Protein Synthesis Inhibitors-Pharmacology - ASYNC (Macrolide/Lincosamide/Tetracyclines)

• 1. Identify which antibiotics are in the protein synthesis inhibitor drug class. 

• 2. Describe how the antimicrobial kills it’s intended target. 

• 3. Choose which antibiotic kills which microbe. 

• 4. Differentiate antibiotics based on potential adverse reactions, drug/drug or drug/food interactions.

• 5. Design a treatment regimen based on available dosage forms.

• 6. Recognize basic mechanisms of resistance  

Learning Objectives

Linezolid, Tedizolid, Tetracyclines, Macrolides, Aminoglycosides, Clindamycin

What ABX target Protein Synthesis?

• N/V/D

• Risk of C.Diff

• Hypersensitivity reactions

Common Side effects for Protein Synthesis Inhibitors

• Mechanism of Action

  • Binds to the 50S subunit of the bacterial ribosomes, leads to inhibition of transpeptidation, translocation, chain elongation, then halts bacterial protein synthesis 

• Metabolism

  • Liver metabolism except for Clarithromycin (is RENALLY excreted)

  • Has post-antibiotic effect (PAE) 

  • High bioavailability (1:1)

• Administration

  • Erythromycin has different salt forms which require different administrations:

  • Base, PCE,  Stearate= Take on an empty stomach

  • Ethylsuccinate (EES) or Delayed release (ERY-TAB) = Take with or without meals

Macrolides MOA, Metabolism, and Administration

•  Erythromycin and Clarithromycin are the largest offenders

  • Inhibition of CYP 450- ↓ metabolism of barbituates, warfarin, carbamazepine, cyclosporine

  • Avoid use with benzodiazepines (increased levels)

Macrolides DDI’s/Food inteactions

•  GI- Cramping/diarrhea

• Hepatotoxicity  

• Ototoxicity

• Metallic taste- Clarithromycin

• QTc prolongation – Erythromycin > Clarithromycin> Azithromycin

• H/o CAD- use Clarithromycin w/ caution, ↑ all cause mortality 1 year

• Use with caution in those with myasthenia gravis

Macrolides adverse reactions

• Target Site modification

  • Methylation altered macrolide binding

    • EX: Resistance to strep Pneumo

• Active Efflux

  • Increase in efflux pumps

    • EX: Resistance to gram (-) rods

What are the mechanisms of resistance to Macrolides?

Spectrum:

• Gram (+) Organisms

• Gram (-) Organisms

• Atypical Organisms (Mycobacterium sp.)

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Clinical uses:

• Community Acquired Pneumonia (CAP)

• Sinusitis

• Otitis Media

• Atypical infections

• Lyme’s disease

Comments:

• LOTS of GI Side effects (especially diarrhea)

Macrolides - ERYTHROMYCIN Spectrum, Clinical Uses, and comments

Spectrum:

• Gram (+) Organisms

• Gram (-) Organisms

• Atypical Organisms (Mycobacterium sp.)

• Better H. FLU Coverage

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Clinical uses:

• Community Acquired Pneumonia (CAP)

• Sinusitis

• Otitis Media

• Atypical infections

• Lyme’s disease

• PLUS MYCOBACTERIAL INFECTIONS

Comments:

• Better tolerated than Erythromycin BUT still has some DDI’s

Macrolides - CLARITHROMYCIN (BIAXIN) - Spectrum, Clinical Uses, and comments

Spectrum:

• Gram (+) Organisms

• Gram (-) Organisms

• Atypical Organisms (Mycobacterium sp.)

• LESS Gram (+) activity

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Clinical uses:

• Community Acquired Pneumonia (CAP)

• Sinusitis

• Otitis Media

• Atypical infections

• Lyme’s disease

• Mycobacterial Infections

• PLUS Frequently used as a one time dose (1gm) for treatment of Chlamydia

Comments:

• Best tolerated

• Once daily administration

• Least amount of drug interactions

Macrolides - AZITHROMYCIN (ZITHROMAX) - Spectrum, Clinical Uses, and comments

Binds to 50S ribosomal subunit which prevents peptide bonds from forming and inhibits bacterial protein synthesis

Clindamycin MOA

• Available in PO, IV and topical 

  • Good oral absorption, but dose limitation due to GI side effects

  • Hepatic metabolism

• Good penetration into tissues, including bone;  poor penetration into CSF

• If using for MRSA infections…..

