Protein Synthesis Inhibitors Flashcards
Why is it interesting and also scary that MRSA resistant?
Methicillin is an antibiotic that is stable to a beta-lactamase producing organism so if something is resistant to methicillin it can be very dangerous because it means it is resistant to something that typically works against bugs that are resistant.
Why is Mycoplasma Pneumoniae resistant to penicillins and cephalosporins?
Because it lacks a peptidoglycan cell wall, not because it produces beta-lactamase. (penicillins and cephalosporins are inhibitors of cell wall synthesis - they will have no effect on this organism).
What do protein synthesis inhibitors target?
target the bacterial ribosome within the cell, not the cell wall.
What is the bacterial ribosome?
It has a smaller (70S) than the mammalian ribosome which is 80S -> it is composed of 50s and 30s subunits as opposed to 60s and 40s in humans -> so protein synthesis inhibitors won’t effect human ribosomes, it’s selective.
Protein Sythesis Inhibitors
tetracyclines
macrolides
chloramphenicol (ind. drug)
clindamycin (ind. drug).
Class of Tetracyclines
tetracycline: prototype, hardly used
doxycycline: Super important!!!
minocycline: acne
demeclocycline
MOA of Tetracyclines
Binds to 30s subunit of bacterial ribosome, believed to block access of amino acyl-tRNA to mRNA-ribosome complex at the acceptor site, thus inhibiting bacterial protein synthesis.
Spectrum of Tetracyclines
Broad spectrum: active against many gram positive and gram negative organisms including anaerobes.
Resistance to Tetracyclines
- any organism resistant to one tetracycline is resistant to all tetracyclines
- cell develops efflux pumps (pumps drug out of cell)
- forms ribosomal protection proteins
Absorption of Tetracyclines
all tetracyclines adequately but incompletely absorbed thru oral ingestion
What decreases absorption?
dairy foods (less of a problem with doxy)
Distribution of Tetracyclines?
concentrate in liver, kidney, spleen, and skin and bind to tissues undergoing calcification –> teeth and bones
- Doesn’t penetrate CSF
- All cross placental barrier and concentrate in fetal bones and dentition
Elimination of tetracyclines
concentration in liver -> metabolized and conjugated–> released in bile –> reabsorbed in intestine and enter urine via glomerular filtration (doxy -> bile and into feces)
What makes doxycycline an acceptable drug for renally compromised patients/
Because instead of being filtered by the kidneys it stays in bile and is excreted into the feces.
Adverse effects of Tetracyclines?
Calcified tissues: deposition in the bone and primary dentition occurs during calcification of growing children -> causes discoloration and hypoplasia of teeth and temporary stunting of bones for growth.
Gastric discomfort: controlled if taken with foods other than dairy products.
Phototoxicity: severe sunburn can occur when the patient taking a tetracycline is exposed to sun or UV rays
Vestibular problems: dizziness, nausea, and vomiting occur with minocycline.
CI’s of Tetracyclines
pregnant women (category D)
Breast feeding women
Children
Tetracyclines routes of administration
Oral, IV, IM (not recommended b/c of pain and inflammation at injection site).
Tetracycline uses
STDs, atypical pneumonia, exacerbations of chronic bronchitis, acne vulgaris, and great alternative for sinusitis and acute prostatitis
Why do you never use tetracyclines for skin infections?
Because of decreased activity against staph aureus
Doxycycline uses:
DOC for mycoplasma pneumonia, chlamydiae (resp for variety of STI’s), rickettsiae (Rocky Mountain Spotted Fever), and excellent for Lyme Disease
Minocycline uses
acne vulgaris (rarely anything else)
Demeclocycline uses
Tx of SIADH because of its inhibiting action of ADH.
*SIADH= syndrome of inappropriate antidiuretic hormone secretion
What are the 3 macrolides?
erythromycin: first one in drug class and prototype, not used nearly as much any more.
azithromycin (Zithromax): most popular macrolide, used extensively in a variety of circumstances.
