone antibiotics? What adverse effect does gatifloxacin (4th gen) have?

Answer 198

Generally well tolerated. - Most common: N/V/D - CNS: headache, dizziness - Rare: hallucinations, seizures, peripheral neuropathy, tendonitis (can be severe due to tendon rupture) - Reversible arthropathy Gatifloxacin - hyperglycemia/hypoglycemia in diabetic patients

Question 199

What is the MOA of the aminoglycosides?

Answer 199

Inhibition of protein synthesis by irreversibly binding to the 30S ribosomal subunit, which disrupts the initiation of protein synthesis and causes misreading of the mRNA. Once inside the periplasmic space of gram neg. organisms, oxygen is required to get through the cytoplasmic membrane. (this doesn't work in anaerobes obviously) AGs are rapidly bacterial in concentration-dependent manner

Question 200

What are the mechanisms of resistance for the aminoglycosides?

Answer 200

1. Alteration in aminoglycoside uptake - chromosomal mutations that influence any part of the binding and/or electrochemical gradient that facilitates aminoglycoside uptake 2. Synthesis of aminoglycoside-modifying enzymes - MOST COMMON; due to a plasmid-mediated resistance factor that enables bacteria to modify the structure of the aminoglycoside, leading to high-level resistance. - Cross resistance with gentamicin and tobramycin, but not amikacin or plazomicin 3. Alteration in ribosomal binding sites - rare, since gent/tobra/amikacin bind to multiple sites; may occur with streptomycin, since it only binds to a single site on the 30S ribosomal subunit

Question 201

What is the spectrum of activity for the aminoglycosides?

Answer 201

Gram (+): never used alone! Always used in low doses with cell-wall active agents to provide synergy; Primarily gentamicin - viridans strep - *Enterococcus* spp. - *Staph aureus* and CNS Gram (-): A,P > T > G (no streptomycin); Higher doses are used, A, G, and T are often used in combo for synergy - PPPEEACKSSS - ***Pseudomonas aeruginosa*** - *Proteus* spp. - *Providencia* spp. - *E. Coli* - *Enterobacter* spp. - *Acinetobacter* spp. (not plazo) - *Citrobacter* spp. - *Klebsiella* spp. - *Salmonella* spp - *Serratia marcescens* - *Shigella* spp. - Plazomicin has some activity against ESBL/AmpC/KPC producing bacteria NO ANAEROBES **Streptomycin** is active against ***Mycobacterium tuberculosis***

Question 202

What are the PK characteristics of the aminoglycosides? How will patient characteristics influence dosing of the aminoglycosides?

Answer 202

absorption - poor PO absorption due to being highly polar cations. Vd and clearance varies due to patient characteristics, which influences dosing for each individual patient. When given IM, so they shouldn't be used in critically ill pts. distribution - distributed primarily in extracellular fluid compartment, but do not get into CSF (meninges are lipophilic), sputum, or adipose tissue. elimination - excreted unchanged by kidney (high urinary concentrations), must adjust dosing in renal insufficiency; supplemental dosing required for HD

Question 203

What is the target peak and trough for gentamicin and tobramycin based on the dosing method, bacteria, and infection type?

Answer 203

Peak:MIC ratio of 10:1 is optimal *need to reach peak w/in 24 hours in pts with G(-) sepsis Standard: - G(-) Moderate infections: Peak 4-6; Trough 0.5-1.5 - G(-) Mod-severe: Peak 6-8; Trough 1-1.5 - G(-) Severe: Peak 8-10; Trough <2 - G(+) synergy: Peak 3-5; Trough 1 Extended interval: single daily dose only for G(-) bacteria in pts with normal renal function - G(-) infections: Peak 13-20; Trough <0.5 or undetectable

Question 204

What are the major clinical uses for the aminoglycosides (esp. regarding combo therapy)?

Answer 204

Aminoglycosides, besides plazomicin, are rarely used alone. - Amikacin/gent/toba are used for serious infections due to G(-) aerobic bacteria - Gentamicin or streptomycin are used in combo for serious infections due to enterococci, viridans streptococci, or staphylococci - plazomicin only used for gram neg

Question 205

What are the major adverse reactions that may occur during aminoglycoside therapy?

