Protein Syn Inhibitors ABX PART 2 - 50S

Question 1

4 drug classes that binds to 50S ribosomes

Answer 1

Macrolides, Lincosamides, Streptogramins, and Oxazolidinones

Question 2

Macrolides, Lincosamides, Streptogramins generally have the same MOA . . .

Answer 2

Block polypeptide exit

Question 3

Macrolides

Drugs and MOA

Answer 3

DRUGS: Erythromycin, Clarithromycin, Azithromycin (Zithromax®, Z-PAK®)

MOA: Bind reversibly to the 50S ribosome, blocks polypeptide
exit tunnel. Generally bacteriostatic

IV or PO

Question 4

Lincosamides

Drug and MOA?

Answer 4

DRUGS: Clindamycin (Cleocin®)

MOA: Bind reversibly to the 50S ribosome, blocks polypeptide
exit tunnel. Generally bacteriostatic

Question 5

Fidaxomicin (Difficid®) is a macrolide antibiotic
for treatment of C. difficile infection (relapsing/recurring)

PK, MOA, and ADME

Answer 5

MOA: Inhibits RNA polymerase subunit = Inhibiting transcription (mRNA) = inhibits protein synthesis.

!!!!!!!!Bactericidal to C. difficile!!!!!!!! THE ONLY BACTERICIDAL MACROLIDE

Absorption: PO administration, minimal systemic absorption

Distribution: Largely confined to GI tract

Metabolism: Intestinal hydrolysis to less active metabolite (OP1118)

Excretion: Feces (92% unchanged)

Question 6

Macrolides
(erythromycin,clarithromycin/azithromycin)
COVERAGE? PK?

Answer 6

Antibacterial Spectrum: Mainly atypicals
 Chlamydial infections
 Helicobacter pylori
 Mycobacterium avium complex (MAC)
 Mycoplasma pneumonia
 Legionella spp. Pneumonia

Pharmacokinetics:
Orally absorbed (food interferes w/ absorption)

Erythromycin – used at low-doses to stimulate GI motility in ICU patients
Clarithromycin – Short half-life, intracellular/extracellular
Azithromycin – LONG half-life (60h), purely intracellular

Question 7

Macrolides & Resistance

Answer 7

1. Inability to take up antibiotic (reduced membrane permeability)
2. Efflux pump
3. Plasmid-associated erythromycin esterase
4. Decreased affinity of the 50S ribosome subunit for the antibiotic due to methylation of an adenine in the 23S bacterial ribosomal RNA (bacterial methylase). Confers macrolide INDUCIBLE resistance to clindamycin (same ribosomal binding site)
5. Clarithromycin and azithromycin show cross-resistance with erythromycin.

Question 7

Macrolides & Resistance (5 ways)

Answer 7

1. Inability to take up antibiotic (reduced membrane permeability)
2. Efflux pump
3. Plasmid-associated erythromycin esterase
4. Decreased affinity of the 50S ribosome subunit for the antibiotic due to methylation of an adenine in the 23S bacterial ribosomal RNA (bacterial methylase). Confers macrolide INDUCIBLE resistance to clindamycin (same ribosomal binding site)
5. Clarithromycin and azithromycin show cross-resistance with erythromycin.

Question 8

Macrolides

(erythromycin, clarithromycin/azithromycin) SIGNIFICANT TOXICITY . .

Answer 8

1. Epigastric distress
2. Ototoxicity (high dose erythromycin)
3. Liver toxicity: acute cholestatic hepatitis (fever, jaundice, impaired liver function), probably as a hypersensitivity reaction
4. Extensively metabolized by liver and inhibits metabolism of a number of drugs through P450 systems …. Erythromycin>Clarithromycin . . . Note: Azithromycin (15) does not interact with P450s (15- vs 14-membered ring)
5. Prolongs the QT interval
6. Eliminates a species of intestinal flora that inactivates digoxin = greater absorption and digoxin toxicity

Question 9

Lincosamides: Clindamycin (Cleocin®)

ACTIVITY? Toxicity?

Answer 9

Lincosamide structurally distinct from the macrolides, but mechanism of action similar!

Active against Gram positive organisms and anaerobes (NOT C. difficile) -SO IT COVERS MRSA, MSSA, S. PNUEMONIA, AND B. FRAGLIS

Most important use is in treatment of severe anaerobic infection (B. fragilis – but now 20% resistant)

Also used for treatment of SSTI caused by streptococci and staphylococci. It is often active against MRSA

Toxicity includes hepatotoxicity and occasional neutropenia

BOXED WARNING: C.difficile-associated diarrhea/colitis

Question 10

Lincosamides: Clindamycin (Cleocin®) PK and stuff

Answer 10

Available IV or ORAL

Does not penetrate into CNS or intracellular

No need for renal adjustment since its hepatically metabolized

Question 11

Streptogramins: Synercid®

Answer 11

• Quinupristin-dalfopristin are two structurally distinct streptogramins that bind to separate sites on the bacterial 50S ribosomal subunit and synergistically inhibit protein synthesis.
• Quinupristin binds at the same site as macrolides/lincosamides and has a similar effect, with inhibition of polypeptide elongation and early termination of protein synthesis.
• Dalfopristin binds at a site nearby, resulting in a conformational change in the 50S ribosome, synergistically enhancing the binding of quinupristin at its target site. Dalfopristin directly interferes with polypeptide-chain formation.

Question 12

Ratio to make Synercid???

Answer 12

The 30:70 ratio of these drugs marketed as Synercid®

The combination is bactericidal

Question 13

Streptogramins: Synercid®

Activity/ to treat/ DI?

Answer 13

1. Indicated for treatment of:
   Vancomycin-resistant Enterococcus (VRE) infections
   Complicated skin infections (MRSA)
2. Activity against Gram + cocci EXCEPT E. faecalis
3. Potential drug interactions due to inhibition of CYP3A4
   (hydrocodone, Abilify®). Drugs metabolized by CYP3A4 that can prolong the QTc interval (cyclosporine) should not be coadministered with quinupristin dalfopristin.
   IV administration -risk of phlebitis

Severe arthralgias/myalgias may occur SO CPK MONITORRRRR

Question 14

Oxazolidinones: Linezolid (Zyvox®)

MOA, PK, Activity

Answer 14

100% Oral bioavailibility

MOA: Binds reversibly to the 23S rRNA of the 50S ribosomal subunit
so prevents formation of the 70S complex (resistance by
mutation of the binding site)

MOA distinct from other protein synthesis inhibitors so no
cross-resistance

Generally bacteriostatic (bactericidal for streptococcus) Active
against aerobic Gram positive bacteria (including MRSA, E.
faecium) SAME COVERAGE AS VANCO AND THEM

Clinical usage: serious Gram positive infections in hospitalized
patients, especially vancomycin-resistant infections

Question 15

2nd Generation Oxazolidinone: Tedizolid (Sivextro®) approved to treat . . .

Answer 15

Approved for acute bacterial skin and skin structure infection
(ABSSSI) (once daily dosing x6 days vs twice daily x10-14 days
for Linezolid)