Protein Synthesis Inhibitors Flashcards
What class of antibiotics bind to bacterial 30S ribosome?
aminoglycosides and tetracyclines
List the 6 aminoglycosides and their distinctions as a drug
- Amikacin - for gentamicin resistant organisms
- **Gentamicin - MOST COMMONLY USED in clinical settings for susceptible organisms: gram(-) aerobic
- Kanamycin - worst nephro- and oto-toxicity; only for TB and topical
- **Neomycin - topical use, bowel sterilization
- **Streptomycin - primarily for mycobacterial TB in hospital setting
- **Tobramycin - pseudomonas aeruginosa
What particular amino glycoside is used to tx:
Brucellosis
Gentamicin + doxycycline; zoonotic infection (NOT tick borne)
What particular amino glycoside is used to tx: Tularemia
Gentamicin
Rabbit-borne disease; most common outbreaks in Martha’s vineyard, off coast of Massachusetts; potential bioweapon*
What particular amino glycoside is used to tx: Plague (Yersinia pestis)
Streptomycin + doxycycline
People who live around prairie dog towns
What particular amino glycoside is used to tx: Pseudomonas aeruginosa
Tobramycin + pipericillin or ticarcillin
What particular amino glycoside is used to tx: Klebsiella
Gentamicin + pipericillin or ticarcillin
What two drugs can be used synergistically to treat streptococcal & enterococcal endocarditis?
beta-lactams and aminoglycosides
What is neomycin used for?
To “Sterilize” bowel prior to colonoscopy or bowel surgery
Aminoglycosides are highly polar and poorly absorbed from GI tract. Oral neomycin acts as a topical antibiotic in the gut and eradicates flora. Its too toxic for parenteral use.
Describe the MOA of aminoglycosides
(1) Passive diffusion through porins
(2) O2-dependent active transport to cytosol
(3) Bind to 30S ribosomal unit
(4) Disrupt protein synthesis (reading error)
(5) Irreversible, BACTERICIDAL effects, POST-antibiotic effects
* Disrupts matching of codon/anticodon –> leading to formation of dysfunctional proteins –> eventually killing the bacteria bc dysfunctional proteins cannot carry out their jobs
Describe the mechanisms of resistance to aminoglycosides
(1) Depletion/deficit of porins (MDR)
(2) O2 deficit/ anaerobic organism(s)
(3) Enzymatic alteration of amino glycoside structure - which impairs its binding to 30S ribosomal unit and/or cell entry –> acetylation, phosphorylation, or adenylation
(4) Mutation of 30S ribosome
What organisms are intrinsically resistant to aminoglycosides?
Anaerobes:
gram(+) rods = Clostridia
gram(-) rods = Bacteroides, Fusobacteria
ALSO - facultative bacteria in a true anaerobic environment
What are the AE of aminoglycosides
(1) *Nephrotoxicity - accumulate in renal cortex
(2) Ototoxicity / vestibular toxicity = 8th CN effect - accumulate in inner ear perilymph
(3) Neuromuscular blockade
Describe the nephrotoxicity seen with aminoglycosides
Accumulates in renal cortex. Risk factors - low BP, loop diuretics (furosemide) and advanced age.
Other nephrotoxic agents (cyclosporin in transplant pts, amphotericin in severe fungal infections)
Describe the ototoxicity seen with aminoglycosides
Aminoglycosides in perilymph damage hair cells
Cochlear hair cells are exposed to higher concentrations of “loop” diuretics than blood level. Loop diuretics disrupt Na+, K+ –> affecting ion transport
Describe neuromuscular blockade by aminoglycosides
Risk is greatest with intra-pleural & intra-peritoneal administration, or large doses, or rapid i.v. infusion. Can produce apnea or resp arrest
May aggravate or reveal myasthenia graves or cause transient myasthenia syndrome
Blockade can be managed with neostigmine or ventilator in extreme cases
It competes with Ach at nicotinic cholinergic receptors - have to give large doses for this to matter such as pts with burn injuries
Describe the potency, intestinal absorption, disruption of gut, photo-toxicity for: tetracycline
Potency = LOW Intestinal absorption = moderate *****Disrupt gut = HIGHEST Photo toxic = low *Not used much *Low intestinal absorption means its resident in gut for long enough time; has tendency to cause gastric irritation. More likely to alter and eradicate commensal bacteria in gut; conferring risk for overgrowth by pathogenic organisms like clostridium difficile
Describe the potency, intestinal absorption, disruption of gut, photo-toxicity for: demeclocycline
Potency: medium Intestinal absorption: moderate disrupt gut: moderate ******Photo toxic: WORST *Not used much
Describe the potency, intestinal absorption, disruption of gut, photo-toxicity for: minocycline
**Potency: HIGH
**Intestinal absorption: COMPLETE (little food interference)
disrupt gut: least
**Photo toxic: High
*Reaches Rx levels in CNS for meningeal carriers - ONLY one that achieves high enough levels in CNS to be used to eradicate meningococcal infections from CARRIERS and not for people who are active
Describe the potency, intestinal absorption, disruption of gut, photo-toxicity for: doxycycline
**Potency: HIGH
**Intestinal absorption: COMPLETE (little food interference)
disrupt gut: least
**Photo toxic: High
*Preferred agent parenterally; preferred with renal impairment
What uniques about tigecycline
Overcomes resistance & MRSA!!!