Answer 205

nephrotoxicity - inc. risk with prolonged high trough concentrations ototoxicity - irreversible rare: neuromuscular blockage, hypersensitivity, sterile abscess formation with IM injection

Question 206

What is the MOA of the fluoroquinolones?

Answer 206

These inhibit DNA synthesis by binding and inhibiting bacterial topoisomerases. They target DNA gyrase and topoisomerase IV. DNA gyrase is the target for the Gram(-) bacteria, topoisomerase IV is the target for the Gram(+) bacteria (*S. aureus*). (concentration-dependent bactericidal activity)

Question 207

What are the mechanisms of resistance to the fluoroquinolones?

Answer 207

1. Alteration in binding sites 2. Efflux pumps 3. Alteration in cell wall permeability (decreased porin proteins) (cross-resistance is usually observes between the FQs)

Question 208

What is the spectrum of activity for the older vs. newer fluoroquinolones and delafloxacin? Which have the best activity against *Staphylococcus aureus*, *Streptococcus pneumoniae*, *Pseudomonas aeruginosa*, atypical bacteria, and anaerobes?

Answer 208

Gram (+): Ciprofloxacin has poor activity against G(+); newer FQs (levofloxacin, moxifloxacin, delafloxacin) have enhanced activity against some G(+); levo and moxifloxacin are the "respiratory quinolones" - group/viridans strep, limited *Entercoccus* - *Streptococcus pneumoniae* including PRSP (not cipro) - MSSA - MRSA (delafloxacin) Gram (-): Enterobacteriaceae: cipro/levo/delafloxacin > gemi/moxifloxacin; HENPECKSSS - *Haemophilus influenzae* - *E. Coli* - *Neisseria* spp. - *Proteus* spp. & *Providencia* spp. - *Enterobacter* spp. - *Citrobacter* spp. - *Klebsiella pneumoniae* - *Serratia marcescens* - *Shigella* spp. - *Salmonella* spp. - **Pseudomonas aeruginosa** (cipro≥levo>dela; NOT moxi or gemi) anaerobes: tovafloxacin has some activity against *Bacteroides fragilis* atypicals: FQs extremely active against *Legionella* other: *Mycobacterium tuberculosis* (cipro, levo, moxi, dela)

Question 209

What are the PK differences between the fluoroquinolones in terms of PO bioavailability, 1/2 life, dosing interval, penetration into CSF, route of excretion, necessity for dose adjustment in renal insufficiency, and removal by hemodialysis?

Answer 209

PO bioavailability: good PO absorption, except delafloxacin (levo/moxi are best) 1/2 life/ dosing interval: - cipro: 4-6 hrs, BID - levo: 6-8 hrs, QD - moxi: 9.2, QD - dela: 4-8, BID penetration into CSF: minimal route of excretion: renal (levo, ofoloxacin, gatifloxacin); hepatic (trovafloxacin, moxifloxacin), both (cipro, delafloxacin) necessity for dose adjustment in renal insufficiency: levo, ofoloxacin, gatifloxacin, cipro, delafloxacin removal by hemodialysis: NONE

Question 210

What are the major adverse effects associated with fluoroquinolone therapy?

Answer 210

- Neurologic: **peripheral neuropathy** - Hepatotoxicty: seen with trovafloxacin, so use was restricted. Also seen a bit with moxifloxacin - Cardiac: prolong **QTc interval**; Use w/ caution in pts with hypokalemia, use of antiarrhythmics (amiodarone, sotalol), preexisting QTc prolongation) - **Articular damage: contraindicated in pediatric patients, avoid in breastfeeding patients** - Tendonitis, tendon rupture: esp w/ older pts and corticosteroid use

Question 211

What are the major drug interactions that may occur with fluoroquinolone antibiotics?

Answer 211

- Divalent/trivalent cations (zinc, iron, ca, al, mg) impair aborption of any oral fluoroquinolone - warfarin - causes inc. prothrombin time Ciprofloxacin also inc. concentrations of theophylline and cyclosporine.

