Protein Synthesis Inhibition Flashcards
What is the tetracycline MOA
✓ Tetracyclines enter susceptible organisms via:
✓ passive diffusion and
✓ also by an energy-dependent transport protein mechanism unique to
the bacterial inner cytoplasmic membrane.
✓ Tetracyclines concentrate intracellularly in susceptible organisms. The
drugs bind reversibly to the 30S subunit of the bacterial ribosome.
✓ This action prevents binding of tRNA to the mRNA–ribosome complex,
thereby inhibiting bacterial protein synthesis
What is the spectrum for tetracycline
✓ The tetracyclines are bacteriostatic antibiotics effective against a wide
variety of organisms, including g+ve & g-ve bacteria, protozoa,
spirochetes, mycobacteria, and atypical species (like Lyme disease, gram - cholera , Chlamydia and rocky mountain fever)
✓ They are commonly used in the treatment of acne(assignment) and
Chlamydia infections (doxycycline).
How is resistance formed against tetracycline
1.
Efflux pump that expels drug out of the cell, thus preventing
intracellular accumulation.
2.
Enzymatic inactivation of the drug.
3.
Production of bacterial proteins that prevent tetracyclines from
binding to the ribosome.
✓ Resistance to ONE tetracycline does NOT confer universal resistance to
all tetracyclines.
What is the PK for tetracycline
- Absorption:
✓ Tetracyclines are adequately absorbed after oral ingestion (Figure 30.4).
✓ Administration with dairy products or other substances that contain
divalent and trivalent cations (for example, Mg+2 and Al+3 antacids or
iron supplements) ↓ absorption, particularly for tetracycline, due to the
formation of nonabsorbable chelates (Figure 30.5).
✓ Tetracyclines and omadacycline should not administered with diary
products, but absorption of doxycycline or minocycline is not affected
by dairy products
✓ Both doxycycline, minocycline and omadacycline are available as oral
and IV preparations. - Distribution:
✓ The tetracyclines concentrate well in the bile, liver, kidney, gingival fluid, and
skin.
✓ Moreover, they bind to tissues undergoing calcification (for example, teeth and
bones) or to tumors that have a high Ca+2 content.
✓ Penetration into most body fluids is adequate.
✓ Only minocycline and doxycycline achieve therapeutic levels in the
cerebrospinal fluid (CSF).
✓ Minocycline also achieves high levels in saliva and tears, rendering it useful in
eradicating the meningococcal carrier state
✓ All tetracyclines cross the placental barrier and concentrate in fetal bones and
dentition
3.Elimination:
✓ In renally compromised patients, doxycycline is preferred, as it is primarily
eliminated via the bile into the feces.
What are the side effects for tetracycline
- Gastric discomfort: epigastric distress resulting from irritation of mucosa
✓ Esophagitis may be ↓ through co-administration with food (other than
dairy products) or fluids and the use of capsules rather than tablets - Effects on calcified tissues:
✓ This may cause discoloration and hypoplasia of teeth and a temporary
stunting of growth. The use of tetracyclines is limited in paediatrics. - Hepatotoxicity:
✓ Rarely hepatotoxicity may occur with:
✓ high doses,
✓ or in pregnant women
✓ and those with preexisting hepatic dysfunction or renal impairment. - Phototoxicity:
✓ Severe sunburn may occur in patients receiving a tetracycline who are
exposed to sun or ultraviolet rays.
✓ This toxicity is encountered with any tetracycline, but more frequently with
tetracycline and demeclocycline. Patients should be advised to wear
adequate sun protection. - Vestibular dysfunction:
✓ Dizziness, vertigo, and tinnitus may occur particularly with minocycline.
Doxycycline may also cause vestibular dysfunction. - Pseudotumor cerebri:
✓ Benign, intracranial hypertension characterized by headache and
blurred vision may occur rarely in adults. - Contraindications:
✓ The tetracyclines should not be used in:
✓ pregnant
✓ or breast-feeding women
✓ or in children less than 8 years of age.
What are Aminoglycosides
✓ Aminoglycosides are used for the treatment of serious infections due to
aerobic g-ve bacilli.
✓ However, their clinical utility is limited by serious toxicities.
✓ The term “aminoglycoside” stems from their structure—two amino
sugars joined by a glycosidic linkage to a central hexose nucleus.
✓ Aminoglycosides are derived from either Streptomyces sp. (have –
mycin suffixes) or Micromonospora sp. (end in -micin).
What is the MOA for Aminoglycosides
✓ Aminoglycosides diffuse through porin channels in the outer membrane
of susceptible organisms.
✓ These organisms also have an oxygen-dependent system that
transports the drug across the cytoplasmic membrane.
✓ Inside the cell, they bind the 30S ribosomal subunit, where they
interfere with assembly of the functional ribosomal apparatus and/or
cause the 30S subunit of the completed ribosome to misread the
genetic code
Antibiotics that disrupt protein synthesis are generally bacteriostatic
✓ however, aminoglycosides are unique in that they are bactericidal.
✓ The bactericidal effect of aminoglycosides is concentration dependent;
✓ that is, efficacy is dependent on Cmax of drug above MIC of the
organism.
✓ For aminoglycosides, the target Cmax is eight to ten times the MIC.
✓ They also exhibit a postantibiotic effect (PAE), which is continued
bacterial suppression after drug levels fall below the MIC.
✓ Because of these properties, a single large dose given once daily is now
more commonly utilized than divided daily doses → ↓risk of
nephrotoxicity and ↑ convenience.
