Protein Synthesis Inhibitors - 30S ribosome Flashcards by Autumn Brubaker

Amikacin

For gentamicin resistant organisms

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Gentamicin

gram (-) aerobic

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Kanamycin

Worst nephro- and oto- toxicity, only for TB and topical

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Neomycin

Topical use

bowel sterilization

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Streptomycin

Primarily for mycobacterial tuberculosis in hospital setting

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Tobramycin

Pseudomonas aeruginosa

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Treatment of Brucellosis

Gentamicin + doxycycline

cow vector

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Treatment of Tularemia

Gentamicin
Tetracycline is effective as alternative

Rabbit vector

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Treatment of Yersinia pestis

Streptomycin + doxycycline

Rat vector

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Treatment of Pseudomonas Aeruginosa

Tobramycin* + pipericillin or ticarcillin

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Treatment of Klebsiella

Gentamicin + pipericillin or ticarcillin

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Pathogenic Gram Negative Rods

Escherischia
Enterobacter
Serrate
Pseudomonas
Acinetobacter
Klebsiella
Yersinia pestis
Brucella
F. tularensis

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MOA of aminoglycosides

Passive diffusion through porins

O2 dependent active transport ot cytosol (must have O2, not anaerobic)

Bind to 30S ribosomal unit- irreversible, bactericidal, post-antibiotic effect

Disrupt protein synthesis - reading errors

Irreversible bactericidal effects

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Gentamicin properties

Strong base, positive charge, water soluble

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Mechanism of Resistance or aminoglycosides

Depletion/deficit of porins (MDR)

O2 deficit/anaerobic organisms

Enzymatic alteration of amino glycoside structure, impairs binding to 30S ribosomal unit and/or cell entry

acetylation
phosphorylation
adenylation

Mutation of 30 s ribosome

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Anaerobes intrinsically resistant to aminoglycosides

Gram + rods - clostridia

Gram - rods- Bacteroides, Fusobacteria

Amino glycoside dosing

total daily dose administered as single injection

Associated with less toxicity, equal efficacy compared to multiple dose regimens

Trough determines safety as level drops below toxic threshold, TID dosing causes drug to accumulate in ear

Pharmacokinetics

highly polar, poorly absorbed from GI tract, rapidly absorbed after IM (peak 60-90 min)

Do not penetrate eye or CNS

Eliminated by glomerular filtration with half life of 2-3 hrs

Accumulate in renal cortex, inner ear perilymph damaging hair cells = nephrotoxic and ototoxic

Renal toxicity of aminoglycosides

Risk factors:
Low BP
Loop diuretics (furosemide)
Advanced age
Other nephrotoxic agents - cyclosporin in transplant patients, amphotericin in severe fungal infections

Neuromuscular blockade by aminoglycosides

Risk greatest with intra-pleural and intra-peritoneal administration or large doses or rapid IV infusion
-can produce apnea or respiratory arrest

may aggravate or reveal myasthenia graves or cause transient myasthenia syndrome

Managed with neostigmine or ventilator in extreme cases

Properties of tetracycline

Potency: low

Intestinal absorption: moderate

Disrupt Gut: high

Phototoxic: low

Properties of Demeclocycline

Potency: Med

Intestinal absorption: Moderate

Disrupt Gut: Moderate

Phototoxic: Worst

Properties of Minocycline

Potency: high

Intestinal absorption: complete, little food interference

Disrupt Gut: least

Phototoxic: high

Reaches therapeutic levels in CNS for meningeal carriers

Doxycycline properties

Potency: high

Intestinal absorption: complete, little food interference

Disrupt Gut: least

Phototoxic: high

Preferred agent parenterally, preferred with renal impairment

Tigecycline properties

phototoxic | Overcomes resistance and MRSA

Uses of Doxycycline for unusual organisms

Rickettsial infections (intracellular) - Rocky Mtn spotted fever, Q fever, typhus Borrelia burgdorferi (Spirochete) - Lyme disease Chlamydia trachomatis - Major STD - urethritis (non-specific), pelvic inflammatory disease, Lymphogranuloma venereum Chlamydia psittaci - psittacosis pneumonia Mycoplasma pneumonia - young adults, close quarters (alternate - erythromycin) Vibrio cholera - Cholera - single dose doxy

MOA of Tetracyclines

Passive diffusion into bacterial cytosol Bind to 30 S ribosomal unit - bacteriostatic, reversible - inhibits rate of protein synthesis Block binding of aminoacyl-tRNA Inhibit protein synthesis Exert bacteriostatic effects

Mechanisms of resistance of tetracyclines

Tetracycline efflux pump - acquired - plasmid encoding Tet A efflux pumps, bacteria thrive with ribosome intact Ribosome protection (methylation of ribosome) - plasmid encoding protecting protein, chromosome encoding protecting protein, bacteria thrive with ribosome intact

Distribution of tetracyclines

Good entry into most body fluids and compartments Cross placenta Enter CNS - seldom reach CNS levels adequate for therapeutic efficacy Minocycline exception - used to eliminate meningococcal carrier state

Metabolism and excretion of tetracyclines

Phase 2 conjugation - glucuronide metabolites Biliary secretion of parent drugs and metabolites Undergo enterohepatic recirculation Doxycycline - safe for renal impairment - only oe

Adverse Effects of Tetracyclines

GI disturbance - superinfection; Ca2+ and Mg2+ antacids and dairy foods interfere with absorption - irritates mucosa, cause epigastric distress Accumulation in teeth and bone - chelates Ca2+ and Mg2+; contraindicated in under 8 yo Fatal hepatotoxicity - fatty liver, especially during pregnancy Phototoxicity Vestibular problems - minocycline Diabetes insipidus - demeclocycline

Tetracycline and the mitochondrial ribosome

Concentrate in liver, enter hepatocytes disrupt metabolic pathways leading to excessive lipid production and deposition in liver especially problematic in pregnancy

Complications with Tetracyclines in pregnancy

Deposit in teeth and bone Fatty liver deposition in pregnancy can lead to fatal hepatitis Contraindicated in pregnancy and breast feeding and children under 8 yo

Tetracycline association with superinfections

Loss of commensal enteric bacteria C. difficile thrives Pseudomembranous colitis occurs - can be life threatening

Tigecycline

Structural modifications of minocycline improves spectrum of activity No drug interactions, biliary excretion Safe in patients with renal impairment Decreased susceptibility to resistance by tet A efflux pumps and ribosomal protection

Spectrum of activity of Tigecycline

Gram + aerobes including MRSA, VRE Gram - Anaerobes - Clostridium perfringens, Bacteroides sp.