Question 212

What are the differences in structure between erythromycin, azithromycin, and clarithromycin? What are the clinical advantages of clarithromycin and azithromycin over erythromycin?

Answer 212

erythromycin - 14 membered macrocyclic lactone ring clarithromycin - 14 membered ring with a methoxy group instead of C-6 hydroxyl group (increases acid stability, enhances antibacterial activity, tissue penetration, and prolongs half life) azithromycin - 15 membered ring (azalide). This improves PO availability, antibacterial activity, tissue penetration, and prolongs half life

Question 213

What is the MOA of the macrolides?

Answer 213

1. Suppress protein synthesis and inhibit bacterial growth by reversibly binding to the 50S ribosomal subunit (bacteriostatic, maybe bactericidal at high concentrations)

Question 214

What are the mechanisms of resistance to the macrolides?

Answer 214

1. active efflux - that that big of a deal bc clarithromycin and azithromycin have really high intracellular concentrations 2. alteration in the binding site - methylation of the 50S binding site (high-level of resistance to all macrolides AND other antibiotics that bind to the 50S ribosome like clindamycin and Synercid) cross-resistance is usually observed

Question 215

What are the differences in spectrum of activity between the macrolides? (esp. atypical)

Answer 215

G(+): clarithryomycin > erythro > azithro - group/viridans strep, *S. pneumoniae* (PSSP) - MSSA (mild/mod infections only) - *Bacillus*, *Corynebacterium* G(-): azithro > clarithro > erythro (NOT enterobacteriaceae) - *Haemophilus influenzae* (not erythro) - *Moraxella catarrhalis* - *Neisseria* spp. Atypicals: Azithro and clarithro are better for *legionella* and *mycoplasma* - ***Legionella pneumophila*** - others Anaerobes: above the diaphragm

Question 216

What are the PK differences among the macrolides in terms of distribution characteristics, 1/2 life, route of excretion, dosage adjustment in renal insufficiency, and removal by HD?

Answer 216

distribution characteristics - all get into tissues and cells, but not the CSF. High intracellular conc., low serum conc. (clarithro/azithro > erythro for intracellular conc.) 1/2 life - erythro 1.4hrs, clarithro 3-7hrs, azithro 68 hours route of excretion - erythro metabolized by primarily CYP450 enzymes, clarithro by CYP450 and some renal, azithro biliary dosage adjustment in renal insufficiency - not needed for erythro or azithro, needed for clarithro if CrCL < 30 removal by HD - NONE! The molecules are large

Question 217

What are the main indications for use of the macrolides?

Answer 217

- Community acquired pneumonia - esp. atypical coverage - STDs - *Mycobacterium avium* Complex Infections

Question 218

What are the major adverse effects with the macrolides? What measures can be employed to alleviate the GI distress or phlebitis with erythromycin therapy?

Answer 218

GI - most common with erythromycin (epigastric distress, abdominal pain, N/V/D) Thrombophlebitis/infusion site irritation - with IV erythro and azithro; can partially avoid by diluting the dose and infusing slowly **QTc prolongation**

Question 219

What major drug interactions are associated with macrolides? Which macrolides cause which drug interactions?

Answer 219

CYP450 - Erythromycin and clarithromycin are inhibitors of CYP450 3A4 and 2C9 - caution with theophylline, carbamazepine, valproate, cyclosporine, digoxin, phenytoin, warfarin Azithromycin doesn't inhibit CYP450, but hypoprothombinemia has been seen when the pt is on warfarin. So need to carefully monitor PT/INR.

Question 220

How can the inactive prontosil be converted to an active antibiotic after oral administration?

Answer 220

Inactive prontosil is a prodrug of the active sulfonamide, p-aminobenzenesulfonamide

Question 221

How is tetrahydrofolic acid formed and why is it a critically important metabolites?

Answer 221

Tetrahydrofolic acid is formed through a series of reactions that starts with dihydropteroate diphosphate + p-aminobenzoic acid (PABA) being converted to dihydropteroic acid by dihydropteroate synthase. This is important because tetrahydrofolic acid eventually turns into thymine and is incorporated into DNA.

Question 222

What is the MOA of the sulfonamides?