What is the spectrum for Aminoglycosides
✓ The aminoglycosides are effective for the majority of aerobic g-ve
bacilli, including those that may be multidrug resistant, such as
Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterobacter sp.
✓ Additionally, aminoglycosides are often combined with a β-lactam
antibiotic to employ a synergistic effect, particularly in the treatment of
Enterococcus faecalis and Enterococcus faecium infective endocarditis.
✓ PENs (CWI) + AG (PSI) —– Good combination
✓ AGs synergize with β-lactam antibiotics because of the PENs action on cell
wall synthesis, which enhances diffusion of AGs into the bacterium
✓ Tetracyclines + PENs—- bad combination
✓ Coadministration of an antibiotic agent that is bacteriostatic plus a second
agent that is bactericidal
✓ Some
therapeutic
applications
of
four
commonly
used
aminoglycosides—amikacin,
gentamicin,
tobramycin,
and
streptomycin
How is resistance formed for Aminoglycosides
1) efflux pumps, 2) ↓ uptake,
and/or 3) modification and inactivation by plasmid-associated synthesis of
enzymes.
Each of these enzymes has its own aminoglycoside specificity; therefore, crossresistance cannot be presumed.
[Note: Amikacin is less vulnerable to these enzymes than other antibiotics in this
group.]
What are the pharmacokinetics for Aminoglycosides
- Absorption:
✓ The highly polar structure of the aminoglycosides prevents adequate
absorption after oral administration → All aminoglycosides (except neomycin)
must be given parenterally to achieve adequate serum levels (Figure 39.8).
✓ Neomycin is NOT given parenterally due to severe nephrotoxicity. It is
administered topically for skin infections or orally for bowel preparation prior
to colorectal surgery. - Distribution:
✓ All the aminoglycosides have similar PK properties.
✓ Due to their hydrophilicity, tissue concentrations may be
subtherapeutic, and penetration into most body fluids is variable.
✓ Note: Due to low distribution into fatty tissue, the aminoglycosides
✓ are dosed based on lean body mass, not actual body weight.
✓ Concentrations in CSF are inadequate, even in the presence of inflamed
meninges. For central nervous system infections, the intrathecal (IT)
route may be utilized.
✓ All aminoglycosides cross the placental barrier and may accumulate in
fetal plasma and amniotic fluid. - Elimination:
✓ More than 90% of the parenteral aminoglycosides are excreted
unchanged in the urine (Figure 39.8).
✓ Accumulation occurs in patients with renal dysfunction, and dose
adjustments are required.
What are the side effects for Aminoglycosides
1.
Ototoxicity: vestibular and auditory, deafness may be irreversible and
has been known to affect developing fetuses.
Vertigo (especially in patients receiving streptomycin) may also occur.
2. Nephrotoxicity: kidney damage ranging from mild, reversible renal
impairment to severe, potentially irreversible, acute tubular necrosis.
3. Neuromuscular blockade: This adverse effect is associated with:
a rapid increase in concentrations (for example, high doses infused over a
short period.)
or concurrent administration with neuromuscular blockers.
Patients with myasthenia gravis are particularly at risk.
Prompt administration of calcium gluconate or neostigmine can reverse
the block that causes neuromuscular paralysis.
4. Allergic reactions: Contact dermatitis is a common reaction to topically
applied neomycin.
✓ Therapeutic drug monitoring of gentamicin, tobramycin, and amikacin
plasma levels is imperative to ensure adequacy of dosing and to
minimize dose-related toxicities (Figure 39.9).
✓ The elderly are particularly susceptible to nephrotoxicity and
ototoxicity.
What are macrolides
✓ Erythromycin was the first of these drugs to find clinical application,
both as a drug of first choice and as an alternative to penicillin in
individuals with an allergy to β-lactam antibiotics.
✓ Clarithromycin a methylated form of erythromycin and azithromycin
have some features in common with, and others that improve upon,
erythromycin.
✓ Telithromycin, a semisynthetic derivative of erythromycin, is the first
“ketolide” antimicrobial agent.
✓ Ketolides and macrolides have similar antimicrobial coverage.
✓ Ketolides are active against many macrolide-resistant gram-positive strains.
What is the MOA for Aminoglycosides
• The macrolides bind irreversibly to a site on the 50S subunit of the bacterial
ribosome→↓ translocation steps of protein synthesis. They may also interfere
with other steps, such as transpeptidation.
• Generally considered to be bacteriostatic, they may be bactericidal at higher
doses. Their binding site is either identical to or in close proximity to that for
clindamycin and chloramphenicol.
What are the spectrums for Aminoglycosides
- Erythromycin: is effective against many of the same organisms as
penicillin G (Figure 39.10), it may be used in patients with penicillin allergy. - Clarithromycin: has activity similar to erythromycin, but it is also
effective against H. influenzae.
Its activity against intracellular pathogens is higher than that of
erythromycin. - Azithromycin: less active against strep. and staph. than erythromycin,
azithromycin is far more active against respiratory infections due to H.
influenzae and Moraxella catarrhalis.
Extensive use of azithromycin has resulted in growing St. pneumoniae
resistance.
Azithromycin is the preferred therapy for urethritis caused by Chlamyida.
trachomatis.
Mycoplasmas. avium is preferentially treated with a macrolide-containing regimen,
including clarithromycin or azithromycin. - Telithromycin: has an antimicrobial spectrum similar to that of azithromycin.
It neutralizes the most common resistance mechanisms
(methylase-mediated and efflux-mediated) that make macrolides ineffective.