  • There are some species that are Clindamycin “S” and Erythromycin “R”

    • It has been found that ~ 50% of these “S” Clindamycin species are actually “R”

    • Must obtain a D-test to test for Clindamycin susp. if you want to use this for MRSA

      • If D-test is positive, then cannot use clindamycin 

• Bacteriostatic

Other Clindamycin Points

NO DDI’s or Food Interactions!!!!

Adverse reactions:

• Diarrhea (2-20%)

• skin rash

• C. DIff colitis

Clindamycin DDI/FOod Interactions and Adverse reactions

• Enzymatic Modification

  • Methylation altered clindamycin binding

  • Example: Resistance to Staph aureus

• Target Site Modification

  • EX: Resistance to Staph Aureus

• Decreased Permeability

  • Resistance to gram (-) rods

Clindamycin Mechanisms of Resistance

Spectrum:

• Anaerobes

  • Especially Mouth Anerobes (Peptostreptococcus, Bacteriodes, Prevotella, Fusobacterium)

• Streptococcal infections

• Staphlococcal infections (MSSA and some MRSA)

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Clinical uses:

• Dental Infections

• Intra-abdominal and pelvic infection (DOC for Pelvic Inflammatory Disease (PID))

• Alternative for Gram + infections with a PCN allergy

• Used in combination with PCN for toxin producing strains for Clostrida  perfingens and S. pyogenes; Commonly occurs with necrotizing fasciitis 

• Can be used topically for acne

Comments:

• LOTS of GI side effects especially diarrhea

• Expensive

• IV and PO doses equivalent, but hard for patients to tolerate oral doses > 450mg at one time

Lincosamide - CLINDAMYCIN (IV/PO) - Spectrum, Clinical Uses, and comments

• Agents: Tetracycline, Doxycycline, Minocycline, Omadacycline, Eravacycline, and Tigecycline

• Mechanism of Action:

  • Binds to 30S subunit to block the docking of transfer RNA carrying a new amino acid for elongating the protein chain

• Metabolism

  • Liver, except tetracycline is eliminated renal

  • Limited use for UTIs (except tetracycline) 

• Spectrum of Activity: Very Broad- Gram +(including MRSA), Gram -, Rickettsia and other Tick borne diseases, Chlamydia, some protozoa

  • Omadacycline, Eravacycline, and Tigecycline= also covers enterococci (including VRE)

• Most agents available PO

  • Tigecycline ONLY available IV

  • Omadacycline has 35% BA, so oral doses are higher; other agents with high BA 

• Bacteriostatic

Tetracyclines Points

• Oral= binds with cations, so avoid administration with iron, MVIs,  calcium containing products, antacids

  • Separate by at least 2 hours

• Take omadacycline on an empty stomach

Tetracyclines DDI/Food Interactions

• PO can cause esophageal irritation (must take while sitting up)

• Photosensitivity; wear sunscreen! 

• Omadacycline= ⬆ heart rate

• Should not be used in pregnancy or children < 8 years old = teeth discoloration

• Minocycline- dizziness/vertigo

Tetracyclines Adverse Reactions

Active Efflux

• Once occurs, confers all tetracyclines except glycycyclines (tigecycline)

Tetracyclines Mechanism of Resistance

Spectrum:

• Gram (+) organisms

  • Including MRSA

  • Streptococcus

• Some Gram (-) organisms

• Atypical Infections

  • Chlamydia/Gonorrhea

• Tick Born disease

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Clinical Uses:

• Tick or Spider Bites

• Lyme’s disease

• CAP

• SSTI’s (especially MRSA concern)

• Atypical Respiratory Infections

Comments:

• Tetracycline Frequent dosage administration

• Lowest accumulation in renal failure

• Good Bone penetration

• Inexpensive

• BID Dosing

Tetracyclines (Tetracycline, Doxycycline, Minocycline) Spectrum, Clinical uses, and comments

Spectrum:

• Gram (+) organisms

  • Including MRSA

  • Streptococcus

• Some Gram (-) organisms

• Atypical Infections

  • Chlamydia/Gonorrhea

• Tick Born disease

• PLUS VRE

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Clinical Uses:

• Complicated intra-abdominal infections

• SSTI’s

• MRSA/VRE infections

• Omadacycline

  • SSTI’s

  • CAP

  • Compicated IAI

Comments:

• LOW serum levels, high tissue levels (CANNOT USE FOR BACTEREMIAS)

• Found to have increased mortality when used for sepsis (HAP)

• Omadacycline + Eravacycline

  • Available IV and PO

Tetracyclines (Tigecycline, Omadacycline, Eravacycline) Spectrum, Clinical uses, and comments