Answer 222

The sulfonamides inhibit the incorporation of p-aminobenzoic acid (PABA) into the folic acid nucleus. They inhibit dihydropteroate synthase.

Question 223

Why are sulfonamides toxic to pathogenic bacteria, but not to humans?

Answer 223

Humans get folic acid from our diet, but bacteria don't.

Question 224

How can the antibiotic activities of the sulfonamides be reversed?

Answer 224

Can be reversed by adding large quantities of PABA to the diet.

Question 225

How does the acidity of p-aminobenzoic acid compare with that of sulfanilamide?

Answer 225

PABA: 4.9 Sulfanilamide: 10.4 PABA is mainly anionic at physiological pH, whereas sulfanilamid is a weak acid at physiological pH.

Question 226

What is the relationship between the pKa of synthetic sulfonamide derivatives and their potencies?

Answer 226

Being more acidic enhances the potency.

Question 227

How do the aromatic substituents on the sulfonamide nitrogen increase acidity?

Answer 227

The aromatic subtituents are electron-withdrawing & have more resonance stabilization of the anion, making the compound more acidic.

Question 228

How does an increase in the acidities of the sulfonamides affect the incidence of crystalluria?

Answer 228

Increase in acidity decreases the incidence of crystalluria. This is because it's more water soluble when it's anionic.

Question 229

Why are sulfonamides used in combo with other antibiotics?

Answer 229

Sulfonamides are used in combination because resistance is too widespread for them to be used alone. Trimethoprim has antifungal activity and it inhibits dihydrofolate reductase, which inhibits sequential steps in biosynthesis of tetrahydrofolic acid.

Question 230

How is sulfasalazine metabolized by interstitial bacteria? What do the metabolites do?

Answer 230

bacteria in the GI tract metabolize it to sulfapyridine and 5-aminosalicylic acid, which has antiinflammatory activity. 5-ASA is used in ulcerative colitis and Crohn's disease.

Question 231

What is the MOA of pyrimethamine? What are its therapeutic uses when combined with certain sulfonamides?

Answer 231

Sulfadiazine is combined with pyrimethamine in chemotherapy to treat acute toxoplasmosis. Pyrimethamine inhibits dihydrofolate reductase.

Question 232

What are the mechanisms of resistance to the sulfonamides?

Answer 232

Resistance is very prevalent for the sulfonamides: 1. Mutations that cause overproduction of PABA (overcome competitive inhibition) 2. Mutations in the target enzyme (dihydropteroate synthase) that decreases its affinity for the sulfonamides 3. Mutations that result in a decrease in cell permeability to the sulfonamides

Question 233

What is the PK of the main sulfonamides (+trimethoprim)?

Answer 233

TMP is absorbed and distributed more rapidly. Its inactive oxidized metabolites are cleared in the urine. SMX is widely distributed in the body, including the CSF. It's not as distributed as TMP.

Question 234

How are the sulfonamides metabolized in humans?

Answer 234

Sulfonamides are metabolized by N-4 N-acetylation and sometimes N-1 glucuronidation. These metabolites have no antibiotic activity. Hydroxylamine and nitroso metabolites are toxic. The human population could be rapid or slow acetylators, which affects the rate of metabolism of sulfonamides in humans.

Question 235

What is the MOA of colistin?

Answer 235

The ammonium cations of colistin displace cations in the bacterila cell membrane (Mg2+ and Ca2+) and facilitate binding of the antibiotic to anionic lipopolysaccharides in the cell membrane.

Question 236

What is the MOA of metronidazole and what is its main therapeutic use?

Answer 236

MOA - Partial reduction of the nitro group in anaerobic bacteria leads to a radical anion that degrades bacterial DNA. Use - Anaerobic bacteria and protozoa. It's drug of choice for mild to moderate *C. difficle*.

Question 237

What are the MOAs and therapeutic uses of lefamulin acetate and pretomanid?

