Protein Synthesis Inhibitors Flashcards
When a drug blocks a reaction that is vital to both
the microbe and host but has greater impact on the microbe, this is referred to as _
Selective toxicity
When the small ribosomal subunit and the first tRNA
arriving at the start codon of the mRNA, this described _
Initiation
What is the common ribosome subunit shared by both bacterial and mammalian species that accounts for a lot of toxicity when treating with antibiotics?
70S ribosome (mitochondrial)
What are the 3 tetracyclines provided as examples? What is their mechanisms of action? What ribosome subunit do they target?
Tetracycline
Doxycycline
Minocycline
- Bind the 30s ribosome, prevent binding of tRNA to A site
The selective toxicity associated with the tetracyclines results from its effects on _
70S mitochondrial ribosomes
Tetracyclines have [broad/narrow] spectrum, are more active against gram [positive/negative] and are bacteriostatic/bacteriocidal
Very broad
Positive
Bacteriostatic
What are the 3 mechanisms by which resistance develops with the tetracyclines?
Decreased intracell. levels (e.g. increased efflux)
Enzymatic inactivation of drug
Protein expression that protects target ribosomes
What is the route of administration of the tetracyclines?
Oral admin
What are 2 conditions that decrease the absorption of tetracyclines?
Divalent / trivalent cations (e.g. dairy)
Increased stomach pH
Tetracyclines have a wide distribution area. In addition to liver, spleen and bone marrow, what 3 notable areas do they accumulate in?
Bone
Dentin
Enamel of unerupted teeth
Tetracyclines do/don’t penetrate the CNS
Tetracyclines do/don’t penetrate the placenta
Do
Do
Most tetracyclines are cleared by the _ (organ). What is the 2 exceptions? How are they cleared?
Kidneys
Docycline - feces
Minocycline - liver - feces
What are 2 major uses for the teracyclines?
Lyme disease
Acne
What are 5 side effects associated with the tetracyclines?
GI irritation (pseudomembranous colitis) Photosensitivity Hepatotoxicity Renal Toxicity Vestibular disturbance
Why shouldn’t tetracyclines be given to pregnant women or children under 8?
Discolors teeth in children
What bacteriocidal antibiotics should not be used in combination with the tetracyclines? Why?
Penicillins
Tetracycline alters the bacteriocidal effects of the penicillins
What are 3 known drug interactions of the tetracyclines?
Digoxin
Oral anticoagulants (warfarin)
Oral hypoglycemics
How is tigecycline related to tetracycline? What is its mechanism of action?
An analogue of tetracycline
Also binds the 30S ribosome, but with higher affinity
What are 2 uses of tigecycline?
Tetracycline resistant bugs
Hershey isolate of MRSA
What is the major aminoglycoside provided as an example? What is its mechanism of action
Gentamycin
Irreversibly binds the 30S ribosome subunit
The aminoglycosides are [ bacteriostatic / bacteriocidal ] ?
Bacteriocidal
What is the antibacterial spectrum of the aminoglycosides? i.e. Gram what is targeted?
Mainly gram - aerobes
When combined with aminoglycosides, what to antibiotics act synergistically against S. aureus and S. epidermis?
Penicillin
Vancomycin
What are 3 mechanisms by which resistance occurs against aminoglycosides?
Mutant ribosome
Decreased uptake / increased efflux
Enzymatic inactivation of drug
What is the major way by which the aminoglycosides are administered?
IM or IV
The aminoglycosides are not well distributed to the cells, eyes or CNS. What is one area it accumulates, one of which is associated with major toxicity? How is it cleared?
Inner ear ***
Renal cortex
Cleared by kidneys
There are 3 major toxicities associated with the aminoglycosides. They are_
Ototoxicity
Vestibular toxicity (vertigo)
Renal toxicity
What is a major factor limiting the use of spreptomycin? When it is used, what is it use for?
High resistance
Mycobacterial infections
What is the major use for gentamycin? When not used IV/IM, what is another way to use this drug?
Severe gram negative infections
Topically, for burns, wounds, skin lesions
Tobramycin in similar to which aminoglycoside? It is slightly more active against what organism? What is its use in cystic fibrosis?
Gentamycin
Pseudomonas
P. aeruginosa respiratory tract infections in cystic fibrosis
Amikacin is a semisynthetic, less toxic derivative of _. It us used to treat bugs resistant to _ and _, as well as used to treat what major disease?
Kanamycin
Tobramycin and gentamycin
Tuberculosis
What aminoglycoside no longer used in the US is similar to gent/tobramycin and less suceptible to enzymatic degradation?
Netilmicin
A topical aminoglycoside that is limited to topical use because of widespread resistance is _
Neomycin / kanamycin
Spectinomycin in not an aminoglycoside, but rather it is a _. It works by _. It is [ bacteriostatic/bacteriocidal ]
Aminocyclitol
Binding the 30S subunit of the ribosome
Bacteriostatic
Regarding its spectrum, spectinomycin works against _
Mostly gram - but also some gram + bacteria
What are 2 major uses of spectinomycin? How is it administered?
MRSA and antibiotic resistant gonorrhea
IM administration
What are the 4 examples of macrolide antibiotics provided?
Azithromycin
Clarithromycin
Erythromycin
Troleandomycin
What is the mechanism by which the macrolide antibiotics work? Are they bactriocidal / static?
Reversibly bind the 50S ribosome subunit.
Bacteriostatic
What are 3 drug (classes) that should not be used with macrolide antibiotics? Why?
Streptogramins
Clindamycin
Chloramphenicol
Site of action very close to each other, competitively inhibit each ther
Regarding spectrum, what is the target of the macrolide antibiotics?
