Protein synthesis and DNA synthesis inhibitors Flashcards
Gentamicin and Amikacin are common members of what class of protein synth inhibitors?
Aminoglycosides
**note Tobramycin and Streptomycin are there but just not as common?**
What is the MOA of aminoglycosides?
Binds 30S ribosomal subunit; Misreads or terminates genetic code; Inhibits bacterial protein synthesis
T/F: Most aminoglycosides are cidal and not static because they eliminate bacterial protein synthesis
What would you do to overcome the fact that these drugs don’t penetrate the gram positive cell wall?
Falsehood. Generally inhibits protein synthesis, not eliminating all protein synthesis so these drugs are static, but can be cidal if we give a high enough dose of the drug
Conc to become cidal depends on amount of drug required to get protein synthesis to a low enough level such that the bacterial cell can’t survive anymore
Synergy with beta-lactams >> holes get punched into bacterial cell wall >> allows the aminoglycosides to get into the bacterial cell
Aminoglycosides work against (gram pos/neg) bugs and have no anaerobic or atypical coverage
Aminoglycosides work against gram neg bugs (+Pseudomonas) and have no anaerobic or atypical coverage
For gram pos, need to use w/ beta lactams otherwise useless when used alone
(S. aureus, Enterococci (for very difficult to treat infections/biofilms/in privileged sites/infections where you need to give a prolonged course)
Because aminoglycosides concentrate highly in the urinary tract system, the only time they would be used alone is in the case of a ___
These drugs are also used for double coverage, which is what?
Because aminoglycosides concentrate highly in the urinary tract system, the only time they would be used alone is in the case of a UTI
These drugs are also used for double coverage, which is giving 2 agents that have activity against the unknown bug in question. Reason for doing double coverage: used when you don’t know what the causative agent is and you suspect resistance/just in the case the bug might be resistant
**when using 2 agents for an unknown infection, the usual 2nd agent is an aminoglycoside**
Clinical indications for aminoglycosides include: endovascular gram +ve infections and ___
Clinical indications for aminoglycosides include: endovascular gram +ve infections and systemic infections (used IV only)
**others: tularemia, plague, brucellosis, restistant MTB infection
Aminoglycosides are contraindicated in Pneumonia (why?), used for complex UTIs and concentrate highly in which parts of the body?
Aminoglycosides are contraindicated in Pneumonia due to low concentration in lungs/inhibited by pH, used for complex UTIs and concentrate highly in the ears and kidney
Adverse events involving aminoglycosides include ototoxicity and ___
- Ototoxicity: Irreversible; Cochlear damage >> hearing loss; Vestibular damage >> vertigo
- Nephrotoxicity/Tubular Necrosis
Variable damage (leading to hemodialysis), irreversible, risk w/ radiocontrast, cyclosporin, Amphotericin B, Vancomycin
What are the 3 main modes used to prevent aminoglycoside adverse events?
3 ways to prevent adverse events: monitor levels, take advantage of PK/PB to improve dosing, avoid other nephrotoxic agents
Since aminoglycoside activity is concentration dependent, how can you exploit this to avoid adverse events?
Give ideal conc for organism to be affected, once a day, wait 24 hours (ear and kidney can start metabolizing drug so it doesn’t accumulate in those sites before the next dose given 24 hours later)
What is a unique (potentially fatal) adverse effect of aminoglycosides? (hint: same etiology for MG and that’s why you wouldn’t use it in patients with MG)
Contraindicated in folks with Myasthenia Gravis and similar conditions because they’ll experience respiratory depression
Another class of drugs that inhibit the 30S bacterial ribosomal subunit are the tetracyclines. Name 3 drugs in that group
Doxycycline, Tetracycline, Minocycline
I was just cyclin down the street and I ran into Mino carrying his tetrad looking backpack and walking his dog Doxy
What is the MOA of tetracyclines? Are they static or cidal?