Answer 237

Lefamulin acetate: - MOA: selective binding to the peptidyl transferase center (PTC) of the 50S ribosomal subunit to prevent bacterial protein synthesis - Use: community-acquired bacterial pneumonia Pretomanid: - MOA: inhibits mycolic acid biosynthesis through an unknown mechanism, and poisons respiration (mitochondria) through the generation of nitric oxide - Use: treatment-resistant tuberculosis

Question 238

What is the definition of disinfectants, antiseptics, and sterilants? What are examples of each?

Answer 238

disinfectants - kills the vegetative form of the microorganism, but not spores, on inanimate surfaces sterilants - kills or removes ALL types of living microorganisms, including spores and viruses antiseptics - applied to living tissue for the purpose of preventing infection

Question 239

What are the MOAs of alcohols, chlorhexidine, and iodine? When is it appropriate to use each agent?

Answer 239

alcohols: - MOA: denature proteins - Use: antiseptics/disinfectants chlorhexidine: - MOA: strongly adsorbs to bacterial membranes, causing leakage of small molecules & precipitation of cytoplasmic proteins - Use: used in water-based formulations as a topical antiseptic. It has moderate activity vs. fungi and viruses. iodine: - MOA: iodinates phenylalanyl and tyrosyl groups in proteins and oxidizes sulfhydryl groups in proteins - can be bactericidal; tincture of iodine is used as an antiseptic.

Question 240

What are the MOAs of povidoneiodine, sodium hypochlorite, and halazone? When is it appropriate to use each agent?

Answer 240

povidone-iodine: (betadine) - MOA: the free iodine is active; iodinates phenylalanyl and tyrosyl groups in proteins and oxidizes sulfhydryl groups in proteins - Use: antiseptic available in many items. It's less likely to produce hypersensitivity reactions. It's a nontoxic, nonvolitile, non staining iodine. sodium hypochlorite: - MOA: function groups present in proteins and nucleic acids are oxidized by hypochlorous acid - Use: disinfectant water halazone: - MOA: in water, produces HOCl, which is germicidal - Use: disinfect small quantities of drinking water

Question 241

What are the MOAs of chloroazodin, oxychlorosene, and phenols? When is it appropriate to use each agent?

Answer 241

chloroazodin - - MOA: in water, produces HOCl, which is germicidal - Use: Dressing wounds, lavage, irrigation oxychlorosene - - MOA: Slowly liberates HOCl in solution - Use: antiseptic to treat local infections, remove necrotic tissue in massive infections, and to treat wounds. phenols - - MOA: disrupt the cell wall and membranes, precipitate proteins, inactivate enzymes - Use: bactericidal, fungicidal, and inactivate lipophilic viruses. NOT sporicidal. Used to disinfect hard surfaces (floors/bench tops/beds)

Question 242

What are the MOAs of quaternary ammonium compounds and formaldehyde and glutaraldehyde? When is it appropriate to use each agent?

Answer 242

quaternary compounds - - MOA: bactericidal action due to inactivation of energy-producing enzymes, denaturation of proteins, and disruption of cell membranes - Use: fungistatic, sporistatic, inhibit algal growth, bactericidal against G(+) and mod. active against gram(-). Used to reduce microbila load on inanimate surfaces (sanitizers). They are inactivated by soaps. aldehydes - - MOA: React with amino groups in proteins and nucleic acids - Use: used to sterilize instruments that cannot be sterilized by steam in an autoclave

Question 243

What are the MOAs of hydrogen peroxide and peracetic acid and ethylene oxide? When is it appropriate to use each agent?

Answer 243

Hydrogen peroxide & peracetic acid: - MOA - oxidizers - Use - mainly used as disinfectant and sterilant - Hydrogen peroxide - used to sterilize respirators, acrylic resin implants, milk and juice cartons, plastic eating utensils, and contact lenses - Peracetic acid - more potent than hydrogen peroxide. It is used to sterilize equipment in the food and beverage industry because its breakdown products are safe and do not smell or taste bad Ethylene oxide: - MOA: reacts covalently with a variety of nucleophilic groups present in biological systems - Use: Used to sterilize equipment that can't be sterilized by heat in an autoclave

Question 244

What chemical species are present when sodium hypochlorite is dissolved in water? What about when chlorine is dissolved in water?