Narrow, accumulate more in the gram + bacteria
How dp erythromycin, clarithromycin and azithromycin compare in their activity against anaerobes?
clarithromycin and
azithromycin are more
effective than erythromycin
against anaerobes
What are the 3 mechanisms by which resistance develops to macrolide antibiotics?
Efflux pumps
Modified bacterial ribosome (methylase)
Drug hydrolysis by esterases
True or false, cross resistance is a problem for macrolide antibiotics?
True
Majority of the macrolides are stable in acid environmets. Which of the macrolide antibiotics is unstable in acid environments? How is this countered?
Erythromycin
Admin. orally in stearate and estolate form (tablets)
Generally, macrolides have poor penetration of the CNS. Which macrolide is able to penetrate abcesses and placenta?
Erythromycin
How are erythromycin and clarithromycin excreted?
erythromycin- in bile
clarithromycin- metabolized
by liver, secreted by kidney
What are 3 main uses for macrolide antibiotics?
- Alternative to penicillin for allergic patients
- Respiratory infections by atypical microbes (legionella)
- Common bacterial infections like acne
What are 2 major toxicities associated with macrolide antibiotics?
GI disturbances
Hepatotoxicity (allergic type cholestatic hepatitis)
How are theophilline, warfarin, carbemazepine, astemizole and protease inhibitors related to macrolide antibiotics? Which macrolide is the exception?
Macrolides inhibit CYP3A4, potentiating the effect of these drugs
Azithromycin is exception, structurally dissimilar
What is the example of a ketolide provided? What macrolide is it related to? What is the mechanism?
Telithromycin
Semisynthetic deriv. of erythromycin
Binds the 50 S ribosome in 2 places (blocks protein synthesis)
How is telithromycin administered? What enzyme metabolizes it? Under what conditions should adjustments be made to the dose?
Oral admin
CYP3A4 50%
Renal insufficiency
What do S. aureus and S. pyogenes have to express to be resistant to telithromycin?
MLS-B
What are 3 main uses of telithromycin?
Community acquired RTIs (pneumonia)
Acute bacterial sinusitis
Chronic bronchitis
What are 3 common side effecrs associated with telithromycin? What are 3 less common side effects associated with telithromycin?
diarrhea, nausea, abdominal pain
visual effects, blurred vision, difficulty focusing
What group of patients should not use telithromycin? What are 2 drugs that are known to interact with telithromycin?
Myesthenia gravis patients
Cisapride and simvastatin
What is the mechanism of action of chloramphenicol? is it bacteriostatic or bacteriocidal? What is its spetrum?
Reversibly binds 50S ribosome
Bacteriostatic
Wide - Most anaerobes, most gram -
What is the major means by which resistance develops to chloramphenicol?
Acetyltransferases modifying the drug
How is chloramphenicol administered? Which does it cross, CNS or placenta? Where is it metabolized? How is it excreted?
Oral or parenteral
Crosses both
Metabolized in liver, excreted in urine
What is a major consideration for the use of chloramphenicol? What drug does it replace (i.e. used only when this drug cannot be used)?
Major toxicity
Tetracycline
What are 4 major toxicities associated with chloramphenicol?
Aplastic anemia
Hematological toxicities
Hypersensitivity
Gray baby syndrome
What is the drug associated with gray baby syndrome? What causes this syndrome?
Chloramphenicol
Inadequate levels of liver
glucuronyl transferase=> can’t
metabolize the drug
Streptogramins are composed of what 2 drugs? How do each of these drugs act individually? Combined?
Quinupristin/dalfopristin
Quin - Binds 50S ribosome
Dal - Binds near by
Each bacteriostatic, combined bacteriocidal (synergy)
What are 2 major uses of streptogramins?
MRSA
Vanco resistant gram positive infections
What are 2 associated adverse effects of streptogramins?
Pain and phlebitis at IV site
Interaction with CYP enzymes (affects other drugs)
Resistance to strpetogramins occurs to each component drug. What are the mechanisms? (2 each)
Quin - Methylases to 50S rib (erm) - lactonases (vgb) Dal Acetyltransferases (vat/sat) Efflux pumps (vga/vgb)
What is the example of the oxazolidinones provided? What is the mechanism of action? How is it administered?
Linezolid
bind novel site in 23S ribosomal RNA of the 50S ribosomal subunit
Oral Drug
Is linezolid bactriostatic / bacteriocidal? What is it used to treat (3)? What is an advantage it has associated with other protein synthesis inhibitors?
Bacteriostatic
MRSA, VREf and multidrug resistant strep. pneumoniae
No cross resistance (different mechanism)
What is the example of the lincosamide provided? What is its mechanism?
Clindamycin
Binds exclusively to the 50S
subunit of bacterial ribosomes
What is the major group of bacteria targeted by clindamycin? Is it bacteriocidal or bacteriostatic?
Majority of gram + bacteria
Mainly bacteriostatic, some bacteriocidal activity
What is the major mechanism by which resistance to clindamycin develops?
Ribosomal methylase (ermA, ermB and ermC)
How is clindamycin administered? It has a wide distribution area includin bone. Where is not not able to accumulate in high concentrations? How is it metabolized? How is it excreted?
Oral or parenteral
CNS
Liver metabolism
Urine and bile excretion
What are 4 uses of clindamycin?
Abcesses
Osteomyelitis
MRSA (other group A strep. infections)
RTIs caused by anaerobes
What are 4 adverse effects assoc. with clindamycin?
Pseudomembranous colitis (C. dificile)
Diarrhea
Skin rash
Stevens-Johnson syndrome
How is muciprocin administered? What is it used for? What is its mechanism? How does resistance develop?
Topically administered Used to treat impetigo from MRSA or Group A strep inhibits isoleucyl tRNA synthetase Resistance is rare