NEW drug
What unusual organisms does doxycycline cover?
(1) **Rickettsial infections (intracellular)
(2) Chlamydia trachomatis = Major STD - urethritis (non-specific), PID, lymphogranuloma venereum
(3) **Chlamydia psittaci = psittacosis pneumonia
(5) **Mycoplasma pneumonia - young adults; close quarters
Describe the rickettsial infections that are covered by doxycycline
Rickettsial infections (intracellular) = tick-born = Rocky Man Spotted Fever, Q fever, typhus
What drug is co-administered with ceftriaxone for tx of gonorrhea?
Doxycycline; 60-70% of female pts with gonorrhea are co-infected with chlamydia
Instead of doxycycline, what is an alternate for tx of mycoplasma pneumonia?
Erythromycin
Describe the MOA of tetracyclines
(1) Passive diffusion into bacterial cytosol
(2) Bind to 30S ribosomal unit
(3) BLOCK binding of aminoacyl-tRNA
(4) Inhibit protein synthesis
(5) Exert bacterio-STATIC effects = inhibits rate of protein synthesis; reversible when drug is cleared out
What are mechanisms of resistance to tetracyclines?
(1) Tetracycline efflux pump (Tet A pump)
2) Ribosome protection (methylation of ribosome
What drug is associated with enterohepatic recirculation?
Tetracyclines = does not get eliminated in smooth exponential decay
What is the only safe tetracycline to use in renal impairment and why?
Doxycycline because it is cleared almost entirely by biliary excretion
What are the AE of tetracyclines?
(1) GI disturbance - superinfection
(2) Accumulation in teeth & bone
(3) Fatal hepatotoxicity (fatty liver, esp. during pregnancy)
(4) Phototoxicity
(5) Vestibular problems - minocycline
(6) Diabetes insipidus - demeclocycline
Describe the complication with tetracyclines and the GI tract
Tetracyclines can irritate gastric mucosa and cause epigastric distress
Pts experiencing gastritis often self-medicate with antacids which contain Ca++ –>antacids & dairy foods interfere with tetracycline absorption
Describe the complication with tetracycline and calcified tissue (bones & teeth)
Tetracyclines chelate Ca++ and Mg++ in calcified tissues = bone and teeth.
In growing children, tetracyclines accumulate in teeth & bones –> CI in children <8YO!
Describe complication with tetracyclines in pregnancy and the liver
Tetracyclines concentrate in the liver and can enter hepatocytes. Bacterial ribosome has an ancestral form of human mito ribosome. Inside mito, tetracyclines can disrupt metabolic pathways leading to excessive lipid production and deposition in liver (can lead to fatal hepatitis) - esp. problematic in pregnancy
When is tetracycline contraindicated?
Pregnancy
Breast feeding
Children <8YO
How can the use of tetracycline lead to a superinfection in the gut?
Causes loss of commensal enteric bacteria
C. difficile thrives –> secretes exotoxin that causes –>
Pseudomembranous colitis - can be life-threatening
Whats better in the new drug tigecycline?
(1) Structural modifications of minocycline improves spectrum of activity
(2) No drug interactions; biliary excretion; safe in pts with renal impairment
(3) Decreased susceptibility to resistance by tet A efflux pumps & ribosomal protection
(4) Spectrum of Activity:***
- Gram(+) aerobes including MRSA, VRE
- Gram negatives
- Anaerobes - Clostridium perfringens, Bacteroides
What are the classes of antibiotics that bind to the 50S ribosome?