Answer 244

When sodium hypochloite is dissolved in water, the product is hypochlorous acid (HOCl) + NaOH When chlorine is dissovled in water, the produce is hypochlorous acid (HOCl) + HCl

Question 245

What germicidal species are formed when sodium hypochlorite or chlorine is dissolved in water?

Answer 245

Hypochlorous acid (HOCl) is the active germicidal species that forms when chlorine is dissolved in water.

Question 246

Which irritating, volatile gas is produces when household bleach is acidified?

Answer 246

chlorine gas when aommia in urine reacts with bleach, it can form chloramine (CINH2), which is also toxic

Question 247

Which sterilants are carcinogenic? Which aren't?

Answer 247

Carcinogenic: - formaldehyde - ethylene oxide Not: - peroxygen compounds (hydrogen peroxide, peracetic acid)

Question 248

How are parabens metabolized?

Answer 248

Parabens are rapidly hydrolyzed to corresponding benzoic acid derivatives, which are rapidly conjugated and excreted

Question 249

Why shouldn't quaternary ammonium compounds be used as antiseptics?

Answer 249

Because they may contain infectious gram-negative bacteria (ex. *Pseudomonas*) that could cause an outbreak. It has been claimed that the newer formulations have overcome this problem.

Question 250

What are the MOAs and mechanisms of resistance of the tetracyclines/analogs?

Answer 250

MOA - inhibit bacterial protein synthesis by reversibly binding to the 30S ribosome, blocking the binding of amino-acyl tRNA to the A site on the mRNA complex. This prevents the addition of amino acid residues to the elongating peptide chain and inhibits protein synthesis. - bacteriostatic Resistance - 1. Decreased accumulation of tetracycline w/in the bacteria due to altermed permeability or efflux pumps 2. Decreases access to the ribosome due to ribosomal protection proteins 3. Enzymatic inactivation of the tetracycline *tigecycline, ervacycline, and omadacyline retain activity against many tetracycline-resistant bacteria because they do NOT seem to be affected by tetracycline-specific efflux and ribosomal protection

Question 251

What is spectrum of activity of the tetracyclines/analogs?

Answer 251

G(+) aerobes: minocycline and doxycycline are the most active - group/viridans strep - *Streptococcus pneumoniae* (PSSP) - Some *Enterococcus* spp. - Some *Staphylococcus aureus* (MSSA) - *Bacillus*, *Listeria*, *Nocardia* *analogs rarely used, but have MSSA/MRSA activity and some VSE/VRE G(-) aerobes: many *Enterobacteriaceae* are relatively resistant - *H. influenzae* - *Haemonphilus ducreyi* - *Campylobacter jejuni* - *Helicobacter pylori* - *Acinetobacter baumannii* (minocycline IV) *analogs cover EEACKSS (*E. coli*, *E. cloaecae*/*aerogenes*, *Acinetobacter baumannii*, *Citrobacter freundii*/*koseri*, *Klebsiella pneumoniae*/*oxytoca*, *Serratia marcescens*, *Stenotrophomonas maltophilia*) Anaerobes: - G(+): *Actinomyces*, *Propionibacterium* spp. *analogs cover the two above + *Peptostreptococcus* and *Clostridium perfringens*, as well as ***Bacteroides* spp.** Misc. organisms: - ***Legionella pneumophilia*** - *Chlamydophila pneumoniae* - *Chalmydophila psittaci* *ervacycline and omadacyline cover atypicals, but not tigecycline

Question 252

What are the MOAs and mechanisms of resistance of TMP-SMX?

Answer 252

MOA - bactericidal together - Sulfamethoxazole: inhibits dihydropteroate synthesis, which inhibits formation of dihydrofolic acid - Trimethoprim: inhibits activity of dihydrofolate reductase, which prevents the reduction of dihydrofolate to tetrahydrofolate Resistance - 1. Altered target sites: point mutations in dihydropteroate synthase and/or altered production or sensitivity of bacterial dihydrofolate reductase

Question 253

What is the spectrum of activity of TMP-SMX?