Binds 30S ribosomal subunit (reversible) and blocks access of tRNA to mRNA (so these are bacteriostatic)
Inhibits bacterial protein synthesis
Lipophilic, allows entry into GN/GP
Resistance in tetracyclines is __ mediated and mechanisms of resistance include active efflux from bacterial cell and ___
Resistance in tetracyclines is plasmid mediated and mechanisms of resistance include active efflux from bacterial cell and #RPPs (ribosomal protection proteins)
Describe how ribosomal protection proteins work to mediate tetracycline resistance
Ribosomal protection proteins bind to a diff part of the composite ribosome such that the tetracycline is displaced and the bacteria can continue making proteins
Tetracyclines cover (gram pos/neg) bugs and (do/don’t include) Pseudmonas
What are the atypicals covered by tetracycline?
Tetracyclines cover both GN and GP bugs and don’t include Pseudmonas
Atypicals: Chlamydia, Mycoplasma
**note also ltd anaerobic activity and Doxy works against CA-MRSA
Clinical indications for tetracyclines include community acquired upper respiratory infections, STIs, esp ___. Other uses include doxy for __ prophylaxis, minocycline for __ (you have it when you eat chocolate) and Rickettsiae
Clinical indications for tetracyclines include community acquired upper respiratory infections, STIs, esp Chlamydia. Other uses include doxy for malaria prophylaxis, minocycline for acne (you have it when you eat chocolate) and Rickettsiae
Why wouldn’t you take tetracyclines with milk, antacids, or iron containing preps?
Why are tetracyclines contra-indicated in pregnant women and young kids?
All of those have divalent cations which decrease gut absorption of the drugs
Binds to tissues undergoing calcification >> concentrates in teeth and bones >> contraindicated in young kids and pregaz women
**deposition in bone and teeth causes staining of teeth, hypoplasia of teeth, and stunted growth**
Another unique side effect of tetracyclines is ___ (aka increased sunburns)
Photosensitivity
Macrolides are another class of drug that inhibit protein synthesis. Name 3 drugs in this group and their MOA
allthemycins #A_C_E
Azithromycin
Clarithromycin
Erythromycin
Bind to 50S ribosomal subunit, blocks translocation and inhibits bacterial protein synthesis
Mechanisms of resistance for macrolides include decreased microbial entry, permeability, ___, target site alterations (erm gene) and enzymatic drug inactivation
Decreased microbial entry, permeability
Efflux pumps
Target Site Alterations (erm gene)
Enzymatic Drug Inactivation
The spectrum of activity of macrolides include (GP/GN), anaerobes and ___
+Gram-negative (not Pseudomonas)
+Gram-positive: Staphylococci, Streptococci (including susceptible pneumococcus but resistance increasing)
+Anaerobes: Some GN anaerobes
+Atypical: Mycoplasma, Legionella, Chlamydia
Clinical indications of macrolides include:
Atypical community acquired pneumonias, STIs caused by ___, traveler’s diarrhea and ___ prophylaxis in HIV
Clinical indications of macrolides include:
Atypical community acquired pneumonias, STIs caused by Chlamydia, traveler’s diarrhea and MAC (Mycobacterium avium complex) prophylaxis in HIV
Macrolides are bacteriostatic/cidal. Azithromycin has a long/short half life and erythromycin is metabolized by which enzyme system?
Macrolides are bacteriostatic. Azithromycin has a long half life and erythromycin is metabolized by CP450s
Adverse effects of macrolide use include ___ (MACRO)
GI Motility issues (epigastric distress)
Arrhythmia (QTc prolongation)
**others you nned to know for step**
Which macrolide is a prokinetic agent used to improve GI motility issues?
Which macrolide is used to treat Mycobacterium avium complex disease and H. pylori infection?
Erythromycin
Gut motility, prokinetic (increases gut motility so it’ll be mainly used for this and not so much infection)
Clarithromycin
Mycobacterium avium complex disease (similar to TB)
H. pylori (causes duodenal ulcers)
There’s one drug in the class of lincosamides which bind the bacterial 50S ribosomal subunit. Name it
That hoe Clinda(mycin)
**recall that this is one of the C-diffogenic ones**
Describe inducible clindamycin resistance. Which gene is induced to lead to resistance?