(1) Macrolides & Ketolides
(2) Clindamycin
(3) Chloramphenicol
(4) Linezolid (Oxazolidinones)
What are the macrolides?
Erythromycin
Clarithromycin
Azithromycin (Zithromax)
What is the intestinal absorption, activity spectrum, and distinctions for: erythromycin
(1) acid labile, poor oral absorption
(2) mainly gram(+) cocci & *****treponema pallidum (syphilis)
(3) use in pts with PENICILLIN ALLERGY
What is the intestinal absorption, activity spectrum, and distinctions for: clarithromycin
(1) good
(2) Extended to gram(-) & chlamydia, legionella, pneumophila, Moraxella
(3) Has active metabolite
What is the intestinal absorption, activity spectrum, and distinctions for: Azithromycin (Zithromax)
(1) Good
(2) Same to clarithromycin + more gram(-)
* *Drug of choice for LEGIONNAIRES’ DISEASE
(3) Has active metabolite. LEAST drug-drug interactions
What is the intestinal absorption, activity spectrum, and distinctions for: telithromycin
= KETOLIDE!
(1) Good
(2) Covers MULTIDRUG RESISTANT S. PNEUMONIA
(3) Has active metabolite
What are macrolides active against? (in general)
Macrolides usually active against many gram(+) organisms including Staphylococcus aureus*, and Group A, B, C, and G Streptococcus
*EXCEPT for methicillin-resistant S. aureus
What are the major indications for macrolide/ketolides
Upper Respiratory tract infections! –> CAP (Community-Acquired Pneumonia)
*Macrolides and ketolides distribute into and concentrate in most body tissues and phagocytic cells. Accumulate at site of infection > levels in plasma
List the organisms covered by macrolides and ketolides
S. pneumonia Hemophilus spp Moraxella catarrhalis Atypical: - Legionella pneumophila - Chlamydiphila pneumonia - Mycoplasma
Whats unique about Azithromycin?
A once daily, 5-day regimen is as effective as 10 day course of the other macrolides
Pathogenic Gram(-) Rods: Name the 3 organisms that are facultative anaerobes and enteric flora?
- Escherischia
- Enterobacter
- Serratia
Pathogenic Gram(-) Rods: Name the organisms that are pure aerobes & nosocomial, opportunistic
- Pseudomonas
2. Acinetobactera
Plague comes from what?
Yersinia Pestis –> Plague - rates
Brucellosis comes from what?
Brucella sp. –> Brucellosis - cows
Tuleremia comes from what?
F. Tularensis –> Tuleremia - rabbits
Describe the MOA of macrolides and ketolides
1Macrolides (erythromycin, clarithromycin, azithromycin) and telithromycin, bind to the 50S subunit of bacterial ribosomes. Macrolides inhibit the translocation step of protein synthesis - the movement of a growing peptide along the ribosome to make room for the next tRNA charged with an amino acid. This leads to inhibition of bacterial protein synthesis
= Irreversible binding to 50S subunit
= Bacterio-STATIC (generally)
What are the mechanisms of resistance to Macrolides?
- Methylation (alteration) of ribosome
2. Macrolide efflux pumps
Describe how methylation of ribosome leads to macrolide resistance?
Methylases encoded by the erm (erythromycin ribosome methylase) genes (ermA, -B, -C, etc.) alter macrolide binding to bacterial ribosomal RNA conferring high level macrolide resistance
Describe how macrolide efflux pumps leads to macrolide resistance?
Transporters encoded by the (macrolide efflux genes (mef E) pump macrolides out of cytosol. Conceptually similar to get pumps but with substrate preference for macro lies. Confer mid-level resistance, The clinical significance is debatable
What organisms are intrinsically resistant due to decreased permeability of the outer envelope?
Enterobacteriaceae, Pseudomonas spp, Acinetobacter spp are intrinsically resistant due to decreased permeability of outer cell envelope
What are the adverse effects and clinical complications for: erythromycin, clarithromycin, azithromycin, telithromycin
(1) GI - N/V/D
(2) Hepatotoxicity (rare, serious) –>
- cholestatic jaundice - erythromycin estolate (hypersensitivity)
- fatal hepatotoxicity - telithromycin
(3) Cardiac - QTc interval prolongation
(4) Drug-Drug interactions - Cyp3A4 interaction
(5) Reversible hearing loss
Describe the adverse cardiac effect from macrolides and ketolides
Macrolides and telithromycin have intrinsic arrhythmogenic capability via blockade of the I(Kr) channel (inward rectifying K+ channel). Prolonged cardiac repolarization (prolonged QT int) which increases risk for tornadoes de pointes arrhythmias
QT interval prolongation: erythromycin > clarithromycin > azithromycin
Why can erythromycin cause sudden cardiac death?