Answer 253

G(+) - *S. aureus*, some MRSA, esp. CA-MRSA - *S. pyogenes* (marginal) - *Nocardia* G(-) - HENPEACKSSS: *H. influenzae*, *E. Coli*, *Neiserria*, *Proteus*, *Enterobacter*, *Acinetobacter*, *Citrobacter*, *Klebsiella*, *Serratia*, *Shigella*, *Salmonella* - *Stenotrophomonas maltophilia* - NO P. aeruginosa anaerobes: NONE other: **Drug of choice for *Pneumocytis carinii/jirovecii***

Question 254

What are the MOAs and mechanisms of resistance of the polymyxins?

Answer 254

MOA - bind to the anionic lipopolysaccharide molecules of the outer membrane of Gram negative bacteria, causing displacement of Ca2+ and Mg2+, which normally stabilize the cell membrane. This leads to changes in cell wall permeability, leakage of cellular contents and subsequent cell death. Resistance - 1. alteration of outer cell membrane: decrease lipopolysaccharides content, reduction in calcium and magnesium content, decreased outer membrane proteins *cross resistance between polymyxin B and colistin

Question 255

What is the spectrum of activity of the polymyxins?

Answer 255

G(+): inactive G(-): excellent; PEEACKSSS - ***Pseudomonas aeruginosa***, *Enterobacter* spp. *E. Coli*, ***Acinetobacter*** (inc. MDR strains), *Citrobacter*, *Klebsiella*, *Salmonella*, *Shigella*, *Stenotrophomonas* - NOT *Burkholderia*, *Proteus*, *Providencia*, *Serratia*, or *Brucella* anaerobes: none

Question 256

What are the MOAs and mechanisms of resistance of clindamycin?

Answer 256

MOA - Inhibits protein synthesis by exclusively binding reversibly to the 50S ribosomal subunit - primarily bacteriostatic, but can display time-dependent bactericidal activity Resistance - 1. Alteration of the ribosomal binding site *not a substrate for macrolide efflux pumps

Question 257

What is the spectrum of activity of clindamycin?

Answer 257

G(+): - group/viridans strep - PSSP - **MSSA and CA-MRSA** Anaerobes: most useful for **above the diaphragm** - G(+): *Peptrostreptococcus* spp., *Clostridium* spp. (not *C. diff*), *Actinomyces*, *Propionibacterium* - G(-): *Bacteroides* spp., *Prevotella* spp., *Fusobacterium* Other: - *Pneumocystis carinii/jirovecii* - *Toxoplasmosis gondii* - *Pasmodium falciparum* and *vivax* (malaria

Question 258

What are the MOAs and mechanisms of resistance of metronidazole?

Answer 258

MOA - Prodrug that is activated by a reductive process. It's selectively toxic towards anaerobic bacteria due to the presence of electron transport components, like ferredoxins, in these bacteria. Ferredoxins donate electrons to metronidazole, forming highly reactive nitro radical anions. These damage bacterial DNA and cause cell death. - Rapidly bactericidal, concentration-dependent Resistance - relatively uncommon 1. Altered growth requirements: Higher oxygen concentrations 2. Altered levels of ferredoxin

Question 259

What is the spectrum of activity of metronidazole?

Answer 259

NO AEROBES G(-) anaerobes: - ***Bacteroides fragilis*** - *B. fragilis* DOT organisms (*B. distasonis*, *ovatus*, *thetaiotamicron*) - *Fusobacterium* - *Prevotella* spp. and *Veilonella* spp. - *Helicobacter pylori* G(+) anaerobe: - *Clostridium* spp. **including *C. difficile*** - *Peptostreptococcus* Other: *Trichomonas vaginalis*, *Entamoeba histolytica*, *Giardia lamblia*, *Gardnerella vaginalis*

Question 260

What is the PK of the tetracyclines/analogs? (PO bioavailability, distribution into CNS, route of elim, removal during HD, dose adjustments)

Answer 260

PO bioavailability - tigecycline and eravacycline are only available IV, tetracycline only available PO - Doxycycline (preferred) and minocycline are best absorbed from GI tract - Administrataion with divalent or trivalent cations impairs the absorption of the tetracyclines. distribution into CNS - only small amounts diffuse into the CSF route of elim - renal: tetracycline, demeclocycline - non-renal: doxycycline, minocycline - biliary/fecal: tetracycline analogs removal during HD - not significant dose adjustments - only tetracycline need renal dose adjustment, tigecycline and eravacycline need dose adjustment in sever hepatic impairment