Erythromycin is a potent inducer of the erm gene
Double disk diffusion: agar plate with a bug growing, two antibiotic disk so one has erythromycin and the other has clindamycin
One has resistance to erythromycin, and the other is susceptible to clindamycin
Circled in red: induced clindamycin resistance (induced by erythromycin); resistance also develops with prolonged clindamycin use
Lincosamides cover (gram pos/neg) bugs and are commonly used for anaerobic infections (including Bacteriodes fragilis)
Lincosamides cover gram pos bugs only (Staphylococci (+ some CA-MRSA, Streptococci) and are commonly used for anaerobic infections (including Bacteriodes fragilis)
Clinical indications for lincosamides include community aspiration pneumonia (aspirating anaerobes), __ infection, human bite wounds and __
Clinical indications for lincosamides include Community aspiration pneumonia (aspirating anaerobes), oral/ENT infection, human bite wounds and abscesses
**also used for skin/soft tissue infection due to CA-MRSA**
T/F: Clindamycin is mainly bacteriostatic but can be bacteriocidal at high enough doses
Adverse effects of lincosamides include ___ (recall this thing can hapen with ANY antibiotic)
Truth. It can indeed
Adverse effects of lincosamides include ___ (recall this thing can hapen with ANY antibiotic)
Oxazolidinones are a class of drugs that also bind the 50S ribosomal subunit. Name the drug(s) in the class and describe the MOA
Linezolid (pretty zolid line) and Tedizolid (think about teddy from Mr. Bean)
Binds to 50S ribosomal subunit and prevents formation of 70S complex
Inhibits translocation process
Inhibits bacterial protein synthesis
How does tedizolid have increased potency against bugs?
Tedizolid has additional target site interactions with the peptidyl transferase binding region of rRNA – Increased Potency
What are the mechanisms of resistance in oxazolidinones?
(Which drug in this class overcomes this resistance?)
Generally uncommon but spontaneous point mutations at drug target site and acquisition of plasmid-mediated resistance gene, cfr
The spectrum of activity for oxazolidinones include __, some atypicals and mycobacteria and nocardia
Gram-positive ONLY
Staphylococci (including MRSA)
Streptococci
Enterococci (including VRE)
No Gram-negative, No Anaerobic
Some atypicals
Other: Mycobacteria, Nocardia
Clinical indications for oxazolidinones includes VRE, ___ and ___
See below
(VRE, Hosp acquired pneumonia due to MRSA and complicated skin/soft tissue infections)
Oxazolidinones (aka Linezolid) are generally bacteriostatic and have __ bioavailability upon one condition. They can also be given orally or IV
Oxazolidinones are generally bacteriostatic and have 100% bioavailability upon one condition: as long as patient has functioning gut. They can also be given orally or IV
Unique advsere effects of oxazolidinones include ___, peripheral neuropathy, ___ due to MOA inhibition, and ___
Unique advsere effects of oxazolidinones include bone marrow suppression (+thrombocytopenia), peripheral neuropathy, serotonin syndrome due to MOA inhibition, and lactic acidosis
**note Serotonin syndrome can be fatal when given with SSRIs, mainly seen with linezolid**
What is the MOA of muporicin? (hint: it’s the only one that has something to do with tRNA binding)
Muporicin: binds bacterial tRNA synthetase (reversible) and inhibits protein and RNA synthesis
What is the spectrum of activity of muporicin?
(imagine that there’s a kid named Mupo wearing a purple shirt and holding clusters of purple grapes and a chain of purple grape candy)
Gram-negatives: No appreciable activity
Gram-positives: Highly active against S. aureus, other Staphylococcus spp, Streptococci
No activity against Enterococci
NO anaerobic coverage
**note: Muporicin is a topical agent that is highly active against skin flora that normally cause disease (Staph and Strept) whereas it has weaker activity against those that don’t cause disease
Clinical indications for Mupirocin include skin infections caused by S. aureus and Streptococcus pyogenes, ___ and prophylaxis against ___
Clinical indications for Mupirocin include **skin infections caused by S. aureus and Streptococcus pyogenes, •MRSA decolonization of nares and prophylaxis against catheter-related infection
**Generally localized skin infections w/o any systemic symptoms/effects
How is Mupirocin administered and what are the adverse effects?
Topical only
Adverse events: Propylene glycol base may irritate mucous membranes or broken down skin
Contact dermatitis