Clarithromycin (Biaxin)
Macrolides MOA
bind irreversibly to a site on the 50S subunit of bacterial ribosome, thus inhibiting the translocation steps of protein synthesis
- Bacteriostatic
Are macrolides stable against b-lactamase producing organisms?
yes, because they are protein inhibitors not cell wall inhibitors
Erythromycin spectrum
effective against same organisms as PCN G -> used in pts allergic to penicillins. Also effective against chlamydial species and mycoplasma pneumoniae and legionella pneumophila
Clarithromycin (Biaxin) spectrum
similar to erythro but also effective against H> influenzae (community acquired pneumonia)
- Use instead of Azithro -> new trend
Azithromycin (Zithromax) spectrum
less active against strep and staph than erythro but more active against respiratory infections due to H. influenzae and Moraxella catarrhalis. Excellent for urethritis caused by Chlamydia trachomatis
Resistance to macrolides?
most strains of staph in hospital isolates are resistant to erythro
clarithro and azithro show cross resistance to erythro
*Not good in skin coverage -> don’t use for staph aureus (MRSA)
Resistance mechanisms to Macrolides
alteration in the binding site of the ribosome.
manifestation of an efflux pump to get the drug out of the cell.
Enzymatic inactivation
Absorption of Macrolides
Erythro: destroyed by gastric acid and therefore need enteric coated tablet, adequately absorbed on oral administration
Clarithro and Azithro: stable to stomach acid and readily absorbed
Distribution of Macrolides
widely distributed in tissue except for CSF
Metabolism of Macrolides
Erythro: cytochrome P450 drug
Clarithro: metabolized by liver and may also interfere with other drugs
Azithro: not a p450 drug and tends to have few interactions with other meds
Excretion of Macrolides
Erythro and azithro primarily concentrated in the bile
Clarithro and its metabolites are eliminated by kidney and liver -> recommended that dosage be adjusted in pts with compromised renal function
Common adverse effects of Macrolides
GI distress including diarrhea big problem with erythro -> leads to poor pt compliance (sometimes used for constipation even)
Azithro and Clarithro are much better tolerated in GI
Ototoxicity: transient deafness has been associated with erythromycin especially at high dosages.
prolonged QT with erythro and clarithro (rare)
Why is Azithro preferred over erythro and clarithro?
Fewer adverse effects
fewer drug interactions
don’t have to worry about adjusting dose with kidney and liver disease unless severe
Long half life -> easy to use and pts are more compliant (daily dosing compared to 2x daily or 4x daily)
Are Macrolides good for staph disease?
Nope, not good for staph just like doxycycline
Why are macrolides liked for tx of chlamydial cervicitis and urethritis STI’s compared to doxy?
because it works really well against chlamydial species
- only have to dose single 1 gram versus a 7-10 day course of doxy
When are macrolides DOC?
Excellent for broad spectrum coverage of both typical and atypical pneumonias, used all the time for exacerbations of chronic bronchitis in the patient with COPD
- used first line alt. for group A strep pharyngitis (strep throat)
Chloramphenicol -> should we use?
Active against wide range of gram + and gram - organisms but because of its HIGH toxicity, its use is restricted to life-threatening infections in which there are no alternatives!!
MOA of chloramphenicol
Binds to bacterial 50S ribosomal subunit and inhibits protein synthesis at the peptidyl transferase reaction
Spectrum of Chloramphenicol
very broad -> including anaerobes
- not effective against pseudomonas or chlamydiae
Pharmacokinetics of Chloramphenicol
completely absorbed orally
Readily enters CSF
Adverse effects of Chloramphenicol
- Hemolytic anemia
- aplastic anemia –> idiosyncratic and usually fatal, occurs independent of dose and may occur after therapy has ceased!
- Gray Baby syndrome -> because of interference with human mitochondrial ribosomes, can lead to poor feeding, depressed breathing, cardiovascular collapse, cyanosis, and death
- can interfere with a number of other drugs
Clindamycin MOA
same as macrolides –> bind to 50s subunit of bacterial ribosome.
Clindamycin spectrum
great coverage against anaerobic bacteria but also active against many gram + cocci: staph and strep
Clindamycin absorption and distribution
well absorbed orally, distributes well into all body fluids except CSF
What is always resistant to clindamycin?
Clostridium difficile -> which is a bug that hangs out in gut and is usually harmless but with the administration of Clindamycin there can potentially be overgrowth of C. difficile which can lead to potentially fatal disease –> pseudomembranous colitis with side effects of diarrhea, nausea, and skin rash
What are the common meds used against anaerobes?
Clindamycin or Metronidazole (Flagyl)
- Excellent in treating infections of the gut and used to treat penetrating wounds of abdomen and gut
What should you think of when you hear anaerobic infection?
gut flora or female genital tract flora