Question 261

What is the PK of TMP-SMX? (PO bioavailability, distribution into CNS, route of elim, dose adjustments)

Answer 261

PO bioavailability - rapidly and well absorbed orally *1:5 ratio of trimethoprim to sulfamethoxazole distribution into CNS - Does get inot the CSF, but not really used for meningitis; gets into saliva, breast milk, urine, and uninflamed prostatic tissue route of elim - renal dose adjustments - dose adjustment needed in pts with CrCL < 30mL/min

Question 262

What is the PK of the polymyxins? (PO bioavailability, distribution into CNS, route of elim, removal during HD, dose adjustments)

Answer 262

PO bioavailability - not absorbed from GI tract, only IV is available in the US distribution into CNS - colistin poor CSF penetration, not well described for polymyxin B route of elim - colistin/polymyxin B nonrenal, colistimethate sodium (CMS, prodrug of colistin) is 50% by renal removal during HD - dose adjustments - none needed for colistin/polymyxin B, dose adjustment needed for CMS when CrCL is < 80mL/min

Question 263

What is the PK of clindamyin? (PO bioavailability, distribution into CNS, route of elim, removal during HD, dose adjustments)

Answer 263

PO bioavailability - almost completely absorbed after PO administration distribution into CNS - does NOT penetrate CSF, even if meninges are inflamed route of elim - primarily metabolized in liver removal during HD - NONE dose adjustments - not necessary

Question 264

What is the PK of metronidazole? (PO bioavailability, distribution into CNS, route of elim, removal during HD, dose adjustments)

Answer 264

PO bioavailability - Almost completely absorbed after PO administration distribution into CNS - DOES penetrate the CSF and brain tissue route of elim - metabolized by the liver, some in urine, some in feces (good for C. diff) removal during HD - yes dose adjustments - dose adjust in renal or hepatic dysfunction

Question 265

What are the major clinical uses for tetracyclines/analogs, TMP-SMX, polymyxins, clindamycin, and metronidazole?

Answer 265

Tetracycines/analogs - outpatient community acquired pneumonia (doxy) or infections to unusual organisms TMP-SMX - UTIs, bacterial prostatitis, ***Pneumocystis carinii/jirovecii* pneumonia** Polymyxins - Very toxic, so use is limited to MDR bacteria; polymyxin preferred for systemic infections, colistin preferred for UTIs Clindamycin - infections due to anaerobes outside of the CNS (pulmonary, diabetic foot, etc.) Metronidazole - infections due to anaerobes below the diaphragm or in the brain, *C. diff*

Question 266

What are the major adverse events associated with tetracyclines/analogs, TMP-SMX, polymyxins, clindamycin, and metronidazole?

Answer 266

Tetracycines/analogs - GI (N/V), photosensitivity, esophageal irritation, **discoloration of primary dentition, do not use in pregnancy/lactation** TMP-SMX - dose related myelosuppression (leukopenia, trombocytopenia), rash, crystalluria, hyperkalemia, **kernicterus in newborn, do not use in pregnancy/lactation** Polymyxins - nephrotoxicity, neurotoxicity Clindamycin - GI (N/V/D, **C. diff**), hepatotoxicity Metronidazole - GI (metallic taste), CNS (peripheral neuropathy), **may be teratogenic, avoid during 1st trimester and during breastfeeding**

Question 267

What are the drug interactions associated with the tetracyclines, TMP-SMX, and metronidazole?

Answer 267

Tetracyclins - impared absorption when given with divalent/trivalent cations (ex. Ca2+, Mg2+) TMP-SMX - warfarin (inc. anticoagulant effects) Metronidazole - warfarin (inc. anticoagulant effect), alcohol (disulfiram reaction)

Question 268

What are the potential therapeutic advantages of the tetracycline analog antibiotics?

Answer 268

They have expanded spectrum of activity that includes many tetracycline-resistant strains. BUT they are bacteriostatic, so they are rarely used.