Erythromycin associated with 2-fold increase in risk of sudden cardiac death overall and 5-fold increase in patients taking drugs that are CYP3A4 inhibitors - which causes elevations in circulating erythromycin levels
What are the safest macrolides in pregnancy?
Erythromycin & azithromycin (category B)
**BUT - beta lactams are still drug of choice compared to all others in setting of pregnancy
When needed to treat CAP and deciding between tetracyclines and macrolides –> in setting of pregnancy choose macrolide because tetracycline is contraindicated due to risk for fatty liver hepatotoxicity and risk towards growing fetus
What is the lincosamide drug name discussed in lecture?
Clindamycin!
*Similar to erythromycin in terms of (1) site & MOA; (2) mechanism of resistance; (3) efficacy vs non-enteric gram(+) cocci
What makes clindamycin distinct?
Anti-microbial spectrum: anaerobes - primary clinical use. –> e.g. abdominal anaerobic infections [Bacteroides fragilis] associated with trauma (gunshot, stabbing)
Main AE: pseudomembranous colitis - caused by overgrowth of C. difficile (manage with (1) metronidazole (2) vancomycin p.o.*****
(Vancomycin = PO!! and NOT IV)
What is the clinical use of chloramphenicol?
RARE clinical use - restricted to life-threatening infections for which there is no alternative (e.g. some meningitis infections)
What are the lethal toxicities of chloramphenicol?
(1) Anaplastic anemia - idiosyncratic
(2) Gray Baby Syndrome - developmental origins
Describe the anaplastic anemia associated with chloramphenicol
Idiosyncratic, life-threatening & may occur after therapy is stopped. Drug can’t be glucuronidated d/t immature liver. Standard hemolytic anemias occur in patients with G6PD deficiency
What causes gray baby syndrome
Caused by chloramphenicol - can penetrate human cells and disrupt their mito protein synthesis
- drug concentration dependent caused by impaired glucuronidation in neonates & impaired renal clearance
What is seen with gray baby syndrome?
- abdominal distention, diarrhea, vomiting, dusky gray color
- circulatory collapse & death
What were the two ontogeny & pediatric catastrophes discussed?
(1) Sulfonamides - kernicterus
neonatal encephalopathy due to bilirubin displacement & poor bilirubin clearance
(2) Chloramphenicol - Gray Baby Syndrome
abdominal distension, diarrhea, vomiting, dusky gray color, circulatory collapse & death - drug concentration dependent
- impaired glucuronidation in neonates
- impaired renal clearance
What was the FDA issued warning about OTC diarrhea drug?
FDA warned consumers to not use an OTC drug called intestinomicina - the El Salvador-manufactured drug is sold in the U.S. as a tx for infectious diarrhea at international grocery stores and specialty stores. Intestinomicina contains chloramphenicol, people with anemia and other low blood cell counts are at greater risk of injury or death from using the drug
What is the site, MOA and resistance of chloramphenicol?
- binds to 50S ribosomal subunit where it inhibits the peptidyl transferase step of protein synthesis
- bacterio-STATIC
- can enter host cells and impair host mito protein synthesis - which produces toxicity
- resistance involves enzymatic medication by acetyltransferase (CAT) –> less active and less binding to 50S ribosome
what is the name of the oxazolidinone
linezolid
when do you use linezolid?
antibiotic used when organisms are vancomycin resistant
- protein synthesis inhibitor
- bacterio-STATIC
- high levels are present in lungs
describe the MOA of linezolid
bind to the 50S ribosomal subunit and interfere with its binding to the initiation complex - keep 30S and 50S from assembling correctly
T/F: linezolid is an CYP450 inhibitor
FALSE - linezolid undergoes NON-enzymatic oxidation
- NOT a CYP450 substrate, inhibitor, or inducer
- RENAL clearance
Long term use with linezolid causes what?
Increased levels of ALT
Decreased platelets
MAO interaction**
Peripheral neuropathy
